TY  - GEN
A1  - Christakoudi, Sofia
A1  - Pagoni, Panagiota
A1  - Ferrari, Pietro
A1  - Cross, Amanda J.
A1  - Tzoulaki, Ioanna
A1  - Muller, David C.
A1  - Weiderpass, Elisabete
A1  - Freisling, Heinz
A1  - Murphy, Neil
A1  - Dossus, Laure
A1  - Turzanski Fortner, Renee
A1  - Agudo, Antonio
A1  - Overvad, Kim
A1  - Perez-Cornago, Aurora
A1  - Key, Timothy J.
A1  - Brennan, Paul
A1  - Johansson, Mattias
A1  - Tjonneland, Anne
A1  - Halkjaer, Jytte
A1  - Boutron-Ruault, Marie-Christine
A1  - Artaud, Fanny
A1  - Severi, Gianluca
A1  - Kaaks, Rudolf
A1  - Schulze, Matthias Bernd
A1  - Bergmann, Manuela M.
A1  - Masala, Giovanna
A1  - Grioni, Sara
A1  - Simeon, Vittorio
A1  - Tumino, Rosario
A1  - Sacerdote, Carlotta
A1  - Skeie, Guri
A1  - Rylander, Charlotta
A1  - Borch, Kristin Benjaminsen
A1  - Quiros, J. Ramon
A1  - Rodriguez-Barranco, Miguel
A1  - Chirlaque, Maria-Dolores
A1  - Ardanaz, Eva
A1  - Amiano, Pilar
A1  - Drake, Isabel
A1  - Stocks, Tanja
A1  - Haggstrom, Christel
A1  - Harlid, Sophia
A1  - Ellingjord-Dale, Merete
A1  - Riboli, Elio
A1  - Tsilidis, Konstantinos K.
T1  - Weight change in middle adulthood and risk of cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort
T2  - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe
N2  - Obesity is a risk factor for several major cancers. Associations of weight change in middle adulthood with cancer risk, however, are less clear. We examined the association of change in weight and body mass index (BMI) category during middle adulthood with 42 cancers, using multivariable Cox proportional hazards models in the European Prospective Investigation into Cancer and Nutrition cohort. Of 241 323 participants (31% men), 20% lost and 32% gained weight (>0.4 to 5.0 kg/year) during 6.9 years (average). During 8.0 years of follow-up after the second weight assessment, 20 960 incident cancers were ascertained. Independent of baseline BMI, weight gain (per one kg/year increment) was positively associated with cancer of the corpus uteri (hazard ratio [HR] = 1.14; 95% confidence interval: 1.05-1.23). Compared to stable weight (+/- 0.4 kg/year), weight gain (>0.4 to 5.0 kg/year) was positively associated with cancers of the gallbladder and bile ducts (HR = 1.41; 1.01-1.96), postmenopausal breast (HR = 1.08; 1.00-1.16) and thyroid (HR = 1.40; 1.04-1.90). Compared to maintaining normal weight, maintaining overweight or obese BMI (World Health Organisation categories) was positively associated with most obesity-related cancers. Compared to maintaining the baseline BMI category, weight gain to a higher BMI category was positively associated with cancers of the postmenopausal breast (HR = 1.19; 1.06-1.33), ovary (HR = 1.40; 1.04-1.91), corpus uteri (HR = 1.42; 1.06-1.91), kidney (HR = 1.80; 1.20-2.68) and pancreas in men (HR = 1.81; 1.11-2.95). Losing weight to a lower BMI category, however, was inversely associated with cancers of the corpus uteri (HR = 0.40; 0.23-0.69) and colon (HR = 0.69; 0.52-0.92). Our findings support avoiding weight gain and encouraging weight loss in middle adulthood.
T3  - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 1373 
KW  - BMI change
KW  - cancer
KW  - middle adulthood
KW  - weight gain
KW  - weight loss
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-573609
SN  - 1866-8372
IS  - 7
ER  - 
TY  - GEN
A1  - Saberi Hosnijeh, Fatemeh
A1  - Casabonne, Delphine
A1  - Nieters, Alexandra
A1  - Solans, Marta
A1  - Naudin, Sabine
A1  - Ferrari, Pietro
A1  - Mckay, James D.
A1  - Benavente, Yolanda
A1  - Weiderpass, Elisabete
A1  - Freisling, Heinz
A1  - Severi, Gianluca
A1  - Boutron Ruault, Marie-Christine
A1  - Besson, Caroline
A1  - Agnoli, Claudia
A1  - Masala, Giovanna
A1  - Sacerdote, Carlotta
A1  - Tumino, Rosario
A1  - Huerta, Jose Maria
A1  - Amiano, Pilar
A1  - Rodriguez-Barranco, Miguel
A1  - Bonet, Catalina
A1  - Barricarte, Aurelio
A1  - Christakoudi, Sofia
A1  - Knuppel, Anika
A1  - Bueno-de-Mesquita, Bas
A1  - Schulze, Matthias Bernd
A1  - Kaaks, Rudolf
A1  - Canzian, Federico
A1  - Spath, Florentin
A1  - Jerkeman, Mats
A1  - Rylander, Charlotta
A1  - Tjonneland, Anne
A1  - Olsen, Anja
A1  - Borch, Kristin Benjaminsen
A1  - Vermeulen, Roel
T1  - Association between anthropometry and lifestyle factors and risk of B-cell lymphoma
BT  - an exposome-wide analysis
T2  - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe
N2  - To better understand the role of individual and lifestyle factors in human disease, an exposome-wide association study was performed to investigate within a single-study anthropometry measures and lifestyle factors previously associated with B-cell lymphoma (BCL). Within the European Prospective Investigation into Cancer and nutrition study, 2402 incident BCL cases were diagnosed from 475 426 participants that were followed-up on average 14 years. Standard and penalized Cox regression models as well as principal component analysis (PCA) were used to evaluate 84 exposures in relation to BCL risk. Standard and penalized Cox regression models showed a positive association between anthropometric measures and BCL and multiple myeloma/plasma cell neoplasm (MM). The penalized Cox models additionally showed the association between several exposures from categories of physical activity, smoking status, medical history, socioeconomic position, diet and BCL and/or the subtypes. PCAs confirmed the individual associations but also showed additional observations. The PC5 including anthropometry, was positively associated with BCL, diffuse large B-cell lymphoma (DLBCL) and MM. There was a significant positive association between consumption of sugar and confectionary (PC11) and follicular lymphoma risk, and an inverse association between fish and shellfish and Vitamin D (PC15) and DLBCL risk. The PC1 including features of the Mediterranean diet and diet with lower inflammatory score showed an inverse association with BCL risk, while the PC7, including dairy, was positively associated with BCL and DLBCL risk. Physical activity (PC10) was positively associated with DLBCL risk among women. This study provided informative insights on the etiology of BCL.
T3  - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 1374 
KW  - exposome
KW  - exposome‐ wide association study
KW  - lifestyle
KW  - lymphoma
KW  - prospective study
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-573562
SN  - 1866-8372
IS  - 9
ER  - 
TY  - GEN
A1  - Dwi Putra, Sulistyo Emantoko
A1  - Reichetzeder, Christoph
A1  - Hasan, Ahmed Abdallah Abdalrahman Mohamed
A1  - Slowinski, Torsten
A1  - Chu, Chang
A1  - Krämer, Bernhard K.
A1  - Kleuser, Burkhard
A1  - Hocher, Berthold
T1  - Being born large for gestational age is associated with increased global placental DNA methylation
T2  - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe
N2  - Being born small (SGA) or large for gestational age (LGA) is associated with adverse birth outcomes and metabolic diseases in later life of the offspring. It is known that aberrations in growth during gestation are related to altered placental function. Placental function is regulated by epigenetic mechanisms such as DNA methylation. Several studies in recent years have demonstrated associations between altered patterns of DNA methylation and adverse birth outcomes. However, larger studies that reliably investigated global DNA methylation are lacking. The aim of this study was to characterize global placental DNA methylation in relationship to size for gestational age. Global DNA methylation was assessed in 1023 placental samples by LC-MS/MS. LGA offspring displayed significantly higher global placental DNA methylation compared to appropriate for gestational age (AGA; p<0.001). ANCOVA analyses adjusted for known factors impacting on DNA methylation demonstrated an independent association between placental global DNA methylation and LGA births (p<0.001). Tertile stratification according to global placental DNA methylation levels revealed a significantly higher frequency of LGA births in the third tertile. Furthermore, a multiple logistic regression analysis corrected for known factors influencing birth weight highlighted an independent positive association between global placental DNA methylation and the frequency of LGA births (p=0.001).
T3  - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 1405 
KW  - fetal origins hypothesis
KW  - birth weight
KW  - repetitive elements
KW  - glucocorticoid receptor
KW  - nutrient transport
KW  - growth restriction
KW  - later health
KW  - pregnancy
KW  - genes
KW  - patterns
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-516289
SN  - 1866-8372
IS  - 1
ER  - 
TY  - JOUR
A1  - Dwi Putra, Sulistyo Emantoko
A1  - Reichetzeder, Christoph
A1  - Hasan, Ahmed Abdallah Abdalrahman Mohamed
A1  - Slowinski, Torsten
A1  - Chu, Chang
A1  - Krämer, Bernhard K.
A1  - Kleuser, Burkhard
A1  - Hocher, Berthold
T1  - Being born large for gestational age is associated with increased global placental DNA methylation
JF  - Scientific Reports
N2  - Being born small (SGA) or large for gestational age (LGA) is associated with adverse birth outcomes and metabolic diseases in later life of the offspring. It is known that aberrations in growth during gestation are related to altered placental function. Placental function is regulated by epigenetic mechanisms such as DNA methylation. Several studies in recent years have demonstrated associations between altered patterns of DNA methylation and adverse birth outcomes. However, larger studies that reliably investigated global DNA methylation are lacking. The aim of this study was to characterize global placental DNA methylation in relationship to size for gestational age. Global DNA methylation was assessed in 1023 placental samples by LC-MS/MS. LGA offspring displayed significantly higher global placental DNA methylation compared to appropriate for gestational age (AGA; p<0.001). ANCOVA analyses adjusted for known factors impacting on DNA methylation demonstrated an independent association between placental global DNA methylation and LGA births (p<0.001). Tertile stratification according to global placental DNA methylation levels revealed a significantly higher frequency of LGA births in the third tertile. Furthermore, a multiple logistic regression analysis corrected for known factors influencing birth weight highlighted an independent positive association between global placental DNA methylation and the frequency of LGA births (p=0.001).
KW  - fetal origins hypothesis
KW  - birth weight
KW  - repetitive elements
KW  - glucocorticoid receptor
KW  - nutrient transport
KW  - growth restriction
KW  - later health
KW  - pregnancy
KW  - genes
KW  - patterns
Y1  - 2020
U6  - https://doi.org/10.1038/s41598-020-57725-0
SN  - 2045-2322
VL  - 10
IS  - 1
SP  - 1
EP  - 10
PB  - Springer Nature
CY  - London
ER  - 
TY  - GEN
A1  - Lang, Judith
A1  - Bohn, Patrick
A1  - Bhat, Hilal
A1  - Jastrow, Holger
A1  - Walkenfort, Bernd
A1  - Cansiz, Feyza
A1  - Fink, Julian
A1  - Bauer, Michael
A1  - Schumacher, Fabian
A1  - Kleuser, Burkhard
A1  - Lang, Karl S.
T1  - Acid ceramidase of macrophages traps herpes simplex virus in multivesicular bodies and protects from severe disease
T2  - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe
N2  - Macrophages have important protective functions during infection with herpes simplex virus type 1 (HSV-1). However, molecular mechanisms that restrict viral propagation and protect from severe disease are unclear. Here we show that macrophages take up HSV-1 via endocytosis and transport the virions into multivesicular bodies (MVBs). In MVBs, acid ceramidase (aCDase) converts ceramide into sphingosine and increases the formation of sphingosine-rich intraluminal vesicles (ILVs). Once HSV-1 particles reach MVBs, sphingosine-rich ILVs bind to HSV-1 particles, which restricts fusion with the limiting endosomal membrane and prevents cellular infection. Lack of aCDase in macrophage cultures or in Asah1(-/-) mice results in replication of HSV-1 and Asah1(-/-) mice die soon after systemic or intravaginal inoculation. The treatment of macrophages with sphingosine enhancing compounds blocks HSV-1 propagation, suggesting a therapeutic potential of this pathway. In conclusion, aCDase loads ILVs with sphingosine, which prevents HSV-1 capsids from penetrating into the cytosol.
T3  - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 1400 
KW  - immunology
KW  - infection
KW  - membrane fusion
KW  - phagocytosis
KW  - sphingolipids
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-515661
SN  - 1866-8372
IS  - 1
ER  - 
TY  - JOUR
A1  - Lang, Judith
A1  - Bohn, Patrick
A1  - Bhat, Hilal
A1  - Jastrow, Holger
A1  - Walkenfort, Bernd
A1  - Cansiz, Feyza
A1  - Fink, Julian
A1  - Bauer, Michael
A1  - Schumacher, Fabian
A1  - Kleuser, Burkhard
A1  - Lang, Karl S.
T1  - Acid ceramidase of macrophages traps herpes simplex virus in multivesicular bodies and protects from severe disease
JF  - Nature Communications
N2  - Macrophages have important protective functions during infection with herpes simplex virus type 1 (HSV-1). However, molecular mechanisms that restrict viral propagation and protect from severe disease are unclear. Here we show that macrophages take up HSV-1 via endocytosis and transport the virions into multivesicular bodies (MVBs). In MVBs, acid ceramidase (aCDase) converts ceramide into sphingosine and increases the formation of sphingosine-rich intraluminal vesicles (ILVs). Once HSV-1 particles reach MVBs, sphingosine-rich ILVs bind to HSV-1 particles, which restricts fusion with the limiting endosomal membrane and prevents cellular infection. Lack of aCDase in macrophage cultures or in Asah1(-/-) mice results in replication of HSV-1 and Asah1(-/-) mice die soon after systemic or intravaginal inoculation. The treatment of macrophages with sphingosine enhancing compounds blocks HSV-1 propagation, suggesting a therapeutic potential of this pathway. In conclusion, aCDase loads ILVs with sphingosine, which prevents HSV-1 capsids from penetrating into the cytosol.
KW  - immunology
KW  - infection
KW  - membrane fusion
KW  - phagocytosis
KW  - sphingolipids
Y1  - 2020
U6  - https://doi.org/10.1038/s41467-020-15072-8
SN  - 2041-1723
VL  - 11
IS  - 1
SP  - 1
EP  - 15
PB  - Nature Publishing Group UK
CY  - London
ER  - 
TY  - GEN
A1  - Harms, Laura M.
A1  - Scalbert, Augustin
A1  - Zamora-Ros, Raul
A1  - Rinaldi, Sabina
A1  - Jenab, Mazda
A1  - Murphy, Neil
A1  - Achaintre, David
A1  - Tjønneland, Anne
A1  - Olsen, Anja
A1  - Overvad, Kim
A1  - Aleksandrova, Krasimira
T1  - Plasma polyphenols associated with lower high-sensitivity C-reactive protein concentrations
BT  - a cross-sectional study within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort
T2  - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe
N2  - Experimental studies have reported on the anti-inflammatory properties of polyphenols. However, results from epidemiological investigations have been inconsistent and especially studies using biomarkers for assessment of polyphenol intake have been scant. We aimed to characterise the association between plasma concentrations of thirty-five polyphenol compounds and low-grade systemic inflammation state as measured by high-sensitivity C-reactive protein (hsCRP). A cross-sectional data analysis was performed based on 315 participants in the European Prospective Investigation into Cancer and Nutrition cohort with available measurements of plasma polyphenols and hsCRP. In logistic regression analysis, the OR and 95 % CI of elevated serum hsCRP (>3 mg/l) were calculated within quartiles and per standard deviation higher level of plasma polyphenol concentrations. In a multivariable-adjusted model, the sum of plasma concentrations of all polyphenols measured (per standard deviation) was associated with 29 (95 % CI 50, 1) % lower odds of elevated hsCRP. In the class of flavonoids, daidzein was inversely associated with elevated hsCRP (OR 0 center dot 66, 95 % CI 0 center dot 46, 0 center dot 96). Among phenolic acids, statistically significant associations were observed for 3,5-dihydroxyphenylpropionic acid (OR 0 center dot 58, 95 % CI 0 center dot 39, 0 center dot 86), 3,4-dihydroxyphenylpropionic acid (OR 0 center dot 63, 95 % CI 0 center dot 46, 0 center dot 87), ferulic acid (OR 0 center dot 65, 95 % CI 0 center dot 44, 0 center dot 96) and caffeic acid (OR 0 center dot 69, 95 % CI 0 center dot 51, 0 center dot 93). The odds of elevated hsCRP were significantly reduced for hydroxytyrosol (OR 0 center dot 67, 95 % CI 0 center dot 48, 0 center dot 93). The present study showed that polyphenol biomarkers are associated with lower odds of elevated hsCRP. Whether diet rich in bioactive polyphenol compounds could be an effective strategy to prevent or modulate deleterious health effects of inflammation should be addressed by further well-powered longitudinal studies.
T3  - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 1404 
KW  - polyphenols
KW  - plasma measurements
KW  - C-reactive protein
KW  - inflammation
KW  - chronic diseases
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-515774
SN  - 1866-8372
IS  - 2
ER  - 
TY  - JOUR
A1  - Harms, Laura M.
A1  - Scalbert, Augustin
A1  - Zamora-Ros, Raul
A1  - Rinaldi, Sabina
A1  - Jenab, Mazda
A1  - Murphy, Neil
A1  - Achaintre, David
A1  - Tjønneland, Anne
A1  - Olsen, Anja
A1  - Overvad, Kim
A1  - Aleksandrova, Krasimira
T1  - Plasma polyphenols associated with lower high-sensitivity C-reactive protein concentrations
BT  - a cross-sectional study within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort
JF  - British Journal of Nutrition
N2  - Experimental studies have reported on the anti-inflammatory properties of polyphenols. However, results from epidemiological investigations have been inconsistent and especially studies using biomarkers for assessment of polyphenol intake have been scant. We aimed to characterise the association between plasma concentrations of thirty-five polyphenol compounds and low-grade systemic inflammation state as measured by high-sensitivity C-reactive protein (hsCRP). A cross-sectional data analysis was performed based on 315 participants in the European Prospective Investigation into Cancer and Nutrition cohort with available measurements of plasma polyphenols and hsCRP. In logistic regression analysis, the OR and 95 % CI of elevated serum hsCRP (>3 mg/l) were calculated within quartiles and per standard deviation higher level of plasma polyphenol concentrations. In a multivariable-adjusted model, the sum of plasma concentrations of all polyphenols measured (per standard deviation) was associated with 29 (95 % CI 50, 1) % lower odds of elevated hsCRP. In the class of flavonoids, daidzein was inversely associated with elevated hsCRP (OR 0 center dot 66, 95 % CI 0 center dot 46, 0 center dot 96). Among phenolic acids, statistically significant associations were observed for 3,5-dihydroxyphenylpropionic acid (OR 0 center dot 58, 95 % CI 0 center dot 39, 0 center dot 86), 3,4-dihydroxyphenylpropionic acid (OR 0 center dot 63, 95 % CI 0 center dot 46, 0 center dot 87), ferulic acid (OR 0 center dot 65, 95 % CI 0 center dot 44, 0 center dot 96) and caffeic acid (OR 0 center dot 69, 95 % CI 0 center dot 51, 0 center dot 93). The odds of elevated hsCRP were significantly reduced for hydroxytyrosol (OR 0 center dot 67, 95 % CI 0 center dot 48, 0 center dot 93). The present study showed that polyphenol biomarkers are associated with lower odds of elevated hsCRP. Whether diet rich in bioactive polyphenol compounds could be an effective strategy to prevent or modulate deleterious health effects of inflammation should be addressed by further well-powered longitudinal studies.
KW  - polyphenols
KW  - plasma measurements
KW  - C-reactive protein
KW  - inflammation
KW  - chronic diseases
Y1  - 2019
U6  - https://doi.org/10.1017/S0007114519002538
SN  - 0007-1145
SN  - 1475-2662
VL  - 123
IS  - 2
SP  - 198
EP  - 208
PB  - Cambridge University Press
CY  - Cambridge
ER  - 
TY  - GEN
A1  - McNulty, Margaret A.
A1  - Goupil, Brad A.
A1  - Albarado, Diana C.
A1  - Castaño-Martinez, Teresa
A1  - Ambrosi, Thomas H.
A1  - Puh, Spela
A1  - Schulz, Tim Julius
A1  - Schürmann, Annette
A1  - Morrison, Christopher D.
A1  - Laeger, Thomas
T1  - FGF21, not GCN2, influences bone morphology due to dietary protein restrictions
T2  - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe
N2  - Background: Dietary protein restriction is emerging as an alternative approach to treat obesity and glucose intolerance because it markedly increases plasma fibroblast growth factor 21 (FGF21) concentrations. Similarly, dietary restriction of methionine is known to mimic metabolic effects of energy and protein restriction with FGF21 as a required mechanism. However, dietary protein has been shown to be required for normal bone growth, though there is conflicting evidence as to the influence of dietary protein restriction on bone remodeling. The purpose of the current study was to evaluate the effect of dietary protein and methionine restriction on bone in lean and obese mice, and clarify whether FGF21 and general control nonderepressible 2 (GCN2) kinase, that are part of a novel endocrine pathway implicated in the detection of protein restriction, influence the effect of dietary protein restriction on bone.

Methods: Adult wild-type (WT) or Fgf21 KO mice were fed a normal protein (18 kcal%; CON) or low protein (4 kcal%; LP) diet for 2 or 27 weeks. In addition, adult WT or Gcn2 KO mice were fed a CON or LP diet for 27 weeks. Young New Zealand obese (NZO) mice were placed on high-fat diets that provided protein at control (16 kcal%; CON), low levels (4 kcal%) in a high-carbohydrate (LP/HC) or high-fat (LP/HF) regimen, or on high-fat diets (protein, 16 kcal%) that provided methionine at control (0.86%; CON-MR) or low levels (0.17%; MR) for up to 9 weeks. Long bones from the hind limbs of these mice were collected and evaluated with micro-computed tomography (mu CT) for changes in trabecular and cortical architecture and mass.

Results: In WT mice the 27-week LP diet significantly reduced cortical bone, and this effect was enhanced by deletion of Fgf21 but not Gcn2. This decrease in bone did not appear after 2 weeks on the LP diet. In addition, Fgf21 KO mice had significantly less bone than their WT counterparts. In obese NZO mice dietary protein and methionine restriction altered bone architecture. The changes were mediated by FGF21 due to methionine restriction in the presence of cystine, which did not increase plasma FGF21 levels and did not affect bone architecture.

Conclusions: This study provides direct evidence of a reduction in bone following long-term dietary protein restriction in a mouse model, effects that appear to be mediated by FGF21.
T3  - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 1406 
KW  - dietary restriction
KW  - protein restriction
KW  - FGF21
KW  - GCN2
KW  - microcomputed tomography
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-516297
SN  - 1866-8372
ER  - 
TY  - JOUR
A1  - McNulty, Margaret A.
A1  - Goupil, Brad A.
A1  - Albarado, Diana C.
A1  - Castaño-Martinez, Teresa
A1  - Ambrosi, Thomas H.
A1  - Puh, Spela
A1  - Schulz, Tim Julius
A1  - Schürmann, Annette
A1  - Morrison, Christopher D.
A1  - Laeger, Thomas
T1  - FGF21, not GCN2, influences bone morphology due to dietary protein restrictions
JF  - Bone Reports
N2  - Background: Dietary protein restriction is emerging as an alternative approach to treat obesity and glucose intolerance because it markedly increases plasma fibroblast growth factor 21 (FGF21) concentrations. Similarly, dietary restriction of methionine is known to mimic metabolic effects of energy and protein restriction with FGF21 as a required mechanism. However, dietary protein has been shown to be required for normal bone growth, though there is conflicting evidence as to the influence of dietary protein restriction on bone remodeling. The purpose of the current study was to evaluate the effect of dietary protein and methionine restriction on bone in lean and obese mice, and clarify whether FGF21 and general control nonderepressible 2 (GCN2) kinase, that are part of a novel endocrine pathway implicated in the detection of protein restriction, influence the effect of dietary protein restriction on bone.

Methods: Adult wild-type (WT) or Fgf21 KO mice were fed a normal protein (18 kcal%; CON) or low protein (4 kcal%; LP) diet for 2 or 27 weeks. In addition, adult WT or Gcn2 KO mice were fed a CON or LP diet for 27 weeks. Young New Zealand obese (NZO) mice were placed on high-fat diets that provided protein at control (16 kcal%; CON), low levels (4 kcal%) in a high-carbohydrate (LP/HC) or high-fat (LP/HF) regimen, or on high-fat diets (protein, 16 kcal%) that provided methionine at control (0.86%; CON-MR) or low levels (0.17%; MR) for up to 9 weeks. Long bones from the hind limbs of these mice were collected and evaluated with micro-computed tomography (mu CT) for changes in trabecular and cortical architecture and mass.

Results: In WT mice the 27-week LP diet significantly reduced cortical bone, and this effect was enhanced by deletion of Fgf21 but not Gcn2. This decrease in bone did not appear after 2 weeks on the LP diet. In addition, Fgf21 KO mice had significantly less bone than their WT counterparts. In obese NZO mice dietary protein and methionine restriction altered bone architecture. The changes were mediated by FGF21 due to methionine restriction in the presence of cystine, which did not increase plasma FGF21 levels and did not affect bone architecture.

Conclusions: This study provides direct evidence of a reduction in bone following long-term dietary protein restriction in a mouse model, effects that appear to be mediated by FGF21.
KW  - dietary restriction
KW  - protein restriction
KW  - FGF21
KW  - GCN2
KW  - microcomputed tomography
Y1  - 2020
U6  - https://doi.org/10.1016/j.bonr.2019.100241
SN  - 2352-1872
VL  - 12
SP  - 1
EP  - 10
PB  - Elsevier
CY  - Amsterdam
ER  - 
TY  - GEN
A1  - Naser, Eyad
A1  - Kadow, Stephanie
A1  - Schumacher, Fabian
A1  - Mohamed, Zainelabdeen H.
A1  - Kappe, Christian
A1  - Hessler, Gabriele
A1  - Pollmeier, Barbara
A1  - Kleuser, Burkhard
A1  - Arenz, Christoph
A1  - Becker, Katrin Anne
A1  - Gulbins, Erich
A1  - Carpinteiro, Alexander
T1  - Characterization of the small molecule ARC39
BT  - a direct and specific inhibitor of acid sphingomyelinase in vitro[S]
T2  - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe
N2  - Inhibition of acid sphingomyelinase (ASM), a lysosomal enzyme that catalyzes the hydrolysis of sphingomyelin into ceramide and phosphorylcholine, may serve as an investigational tool or a therapeutic intervention to control many diseases. Specific ASM inhibitors are currently not sufficiently characterized. Here, we found that 1-aminodecylidene bis-phosphonic acid (ARC39) specifically and efficiently (>90%) inhibits both lysosomal and secretory ASM in vitro. Results from investigating sphingomyelin phosphodiesterase 1 (SMPD1/Smpd1) mRNA and ASM protein levels suggested that ARC39 directly inhibits ASM's catalytic activity in cultured cells, a mechanism that differs from that of functional inhibitors of ASM. We further provide evidence that ARC39 dose- and time-dependently inhibits lysosomal ASM in intact cells, and we show that ARC39 also reduces platelet- and ASM-promoted adhesion of tumor cells. The observed toxicity of ARC39 is low at concentrations relevant for ASM inhibition in vitro, and it does not strongly alter the lysosomal compartment or induce phospholipidosis in vitro. When applied intraperitoneally in vivo, even subtoxic high doses administered short-term induced sphingomyelin accumulation only locally in the peritoneal lavage without significant accumulation in plasma, liver, spleen, or brain. These findings require further investigation with other possible chemical modifications. In conclusion, our results indicate that ARC39 potently and selectively inhibits ASM in vitro and highlight the need for developing compounds that can reach tissue concentrations sufficient for ASM inhibition in vivo.
T3  - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 1407 
KW  - sphingolipids
KW  - sphingomyelin
KW  - cerami-des
KW  - lipid metabolism
KW  - enzymology
KW  - lysosome
KW  - lysosomal hydrolases
KW  - acid ceramidase
KW  - bisphosphonates
KW  - functional inhibitors of acid sphin-gomyelinase
KW  - 1-aminodecylidene bis-phosphonic acid
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-516635
SN  - 1866-8372
IS  - 6
ER  - 
TY  - JOUR
A1  - Naser, Eyad
A1  - Kadow, Stephanie
A1  - Schumacher, Fabian
A1  - Mohamed, Zainelabdeen H.
A1  - Kappe, Christian
A1  - Hessler, Gabriele
A1  - Pollmeier, Barbara
A1  - Kleuser, Burkhard
A1  - Arenz, Christoph
A1  - Becker, Katrin Anne
A1  - Gulbins, Erich
A1  - Carpinteiro, Alexander
T1  - Characterization of the small molecule ARC39
BT  - a direct and specific inhibitor of acid sphingomyelinase in vitro[S]
JF  - Journal of Lipid Research
N2  - Inhibition of acid sphingomyelinase (ASM), a lysosomal enzyme that catalyzes the hydrolysis of sphingomyelin into ceramide and phosphorylcholine, may serve as an investigational tool or a therapeutic intervention to control many diseases. Specific ASM inhibitors are currently not sufficiently characterized. Here, we found that 1-aminodecylidene bis-phosphonic acid (ARC39) specifically and efficiently (>90%) inhibits both lysosomal and secretory ASM in vitro. Results from investigating sphingomyelin phosphodiesterase 1 (SMPD1/Smpd1) mRNA and ASM protein levels suggested that ARC39 directly inhibits ASM's catalytic activity in cultured cells, a mechanism that differs from that of functional inhibitors of ASM. We further provide evidence that ARC39 dose- and time-dependently inhibits lysosomal ASM in intact cells, and we show that ARC39 also reduces platelet- and ASM-promoted adhesion of tumor cells. The observed toxicity of ARC39 is low at concentrations relevant for ASM inhibition in vitro, and it does not strongly alter the lysosomal compartment or induce phospholipidosis in vitro. When applied intraperitoneally in vivo, even subtoxic high doses administered short-term induced sphingomyelin accumulation only locally in the peritoneal lavage without significant accumulation in plasma, liver, spleen, or brain. These findings require further investigation with other possible chemical modifications. In conclusion, our results indicate that ARC39 potently and selectively inhibits ASM in vitro and highlight the need for developing compounds that can reach tissue concentrations sufficient for ASM inhibition in vivo.
KW  - sphingolipids
KW  - sphingomyelin
KW  - cerami-des
KW  - lipid metabolism
KW  - enzymology
KW  - lysosome
KW  - lysosomal hydrolases
KW  - acid ceramidase
KW  - bisphosphonates
KW  - functional inhibitors of acid sphin-gomyelinase
KW  - 1-aminodecylidene bis-phosphonic acid
Y1  - 2021
U6  - https://doi.org/10.1194/jlr.RA120000682
SN  - 1539-7262
SN  - 0022-2275
VL  - 61
IS  - 6
SP  - 896
EP  - 910
PB  - American Society for Biochemistry and Molecular Biology
CY  - Bethesda
ER  - 
TY  - GEN
A1  - Weber, Daniela
A1  - Kochlik, Bastian Max
A1  - Demuth, Ilja
A1  - Steinhagen-Thiessen, Elisabeth
A1  - Grune, Tilman
A1  - Norman, Kristina
T1  - Plasma carotenoids, tocopherols and retinol
BT  - Association with age in the Berlin Aging Study II
T2  - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe
N2  - Regular consumption of fruits and vegetables, which is related to high plasma levels of lipid-soluble micro-nutrients such as carotenoids and tocopherols, is linked to lower incidences of various age-related diseases. Differences in lipid-soluble micronutrient blood concentrations seem to be associated with age. Our retrospective analysis included men and women aged 22-37 and 60-85 years from the Berlin Aging Study II. Participants with simultaneously available plasma samples and dietary data were included (n = 1973). Differences between young and old groups were found for plasma lycopene, alpha-carotene, alpha-tocopherol, beta-cryptoxanthin (only in women), and gamma-tocopherol (only in men). beta-Carotene, retinol and lutein/zeaxanthin did not differ between young and old participants regardless of the sex. We found significant associations for lycopene, alpha-carotene (both inverse), alpha-tocopherol, gamma-tocopherol, and beta-carotene (all positive) with age. Adjusting for BMI, smoking status, season, cholesterol and dietary intake confirmed these associations, except for beta-carotene. These micronutrients are important antioxidants and associated with lower incidence of age-related diseases, therefore it is important to understand the underlying mechanisms in order to implement dietary strategies for the prevention of age-related diseases. To explain the lower lycopene and alpha-carotene concentration in older subjects, bioavailability studies in older participants are necessary.
T3  - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 1409 
KW  - carotenoids
KW  - tocopherols
KW  - micronutrients
KW  - age
KW  - plasma
KW  - food frequency questionnaire
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-515996
SN  - 1866-8372
ER  - 
TY  - JOUR
A1  - Weber, Daniela
A1  - Kochlik, Bastian Max
A1  - Demuth, Ilja
A1  - Steinhagen-Thiessen, Elisabeth
A1  - Grune, Tilman
A1  - Norman, Kristina
T1  - Plasma carotenoids, tocopherols and retinol
BT  - Association with age in the Berlin Aging Study II
JF  - Redox Biology
N2  - Regular consumption of fruits and vegetables, which is related to high plasma levels of lipid-soluble micro-nutrients such as carotenoids and tocopherols, is linked to lower incidences of various age-related diseases. Differences in lipid-soluble micronutrient blood concentrations seem to be associated with age. Our retrospective analysis included men and women aged 22-37 and 60-85 years from the Berlin Aging Study II. Participants with simultaneously available plasma samples and dietary data were included (n = 1973). Differences between young and old groups were found for plasma lycopene, alpha-carotene, alpha-tocopherol, beta-cryptoxanthin (only in women), and gamma-tocopherol (only in men). beta-Carotene, retinol and lutein/zeaxanthin did not differ between young and old participants regardless of the sex. We found significant associations for lycopene, alpha-carotene (both inverse), alpha-tocopherol, gamma-tocopherol, and beta-carotene (all positive) with age. Adjusting for BMI, smoking status, season, cholesterol and dietary intake confirmed these associations, except for beta-carotene. These micronutrients are important antioxidants and associated with lower incidence of age-related diseases, therefore it is important to understand the underlying mechanisms in order to implement dietary strategies for the prevention of age-related diseases. To explain the lower lycopene and alpha-carotene concentration in older subjects, bioavailability studies in older participants are necessary.
KW  - carotenoids
KW  - tocopherols
KW  - micronutrients
KW  - age
KW  - plasma
KW  - food frequency questionnaire
Y1  - 2020
U6  - https://doi.org/10.1016/j.redox.2020.101461
SN  - 2213-2317
VL  - 32
SP  - 1
EP  - 8
PB  - Elsevier
CY  - Amsterdam
ER  - 
TY  - GEN
A1  - Olayide, Priscilla
A1  - Large, Annabel
A1  - Stridh, Linnea
A1  - Rabbi, Ismail
A1  - Baldermann, Susanne
A1  - Stavolone, Livia
A1  - Alexandersson, Erik
T1  - Gene expression and metabolite profiling of thirteen Nigerian cassava landraces to elucidate starch and carotenoid composition
T2  - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe
N2  - The prevalence of vitamin A deficiency in sub-Saharan Africa necessitates effective approaches to improve provitamin A content of major staple crops. Cassava holds much promise for food security in sub-Saharan Africa, but a negative correlation between beta-carotene, a provitamin A carotenoid, and dry matter content has been reported, which poses a challenge to cassava biofortification by conventional breeding. To identify suitable material for genetic transformation in tissue culture with the overall aim to increase beta-carotene and maintain starch content as well as better understand carotenoid composition, root and leaf tissues from thirteen field-grown cassava landraces were analyzed for agronomic traits, carotenoid, chlorophyll, and starch content. The expression of five genes related to carotenoid biosynthesis were determined in selected landraces. Analysis revealed a weak negative correlation between starch and beta-carotene content, whereas there was a strong positive correlation between root yield and many carotenoids including beta-carotene. Carotenoid synthesis genes were expressed in both white and yellow cassava roots, but phytoene synthase 2 (PSY2), lycopene-epsilon-cyclase (LCY epsilon), and beta-carotenoid hydroxylase (CHY beta) expression were generally higher in yellow roots. This study identified lines with reasonably high content of starch and beta-carotene that could be candidates for biofortification by further breeding or plant biotechnological means.
T3  - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 1415 
KW  - carotenoid biosynthesis
KW  - ultra-high performance liquid chromatography-mass spectrometry (UHPLC-MS)
KW  - provitamin A
KW  - biofortification
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-517834
SN  - 1866-8372
IS  - 3
ER  - 
TY  - JOUR
A1  - Olayide, Priscilla
A1  - Large, Annabel
A1  - Stridh, Linnea
A1  - Rabbi, Ismail
A1  - Baldermann, Susanne
A1  - Stavolone, Livia
A1  - Alexandersson, Erik
T1  - Gene expression and metabolite profiling of thirteen Nigerian cassava landraces to elucidate starch and carotenoid composition
JF  - Agronomy
N2  - The prevalence of vitamin A deficiency in sub-Saharan Africa necessitates effective approaches to improve provitamin A content of major staple crops. Cassava holds much promise for food security in sub-Saharan Africa, but a negative correlation between beta-carotene, a provitamin A carotenoid, and dry matter content has been reported, which poses a challenge to cassava biofortification by conventional breeding. To identify suitable material for genetic transformation in tissue culture with the overall aim to increase beta-carotene and maintain starch content as well as better understand carotenoid composition, root and leaf tissues from thirteen field-grown cassava landraces were analyzed for agronomic traits, carotenoid, chlorophyll, and starch content. The expression of five genes related to carotenoid biosynthesis were determined in selected landraces. Analysis revealed a weak negative correlation between starch and beta-carotene content, whereas there was a strong positive correlation between root yield and many carotenoids including beta-carotene. Carotenoid synthesis genes were expressed in both white and yellow cassava roots, but phytoene synthase 2 (PSY2), lycopene-epsilon-cyclase (LCY epsilon), and beta-carotenoid hydroxylase (CHY beta) expression were generally higher in yellow roots. This study identified lines with reasonably high content of starch and beta-carotene that could be candidates for biofortification by further breeding or plant biotechnological means.
KW  - carotenoid biosynthesis
KW  - ultra-high performance liquid chromatography-mass spectrometry (UHPLC-MS)
KW  - provitamin A
KW  - biofortification
Y1  - 2020
U6  - https://doi.org/10.3390/agronomy10030424
SN  - 2073-4395
VL  - 10
IS  - 3
SP  - 1
EP  - 16
PB  - MDPI
CY  - Basel
ER  - 
TY  - GEN
A1  - Kessler, Katharina
A1  - Hornemann, Silke
A1  - Rudovich, Natalia
A1  - Weber, Daniela
A1  - Grune, Tilman
A1  - Kramer, Achim
A1  - Pfeiffer, Andreas F. H.
A1  - Pivovarova-Ramich, Olga
T1  - Saliva samples as a tool to study the effect of meal timing on metabolic and inflammatory biomarkers
T2  - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe
N2  - Meal timing affects metabolic regulation in humans. Most studies use blood samples fortheir investigations. Saliva, although easily available and non-invasive, seems to be rarely used forchrononutritional studies. In this pilot study, we tested if saliva samples could be used to studythe effect of timing of carbohydrate and fat intake on metabolic rhythms. In this cross-over trial, 29 nonobese men were randomized to two isocaloric 4-week diets: (1) carbohydrate-rich meals until13:30 and high-fat meals between 16:30 and 22:00 or (2) the inverse order of meals. Stimulated salivasamples were collected every 4 h for 24 h at the end of each intervention, and levels of hormones andinflammatory biomarkers were assessed in saliva and blood. Cortisol, melatonin, resistin, adiponectin, interleukin-6 and MCP-1 demonstrated distinct diurnal variations, mirroring daytime reports inblood and showing significant correlations with blood levels. The rhythm patterns were similar forboth diets, indicating that timing of carbohydrate and fat intake has a minimal effect on metabolicand inflammatory biomarkers in saliva. Our study revealed that saliva is a promising tool for thenon-invasive assessment of metabolic rhythms in chrononutritional studies, but standardisation of sample collection is needed in out-of-lab studies.
T3  - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 1425 
KW  - meal timing
KW  - saliva
KW  - circadian clock
KW  - adiponectin
KW  - resistin
KW  - visfatin
KW  - insulin
KW  - melatonin
KW  - cortisol
KW  - cytokines
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-512079
SN  - 1866-8372
IS  - 2
ER  - 
TY  - JOUR
A1  - Kessler, Katharina
A1  - Hornemann, Silke
A1  - Rudovich, Natalia
A1  - Weber, Daniela
A1  - Grune, Tilman
A1  - Kramer, Achim
A1  - Pfeiffer, Andreas F. H.
A1  - Pivovarova-Ramich, Olga
T1  - Saliva samples as a tool to study the effect of meal timing on metabolic and inflammatory biomarkers
JF  - Nutrients
N2  - Meal timing affects metabolic regulation in humans. Most studies use blood samples fortheir investigations. Saliva, although easily available and non-invasive, seems to be rarely used forchrononutritional studies. In this pilot study, we tested if saliva samples could be used to studythe effect of timing of carbohydrate and fat intake on metabolic rhythms. In this cross-over trial, 29 nonobese men were randomized to two isocaloric 4-week diets: (1) carbohydrate-rich meals until13:30 and high-fat meals between 16:30 and 22:00 or (2) the inverse order of meals. Stimulated salivasamples were collected every 4 h for 24 h at the end of each intervention, and levels of hormones andinflammatory biomarkers were assessed in saliva and blood. Cortisol, melatonin, resistin, adiponectin, interleukin-6 and MCP-1 demonstrated distinct diurnal variations, mirroring daytime reports inblood and showing significant correlations with blood levels. The rhythm patterns were similar forboth diets, indicating that timing of carbohydrate and fat intake has a minimal effect on metabolicand inflammatory biomarkers in saliva. Our study revealed that saliva is a promising tool for thenon-invasive assessment of metabolic rhythms in chrononutritional studies, but standardisation of sample collection is needed in out-of-lab studies.
KW  - meal timing
KW  - saliva
KW  - circadian clock
KW  - adiponectin
KW  - resistin
KW  - visfatin
KW  - insulin
KW  - melatonin
KW  - cortisol
KW  - cytokines
Y1  - 2020
U6  - https://doi.org/10.3390/nu12020340
SN  - 2072-6643
IS  - 2
SP  - 1
EP  - 12
PB  - MDPI
CY  - Basel
ER  - 
TY  - GEN
A1  - Schedlbauer, Carola
A1  - Blaue, Dominique
A1  - Raila, Jens
A1  - Vervuert, Ingrid
T1  - Alterations of serum vitamin E and vitamin A concentrations of ponies and horses during experimentally induced obesity
T2  - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe
N2  - Vitamin A, vitamin E and retinol-binding protein 4 (RBP4) are a focus of current obesity research in humans. The impact of body weight (BW) gain on fat-soluble vitamins and its associated parameters in equines has not been previously reported. Ten Shetland ponies and 9 Warmblood horses, all adult geldings, non-obese and healthy, were fed an excessive energy diet for 20 months to induce BW gain. Serum alpha-tocopherol (vitamin E), retinol (vitamin A), retinol-binding protein 4 (RBP4) and retinol/RBP4 ratio were analysed before BW gain induction and at six timepoints during the BW gaining period. The mean (+/- SD) % BW gain achieved during two years of excess energy intake was 29.9 +/- 19.4% for ponies and 17 +/- 6.74% for horses. Serum alpha-tocopherol increased significantly in ponies and horses during excess energy intake and circulating alpha-tocopherol levels correlated positively with alpha-tocopherol intake (r = .6; p < .001). Serum retinol concentrations showed variations during the study but without relation to intake. Serum RBP4 decreased at the end of the study. The retinol/RBP4 ratio increased with BW gain without differences between ponies and horses. In comparison with human research, the increase in the retinol/RBP4 ratio was unexpected and needs further elucidation.
T3  - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 1429 
KW  - body weight gain
KW  - equine
KW  - laminitis
KW  - retinol-binding protein 4
KW  - α-tocophero
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-519515
SN  - 1866-8372
IS  - 5
ER  - 
TY  - CHAP
A1  - Schenke, Maren
A1  - Schjeide, Brit-Maren
A1  - Püschel, Gerhard
A1  - Seeger, Bettina
T1  - Human motor neurons diffentiated from plutipotent stem cells as superior traged cells for botulinum neuotoxin potency testing
BT  - In: German Pharm-Tox Summit 2020: abstracts of the 86th Annual Meeting of the German Society for Experimental and Clinical Pharmacology and Toxicology (DGPT)
T2  - Naunyn-Schmiedeberg's archives of pharmacology
Y1  - 2020
U6  - https://doi.org/10.1007/s00210-020-01828-y
SN  - 0028-1298
SN  - 1432-1912
VL  - 393
IS  - SUPPL 1
SP  - S10
EP  - S10
PB  - Springer
CY  - Berlin ; Heidelberg
ER  - 
TY  - JOUR
A1  - Fink, Julian
A1  - Schumacher, Fabian
A1  - Schlegel, Jan
A1  - Stenzel, Philipp
A1  - Wigger, Dominik
A1  - Sauer, Markus
A1  - Kleuser, Burkhard
A1  - Seibel, Jürgen
T1  - Azidosphinganine enables metabolic labeling and detection of sphingolipid de novo synthesis
JF  - Organic & biomolecular chemistry : an international journal of synthetic, physical and biomolecular organic chemistry
N2  - Here were report the combination of biocompatible click chemistry of omega-azidosphinganine with fluorescence microscopy and mass spectrometry as a powerful tool to elaborate the sphingolipid metabolism. The azide probe was efficiently synthesized over 13 steps starting from l-serine in an overall yield of 20% and was used for live-cell fluorescence imaging of the endoplasmic reticulum in living cells by bioorthogonal click reaction with a DBCO-labeled fluorophore revealing that the incorporated analogue is mainly localized in the endoplasmic membrane like the endogenous species. A LC-MS(/MS)-based microsomal in vitro assay confirmed that omega-azidosphinganine mimics the natural species enabling the identification and analysis of metabolic breakdown products of sphinganine as a key starting intermediate in the complex sphingolipid biosynthetic pathways. Furthermore, the sphinganine-fluorophore conjugate after click reaction was enzymatically tolerated to form its dihydroceramide and ceramide metabolites. Thus, omega-azidosphinganine represents a useful biofunctional tool for metabolic investigations both by in vivo fluorescence imaging of the sphingolipid subcellular localization in the ER and by in vitro high-resolution mass spectrometry analysis. This should reveal novel insights of the molecular mechanisms sphingolipids and their processing enzymes have e.g. in infection.
Y1  - 2021
U6  - https://doi.org/10.1039/d0ob02592e
SN  - 1477-0520
SN  - 1477-0539
VL  - 19
IS  - 10
SP  - 2203
EP  - 2212
PB  - Royal Society of Chemistry
CY  - Cambridge
ER  - 
TY  - JOUR
A1  - Bishop, Christopher Allen
A1  - Machate, Tina
A1  - Henning, Thorsten
A1  - Henkel-Oberländer, Janin
A1  - Püschel, Gerhard
A1  - Weber, Daniela
A1  - Grune, Tilman
A1  - Klaus, Susanne
A1  - Weitkunat, Karolin
T1  - Detrimental effects of branched-chain amino acids in glucose tolerance can be attributed to valine induced glucotoxicity in skeletal muscle
JF  - Nutrition & Diabetes
N2  - Objective: 
Current data regarding the roles of branched-chain amino acids (BCAA) in metabolic health are rather conflicting, as positive and negative effects have been attributed to their intake. 

Methods:
To address this, individual effects of leucine and valine were elucidated in vivo (C57BL/6JRj mice) with a detailed phenotyping of these supplementations in high-fat (HF) diets and further characterization with in vitro approaches (C2C12 myocytes). 

Results:
 Here, we demonstrate that under HF conditions, leucine mediates beneficial effects on adiposity and insulin sensitivity, in part due to increasing energy expenditure-likely contributing partially to the beneficial effects of a higher milk protein intake. On the other hand, valine feeding leads to a worsening of HF-induced health impairments, specifically reducing glucose tolerance/ insulin sensitivity. These negative effects are driven by an accumulation of the valine-derived metabolite 3-hydroxyisobutyrate (3HIB). Higher plasma 3-HIB levels increase basal skeletal muscle glucose uptake which drives glucotoxicity and impairs myocyte insulin signaling. 

Conclusion:
These data demonstrate the detrimental role of valine in an HF context and elucidate additional targetable pathways in the etiology of BCAA-induced obesity and insulin resistance.
Y1  - 2022
U6  - https://doi.org/10.1038/s41387-022-00200-8
SN  - 2044-4052
VL  - 12
IS  - 1
PB  - Nature Publishing Group
CY  - London
ER  - 
TY  - JOUR
A1  - Nicolai, Merle Marie
A1  - Witt, Barbara
A1  - Friese, Sharleen
A1  - Michaelis, Vivien
A1  - Hölz-Armstrong, Lisa
A1  - Martin, Maximilian
A1  - Ebert, Franziska
A1  - Schwerdtle, Tanja
A1  - Bornhorst, Julia
T1  - Mechanistic studies on the adverse effects of manganese overexposure in differentiated LUHMES cells
JF  - Food and chemical toxicology
N2  - Manganese (Mn) is an essential trace element, but overexposure is associated with toxicity and neurological dysfunction. Accumulation of Mn can be observed in dopamine-rich regions of the brain in vivo and Mn-induced oxidative stress has been discussed extensively. Nevertheless, Mn-induced DNA damage, adverse effects of DNA repair, and possible resulting consequences for the neurite network are not yet characterized. For this, LUHMES cells were used, as they differentiate into dopaminergic-like neurons and form extensive neurite networks. Experiments were conducted to analyze Mn bioavailability and cytotoxicity of MnCl2, indicating a dose-dependent uptake and substantial cytotoxic effects. DNA damage, analyzed by means of 8-oxo-7,8-dihydro-2'-guanine (8oxodG) and single DNA strand break formation, showed significant dose- and time-dependent increase of DNA damage upon 48 h Mn exposure. Furthermore, the DNA damage response was increased which was assessed by analytical quantification of poly(ADP-ribosyl)ation (PARylation). Gene expression of the respective DNA repair genes was not significantly affected. Degradation of the neuronal network is significantly altered by 48 h Mn exposure. Altogether, this study contributes to the characterization of Mn-induced neurotoxicity, by analyzing the adverse effects of Mn on genome integrity in dopaminergic-like neurons and respective outcomes.
KW  - Manganese
KW  - Dopaminergic neurons
KW  - DNA integrity
KW  - DNA repair
KW  - Neurodegeneration
KW  - Oxidative stress
KW  - Genotoxicity
Y1  - 2022
U6  - https://doi.org/10.1016/j.fct.2022.112822
SN  - 0278-6915
SN  - 1873-6351
VL  - 161
PB  - Elsevier
CY  - Oxford
ER  - 
TY  - JOUR
A1  - Klaus, Susanne
A1  - Igual Gil, Carla
A1  - Ost, Mario
T1  - Regulation of diurnal energy balance by mitokines
JF  - Cellular and molecular life sciences : CMLS
N2  - The mammalian system of energy balance regulation is intrinsically rhythmic with diurnal oscillations of behavioral and metabolic traits according to the 24 h day/night cycle, driven by cellular circadian clocks and synchronized by environmental or internal cues such as metabolites and hormones associated with feeding rhythms. Mitochondria are crucial organelles for cellular energy generation and their biology is largely under the control of the circadian system. Whether mitochondrial status might also feed-back on the circadian system, possibly via mitokines that are induced by mitochondrial stress as endocrine-acting molecules, remains poorly understood. Here, we describe our current understanding of the diurnal regulation of systemic energy balance, with focus on fibroblast growth factor 21 (FGF21) and growth differentiation factor 15 (GDF15), two well-known endocrine-acting metabolic mediators. FGF21 shows a diurnal oscillation and directly affects the output of the brain master clock. Moreover, recent data demonstrated that mitochondrial stress-induced GDF15 promotes a day-time restricted anorexia and systemic metabolic remodeling as shown in UCP1-transgenic mice, where both FGF21 and GDF15 are induced as myomitokines. In this mouse model of slightly uncoupled skeletal muscle mitochondria GDF15 proved responsible for an increased metabolic flexibility and a number of beneficial metabolic adaptations. However, the molecular mechanisms underlying energy balance regulation by mitokines are just starting to emerge, and more data on diurnal patterns in mouse and man are required. This will open new perspectives into the diurnal nature of mitokines and action both in health and disease.
KW  - Mitochondria
KW  - FGF21
KW  - GDF15
KW  - Circadian rhythm
KW  - Hormones
KW  - Nutrition
Y1  - 2021
U6  - https://doi.org/10.1007/s00018-020-03748-9
SN  - 1420-682X
SN  - 1420-9071
VL  - 78
IS  - 7
SP  - 3369
EP  - 3384
PB  - Springer International Publishing AG
CY  - Cham (ZG)
ER  - 
TY  - JOUR
A1  - Schweigert, Florian J.
ED  - Kollodzeiski, Ulrike
ED  - Hafner, Johann Evangelist
T1  - Hässlich aber gut
BT  - Insekten als Nahrungsmittel – Warum wir uns ekeln
JF  - Du sollst nicht essen: Warum Menschen auf Nahrung verzichten – interdisziplinäre Zugänge
Y1  - 2024
SN  - 978-3-98740-007-0
SN  - 978-3-98740-008-7
U6  - https://doi.org/10.5771/9783987400087
SP  - 47
EP  - 59
PB  - Ergon Verlag
CY  - Baden-Baden
ER  - 
TY  - GEN
A1  - Kollodzeiski, Ulrike
A1  - Hafner, Johann Evangelist
A1  - Lippert, Rachel N.
A1  - Bartelmeß, Tina
A1  - Schweigert, Florian J.
A1  - Bigalke, Bernadett
A1  - Krochmalnik, Daniel
A1  - Sancı, Kadir
A1  - Kardas, Arhan
A1  - Dietzel, Irene
A1  - Yilmaz, Rümeysa
A1  - Olhoeft, Netanel
A1  - Struß, Lukas
ED  - Kollodzeiski, Ulrike
ED  - Hafner, Johann Evangelist
T1  - Du sollst nicht essen
BT  - Warum Menschen auf Nahrung verzichten – interdisziplinäre Zugänge
T2  - Zweitveröffentlichungen der Universität Potsdam : Philosophische Reihe
N2  - Zwar sind Menschen biologisch gesehen Allesesser, dennoch gibt es keine Gemeinschaft, die alle ihr zur Verfügung stehenden Nahrungsmittel voll ausschöpft. Immer wird etwas nicht gegessen. Warum wir nicht essen, was wir nicht essen – das beleuchtet dieser Sammelband aus neuro-, ernährungs-, gesellschafts- und religionswissenschaftlicher Perspektive. Ein „religiöser Nutriscore“ gibt Auskunft über die wichtigsten Verzichtsregeln in Judentum, Christentum und Islam. Eine Fotostrecke veranschaulicht, wie bestimmte Speisen zu Festen und Feiertagen zu einem heiligen Essen werden. Nicht zuletzt werden Wege aufgezeigt, wie Menschen, die verschiedene Speiseregeln befolgen, dennoch zusammen essen können – inklusive Praxistest in der Unimensa.
T3  - Zweitveröffentlichungen der Universität Potsdam : Philosophische Reihe - 191 
KW  - Speisegebot
KW  - Ernährungsgewohnheit
KW  - Religiöses Leben
KW  - Judentum
KW  - Christentum
KW  - Islam
Y1  - 2024
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-627542
SN  - 1866-8380
IS  - 191
EP  - 172
ER  - 
TY  - BOOK
A1  - Kollodzeiski, Ulrike
A1  - Hafner, Johann Evangelist
A1  - Lippert, Rachel N.
A1  - Bartelmeß, Tina
A1  - Schweigert, Florian J.
A1  - Bigalke, Bernadett
A1  - Krochmalnik, Daniel
A1  - Sancı, Kadir
A1  - Kardas, Arhan
A1  - Dietzel, Irene
A1  - Yilmaz, Rümeysa
A1  - Olhoeft, Netanel
A1  - Struß, Lukas
ED  - Kollodzeiski, Ulrike
ED  - Hafner, Johann Evangelist
T1  - Du sollst nicht essen
BT  - Warum Menschen auf Nahrung verzichten – interdisziplinäre Zugänge
N2  - Zwar sind Menschen biologisch gesehen Allesesser, dennoch gibt es keine Gemeinschaft, die alle ihr zur Verfügung stehenden Nahrungsmittel voll ausschöpft. Immer wird etwas nicht gegessen. Warum wir nicht essen, was wir nicht essen – das beleuchtet dieser Sammelband aus neuro-, ernährungs-, gesellschafts- und religionswissenschaftlicher Perspektive. Ein „religiöser Nutriscore“ gibt Auskunft über die wichtigsten Verzichtsregeln in Judentum, Christentum und Islam. Eine Fotostrecke veranschaulicht, wie bestimmte Speisen zu Festen und Feiertagen zu einem heiligen Essen werden. Nicht zuletzt werden Wege aufgezeigt, wie Menschen, die verschiedene Speiseregeln befolgen, dennoch zusammen essen können – inklusive Praxistest in der Unimensa.
KW  - Speisegebot
KW  - Ernährungsgewohnheit
KW  - Religiöses Leben
KW  - Judentum
KW  - Christentum
KW  - Islam
Y1  - 2024
SN  - 978-3-98740-007-0
SN  - 978-3-98740-008-7
U6  - https://doi.org/10.5771/9783987400087
EP  - 172
PB  - Ergon Verlag
CY  - Baden-Baden
ER  - 
TY  - JOUR
A1  - Burkhardt, Wiebke
A1  - Rausch, Theresa
A1  - Klopfleisch, Robert
A1  - Blaut, Michael
A1  - Braune, Annett
T1  - Impact of dietary sulfolipid-derived sulfoquinovose on gut microbiota composition and inflammatory status of colitis-prone interleukin-10-deficient mice
JF  - International journal of medical microbiology : IJMM
N2  - The interplay between diet, intestinal microbiota and host is a major factor impacting health. A diet rich in unsaturated fatty acids has been reported to stimulate the growth of Bilophila wadsworthia by increasing the proportion of the sulfonated bile acid taurocholate (TC). The taurine-induced overgrowth of B. wadsworthia promoted the development of colitis in interleukin-10-deficient (IL-10(-/-)) mice. This study aimed to investigate whether intake of the sulfonates sulfoquinovosyl diacylglycerols (SQDG) with a dietary supplement or their degradation product sulfoquinovose (SQ), stimulate the growth of B. wadsworthia in a similar manner and, thereby, cause intestinal inflammation. Conventional IL-10(-/-) mice were fed a diet supplemented with the SQDG-rich cyanobacterium Arthrospira platensis (Spirulina). SQ or TC were orally applied to conventional IL-10(-/-) mice and gnotobiotic IL-10(-/-) mice harboring a simplified human intestinal microbiota with or without B. wadsworthia. Analyses of inflammatory parameters revealed that none of the sulfonates induced severe colitis, but both, Spirulina and TC, induced expression of pro-inflammatory cytokines in cecal mucosa. Cell numbers of B. wadsworthia decreased almost two orders of magnitude by Spirulina feeding but slightly increased in gnotobiotic SQ and conventional TC mice. Changes in microbiota composition were observed in feces as a result of Spirulina or TC feeding in conventional mice. In conclusion, the dietary sulfonates SQDG and their metabolite SQ did not elicit bacteria-induced intestinal inflammation in IL-10(-/-) mice and, thus, do not promote colitis.
KW  - Sulfonate
KW  - Sulfoquinovose
KW  - Spirulina
KW  - Inflammatory bowel disease
KW  - Bilophila wadsworthia
KW  - Taurocholate
Y1  - 2021
U6  - https://doi.org/10.1016/j.ijmm.2021.151494
SN  - 1618-0607
VL  - 311
IS  - 3
PB  - Elsevier
CY  - München
ER  - 
TY  - GEN
A1  - Rodríguez Sillke, Yasmina
A1  - Schumann, Michael
A1  - Lissner, Donata
A1  - Branchi, Frederica
A1  - Glauben, Rainer
A1  - Siegmund, Britta
T1  - Small intestinal inflammation but not colitis drives pro-inflammatory nutritional antigen-specific T-cell response
T2  - Journal of Crohn's and Colitis
N2  - Background: 
Inflammatory bowel disease (IBD) represents a dysregulation of the mucosal immune system. The pathogenesis of Crohn’s disease (CD) and ulcerative colitis (UC) is linked to the loss of intestinal tolerance and barrier function. The healthy mucosal immune system has previously been shown to be inert against food antigens. Since the small intestine is the main contact surface for antigens and therefore the immunological response, the present study served to analyse food-antigen-specific T cells in the peripheral blood of IBD patients.

Methods: 
Peripheral blood mononuclear cells of CD, with an affected small intestine, and UC (colitis) patients, either active or in remission, were stimulated with the following food antigens: gluten, soybean, peanut and ovalbumin. Healthy controls and celiac disease patients were included as controls. Antigen-activated CD4+ T cells in the peripheral blood were analysed by a magnetic enrichment of CD154+ effector T cells and a cytometric antigen-reactive T-cell analysis (‘ARTE’ technology) followed by characterisation of the ef- fector response.

Results:
The effector T-cell response of antigen-specific T cells were compared between CD with small intestinal inflammation and UC where inflammation was restricted to the colon. Among all tested food antigens, the highest frequency of antigen-specific T cells (CD4+CD154+) was found for gluten. Celiac disease patients were included as control, since gluten has been identified as the disease- causing antigen. The highest frequency of gluten antigen-specific T cells was revealed in active CD when compared with UC, celiac disease on a gluten-free diet (GFD) and healthy controls. Ovalbuminspecific T cells were almost undetectable, whereas the reaction to soybean and peanut was slightly higher. But again, the strong- est reaction was observed in CD with small intestinal involvement compared with UC. Remarkably, in celiac disease on a GFD only
antigen-specific cells for gluten were detected. These gluten-specific T cells were characterised by up-regulation of the pro-inflammatory cytokines IFN-γ, IL-17A and TNF-α. IFN-g was exclusively elevated in CD patients with active disease. Gluten-specific T-cells expressing IL-17A were increased in all IBD patients. Furthermore, T cells of CD patients, independent of disease activity, revealed a high expression of the pro-inflammatory cytokine TNF-α.

Conclusion:
The ‘ARTE’-technique allows to analyse and quantify food antigen specific T cells in the peripheral blood of IBD patients indicating a potential therapeutic insight. These data provide evidence that small intestinal inflammation in CD is key for the development of a systemic pro-inflammatory effector T-cell response driven by food antigens.
Y1  - 2020
U6  - https://doi.org/10.1093/ecco-jcc/jjz203.172
SN  - 1873-9946
SN  - 1876-4479
VL  - 14
SP  - S154
EP  - S155
PB  - Oxford Univ. Press
CY  - Oxford
ER  - 
TY  - JOUR
A1  - Volk, Christin
A1  - Brandsch, Corinna
A1  - Schlegelmilch, Ulf
A1  - Wensch-Dorendorf, Monika
A1  - Hirche, Frank
A1  - Simm, Andreas
A1  - Gargum, Osama
A1  - Wiacek, Claudia
A1  - Braun, Peggy G.
A1  - Kopp, Johannes F.
A1  - Schwerdtle, Tanja
A1  - Treede, Hendrik
A1  - Stangl, Gabriele I.
T1  - Postprandial metabolic response to rapeseed protein in healthy subjects
JF  - Nutrients
N2  - Plant proteins have become increasingly important for ecological reasons. Rapeseed is a novel source of plant proteins with high biological value, but its metabolic impact in humans is largely unknown. A randomized, controlled intervention study including 20 healthy subjects was conducted in a crossover design. All participants received a test meal without additional protein or with 28 g of rapeseed protein isolate or soy protein isolate (control). Venous blood samples were collected over a 360-min period to analyze metabolites; satiety was assessed using a visual analog scale. Postprandial levels of lipids, urea, and amino acids increased following the intake of both protein isolates. The postprandial insulin response was lower after consumption of the rapeseed protein than after intake of the soy protein (p< 0.05), whereas the postmeal responses of glucose, lipids, interleukin-6, minerals, and urea were comparable between the two protein isolates. Interestingly, the rapeseed protein exerted stronger effects on postprandial satiety than the soy protein (p< 0.05). The postmeal metabolism following rapeseed protein intake is comparable with that of soy protein. The favorable effect of rapeseed protein on postprandial insulin and satiety makes it a valuable plant protein for human nutrition.
KW  - rapeseed protein
KW  - soy protein
KW  - postprandial study
KW  - metabolic response
KW  - healthy subjects
Y1  - 2020
U6  - https://doi.org/10.3390/nu12082270
SN  - 2072-6643
VL  - 12
IS  - 8
PB  - MDPI
CY  - Basel
ER  - 
TY  - JOUR
A1  - Schulze, Matthias Bernd
T1  - Dietary linoleic acid: will modifying dietary fat quality reduce the risk of type 2 diabetes?
JF  - Diabetes care
Y1  - 2021
U6  - https://doi.org/10.2337/dci21-0031
SN  - 0149-5992
SN  - 1935-5548
VL  - 44
IS  - 9
SP  - 1913
EP  - 1915
PB  - American Diabetes Association
CY  - Alexandria
ER  - 
TY  - CHAP
A1  - Schenke, Maren
A1  - Schjeide, Brit-Maren
A1  - Püschel, Gerhard Paul
A1  - Seeger, Bettina
T1  - Serotype-specific sensitivity to Botulinum neurotoxins of iPSC-derived motor neurons
T2  - Naunyn-Schmiedeberg's archives of pharmacology
Y1  - 2021
U6  - https://doi.org/10.1007/s00210-021-02066-6
SN  - 0028-1298
SN  - 1432-1912
VL  - 394
IS  - Suppl. 1
SP  - S4
EP  - S4
PB  - Springer
CY  - Berlin ; Heidelberg
ER  - 
TY  - JOUR
A1  - Jannasch, Franziska
A1  - Nickel, Daniela V.
A1  - Bergmann, Manuela M.
A1  - Schulze, Matthias Bernd
T1  - A new evidence-based diet score to capture associations of food consumption and chronic disease risk
JF  - Nutrients / Molecular Diversity Preservation International (MDPI)
N2  - Previously, the attempt to compile German dietary guidelines into a diet score was predominantly not successful with regards to preventing chronic diseases in the EPIC-Potsdam study. Current guidelines were supplemented by the latest evidence from systematic reviews and expert papers published between 2010 and 2020 on the prevention potential of food groups on chronic diseases such as type 2 diabetes, cardiovascular diseases and cancer. A diet score was developed by scoring the food groups according to a recommended low, moderate or high intake. The relative validity and reliability of the diet score, assessed by a food frequency questionnaire, was investigated. The consideration of current evidence resulted in 10 key food groups being preventive of the chronic diseases of interest. They served as components in the diet score and were scored from 0 to 1 point, depending on their recommended intake, resulting in a maximum of 10 points. Both the reliability (r = 0.53) and relative validity (r = 0.43) were deemed sufficient to consider the diet score as a stable construct in future investigations. This new diet score can be a promising tool to investigate dietary intake in etiological research by concentrating on 10 key dietary determinants with evidence-based prevention potential for chronic diseases.
KW  - diet score
KW  - dietary guidelines
KW  - food groups
KW  - chronic disease
KW  - type 2
KW  - diabetes
KW  - cardiovascular disease
KW  - cancer
KW  - prevention
KW  - reliability;
KW  - validity
Y1  - 2022
U6  - https://doi.org/10.3390/nu14112359
SN  - 2072-6643
VL  - 14
IS  - 11
PB  - MDPI
CY  - Basel
ER  - 
TY  - JOUR
A1  - Xiong, Chan
A1  - Stiboller, Michael
A1  - Glabonjat, Ronald A.
A1  - Rieger, Jaqueline
A1  - Paton, Lhiam
A1  - Francesconi, Kevin A.
T1  - Transport of arsenolipids to the milk of a nursing mother after consuming salmon fish
JF  - Journal of trace elements in medicine and biology
N2  - Objective: 
We address two questions relevant to infants' exposure to potentially toxic arsenolipids, namely, are the arsenolipids naturally present in fish transported intact to a mother's milk, and what is the efficiency of this transport.

Methods: 
We investigated the transport of arsenolipids and other arsenic species present in fish to mother's milk by analyzing the milk of a single nursing mother at 15 sampling times over a 3-day period after she had consumed a meal of salmon. Total arsenic values were obtained by elemental mass spectrometry, and arsenic species were measured by HPLC coupled to both elemental and molecular mass spectrometry.

Results: 
Total arsenic increased from background levels (0.1 mu g As kg(-1)) to a peak value of 1.72 lig As kg(-1) eight hours after the fish meal. The pattern for arsenolipids was similar to that of total arsenic, increasing from undetectable background levels (< 0.01 mu g As kg(-1)) to a peak after eight hours of 0.45 mu g As kg(-1). Most of the remaining total arsenic in the milk was accounted for by arsenobetaine. The major arsenolipids in the salmon were arsenic hydrocarbons (AsHCs; 55 % of total arsenolipids), and these compounds were also the dominant arsenolipids in the milk where they contributed over 90 % of the total arsenolipids. 

Conclusions:
Our study has shown that ca 2-3 % of arsenic hydrocarbons, natural constituents of fish, can be directly transferred unchanged to the milk of a nursing mother. In view of the potential neurotoxicity of AsHCs, the effects of these compounds on the brain developmental stage of infants need to be investigated.
KW  - human milk
KW  - arsenolipids
KW  - salmon fish
KW  - HPLC/ICPMS
KW  - HPLC/HR-ESMS
Y1  - 2020
U6  - https://doi.org/10.1016/j.jtemb.2020.126502
SN  - 0946-672X
VL  - 61
PB  - Elsevier
CY  - München
ER  - 
TY  - JOUR
A1  - Gellner, Anne-Kathrin
A1  - Sitter, Aileen
A1  - Rackiewicz, Michal
A1  - Sylvester, Marc
A1  - Philipsen, Alexandra
A1  - Zimmer, Andreas
A1  - Stein, Valentin
T1  - Stress vulnerability shapes disruption of motor cortical neuroplasticity
JF  - Translational Psychiatry
N2  - Chronic stress is a major cause of neuropsychiatric conditions such as depression. Stress vulnerability varies individually in mice and humans, measured by behavioral changes. In contrast to affective symptoms, motor retardation as a consequence of stress is not well understood. We repeatedly imaged dendritic spines of the motor cortex in Thy1-GFP M mice before and after chronic social defeat stress. Susceptible and resilient phenotypes were discriminated by symptom load and their motor learning abilities were assessed by a gross and fine motor task. Stress phenotypes presented individual short- and long-term changes in the hypothalamic-pituitary-adrenal axis as well as distinct patterns of altered motor learning. Importantly, stress was generally accompanied by a marked reduction of spine density in the motor cortex and spine dynamics depended on the stress phenotype. We found astrogliosis and altered microglia morphology along with increased microglia-neuron interaction in the motor cortex of susceptible mice. In cerebrospinal fluid, proteomic fingerprints link the behavioral changes and structural alterations in the brain to neurodegenerative disorders and dysregulated synaptic homeostasis. Our work emphasizes the importance of synaptic integrity and the risk of neurodegeneration within depression as a threat to brain health.
Y1  - 2022
U6  - https://doi.org/10.1038/s41398-022-01855-8
SN  - 2158-3188
VL  - 12
IS  - 1
PB  - Nature Publishing Group
CY  - London
ER  - 
TY  - JOUR
A1  - Stepanovska, Bisera
A1  - Zivkovic, Aleksandra
A1  - Enzmann, Gaby
A1  - Tietz, Silvia
A1  - Homann, Thomas
A1  - Kleuser, Burkhard
A1  - Engelhardt, Britta
A1  - Stark, Holger
A1  - Huwiler, Andrea
T1  - Morpholino analogues of fingolimod as novel and selective S1P1 ligands with in vivo efficacy in a mouse model of experimental antigen-induced encephalomyelitis
JF  - International journal of molecular sciences
N2  - Multiple sclerosis (MS) is a chronic, inflammatory, autoimmune disease of the central nervous system (CNS) which is associated with lower life expectancy and disability. The experimental antigen-induced encephalomyelitis (EAE) in mice is a useful animal model of MS, which allows exploring the etiopathogenetic mechanisms and testing novel potential therapeutic drugs. A new therapeutic paradigm for the treatment of MS was introduced in 2010 through the sphingosine 1-phosphate (S1P) analogue fingolimod (FTY720, Gilenya(R)), which acts as a functional S1P(1) antagonist on T lymphocytes to deplete these cells from the blood. In this study, we synthesized two novel structures, ST-1893 and ST-1894, which are derived from fingolimod and chemically feature a morpholine ring in the polar head group. These compounds showed a selective S1P(1) activation profile and a sustained S1P(1) internalization in cultures of S1P(1)-overexpressing Chinese hamster ovary (CHO)-K1 cells, consistent with a functional antagonism. In vivo, both compounds induced a profound lymphopenia in mice. Finally, these substances showed efficacy in the EAE model, where they reduced clinical symptoms of the disease, and, on the molecular level, they reduced the T-cell infiltration and several inflammatory mediators in the brain and spinal cord. In summary, these data suggest that S1P(1)-selective compounds may have an advantage over fingolimod and siponimod, not only in MS but also in other autoimmune diseases.
KW  - ST-1893
KW  - ST-1894
KW  - morpholino analogues of fingolimod
KW  - sphingosine
KW  - 1-phosphate
KW  - immunomodulator
KW  - lymphopenia
KW  - multiple sclerosis
KW  - experimental antigen-induced encephalomyelitis
Y1  - 2020
U6  - https://doi.org/10.3390/ijms21186463
SN  - 1422-0067
VL  - 21
IS  - 18
PB  - MDPI
CY  - Basel
ER  - 
TY  - JOUR
A1  - Birukov, Anna
A1  - Cuadrat, Rafael R. C.
A1  - Polemiti, Elli
A1  - Eichelmann, Fabian
A1  - Schulze, Matthias Bernd
T1  - Advanced glycation end-products, measured as skin autofluorescence, associate with vascular stiffness in diabetic, pre-diabetic and normoglycemic individuals
BT  - a cross-sectional study
JF  - Cardiovascular diabetology
N2  - Background Advanced glycation end-products are proteins that become glycated after contact with sugars and are implicated in endothelial dysfunction and arterial stiffening. We aimed to investigate the relationships between advanced glycation end-products, measured as skin autofluorescence, and vascular stiffness in various glycemic strata. Methods We performed a cross-sectional analysis within the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam cohort, comprising n = 3535 participants (median age 67 years, 60% women). Advanced glycation end-products were measured as skin autofluorescence with AGE-Reader (TM), vascular stiffness was measured as pulse wave velocity, augmentation index and ankle-brachial index with Vascular Explorer (TM). A subset of 1348 participants underwent an oral glucose tolerance test. Participants were sub-phenotyped into normoglycemic, prediabetes and diabetes groups. Associations between skin autofluorescence and various indices of vascular stiffness were assessed by multivariable regression analyses and were adjusted for age, sex, measures of adiposity and lifestyle, blood pressure, prevalent conditions, medication use and blood biomarkers. Results Skin autofluorescence associated with pulse wave velocity, augmentation index and ankle-brachial index, adjusted beta coefficients (95% CI) per unit skin autofluorescence increase: 0.38 (0.21; 0.55) for carotid-femoral pulse wave velocity, 0.25 (0.14; 0.37) for aortic pulse wave velocity, 1.00 (0.29; 1.70) for aortic augmentation index, 4.12 (2.24; 6.00) for brachial augmentation index and - 0.04 (- 0.05; - 0.02) for ankle-brachial index. The associations were strongest in men, younger individuals and were consistent across all glycemic strata: for carotid-femoral pulse wave velocity 0.36 (0.12; 0.60) in normoglycemic, 0.33 (- 0.01; 0.67) in prediabetes and 0.45 (0.09; 0.80) in diabetes groups; with similar estimates for aortic pulse wave velocity. Augmentation index was associated with skin autofluorescence only in normoglycemic and diabetes groups. Ankle-brachial index inversely associated with skin autofluorescence across all sex, age and glycemic strata. Conclusions Our findings indicate that advanced glycation end-products measured as skin autofluorescence might be involved in vascular stiffening independent of age and other cardiometabolic risk factors not only in individuals with diabetes but also in normoglycemic and prediabetic conditions. Skin autofluorescence might prove as a rapid and non-invasive method for assessment of macrovascular disease progression across all glycemic strata.
KW  - Advanced glycation end-products
KW  - AGE
KW  - Ankle-brachial index
KW  - Augmentation
KW  - index
KW  - Prediabetes
KW  - Glycemia
KW  - Pulse wave velocity
KW  - Skin
KW  - autofluorescence
KW  - Vascular stiffness
Y1  - 2021
U6  - https://doi.org/10.1186/s12933-021-01296-5
SN  - 1475-2840
VL  - 20
IS  - 1
PB  - BioMed Central
CY  - London
ER  - 
TY  - JOUR
A1  - Pedro Ernesto, Pinho Tavares Leal
A1  - da Silva, Alexandre Alves
A1  - Rocha-Gomes, Arthur
A1  - Riul, Tania Regina
A1  - Cunha, Rennan Augusto
A1  - Reichetzeder, Christoph
A1  - Villela, Daniel Campos
T1  - High-salt diet in the pre- and postweaning periods leads to amygdala oxidative stress and changes in locomotion and anxiety-like behaviors of male wistar rats
JF  - Frontiers in behavioral neuroscience
N2  - High-salt (HS) diets have recently been linked to oxidative stress in the brain, a fact that may be a precursor to behavioral changes, such as those involving anxiety-like behavior. However, to the best of our knowledge, no study has evaluated the amygdala redox status after consuming a HS diet in the pre- or postweaning periods. This study aimed to evaluate the amygdala redox status and anxiety-like behaviors in adulthood, after inclusion of HS diet in two periods: preconception, gestation, and lactation (preweaning); and only after weaning (postweaning). Initially, 18 females and 9 male Wistar rats received a standard (n = 9 females and 4 males) or a HS diet (n = 9 females and 5 males) for 120 days. After mating, females continued to receive the aforementioned diets during gestation and lactation. Weaning occurred at 21-day-old Wistar rats and the male offspring were subdivided: control-control (C-C)-offspring of standard diet fed dams who received a standard diet after weaning (n = 9-11), control-HS (C-HS)-offspring of standard diet fed dams who received a HS diet after weaning (n = 9-11), HS-C-offspring of HS diet fed dams who received a standard diet after weaning (n = 9-11), and HS-HS-offspring of HS diet fed dams who received a HS diet after weaning (n = 9-11). At adulthood, the male offspring performed the elevated plus maze and open field tests. At 152-day-old Wistar rats, the offspring were euthanized and the amygdala was removed for redox state analysis. The HS-HS group showed higher locomotion and rearing frequency in the open field test. These results indicate that this group developed hyperactivity. The C-HS group had a higher ratio of entries and time spent in the open arms of the elevated plus maze test in addition to a higher head-dipping frequency. These results suggest less anxiety-like behaviors. In the analysis of the redox state, less activity of antioxidant enzymes and higher levels of the thiobarbituric acid reactive substances (TBARS) in the amygdala were shown in the amygdala of animals that received a high-salt diet regardless of the period (pre- or postweaning). In conclusion, the high-salt diet promoted hyperactivity when administered in the pre- and postweaning periods. In animals that received only in the postweaning period, the addition of salt induced a reduction in anxiety-like behaviors. Also, regardless of the period, salt provided amygdala oxidative stress, which may be linked to the observed behaviors.
KW  - high-sodium
KW  - open-field
KW  - elevated plus-maze
KW  - pre-natal
KW  - post-natal
KW  - redox state
Y1  - 2022
U6  - https://doi.org/10.3389/fnbeh.2021.779080
SN  - 1662-5153
VL  - 15
PB  - Frontiers Media
CY  - Lausanne
ER  - 
TY  - JOUR
A1  - Aga-Barfknecht, Heja
A1  - Soultoukis, George A.
A1  - Stadion, Mandy
A1  - Garcia-Carrizo, Francisco
A1  - Jähnert, Markus
A1  - Gottmann, Pascal
A1  - Vogel, Heike
A1  - Schulz, Tim Julius
A1  - Schürmann, Annette
T1  - Distinct adipogenic and fibrogenic differentiation capacities of mesenchymal stromal cells from pancreas and white adipose tissue
JF  - International journal of molecular sciences
N2  - Pancreatic steatosis associates with beta-cell failure and may participate in the development of type-2-diabetes. Our previous studies have shown that diabetes-susceptible mice accumulate more adipocytes in the pancreas than diabetes-resistant mice. In addition, we have demonstrated that the co-culture of pancreatic islets and adipocytes affect insulin secretion. The aim of this current study was to elucidate if and to what extent pancreas-resident mesenchymal stromal cells (MSCs) with adipogenic progenitor potential differ from the corresponding stromal-type cells of the inguinal white adipose tissue (iWAT). miRNA (miRNome) and mRNA expression (transcriptome) analyses of MSCs isolated by flow cytometry of both tissues revealed 121 differentially expressed miRNAs and 1227 differentially expressed genes (DEGs). Target prediction analysis estimated 510 DEGs to be regulated by 58 differentially expressed miRNAs. Pathway analyses of DEGs and miRNA target genes showed unique transcriptional and miRNA signatures in pancreas (pMSCs) and iWAT MSCs (iwatMSCs), for instance fibrogenic and adipogenic differentiation, respectively. Accordingly, iwatMSCs revealed a higher adipogenic lineage commitment, whereas pMSCs showed an elevated fibrogenesis. As a low degree of adipogenesis was also observed in pMSCs of diabetes-susceptible mice, we conclude that the development of pancreatic steatosis has to be induced by other factors not related to cell-autonomous transcriptomic changes and miRNA-based signals.
KW  - MSCs
KW  - fatty pancreas
KW  - WAT
KW  - lineage commitment
KW  - transcriptomics
KW  - miRNAs
Y1  - 2022
U6  - https://doi.org/10.3390/ijms23042108
SN  - 1422-0067
VL  - 23
IS  - 4
PB  - Molecular Diversity Preservation International
CY  - Basel
ER  - 
TY  - JOUR
A1  - Knoche, Lisa
A1  - Lisec, Jan
A1  - Schwerdtle, Tanja
A1  - Koch, Matthias
T1  - LC-HRMS-Based identification of transformation products of the drug salinomycin generated by electrochemistry and liver microsome
JF  - Antibiotics
N2  - The drug salinomycin (SAL) is a polyether antibiotic and used in veterinary medicine as coccidiostat and growth promoter. Recently, SAL was suggested as a potential anticancer drug. However, transformation products (TPs) resulting from metabolic and environmental degradation of SAL are incompletely known and structural information is missing. In this study, we therefore systematically investigated the formation and identification of SAL derived TPs using electrochemistry (EC) in an electrochemical reactor and rat and human liver microsome incubation (RLM and HLM) as TP generating methods. Liquid chromatography (LC) coupled to high-resolution mass spectrometry (HRMS) was applied to determine accurate masses in a suspected target analysis to identify TPs and to deduce occurring modification reactions of derived TPs. A total of 14 new, structurally different TPs were found (two EC-TPs, five RLM-TPs, and 11 HLM-TPs). The main modification reactions are decarbonylation for EC-TPs and oxidation (hydroxylation) for RLM/HLM-TPs. Of particular interest are potassium-based TPs identified after liver microsome incubation because these might have been overlooked or declared as oxidated sodium adducts in previous, non-HRMS-based studies due to the small mass difference between K and O + Na of 21 mDa. The MS fragmentation pattern of TPs was used to predict the position of identified modifications in the SAL molecule. The obtained knowledge regarding transformation reactions and novel TPs of SAL will contribute to elucidate SAL-metabolites with regards to structural prediction.
KW  - salinomycin
KW  - ionophore antibiotics
KW  - transformation product
KW  - electrochemistry
KW  - rat
KW  - human liver microsomes
KW  - HRMS
Y1  - 2022
U6  - https://doi.org/10.3390/antibiotics11020155
SN  - 2079-6382
VL  - 11
IS  - 2
PB  - MDPI
CY  - Basel
ER  - 
TY  - JOUR
A1  - Schiborn, Catarina
A1  - Schulze, Matthias Bernd
T1  - Precision prognostics for the development of complications in diabetes
JF  - Diabetologia : journal of the European Association for the Study of Diabetes (EASD)
N2  - Individuals with diabetes face higher risks for macro- and microvascular complications than their non-diabetic counterparts. The concept of precision medicine in diabetes aims to optimise treatment decisions for individual patients to reduce the risk of major diabetic complications, including cardiovascular outcomes, retinopathy, nephropathy, neuropathy and overall mortality. In this context, prognostic models can be used to estimate an individual's risk for relevant complications based on individual risk profiles. This review aims to place the concept of prediction modelling into the context of precision prognostics. As opposed to identification of diabetes subsets, the development of prediction models, including the selection of predictors based on their longitudinal association with the outcome of interest and their discriminatory ability, allows estimation of an individual's absolute risk of complications. As a consequence, such models provide information about potential patient subgroups and their treatment needs. This review provides insight into the methodological issues specifically related to the development and validation of prediction models for diabetes complications. We summarise existing prediction models for macro- and microvascular complications, commonly included predictors, and examples of available validation studies. The review also discusses the potential of non-classical risk markers and omics-based predictors. Finally, it gives insight into the requirements and challenges related to the clinical applications and implementation of developed predictions models to optimise medical decision making.
KW  - Cardiovascular diseases
KW  - Complications in diabetes
KW  - Macrovascular
KW  - complications
KW  - Microvascular complications
KW  - Personalised medicine
KW  - Precision medicine
KW  - Precision prognostics
KW  - Review
KW  - Risk prediction
KW  - Risk
KW  - scores
Y1  - 2022
U6  - https://doi.org/10.1007/s00125-022-05731-4
SN  - 0012-186X
SN  - 1432-0428
PB  - Springer
CY  - New York
ER  - 
TY  - JOUR
A1  - Solger, Franziska
A1  - Kunz, Tobias C.
A1  - Fink, Julian
A1  - Paprotka, Kerstin
A1  - Pfister, Pauline
A1  - Hagen, Franziska
A1  - Schumacher, Fabian
A1  - Kleuser, Burkhard
A1  - Seibel, Jürgen
A1  - Rudel, Thomas
T1  - A role of sphingosine in the intracellular survival of Neisseria gonorrhoeae
JF  - Frontiers in Cellular and Infection Microbiology
N2  - Obligate human pathogenic Neisseria gonorrhoeae are the second most frequent bacterial cause of sexually transmitted diseases. These bacteria invade different mucosal tissues and occasionally disseminate into the bloodstream. Invasion into epithelial cells requires the activation of host cell receptors by the formation of ceramide-rich platforms. Here, we investigated the role of sphingosine in the invasion and intracellular survival of gonococci. Sphingosine exhibited an anti-gonococcal activity in vitro. We used specific sphingosine analogs and click chemistry to visualize sphingosine in infected cells. Sphingosine localized to the membrane of intracellular gonococci. Inhibitor studies and the application of a sphingosine derivative indicated that increased sphingosine levels reduced the intracellular survival of gonococci. We demonstrate here, that sphingosine can target intracellular bacteria and may therefore exert a direct bactericidal effect inside cells.
KW  - Neisseria gonorrhoeae
KW  - sphingosine
KW  - sphingolipids
KW  - sphingosine kinases
KW  - invasion
KW  - survival
KW  - click chemistry
Y1  - 2020
U6  - https://doi.org/10.3389/fcimb.2020.00215
SN  - 2235-2988
VL  - 10
PB  - Frontiers Media
CY  - Lausanne
ER  - 
TY  - JOUR
A1  - Fechner, Carolin
A1  - Hackethal, Christin
A1  - Höpfner, Tobias
A1  - Dietrich, Jessica
A1  - Bloch, Dorit
A1  - Lindtner, Oliver
A1  - Sarvan, Irmela
T1  - Results of the BfR MEAL Study
BT  - in Germany, mercury is mostly contained in fish and seafood while cadmium, lead, and nickel are present in a broad spectrum of foods
JF  - Food chemistry: X
N2  - The BfR MEAL Study provides representative levels of substances in foods consumed in Germany. Mercury, cadmium, lead, and nickel are contaminants present in foods introduced by environmental and industrial processes. Levels of these elements were investigated in 356 foods. Foods were purchased representatively, prepared as consumed and pooled with similar foods before analysis. Highest mean levels of mercury were determined in fish and seafood, while high levels of cadmium, lead, and nickel were present in cocoa products and legumes, nuts, oilseeds, and spices. The sampling by region, season, and production type showed minor differences in element levels for specific foods, however no tendency over all foods or for some food groups was apparent. The data on mercury, cadmium, lead, and nickel provide a comprehensive basis for chronic dietary exposure assessment of the population in Germany. All levels found were below regulated maximum levels.
KW  - Total diet study
KW  - BfR MEAL Study
KW  - Metals
KW  - Contaminants
KW  - Unprepared and
KW  - prepared foods
KW  - Regionality
KW  - Seasonality
KW  - Organic and conventional type of production
Y1  - 2022
U6  - https://doi.org/10.1016/j.fochx.2022.100326
SN  - 2590-1575
VL  - 14
PB  - Elsevier
CY  - Amsterdam
ER  - 
TY  - JOUR
A1  - Witt, Barbara
A1  - Stiboller, Michael
A1  - Raschke, Stefanie
A1  - Friese, Sharleen
A1  - Ebert, Franziska
A1  - Schwerdtle, Tanja
T1  - Characterizing effects of excess copper levels in a human astrocytic cell line with focus on oxidative stress markers
JF  - Journal of trace elements in medicine and biology : organ of the Society for Minerals and Trace Elements, GMS
N2  - Background: Being an essential trace element, copper is involved in diverse physiological processes. However, excess levels might lead to adverse effects. Disrupted copper homeostasis, particularly in the brain, has been associated with human diseases including the neurodegenerative disorders Wilson and Alzheimer?s disease. In this context, astrocytes play an important role in the regulation of the copper homeostasis in the brain and likely in the prevention against neuronal toxicity, consequently pointing them out as a potential target for the neurotoxicity of copper. Major toxic mechanisms are discussed to be directed against mitochondria probably via oxidative stress. However, the toxic potential and mode of action of copper in astrocytes is poorly understood, so far. Methods: In this study, excess copper levels affecting human astrocytic cell model and their involvement in the neurotoxic mode of action of copper, as well as, effects on the homeostasis of other trace elements (Mn, Fe, Ca and Mg) were investigated. Results: Copper induced substantial cytotoxic effects in the human astrocytic cell line following 48 h incubation (EC30: 250 ?M) and affected mitochondrial function, as observed via reduction of mitochondrial membrane potential and increased ROS production, likely originating from mitochondria. Moreover, cellular GSH metabolism was altered as well. Interestingly, not only cellular copper levels were affected, but also the homeostasis of other elements (Ca, Fe and Mn) were disrupted. Conclusion: One potential toxic mode of action of copper seems to be effects on the mitochondria along with induction of oxidative stress in the human astrocytic cell model. Moreover, excess copper levels seem to interact with the homeostasis of other essential elements such as Ca, Fe and Mn. Disrupted element homeostasis might also contribute to the induction of oxidative stress, likely involved in the onset and progression of neurodegenerative disorders. These insights in the toxic mechanisms will help to develop ideas and approaches for therapeutic strategies against copper-mediated diseases.
KW  - Copper
KW  - Astrocytes
KW  - Toxicity
KW  - Mitochondria
KW  - ROS
KW  - Trace elements
Y1  - 2021
U6  - https://doi.org/10.1016/j.jtemb.2021.126711
SN  - 1878-3252
VL  - 65
PB  - Elsevier
CY  - München
ER  - 
TY  - JOUR
A1  - Schell, Mareike
A1  - Wardelmann, Kristina
A1  - Kleinridders, Andre
T1  - Untangling the effect of insulin action on brain mitochondria and metabolism
JF  - Journal of neuroendocrinology
N2  - The regulation of energy homeostasis is controlled by the brain and, besides requiring high amounts of energy, it relies on functional insulin/insulin-like growth factor (IGF)-1 signalling in the central nervous system. This energy is mainly provided by mitochondria in form of ATP. Thus, there is an intricate interplay between mitochondrial function and insulin/IGF-1 action to enable functional brain signalling and, accordingly, propagate a healthy metabolism. To adapt to different nutritional conditions, the brain is able to sense the current energy status via mitochondrial and insulin signalling-dependent pathways and exerts an appropriate metabolic response. However, regional, cell type and receptor-specific consequences of this interaction occur and are linked to diverse outcomes such as altered nutrient sensing, body weight regulation or even cognitive function. Impairments of this cross-talk can lead to obesity and glucose intolerance and are linked to neurodegenerative diseases, yet they also induce a self-sustainable, dysfunctional 'metabolic triangle' characterised by insulin resistance, mitochondrial dysfunction and inflammation in the brain. The identification of causal factors deteriorating insulin action, mitochondrial function and concomitantly a signature of metabolic stress in the brain is of utter importance to offer novel mechanistic insights into development of the continuously rising prevalence of non-communicable diseases such as type 2 diabetes and neurodegeneration. This review aims to determine the effect of insulin action on brain mitochondrial function and energy metabolism. It precisely outlines the interaction and differences between insulin action, insulin-like growth factor (IGF)-1 signalling and mitochondrial function; distinguishes between causality and association; and reveals its consequences for metabolism and cognition. We hypothesise that an improvement of at least one signalling pathway can overcome the vicious cycle of a self-perpetuating metabolic dysfunction in the brain present in metabolic and neurodegenerative diseases.
KW  - brain
KW  - energy homeostasis
KW  - inflammation
KW  - insulin signalling
KW  - metabolism
KW  - mitochondrial function
Y1  - 2021
U6  - https://doi.org/10.1111/jne.12932
SN  - 0953-8194
SN  - 1365-2826
VL  - 33
IS  - 4
PB  - Wiley
CY  - Hoboken
ER  - 
TY  - CHAP
A1  - Wandt, Viktoria Klara Veronika
A1  - Winkelbeiner, Nicola
A1  - Loßow, Kristina
A1  - Kopp, Johannes
A1  - Simon, Luise
A1  - Ebert, Franziska
A1  - Kipp, Anna Patricia
A1  - Schwerdtle, Tanja
T1  - Trace elements, ageing, and sex. Impact on genome stability
BT  - Abstracts of the 87th Annual Meeting of the German Society for Experimental and Clinical Pharmacology and Toxicology (DGPT) with contribution of the Arbeitsgemeinschaft für Angewandte Humanpharmakologie e. V. (AGAH)
T2  - Naunyn-Schmiedeberg's archives of pharmacology
Y1  - 2021
U6  - https://doi.org/10.1007/s00210-021-02066-6
SN  - 0028-1298
SN  - 1432-1912
VL  - 394
IS  - Suppl. 1
SP  - S13
EP  - S13
PB  - Springer
CY  - Berlin ; Heidelberg
ER  - 
TY  - THES
A1  - Koelman, Liselot A.
T1  - The role of diet in immune health and ageing
BT  - integrating intervention and observational evidence
Y1  - 2023
ER  - 
TY  - THES
A1  - Haß, Ulrike
T1  - Vergleich anti-inflammatorischer Ernährungsstrategien auf  Inflammation und Muskelfunktion bei älteren Erwachsenen
T1  - Comparison of anti-inflammatory dietary approaches on inflammation and muscle function in old adults
N2  - Mit dem Alter kann eine Zunahme leichtgradiger Entzündungsprozesse beobachtet werden, von denen angenommen wird, dass sie den typischen, altersbedingten Verlust an Muskelmasse, -kraft und -funktion „befeuern“. Diese als Inflammaging bezeichneten Prozesse können auf ein komplexes Zusammenspiel aus einem dysfunktionalen (viszeralen) Fettgewebe, einer Dysbiose und damit einhergehender mikrobiellen Translokation und geringeren Abwehrfähigkeit sowie einer insgesamt zunehmenden Immunseneszenz zurückgeführt werden. In Summa begünstigt ein pro-inflammatorisches Milieu metabolische Störungen und chronische, altersassoziierte Erkrankungen, die das Entzündungsgeschehen aufrechterhalten oder vorantreiben. Neben einem essenziellen Bewegungsmangel trägt auch eine westlich geprägte, industrialisierte Ernährungsweise zum Entzündungsgeschehen und zur Entwicklung chronischer Erkrankungen bei. Daher liegt die Vermutung nahe, dem Entzündungsgeschehen mit ausreichend Bewegung und einer anti-inflammatorischen Ernährung entgegenzuwirken. In dieser Hinsicht werden insbesondere Omega-3-Fettsäuren (Omega-3) mit anti-inflammatorischen Eigenschaften verbunden. Obwohl ein Zusammenhang zwischen dem ernährungsbedingten Inflammationspotenzial bzw. der Zufuhr von Omega-3 und dem Inflammationsprofil bereits untersucht wurde, fehlen bislang Untersuchungen insbesondere bei älteren Erwachsenen, die den Link zwischen dem Inflammationspotenzial der Ernährung und Sarkopenie-relevanten Muskelparametern herstellen. 
Aufgrund des Proteinmehrbedarfs zum Erhalt der funktionellen Muskulatur im Alter wurde bereits eine Vielzahl an Sport- und Ernährungsinterventionen durchgeführt, die eine Verbesserung des Muskelstatus mit Hilfe von strukturiertem Krafttraining und einer proteinreichen Ernährung zeigen. Es gibt zudem Hinweise, dass Omega-3 auch die Proteinsynthese verstärken könnten. Unklar ist jedoch, inwiefern eine anti-inflammatorische Ernährung mit Fokus auf Omega-3 sowohl die Entzündungsprozesse als auch den Muskelproteinmetabolismus und die neuromuskuläre Funktionalität im Alter günstig unterstützen kann. Dies vor allem im Hinblick auf die Muskelleistung, die eng mit der Sturzneigung und der Autonomie im Alltag verknüpft ist, aber in Interventionsstudien mit älteren Erwachsenen bisher wenig Berücksichtigung erhielt. Darüber hinaus werden häufig progressive Trainingselemente genutzt, die nach Studienabschluss oftmals wenig Anschluss im Lebensalltag der Betroffenen finden und somit wenig nachhaltig sind. Ziel dieser Arbeit war demnach die Evaluierung einer proteinreichen und zusätzlich mit Omega-3 supplementierten Ernährung in Kombination mit einem wöchentlichen Vibrationstraining und altersgemäßen Bewegungsprogramm auf Inflammation und neuromuskuläre Funktion bei älteren, selbständig lebenden Erwachsenen.
Hierzu wurden zunächst mögliche Zusammenhänge zwischen dem ernährungsbedingten Inflammationspotenzial, ermittelt anhand des Dietary Inflammatory Index, und dem Muskelstatus sowie dem Inflammationsprofil im Alter eruiert. Dazu dienten die Ausgangswerte von älteren, selbständig lebenden Erwachsenen einer postprandialen Interventionsstudie (POST-Studie), die im Querschnitt analysiert wurden. Die Ergebnisse bestätigten, dass eine pro-inflammatorische Ernährung sich einerseits in einem stärkeren Entzündungsgeschehen widerspiegelt und andererseits mit Sarkopenie-relevanten Parametern, wie einer geringeren Muskelmasse und Gehgeschwindigkeit, ungünstig assoziiert ist. Darüber hinaus zeigten sich diese Zusammenhänge auch in Bezug auf die Handgreifkraft bei den inaktiven, älteren Erwachsenen der Studie.
Anschließend wurde in einer explorativ ausgerichteten Pilot-Interventionsstudie (AIDA-Studie) in einem dreiarmigen Design untersucht, inwieweit sich eine Supplementierung mit Omega-3 unter Voraussetzung einer optimierten Proteinzufuhr und altersgemäßen Sportintervention mit Vibrationstraining auf die neuromuskuläre Funktion und Inflammation bei selbständig lebenden, älteren Erwachsenen auswirkt. Nach acht Wochen Intervention zeigte sich, dass eine mit Omega-3 supplementierte, proteinreiche Ernährung die Muskelleistung insbesondere bei den älteren Männern steigerte. Während sich die Kontrollgruppe nach acht Wochen Sportintervention nicht verbesserte, bestätigte sich zusätzlich eine Verbesserung der Beinkraft und der Testzeit beim Stuhl-Aufsteh-Test der älteren Erwachsenen mit einer proteinreichen Ernährung in Kombination mit der Sportintervention. 
Darüber hinaus wurde deutlich, dass die zusätzliche Omega-3-Supplementierung insbesondere bei den Männern eine Reduktion der pro-inflammatorischen Zytokine im Serum zur Folge hatte. Allerdings spiegelten sich diese Beobachtungen nicht auf Genexpressionsebene in mononukleären Immunzellen oder in der LPS-induzierten Sekretion der Zytokine und Chemokine in Vollblutzellkulturen wider. Dies erfordert weitere Untersuchungen.
N2  - With aging, a persistent low-grade inflammatory process can be observed, which is thought to "fuel" the typical age-related loss of muscle mass, strength and function. These processes, also known as inflammaging, can be attributed to a complex interplay of dysfunctional (visceral) adipose tissue, dysbiosis and associated microbial translocation, with a reduced immune defence and overall increasing immunosenescence. This pro-inflammatory milieu favours metabolic disorders and chronic, age-associated diseases, which in turn maintain or increase the inflammatory process. Additionally, inactivity and a westernized diet contribute to inflammation and the development of chronic diseases. Therefore, it is assumed that regular exercise and an anti-inflammatory diet can counteract inflammaging. In particular, omega-3 fatty acids (omega-3) are known for their anti-inflammatory properties. Although it has been shown that the dietary inflammatory load as well as the intake of omega-3 is associated with inflammation, studies that establish the link between the diet-related inflammatory load and sarcopenia-relevant muscle parameters are still lacking, especially in older adults.
Due to the higher protein requirement to maintain muscle function in higher age, exercise and nutritional interventions have been extensively studied and consistently show improvements in muscle status with resistance exercise and high-protein diets. Experimental investigations indicate that omega-3 may also support protein synthesis. However, it is unclear to what extent an anti-inflammatory diet with focus on omega-3 can support the inflammatory processes as well as muscle protein metabolism and neuromuscular function in higher age. In particular muscle power, which is a key element of functionality and strongly related with fall risk, received little attention in interventional studies with older adults so far. In addition, exercise studies often use elements of progressive resistance training protocols, which, however, are seldom sustained by the participants in everyday life after intervention. Therefore, the aim of this work was to evaluate a high-protein diet supplemented with omega-3 in combination with an age-appropriate, home-based resistance exercise program and weekly vibration training on inflammation and neuromuscular function in community-dwelling older adults.
For this purpose, cross-sectional associations between the diet-related inflammatory load, as determined by the Dietary Inflammatory Index, and muscle status as well as inflammation were investigated by baseline values of community-dwelling older adults, who participated in a postprandial intervention study (POST study). This cross-sectional analysis confirmed that a pro-inflammatory diet was reflected in a higher systemic inflammation and at the same time was associated with unfavourable sarcopenia-relevant parameters such as lower muscle mass and slower gait speed. In addition, a higher dietary inflammatory load and higher inflammation were both found to be associated with lower hand grip strength in inactive, older adults.
Subsequently, the effects of an omega-3 supplemented, high-protein diet in combination with age-appropriate resistance exercises and weekly vibration training on neuromuscular function and inflammation were examined in community-dwelling older adults. For this purpose, an 8-week exploratory pilot trial in a three-arm study design (AIDA study) was carried out. It was shown that a high-protein diet, additionally supplemented with omega-3 increased muscle power particularly in older men. While the control group did not improve after eight weeks of exercise intervention, there was an improvement in leg strength and chair rise time in older adults receiving a high-protein diet combined with the exercise intervention.
Moreover, an additional omega-3 supplementation resulted in a reduction of circulating pro-inflammatory cytokines in particular in older men. However, these observations in serum were not reflected on gene expression levels in mononuclear immune cells or in lipopolysaccharide-induced secretion of the cytokines and chemokines in whole blood cultures and requires further investigation.
KW  - Ernährung
KW  - nutrition
KW  - Gerontologie
KW  - gerontology
KW  - Sport
KW  - exercise
KW  - Muskelschwund
KW  - sarcopenia
KW  - Hoch-Protein Diät
KW  - high protein diet
KW  - Omega-3 Fettsäuren
KW  - omega-3 fatty acid
Y1  - 2023
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-611976
ER  - 
TY  - THES
A1  - Wittek, Laura
T1  - Comparison of metabolic cages - analysis of refinement measures on the welfare and metabolic parameters of laboratory mice
T1  - Der Vergleich von Stoffwechselkäfigen - Analyse von Refinement-Maßnahmen auf das Wohlbefinden und Stoffwechselparameter von Labormäusen
N2  - Housing in metabolic cages can induce a pronounced stress response. Metabolic cage systems imply housing mice on metal wire mesh for the collection of urine and feces in addition to monitoring food and water intake. Moreover, mice are single-housed, and no nesting, bedding, or enrichment material is provided, which is often argued to have a not negligible impact on animal welfare due to cold stress. We therefore attempted to reduce stress during metabolic cage housing for mice by comparing an innovative metabolic cage (IMC) with a commercially available metabolic cage from Tecniplast GmbH (TMC) and a control cage. Substantial refinement measures were incorporated into the IMC cage design. In the frame of a multifactorial approach for severity assessment, parameters such as body weight, body composition, food intake, cage and body surface temperature (thermal imaging), mRNA expression of uncoupling protein 1 (Ucp1) in brown adipose tissue (BAT), fur score, and fecal corticosterone metabolites (CMs) were included. Female and male C57BL/6J mice were single-housed for 24 h in either conventional Macrolon cages (control), IMC, or TMC for two sessions. Body weight decreased less in the IMC (females—1st restraint: 6.94%; 2nd restraint: 6.89%; males—1st restraint: 8.08%; 2nd restraint: 5.82%) compared to the TMC (females—1st restraint: 13.2%; 2nd restraint: 15.0%; males—1st restraint: 13.1%; 2nd restraint: 14.9%) and the IMC possessed a higher cage temperature (females—1st restraint: 23.7°C; 2nd restraint: 23.5 °C; males—1st restraint: 23.3 °C; 2nd restraint: 23.5 °C) compared with the TMC (females—1st restraint: 22.4 °C; 2nd restraint: 22.5 °C; males—1st restraint: 22.6 °C; 2nd restraint: 22.4 °C). The concentration of fecal corticosterone metabolites in the TMC (females—1st restraint: 1376 ng/g dry weight (DW); 2nd restraint: 2098 ng/g DW; males—1st restraint: 1030 ng/g DW; 2nd restraint: 1163 ng/g DW) was higher compared to control cage housing (females—1st restraint:
640 ng/g DW; 2nd restraint: 941 ng/g DW; males—1st restraint: 504 ng/g DW; 2nd restraint: 537 ng/g DW). Our results show the stress potential induced by metabolic cage restraint that is markedly influenced by the lower housing temperature. The IMC represents a first attempt to target cold stress reduction during metabolic cage application thereby producing more animal welfare friendly data.
N2  - Die Unterbringung in Stoffwechselkäfigen kann eine ausgeprägte Stressreaktion hervorrufen. Mäuse werden in Stoffwechselkäfigen auf Metallgittern gehalten, um zusätzlich zur Überwachung der Futter- und Wasseraufnahme Urin und Kot aufzufangen. Darüber hinaus werden die Mäuse einzeln gehalten und es wird kein Nist-, Einstreu- oder Anreicherungs-Material zur Verfügung gestellt, was oft als Ursache für Kältestress angeführt wird, welcher sich auf das Wohlergehen der Tiere auswirkt. Wir haben daher versucht, den Stress bei der Haltung von Mäusen in Stoffwechselkäfigen zu reduzieren, indem wir einen innovativen Stoffwechselkäfig (IMC) mit einem kommerziell erhältlichen Stoffwechselkäfig der Tecniplast GmbH (TMC) und einem Kontrollkäfig verglichen haben. Für das Käfigdesign des IMC wurden wesentliche Refinement-Maßnahmen realisiert. Im Rahmen einer multifaktoriellen Beurteilung des Schweregrades wurden Parameter wie Körpergewicht, Körperzusammensetzung, Nahrungsaufnahme, Käfig- und Körperoberflächentemperatur (Wärmebildaufnahmen), mRNA-Expression von Uncoupling Protein 1 (Ucp1) im braunen Fettgewebe (BAT), Fur Score und fäkale Corticosteron-Metabolite (CMs) einbezogen. Weibliche und männliche C57BL/6J-Mäuse wurden für jeweils 24 Stunden entweder in konventionellen Macrolon-Käfigen (Kontrolle), IMC oder TMC zweimal untergebracht. Das Körpergewicht nahm in dem IMC weniger ab (Weibchen - 1. Haltung: -6,94%; 2. Haltung: -6,89%; Männchen - 1. Haltung: -8,08%; 2. Haltung: -5,82%) als in dem TMC (Weibchen - 1. Haltung: -13,2%; 2. Haltung: -15,0%; Männchen - 1. Haltung: -13,1%; 2. Haltung: -14,9%) und der IMC wies eine höhere Käfigtemperatur (Weibchen - 1. Haltung: 23,7 °C; 2. Haltung 23,5 °C; Männchen - 1. Haltung: 23,3 °C; 2. Haltung: 23,5 °C) im Vergleich zum TMC auf (Weibchen - 1. Haltung: 22,4 °C; 2. Haltung: 22,5 °C; Männchen - 1. Haltung: 22,6 °C; 2. Haltung:  22,4 °C). Die Konzentration der fäkalen Corticosteron-Metabolite im TMC (Weibchen - 1. Haltung: 1376 ng/g Trockengewicht (DW); 2. Haltung: 2098 ng/g DW; Männchen – 1. Haltung: 1030 ng/g DW; 2. Haltung: 1163 ng/g DW) war im Vergleich zur Kontrollkäfighaltung höher (Weibchen - 1. Haltung: 640 ng/g DW; 2. Haltung: 941 ng/g DW; Männchen - 1. Haltung: 504 ng/g DW; 2. Haltung: 537 ng/g DW). Unsere Ergebnisse zeigen das Stresspotenzial, welches durch die Haltung in Stoffwechselkäfigen ausgelöst wird, und dass durch die niedrigere Haltungstemperatur deutlich beeinflusst wird. Der IMC stellt einen ersten Versuch dar, den Kältestress während der Anwendung des Stoffwechselkäfigs zu reduzieren und dadurch tierschutzgerechtere Daten zu produzieren.
KW  - metabolic cage
KW  - laboratory mice
KW  - refinement
KW  - animal welfare
KW  - Tierschutz
KW  - Labormäuse
KW  - Stoffwechselkäfig
KW  - Refinement
Y1  - 2023
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-611208
ER  - 
TY  - JOUR
A1  - Hackethal, Christin
A1  - Kopp, Johannes Florian
A1  - Sarvan, Irmela
A1  - Schwerdtle, Tanja
A1  - Lindtner, Oliver
T1  - Total arsenic and water-soluble arsenic species in foods of the first German total diet study (BfR MEAL Study)
JF  - Food chemistry
N2  - Arsenic can occur in foods as inorganic and organic forms. Inorganic arsenic is more toxic than most watersoluble organic arsenic compounds such as arsenobetaine, which is presumed to be harmless for humans. Within the first German total diet study, total arsenic, inorganic arsenic, arsenobetaine, dimethylarsinic acid and monomethylarsonic acid were analyzed in various foods. Highest levels of total arsenic were found in fish, fish products and seafood (mean: 1.43 mg kg(-1); n = 39; min-max: 0.01-6.15 mg kg(-1)), with arsenobetaine confirmed as the predominant arsenic species (1.233 mg kg 1; n = 39; min-max: 0.01-6.23 mg kg (1)). In contrast, inorganic arsenic was determined as prevalent arsenic species in terrestrial foods (0.02 mg kg (1); n = 38; min-max: 0-0.11 mg kg (1)). However, the toxicity of arsenic species varies and measurements are necessary to gain information about the composition and changes of arsenic species in foods due to household processing of foods.
KW  - Occurrence data
KW  - Food
KW  - Total arsenic
KW  - Arsenic speciation
KW  - Inductively
KW  - coupled plasma mass spectrometry
Y1  - 2021
U6  - https://doi.org/10.1016/j.foodchem.2020.128913
SN  - 0308-8146
SN  - 1873-7072
VL  - 346
PB  - Elsevier
CY  - Amsterdam [u.a.]
ER  - 
TY  - JOUR
A1  - Raupbach, Jana
A1  - Ott, Christiane
A1  - König, Jeannette
A1  - Grune, Tilman
T1  - Proteasomal degradation of glycated proteins depends on substrate unfolding: Preferred degradation of moderately modified myoglobin
JF  - Free radical biology and medicine : the official journal of the Oxygen Society, a constituent member of the International Society for Free Radical Research
N2  - The Maillard reaction generates protein modifications which can accumulate during hyperglycemia or aging and may have inflammatory consequences. The proteasome is one of the major intracellular systems involved in the proteolytic degradation of modified proteins but its role in the degradation of glycated proteins is scarcely studied. In this study, chemical and structural changes of glycated myoglobin were analyzed and its degradation by 20S proteasome was studied. Myoglobin was incubated with physiological (5-10 mM), moderate (50-100 mM) and severe levels (300 mM) of glucose or methylglyoxal (MGO, 50 mM). Glycation increased myoglobin's fluorescence and surface hydrophobicity. Severe glycation generated crosslinked proteins as shown by gel electrophoresis. The concentration of advanced glycation endproducts (AGEs) N-epsilon-carboxymethyl lysine (CML), N-epsilon-carboxyethyl lysine (CEL), methylglyoxal-derived hydroimidazolone-1 (MG-H1), pentosidine and pyrraline was analyzed after enzymatic hydrolysis followed by UPLC-MS/MS. Higher concentrations of glucose increased all analyzed AGEs and incubation with MGO led to a pronounced increase of CEL and MG-H1. The binding of the heme group to apo-myoglobin was decreased with increasing glycation indicating the loss of tertiary protein structure. Proteasomal degradation of modified myoglobin compared to native myoglobin depends on the degree of glycation: physiological conditions decreased proteasomal degradation whereas moderate glycation increased degradation. Severe glycation again decreased proteolytic cleavage which might be due to crosslinking of protein monomers. The activity of the proteasomal subunit beta 5 is influenced by the presence of glycated myoglobin. In conclusion, the role of the proteasome in the degradation of glycated proteins is highly dependent on the level of glycation and consequent protein unfolding.
KW  - Glycation
KW  - Myoglobin
KW  - Heme
KW  - Advanced glycation endproducts
KW  - 20S
KW  - proteasome
Y1  - 2020
U6  - https://doi.org/10.1016/j.freeradbiomed.2019.11.024
SN  - 0891-5849
SN  - 1873-4596
VL  - 152
SP  - 516
EP  - 524
PB  - Elsevier
CY  - New York
ER  - 
TY  - JOUR
A1  - Gohlke, Sabrina
A1  - Mancini, Carola
A1  - Garcia-Carrizo, Francisco
A1  - Schulz, Tim J.
T1  - Loss of the ciliary gene Bbs4 results in defective thermogenesis due to metabolic inefficiency and impaired lipid metabolism
JF  - The FASEB journal : the official journal of the Federation of American Societies for Experimental Biology
N2  - Adipose tissue is central to the regulation of energy balance. While white adipose tissue (WAT) is responsible for triglyceride storage, brown adipose tissue specializes in energy expenditure. Deterioration of brown adipocyte function contributes to the development of metabolic complications like obesity and diabetes. These disorders are also leading symptoms of the Bardet-Biedl syndrome (BBS), a hereditary disorder in humans which is caused by dysfunctions of the primary cilium and which therefore belongs to the group of ciliopathies. The cilium is a hair-like organelle involved in cellular signal transduction. The BBSome, a supercomplex of several Bbs gene products, localizes to the basal body of cilia and is thought to be involved in protein sorting to and from the ciliary membrane. The effects of a functional BBSome on energy metabolism and lipid mobilization in brown and white adipocytes were tested in whole-body Bbs4 knockout mice that were subjected to metabolic challenges. Chronic cold exposure reveals cold-intolerance of knockout mice but also ameliorates the markers of metabolic pathology detected in knockouts prior to cold. Hepatic triglyceride content is markedly reduced in knockout mice while circulating lipids are elevated, altogether suggesting that defective lipid metabolism in adipose tissue creates increased demand for systemic lipid mobilization to meet energetic demands of reduced body temperatures. These findings taken together suggest that Bbs4 is essential for the regulation of adipose tissue lipid metabolism, representing a potential target to treat metabolic disorders.
KW  - adipose tissue
KW  - Bbs4
KW  - BBsome
KW  - browning
KW  - cilium
KW  - lipid metabolism
Y1  - 2021
U6  - https://doi.org/10.1096/fj.202100772RR
SN  - 1530-6860
VL  - 35
IS  - 11
PB  - Wiley
CY  - Hoboken
ER  - 
TY  - JOUR
A1  - Häseli, Steffen
A1  - Deubel, Stefanie
A1  - Jung, Tobias
A1  - Grune, Tilman
A1  - Ott, Christiane
T1  - Cardiomyocyte contractility and autophagy in a premature senescence model of cardiac aging
JF  - Oxidative medicine and cellular longevity
N2  - Globally, cardiovascular diseases are the leading cause of death in the aging population. While the clinical pathology of the aging heart is thoroughly characterized, underlying molecular mechanisms are still insufficiently clarified. The aim of the present study was to establish an in vitro model system of cardiomyocyte premature senescence, culturing heart muscle cells derived from neonatal C57Bl/6J mice for 21 days. Premature senescence of neonatal cardiac myocytes was induced by prolonged culture time in an oxygen-rich postnatal environment. Age-related changes in cellular function were determined by senescence-associated beta-galactosidase activity, increasing presence of cell cycle regulators, such as p16, p53, and p21, accumulation of protein aggregates, and restricted proteolysis in terms of decreasing (macro-)autophagy. Furthermore, the culture system was functionally characterized for alterations in cell morphology and contractility. An increase in cellular size associated with induced expression of atrial natriuretic peptides demonstrated a stress-induced hypertrophic phenotype in neonatal cardiomyocytes. Using the recently developed analytical software tool Myocyter, we were able to show a spatiotemporal constraint in spontaneous contraction behavior during cultivation. Within the present study, the 21-day culture of neonatal cardiomyocytes was defined as a functional model system of premature cardiac senescence to study age-related changes in cardiomyocyte contractility and autophagy.
Y1  - 2020
U6  - https://doi.org/10.1155/2020/8141307
SN  - 1942-0994
VL  - 2020
IS  - Special Issue
PB  - Landes Bioscience
CY  - Austin, Tex.
ER  - 
TY  - JOUR
A1  - Ost, Mario
A1  - Igual Gil, Carla
A1  - Coleman, Verena
A1  - Keipert, Susanne
A1  - Efstathiou, Sotirios
A1  - Vidic, Veronika
A1  - Weyers, Miriam
A1  - Klaus, Susanne
T1  - Muscle-derived GDF15 drives diurnal anorexia and systemic metabolic remodeling during mitochondrial stress
JF  - EMBO reports
N2  - Mitochondrial dysfunction promotes metabolic stress responses in a cell-autonomous as well as organismal manner. The wasting hormone growth differentiation factor 15 (GDF15) is recognized as a biomarker of mitochondrial disorders, but its pathophysiological function remains elusive. To test the hypothesis that GDF15 is fundamental to the metabolic stress response during mitochondrial dysfunction, we investigated transgenic mice (Ucp1-TG) with compromised muscle-specific mitochondrial OXPHOS capacity via respiratory uncoupling. Ucp1-TG mice show a skeletal muscle-specific induction and diurnal variation of GDF15 as a myokine. Remarkably, genetic loss of GDF15 in Ucp1-TG mice does not affect muscle wasting or transcriptional cell-autonomous stress response but promotes a progressive increase in body fat mass. Furthermore, muscle mitochondrial stress-induced systemic metabolic flexibility, insulin sensitivity, and white adipose tissue browning are fully abolished in the absence of GDF15. Mechanistically, we uncovered a GDF15-dependent daytime-restricted anorexia, whereas GDF15 is unable to suppress food intake at night. Altogether, our evidence suggests a novel diurnal action and key pathophysiological role of mitochondrial stress-induced GDF15 in the regulation of systemic energy metabolism.
KW  - anorexia
KW  - GDF15
KW  - integrated stress response
KW  - mitochondrial dysfunction
KW  - muscle wasting
Y1  - 2020
U6  - https://doi.org/10.15252/embr.201948804
SN  - 1469-221X
SN  - 1469-3178
VL  - 21
IS  - 3
PB  - Wiley
CY  - Hoboken
ER  - 
TY  - JOUR
A1  - Kehm, Richard
A1  - Jähnert, Markus
A1  - Deubel, Stefanie
A1  - Flore, Tanina
A1  - König, Jeannette
A1  - Jung, Tobias
A1  - Stadion, Mandy
A1  - Jonas, Wenke
A1  - Schürmann, Annette
A1  - Grune, Tilman
A1  - Höhn, Annika
T1  - Redox homeostasis and cell cycle activation mediate beta-cell mass expansion in aged, diabetes-prone mice under metabolic stress conditions: role of thioredoxin-interacting protein (TXNIP)
JF  - Redox Biology
N2  - Overnutrition contributes to insulin resistance, obesity and metabolic stress, initiating a loss of functional beta-cells and diabetes development. Whether these damaging effects are amplified in advanced age is barely investigated. Therefore, New Zealand Obese (NZO) mice, a well-established model for the investigation of human obesity-associated type 2 diabetes, were fed a metabolically challenging diet with a high-fat, carbohydrate restricted period followed by a carbohydrate intervention in young as well as advanced age. Interestingly, while young NZO mice developed massive hyperglycemia in response to carbohydrate feeding, leading to beta-cell dysfunction and cell death, aged counterparts compensated the increased insulin demand by persistent beta-cell function and beta-cell mass expansion. Beta-cell loss in young NZO islets was linked to increased expression of thioredoxin-interacting protein (TXNIP), presumably initiating an apoptosis-signaling cascade via caspase-3 activation. In contrast, islets of aged NZOs exhibited a sustained redox balance without changes in TXNIP expression, associated with higher proliferative potential by cell cycle activation. These findings support the relevance of a maintained proliferative potential and redox homeostasis for preserving islet functionality under metabolic stress, with the peculiarity that this adaptive response emerged with advanced age in diabetesprone NZO mice.
KW  - aging
KW  - redox homeostasis
KW  - metabolic stress
KW  - beta-cells
KW  - cell cycle
KW  - thioredoxin-interacting protein
Y1  - 2020
U6  - https://doi.org/10.1016/j.redox.2020.101748
SN  - 2213-2317
VL  - 37
PB  - Elsevier
CY  - Amsterdam
ER  - 
TY  - JOUR
A1  - Nicolai, Merle Marie
A1  - Baesler, Jessica
A1  - Aschner, Michael
A1  - Schwerdtle, Tanja
A1  - Bornhorst, Julia
T1  - Consequences of manganese overload in C. elegans
BT  - oxidative stress and DNA damage
JF  - Naunyn-Schmiedeberg's archives of pharmacology / ed. for the Deutsche Gesellschaft für Experimentelle und Klinische Pharmakologie und Toxikologie
Y1  - 2020
U6  - https://doi.org/10.1007/s00210-020-01828-y
SN  - 0028-1298
SN  - 1432-1912
VL  - 393
IS  - SUPPL 1
SP  - 9
EP  - 9
PB  - Springer
CY  - New York
ER  - 
TY  - JOUR
A1  - Borremans, An
A1  - Bußler, Sara
A1  - Sagu Tchewonpi, Sorel
A1  - Rawel, Harshadrai Manilal
A1  - Schlüter, Oliver K.
A1  - Leen, Van Campenhout
T1  - Effect of blanching plus fermentation on selected functional properties of mealworm (Tenebrio molitor) powders
JF  - Foods : open access journal
N2  - The aim of this study was to determine the effect of blanching followed by fermentation of mealworms (Tenebrio molitor) with commercial meat starter cultures on the functional properties of powders produced from the larvae. Full fat and defatted powder samples were prepared from non-fermented and fermented mealworm pastes. Then the crude protein, crude fat, and dry matter contents, pH, bulk density, colour, water and oil binding capacity, foaming capacity and stability, emulsion capacity and stability, protein solubility, quantity of free amino groups, and protein composition of the powders were evaluated. Regardless of the starter culture used, the blanching plus fermentation process reduced the crude and soluble protein contents of the full fat powders and in general impaired their water and oil binding, foaming, and emulsifying properties. Defatting of the powders improved most functional properties studied. The o-phthaldialdehyde assay revealed that the amount of free amino groups was higher in the fermented powders while sodium dodecyl sulfate polyacrylamide gel electrophoresis demonstrated that the soluble proteins of the fermented powders were composed of molecules of lower molecular mass compared to non-fermented powders. As molecular sizes of the soluble proteins decreased, it was clear that the protein structure was also modified by the fermentation process, which in turn led to changes in functional properties. In general, it was concluded that fermentation of mealworms with blanching as a pre-treatment does not contribute to the functional properties studied in this work. Nevertheless, the results confirmed that the properties of non-fermented powders are comparable to other food protein sources.
KW  - mealworm
KW  - fermentation
KW  - functional properties
KW  - insect proteins
KW  - SDS-PAGE
Y1  - 2020
U6  - https://doi.org/10.3390/foods9070917
SN  - 2304-8158
VL  - 9
IS  - 7
PB  - MDPI
CY  - Basel
ER  - 
TY  - JOUR
A1  - Stadion, Mandy
A1  - Schürmann, Annette
T1  - Intermittierendes Fasten
BT  - was gibt es Neues aus der Wissenschaft?
BT  - what’s new from science?
JF  - Der Diabetologe
N2  - Obesity increases the risk of metabolic disorders and can lead to type 2 diabetes. Therefore, the treatment and prevention of obesity represent important medical challenges. Increased physical activity and a reduction in daily caloric intake of 25-30% are often recommended. Another possibility is intermittent fasting, by limiting dietary caloric content over certain times, i.e. one or more days a week or for more than 14 h a day. Animal and human studies provide evidence that intermittent fasting in obesity leads to a reduction in body fat mass as well as to improvements of metabolic parameters and insulin sensitivity. These positive effects are mediated not only by the decrease in body mass, but also by the activation of metabolic pathways and cellular processes that are specific for fasting conditions. In this article, we describe the current knowledge about the mechanisms induced by intermittent fasting and present results from randomized controlled human trials.
N2  - Übergewicht und Adipositas erhöhen die Risiken für Stoffwechselstörungen und können zu einem Typ-2-Diabetes führen. Deshalb stellen die Behandlung und Prävention von Fettleibigkeit eine große medizinische Herausforderung dar. Häufig werden eine erhöhte körperliche Aktivität und die Reduktion der täglichen Kalorienaufnahme um 25–30 % angeraten. Eine andere Möglichkeit bietet intermittierendes Fasten, also eine Kalorieneinschränkung über bestimmte Zeiten, d. h. an einem oder mehreren Tagen pro Woche oder über mehr als 14 h pro Tag. Tier- und Humanstudien lieferten Hinweise darauf, dass intermittierendes Fasten bei Adipositas zu einer Verringerung der Körperfettmasse sowie zu Verbesserungen der Stoffwechselparameter und der Insulinsensitivität führt. Diese positiven Effekte werden nicht nur allein durch die Abnahme der Körpermasse, sondern auch durch die Aktivierung von Stoffwechselwegen und zellulären Prozessen ausgelöst, die für Fastenbedingungen spezifisch sind. In diesem Artikel beschreiben wir die derzeit bekannten Mechanismen, die durch intermittierendes Fasten induziert werden, und stellen Ergebnisse aus randomisierten kontrollierten Studien am Menschen vor.
T2  - Intermittent fasting
KW  - Glucose metabolism disorders
KW  - Lipid metabolism
KW  - Insulin sensitivity
KW  - Energy metabolism
KW  - Circadian rhythm
KW  - Glukosestoffwechselstörungen
KW  - Fettstoffwechsel
KW  - Insulinsensitivität
KW  - Energiestoffwechsel
KW  - Zirkadianer Rhythmus
Y1  - 2020
U6  - https://doi.org/10.1007/s11428-020-00666-z
SN  - 1860-9716
SN  - 1860-9724
VL  - 16
IS  - 7
SP  - 641
EP  - 646
PB  - Springer Medizin
CY  - Berlin
ER  - 
TY  - JOUR
A1  - Grune, Tilman
T1  - Oxidized protein aggregates
BT  - formation and biological effects
JF  - Free radical biology and medicine : the official journal of the Oxygen Society, a constituent member of the International Society for Free Radical Research
N2  - The study of protein aggregates has a long history. While in the first decades until the 80ies of the 20th century only the observation of the presence of such aggregates was reported, later the biochemistry of the formation and the biological effects of theses aggregates were described. 
This review focusses on the complexity of the biological effects of protein aggregates and its potential role in the aging process.
Y1  - 2020
U6  - https://doi.org/10.1016/j.freeradbiomed.2020.02.014
SN  - 0891-5849
SN  - 1873-4596
VL  - 150
SP  - 120
EP  - 124
PB  - Elsevier
CY  - New York
ER  - 
TY  - JOUR
A1  - Wright, Stephanie L.
A1  - Ulke, Jannis
A1  - Font, Anna
A1  - Chan, Ka Lung Andrew
A1  - Kelly, Frank J.
T1  - Atmospheric microplastic deposition in an urban environment and an evaluation of transport
JF  - Environment international
N2  - Microplastics are a global environmental issue contaminating aquatic and terrestrial environments. They have been reported in atmospheric deposition, and indoor and outdoor air, raising concern for public health due to the potential for exposure. Moreover, the atmosphere presents a new vehicle for microplastics to enter the wider environment, yet our knowledge of the quantities, characteristics and pathways of airborne microplastics is sparse. Here we show microplastics in atmospheric deposition in a major population centre, central London. Microplastics were found in all samples, with deposition rates ranging from 575 to 1008 microplastics/m(2)/d. They were found in various shapes, of which fibrous microplastics accounted for the great majority (92%). Across all samples, 15 different petrochemical-based polymers were identified. Bivariate polar plots indicated dependency on wind, with different source areas for fibrous and non-fibrous airborne microplastics. This is the first evidence of airborne microplastics in London and confirms the need to include airborne pathways when consolidating microplastic impacts on the wider environment and human health.
KW  - microplastics
KW  - atmospheric deposition
KW  - air pollution
KW  - urban
Y1  - 2020
U6  - https://doi.org/10.1016/j.envint.2019.105411
SN  - 0160-4120
SN  - 1873-6750
VL  - 136
PB  - Elsevier, Pergamon Press
CY  - New York, NY [u.a.]
ER  - 
TY  - THES
A1  - Lopes Fernando, Raquel Sofia
T1  - The impact of aging on proteolytic systems, transcriptome and metabolome of slow and fast muscle fiber types
N2  - Aging is a complex process characterized by several factors, including loss of genetic and epigenetic information, accumulation of chronic oxidative stress, protein damage and aggregates and it is becoming an emergent drug target. Therefore, it is the utmost importance to study aging and agerelated diseases, to provide treatments to develop a healthy aging process. Skeletal muscle is one of the earliest tissues affected by age-related changes with progressive loss of muscle mass and function from 30 years old, effect known as sarcopenia. Several studies have shown the accumulation of protein aggregates in different animal models, as well as in humans, suggesting impaired proteostasis, a hallmark of aging, especially regarding degradation systems. Thus, different publications have explored the role of the main proteolytic systems in skeletal muscle from rodents and humans, like ubiquitin proteasomal system (UPS) and autophagy lysosomal system (ALS), however with contradictory results. Yet, most of the published studies are performed in muscles that comprise more than one fiber type, that means, muscles composed by slow and fast fibers. These fiber types, exhibit different metabolism and contraction speed; the slow fibers or type I display an oxidative metabolism, while fast fibers function towards a glycolytic metabolism ranging from fast oxidative to fast glycolytic fibers. To this extent, the aim of this thesis sought to understand on how aging impacts both fiber types not only regarding proteostasis but also at a metabolome and transcriptome network levels. Therefore, the first part of this thesis, presents the differences between slow oxidative (from Soleus muscle) and fast glycolytic fibers (Extensor digitorum longus, EDL) in terms of degradation systems and how they cope with oxidative stress during aging, while the second part explores the differences between young and old EDL muscle transcriptome and metabolome, unraveling molecular features. More specifically, the results from the present work show that slow oxidative muscle performs better at maintaining the function of UPS and ALS during aging than EDL muscle, which is clearly affected, accounting for the decline in the catalytic activity rates and accumulation of autophagy-related proteins. Strinkingly, transcriptome and metabolome analyses reveal that fast glycolytic muscle evidences significant downregulation of mitochondrial related processes and damaged mitochondria morphology during aging, despite of having a lower oxidative metabolism compared to oxidative fibers. Moreover, predictive analyses reveal a negative association between aged EDL gene signature and lifespan extending interventions such as caloric restriction (CR). Although, CR intervention does not alter the levels of mitochondrial markers in aged EDL muscle, it can reverse the higher mRNA levels of muscle damage markers. Together, the results from this thesis give new insights about how different metabolic muscle fibers cope with age-related changes and why fast glycolytic fibers are more susceptible to aging than slow oxidative fibers.
N2  - Altern ist ein komplexer Prozess, der durch mehrere Faktoren gekennzeichnet ist, darunter der Verlust genetischer und epigenetischer Informationen, oxidativer Stress, sowie die Anhäufung von Proteinschäden und Aggregaten. Daher ist es von größter Bedeutung, das Altern und altersbedingte Krankheiten zu erforschen, um Arzneimittel und andere Behandlungen für einen gesunden Alterungsprozess zu entwickeln. Die Skelettmuskulatur ist eines der ersten Gewebe, das von altersbedingten Veränderungen betroffen ist. Ab einem Alter von 30 Jahren kommt es zu einem fortschreitenden Verlust der Muskelmasse und -funktion, der auch als Sarkopenie bezeichnet wird. Mehrere Studien haben die Anhäufung von Proteinaggregaten beim Altern in verschiedenen Tiermodellen und auch beim Menschen gezeigt, was auf eine gestörte Proteostase, insbesondere hinsichtlich der Abbauprozesse schließen lässt. Demnach wurde weiterführend die Rolle der wichtigsten proteolytischen Systeme, das Ubiquitin Proteasom System (UPS) und AutophagieLysosomale System (ALS), im alternden Skelettmuskel von Nagetieren und Menschen untersucht. Die Ergebnisse waren widersprüchlich, jedoch wurden die meisten der veröffentlichten Studien an Muskeln durchgeführt, die aus mehr als einem Muskelfasertyp bestehen, d.h. Muskeln, die aus langsamen und schnellen Muskelfasern zusammengesetzt sind. Diese Muskelfasertypen unterscheiden sich hinsichtlich des Stoffwechsels und der Kontraktionsgeschwindigkeit. Die langsamen Fasern oder der Typ I haben einen oxidativen Stoffwechsel, während die schnellen Fasern einen glykolytischen Stoffwechsel aufweisen und aus schnellen oxidativen bis zu schnellen glykolytischen Fasern bestehen können. Insofern war es das Ziel dieser Arbeit zu verstehen, wie sich das Altern auf beide Fasertypen auswirkt, und zwar nicht nur im Hinblick auf die Proteostase, sondern auch auf das Metabolom und Transkriptom. Im ersten Teil dieser Arbeit werden die Unterschiede zwischen langsamen oxidativen (Soleus-Muskel) und schnellen glykolytischen Fasern (Extensor digitorum longus-Muskel; EDL) in Bezug auf die Proteinabbausysteme und die Art und Weise, wie sie mit oxidativem Stress während des Alterns umgehen, dargestellt. Im zweiten Teil werden die Unterschiede zwischen dem Transkriptom und dem Metabolom des jungen und alten EDL-Muskels untersucht, um die molekularen Merkmale zu entschlüsseln. Im Einzelnen zeigen die Ergebnisse der vorliegenden Arbeit, dass der langsam oxidierende Muskel im Vergleich zum EDL-Muskel besser in der Lage ist, die Funktion von UPS und ALS während des Alterns aufrechtzuerhalten. Die Funktionalität des UPS und ALS ist im alternden EDL-Muskels vermindert, was durch den Rückgang der katalytischen Aktivitätsraten und die Anhäufung von mit Autophagie-assoziierten Proteinen gezeigt wurde. Transkriptom- und Metabolomanalysen zeigen, dass schnelle glykolytische Muskeln eine signifikante Herabregulierung mitochondrialer Prozesse und eine geschädigte Mitochondrienmorphologie während des Alterns aufweisen, obwohl sie im Vergleich zu oxidativen Fasern durch einen geringeren oxidativen Stoffwechsel charakterisiert sind. Darüber hinaus ergeben prädiktive Analysen einen negativen Zusammenhang zwischen der Gensignatur des gealterten EDL-Muskels und lebensverlängernden Maßnahmen wie der kalorischenRestriktion. Obwohl die kalorischen Restriktion Intervention die Werte der mitochondrialen Marker im gealterten EDL-Muskel nicht verändert, kann sie die höheren mRNA-Werte der Muskelschädigungsmarker umkehren. Zusammenfassend liefern die Ergebnisse dieser Arbeit neue Erkenntnisse darüber, wie verschiedene metabolische Muskelfasern mit altersbedingten. Veränderungen umgehen und warum schnelle glykolytische Fasern anfälliger für die Alterung als langsame oxidative Fasern sind.
KW  - skeletal muscle aging
KW  - proteostasis
KW  - slow and fast fiber types
KW  - transcriptomics
KW  - metabolomics
KW  - sarcopenia
KW  - Skelettmuskelalterung
KW  - Proteostase
KW  - langsame und schnelle Fasertypen
KW  - Transkriptom
KW  - Metabolom
KW  - ubiquitin proteasomal system
KW  - autophagy lysosomal system
KW  - Ubiquitin Proteasom System
KW  - Autophagie Lysosomale System
Y1  - 2023
U6  - https://doi.org/10.25932/publishup-60579
ER  - 
TY  - JOUR
A1  - Weitkunat, Karolin
A1  - Bishop, Christopher Allen
A1  - Wittmüss, Maria
A1  - Machate, Tina
A1  - Schifelbein, Tina
A1  - Schulze, Matthias Bernd
A1  - Klaus, Susanne
T1  - Effect of microbial status on hepatic odd-chain fatty acids is diet-dependent
JF  - Nutrients / Molecular Diversity Preservation International (MDPI)
N2  - Odd-chain fatty acids (OCFA) are inversely associated with type-2-diabetes in epidemiological studies. They are considered as a biomarker for dairy intake because fermentation in ruminants yields high amounts of propionate, which is used as the primer for lipogenesis. Recently, we demonstrated endogenous OCFA synthesis from propionate in humans and mice, but how this is affected by microbial colonization is still unexplored. Here, we investigated the effect of increasing microbiota complexity on hepatic lipid metabolism and OCFA levels in different dietary settings. Germ-free (GF), gnotobiotic (SIH, simplified human microbiota) or conventional (CONV) C3H/HeOuJ-mice were fed a CHOW or high-fat diet with inulin (HFI) to induce microbial fermentation. We found that hepatic lipogenesis was increased with increasing microbiota complexity, independently of diet. In contrast, OCFA formation was affected by diet as well as microbiota. On CHOW, hepatic OCFA and intestinal gluconeogenesis decreased with increasing microbiota complexity (GF > SIH > CONV), while cecal propionate showed a negative correlation with hepatic OCFA. On HFI, OCFA levels were highest in SIH and positively correlated with cecal propionate. The propionate content in the CHOW diet was 10 times higher than that of HFI. We conclude that bacterial propionate production affects hepatic OCFA formation, unless this effect is masked by dietary propionate intake.
KW  - pentadecanoic acid (C15:0)
KW  - heptadecanoic acid (C17:0)
KW  - type-2-diabetes
KW  - fatty acid synthesis
KW  - acetate
KW  - propionate
KW  - probiotics
KW  - gut microbiota
KW  - prebiotics
KW  - inulin
Y1  - 2021
U6  - https://doi.org/10.3390/nu13051546
SN  - 2072-6643
VL  - 13
IS  - 5
PB  - MDPI
CY  - Basel
ER  - 
TY  - THES
A1  - Raschke, Stefanie
T1  - Characterization of selenium and copper in cell systems of the neurovascular unit
T1  - Charakterisierung von Selen und Kupfer in Zellsystemen der neurovaskulären Einheit
N2  - The trace elements, selenium (Se) and copper (Cu) play an important role in maintaining normal brain function. Since they have essential functions as cofactors of enzymes or structural components of proteins, an optimal supply as well as a well-defined homeostatic regulation are crucial. Disturbances in trace element homeostasis affect the health status and contribute to the incidence and severity of various diseases. The brain in particular is vulnerable to oxidative stress due to its extensive oxygen consumption and high energy turnover, among other factors. As components of a number of antioxidant enzymes, both elements are involved in redox homeostasis. However, high concentrations are also associated with the occurrence of oxidative stress, which can induce cellular damage. Especially high Cu concentrations in some brain areas are associated with the development and progression of neurodegenerative diseases such as Alzheimer's disease (AD). In contrast, reduced Se levels were measured in brains of AD patients. The opposing behavior of Cu and Se renders the study of these two trace elements as well as the interactions between them being particularly relevant and addressed in this work.
N2  - Die Spurenelemente Selen (Se) und Kupfer (Cu) spielen eine wichtige Rolle bei der Aufrechterhaltung einer normalen Ge¬hirnfunktion. Da sie wesentliche Funktionen als Cofaktoren von Enzymen oder Strukturbestandteile von Proteinen haben, sind eine optimale Versorgung sowie eine genau definierte homöostatische Regulierung von entscheidender Bedeutung. Störungen der Spurenelement-homöostase beeinträchtigen den Gesund¬heitszustand und tragen zum Auftreten und zur Schwere verschiedener Krankheiten bei. Insbesondere das Gehirn ist aufgrund seines hohen Sauerstoffverbrauchs und seines hohen Energieumsatzes anfällig für oxi¬dativen Stress. Als Bestandteile einer Reihe von antioxidativen Enzymen sind beide Elemente an der Redox-Homöostase beteiligt. Hohe Konzentrationen werden jedoch auch mit dem Auftreten von oxidati¬vem Stress in Verbindung gebracht, der zu Zellschäden führen kann. Besonders hohe Cu-Konzentrationen in einigen Hirnregionen werden mit der Entwicklung und der Progression neurodegenerativer Erkran¬kungen wie Alzheimer in Verbindung gebracht. Im Gegensatz dazu wurden in den Gehirnen von Alzheimer-Patienten geringere Se-Konzentrationen gemessen. Das gegensätzliche Verhalten von Cu und Se verdeutlicht die Relevanz der Untersuchung dieser beiden Spurenelemente sowie deren Wechselwirkungen und wird in dieser Arbeit thematisiert.
KW  - selenium
KW  - copper
KW  - Selen
KW  - Kupfer
KW  - Blut-Hirn-Schranke
KW  - Neuronen
KW  - Astrozyten
KW  - blood-brain barrier
KW  - neurons
KW  - astrocytes
Y1  - 2023
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-603666
ER  - 
TY  - GEN
A1  - Kotthoff, Lisa
A1  - Lisec, Jan
A1  - Schwerdtle, Tanja
A1  - Koch, Matthias
T1  - Prediction of transformation products of monensin by electrochemistry compared to microsomal assay and hydrolysis
T2  - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe
N2  - The knowledge of transformation pathways and identification of transformation products (TPs) of veterinary drugs is important for animal health, food, and environmental matters. The active agent Monensin (MON) belongs to the ionophore antibiotics and is widely used as a veterinary drug against coccidiosis in broiler farming. However, no electrochemically (EC) generated TPs of MON have been described so far. In this study, the online coupling of EC and mass spectrometry (MS) was used for the generation of oxidative TPs. EC-conditions were optimized with respect to working electrode material, solvent, modifier, and potential polarity. Subsequent LC/HRMS (liquid+ chromatography/high resolution mass spectrometry) and MS/MS experiments were performed to identify the structures of derived TPs by a suspected target analysis. The obtained EC-results were compared to TPs observed in metabolism tests with microsomes and hydrolysis experiments of MON. Five previously undescribed TPs of MON were identified in our EC/MS based study and one TP, which was already known from literature and found by a microsomal assay, could be confirmed. Two and three further TPs were found as products in microsomal tests and following hydrolysis, respectively. We found decarboxylation, O-demethylation and acid-catalyzed ring-opening reactions to be the major mechanisms of MON transformation
T3  - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 1340 
KW  - transformation products
KW  - monensin
KW  - veterinary drugs
KW  - electrochemistry
KW  - hydrolysis
KW  - LC/HRMS
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-473262
SN  - 1866-8372
IS  - 1340
ER  - 
TY  - GEN
A1  - Rancan, Fiorenza
A1  - Volkmann, Hildburg
A1  - Giulbudagian, Michael
A1  - Schumacher, Fabian
A1  - Stanko, Jessica Isolde
A1  - Kleuser, Burkhard
A1  - Blume-Peytavi, Ulrike
A1  - Calderón, Marcelo
A1  - Vogt, Annika
T1  - Dermal Delivery of the High-Molecular-Weight Drug Tacrolimus by Means of Polyglycerol-Based Nanogels
T2  - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe
N2  - Polyglycerol-based thermoresponsive nanogels (tNGs) have been shown to have excellent skin hydration properties and to be valuable delivery systems for sustained release of drugs into skin. In this study, we compared the skin penetration of tacrolimus formulated in tNGs with a commercial 0.1% tacrolimus ointment. The penetration of the drug was investigated in ex vivo abdominal and breast skin, while different methods for skin barrier disruption were investigated to improve skin permeability or simulate inflammatory conditions with compromised skin barrier. The amount of penetrated tacrolimus was measured in skin extracts by liquid chromatography tandem-mass spectrometry (LC-MS/MS), whereas the inflammatory markers IL-6 and IL-8 were detected by enzyme-linked immunosorbent assay (ELISA). Higher amounts of tacrolimus penetrated in breast as compared to abdominal skin or in barrier-disrupted as compared to intact skin, confirming that the stratum corneum is the main barrier for tacrolimus skin penetration. The anti-proliferative effect of the penetrated drug was measured in skin tissue/Jurkat cells co-cultures. Interestingly, tNGs exhibited similar anti-proliferative effects as the 0.1% tacrolimus ointment. We conclude that polyglycerol-based nanogels represent an interesting alternative to paraffin-based formulations for the treatment of inflammatory skin conditions.
T3  - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 1339 
KW  - tacrolimus formulation
KW  - nanogels
KW  - skin penetration
KW  - drug delivery
KW  - human excised skin
KW  - Jurkat cells
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-473270
SN  - 1866-8372
IS  - 1339
ER  - 
TY  - JOUR
A1  - Wetzel, Alexandra Nicole
A1  - Scholtka, Bettina
A1  - Schumacher, Fabian
A1  - Rawel, Harshadrai Manilal
A1  - Geisendörfer, Birte
A1  - Kleuser, Burkhard
T1  - Epigenetic DNA methylation of EBI3 modulates human interleukin-35 formation via NFkB signaling
BT  - a promising therapeutic option in ulcerative colitis
JF  - International journal of molecular sciences
N2  - Ulcerative colitis (UC), a severe chronic disease with unclear etiology that is associated with increased risk for colorectal cancer, is accompanied by dysregulation of cytokines. Epstein-Barr virus-induced gene 3 (EBI3) encodes a subunit in the unique heterodimeric IL-12 cytokine family of either pro- or anti-inflammatory function. After having recently demonstrated that upregulation of EBI3 by histone acetylation alleviates disease symptoms in a dextran sulfate sodium (DSS)-treated mouse model of chronic colitis, we now aimed to examine a possible further epigenetic regulation of EBI3 by DNA methylation under inflammatory conditions. Treatment with the DNA methyltransferase inhibitor (DNMTi) decitabine (DAC) and TNF alpha led to synergistic upregulation of EBI3 in human colon epithelial cells (HCEC). Use of different signaling pathway inhibitors indicated NF kappa B signaling was necessary and proportional to the synergistic EBI3 induction. MALDI-TOF/MS and HPLC-ESIMS/MS analysis of DAC/TNF alpha-treated HCEC identified IL-12p35 as the most probable binding partner to form a functional protein. EBI3/IL-12p35 heterodimers (IL-35) induce their own gene upregulation, something that was indeed observed in HCEC cultured with media from previously DAC/TNF alpha-treated HCEC. These results suggest that under inflammatory and demethylating conditions the upregulation of EBI3 results in the formation of anti-inflammatory IL-35, which might be considered as a therapeutic target in colitis.
KW  - decitabine
KW  - DNMT inhibitor
KW  - EBI3
KW  - inhibitory cytokines
KW  - interleukin-35
KW  - TNF alpha
KW  - Ulcerative colitis
Y1  - 2021
U6  - https://doi.org/10.3390/ijms22105329
SN  - 1422-0067
VL  - 22
IS  - 10
PB  - MDPI
CY  - Basel
ER  - 
TY  - JOUR
A1  - Gehre, Christian
A1  - Flechner, Marie
A1  - Kammerer, Sarah
A1  - Küpper, Jan-Heiner
A1  - Coleman, Charles Dominic
A1  - Püschel, Gerhard Paul
A1  - Uhlig, Katja
A1  - Duschl, Claus
T1  - Real time monitoring of oxygen uptake of hepatocytes in a microreactor using optical microsensors
JF  - Scientific reports
N2  - Most in vitro test systems for the assessment of toxicity are based on endpoint measurements and cannot contribute much to the establishment of mechanistic models, which are crucially important for further progress in this field. Hence, in recent years, much effort has been put into the development of methods that generate kinetic data. Real time measurements of the metabolic activity of cells based on the use of oxygen sensitive microsensor beads have been shown to provide access to the mode of action of compounds in hepatocytes. However, for fully exploiting this approach a detailed knowledge of the microenvironment of the cells is required. In this work, we investigate the cellular behaviour of three types of hepatocytes, HepG2 cells, HepG2-3A4 cells and primary mouse hepatocytes, towards their exposure to acetaminophen when the availability of oxygen for the cell is systematically varied. We show that the relative emergence of two modes of action, one NAPQI dependent and the other one transient and NAPQI independent, scale with expression level of CYP3A4. The transient cellular response associated to mitochondrial respiration is used to characterise the influence of the initial oxygen concentration in the wells before exposure to acetaminophen on the cell behaviour. A simple model is presented to describe the behaviour of the cells in this scenario. It demonstrates the level of control over the role of oxygen supply in these experiments. This is crucial for establishing this approach into a reliable and powerful method for the assessment of toxicity.
Y1  - 2020
U6  - https://doi.org/10.1038/s41598-020-70785-6
SN  - 2045-2322
VL  - 10
IS  - 1
PB  - Macmillan Publishers Limited, part of Springer Nature
CY  - [London]
ER  - 
TY  - JOUR
A1  - Schiborn, Catarina
A1  - Schulze, Matthias Bernd
T1  - Diabetes risk scores
T1  - Diabetesrisikoscores
BT  - use in diabetes prevention
BT  - Einsatz in der Diabetesprävention
JF  - Der Diabetologe
N2  - Risk scores are used to identify high-risk individuals for type 2 diabetes (T2DM) who benefit from preventive measures. The DIfE-DEUTSCHER DIABETES-RISIKO-TEST (R) (DRT) is used to determine the absolute 5-year risk for T2DM. Since the calculation is based on non-clinical information, the test can be used independently of a doctor's visit. Data from prospective population-based long-term studies serve as the basis for the development of risk scores. As in the case of the DRT, the very good predictive quality of a score should be confirmed in independent populations. In addition to the use by doctors and for individual self-anamnesis, non-clinical risk scores can be used in the context of broader, population-based prevention concepts and information offers to reduce the risk of disease. Prevention services billable by health insurance companies should support the integration of health-promoting behavior into everyday life within the meaning of the German Prevention Act. Although obesity and diet are relevant lifestyle risk factors for T2DM, the proportion of preventive courses taken on this topic is only 3% of the courses billed. Appropriate recommendations in medical examinations could promote more extensive use. The use of risk scores as the basis for systematic and targeted recommendations for behavioral prevention could also support this, as is already established in guidelines for cardiovascular prevention. The further development of implementation research is also important for the efficient use of risk scores.
N2  - Risikoscores werden zur Identifizierung von Hochrisikopersonen für Typ-2-Diabetes (T2DM) eingesetzt, die von Präventionsmaßnahmen profitieren. Der DIfE – DEUTSCHER DIABETES-RISIKO-TEST® (DRT [DIfE: Deutsches Institut für Ernährungsforschung Potsdam‐Rehbrücke]) wird genutzt, um das absolute 5‑Jahres-Risiko für T2DM zu bestimmen. Da die Berechnung auf nichtklinischen Informationen basiert, kann der Test unabhängig von einem Arztbesuch genutzt werden. Als Grundlage für die Entwicklung von Risikoscores dienen Daten aus prospektiven populationsbezogenen Langzeitstudien. Die sehr gute Vorhersagegüte eines Scores sollte, wie im Fall des DRT, in unabhängigen Populationen bestätigt werden. Neben dem Einsatz durch Ärzte/‑innen und zur individuellen Selbstanamnese können nichtklinische Risikoscores im Kontext breiterer, bevölkerungsbezogener Präventionskonzepte und Informationsangebote zur Senkung des Erkrankungsrisikos Anwendung finden. Durch Krankenkassen abrechenbare Präventionsleistungen sollen im Sinne des deutschen Präventionsgesetzes die Integration von gesundheitsförderndem Verhalten in den Alltag unterstützen. Obwohl Übergewicht und Ernährung relevante Lebensstilrisikofaktoren für T2DM sind, beträgt der Anteil der in Anspruch genommenen Präventionskurse in diesem Bereich nur 3 % der abgerechneten Kurse. Entsprechende Empfehlungen in ärztlichen Untersuchungen könnten eine umfangreichere Inanspruchnahme fördern. Die Verwendung von Risikoscores als Grundlage für systematische und gezielte Handlungsempfehlungen hinsichtlich einer Verhaltensprävention könnte dies, wie es bereits in Richtlinien der kardiovaskulären Prävention etabliert ist, darüber hinaus unterstützen. Auch die Weiterentwicklung der Implementationsforschung ist für den effizienten Einsatz von Risikoscores von Bedeutung.
KW  - Type 2 diabetes
KW  - preventive measures
KW  - risk assessment
KW  - life style
KW  - behavior
KW  - screening
KW  - Typ-2-Diabetes
KW  - Prävention
KW  - Risikoeinschätzung
KW  - Lebensstil
KW  - Verhalten
Y1  - 2020
U6  - https://doi.org/10.1007/s11428-020-00592-0
SN  - 1860-9716
SN  - 1860-9724
VL  - 16
IS  - 3
SP  - 226
EP  - 233
PB  - Springer
CY  - Heidelberg
ER  - 
TY  - JOUR
A1  - Dünkelberg, Sophie
A1  - Maywald, Martina
A1  - Schmitt, Anne Kristina
A1  - Schwerdtle, Tanja
A1  - Meyer, Sören
A1  - Rink, Lothar
T1  - The interaction of sodium and zinc in the priming of T cell subpopulations regarding Th17 and Treg cells
JF  - Molecular nutrition & food research : bioactivity, chemistry, immunology, microbiology, safety, technology
N2  - Scope:
Nutrition is a critical determinant of a functional immune system. The aim of this study is to investigate the molecular mechanisms by which immune cells are influenced by zinc and sodium.

Methods and Results:
 Mixed lymphocyte cultures and Jurkat cells are generated and incubated with zinc, sodium, or a combination of both for further tests. Zinc induces the number of regulatory T cells (Treg) and decreases T helper 17 cells (Th17), and sodium has the opposite effect. The transforming growth factor beta receptor signaling pathway is also enhanced by zinc and reduced by sodium as indicated by contrary phosphoSmad 2/3 induction. Antagonistic effects can also be seen on zinc transporter and metallothionein-1 (MT-1) mRNA expression: zinc declines Zip10 mRNA expression while sodium induces it, whereas MT-1 mRNA expression is induced by zinc while it is reduced by sodium. 

Conclusion:
This data indicate that zinc and sodium display opposite effects regarding Treg and Th17 induction in MLC, respectively, resulting in a contrary effect on the immune system. Additionally, it reveals a direct interaction of zinc and sodium in the priming of T cell subpopulations and shows that Zip10 and MT-1 play a significant role in those differentiation pathways.
KW  - Foxp3
KW  - regulatory T cells
KW  - sodium
KW  - T helper 17 cells
KW  - zinc
Y1  - 2020
U6  - https://doi.org/10.1002/mnfr.201900245
SN  - 1613-4133
VL  - 64
IS  - 2
PB  - Wiley-VCH
CY  - Weinheim
ER  - 
TY  - JOUR
A1  - Kotthoff, Lisa
A1  - O'Callaghan, Sarah-Louise
A1  - Lisec, Jan
A1  - Schwerdtle, Tanja
A1  - Koch, Matthias
T1  - Structural annotation of electro- and photochemically generated transformation products of moxidectin using high-resolution mass spectrometry
JF  - Analytical and bioanalytical chemistry : a merger of Fresenius' journal of analytical chemistry, Analusis and Quimica analitica
N2  - Moxidectin (MOX) is a widely used anthelmintic drug for the treatment of internal and external parasites in food-producing and companion animals. Transformation products (TPs) of MOX, formed through metabolic degradation or acid hydrolysis, may pose a potential environmental risk, but only few were identified so far. In this study, we therefore systematically characterized electro- and photochemically generated MOX TPs using high-resolution mass spectrometry (HRMS). Oxidative electrochemical (EC) TPs were generated in an electrochemical reactor and photochemical (PC) TPs by irradiation with UV-C light. Subsequent HRMS measurements were performed to identify accurate masses and deduce occurring modification reactions of derived TPs in a suspected target analysis. In total, 26 EC TPs and 59 PC TPs were found. The main modification reactions were hydroxylation, (de-)hydration, and derivative formation with methanol for EC experiments and isomeric changes, (de-)hydration, and changes at the methoxime moiety for PC experiments. In addition, several combinations of different modification reactions were identified. For 17 TPs, we could predict chemical structures through interpretation of acquired MS/MS data. Most modifications could be linked to two specific regions of MOX. Some previously described metabolic reactions like hydroxylation or O-demethylation were confirmed in our EC and PC experiments as reaction type, but the corresponding TPs were not identical to known metabolites or degradation products. The obtained knowledge regarding novel TPs and reactions will aid to elucidate the degradation pathway of MOX which is currently unknown.
KW  - veterinary drug
KW  - moxidectin
KW  - transformation products
KW  - electrochemistry
KW  - photochemistry
KW  - LC
KW  - HRMS
Y1  - 2020
U6  - https://doi.org/10.1007/s00216-020-02572-1
SN  - 1618-2642
SN  - 1618-2650
VL  - 412
IS  - 13
SP  - 3141
EP  - 3152
PB  - Springer
CY  - Heidelberg
ER  - 
TY  - JOUR
A1  - Ouni, Meriem
A1  - Schürmann, Annette
T1  - Epigenetic contribution to obesity
JF  - Mammalian genome
N2  - Obesity is a worldwide epidemic and contributes to global morbidity and mortality mediated via the development of nonalcoholic fatty liver disease (NAFLD), type 2 diabetes (T2D), cardiovascular (CVD) and other diseases. It is a consequence of an elevated caloric intake, a sedentary lifestyle and a genetic as well as an epigenetic predisposition. This review summarizes changes in DNA methylation and microRNAs identified in blood cells and different tissues in obese human and rodent models. It includes information on epigenetic alterations which occur in response to fat-enriched diets, exercise and metabolic surgery and discusses the potential of interventions to reverse epigenetic modifications.
Y1  - 2020
U6  - https://doi.org/10.1007/s00335-020-09835-3
SN  - 0938-8990
SN  - 1432-1777
VL  - 31
IS  - 5-6
SP  - 134
EP  - 145
PB  - Springer
CY  - New York, NY ; Berlin ; Heidelberg [u.a.]
ER  - 
TY  - JOUR
A1  - Klaus, Susanne
A1  - Ost, Mario
T1  - Mitochondrial uncoupling and longevity
BT  - a role for mitokines?
JF  - Experimental gerontology
N2  - Aging has been viewed both as a random process due to accumulation of molecular and cellular damage over time and as a programmed process linked to cellular pathway important for growth and maturation. These views converge on mitochondria as both the major producer of damaging reactive oxidant species (ROS) and as signaling organelles. A finite proton leak across the inner mitochondrial membrane leading to a slight uncoupling of oxidative phosphorylation and respiration is an intrinsic property of all mitochondria and according to the "uncoupling to survive" hypothesis it has evolved to protect against ROS production to minimize oxidative damage. This hypothesis is supported by evidence linking an increased endogenous, uncoupling protein (UCP1) mediated, as well as experimentally induced mitochondrial uncoupling to an increased lifespan in rodents. This is possibly due to the synergistic activation of molecular pathways linked to life extending effects of caloric restriction as well as a mitohormetic response. Mitohormesis is an adaptive stress response through mitonuclear signaling which increases stress resistance resulting in health promoting effects. Part of this response is the induction of fibroblast growth factor 21 (FGF21) and growth and differentiation factor 15 (GDF15), two stress-induced mitokines which elicit beneficial systemic metabolic effects via endocrine action.
KW  - Uncoupling proteins
KW  - Energy metabolism
KW  - Skeletal muscle
KW  - Mitohormesis
KW  - GDF15
KW  - FGF21
Y1  - 2019
U6  - https://doi.org/10.1016/j.exger.2019.110796
SN  - 0531-5565
SN  - 1873-6815
VL  - 130
PB  - Elsevier Science
CY  - Amsterdam
ER  - 
TY  - JOUR
A1  - Knoche, Lisa
A1  - Lisec, Jan
A1  - Koch, Matthias
T1  - Analysis of electrochemical and liver microsomal transformation products of lasalocid by LC/HRMS
JF  - Rapid communications in mass spectrometry : RCM
N2  - Rationale:
Lasalocid (LAS), an ionophore, is used in cattle and poultry farming as feed additive for its antibiotic and growth-promoting properties. Literature on transformation products (TP) resulting from LAS degradation is limited. So far, only hydroxylation is found to occur as the metabolic reaction during the LAS degradation. To investigate potential TPs of LAS, we used electrochemistry (EC) and liver microsome (LM) assays to synthesize TPs, which were identified using liquid chromatography high-resolution mass spectrometry (LC/HRMS). 

Methods:
Electrochemically produced TPs were analyzed online by direct coupling of the electrochemical cell to the electrospray ionization (ESI) source of a Sciex Triple-TOF high resolution mass spectrometer. Then, EC-treated LAS solution was collected and analyzed offline using LC/HRMS to confirm stable TPs and improve their annotation with a chemical structure due to informative MS/MS spectra. In a complementary approach, TPs formed by rat and human microsomal incubation were investigated using LC/HRMS. The resulting data were used to investigate LAS modification reactions and elucidate the chemical structure of obtained TPs.

Results:
The online measurements identified a broad variety of TPs, resulting from modification reactions like (de-)hydrogenation, hydration, methylation, oxidation as well as adduct formation with methanol. We consistently observed different ion complexations of LAS and LAS-TPs (Na+; 2Na(+) K+; NaNH4+; KNH4+). Two stable methylated EC-TPs were found, structurally annotated, and assigned to a likely modification reaction. Using LM incubation, seven TPs were formed, mostly by oxidation/hydroxylation. After the identification of LM-TPs as Na+-complexes, we identified LM-TPs as K+-complexes.

Conclusion:
We identified and characterized TPs of LAS using EC- and LM-based methods. Moreover, we found different ion complexes of LAS-based TPs. This knowledge, especially the different ion complexes, may help elucidate the metabolic and environmental degradation pathways of LAS.
Y1  - 2022
U6  - https://doi.org/10.1002/rcm.9349
SN  - 0951-4198
SN  - 1097-0231
VL  - 36
IS  - 18
PB  - Wiley
CY  - New York, NY
ER  - 
TY  - JOUR
A1  - Cencetti, Francesca
A1  - Bruno, Gennaro
A1  - Bernacchioni, Caterina
A1  - Japtok, Lukasz
A1  - Puliti, Elisa
A1  - Donati, Chiara
A1  - Bruni, Paola
T1  - Sphingosine 1-phosphate lyase blockade elicits myogenic differentiation of murine myoblasts acting via Spns2/S1P(2) receptor axis
JF  - Biochimica et biophysica acta : Molecular and cell biology of lipids
N2  - The bioactive sphingolipid sphingosine 1-phosphate (S1P) has emerged in the last three decades as main regulator of key cellular processes including cell proliferation, survival, migration and differentiation. A crucial role for this sphingolipid has been recognized in skeletal muscle cell biology both in vitro and in vivo. S1P lyase (SPL) is responsible for the irreversible degradation of S1P and together with sphingosine kinases, the S1P producing enzymes, regulates cellular S1P levels. In this study is clearly showed that the blockade of SPL by pharmacological or RNA interference approaches induces myogenic differentiation of C2C12 myoblasts. Moreover, down-regulation of the specific S1P transporter spinster homolog 2 (Spns2) abrogates myogenic differentiation brought about by SPL inhibition or down-regulation, pointing at a role of extracellular S1P in the pro-myogenic action induced by SPL blockade. Furthermore, also S1P(2) receptor down-regulation was found to abrogate the pro-myogenic effect of SPL blockade. These results provide further proof that inside-out S1P signaling is critically implicated in skeletal muscle biology and provide support to the concept that the specific targeting of SPL could represent an exploitable strategy to treat skeletal muscle disorders.
KW  - Sphingosine 1-phosphate
KW  - Myogenic differentiation
Y1  - 2020
U6  - https://doi.org/10.1016/j.bbalip.2020.158759
SN  - 1388-1981
SN  - 1879-2618
VL  - 1865
IS  - 9
PB  - Elsevier
CY  - Amsterdam
ER  - 
TY  - JOUR
A1  - Bishop, Christopher Allen
A1  - Schulze, Matthias Bernd
A1  - Klaus, Susanne
A1  - Weitkunat, Karolin
T1  - The branched-chain amino acids valine and leucine have differential effects on hepatic lipid metabolism
JF  - The FASEB journal : the official journal of the Federation of American Societies for Experimental Biology
N2  - Dairy intake, as a source of branched-chain amino acids (BCAA), has been linked to a lower incidence of type-2-diabetes and increased circulating odd-chain fatty acids (OCFA). To understand this connection, we aimed to investigate differences in BCAA metabolism of leucine and valine, a possible source of OCFA, and their role in hepatic metabolism. Male mice were fed a high-fat diet supplemented with leucine and valine for 1 week and phenotypically characterized with a focus on lipid metabolism. Mouse primary hepatocytes were treated with the BCAA or a Ppar alpha activator WY-14643 to systematically examine direct hepatic effects and their mechanisms. Here, we show that only valine supplementation was able to increase hepatic and circulating OCFA levels via two pathways; a PPAR alpha-dependent induction of alpha-oxidation and an increased supply of propionyl-CoA for de novo lipogenesis. Meanwhile, we were able to confirm leucine-mediated effects on the inhibition of food intake and transport of fatty acids, as well as induction of S6 ribosomal protein phosphorylation. Taken together, these data illustrate differential roles of the BCAA in lipid metabolism and provide preliminary evidence that exclusively valine contributes to the endogenous formation of OCFA which is important for a better understanding of these metabolites in metabolic health.
KW  - fatty acid metabolism
KW  - leucine
KW  - liver
KW  - OCFA
KW  - valine
Y1  - 2020
U6  - https://doi.org/10.1096/fj.202000195R
SN  - 0892-6638
SN  - 1530-6860
VL  - 34
IS  - 7
SP  - 9727
EP  - 9739
PB  - Wiley
CY  - Hoboken
ER  - 
TY  - JOUR
A1  - Schedlbauer, Carola
A1  - Blaue, Dominique
A1  - Raila, Jens
A1  - Vervuert, Ingrid
T1  - Alterations of serum vitamin E and vitamin A concentrations of ponies and horses during experimentally induced obesity
JF  - Journal of animal physiology and animal nutrition
JF  - Zeitschrift für Tierphysiologie, Tierernährung und Futtermittelkunde
N2  - Vitamin A, vitamin E and retinol-binding protein 4 (RBP4) are a focus of current obesity research in humans. The impact of body weight (BW) gain on fat-soluble vitamins and its associated parameters in equines has not been previously reported. Ten Shetland ponies and 9 Warmblood horses, all adult geldings, non-obese and healthy, were fed an excessive energy diet for 20 months to induce BW gain. Serum alpha-tocopherol (vitamin E), retinol (vitamin A), retinol-binding protein 4 (RBP4) and retinol/RBP4 ratio were analysed before BW gain induction and at six timepoints during the BW gaining period. The mean (+/- SD) % BW gain achieved during two years of excess energy intake was 29.9 +/- 19.4% for ponies and 17 +/- 6.74% for horses. Serum alpha-tocopherol increased significantly in ponies and horses during excess energy intake and circulating alpha-tocopherol levels correlated positively with alpha-tocopherol intake (r = .6; p < .001). Serum retinol concentrations showed variations during the study but without relation to intake. Serum RBP4 decreased at the end of the study. The retinol/RBP4 ratio increased with BW gain without differences between ponies and horses. In comparison with human research, the increase in the retinol/RBP4 ratio was unexpected and needs further elucidation.
KW  - body weight gain
KW  - equine
KW  - laminitis
KW  - retinol-binding protein 4
KW  - alpha-tocopherol
Y1  - 2020
U6  - https://doi.org/10.1111/jpn.13385
SN  - 0931-2439
SN  - 1439-0396
VL  - 104
IS  - 5
SP  - 1501
EP  - 1508
PB  - Wiley
CY  - Hoboken
ER  - 
TY  - JOUR
A1  - Scholz-Ahrens, Katharina Elisabeth
A1  - Ahrens, Frank
A1  - Barth, Christian A.
T1  - Nutritional and health attributes of milk and milk imitations
JF  - European journal of nutrition
N2  - Purpose Modern food technology allows designing products aiming to simulate and replace traditional food. In affluent societies there is a rising tendency to consume foods derived from plants including milk imitations or plant drinks based on cereals, nuts, legumes, oil seeds or other plant families. Herein we review production and composition of such drinks, summarize consumers' motivations to change from milk to plant drinks and highlight nutritional and health implications of consuming plant drinks instead of milk, in particular if non-fortified and if consumed by infants, children, adolescents and the elderly. Results Whereas the macronutrient concentrations of some plant drinks (soy) may approach in some cases (protein) that of cow's milk, the nutritional quality of most plant drinks, e.g., the biological value of protein and the presence and amount of vitamins and essential minerals with high bioavailability does not. If cow's milk is exchanged for non-fortified and non-supplemented plant drinks consumers may risk deficiencies of calcium, zinc, iodine, vitamins B2, B12, D, A, and indispensable amino acids, particularly in infants and toddlers who traditionally consume significant portions of milk. The vegetable nature, appearance and taste of such plant drinks may be appealing to adult consumers and be chosen for adding variety to the menu. However, in young children fed exclusively such plant drinks severe metabolic disturbances may occur. Conclusion Parents, dietitians, physicians and consumers should be aware of such potential risks, if non-fortified plant drinks are consumed instead of milk.
KW  - cow's milk
KW  - plant drinks
KW  - nutrient bioavailability
KW  - human nutrition
KW  - health risks
Y1  - 2020
U6  - https://doi.org/10.1007/s00394-019-01936-3
SN  - 1436-6207
SN  - 1436-6215
VL  - 59
IS  - 1
SP  - 19
EP  - 34
PB  - Springer
CY  - Heidelberg
ER  - 
TY  - JOUR
A1  - Wiedmer, Petra
A1  - Jung, Tobias
A1  - Castro, Jose Pedro
A1  - Pomatto, Laura C. D.
A1  - Sun, Patrick Y.
A1  - Davies, Kelvin J. A.
A1  - Grune, Tilman
T1  - Sarcopenia
BT  - molecular mechanisms and open questions
JF  - Ageing research reviews : ARR
N2  - Sarcopenia represents a muscle-wasting syndrome characterized by progressive and generalized degenerative loss of skeletal muscle mass, quality, and strength occurring during normal aging. Sarcopenia patients are mainly suffering from the loss in muscle strength and are faced with mobility disorders reducing their quality of life and are, therefore, at higher risk for morbidity (falls, bone fracture, metabolic diseases) and mortality. <br /> Several molecular mechanisms have been described as causes for sarcopenia that refer to very different levels of muscle physiology. These mechanisms cover e. g. function of hormones (e. g. IGF-1 and Insulin), muscle fiber composition and neuromuscular drive, myo-satellite cell potential to differentiate and proliferate, inflammatory pathways as well as intracellular mechanisms in the processes of proteostasis and mitochondrial function. <br /> In this review, we describe sarcopenia as a muscle-wasting syndrome distinct from other atrophic diseases and summarize the current view on molecular causes of sarcopenia development as well as open questions provoking further research efforts for establishing efficient lifestyle and therapeutic interventions.
KW  - molecular pathways
KW  - proteostasis
KW  - proteasome
KW  - autophagy
KW  - mitochondria,
KW  - muscle fibre composition
Y1  - 2020
U6  - https://doi.org/10.1016/j.arr.2020.101200
SN  - 1568-1637
SN  - 1872-9649
VL  - 65
PB  - Elsevier
CY  - Clare
ER  - 
TY  - JOUR
A1  - Rothwell, Joseph A.
A1  - Murphy, Neil
A1  - Aleksandrova, Krasimira
A1  - Schulze, Matthias Bernd
A1  - Bešević, Jelena
A1  - Kliemann, Nathalie
A1  - Jenab, Mazda
A1  - Ferrari, Pietro
A1  - Achaintre, David
A1  - Gicquiau, Audrey
A1  - Vozar, Béatrice
A1  - Scalbert, Augustin
A1  - Huybrechts, Inge
A1  - Freisling, Heinz
A1  - Prehn, Cornelia
A1  - Adamski, Jerzy
A1  - Cross, Amanda J.
A1  - Pala, Valeria Maria
A1  - Boutron-Ruault, Marie-Christine
A1  - Dahm, Christina C.
A1  - Overvad, Kim
A1  - Gram, Inger Torhild
A1  - Sandanger, Torkjel M.
A1  - Skeie, Guri
A1  - Jakszyn, Paula
A1  - Tsilidis, Kostas K.
A1  - Hughes, David J.
A1  - van Guelpen, Bethany
A1  - Bodén, Stina
A1  - Sánchez, Maria-José
A1  - Schmidt, Julie A.
A1  - Katzke, Verena
A1  - Kühn, Tilman
A1  - Colorado-Yohar, Sandra
A1  - Tumino, Rosario
A1  - Bueno-de-Mesquita, Bas
A1  - Vineis, Paolo
A1  - Masala, Giovanna
A1  - Panico, Salvatore
A1  - Eriksen, Anne Kirstine
A1  - Tjønneland, Anne
A1  - Aune, Dagfinn
A1  - Weiderpass, Elisabete
A1  - Severi, Gianluca
A1  - Chajès, Véronique
A1  - Gunter, Marc J.
T1  - Metabolic signatures of healthy lifestyle patterns and colorectal cancer risk in a European cohort
JF  - Clinical gastroenterology and hepatology
N2  - BACKGROUND & AIMS: Colorectal cancer risk can be lowered by adherence to the World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) guidelines. We derived metabolic signatures of adherence to these guidelines and tested their associations with colorectal cancer risk in the European Prospective Investigation into Cancer and Nutrition cohort.

METHODS: Scores reflecting adherence to the WCRF/AICR recommendations (scale, 1-5) were calculated from participant data on weight maintenance, physical activity, diet, and alcohol among a discovery set of 5738 cancer-free European Prospective Investigation into Cancer and Nutrition participants with metabolomics data. Partial least-squares regression was used to derive fatty acid and endogenous metabolite signatures of the WCRF/AICR score in this group. In an independent set of 1608 colorectal cancer cases and matched controls, odds ratios (ORs) and 95% CIs were calculated for colorectal cancer risk per unit increase in WCRF/AICR score and per the corresponding change in metabolic signatures using multivariable conditional logistic regression.

RESULTS: Higher WCRF/AICR scores were characterized by metabolic signatures of increased odd-chain fatty acids, serine, glycine, and specific phosphatidylcholines. Signatures were inversely associated more strongly with colorectal cancer risk (fatty acids: OR, 0.51 per unit increase; 95% CI, 0.29-0.90; endogenous metabolites: OR, 0.62 per unit change; 95% CI, 0.50-0.78) than the WCRF/AICR score (OR, 0.93 per unit change; 95% CI, 0.86-1.00) overall. Signature associations were stronger in male compared with female participants.

CONCLUSIONS: Metabolite profiles reflecting adherence to WCRF/AICR guidelines and additional lifestyle or biological risk factors were associated with colorectal cancer. Measuring a specific panel of metabolites representative of a healthy or unhealthy lifestyle may identify strata of the population at higher risk of colorectal cancer.
KW  - colorectal neoplasm
KW  - risk factors
KW  - World Cancer Research Fund/American Institute for Cancer Research Recommendations
KW  - targeted metabolomics
Y1  - 2020
U6  - https://doi.org/10.1016/j.cgh.2020.11.045
SN  - 1542-3565
SN  - 1542-7714
VL  - 20
SP  - E1061
EP  - E1082
PB  - Elsevier
CY  - New York, NY
ER  - 
TY  - JOUR
A1  - Bußler, Sara
A1  - Rawel, Harshadrai Manilal
A1  - Schlüter, Oliver K.
T1  - Impact of plasma processed air (PPA) on phenolic model systems
BT  - suggested mechanisms and relevance for food applications
JF  - Innovative food science & emerging technologies : the official journal of the European Federation of Food Science and Technology
N2  - Cold plasma is considered to be a novel, non-thermal, chemical-free and eco-friendly disinfection and surface modification technology. Plasma treatment of air to generate the so called plasma processed air (PPA) induces the formation of reactive oxygen (ROS) and nitrogen species (RNS). As a result, PPA has a different chemical composition compared to untreated air and suits therefore as an alternative method for microbial disinfection. However, depending on the product properties of the food matrix and its composition, a number of plasmainduced reactions also need to be taken into consideration. 
This necessitates also the elucidation and understanding of the basic interactions of plasma species with bioactive compounds. The intention here is to avoid the degradation of these valuable substances and to prevent other undesirable effects in future food related applications.
In the present study, the effects of PPA treatment on selected antioxidants such as pyrocatechol and derivatives of hydroxycinnimic acid were investigated in model systems to specify possible reactions induced. Antioxidant capacity, pH value, UV-Vis spectroscopy, RP-HPLC and LC-MS analysis were applied to identify reaction products providing information on possible changes induced in food matrices by PPA treatment. 
Exposure to PPA caused a perceptible color change towards yellow-brown accompanied by a strong reduction of the pH and the formation of insoluble sediments in the model solutions. The accumulation of nitrate, nitrite, but not of hydrogen peroxide was shown. LC-MS analysis demonstrated the formation of plasma-modified derivatives in all tested systems. The main reactions in liquid model solutions exposed to PPA were attributed to oxidation, nitration and polymerization of the phenolic compounds.
KW  - cold atmospheric pressure plasma
KW  - reactive oxygen and nitrogen species
KW  - food safety
KW  - antioxidative phenolic ingredients
KW  - phenol oxidation
KW  - phenol nitration
KW  - plasma process indicators
Y1  - 2020
U6  - https://doi.org/10.1016/j.ifset.2020.102432
SN  - 1466-8564
SN  - 1878-5522
VL  - 64
PB  - Elsevier
CY  - Oxford
ER  - 
TY  - JOUR
A1  - Zhou, Suqiong
A1  - Pan, Yuanwei
A1  - Zhang, Jianguang
A1  - Li, Yan
A1  - Neumann, Falko
A1  - Schwerdtle, Tanja
A1  - Li, Wenzhong
A1  - Haag, Rainer
T1  - Dendritic polyglycerol-conjugated gold nanostars with different densities of functional groups to regulate osteogenesis in human mesenchymal stem cells
JF  - Nanoscale
N2  - Nanomaterials play an important role in mimicking the biochemical and biophysical cues of the extracellular matrix in human mesenchymal stem cells (MSCs). Increasing studies have demonstrated the crucial impact of functional groups on MSCs, while limited research is available on how the functional group's density on nanoparticles regulates MSC behavior. Herein, the effects of dendritic polyglycerol (dPG)-conjugated gold nanostars (GNSs) with different densities of functional groups on the osteogenesis of MSCs are systematically investigated. dPG@GNS nanocomposites have good biocompatibility and the uptake by MSCs is in a functional group density-dependent manner. The osteogenic differentiation of MSCs is promoted by all dPG@GNS nanocomposites, in terms of alkaline phosphatase activity, calcium deposition, and expression of osteogenic protein and genes. Interestingly, the dPGOH@GNSs exhibit a slight upregulation in the expression of osteogenic markers, while the different charged densities of sulfate and amino groups show more efficacy in the promotion of osteogenesis. Meanwhile, the sulfated nanostars dPGS20@GNSs show the highest enhancement. Furthermore, various dPG@GNS nanocomposites exerted their effects by regulating the activation of Yes-associated protein (YAP) to affect osteogenic differentiation. These results indicate that dPG@GNS nanocomposites have functional group density-dependent influence on the osteogenesis of MSCs, which may provide a new insight into regulating stem cell fate.
Y1  - 2020
U6  - https://doi.org/10.1039/d0nr06570f
SN  - 2040-3364
SN  - 2040-3372
VL  - 12
IS  - 47
SP  - 24006
EP  - 24019
PB  - Royal Society of Chemistry
CY  - Cambridge
ER  - 
TY  - THES
A1  - Prada, Marcela
T1  - Fatty acid biomarkers of intake and metabolism and their association with type 2 diabetes
N2  - Background: The role of fatty acid (FA) intake and metabolism in type 2 diabetes (T2D) incidence is controversial. Some FAs are not synthesised endogenously and, therefore, these circulating FAs reflect dietary intake, for example, the trans fatty acids (TFAs), saturated odd chain fatty acids (OCFAs), and linoleic acid, an n-6 polyunsaturated fatty acids (PUFA).  It remains unclear if intake of TFA influence T2D risk and whether industrial TFAs (iTFAs) and ruminant TFAs (rTFAs) exert the same effect. Unlike even chain saturated FAs, the OCFAs have been inversely associated with T2D risk, but this association is poorly understood. Furthermore, the associations of n-6 PUFAs intake with T2D risk are still debated, while delta-5 desaturase (D5D), a key enzyme in the metabolism of PUFAs, has been consistently related to T2D risk. To better understand these relationships, the FA composition in circulating lipid fractions can be used as biomarkers of dietary intake and metabolism. The exploration of TFAs subtypes in plasma phospholipids and OCFAs and n-6 PUFAs within a wide range of lipid classes may give insights into the pathophysiology of T2D.
Aim: This thesis aimed mainly to analyse the association of TFAs, OCFAs and n-6 PUFAs with self-reported dietary intake and prospective T2D risk, using seven types of TFAs in plasma phospholipids and deep lipidomics profiling data from fifteen lipid classes.
Methods: A prospective case-cohort study was designed within the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam study, including all the participants who developed T2D (median follow-up 6.5 years) and a random subsample of the full cohort (subcohort: n=1248; T2D cases: n=820). The main analyses included two lipid profiles. The first was an assessment of seven TFA in plasma phospholipids, with a modified method for analysis of FA with very low abundances. The second lipid profile was derived from a high-throughout lipid profiling technology, which identified 940 distinct molecular species and allowed to quantify OCFAs and PUFAs composition across 15 lipid classes. Delta-5 desaturase (D5D) activity was estimated as 20:4/20:3-ratio. Using multivariable Cox regression models, we examined the associations of TFA subtypes with incident T2D and class-specific associations of OCFA and n-6 PUFAs with T2D risk.
Results: 16:1n-7t, 18:1n-7t, and c9t11-CLA were positively correlated with the intake of fat-rich dairy foods. iTFA 18:1 isomers were positively correlated with margarine. After adjustment for confounders and other TFAs, higher plasma phospholipid concentrations of two rTFAs were associated with a lower incidence of T2D: 18:1n-7t and t10c12-CLA. In contrast, the rTFA c9t11-CLA was associated with a higher incidence of T2D. rTFA 16:1n-7t and iTFAs (18:1n-6t, 18:1n-9t, 18:2n-6,9t) were not statistically significantly associated with T2D risk. 
We observed heterogeneous integration of OCFA in different lipid classes, and the contribution of 15:0 versus 17:0 to the total OCFA abundance differed across lipid classes. Consumption of fat-rich dairy and fiber-rich foods were positively and red meat inversely correlated to OCFA abundance in plasma phospholipid classes. In women only, higher abundances of 15:0 in phosphatidylcholines (PC) and diacylglycerols (DG), and 17:0 in PC, lysophosphatidylcholines (LPC), and cholesterol esters (CE) were inversely associated with T2D risk. In men and women, a higher abundance of 15:0 in monoacylglycerols (MG) was also inversely associated with T2D. Conversely, a higher 15:0 concentration in LPC and triacylglycerols (TG) was associated with higher T2D risk in men. Women with a higher concentration of 17:0 as free fatty acids (FFA) also had higher T2D incidence.
The integration of n-6 PUFAs in lipid classes was also heterogeneous. 18:2 was highly abundant in phospholipids (particularly PC), CE, and TG; 20:3 represented a small fraction of FA in most lipid classes, and 20:4 accounted for a large proportion of circulating phosphatidylinositol (PI) and phosphatidylethanolamines (PE). Higher concentrations of 18:2 were inversely associated with T2D risk, especially within DG, TG, and LPC. However, 18:2 as part of MG was positively associated with T2D risk. Higher concentrations of 20:3 in phospholipids (PC, PE, PI), FFA, CE, and MG were linked to higher T2D incidence. 20:4 was unrelated to risk in most lipid classes, except positive associations were observed for 20:4 enriched in FFA and PE. The estimated D5D activities in PC, PE, PI, LPC, and CE were inversely associated with T2D and explained variance of estimated D5D activity by genomic variation in the FADS locus was only substantial in those lipid classes.
Conclusion: The TFAs' conformation is essential in their relationship to diabetes risk, as indicated by plasma rTFA subtypes concentrations having opposite directions of associations with diabetes risk. Plasma OCFA concentration is linked to T2D risk in a lipid class and sex-specific manner. Plasma n-6 PUFA concentrations are associated differently with T2D incidence depending on the specific FA and the lipid class. Overall, these results highlight the complexity of circulating FAs and their heterogeneous association with T2D risk depending on the specific FA structure, lipid class, and sex. My results extend the evidence of the relationship between diet, lipid metabolism, and subsequent T2D risk. In addition, my work generated several potential new biomarkers of dietary intake and prospective T2D risk.
N2  - Die Rolle der Fettsäureaufnahme und des Fettsäurestoffwechsels bei der Prävention von Typ-2-Diabetes (T2D) ist nach wie vor umstritten. Die Fettsäure (FS)-Zusammensetzung in den Blutfettfraktionen kann als Biomarker für die Nahrungsaufnahme und den Stoffwechsel verwendet werden, um die Beziehung zwischen den FS und dem T2D-Risiko besser zu verstehen. Das Hauptziel dieser Arbeit war es, den Zusammenhang zwischen zirkulierenden trans-FS (TFS), ungeradkettigen gesättigten FS (UGFS) und n-6 poly ungesättigte FS (PUFS), die in verschiedenen Lipidklassen angereichert sind, mit dem T2D-Risiko zu untersuchen.
Mit einer eingebetten Fall-Kohorten-Studie, die im Rahmen der prospektiven EPIC-Potsdam-Studie konzipiert wurde, untersuchte diese Arbeit zwei Lipidprofile im Hinblick auf das T2D-Risiko: (1) Sieben TFS-Subtypen in Plasma-Phospholipiden und (2) die Zusammensetzung von UGFS und PUFA in 15 Plasma-Lipidklassen. Die Aktivität der Delta-5-Desaturase (D5D) wurde als 20:4/20:3-Verhältnis geschätzt. Assoziationen mit dem Auftreten von T2D wurden mit multivariablen Cox-Regressionsmodellen untersucht.
Von den üblicherweise aus Milchprodukten stammenden TFS waren 18:1n-7t und t10c12-CLA mit einer geringeren T2D-Inzidenz, c9t11-CLA mit einer höheren Inzidenz und 16:1n-7t nicht mit dem T2D-Risiko assoziiert. TFS aus industriellen Quellen (18:1n-6t, 18:1n-9t, 18:2n-6t) zeigten keinen statistisch signifikanten Zusammenhang mit dem T2D-Risiko. Die UGFS-Konzentration im Plasma war mit dem T2D-Risiko auf lipidklassen- und geschlechtsspezifische Weise assoziiert, wobei bei Frauen stärkere inverse Zusammenhänge für 15:0 in Monoacylglycerinen (MG), Phosphatidylcholinen (PC) und Diacylglycerinen (DG) sowie für 17:0 in PC, Lysophosphatidylcholinen (LPC) und Cholesterinestern (CE) beobachtet wurden. Höhere Konzentrationen von 18:2 waren in DG, TG und LPC invers mit dem T2D-Risiko assoziiert, während MG(18:2) positiv mit dem T2D-Risiko assoziiert war. Höhere Konzentrationen von 20:3 in Phospholipiden (PC, PE, Phosphatidylinositole (PI)), Fettsäuren (FFS), CE und MG waren mit einer höheren T2D-Inzidenz verbunden. 20:4 stand in den meisten Lipidklassen in keinem statistisch singifikanten Zusammenhang mit dem Risiko, außer bei in FFS und PE angereichertem 20:4, das positiv assoziiert war. Die geschätzten D5D-Aktivitäten in PC, PE, PI, LPC und CE waren invers mit dem T2D-Risiko assoziiert.
Zusammenfassend ist die Konformation der TFS für ihren Zusammenhang mit dem Diabetesrisiko entscheidend. Die Assoziationen der UGFS-Plasma-Konzentrationen mit dem T2D-Risiko zeigten lipidklassen- und geschlechtsspezifische Unterschiede. Die Plasma-Konzentrationen der n-6-PUFA waren je nach spezifischer FA und Lipidklasse unterschiedlich mit der T2D-Inzidenz assoziiert. Insgesamt unterstreichen diese Ergebnisse die Komplexität der zirkulierenden FAs und ihren heterogenen Zusammenhang mit dem T2D-Risiko in Abhängigkeit der spezifischen FA-Struktur, der Lipidklasse und des Geschlechtes.
KW  - fatty acids
KW  - lipidomics
KW  - type 2 diabetes
KW  - trans fatty acids
KW  - odd chain fatty acids
KW  - polyunsaturated fatty acids
KW  - Fettsäuren
KW  - Lipidomics
KW  - Typ-2-Diabetes
KW  - Biomarker
KW  - Lipidstoffwechsel
KW  - Trans-Fettsäuren
KW  - ungeradkettige Fettsäuren
KW  - poly ungesättigte Fettsäuren
Y1  - 2023
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-581598
ER  - 
TY  - JOUR
A1  - Jonas, Wenke
A1  - Schürmann, Annette
T1  - Genetic and epigenetic factors determining NAFLD risk
JF  - Molecular metabolism
N2  - Background: Hepatic steatosis is a common chronic liver disease that can progress into more severe stages of NAFLD or promote the development of life-threatening secondary diseases for some of those affected. These include the liver itself (nonalcoholic steatohepatitis or NASH; fibrosis and cirrhosis, and hepatocellular carcinoma) or other organs such as the vessels and the heart (cardiovascular disease) or the islets of Langerhans (type 2 diabetes). In addition to elevated caloric intake and a sedentary lifestyle, genetic and epigenetic predisposition contribute to the development of NAFLD and the secondary diseases. Scope of review: We present data from genome-wide association studies (GWAS) and functional studies in rodents which describe polymorphisms identified in genes relevant for the disease as well as changes caused by altered DNA methylation and gene regulation via specific miRNAs. The review also provides information on the current status of the use of genetic and epigenetic factors as risk markers. Major conclusion: With our overview we provide an insight into the genetic and epigenetic landscape of NAFLD and argue about the applicability of currently defined risk scores for risk stratification and conclude that further efforts are needed to make the scores more usable and meaningful.
KW  - NAFLD
KW  - genetic variants
KW  - epigenetics
KW  - risk score
Y1  - 2020
U6  - https://doi.org/10.1016/j.molmet.2020.101111
SN  - 2212-8778
VL  - 50
PB  - Elsevier
CY  - Amsterdam
ER  - 
TY  - THES
A1  - Rausch, Theresa
T1  - Role of intestinal bacteria in the conversion of dietary sulfonates
N2  - Over the last decades, interest in the impact of the intestinal microbiota on host health has steadily increased. Diet is a major factor that influences the gut microbiota and thereby indirectly affects human health. For example, a high fat diet rich in saturated fatty acids led to an intestinal proliferation of the colitogenic bacterium Bilophila (B.) wadsworthia by stimulating the release of the bile acid taurocholate (TC). TC contains the sulfonated head group taurine, which undergoes conversion to sulfide (H2S) by B. wadsworthia. In a colitis prone murine animal model (IL10 /  mice), the bloom of B. wadsworthia was accompanied by an exacerbation of intestinal inflammation. B. wadsworthia is able to convert taurine and also other sulfonates to H2S, indicating the potential association of sulfonate utilization and the stimulation of colitogenic bacteria. 
This potential link raised the question, whether dietary sulfonates or their sulfonated metabolites stimulate the growth of colitogenic bacteria such as B. wadsworthia and whether these bacteria convert sulfonates to H2S. Besides taurine, which is present in meat, fish and life-style beverages, other dietary sulfonates are part of daily human nutrition. Sulfolipids such as sulfoquinovosyldiacylglycerols (SQDG) are highly abundant in salad, parsley and the cyanobacterium Arthrospira platensis (Spirulina). Based on previous findings, Escherichia (E.) coli releases the polar headgroup sulfoquinovose (SQ) from SQDG. Moreover, E. coli is able to convert SQ to 2,3 dihydroxypropane 1 sulfonate (DHPS) under anoxic conditions. DHPS is also converted to H2S by B. wadsworthia or by other potentially harmful gut bacteria such as members of the genus Desulfovibrio. However, only few studies report the conversion of sulfonates to H2S by bacteria directly isolated from the human intestinal tract. Most sulfonate utilizing bacteria were obtained from environmental sources such as soil or lake sediment or from potentially intestinal sources such as sewage.
In the present study, fecal slurries from healthy human subjects were incubated with sulfonates under strictly anoxic conditions, using formate and lactate as electron donors. Fecal slurries that converted sulfonates to H2S, were used as a source for the isolation of H2S forming bacteria. Isolates were identified based on their 16S ribosomal RNA (16S rRNA) gene sequence. In addition, conventional C57BL/6 mice were fed a semisynthetic diet supplemented with the SQDG rich Spirulina (SD) or a Spirulina free control diet (CD). During the intervention, body weight, water and food intake were monitored and fecal samples were collected. After three weeks, mice were killed and organ weight and size were measured, intestinal sulfonate concentrations were quantified, gut microbiota composition was determined and parameters of intestinal and hepatic fat metabolism were analyzed. 
Human fecal slurries converted taurine, isethionate, cysteate, 3 sulfolacate, SQ and DHPS to H2S. However, inter individual differences in the degradation of these sulfonates were observed. Taurine, isethionate, and 3 sulfolactate were utilized by fecal microbiota of all donors, while SQ, DHPS and cysteate were converted to H2S only by microbiota from certain individuals. Bacterial isolates from human feces able to convert sulfonates to H2S were identified as taurine-utilizing Desulfovibrio strains, taurine- and isethionate-utilizing B. wadsworthia, or as SQ- and 3-sulfolactate- utilizing E. coli. In addition, a co culture of E. coli and B. wadsworthia led to complete degradation of SQ to H2S, with DHPS as an intermediate. Of the human fecal isolates, B. wadsworthia and Desulfovibrio are potentially harmful. E. coli strains might be also pathogenic, but isolated E. coli strains from human feces were identified as commensal gut bacteria. 
Feeding SD to mice increased the cecal and fecal SQ concentration and altered the microbiota composition, but the relative abundance of SQDG  or SQ converting bacteria and colitogenic bacteria was not enriched in mice fed SD for 21 days. SD did not affect the relative abundance of Enterobacteriaceae, to which the SQDG- and SQ-utilizing E. coli strain belong to. Furthermore, the abundance of B. wadsworthia decreased from day 2 to day 9 in feces, but recovered afterwards in the same mice. In cecum, the family Desulfovibrionaceae, to which B. wadsworthia and Desulfovibrio belong to, were reduced. No changes in the number of B. wadsworthia in cecal contents or of Desulfovibrionaceae in feces were observed. SD led to a mild activation of the immune system, which was not observed in control mice fed CD. Mice fed SD had an increased body weight, a higher adipose tissue weight, and a decreased liver weight compared to the control mice, suggesting an impact of Spirulina supplementation on fat metabolism. However, expression levels of genes involved in intestinal and hepatic intracellular lipid uptake and availability were reduced. Further investigations on the lipid metabolism at protein level could help to clarify these discrepancies.
In summary, humans differ in the ability of their fecal microbiota to utilize dietary sulfonates. While sulfonates stimulated the proliferation of potentially colitogenic isolates from human fecal slurries, the increased availability of SQ in Spirulina fed conventional mice did not lead to an enrichment of such bacteria. Presence or absence of these bacteria may explain the inter individual differences in sulfonate conversion observed for fecal slurries. This work provides new insights in the ability of intestinal bacteria to utilize sulfonates and thus, contributes to a better understanding of microbiota-mediated effects on dietary sulfonate utilization. Interestingly, feeding of the Spirulina-supplemented diet led to body-weight gain in mice in the first two days of intervention, the reasons for which are unknown.
N2  - Die Darmmikrobiota hat auf die menschliche Gesundheit einen großen Einfluss. Nahrungskom-ponente sind die Hauptquelle für bakterielle Substrate und beeinflussen somit das Wachstum von Darmbakterien. In einer Studie mit Mäusen führte z.B. eine Hochfettdiät zu einer erhöhten Freisetzung der Gallensäure Taurocholat (TC), was wiederum zur Anreicherung des kolitogenen Bakteriums Bilophila (B.) wadsworthia führte. In einem Interleukin-10-defizienten Maus-Model für Kolitis, führte eine erhöhte intestinale Verfügbarkeit von TC zu Darmentzündungen und Wachstum von B. wadsworthia. TC enthält den sulfonierten Taurin-Rest, der auch in Nahrungsmitteln wie Fisch und Fleisch enthalten ist, und von B. wadsworthia genutzt und zu Sulfid (H2S) reduziert werden kann. Bisher gibt es jedoch nur wenige Studien, welche die Umwandlung von Sulfonaten in H2S durch Darmbakterien belegen, wobei auch H2S mit Darmentzündungen in Verbindung gebracht wird.

Aus diesen Literaturdaten resultierten die Fragen, ob Sulfonate aus der Nahrung das Wachstum von kolitogenen Bakterien wie B. wadsworthia stimulieren und ob diese Bakterien Sulfonate zu H2S umwandeln können. Weitere Nahrungsmittel-Sulfonate sind die Sulfolipide Sulfoquinovosyldiacylglycerole (SQDG) in Salaten, Petersilie und Spirulina. Escherichia (E.) coli kann Sulfoquinovose (SQ) aus SQDG abspalten und in 2,3-Dihydroxypropan-1-sulfonat (DHPS) umwandeln, welches wiederum von B. wadsworthia oder einem Desulfovibrio-Stamm, einem anderen potenziell kolitogenem Darmbakterium, verwendet und zu H2S reduziert werden kann. 

In der vorliegenden Arbeit wurden Fäzes-Suspensionen von gesunden Menschen unter strikt anoxischen Bedingungen mit Sulfonaten und Formiat und Laktat als Elektronendonoren inkubiert. Aus den Fäzes-Suspensionen wurden H2S-bildende Bakterienstämme isoliert und identifiziert. Zusätzlich wurden konventionelle C57BL/6-Mäuse mit einer semisynthetischen Diät, welche mit SQDG-reicher Spirulina supplementiert war (SD), gefüttert. Während des Versuchs wurde das Körpergewicht der Mäuse, deren Wasser- und Nahrungsaufnahme bestimmt und Fäzesproben gesammelt. Nach drei Wochen wurden die intestinale Sulfonatkonzentration, die Zusammensetzung der Mikrobiota und die Parameter des hepatischen und intestinalen Fettstoffwechsels bestimmt.

Die Ergebnisse zeigten, dass humane Fäzes-Suspensionen Taurin, Isethionat, Cysteat, 3-Sulfolaktat, SQ und DHPS mit interindividuellen Unterschieden zu H2S umwandeln. Als Sulfonat-umsetzende Bakterien wurden Stämme der Gattung Desulfovibrio, B. wadsworthia oder E. coli isoliert, wobei die Desulfovibrio-Stämme Taurin, B. wadsworthia Taurin und Isethionat und E. coli SQ und 3-Sulfolaktat zu H2S reduzieren konnten. Eine Kokultivierung von E. coli und B. wadsworthia zeigte den vollständigen Abbau von SQ über DHPS zu H2S. Die Gabe von SD an Mäuse erhöhte die intestinale SQ-Konzentration und veränderte die Mikrobiota-Zusammensetzung, jedoch war die Zellzahl von SQDG- oder SQ-umwandelnden Bakterien und kolitogenen Bakterien nicht erhöht. Die Zellzahl von B. wadsworthia in denselben Mäusen von Tag 2 bis 9 ab, normalisierte sich danach aber wieder. Im Zäkum war die Familie der Desulfovibrionaceae reduziert, zu welcher B. wadsworthia und Desulfovibrio-Stämme gehören. SD führte zu einer schwachen Aktivierung des Immunsystems und zur Erhöhung des Körpergewichtes. Zusammenfassend lässt sich sagen, dass Darmbakterien in der Lage sind, Sulfonate aus der Nahrung mit interindividuellen Unterschieden zu verwerten. Das Vorkommen von Bakterien könnte diese Unterschiede erklären. Diese Studie ermöglicht es uns, die biologische Rolle der mit der Nahrung aufgenommenen Sulfonate zu verstehen und könnte neue Erkenntnisse über die Fähigkeit der Darmbakterien zur Verwertung von Sulfonaten liefern.
T2  - Die Rolle von Darmbakterien bei der Umsetzung von Nahrungsmittel-Sulfonaten
KW  - microbiology
KW  - Bilophila wadsworthia
KW  - sulfide
KW  - intestinal
KW  - Bilophila wadsworthia
KW  - intestinal
KW  - Mikrobiologie
KW  - Sulfid
KW  - dietary sulfonates
KW  - Nahrungssulfonate
Y1  - 2023
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-574036
ER  - 
TY  - JOUR
A1  - Saberi Hosnijeh, Fatemeh
A1  - Casabonne, Delphine
A1  - Nieters, Alexandra
A1  - Solans, Marta
A1  - Naudin, Sabine
A1  - Ferrari, Pietro
A1  - Mckay, James D.
A1  - Benavente, Yolanda
A1  - Weiderpass, Elisabete
A1  - Freisling, Heinz
A1  - Severi, Gianluca
A1  - Boutron Ruault, Marie-Christine
A1  - Besson, Caroline
A1  - Agnoli, Claudia
A1  - Masala, Giovanna
A1  - Sacerdote, Carlotta
A1  - Tumino, Rosario
A1  - Huerta, Jose Maria
A1  - Amiano, Pilar
A1  - Rodriguez-Barranco, Miguel
A1  - Bonet, Catalina
A1  - Barricarte, Aurelio
A1  - Christakoudi, Sofia
A1  - Knuppel, Anika
A1  - Bueno-de-Mesquita, Bas
A1  - Schulze, Matthias Bernd
A1  - Kaaks, Rudolf
A1  - Canzian, Federico
A1  - Spath, Florentin
A1  - Jerkeman, Mats
A1  - Rylander, Charlotta
A1  - Tjonneland, Anne
A1  - Olsen, Anja
A1  - Borch, Kristin Benjaminsen
A1  - Vermeulen, Roel
T1  - Association between anthropometry and lifestyle factors and risk of B-cell lymphoma
BT  - an exposome-wide analysis
JF  - International journal of cancer
N2  - To better understand the role of individual and lifestyle factors in human disease, an exposome-wide association study was performed to investigate within a single-study anthropometry measures and lifestyle factors previously associated with B-cell lymphoma (BCL). Within the European Prospective Investigation into Cancer and nutrition study, 2402 incident BCL cases were diagnosed from 475 426 participants that were followed-up on average 14 years. Standard and penalized Cox regression models as well as principal component analysis (PCA) were used to evaluate 84 exposures in relation to BCL risk. Standard and penalized Cox regression models showed a positive association between anthropometric measures and BCL and multiple myeloma/plasma cell neoplasm (MM). The penalized Cox models additionally showed the association between several exposures from categories of physical activity, smoking status, medical history, socioeconomic position, diet and BCL and/or the subtypes. PCAs confirmed the individual associations but also showed additional observations. The PC5 including anthropometry, was positively associated with BCL, diffuse large B-cell lymphoma (DLBCL) and MM. There was a significant positive association between consumption of sugar and confectionary (PC11) and follicular lymphoma risk, and an inverse association between fish and shellfish and Vitamin D (PC15) and DLBCL risk. The PC1 including features of the Mediterranean diet and diet with lower inflammatory score showed an inverse association with BCL risk, while the PC7, including dairy, was positively associated with BCL and DLBCL risk. Physical activity (PC10) was positively associated with DLBCL risk among women. This study provided informative insights on the etiology of BCL.
KW  - exposome
KW  - exposome‐ wide association study
KW  - lifestyle
KW  - lymphoma
KW  - prospective study
Y1  - 2020
U6  - https://doi.org/10.1002/ijc.33369
SN  - 0020-7136
SN  - 1097-0215
VL  - 148
IS  - 9
SP  - 2115
EP  - 2128
PB  - Wiley
CY  - Hoboken
ER  - 
TY  - THES
A1  - Drobyshev, Evgenii
T1  - Toxic or beneficial? What is the role of food-relevant selenium species selenoneine?
T1  - Giftig oder nützlich? Welche Rolle spielt die lebensmittelrelevante Selenspezies Selenonein?
N2  - Selenium (Se) is an essential trace element that is ubiquitously present in the environment in small concentrations. Essential functions of Se in the human body are manifested through the wide range of proteins, containing selenocysteine as their active center. Such proteins are called selenoproteins which are found in multiple physiological processes like antioxidative defense and the regulation of thyroid hormone functions. Therefore, Se deficiency is known to cause a broad spectrum of physiological impairments, especially in endemic regions with low Se content. Nevertheless, being an essential trace element, Se could exhibit toxic effects, if its intake exceeds tolerable levels. Accordingly, this range between deficiency and overexposure represents optimal Se supply. However, this range was found to be narrower than for any other essential trace element. Together with significantly varying Se concentrations in soil and the presence of specific bioaccumulation factors, this represents a noticeable difficulty in the assessment of Se
epidemiological status. While Se is acting in the body through multiple selenoproteins, its intake occurs mainly in form of small organic or inorganic molecular mass species. Thus, Se exposure not only depends on daily intake but also on the respective chemical form, in which it is present.
The essential functions of selenium have been known for a long time and its primary forms in different food sources have been described. Nevertheless, analytical capabilities for a comprehensive investigation of Se species and their derivatives have been introduced only in the last decades. A new Se compound was identified in 2010 in the blood and tissues of bluefin tuna. It was called selenoneine (SeN) since it is an isologue of naturally occurring antioxidant ergothioneine (ET), where Se replaces sulfur. In the following years, SeN was identified in a number of edible fish species and attracted attention as a new dietary Se source and potentially strong antioxidant. Studies in populations whose diet largely relies on fish revealed that SeN
represents the main non-protein bound Se pool in their blood. First studies, conducted with enriched fish extracts, already demonstrated the high antioxidative potential of SeN and its possible function in the detoxification of methylmercury in fish. Cell culture studies demonstrated, that SeN can utilize the same transporter as ergothioneine, and SeN metabolite was found in human urine.
Until recently, studies on SeN properties were severely limited due to the lack of ways to obtain the pure compound. As a predisposition to this work was firstly a successful approach to SeN synthesis in the University of Graz, utilizing genetically modified yeasts. In the current study, by use of HepG2 liver carcinoma cells, it was demonstrated, that SeN does not cause toxic effectsup to 100 μM concentration in hepatocytes. Uptake experiments showed that SeN is not bioavailable to the used liver cells.
In the next part a blood-brain barrier (BBB) model, based on capillary endothelial cells from the porcine brain, was used to describe the possible transfer of SeN into the central nervous system (CNS). The assessment of toxicity markers in these endothelial cells and monitoring of barrier conditions during transfer experiments demonstrated the absence of toxic effects from SeN on the BBB endothelium up to 100 μM concentration. Transfer data for SeN showed slow but substantial transfer. A statistically significant increase was observed after 48 hours following SeN incubation from the blood-facing side of the barrier. However, an increase in Se content was clearly visible already after 6 hours of incubation with 1 μM of SeN. While the transfer rate of SeN after application of 0.1 μM dose was very close to that for 1 μM, incubation with 10 μM of SeN resulted in a significantly decreased transfer rate. Double-sided application of SeN caused no side-specific transfer of SeN, thus suggesting a passive diffusion mechanism of SeN across the BBB. This data is in accordance with animal studies, where ET accumulation was observed in the rat brain, even though rat BBB does not have the primary ET transporter – OCTN1. Investigation of capillary endothelial cell monolayers after incubation with SeN and reference selenium compounds showed no significant increase of intracellular selenium concentration. Speciesspecific Se measurements in medium samples from apical and basolateral compartments, as good as in cell lysates, showed no SeN metabolization. Therefore, it can be concluded that SeN may reach the brain without significant transformation.
As the third part of this work, the assessment of SeN antioxidant properties was performed in Caco-2 human colorectal adenocarcinoma cells. Previous studies demonstrated that the intestinal epithelium is able to actively transport SeN from the intestinal lumen to the blood side and accumulate SeN. Further investigation within current work showed a much higher antioxidant potential of SeN compared to ET. The radical scavenging activity after incubation with SeN was close to the one observed for selenite and selenomethionine. However, the SeN effect on the viability of intestinal cells under oxidative conditions was close to the one caused by ET. To answer the question if SeN is able to be used as a dietary Se source and induce the activity of selenoproteins, the activity of glutathione peroxidase (GPx) and the secretion of selenoprotein P (SelenoP) were measured in Caco-2 cells, additionally. As expected, reference selenium compounds selenite and selenomethionine caused efficient induction of GPx activity. In contrast to those SeN had no effect on GPx activity. To examine the possibility of SeN being embedded into the selenoproteome, SelenoP was measured in a culture medium. Even though Caco-2 cells effectively take up SeN in quantities much higher than selenite or selenomethionine, no secretion of SelenoP was observed after SeN incubation.
Summarizing, we can conclude that SeN can hardly serve as a Se source for selenoprotein synthesis. However, SeN exhibit strong antioxidative properties, which appear when sulfur in ET is exchanged by Se. Therefore, SeN is of particular interest for research not as part of Se metabolism, but important endemic dietary antioxidant.
N2  - Selen (Se) ist ein essentielles Spurenelement, das in geringen Konzentrationen ubiquitär in der Umwelt vorkommt. Essentielle Funktionen von Se im menschlichen Körper manifestieren sich in einer Vielzahl von Proteinen, die Selenocystein als aktives Zentrum enthalten. Solche Proteine werden Selenoproteine genannt, die in zahlreichen physiologischen Prozessen wie der antioxidativen Abwehr und der Regulierung der Schilddrüsenhormonfunktionen vorkommen. Daher ist bekannt, dass ein Se-Mangel ein breites Spektrum physiologischer Beeinträchtigungen verursacht, insbesondere in solchen Regionen mit niedrigem Se-Bodengahlten. Dennoch kann Se als essentielles Spurenelement auch toxische Wirkungen entfalten, wenn seine Aufnahme das tolerierbare Maß überschreitet. Dementsprechend stellt dieser Bereich zwischen Mangel und Überbelichtung eine optimale Se-Versorgung dar. Dieser Bereich erwies sich jedoch als enger als bei jedem anderen essentiellen Spurenelement. Zusammen mit stark schwankenden SeKonzentrationen im Boden und dem Vorliegen spezifischer Bioakkumulationsfaktoren stellt dies eine deutliche Schwierigkeit bei der Beurteilung des epidemiologischen Selenstatus dar. Während im Körper mehrere Selenoproteine vorliegen, erfolgt seine Aufnahme hauptsächlich in Form kleiner organischer oder anorganischer Moleküle. Somit hängt die Se-Exposition nicht nur von der täglichen Aufnahme ab, sondern auch von der jeweiligen chemischen Form, in der es vorliegt.
Die essentiellen Funktionen von Selen sind seit langem bekannt und seine Primärformen in verschiedenen Nahrungsquellen dominierenden Formen wurden bereits gut beschrieben. Dennoch wurden erst in den letzten Jahrzehnten neue analytische Möglichkeiten für eine umfassendere Untersuchung von Se-Spezies und ihren Derivaten entwickelt. Beispielsweise wurde 2010 eine neue Se-Verbindung im Blut und im Gewebe von Rotem Thunfisch identifiziert. Es wurde Selenonein (SeN) genannt, da es ein Isolog des natürlich vorkommenden Antioxidans Ergothionein (ET) ist, bei dem Se durch Schwefel ersetzt ist. In den folgenden Jahren wurde SeN in einer Reihe von essbaren Fischarten identifiziert und erregte einerseits als neue Nahrungsquelle für Se und andererseits als potenziell starkes Antioxidans Aufmerksamkeit. Studien an Probanden, deren Ernährung hauptsächlich von Fisch geprägt ist, haben gezeigt, dass SeN den hauptsächlichen nicht-proteingebundenen Se-Pool in ihrem Blut darstellt. Erste Studien mit angereicherten Fischextrakten zeigten bereits das hohe antioxidative Potenzial von SeN und seine mögliche Funktion bei der Entgiftung von Methylquecksilber im Fisch. Zellkulturstudien zeigten, dass SeN den gleichen Transporter wie Ergothionein nutzen kann und ein weiterer SeN-Metabolit wurde im menschlichen Urin gefunden.
Bis vor kurzem waren Studien zu den Eigenschaften von SeN aufgrund fehlender Möglichkeiten, die reine Verbindung zu erwerben, stark eingeschränkt. Als wichtige Grundlage für die vorliegende Arbeit diente zunächst die erfolgreiche Synthese des SeN, welche an der Universität Graz unter Verwendung gentechnisch veränderter Hefen erfolgte. In der aktuellen Studie wurde unter Verwendung von HepG2-Leberkarzinomzellen gezeigt, dass SeN in physiologisch relevanten Konzentrationen keine toxischen Effekte in diesen Hepatozyten induziert. Bioverfügbarkeitsexperimente zeigten, dass SeN für die verwendeten Leberzellen nicht bioverfügbar ist.
Im nächsten Teil wurde ein Modell der Blut-Hirn-Schranke (BHS) verwendet, das auf kapillaren Endothelzellen aus dem Schweinehirn basiert, um den möglichen Transfer von SeN in das zentrale Nervensystem (ZNS) zu untersuchen. Die Bewertung von Toxizitätsmarkern in diesen Endothelzellen und die online Überwachung der Barriere-Bedingungen während der Transferexperimente zeigten, dass bei physiologisch relevanten Konzentrationen keine toxischen Wirkungen von SeN auf das BHS-Endothel auftreten. Daten bezüglich des Übergangs der Selenspezies SeN zeigten zwar eine langsame, jedoch eine nicht zu vernachlässigenden Menge, die die Barriere passieren kann. Die gleichzeitige Inkubation von SeN auf beiden Barriere-Seiten verursachte keinen seitenspezifischen Transfer von SeN, was auf einen passiven Diffusionsmechanismus von SeN über die BHS hindeutet. Diese Daten stimmen mit Tierstudien überein, in denen eine ET-Akkumulation im Rattengehirn beobachtet wurde, obwohl die BHS der Ratte nicht über den primären ET-Transporter – OCTN1 – verfügt. Die Untersuchung von Monolayern aus kapillaren Endothelzellen nach Inkubation mit SeN und Referenzselenverbindungen zeigte keinen signifikanten Anstieg der intrazellulären Selenkonzentration. Speziesspezifische Se-Messungen in Mediumproben aus den apikalen und basolateralen Kompartimenten, sowie in den Zelllysaten zeigten keine SeN-Metabolisierung. Daraus kann geschlossen werden, dass SeN das Gehirn ohne signifikante Transformation erreichen kann.
Als dritter Teil dieser Arbeit wurde die Bewertung der antioxidativen Eigenschaften von SeN in menschlichen Caco-2, also kolorektale Adenokarzinomzellen, durchgeführt. Frühere Studien zeigten, dass das Darmepithel in der Lage ist, SeN aktiv vom Darmlumen zur Blutseite zu transportieren und dort SeN anzureichern. Weitere Untersuchungen im Rahmen der aktuellen Arbeiten zeigten ein viel höheres antioxidatives Potenzial von SeN im Vergleich zu ET. Die Aktivität als Radikalfänger nach Inkubation mit SeN war ähnlich wie bei Selenit und Selenomethionin. Wobei die Wirkung von SeN auf die Lebensfähigkeit von Darmzellen unter oxidativen Bedingungen jedoch ähnlich der durch ET verursachten war. Um die Frage zu beantworten, ob SeN als diätetische Se-Quelle verwendet werden kann um die Aktivität von Selenoproteinen zu induzieren, wurden zusätzlich die Aktivität der Glutathionperoxidase (GPx)
und die Sekretion von Selenoprotein P (SelenoP) in Caco-2-Zellen gemessen. Wie erwartet, bewirkten die Referenz-Selenverbindungen Selenit und Selenomethionin eine effiziente Induktion der GPx-Aktivität, im Gegensatz zu diesen hatte SeN keinen Einfluss auf die GPx-Aktivität. Um die Möglichkeit einer Einbettung von SeN in das Selenoproteom zu untersuchen,
wurde SelenoP im Kulturmedium gemessen. Obwohl Caco-2-Zellen SeN effektiv in viel höherenMengen als Selenit oder Selenomethionin aufnehmen, wurde nach der SeN-Inkubation keine Sekretion von SelenoP beobachtet.
Zusammenfassend können wir schlussfolgern, dass SeN kaum als Se-Quelle für die Selenoproteinsynthese dienen kann. SeN weist jedoch starke antioxidative Eigenschaften auf, die auftreten, wenn Schwefel in ET durch Se ausgetauscht wird. Daher ist SeN von besonderem Interesse für die Forschung, nicht als Teil des Se-Stoffwechsels, sondern als wichtiges endemisches diätetisches Antioxidans.
KW  - selenium
KW  - selenoneine
KW  - HepG2
KW  - Caco-2
KW  - PBCEC
KW  - Caco-2
KW  - HepG2
KW  - PBCEC
KW  - Selen
KW  - Selenonein
Y1  - 2023
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-573794
ER  - 
TY  - JOUR
A1  - Samaha, Doaa
A1  - Hamdo, Housam H.
A1  - Cong, Xiaojing
A1  - Schumacher, Fabian
A1  - Banhart, Sebastian
A1  - Aglar, Öznur
A1  - Möller, Heiko Michael
A1  - Heuer, Dagmar
A1  - Kleuser, Burkhard
A1  - Saied, Essa M.
A1  - Arenz, Christoph
T1  - Liposomal FRET assay identifies potent drug-like inhibitors of the Ceramide Transport Protein (CERT)
JF  - Chemistry - a European journal
N2  - Ceramide transfer protein (CERT) mediates non-vesicular transfer of ceramide from endoplasmic reticulum to Golgi apparatus and thus catalyzes the rate-limiting step of sphingomyelin biosynthesis. Usually, CERT ligands are evaluated in tedious binding assays or non-homogenous transfer assays using radiolabeled ceramides. Herein, a facile and sensitive assay for CERT, based on Forster resonance energy transfer (FRET), is presented. To this end, we mixed donor and acceptor vesicles, each containing a different fluorescent ceramide species. By CERT-mediated transfer of fluorescent ceramide, a FRET system was established, which allows readout in 96-well plate format, despite the high hydrophobicity of the components. Screening of a 2 000 compound library resulted in two new potent CERT inhibitors. One is approved for use in humans and one is approved for use in animals. Evaluation of cellular activity by quantitative mass spectrometry and confocal microscopy showed inhibition of ceramide trafficking and sphingomyelin biosynthesis.
KW  - enzyme assays
KW  - Forster resonance energy transfer (FRET)
KW  - liposomes
KW  - sphingolipids
KW  - transport proteins
Y1  - 2020
U6  - https://doi.org/10.1002/chem.202003283
SN  - 0947-6539
SN  - 1521-3765
VL  - 26
IS  - 70
SP  - 16616
EP  - 16621
PB  - Wiley-VCH
CY  - Weinheim
ER  - 
TY  - THES
A1  - Polemiti, Elli
T1  - Identifying risk of microvascular and macrovascular complications of type 2 diabetes
T1  - Identifizierung des Risikos mikrovaskulärer und makrovaskulärer Komplikationen bei Typ-2-Diabetes
BT  - findings from the European Prospective Investigation into Cancer and Nutrition-Potsdam Study
BT  - Ergebnisse der europäischen prospektiven Krebsforschung und Ernährungs-Potsdamer Studie
N2  - Diabetes is hallmarked by high blood glucose levels, which cause progressive generalised vascular damage, leading to microvascular and macrovascular complications. Diabetes-related complications cause severe and prolonged morbidity and are a major cause of mortality among people with diabetes. Despite increasing attention to risk factors of type 2 diabetes, existing evidence is scarce or inconclusive regarding vascular complications and research investigating both micro- and macrovascular complications is lacking. This thesis aims to contribute to current knowledge by identifying risk factors – mainly related to lifestyle – of vascular complications, addressing methodological limitations of previous literature and providing comparative data between micro- and macrovascular complications.
To address this overall aim, three specific objectives were set. The first was to investigate the effects of diabetes complication burden and lifestyle-related risk factors on the incidence of (further) complications. Studies suggest that diabetes complications are interrelated. However, they have been studied mainly independently of individuals’ complication burden. A five-state time-to-event model was constructed to examine the longitudinal patterns of micro- (kidney disease, neuropathy and retinopathy) and macrovascular complications (myocardial infarction and stroke) and their association with the occurrence of subsequent complications. Applying the same model, the effect of modifiable lifestyle factors, assessed alone and in combination with complication load, on the incidence of diabetes complications was studied. The selected lifestyle factors were body mass index (BMI), waist circumference, smoking status, physical activity, and intake of coffee, red meat, whole grains, and alcohol. Analyses were conducted in a cohort of 1199 participants with incident type 2 diabetes from the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam, who were free of vascular complications at diabetes diagnosis. During a median follow-up time of 11.6 years, 96 cases of macrovascular complications (myocardial infarction and stroke) and 383 microvascular complications (kidney disease, neuropathy and retinopathy) were identified. In multivariable-adjusted models, the occurrence of a microvascular complication was associated with a higher incidence of further micro- (Hazard ratio [HR] 1.90; 95% Confidence interval [CI] 0.90, 3.98) and macrovascular complications (HR 4.72; 95% CI 1.25, 17.68), compared with persons without a complication burden. In addition, participants who developed a macrovascular event had a twofold higher risk of future microvascular complications (HR 2.26; 95% CI 1.05, 4.86). The models were adjusted for age, sex, state duration, education, lifestyle, glucose-lowering medication, and pre-existing conditions of hypertension and dyslipidaemia. Smoking was positively associated with macrovascular disease, while an inverse association was observed with higher coffee intake. Whole grain and alcohol intake were inversely associated with microvascular complications, and a U-shaped association was observed for red meat intake. BMI and waist circumference were positively associated with microvascular events. The associations between lifestyle factors and incidence of complications were not modified by concurrent complication burden, except for red meat intake and smoking status, where the associations were attenuated among individuals with a previous complication.
The second objective was to perform an in-depth investigation of the association between BMI and BMI change and risk of micro- and macrovascular complications. There is an ongoing debate on the association between obesity and risk of macrovascular and microvascular outcomes in type 2 diabetes, with studies suggesting a protective effect among people with overweight or obesity. These findings, however, might be limited due to suboptimal control for smoking, pre-existing chronic disease, or short-follow-up. After additional exclusion of persons with cancer history at diabetes onset, the associations between pre-diagnosis BMI and relative annual change between pre- and post-diagnosis BMI and incidence of complications were evaluated in multivariable-adjusted Cox models. The analyses were adjusted for age, sex, education, smoking status and duration, physical activity, alcohol consumption, adherence to the Mediterranean diet, and family history of diabetes and cardiovascular disease (CVD). Among 1083 EPIC-Potsdam participants, 85 macrovascular and 347 microvascular complications were identified during a median follow-up period of 10.8 years. Higher pre-diagnosis BMI was associated with an increased risk of total microvascular complications (HR per 5 kg/m2 1.21; 95% CI 1.07, 1.36), kidney disease (HR 1.39; 95% CI 1.21, 1.60) and neuropathy (HR 1.12; 95% CI 0.96, 1.31); but no association was observed for macrovascular complications (HR 1.05; 95% CI 0.81, 1.36). Effect modification was not evident by sex, smoking status, or age groups. In analyses according to BMI change categories, BMI loss of more than 1% indicated a decreased risk of total microvascular complications (HR 0.62; 95% CI 0.47, 0.80), kidney disease (HR 0.57; 95% CI 0.40, 0.81) and neuropathy (HR 0.73; 95% CI 0.52, 1.03), compared with participants with a stable BMI. No clear association was observed for macrovascular complications (HR 1.04; 95% CI 0.62, 1.74). The impact of BMI gain on diabetes-related vascular disease was less evident. Associations were consistent across strata of age, sex, pre-diagnosis BMI, or medication but appeared stronger among never-smokers than current or former smokers.
The last objective was to evaluate whether individuals with a high-risk profile for diabetes and cardiovascular disease (CVD) also have a greater risk of complications. Within the EPIC-Potsdam study, two accurate prognostic tools were developed, the German Diabetes Risk Score (GDRS) and the CVD Risk Score (CVDRS), which predict the 5-year type 2 diabetes risk and 10-year CVD risk, respectively. Both scores provide a non-clinical and clinical version. Components of the risk scores include age, sex, waist circumference, prevalence of hypertension, family history of diabetes or CVD, lifestyle factors, and clinical factors (only in clinical versions). The association of the risk scores with diabetes complications and their discriminatory performance for complications were assessed. In crude Cox models, both versions of GDRS and CVDRS were positively associated with macrovascular complications and total microvascular complications, kidney disease and neuropathy. Higher GDRS was also associated with an elevated risk of retinopathy. The discrimination of the scores (clinical and non-clinical) was poor for all complications, with the C-index ranging from 0.58 to 0.66 for macrovascular complications and from 0.60 to 0.62 for microvascular complications.
In conclusion, this work illustrates that the risk of complication development among individuals with type 2 diabetes is related to the existing complication load, and attention should be given to regular monitoring for future complications. It underlines the importance of weight management and adherence to healthy lifestyle behaviours, including high intake of whole grains, moderation in red meat and alcohol consumption and avoidance of smoking to prevent major diabetes-associated complications, regardless of complication burden. Risk scores predictive for type 2 diabetes and CVD were related to elevated risks of complications. By optimising several lifestyle and clinical factors, the risk score can be improved and may assist in lowering complication risk.
N2  - Diabetes ist durch einen hohen Blutzuckerspiegel gekennzeichnet, der eine fortschreitende allgemeine Gefäßschädigung verursacht, die zu mikro- und makrovaskulären Komplikationen führt. Diabetesbedingte Komplikationen verursachen eine schwere und langanhaltende Morbidität und sind eine der Hauptursachen für die Mortalität von Menschen mit Diabetes. Trotz der zunehmenden Aufmerksamkeit der Erforschung der Risikofaktoren des Typ-2-Diabetes, ist die vorhandene Studienlage in Bezug auf vaskuläre Komplikationen nicht ein-deutig und nicht ausreichend. Diese Arbeit soll zum aktuellen Wissensstand beitragen, indem sie Risikofaktoren – hauptsächlich lebensstilbedingte Faktoren – für vaskuläre Komplikationen identifiziert, methodische Schwächen bisheriger Studien adressiert und vergleichende Daten zwischen mikro- und makrovaskulären Komplikationen liefert.
Um dieses übergeordnete Ziel zu erreichen, wurden drei spezifische Ziele gesetzt. Das erste war die Untersuchung des Einflusses der Diabetes-Komplikationslast und lebensstilbezogener Risikofaktoren auf das Auftreten weiterer Komplikationen. Studien legen nahe, dass Diabeteskomplikationen in Wechselbeziehung zueinanderstehen. Allerdings wurden sie bisher hauptsächlich unabhängig von der individuellen Komplikationslast untersucht. Es wurde daher ein fünfstufiges Time-to-Event-Modell konstruiert, um die longitudinalen Muster von mikro- und makrovaskulären Komplikationen und deren Zusammenhang mit dem Auftreten von Folgekomplikationen zu untersuchen. Unter Anwendung desselben Modells wurde die Auswirkung modifizierbarer Lebensstilfaktoren, die allein und in Kombination mit der Komplikationslast untersucht wurden, auf das Auftreten von Diabeteskomplikatio-nen untersucht. Die ausgewählten Risikofaktoren waren der Body-Mass-Index (BMI), der Taillenumfang, der Raucherstatus, die körperliche Aktivität und der Konsum von Kaffee, rotem Fleisch, Vollkornprodukten und Alkohol. Die Analysen wurden in einer Kohorte von 1199 Teilnehmern mit neu diagnostiziertem Typ-2-Diabetes aus der European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam durchgeführt, die zum Zeitpunkt der Diabetesdiagnose frei von vaskulären Komplikationen waren. Während einer Nachbeobachtungszeit von 11,6 Jahren wurden 96 Fälle mit makrovaskulären Komplikati-onen (Myokardinfarkt und Schlaganfall) und 383 Fälle mit mikrovaskulären Komplikationen (Nierenerkrankungen, Neuropathie und Retinopathie) identifiziert.
Das Auftreten einer mikrovaskulären Komplikation war mit einer höheren Inzidenz weiterer mikrovaskulärer Ereignisse (Hazard Ratio [HR] 1,90; 95% Konfidenzintervall [CI] 0,90, 3,98) und makrovaskulärer Komplikationen (HR 4,72; 95% CI 1,25, 17,68) assoziiert, verglichen mit Personen ohne Komplikationen. Darüber hinaus hatten Teilnehmende, die ein makrovaskuläres Ereignis entwickelten, ein doppelt so hohes Risiko für mikrovaskuläre Komplikationen (HR 2,26; 95% CI 1,05, 4,86). Die Modelle wurden für Alter, Geschlecht, Komplikationsdauer, Bildung, Lebensstil, glukosesenkende Medikamente und Vorerkrankungen wie Bluthochdruck und Dyslipidämie adjustiert. Rauchen war posi-tiv mit makrovaskulären Erkrankungen assoziiert, während eine inverse Assoziation für einen höheren Kaffeekonsum beobachtet wurde. Vollkorn- und Alkoholkonsum waren invers mit mikrovaskulären Komplikationen assoziiert, und eine U-förmige Assoziation wurde für den Konsum von rotem Fleisch beobachtet. BMI und Taillenumfang waren positiv mit mikrovaskulären Ereignissen assoziiert. Die Zusammenhänge zwischen Lebensstilfaktoren und Komplikationen wurden durch gleichzeitige Komplikationsbelastung nicht verändert, mit Ausnahme für den Verzehr von rotem Fleisch und dem Raucherstatus, dort waren die Assoziationen bei Personen mit Komplikationen abgeschwächt.
Das zweite Ziel war die Untersuchung des Zusammenhangs zwischen BMI und BMI-Änderung und dem Risiko für mikro- und makrovaskuläre Komplikationen. Es gibt eine anhaltende Debatte über den Zusammenhang zwischen Adipositas und dem Risiko für makrovaskuläre und mikrovaskuläre Folgeerkrankungen bei Typ-2-Diabetes, bei der einige Studien einen protektiven Zusammenhang bei Menschen mit Übergewicht oder Adipositas nahelegen. Diese Ergebnisse könnten auf methodische Schwächen zurückzuführen sein, einschließlich einer suboptimalen Adjustierung für Rauchen, bestehende chronische Erkrankungen und eine kurze Nachbeobachtungszeit. Nach zusätzlichem Ausschluss von Personen mit einer bestehenden Krebserkrankung zu Diabetesbeginn, wurden die Zusam-menhänge zwischen BMI vor der Diagnose und die relative jährliche Veränderung zwischen BMI vor und nach der Diagnose hinsichtlich der Inzidenz von Komplikationen in Cox-Modellen ausgewertet. Die Analysen wurden für Alter, Geschlecht, Bildung, Raucherstatus und -dauer, körperliche Aktivität, Alkoholkonsum, Einhaltung der mediterranen Ernährung und Familienanamnese von Diabetes und kardiovaskulären Erkrankungen (CVD) adjustiert. Unter den 1083 Teilnehmern wurden 85 makrovaskuläre und 347 mikrovaskuläre Komplikationen während einer Nachbeobachtungszeit von 10,8 Jahren identifiziert. Ein höherer BMI vor der Diagnose war mit einem erhöhten Risiko für mikrovaskuläre Komplikationen insgesamt (HR pro 5 kg/m2 1,21; 95% CI 1,07, 1,36), Nierenerkrankungen (HR 1,39; 95% CI 1,21, 1,60) und Neuropathie (HR 1,12; 95% CI 0,96, 1,31) assozi-iert; für makrovaskuläre Komplikationen wurde jedoch kein Zusammenhang beobachtet (HR 1,05; 95% CI 0,81, 1,36). Analysen nach BMI-Kategorien bestätigten diese Ergebnisse. Es gab keine Hinweise für Effektmodifikation mit Geschlecht, Raucherstatus oder Alter. In den Analysen für BMI-Änderung zeigte sich, dass eine BMI-Abnahme von mehr als 1 % mit einem verringerten Risiko für mikrovaskuläre Komplikationen (HR 0,62; 95% CI 0,47, 0,80), Nierenerkrankungen (HR 0,57; 95% CI 0,40, 0,81) und Neuropathie (HR 0,73; 95% CI 0,52, 1,03) verbunden war, verglichen mit Teilnehmern mit einem stabilen BMI. Für makrovaskuläre Komplikationen wurde kein eindeutiger Zusammenhang beobachtet (HR 1,04; 95% CI 0,62, 1,74). Die Assoziationen waren in den Strata nach Alter, Ge-schlecht, BMI vor der Diagnose oder Medikation hinweg konsistent, schienen aber bei lebenslangen Nichtrauchern stärker zu sein als bei Rauchern oder ehemaligen Rauchern.
Das letzte Ziel war es zu untersuchen, ob Personen mit einem Hochrisikoprofil für Di-abetes und CVD auch ein höheres Risiko für Komplikationen haben. Im Rahmen der EPIC-Potsdam-Studie wurden zwei präzise Prognoseinstrumente entwickelt, der German Diabetes Risk Score (GDRS) und der CVD Risk Score (CVDRS), die das 5-Jahres-Risiko für Typ-2-Diabetes bzw. das 10-Jahres-Risiko für CVD vorhersagen. Beide Scores sind als nicht-klinische und klinische Version verfügbar. Zu den Komponenten der Risikoscores gehören Alter, Geschlecht, Taillenumfang, Prävalenz von Bluthochdruck, familiäre Krankheitsvorgeschichte (Diabetes oder CVD), modifizierbare Lebensstilfaktoren und klinische Parameter (nur in den klinischen Versionen). Die Assoziation der Risikoscores mit Diabeteskomplikationen und ihre Diskriminierungsfähigkeit für Komplikationen wurden bewertet. In unadjustierten Cox-Modellen waren beide Versionen (GDRS und CVDRS) positiv mit makrovaskulären Komplikationen und insgesamt mit mikrovaskulären Komplikatio-nen, Nierenerkrankungen und Neuropathie in Personen mit Typ-2-Diabetes assoziiert. Ein höherer GDRS war auch mit einem erhöhten Risiko für eine Retinopathie assoziiert. Die Diskriminierung der Scores (klinisch und nicht-klinisch) war für alle Komplikationen gering, wobei der C-Index für makrovaskuläre Komplikationen von 0,58 bis 0,66 und für mikrovaskuläre Komplikationen von 0,60 bis 0,62 reichte.
Zusammenfassend zeigt diese Arbeit, dass das Risiko für die Entwicklung von Komplikati-onen bei Personen mit Typ-2-Diabetes mit der bestehenden Komplikationslast zusammenhängt und dass eine regelmäßige Überwachung von zukünftigen Komplikationen wichtig ist. Sie unterstreicht die Bedeutung des Gewichtsmanagements und der Einhaltung gesunder Lebensgewohnheiten, einschließlich eines hohen Verzehrs von Vollkornprodukten, eines moderaten Konsums von rotem Fleisch und Alkohol, sowie des Verzichts auf das Rauchen, um schwere diabetesassoziierte Komplikationen, unabhängig von der Komplikationslast, zu verhindern. Die Risiko-Scores für Typ-2-Diabetes und Herz-Kreislauf-Erkrankungen waren mit einem erhöhten Komplikations-Risiko assoziiert. Durch die Optimierung des Lebens-stils und der klinischen Faktoren kann der Risikoscore verbessert werden, was das Auftreten von diabetesassoziierten Komplikationen verringern könnte.
KW  - type 2 diabetes
KW  - microvascular complications
KW  - macrovascular complications
KW  - nephropathy
KW  - neuropathy
KW  - retinopathy
KW  - CVD
KW  - myocardial infarction
KW  - stroke
KW  - lifestyle
KW  - diet
KW  - obesity
KW  - BMI
KW  - weight loss
KW  - risk scores
KW  - coffee
KW  - whole grains
KW  - physical activity
KW  - red meat
KW  - smoking
KW  - alcohol intake
KW  - Body-Mass-Index
KW  - Herzkreislauferkrankungen
KW  - Alkoholkonsum
KW  - Kaffee
KW  - Diät
KW  - Lebensstil
KW  - makrovaskuläre Komplikationen
KW  - mikrovaskuläre Komplikationen
KW  - Herzinfarkt
KW  - Nephropathie
KW  - Neuropathie
KW  - Adipositas
KW  - körperliche Aktivität
KW  - rotes Fleisch
KW  - Retinopathie
KW  - Risikobewertungen
KW  - Rauchen
KW  - Schlaganfall
KW  - Typ 2 Diabetes
KW  - Gewichtsverlust
KW  - Vollkorn
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-571038
ER  - 
TY  - GEN
A1  - Schäfer, Marjänn Helena
A1  - Kakularam, Kumar Reddy
A1  - Reisch, Florian
A1  - Rothe, Michael
A1  - Stehling, Sabine
A1  - Heydeck, Dagmar
A1  - Püschel, Gerhard Paul
A1  - Kuhn, Hartmut
T1  - Male Knock-in Mice Expressing an Arachidonic Acid Lipoxygenase 15B (Alox15B) with Humanized Reaction Specificity Are Prematurely Growth Arrested When Aging
T2  - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe
N2  - Mammalian arachidonic acid lipoxygenases (ALOXs) have been implicated in cell differentiation and in the pathogenesis of inflammation. The mouse genome involves seven functional Alox genes and the encoded enzymes share a high degree of amino acid conservation with their human orthologs. There are, however, functional differences between mouse and human ALOX orthologs. Human ALOX15B oxygenates arachidonic acid exclusively to its 15-hydroperoxy derivative (15S-HpETE), whereas 8S-HpETE is dominantly formed by mouse Alox15b. The structural basis for this functional difference has been explored and in vitro mutagenesis humanized the reaction specificity of the mouse enzyme. To explore whether this mutagenesis strategy may also humanize the reaction specificity of mouse Alox15b in vivo, we created Alox15b knock-in mice expressing the arachidonic acid 15-lipoxygenating Tyr603Asp+His604Val double mutant instead of the 8-lipoxygenating wildtype enzyme. These mice are fertile, display slightly modified plasma oxylipidomes and develop normally up to an age of 24 weeks. At later developmental stages, male Alox15b-KI mice gain significantly less body weight than outbred wildtype controls, but this effect was not observed for female individuals. To explore the possible reasons for the observed gender-specific growth arrest, we determined the basic hematological parameters and found that aged male Alox15b-KI mice exhibited significantly attenuated red blood cell parameters (erythrocyte counts, hematocrit, hemoglobin). Here again, these differences were not observed in female individuals. These data suggest that humanization of the reaction specificity of mouse Alox15b impairs the functionality of the hematopoietic system in males, which is paralleled by a premature growth arrest.
T3  - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 1295 
KW  - eicosanoids
KW  - lipid peroxidation
KW  - oxidative stress
KW  - polyenoic fatty acids
KW  - erythropoiesis
Y1  - 2023
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-576491
SN  - 1866-8372
IS  - 1295
ER  - 
TY  - JOUR
A1  - Schäfer, Marjänn Helena
A1  - Kakularam, Kumar Reddy
A1  - Reisch, Florian
A1  - Rothe, Michael
A1  - Stehling, Sabine
A1  - Heydeck, Dagmar
A1  - Püschel, Gerhard Paul
A1  - Kuhn, Hartmut
T1  - Male Knock-in Mice Expressing an Arachidonic Acid Lipoxygenase 15B (Alox15B) with Humanized Reaction Specificity Are Prematurely Growth Arrested When Aging
JF  - Biomedicines
N2  - Mammalian arachidonic acid lipoxygenases (ALOXs) have been implicated in cell differentiation and in the pathogenesis of inflammation. The mouse genome involves seven functional Alox genes and the encoded enzymes share a high degree of amino acid conservation with their human orthologs. There are, however, functional differences between mouse and human ALOX orthologs. Human ALOX15B oxygenates arachidonic acid exclusively to its 15-hydroperoxy derivative (15S-HpETE), whereas 8S-HpETE is dominantly formed by mouse Alox15b. The structural basis for this functional difference has been explored and in vitro mutagenesis humanized the reaction specificity of the mouse enzyme. To explore whether this mutagenesis strategy may also humanize the reaction specificity of mouse Alox15b in vivo, we created Alox15b knock-in mice expressing the arachidonic acid 15-lipoxygenating Tyr603Asp+His604Val double mutant instead of the 8-lipoxygenating wildtype enzyme. These mice are fertile, display slightly modified plasma oxylipidomes and develop normally up to an age of 24 weeks. At later developmental stages, male Alox15b-KI mice gain significantly less body weight than outbred wildtype controls, but this effect was not observed for female individuals. To explore the possible reasons for the observed gender-specific growth arrest, we determined the basic hematological parameters and found that aged male Alox15b-KI mice exhibited significantly attenuated red blood cell parameters (erythrocyte counts, hematocrit, hemoglobin). Here again, these differences were not observed in female individuals. These data suggest that humanization of the reaction specificity of mouse Alox15b impairs the functionality of the hematopoietic system in males, which is paralleled by a premature growth arrest.
KW  - eicosanoids
KW  - lipid peroxidation
KW  - oxidative stress
KW  - polyenoic fatty acids
KW  - erythropoiesis
Y1  - 2022
U6  - https://doi.org/10.3390/biomedicines10061379
SN  - 2227-9059
VL  - 10
SP  - 1
EP  - 22
PB  - MDPI
CY  - Basel, Schweiz
ET  - 6
ER  - 
TY  - JOUR
A1  - Christakoudi, Sofia
A1  - Pagoni, Panagiota
A1  - Ferrari, Pietro
A1  - Cross, Amanda J.
A1  - Tzoulaki, Ioanna
A1  - Muller, David C.
A1  - Weiderpass, Elisabete
A1  - Freisling, Heinz
A1  - Murphy, Neil
A1  - Dossus, Laure
A1  - Turzanski Fortner, Renee
A1  - Agudo, Antonio
A1  - Overvad, Kim
A1  - Perez-Cornago, Aurora
A1  - Key, Timothy J.
A1  - Brennan, Paul
A1  - Johansson, Mattias
A1  - Tjonneland, Anne
A1  - Halkjaer, Jytte
A1  - Boutron-Ruault, Marie-Christine
A1  - Artaud, Fanny
A1  - Severi, Gianluca
A1  - Kaaks, Rudolf
A1  - Schulze, Matthias Bernd
A1  - Bergmann, Manuela M.
A1  - Masala, Giovanna
A1  - Grioni, Sara
A1  - Simeon, Vittorio
A1  - Tumino, Rosario
A1  - Sacerdote, Carlotta
A1  - Skeie, Guri
A1  - Rylander, Charlotta
A1  - Borch, Kristin Benjaminsen
A1  - Quiros, J. Ramon
A1  - Rodriguez-Barranco, Miguel
A1  - Chirlaque, Maria-Dolores
A1  - Ardanaz, Eva
A1  - Amiano, Pilar
A1  - Drake, Isabel
A1  - Stocks, Tanja
A1  - Häggström, Christel
A1  - Harlid, Sophia
A1  - Ellingjord-Dale, Merete
A1  - Riboli, Elio
A1  - Tsilidis, Konstantinos K.
T1  - Weight change in middle adulthood and risk of cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort
JF  - International journal of cancer
N2  - Obesity is a risk factor for several major cancers. Associations of weight change in middle adulthood with cancer risk, however, are less clear. We examined the association of change in weight and body mass index (BMI) category during middle adulthood with 42 cancers, using multivariable Cox proportional hazards models in the European Prospective Investigation into Cancer and Nutrition cohort. Of 241 323 participants (31% men), 20% lost and 32% gained weight (>0.4 to 5.0 kg/year) during 6.9 years (average). During 8.0 years of follow-up after the second weight assessment, 20 960 incident cancers were ascertained. Independent of baseline BMI, weight gain (per one kg/year increment) was positively associated with cancer of the corpus uteri (hazard ratio [HR] = 1.14; 95% confidence interval: 1.05-1.23). Compared to stable weight (+/- 0.4 kg/year), weight gain (>0.4 to 5.0 kg/year) was positively associated with cancers of the gallbladder and bile ducts (HR = 1.41; 1.01-1.96), postmenopausal breast (HR = 1.08; 1.00-1.16) and thyroid (HR = 1.40; 1.04-1.90). Compared to maintaining normal weight, maintaining overweight or obese BMI (World Health Organisation categories) was positively associated with most obesity-related cancers. Compared to maintaining the baseline BMI category, weight gain to a higher BMI category was positively associated with cancers of the postmenopausal breast (HR = 1.19; 1.06-1.33), ovary (HR = 1.40; 1.04-1.91), corpus uteri (HR = 1.42; 1.06-1.91), kidney (HR = 1.80; 1.20-2.68) and pancreas in men (HR = 1.81; 1.11-2.95). Losing weight to a lower BMI category, however, was inversely associated with cancers of the corpus uteri (HR = 0.40; 0.23-0.69) and colon (HR = 0.69; 0.52-0.92). Our findings support avoiding weight gain and encouraging weight loss in middle adulthood.
KW  - BMI change
KW  - cancer
KW  - middle adulthood
KW  - weight gain
KW  - weight loss
Y1  - 2020
U6  - https://doi.org/10.1002/ijc.33339
SN  - 0020-7136
SN  - 1097-0215
VL  - 148
IS  - 7
SP  - 1637
EP  - 1651
PB  - Wiley
CY  - Hoboken
ER  - 
TY  - JOUR
A1  - Reichetzeder, Christoph
T1  - Overweight and obesity in pregnancy
BT  - their impact on epigenetics
JF  - European journal of clinical nutrition
N2  - Over the last few decades, the prevalence of obesity has risen to epidemic proportions worldwide. Consequently, the number of obesity in pregnancy has risen drastically. Gestational overweight and obesity are associated with impaired outcomes for mother and child. Furthermore, studies show that maternal obesity can lead to long-term consequences in the offspring, increasing the risk for obesity and cardiometabolic disease in later life. In addition to genetic mechanisms, mounting evidence demonstrates the induction of epigenetic alterations by maternal obesity, which can affect the offspring's phenotype, thereby influencing the later risk of obesity and cardiometabolic disease. Clear evidence in this regard comes from various animal models of maternal obesity. Evidence derived from clinical studies remains limited. The current article gives an overview of pathophysiological changes associated with maternal obesity and their consequences on placental structure and function. Furthermore, a short excurse is given on epigenetic mechanisms and emerging data regarding a putative interaction between metabolism and epigenetics. Finally, a summary of important findings of animal and clinical studies investigating maternal obesity-related epigenetic effects is presented also addressing current limitations of clinical studies.
Y1  - 2021
U6  - https://doi.org/10.1038/s41430-021-00905-6
SN  - 0954-3007
SN  - 1476-5640
VL  - 75
IS  - 12
SP  - 1710
EP  - 1722
PB  - Springer Nature
CY  - London
ER  - 
TY  - JOUR
A1  - Shahid, Muhammad
A1  - Manchi, G.
A1  - Slunsky, Pavel
A1  - Naseer, O.
A1  - Fatima, A.
A1  - Leo, B.
A1  - Raila, Jens
T1  - A systemic review of existing serological possibilities to diagnose canine osteoarthritis with a particular focus on extracellular matrix proteoglycans and protein
JF  - Polish journal of veterinary sciences : PJVS : the journal of Committee of Veterinary Sciences of Polish Academy of Sciences and University of Warmia and Mazury in Olsztyn
N2  - Extra-cellular matrix (ECM) components are important and their stabilization is significant in maintaining normal healthy joint environment. In osteoarthritis (OA), ECM components are altered and indicate disease progression. The joint ECM is composed of proteoglycans (aggrecan, perlecan,inter α-trypsin inhibitor), glycoproteins (fibronectin, lubricin, COMP) and collagen types (most abundantly collagen type II) which represent structural and functional transformation during disease advancement. ECM investigation revealed significant biomarkers of OA that could be used as a diagnostic and therapeutic tool in different canine orthopedic diseases. This review deliberates our current findings of how the components of ECM change at the molecular level during disease progression in canine OA.
KW  - extra-cellular matrix
KW  - canine osteoarthritis
KW  - biomarker
KW  - synovial fluid
KW  - proteomix analysis
Y1  - 2017
U6  - https://doi.org/10.1515/pjvs-2017-0024
SN  - 1505-1773
SN  - 2300-2557
VL  - 20
IS  - 1
SP  - 189
EP  - 201
PB  - De Gruyter
CY  - Berlin
ER  - 
TY  - GEN
A1  - Püschel, Gerhard Paul
A1  - Klauder, Julia
A1  - Henkel-Oberländer, Janin
T1  - Macrophages, Low-Grade Inflammation, Insulin Resistance and Hyperinsulinemia: A Mutual Ambiguous Relationship in the Development of Metabolic Diseases
T2  - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe
N2  - Metabolic derangement with poor glycemic control accompanying overweight and obesity is associated with chronic low-grade inflammation and hyperinsulinemia. Macrophages, which present a very heterogeneous population of cells, play a key role in the maintenance of normal tissue homeostasis, but functional alterations in the resident macrophage pool as well as newly recruited monocyte-derived macrophages are important drivers in the development of low-grade inflammation. While metabolic dysfunction, insulin resistance and tissue damage may trigger or advance pro-inflammatory responses in macrophages, the inflammation itself contributes to the development of insulin resistance and the resulting hyperinsulinemia. Macrophages express insulin receptors whose downstream signaling networks share a number of knots with the signaling pathways of pattern recognition and cytokine receptors, which shape macrophage polarity. The shared knots allow insulin to enhance or attenuate both pro-inflammatory and anti-inflammatory macrophage responses. This supposedly physiological function may be impaired by hyperinsulinemia or insulin resistance in macrophages. This review discusses the mutual ambiguous relationship of low-grade inflammation, insulin resistance, hyperinsulinemia and the insulin-dependent modulation of macrophage activity with a focus on adipose tissue and liver.
T3  - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 1279 
KW  - NAFLD/MAFLD
KW  - type 2 diabetes
KW  - obesity
KW  - vicious cycle
KW  - TLR signaling
KW  - M1/M2 differentiation
KW  - Akt pathway
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-570106
SN  - 1866-8372
IS  - 1279
SP  - 1
EP  - 30
ER  - 
TY  - JOUR
A1  - Püschel, Gerhard
A1  - Klauder, Julia
A1  - Henkel-Oberländer, Janin
T1  - Macrophages, low-grade inflammation, insulin resistance and hyperinsulinemia
BT  - A mutual ambiguous relationship in the development of metabolic diseases
JF  - Journal of Clinical Medicine : open access journal
N2  - Metabolic derangement with poor glycemic control accompanying overweight and obesity is associated with chronic low-grade inflammation and hyperinsulinemia. Macrophages, which present a very heterogeneous population of cells, play a key role in the maintenance of normal tissue homeostasis, but functional alterations in the resident macrophage pool as well as newly recruited monocyte-derived macrophages are important drivers in the development of low-grade inflammation. While metabolic dysfunction, insulin resistance and tissue damage may trigger or advance pro-inflammatory responses in macrophages, the inflammation itself contributes to the development of insulin resistance and the resulting hyperinsulinemia. Macrophages express insulin receptors whose downstream signaling networks share a number of knots with the signaling pathways of pattern recognition and cytokine receptors, which shape macrophage polarity. The shared knots allow insulin to enhance or attenuate both pro-inflammatory and anti-inflammatory macrophage responses. This supposedly physiological function may be impaired by hyperinsulinemia or insulin resistance in macrophages. This review discusses the mutual ambiguous relationship of low-grade inflammation, insulin resistance, hyperinsulinemia and the insulin-dependent modulation of macrophage activity with a focus on adipose tissue and liver.
KW  - NAFLD/MAFLD
KW  - type 2 diabetes
KW  - obesity
KW  - vicious cycle
KW  - TLR signaling
KW  - M1/M2 differentiation
KW  - Akt pathway
Y1  - 2022
U6  - https://doi.org/10.3390/jcm11154358
SN  - 2077-0383
VL  - 11
IS  - 15
SP  - 1
EP  - 30
PB  - MDPI
CY  - Basel, Schweiz
ER  - 
TY  - THES
A1  - Buczkowski, Agnes Johanna
T1  - Vergleichende Untersuchungen von Schlüsselkomponenten aus Dämpfen der E-Zigarette
T1  - Comparative studies of key components from e-cigarette vapours
N2  - Respiratorische Erkrankungen stellen zunehmend eine relevante globale Problematik dar. Die Erweiterung bzw. Modifizierung von Applikationswegen möglicher Arzneimittel für gezielte topische Anwendungen ist dabei von größter Bedeutung. Die Variation eines bekannten Applikationsweges durch unterschiedliche technologische Umsetzungen kann die Vielfalt der Anwendungsmöglichkeiten, aber auch die Patienten-Compliance erhöhen. Die einfache und flexible Verfahrensweise durch schnelle Verfügbarkeit und eine handliche Technologie sind heutzutage wichtige Eigenschaften im Entwicklungsprozess eines Produktes. Eine direkte topische Behandlung von Atemwegserkrankungen am Wirkort in Form einer inhalativen Applikation bietet dabei viele Vorteile gegenüber einer systemischen Therapie. Die medizinische Inhalation von Wirkstoffen über die Lunge ist jedoch eine komplexe Herausforderung. Inhalatoren gehören zu den erklärungsbedürftigen Applikationsformen, die zur Erhöhung der konsequenten Einhaltung der Verordnung so einfach, wie möglich gestaltet werden müssen. Parallel besitzen und nutzen weltweit annähernd 68 Millionen Menschen die Technologie eines inhalativen Applikators zur bewussten Schädigung ihrer Gesundheit in Form einer elektronischen Zigarette. Diese bekannte Anwendung bietet die potentielle Möglichkeit einer verfügbaren, kostengünstigen und qualitätsgeprüften Gesundheitsmaßnahme zur Kontrolle, Prävention und Heilung von Atemwegserkrankungen. Sie erzeugt ein Aerosol durch elektrothermische Erwärmung eines sogenannten Liquids, das durch Kapillarkräfte eines Trägermaterials an ein Heizelement gelangt und verdampft. Ihr Bekanntheitsgrad zeigt, dass eine beabsichtigte Wirkung in den Atemwegen eintritt. Diese Wirkung könnte jedoch auch auf potentielle pharmazeutische Einsatzgebiete übertragbar sein. Die Vorteile der pulmonalen Verabreichung sind dabei vielfältig. Im Vergleich zur peroralen Applikation gelangt der Wirkstoff gezielt zum Wirkort. Wenn eine systemische Applikation zu Arzneimittelkonzentrationen unterhalb der therapeutischen Wirksamkeit in der Lunge führt, könnte eine inhalative Darreichung bereits bei niedriger Dosierung die gewünschten höheren Konzentrationen am Wirkort hervorrufen. Aufgrund der großen Resorptionsfläche der Lunge sind eine höhere Bioverfügbarkeit und ein schnellerer Wirkungseintritt infolge des fehlenden First-Pass-Effektes möglich. Es kommt ebenfalls zu minimalen systemischen Nebenwirkungen. Die elektronische Zigarette erzeugt wie die medizinischen Inhalatoren lungengängige Partikel. Die atemzuggesteuerte Technik ermöglicht eine unkomplizierte und intuitive Anwendung. Der prinzipielle Aufbau besteht aus einer elektrisch beheizten Wendel und einem Akku. Die Heizwendel ist von einem sogenannten Liquid in einem Tank umgeben und erzeugt das Aerosol. Das Liquid beinhaltet eine Basismischung bestehend aus Propylenglycol, Glycerin und reinem Wasser in unterschiedlichen prozentualen Anteilen. Es besteht die Annahme, dass das Basisliquid auch mit pharmazeutischen Wirkstoffen für die pulmonale Applikation beladen werden kann. Aufgrund der thermischen Belastung durch die e-Zigarette müssen potentielle Wirkstoffe sowie das Vehikel eine thermische Stabilität aufweisen. 
Die potentielle medizinische Anwendung der Technologie einer handelsüblichen e-Zigarette wurde anhand von drei Schwerpunkten an vier Wirkstoffen untersucht. Die drei ätherischen Öle Eucalyptusöl, Minzöl und Nelkenöl wurden aufgrund ihrer leichten Flüchtigkeit und der historischen pharmazeutischen Anwendung anhand von Inhalationen bei Erkältungssymptomen bzw. im zahnmedizinischen Bereich gewählt. Das eingesetzte Cannabinoid Cannabidiol (CBD) hat einen aktuellen Bezug zu dem pharmazeutischen Markt Deutschlands zur Legalisierung von cannabishaltigen Produkten und der medizinischen Forschung zum inhalativen Konsum. Es wurden relevante wirkstoffhaltige Flüssigformulierungen entwickelt und hinsichtlich ihrer Verdampfbarkeit zu Aerosolen bewertet. In den quantitativen und qualitativen chromatographischen Untersuchungen konnten spezifische Verdampfungsprofile der Wirkstoffe erfasst und bewertet werden. Dabei stieg die verdampfte Masse der Leitsubstanzen 1,8-Cineol (Eucalyptusöl), Menthol (Minzöl) und Eugenol (Nelkenöl) zwischen 33,6 µg und 156,2 µg pro Zug proportional zur Konzentration im Liquid im Bereich zwischen 0,5% und 1,5% bei einer Leistung von 20 Watt. Die Freisetzungsrate von Cannabidiol hingegen schien unabhängig von der Konzentration im Liquid im Mittelwert bei 13,3 µg pro Zug zu liegen. Dieses konnte an fünf CBD-haltigen Liquids im Konzentrationsbereich zwischen 31 µg/g und 5120 µg/g Liquid gezeigt werden. Außerdem konnte eine Steigerung der verdampften Massen mit Zunahme der Leistung der e-Zigarette festgestellt werden. Die Interaktion der Liquids bzw. Aerosole mit den Bestandteilen des Speichels sowie weiterer gastrointestinaler Flüssigkeiten wurde über die Anwendung von zugehörigen in vitro Modellen und Einsatz von Enzymaktivitäts-Assays geprüft. In den Untersuchungen wurden Änderungen von Enzymaktivitäten anhand des oralen Schlüsselenzyms α-Amylase sowie von Proteasen ermittelt. Damit sollte exemplarisch ein möglicher Einfluss auf physiologische bzw. metabolische Prozesse im humanen Organismus geprüft werden. Das Bedampfen von biologischen Suspensionen führte bei niedriger Leistung der e-Zigarette (20 Watt) zu keiner bzw. einer leichten Änderung der Enzymaktivität. Die Anwendung einer hohen Leistung (80 Watt) bewirkte tendenziell das Herabsetzen der Enzymaktivitäten. Die Erhöhung der Enzymaktivitäten könnte zu einem enzymatischen Abbau von Schleimstoffen wie Mucinen führen, was wiederum die effektive, mechanische Abwehr gegenüber bakteriellen Infektionen zur Folge hätte. Da eine Anwendung der Applikation insbesondere bei bakteriellen Atemwegserkrankungen denkbar wäre, folgten abschließend Untersuchungen der antibakteriellen Eigenschaften der Liquids bzw. Aerosole in vitro. Es wurden sechs klinisch relevante bakterielle Krankheitserreger ausgewählt, die nach zwei Charakteristika gruppiert werden können. Die drei multiresistenten Bakterien Pseudomonas aeruginosa, Klebsiella pneumoniae und Methicillin-resistenter Staphylococcus aureus können mithilfe von üblichen Therapien mit Antibiotika nicht abgetötet werden und haben vor allem eine nosokomiale Relevanz. Die zweite Gruppe weist Eigenschaften auf, die vordergründig assoziiert sind mit respiratorischen Erkrankungen. Die Bakterien Streptococcus pneumoniae, Moraxella catarrhalis und Haemophilus influenzae sind repräsentativ beteiligt an Atemwegserkrankungen mit diverser Symptomatik. Die Bakterienarten wurden mit den jeweiligen Liquids behandelt bzw. bedampft und deren grundlegende Dosis-Wirkungsbeziehung charakterisiert. Dabei konnte eine antibakterielle Aktivität der Formulierungen ermittelt werden, die durch Zugabe eines Wirkstoffes die bereits antibakterielle Wirkung der Bestandteile Glycerin und Propylenglycol verstärkte. Die hygroskopischen Eigenschaften dieser Substanzen sind vermutlich für eine Wirkung in aerosolierter Form verantwortlich. Sie entziehen die Feuchtigkeit aus der Luft und haben einen austrocknenden Effekt auf die Bakterien. Das Bedampfen der Bakterienarten Streptococcus pneumoniae, Moraxella catarrhalis und Haemophilus influenzae hatte einen antibakteriellen Effekt, der zeitlich abhängig von der Leistung der e-Zigarette war. 
Die Ergebnisse der Untersuchungen führen zu dem Schluss, dass jeder Wirkstoff bzw. jede Substanzklasse individuell zu bewerten ist und somit Inhalator und Formulierung aufeinander abgestimmt werden müssen. Der Einsatz der e-Zigarette als Medizinprodukt zur Applikation von Arzneimitteln setzt stets Prüfungen nach Europäischem Arzneibuch voraus. Durch Modifizierungen könnte eine Dosierung gut kontrollierbar gemacht werden, aber auch die Partikelgrößenverteilung kann insoweit reguliert werden, dass die Wirkstoffe je nach Partikelgröße zu einem geeigneten Applikationsort wie Mund, Rachen oder Bronchien transportiert werden. Der Vergleich mit den Eigenschaften anderer medizinischer Inhalatoren führt zu dem Schluss, dass die Technologie der e-Zigarette durchaus eine gleichartige oder bessere Performance für thermisch stabile Wirkstoffe bieten könnte. Dieses fiktive Medizinprodukt könnte aus einer hersteller-unspezifisch produzierten, wieder aufladbaren Energiequelle mit Universalgewinde zum mehrfachen Gebrauch und einer hersteller- und wirkstoffspezifisch produzierten Einheit aus Verdampfer und Arzneimittel bestehen. Das Arzneimittel, ein medizinisches Liquid (Vehikel und Wirkstoff) kann in dem Tank des Verdampfers mit konstanten, nicht variablen Parametern patientenindividuell produziert werden. Inhalative Anwendungen werden perspektivisch wohl nicht zuletzt aufgrund der aktuellen COVID-19-Pandemie eine zunehmende Rolle spielen. Der Bedarf nach alternativen Therapieoptionen wird weiter ansteigen. Diese Arbeit liefert einen Beitrag zum Einsatz der Technologie der elektronischen Zigarette als electronic nicotin delivery system (ENDS) nach Modifizierung zu einem potentiellen pulmonalen Applikationssystem als electronic drug delivery system (EDDS) von inhalativen, thermisch stabilen Arzneimitteln in Form eines Medizinproduktes.
N2  - Respiratory diseases increasingly represent a globally relevant problem. The extension or modification of application routes of possible drugs for targeted topical applications is thereby of utmost importance. The variation of a known application route through different technological implementations can increase the diversity of application possibilities, but also patient compliance. Simple and flexible procedures through rapid availability and a convenient technology are nowadays important characteristics in the development process of a product. Direct topical treatment of respiratory diseases at the site of action in form of inhaled application offers many advantages over systemic therapy. However, medical inhalation of active substances via lung is a complex challenge. Inhalers are one of the forms of application that require explanation and must be made as simple as possible to increase consistent adherence to the prescription. In parallel, approximately 68 million people worldwide own and use the technology of an inhaler to deliberately harm their health in form of an electronic cigarette. This well-known application offers the potential possibility of an available, cost-effective and quality-assured health measure to control, prevent and cure respiratory diseases. It produces an aerosol by electro-thermal heating of a so-called liquid, which reaches a heating element through capillary forces of a carrier material and vaporizes. Its popularity indicates that an intended effect occurs in the respiratory tract. However, this effect could also be transferable to potential pharmaceutical applications. The advantages of pulmonary administration are manifold. Compared to peroral application, the active ingredient reaches the site of action in a targeted manner. If systemic application results to drug concentrations below the therapeutic efficacy in the lung, inhalation could produce the desired higher concentrations at the site of action even at low doses. Due to the large absorption surface of the lungs, a higher bioavailability and a faster onset of action is possible as a result of the lack of first-pass effect. There are also minimal systemic side effects. Like medical inhalers, the electronic cigarette produces respirable particles. The breath-controlled technology enables uncomplicated and intuitive use. The basic construction consists of an electrically heated coil and a rechargeable battery. The heating coil is surrounded by a so-called liquid in a tank and generates the aerosol. The liquid contains a base mixture consisting of propylene glycol, glycerine and pure water in varying percentages. It is assumed that the base liquid can also be loaded with active pharmaceutical ingredients for pulmonary application. Due to thermal load of the e-cigarette, potential active ingredients as well as vehicles must exhibit thermal stability. 
The potential medical application of the technology of a commercially available e-cigarette was investigated on the basis of three focal investigations for four active ingredients. The three essential oils eucalyptus oil, mint oil and clove oil were chosen due to their light volatility and the historical pharmaceutical application based on inhalations for cold symptoms or in the dental field, respectively. The choice of the cannabinoid cannabidiol (CBD) used is currently related to the pharmaceutical market situation in Germany while considering the legalization of cannabis-containing products and medical research on inhaled consumption. Relevant liquid formulations containing active ingredients were developed and evaluated with regard to their evaporability to aerosols. In quantitative and qualitative chromatographic investigations, specific vaporization profiles of the active substances were recorded and evaluated. The evaporated mass of analytical markers 1,8-cineole (eucalyptus oil), menthol (mint oil) and eugenol (clove oil) increased between 33.6 µg and 156.2 µg per puff proportional to the concentration in liquids in the range between 0.5% and 1.5% at a power application of 20 watts. The release rate of cannabidiol, on the other hand, appeared to average 13.3 µg per puff regardless of the concentration in the liquid. This was demonstrated on five CBD-containing liquids in the concentration range between 31 µg/g and 5120 µg/g liquid. In addition, an increased vaporized mass with increased power of e-cigarette could be observed. The interaction of the liquids or aerosols with the components of saliva and other gastrointestinal fluids was tested by application of associated in vitro models and the use of enzyme activity assays. In the studies, changes in enzyme activities were determined using the key oral enzyme α-amylase as well as proteases. The aim was to test a possible influence on physiological or metabolic processes in the human organism as an example. Treatment of biological suspensions with aerosol resulted in no or a slight change in enzyme activity at low power of e-cigarette (20 watts). The application of high power (80 watts) tended to decrease enzyme activities. The increase in enzyme activities could lead to enzymatic degradation of mucins, which in turn could reduce effective mechanical defense against bacterial infections. Since an application would be conceivable in particular for bacterial respiratory diseases, concluding investigations of the antibacterial properties of the liquids or aerosols in vitro followed. Six clinically relevant bacterial pathogens were selected, which can be grouped according to two characteristics. The three multi-resistant bacteria Pseudomonas aeruginosa, Klebsiella pneumoniae and methicillin-resistant Staphylococcus aureus cannot be killed by standard antibiotic therapies and are primarily of nosocomial relevance. The second group exhibits characteristics that are mainly associated with respiratory diseases. The bacteria Streptococcus pneumoniae, Moraxella catarrhalis and Haemophilus influenzae are representatively involved in respiratory diseases with diverse symptoms. These bacterial species were treated with the respective liquids or aerosols and their basic dose-response relationship was characterized. Antibacterial activity of formulations could be determined, which enhanced the already antimicrobial effect of the vehicle components glycerine and propylene glycol by addition of active pharmaceutical ingredients. The hygroscopic properties of these substances are probably responsible for an effect in aerosolized form. They remove moisture from air and have a desiccating effect on bacteria. The treatment of bacterial species Streptococcus pneumoniae, Moraxella catarrhalis and Haemophilus influenzae with aerosol had an antibacterial effect that was time-dependent on the applied power of e-cigarette. 
The results of investigations lead to the conclusion that each active pharmaceutical ingredient or substance class must be evaluated individually and thus inhaler and formulation must be matched to each other. The use of e-cigarette as a medical device for the application of medicinal products would definitely requires tests according to the European Pharmacopoeia. Modifications could make a dosage well controllable, but also the particle size distribution can be regulated to the extent that the active ingredients are transported to a suitable application site such as mouth, throat or bronchi depending on the particle size. The comparison with properties of other medical inhalers leads to the conclusion that the technology of e-cigarette could well offer similar or better performance for thermally stable active ingredients. This fictitious medical device could consist of a manufacturer-unspecifically produced, rechargeable energy source with a universal thread for multiple use and a manufacturer- and active substance-specifically produced unit consisting of vaporizer and personalized drug content. The drug, a medical liquid (vehicle and active ingredient) can be produced in the tank of the vaporizer with constant, non-variable parameters specific to the patient. Inhaled applications will probably play an increasing role in the future, not least because of the current
COVID-19 pandemic. The need for alternative therapeutic options will continue to increase. This work provides a contribution to the use of electronic nicotine delivery system (ENDS) after modification to a potential pulmonary application system as an electronic drug delivery system (EDDS) of inhaled, thermally stable drugs in form of a medical device.
KW  - e-Zigarette
KW  - Medizinprodukt
KW  - inhalative Applikation
KW  - ätherische Öle
KW  - Cannabidiol (CBD)
KW  - Atemwegserkrankungen
KW  - antibakterielles Aerosol
KW  - e-cigarette
KW  - electronic nicotin delivery system (ENDS)
KW  - electronic drug delivery system (EDDS)
KW  - essential oils
KW  - cannabidiol (CBD)
KW  - respiratory diseases
KW  - antibacterial aerosol
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-565617
ER  - 
TY  - THES
A1  - Geisendörfer, Birte
T1  - Autologer Ansatz zur Entwicklung von 2D- und 3D-Kokultivierungsmethoden für die Bestimmung des sensibilisierenden Potenzials von Xenobiotika
N2  - Die allergische Kontaktdermatitis ist eine immunologisch bedingte Hauterkrankung mit insbesondere in den westlichen Industrienationen hoher und weiter ansteigender Prävalenz. Es handelt sich hierbei um eine Hypersensitivitätsreaktion vom Typ IV, die sich nach Allergenkontakt durch Juckreiz, Rötung, Bläschenbildung und Abschälung der Haut äußert. Zahlreiche Xenobiotika besitzen das Potenzial, Kontaktallergien auszulösen, darunter Konservierungsstoffe, Medikamente, Duftstoffe und Chemikalien. Die wirksamste Maßnahme zur Eindämmung der Erkrankung ist die Expositionsprophylaxe, also die Vermeidung des Kontakts mit den entsprechenden Substanzen. Dies wiederum setzt die Kenntnis des jeweiligen sensibilisierenden Potenzials einer Substanz voraus, dessen Bestimmung aus diesem Grund eine hohe toxikologische Relevanz besitzt. Zu diesem Zweck existieren von der OECD veröffentlichte Testleitlinien, welche auf entsprechend validierten Testmethoden basieren. Goldstandard bei der Prüfung auf hautsensibilisierendes Potenzial war über lange Zeit der murine Lokale Lymphknotentest. Seit der 7. Änderung der EU-Kosmetikrichtlinie, welche Tierversuche für Kosmetika und deren Inhaltsstoffe untersagt, wurden vermehrt Alternativmethoden in die OECD-Testleitlinien implementiert.. Die bestehenden in vitro Methoden sind jedoch alleinstehend nur begrenzt aussagekräftig, da sie lediglich singuläre Mechanismen bei der Entstehung einer Kontaktallergie abbilden. Die Entwicklung von Testmethoden, welche mehrere dieser Schlüsselereignisse berücksichtigen, erscheint daher richtungsweisend. Einen vielversprechenden Ansatz liefert hierbei der Loose-fit coculture-based sensitisation assay (LCSA), welcher eine Kokultur aus primären Keratinozyten und PBMC darstellt. Bei der Kokultivierung von Immunzellen mit anderen Zelltypen stellt sich allerdings die Frage, inwiefern die Nutzung von Zellen derselben Spender*innen (autologe Kokultur) bzw. verschiedener Spender*innen (allogene Kokultur) einen Einfluss nimmt. Zu diesem Zweck wurden im Rahmen dieser Arbeit Hautzellen spenderspezifisch aus gezupften Haarfollikeln isoliert und der LCSA mit den generierten HFDK in autologen und allogenen Ansätzen verglichen. Zusätzlich wurde auch ein Vergleich zwischen der Nutzung von HFDK und NHK, welche aus humaner Vorhaut isoliert wurden, im LCSA durchgeführt. Dabei ergaben sich keine signifikanten Unterschiede zwischen autologen und allogenen Kokulturen bzw. zwischen der Verwendung von HFDK und NHK. Die Verwendung allogener Zellen aus anonymem Spendermaterial sowie die Nutzung von Keratinozyten aus unterschiedlichen Quellen scheint im Rahmen des LCSA problemlos möglich. Einige der getesteten Kontaktallergene, darunter DNCB und NiCl2, erwiesen sich im LCSA jedoch als problematisch und konnten nicht zufriedenstellend als sensibilisierend detektiert werden. Daher wurde eine Optimierung der Kokultur durch Verwendung ex vivo differenzierter Langerhans Zellen (MoLC) angestrebt, welche ein besseres Modell primärer epidermaler Langerhans Zellen darstellen als die dendritischen Zellen aus dem LCSA. Zusätzlich wurden weitere, den Erfolg der Kokultur beeinflussende Faktoren, wie die Art und Zusammensetzung des Mediums und die Kokultivierungsdauer, untersucht und angepasst. Das schlussendlich etablierte Kokultivierungsprotokoll führte zu einer maßgeblich verstärkten Expression von CD207 (Langerin) auf den MoLC, was auf eine wirkungsvolle Interaktion zwischen Haut- und Immunzellen in der Kokultur hindeutete. Des Weiteren konnten DNCB und NiCl2 im Gegensatz zum LCSA durch Verwendung des kostimulatorischen Moleküls CD86 sowie des Reifungsmarkers CD83 als Ausleseparameter eindeutig als Kontaktallergene identifiziert werden. Die Untersuchungen zur Kokultur von MoLC und HFDK wurden jeweils vergleichend in autologen und allogenen Ansätzen durchgeführt. Ähnlich wie beim LCSA kam es aber auch hier zu keinen signifikanten Unterschieden, weder hinsichtlich der Expression von Charakterisierungs- und Aktivierungsmarkern auf MoLC noch hinsichtlich der Zytokinsekretion in den Zellkulturüberstand. Die Hinweise aus zahlreichen Studien im Mausmodell, dass Zellen des angeborenen Immunsystems zur Erkennung von und Aktivierung durch allogene Zellen bzw. Gewebe in der Lage sind, bestätigten sich im Rahmen dieser Arbeit dementsprechend nicht. Aus diesem Grund wurden abschließend CD4+ T-Lymphozyten, die Effektorzellen des adaptiven Immunsystems, in die Kokultur aus MoLC und autologen bzw. allogenen HFDK integriert. Überraschenderweise traten auch hier keine verstärkten Aktivierungen in allogener Kokultur im Vergleich zur autologen Kokultur auf. Die Nutzung autologer Primärzellen scheint im Rahmen der hier getesteten Methoden nicht notwendig zu sein, was die Validierung von Kokulturen und deren Implementierung in die OECD-Testleitlinien erleichtern dürfte. Zuletzt wurde eine Kokultivierung primärer Haut- und Immunzellen auch im 3D-Vollhautmodell durchgeführt, wobei autologe MoLC in die Epidermisäquivalente entsprechender Modelle integriert werden sollten. Obwohl die erstellten Hautmodelle unter Verwendung autologer Haarfollikel-generierter Keratinozyten und Fibroblasten eine zufriedenstellende Differenzierung und Stratifizierung aufwiesen, gestaltete sich die Inkorporation der MoLC als problematisch und konnte im Rahmen dieser Arbeit nicht erreicht werden.
KW  - Kontaktallergie
KW  - Langerhans Zellen
KW  - Alternativmethoden
KW  - Kokultur
KW  - Hautmodell
Y1  - 2022
ER  - 
TY  - JOUR
A1  - Wilhelmi, Ilka
A1  - Grunwald, Stephan
A1  - Gimber, Niclas
A1  - Popp, Oliver
A1  - Dittmar, Gunnar
A1  - Arumughan, Anup
A1  - Wanker, Erich E.
A1  - Laeger, Thomas
A1  - Schmoranzer, Jan
A1  - Daumke, Oliver
A1  - Schürmann, Annette
T1  - The ARFRP1-dependent Golgi scaffolding protein GOPC is required for insulin secretion from pancreatic 13-cells
JF  - Molecular metabolism
N2  - Objective: Hormone secretion from metabolically active tissues, such as pancreatic islets, is governed by specific and highly regulated signaling pathways. Defects in insulin secretion are among the major causes of diabetes. The molecular mechanisms underlying regulated insulin secretion are, however, not yet completely understood. In this work, we studied the role of the GTPase ARFRP1 on insulin secretion from pancreatic 13-cells. <br /> Methods: A 13-cell-specific Arfrp1 knockout mouse was phenotypically characterized. Pulldown experiments and mass spectrometry analysis were employed to screen for new ARFRP1-interacting proteins. Co-immunoprecipitation assays as well as super-resolution microscopy were applied for validation. <br /> Results: The GTPase ARFRP1 interacts with the Golgi-associated PDZ and coiled-coil motif-containing protein (GOPC). Both proteins are co localized at the trans-Golgi network and regulate the first and second phase of insulin secretion by controlling the plasma membrane localization of the SNARE protein SNAP25. Downregulation of both GOPC and ARFRP1 in Min6 cells interferes with the plasma membrane localization of SNAP25 and enhances its degradation, thereby impairing glucose-stimulated insulin release from 13-cells. In turn, overexpression of SNAP25 as well as GOPC restores insulin secretion in islets from 13-cell-specific Arfrp1 knockout mice. <br /> Conclusion: Our results identify a hitherto unrecognized pathway required for insulin secretion at the level of trans-Golgi sorting. (c) 2020 The Authors. Published by Elsevier GmbH. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
KW  - Insulin secretion
KW  - Endosomal sorting
KW  - SNARE proteins
KW  - trans-Golgi
KW  - network
Y1  - 2020
U6  - https://doi.org/10.1016/j.molmet.2020.101151
SN  - 2212-8778
VL  - 45
PB  - Elsevier
CY  - Amsterdam
ER  - 
TY  - THES
A1  - Wetzel, Alexandra
T1  - Epigenetische Regulation des Epstein-Barr Virus-induzierten Gens 3 (EBI3) und dessen Bedeutung bei Colitis ulcerosa
N2  - Epigenetische Mechanismen spielen eine entscheidende Rolle bei der Pathogenese von Colitis ulcerosa (CU). Ihr Einfluss auf das beobachtete Ungleichgewicht zwischen pro- und anti-inflammatorischen Cytokinen ist hingegen weitgehend unerforscht. Einige der wichtigsten immunmodulatorischen Cytokine sind die Mitglieder der heterodimeren Interleukin- (IL-) 12-Familie, die durch das Kombinieren einer der drei α-Ketten (IL-12p35, IL-27p28, IL-23p19) mit den ß-Untereinheiten IL-12p40 oder EBI3 (Epstein-Barr Virus-induziertes Gen 3) charakterisiert sind. IL-35 (IL-12p35/EBI3) spielt eine bedeutende anti-inflammatorische Rolle bei verschiedenen Erkrankungen, wohingegen seine Level bei chronischen Entzündungen erniedrigt sind. Eine mögliche Ursache könnte eine transkriptionelle Stilllegung über epigenetische Modifikationen sein. Tatsächlich konnte durch die Stimulation mit dem DNA-Methyltransferase-Inhibitor (DNMTi) Decitabin (DAC; Dacogen®) eine Induktion von EBI3 in humanen Epithelzellen aus gesundem Colon (HCEC) erreicht werden, die als Modell für ein lokales Entzündungsgeschehen dienten. Diese Regulation über DNA-Methylierung konnte in weiteren humanen Zellen unterschiedlichen Ursprungs sowie durch Stimulation von HCEC-Zellen mit zwei weiteren DNMTi, dem Cytosin-Analogon Azacytidin (AZA; Vidaza®) und dem natürlich vorkommenden, epigenetisch wirksamen Polyphenol Epigallocatechingallat (EGCG), verifiziert werden. Die kombinierte Inkubation mit Tumor-Nekrose-Faktor α (TNFα) resultierte jeweils in einer über-additiven Induktion von EBI3. 
Weiterführende Untersuchungen zeigten, dass TNFα trotz Beeinflussung der epigenetischen DNMT- und Ten-eleven Translocation- (TET-) Enzyme keinen Einfluss auf die globalen Methylierungs- oder Hydroxymethylierungslevel hatte, jedoch eine genspezifische DNA-Hypomethylierung im EBI3-Promotor induzierte. Durch Nutzung verschiedener Inhibitoren konnte darüber hinaus nachgewiesen werden, dass der beobachtete synergistische Effekt der gemeinsamen DAC und TNFα-Stimulation hauptsächlich über NFκB (Nuclear factor “kappa-light-chain-enhancer” of activated B-cells) vermittelt wird. Ein Teil verläuft dabei über p38 MAPK (mitogen-activated protein kinases), während die JNK- (c-Jun N-terminale Kinasen-) und ERK- (extracellular-signal-regulated kinases) Signalwege keine Rolle spielen. 
In der vorliegenden Arbeit wurde zudem gezeigt, dass die DNA-Hypomethylierung während eines entzündlichen Zustandes auch in einer erhöhten EBI3-Proteinexpression resultiert. Die Höhe der immunologisch detektierten Banden wies auf eine Dimerbildung sowohl im Zelllysat als auch im Überstand hin. Humane Colonepithelzellen sind demnach in der Lage, Cytokine zu bilden und zu sezernieren, was die Bedeutung von Nicht-Immunzellen bei der lokalen Immunantwort unterstreicht. Mittels Genexpressionsanalysen wurden IL-12p35 und IL-23p19 als mögliche Bindungspartner identifiziert. Aufgrund kreuzreaktiver Antikörper ist ein direkter Nachweis der EBI3-Dimere derzeit nicht möglich. Die stattdessen genutzte Kombination verschiedener Methoden dient als geeigneter Ersatz für die problematischen Antikörper-basierten Analysen wie Immunpräzipitation oder ELISA. Durch molekularbiologische, immunologische und massenspektrometrische Methoden konnte IL-35 identifiziert werden, während IL-39 (IL-23p19/EBI3) nicht detektiert wurde. Dies ist in Einklang mit den Erkenntnissen mehrerer Forschungsgruppen, die eine Bildung des nativen humanen Dimers aus IL-23p19 und EBI3 bezweifeln. Des Weiteren wurde die biologische Aktivität des behandlungsinduzierten IL 35-Proteins durch einen Funktionsassay nachgewiesen.
Neben einer DNMTi-bedingten transkriptionellen Aktivierung konnte eine Regulation von EBI3 über Histonacetylierungen gezeigt werden. Der EBI3-induzierende Effekt des Histondeacetylasen-Inhibitors (HDACi) Trichostatin A (TSA) wurde durch SAHA (suberoylanilide hydroxamic acid (Vorinostat; Zolinza®)) verifiziert. Ähnlich zu der Stimulation mit den hypomethylierenden Substanzen wurde ein synergistischer Effekt bei paralleler Inkubation mit TNFα beobachtet, der in einer gesteigerten Bildung des EBI3-Proteins resultierte.
Um die Befunde in einem komplexeren in vivo-Modell zu untersuchen, wurde eine chronische Colitis in Ebi3-defizienten Mäusen und dem dazugehörigen Wildtypstamm C57BL/6 durch zyklische Applikation von Natriumdextransulfat (Dextran sodium sulfate (DSS)) induziert. Der Vergleich klinischer Parameter wie Mortalitätsrate und Körper- sowie Milzgewicht wies bei Abwesenheit von Ebi3 signifikant stärkere colitische Symptome auf. Dies bestätigte die zentrale Rolle von Ebi3 in der Colitisentwicklung und deutete auf eine bevorzugte Bildung des anti-inflammatorisch wirkenden IL-35 statt des pro-inflammatorischen IL-39 in den Wildtyptieren hin. Durch zusätzliche therapeutische Behandlung der C57BL/6-Mäuse nach der DSS-Gabe konnte die in der Literatur beschriebene positive Wirkung von SAHA auf die Colitismanifestation bestätigt werden. Im Gegensatz dazu war der HDACi in den Ebi3-defizienten Tieren nicht in der Lage, die colitischen Parameter zu verbessern beziehungsweise verschlimmerte den Krankheitsphänotyp. Expressionsanalysen von Up- und Downstream-Target-Genen lieferten weitere Hinweise darauf, dass bei Anwesenheit von Ebi3 IL-35 statt IL-39 gebildet wird, was in Einklang mit den in vitro-Untersuchungen steht.
Die vorliegende Arbeit konnte durch den Vergleich der C57BL/6-Mäuse mit den Ebi3-defizienten Tieren neue Erkenntnisse über die Wirkungsweise von SAHA erbringen. Histonacetylierende Bedingungen verbessern colitische Symptome über einen Mechanismus, der die epigenetische Induktion von Ebi3 mit nachfolgender IL-35-Bildung involviert. Durch Kooperation der epigenetischen Mechanismen Hypomethylierung und Histonacetylierung wurde der stärkste Effekt auf die EBI3-Induktion bewirkt. 

Insgesamt konnte in der vorliegenden Arbeit durch in vitro- und in vivo-Analysen die epigenetische und NFκB-vermittelte Induktion von EBI3 über DNA-Demethylierung und Histonacetylierung mit nachfolgender IL-35-Bildung und –Sezernierung nachgewiesen werden. Da IL-35 in der Lage ist, colitische Symptome zu mildern, stellt die epigenetische Reaktivierbarkeit von EBI3 durch DNMTi und HDACi eine vielversprechende Alternative für die derzeit genutzten, oft nicht oder nur kurzfristig wirksamen Therapien bei der Behandlung einer CU dar. Einer übermäßigen Immunantwort während schubweiser entzündlicher Phasen könnte entgegengewirkt und Komplikationen wie die Bildung Colitis-assoziierter Karzinome verhindert werden.
N2  - Aberrant epigenetic alterations are becoming increasingly relevant in the development of multiple diseases. Epigenetic mechanisms also play a crucial role in the pathogenesis of ulcerative colitis (CU). In contrast, their influence on the observed imbalance between pro- and anti-inflammatory cytokines is largely unexplored. Several of the most important immunomodulatory cytokines are the members of the heterodimeric interleukin- (IL-) 12 family, which are characterized by combining one of the three α-chains (IL-12p35, IL-27p28, IL-23p19) with the ß-subunits IL-12p40 or EBI3 (Epstein-Barr virus induced gene 3). IL-35 (IL-12p35/EBI3) plays a significant anti-inflammatory role in various diseases, while its levels are decreased in chronic inflammation. One possible reason could be transcriptional silencing via epigenetic modifications. Indeed, stimulation with the DNA methyltransferase inhibitor (DNMTi) decitabine (DAC; Dacogen®) resulted in reactivation of EBI3 in Human Colon Epithelial Cells (HCEC) generated from healthy tissue, which served as a model for a local inflammatory process. This regulation via DNA methylation could be verified in other human cells of different origin as well as by stimulating HCEC cells with two additional DNMTi, the cytosine analog azacytidine (AZA; Vidaza®) and the naturally occurring, epigenetically active polyphenol epigallocatechin gallate (EGCG). Combined incubation with tumor necrosis factor α (TNFα) resulted in synergistic induction of EBI3. 
Further studies showed that TNFα had no effect on global methylation or hydroxymethylation levels despite its influence on epigenetic DNMT and ten-eleven translocation (TET) enzymes, but induced gene-specific DNA hypomethylation in the EBI3 promoter. Moreover, by using several inhibitors, it has been demonstrated that the synergistic effect of DAC and TNFα stimulation is mediated mainly via NFκB (nuclear factor "kappa-light-chain-enhancer" of activated B-cells). Part of this occurs via p38 MAPK (mitogen-activated protein kinases), while the JNK (c-Jun N-terminal kinases) and ERK (extracellular-signal-regulated kinases) signaling pathways are not involved.
In the present work, it was also shown that DNA hypomethylation during an inflammatory condition also results in increased EBI3 protein expression. The level of immunologically detected bands indicated dimer formation in both cell lysate and supernatant. Human epithelial cells are therefore capable of producing and secreting cytokines, underlining the importance of non-immune cells in the local immune response. Gene expression analyses identified IL-12p35 and IL-23p19 as possible binding partners. Due to cross-reactive antibodies, direct detection of EBI3 dimers is currently not possible. The combination of different methods used instead serves as a suitable alternative to the problematic antibody-based analyses such as immunoprecipitation or ELISA. Molecular biology, immunology, and mass spectrometry methods identified IL-35, whereas IL-39 (IL-23p19/EBI3) was not detected. This is in agreement with the findings of several research groups that doubt formation of the native human dimer. Furthermore, the biological activity of treatment-induced IL-35 protein was detected by a functional assay. 
In addition to DNMTi-induced reactivation, regulation of EBI3 via histone acetylation was demonstrated. The EBI3-inducing effect of the histone deacetylase inhibitor (HDACi) trichostatin A (TSA) was verified by SAHA (suberoylanilide hydroxamic acid (Vorinostat; Zolinza®)). Similar to stimulation with the hypomethylating agents, a synergistic effect was observed with parallel incubation with TNFα, resulting in increased EBI3 protein formation.
To investigate the effects in a more complex in vivo model, chronic colitis was induced in Ebi3-deficient mice and the corresponding wild-type strain C57BL/6 by cyclic application of dextran sodium sulfate (DSS). Comparison of clinical parameters such as mortality rate and body as well as spleen weight showed significantly more severe colitic symptoms in the absence of Ebi3. This confirmed the central role of Ebi3 in colitis development and indicated preferential formation of the anti-inflammatory IL-35 rather than the pro-inflammatory IL-39 in wild-type animals. Additional therapeutic treatment of C57BL/6 mice after DSS administration confirmed the beneficial effect of SAHA on colitis manifestation reported in the literature. In contrast, HDACi in the Ebi3-deficient animals was not able to improve colitic parameters and even appeared to exacerbate the disease phenotype. Expression analyses of up- and downstream target genes provided further evidence that IL-35 rather than IL-39 is produced in the presence of Ebi3, consistent with the in vitro studies. 
Thus, comparison of the C57BL/6 mice with the Ebi3-deficient animals could provide insights into the mode of action of SAHA. Histone acetylating conditions ameliorate colitic symptoms via a mechanism involving epigenetic induction of Ebi3 followed by IL-35 formation. Based on the cooperation of epigenetic mechanisms and the drastic EBI3 induction shown by parallel hypomethylating and histone acetylating conditions, combined treatment with low-dose DNMTi and HDACi represents a therapeutic option for CU.

In summary, the present work demonstrated epigenetic and NFκB-mediated reactivation of EBI3 via DNA demethylation and histone acetylation with subsequent IL-35 formation and secretion by in vitro and in vivo analyses. Since IL-35 is able to alleviate colitic symptoms, the epigenetic inducibility of EBI3 by DNMTi and HDACi represents a promising alternative for the currently used therapies in the treatment of CU, which are often not successful or only short-term effective. An excessive immune response during relapsing inflammatory phases could be counteracted and complications such as the formation of colitis-associated carcinomas prevented.
KW  - Epigenetik
KW  - Epstein-Barr Virus-induziertes Gen 3
KW  - Colitis ulcerosa
Y1  - 2022
ER  - 
TY  - JOUR
A1  - Zheng, Ju-Sheng
A1  - Luan, Jian'an
A1  - Sofianopoulou, Eleni
A1  - Imamura, Fumiaki
A1  - Stewart, Isobel D.
A1  - Day, Felix R.
A1  - Pietzner, Maik
A1  - Wheeler, Eleanor
A1  - Lotta, Luca A.
A1  - Gundersen, Thomas E.
A1  - Amiano, Pilar
A1  - Ardanaz, Eva
A1  - Chirlaque, Maria-Dolores
A1  - Fagherazzi, Guy
A1  - Franks, Paul W.
A1  - Kaaks, Rudolf
A1  - Laouali, Nasser
A1  - Mancini, Francesca Romana
A1  - Nilsson, Peter M.
A1  - Onland-Moret, N. Charlotte
A1  - Olsen, Anja
A1  - Overvad, Kim
A1  - Panico, Salvatore
A1  - Palli, Domenico
A1  - Ricceri, Fulvio
A1  - Rolandsson, Olov
A1  - Spijkerman, Annemieke M. W.
A1  - Sanchez, Maria-Jose
A1  - Schulze, Matthias Bernd
A1  - Sala, Nuria
A1  - Sieri, Sabina
A1  - Tjonneland, Anne
A1  - Tumino, Rosario
A1  - van der Schouw, Yvonne T.
A1  - Weiderpass, Elisabete
A1  - Riboli, Elio
A1  - Danesh, John
A1  - Butterworth, Adam S.
A1  - Sharp, Stephen J.
A1  - Langenberg, Claudia
A1  - Forouhi, Nita G.
A1  - Wareham, Nicholas J.
T1  - Plasma vitamin C and type 2 diabetes
BT  - genome-wide association study and Mendelian randomization analysis in European populations
JF  - Diabetes care
N2  - OBJECTIVE: Higher plasma vitamin C levels are associated with lower type 2 diabetes risk, but whether this association is causal is uncertain. To investigate this, we studied the association of genetically predicted plasma vitamin C with type 2 diabetes.

RESEARCH DESIGN AND METHODS: We conducted genome-wide association studies of plasma vitamin C among 52,018 individuals of European ancestry to discover novel genetic variants. We performed Mendelian randomization analyses to estimate the association of genetically predicted differences in plasma vitamin C with type 2 diabetes in up to 80,983 case participants and 842,909 noncase participants. We compared this estimate with the observational association between plasma vitamin C and incident type 2 diabetes, including 8,133 case participants and 11,073 noncase participants. 

RESULTS: We identified 11 genomic regions associated with plasma vitamin C (P < 5 x 10(-8)), with the strongest signal at SLC23A1, and 10 novel genetic loci including SLC23A3, CHPT1, BCAS3, SNRPF, RER1, MAF, GSTA5, RGS14, AKT1, and FADS1. Plasma vitamin C was inversely associated with type 2 diabetes (hazard ratio per SD 0.88; 95% CI 0.82, 0.94), but there was no association between genetically predicted plasma vitamin C (excluding FADS1 variant due to its apparent pleiotropic effect) and type 2 diabetes (1.03; 95% CI 0.96, 1.10).

CONCLUSIONS: These findings indicate discordance between biochemically measured and genetically predicted plasma vitamin C levels in the association with type 2 diabetes among European populations. The null Mendelian randomization findings provide no strong evidence to suggest the use of vitamin C supplementation for type 2 diabetes prevention.
Y1  - 2020
U6  - https://doi.org/10.2337/dc20-1328
SN  - 0149-5992
SN  - 1935-5548
VL  - 44
IS  - 1
SP  - 98
EP  - 106
PB  - American Diabetes Association
CY  - Alexandria
ER  -