TY - JOUR
A1 - Henning, Thorsten
A1 - Kochlik, Bastian Max
A1 - Kusch, Paula
A1 - Strauss, Matthias
A1 - Juric, Viktorija
A1 - Pignitter, Marc
A1 - Marusch, Frank
A1 - Grune, Tilman
A1 - Weber, Daniela
T1 - Pre-Operative assessment of micronutrients, amino acids, phospholipids and oxidative stress in bariatric surgery candidates
JF - Antioxidants : open access journal
N2 - Obesity has been linked to lower concentrations of fat-soluble micronutrients and higher concentrations of oxidative stress markers as well as an altered metabolism of branched chain amino acids and phospholipids. In the context of morbid obesity, the aim of this study was to investigate whether and to which extent plasma status of micronutrients, amino acids, phospholipids and oxidative stress differs between morbidly obese (n = 23) and non-obese patients (n = 13). In addition to plasma, malondialdehyde, retinol, cholesterol and triglycerides were assessed in visceral and subcutaneous adipose tissue in both groups. Plasma gamma-tocopherol was significantly lower (p < 0.011) in the obese group while other fat-soluble micronutrients showed no statistically significant differences between both groups. Branched-chain amino acids (all p < 0.008) and lysine (p < 0.006) were significantly higher in morbidly obese patients compared to the control group. Malondialdehyde concentrations in both visceral (p < 0.016) and subcutaneous (p < 0.002) adipose tissue were significantly higher in the morbidly obese group while plasma markers of oxidative stress showed no significant differences between both groups. Significantly lower plasma concentrations of phosphatidylcholine, phosphatidylethanolamine, lyso-phosphatidylethanolamine (all p < 0.05) and their corresponding ether-linked analogs were observed, which were all reduced in obese participants compared to the control group. Pre-operative assessment of micronutrients in patients undergoing bariatric surgery is recommended for early identification of patients who might be at higher risk to develop a severe micronutrient deficiency post-surgery. Assessment of plasma BCAAs and phospholipids in obese patients might help to differentiate between metabolic healthy patients and those with metabolic disorders.
KW - obesity
KW - micronutrients
KW - oxidative stress
KW - amino acids
KW - phospholipids
KW - vitamins
KW - plasma
Y1 - 2022
U6 - https://doi.org/10.3390/antiox11040774
SN - 2076-3921
VL - 11
IS - 4
PB - MDPI
CY - Basel
ER -
TY - JOUR
A1 - Hoffmann, Holger
A1 - Ott, Christiane
A1 - Raupbach, Jana
A1 - Andernach, Lars
A1 - Renz, Matthias
A1 - Grune, Tilman
A1 - Hanschen, Franziska S.
T1 - Assessing bioavailability and bioactivity of 4-Hydroxythiazolidine-2-Thiones, newly discovered glucosinolate degradation products formed during domestic boiling of cabbage
JF - Frontiers in nutrition
N2 - Glucosinolates are plant secondary metabolites found in cruciferous vegetables (Brassicaceae) that are valued for their potential health benefits. Frequently consumed representatives of these vegetables, for example, are white or red cabbage, which are typically boiled before consumption. Recently, 3-alk(en)yl-4-hydroxythiazolidine-2-thiones were identified as a class of thermal glucosinolate degradation products that are formed during the boiling of cabbage. Since these newly discovered compounds are frequently consumed, this raises questions about their potential uptake and their possible bioactive functions. Therefore, 3-allyl-4-hydroxythiazolidine-2-thione (allyl HTT) and 4-hydroxy-3-(4-(methylsulfinyl) butyl)thiazolidine-2-thione (4-MSOB HTT) as degradation products of the respective glucosinolates sinigrin and glucoraphanin were investigated. After consumption of boiled red cabbage broth, recoveries of consumed amounts of the degradation products in urine collected for 24 h were 18 +/- 5% for allyl HTT and 21 +/- 4% for 4-MSOB HTT (mean +/- SD, n = 3). To investigate the stability of the degradation products during uptake and to elucidate the uptake mechanism, both an in vitro stomach and an in vitro intestinal model were applied. The results indicate that the uptake of allyl HTT and 4-MSOB HTT occurs by passive diffusion. Both compounds show no acute cell toxicity, no antioxidant potential, and no change in NAD(P)H dehydrogenase quinone 1 (NQO1) activity up to 100 mu M. However, inhibition of glycogen synthase kinases-3 (GSK-3) in the range of 20% for allyl HTT for the isoform GSK-3 beta and 29% for 4-MSOB HTT for the isoform GSK-3 alpha at a concentration of 100 mu M was found. Neither health-promoting nor toxic effects of 3-alk(en)yl-4-hydroxythiazolidine-2-thiones were found in the four tested assays carried out in this study, which contrasts with the properties of other glucosinolate degradation products, such as isothiocyanates.
KW - stomach model
KW - glycogen synthase kinase-3
KW - cytotoxicity
KW - antioxidant potential
KW - intestinal model
KW - cellular uptake
KW - isothiocyanate
Y1 - 2022
U6 - https://doi.org/10.3389/fnut.2022.941286
SN - 2296-861X
VL - 9
PB - Frontiers Media
CY - Lausanne
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 - 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 - 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 - 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 - 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 - 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 - 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 - 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.
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.
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 - GEN
A1 - Raupbach, Jana
A1 - Ott, Christiane
A1 - König, Jeannette
A1 - Grune, Tilman
T1 - Proteasomal degradation of glycated proteins depends on substrate unfolding
BT - preferred degradation of moderately modified myoglobin
T2 - Postprints der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe
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 proteasome
Y1 - 2022
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-527570
SN - 1866-8372
SP - 516
EP - 524
ER -
TY - JOUR
A1 - Castro, Jose Pedro
A1 - Wardelmann, Kristina
A1 - Grune, Tilman
A1 - Kleinridders, Andre
T1 - Mitochondrial Chaperones in the Brain
BT - safeguarding Brain Health and Metabolism?
JF - Frontiers in Endocrinology
N2 - The brain orchestrates organ function and regulates whole body metabolism by the concerted action of neurons and glia cells in the central nervous system. To do so, the brain has tremendously high energy consumption and relies mainly on glucose utilization and mitochondrial function in order to exert its function. As a consequence of high rate metabolism, mitochondria in the brain accumulate errors over time, such as mitochondrial DNA (mtDNA) mutations, reactive oxygen species, and misfolded and aggregated proteins. Thus, mitochondria need to employ specific mechanisms to avoid or ameliorate the rise of damaged proteins that contribute to aberrant mitochondrial function and oxidative stress. To maintain mitochondria homeostasis (mitostasis), cells evolved molecular chaperones that shuttle, refold, or in coordination with proteolytic systems, help to maintain a low steady-state level of misfolded/aggregated proteins. Their importance is exemplified by the occurrence of various brain diseases which exhibit reduced action of chaperones. Chaperone loss (expression and/or function) has been observed during aging, metabolic diseases such as type 2 diabetes and in neurode-generative diseases such as Alzheimer's (AD), Parkinson's (PD) or even Huntington's (HD) diseases, where the accumulation of damage proteins is evidenced. Within this perspective, we propose that proper brain function is maintained by the joint action of mitochondrial chaperones to ensure and maintain mitostasis contributing to brain health, and that upon failure, alter brain function which can cause metabolic diseases.
KW - insulin signaling
KW - brain
KW - chaperones
KW - mitochondria homeostasis
KW - mitochondrial dysfunction
KW - neurodegeneration
Y1 - 2018
U6 - https://doi.org/10.3389/fendo.2018.00196
SN - 1664-2392
VL - 9
PB - Frontiers Research Foundation
CY - Lausanne
ER -
TY - JOUR
A1 - Nowotny, Kerstin
A1 - Castro, Jose Pedro
A1 - Hugo, Martin
A1 - Braune, Sabine
A1 - Weber, Daniela
A1 - Pignitter, Marc
A1 - Somoza, Veronika
A1 - Bornhorst, Julia
A1 - Schwerdtle, Tanja
A1 - Grune, Tilman
T1 - Oxidants produced by methylglyoxal-modified collagen trigger ER stress and apoptosis in skin fibroblasts
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 - Methylglyoxal (MG), a highly reactive dicarbonyl, interacts with proteins to form advanced glycation end products (AGEs). AGEs include a variety of compounds which were shown to have damaging potential and to accumulate in the course of different conditions such as diabetes mellitus and aging. After confirming collagen as a main target for MG modifications in vivo within the extracellular matrix, we show here that MG-collagen disrupts fibroblast redox homeostasis and induces endoplasmic reticulum (ER) stress and apoptosis. In particular, MG-collagen-induced apoptosis is associated with the activation of the PERK-eIF2 alpha pathway and caspase-12. MG-collagen contributes to altered redox homeostasis by directly generating hydrogen peroxide and oxygen-derived free radicals. The induction of ER stress in human fibroblasts was confirmed using collagen extracts isolated from old mice in which MG-derived AGEs were enriched. In conclusion, MG-derived AGEs represent one factor contributing to diminished fibroblast function during aging.
KW - Advanced glycation end products
KW - Aging
KW - Apoptosis
KW - Collagen
KW - ER stress
KW - Methylglyoxal
KW - Redox homeostasis
Y1 - 2018
U6 - https://doi.org/10.1016/j.freeradbiomed.2018.03.022
SN - 0891-5849
SN - 1873-4596
VL - 120
SP - 102
EP - 113
PB - Elsevier
CY - New York
ER -
TY - GEN
A1 - Fernando, Raquel
A1 - Drescher, Cathleen
A1 - Deubel, Stefanie
A1 - Grune, Tilman
A1 - Castro, Jose Pedro
T1 - Distinct proteasomal activity for fast and slow twitch skeletal muscle during aging
T2 - Free radical biology and medicine : the official journal of the Oxygen Society, a constituent member of the International Society for Free Radical Research
N2 - Skeletal muscle alterations during aging lead to dysfunctional metabolism, correlating with frailty and early mortality. The loss of proteostasis is a hallmark of aging. Whether proteostasis loss plays a role in muscle aging remains elusive. To address this question we collected muscles, Soleus (SOL, type I) and Extensor digitorum longus (EDL, type II), from young (4 months) and old (25 months) C57BL/6 mice and evaluated the proteasomal system. Initial work showed decreased 26 S activity in old SOL. EDL displayed lower proteasomal activity in both ages compared to any of the SOL ages. Moreover, in order to understand if during aging there is the so-called “fiber switch from fast-to-slow”, we performed western blots against sMHC and fMHC (slow and fast myosin heavy chain, respectively). Preliminary results suggest that young SOL is composed by slow twitch fibers but also contains fast twitch fibers, while young EDL seems to be mostly composed by fast twitch fibers that level down during aging, suggesting the switch. As a conclusion, EDL seems to have less proteasomal activity, however, if this is a contributor or a consequence to the muscle fiber switch during aging still needs further investigation.
Y1 - 2018
U6 - https://doi.org/10.1016/j.freeradbiomed.2018.04.393
SN - 0891-5849
SN - 1873-4596
VL - 120
SP - S119
EP - S119
PB - Elsevier
CY - New York
ER -
TY - JOUR
A1 - Koelman, Liselot A.
A1 - Pivovarova-Ramich, Olga
A1 - Pfeiffer, Andreas F. H.
A1 - Grune, Tilman
A1 - Aleksandrova, Krasimira
T1 - Cytokines for evaluation of chronic inflammatory status in ageing research
BT - reliability and phenotypic characterisation
JF - Immunity & Ageing
N2 - Background: There is a growing interest in the role of inflammageing for chronic disease development. Cytokines are potent soluble immune mediators that can be used as target biomarkers of inflammageing; however, their measurement in human samples has been challenging. This study aimed to assess the reliability of a pro- and anti-inflammatory cytokine panel in a sample of healthy people measured with a novel electrochemiluminescent multiplex immunoassay platform (Meso Scale Discovery, MSD), and to characterize their associations with metabolic and inflammatory phenotypes.
KW - Reliability
KW - Cytokines
KW - Multiplex platforms
KW - Inflammaging
KW - Biomarkers
KW - Ageing
KW - BMI
Y1 - 2019
U6 - https://doi.org/10.1186/s12979-019-0151-1
SN - 1742-4933
VL - 16
PB - BMC
CY - London
ER -
TY - JOUR
A1 - Castro, Jose Pedro
A1 - Fernando, Raquel
A1 - Reeg, Sandra
A1 - Meinl, Walter
A1 - Almeida, Henrique
A1 - Grune, Tilman
T1 - Non-enzymatic cleavage of Hsp90 by oxidative stress leads to actin aggregate formation
BT - A novel gain-of-function mechanism
JF - Redox Biology
N2 - Aging is accompanied by the accumulation of oxidized proteins. To remove them, cells employ the proteasomal and autophagy-lysosomal systems; however, if the clearance rate is inferior to its formation, protein aggregates form as a hallmark of proteostasis loss. In cells, during stress conditions, actin aggregates accumulate leading to impaired proliferation and reduced proteasomal activity, as observed in cellular senescence. The heat shock protein 90 (Hsp90) is a molecular chaperone that binds and protects the proteasome from oxidative inactivation. We hypothesized that in oxidative stress conditions a malfunction of Hsp90 occurs resulting in the aforementioned protein aggregates. Here, we demonstrate that upon oxidative stress Hsp90 loses its function in a highly specific non-enzymatic iron-catalyzed oxidation event and its breakdown product, a cleaved form of Hsp90 (Hsp90cl), acquires a new function in mediating the accumulation of actin aggregates. Moreover, the prevention of Hsp90 cleavage reduces oxidized actin accumulation, whereas transfection of the cleaved form of Hsp90 leads to an enhanced accumulation of oxidized actin. This indicates a clear role of the Hsp90cl in the aggregation of oxidized proteins.
KW - Oxidative stress
KW - Protein oxidation
KW - Heat shock protein 90
KW - Proteasome
KW - Protein aggregates
Y1 - 2019
U6 - https://doi.org/10.1016/j.redox.2019.101108
SN - 2213-2317
VL - 21
PB - Elsevier
CY - Amsterdam
ER -
TY - JOUR
A1 - Fernando, Raquel
A1 - Drescher, Cathleen
A1 - Nowotny, Kerstin
A1 - Grune, Tilman
A1 - Castro, Jose Pedro
T1 - Impaired proteostasis during skeletal muscle aging
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 - Aging is a complex phenomenon that has detrimental effects on tissue homeostasis. The skeletal muscle is one of the earliest tissues to be affected and to manifest age-related changes such as functional impairment and the loss of mass. Common to these alterations and to most of tissues during aging is the disruption of the proteostasis network by detrimental changes in the ubiquitin-proteasomal system (UPS) and the autophagy-lysosomal system (ALS). In fact, during aging the accumulation of protein aggregates, a process mainly driven by increased levels of oxidative stress, has been observed, clearly demonstrating UPS and ALS dysregulation. Since the UPS and ALS are the two most important pathways for the removal of misfolded and aggregated proteins and also of damaged organelles, we provide here an overview on the current knowledge regarding the connection between the loss of proteostasis and skeletal muscle functional impairment and also how redox regulation can play a role during aging. Therefore, this review serves for a better understanding of skeletal muscle aging in regard to the loss of proteostasis and how redox regulation can impact its function and maintenance.
KW - Skeletal muscle
KW - Proteostasis
KW - Proteasome and lysosome
KW - Oxidative stress
KW - Redox regulation
KW - Aging
Y1 - 2018
U6 - https://doi.org/10.1016/j.freeradbiomed.2018.08.037
SN - 0891-5849
SN - 1873-4596
VL - 132
SP - 58
EP - 66
PB - Elsevier
CY - New York
ER -
TY - JOUR
A1 - Fernando, Raquel
A1 - Drescher, Cathleen
A1 - Deubel, Stefanie
A1 - Jung, Tobias
A1 - Ost, Mario
A1 - Klaus, Susanne
A1 - Grune, Tilman
A1 - Castro, Jose Pedro
T1 - Low proteasomal activity in fast skeletal muscle fibers is not associated with increased age-related oxidative damage
JF - Experimental gerontology
N2 - The skeletal muscle is a crucial tissue for maintaining whole body homeostasis. Aging seems to have a disruptive effect on skeletal muscle homeostasis including proteostasis. However, how aging specifically impacts slow and fast twitch fiber types remains elusive. Muscle proteostasis is largely maintained by the proteasomal system. Here we characterized the proteasomal system in two different fiber types, using a non-sarcopenic aging model. By analyzing the proteasomal activity and amount, as well as the polyubiquitinated proteins and the level of protein oxidation in Musculus soleus (Sol) and Musculus extensor digitorum longus (EDL), we found that the slow twitch Sol muscle shows an overall higher respiratory and proteasomal activity in young and old animals. However, especially during aging the fast twitch EDL muscle reduces protein oxidation by an increase of antioxidant capacity. Thus, under adaptive non-sarcopenic conditions, the two fibers types seem to have different strategies to avoid age-related changes.
KW - Proteasomal system
KW - Skeletal muscle
KW - Fast and slow fibers
KW - Polyubiquitination
KW - Oxidized proteins
KW - Antioxidants
KW - Aging
KW - Mitochondrial respiration
Y1 - 2018
U6 - https://doi.org/10.1016/j.exger.2018.10.018
SN - 0531-5565
SN - 1873-6815
VL - 117
SP - 45
EP - 52
PB - Elsevier
CY - Oxford
ER -
TY - JOUR
A1 - Schröter, David
A1 - Neugart, Susanne
A1 - Schreiner, Monika
A1 - Grune, Tilman
A1 - Rohn, Sascha
A1 - Ott, Christiane
T1 - Amaranth’s 2-Caffeoylisocitric Acid—An Anti-Inflammatory Caffeic Acid Derivative That Impairs NF-κB Signaling in LPS-Challenged RAW 264.7 Macrophages
JF - Nutrients
N2 - For centuries, Amaranthus sp. were used as food, ornamentals, and medication. Molecular mechanisms, explaining the health beneficial properties of amaranth, are not yet understood, but have been attributed to secondary metabolites, such as phenolic compounds. One of the most abundant phenolic compounds in amaranth leaves is 2-caffeoylisocitric acid (C-IA) and regarding food occurrence, C-IA is exclusively found in various amaranth species. In the present study, the anti-inflammatory activity of C-IA, chlorogenic acid, and caffeic acid in LPS-challenged macrophages (RAW 264.7) has been investigated and cellular contents of the caffeic acid derivatives (CADs) were quantified in the cells and media. The CADs were quantified in the cell lysates in nanomolar concentrations, indicating a cellular uptake. Treatment of LPS-challenged RAW 264.7 cells with 10 µM of CADs counteracted the LPS effects and led to significantly lower mRNA and protein levels of inducible nitric oxide synthase, tumor necrosis factor alpha, and interleukin 6, by directly decreasing the translocation of the nuclear factor κB/Rel-like containing protein 65 into the nucleus. This work provides new insights into the molecular mechanisms that attribute to amaranth’s anti-inflammatory properties and highlights C-IA’s potential as a health-beneficial compound for future research.
KW - inflammation
KW - caffeic acid derivatives
KW - RAW 264
KW - 7 macrophages
KW - NF-kappa B
KW - amaranth
Y1 - 2019
U6 - https://doi.org/10.3390/nu11030571
SN - 2072-6643
VL - 11
IS - 3
PB - MDPI
CY - Basel
ER -
TY - JOUR
A1 - Kehm, Richard
A1 - Rückriemen, Jana
A1 - Weber, Daniela
A1 - Deubel, Stefanie
A1 - Grune, Tilman
A1 - Höhn, Annika
T1 - Endogenous advanced glycation end products in pancreatic islets after short-term carbohydrate intervention in obese, diabetes-prone mice
JF - Nutrition & Diabetes
N2 - Diet-induced hyperglycemia is described as one major contributor to the formation of advanced glycation end products (AGEs) under inflammatory conditions, crucial in type 2 diabetes progression. Previous studies have indicated high postprandial plasma AGE-levels in diabetic patients and after long-term carbohydrate feeding in animal models. Pancreatic islets play a key role in glucose metabolism; thus, their susceptibility to glycation reactions due to high amounts of dietary carbohydrates is of special interest. Therefore, diabetes-prone New Zealand Obese (NZO) mice received either a carbohydrate-free, high-fat diet (CFD) for 11 weeks or were additionally fed with a carbohydrate-rich diet (CRD) for 7 days. In the CRD group, hyperglycemia and hyperinsulinemia were induced accompanied by increasing plasma 3-nitrotyrosine (3-NT) levels, higher amounts of 3-NT and inducible nitric oxide synthase (iNOS) within pancreatic islets. Furthermore, N-epsilon-carboxymethyllysine (CML) was increased in the plasma of CRD-fed NZO mice and substantially higher amounts of arg-pyrimidine, pentosidine and the receptor for advanced glycation end products (RAGE) were observed in pancreatic islets. These findings indicate that a short-term intervention with carbohydrates is sufficient to form endogenous AGEs in plasma and pancreatic islets of NZO mice under hyperglycemic and inflammatory conditions.
Y1 - 2019
U6 - https://doi.org/10.1038/s41387-019-0077-x
SN - 2044-4052
VL - 9
PB - Nature Publ. Group
CY - London
ER -
TY - JOUR
A1 - Castaño Martínez, María Teresa
A1 - Schumacher, Fabian
A1 - Schumacher, Silke
A1 - Kochlik, Bastian Max
A1 - Weber, Daniela
A1 - Grune, Tilman
A1 - Biemann, Ronald
A1 - McCann, Adrian
A1 - Abraham, Klaus
A1 - Weikert, Cornelia
A1 - Kleuse, Burkhard
A1 - Schürmann, Annette
A1 - Laeger, Thomas
T1 - Methionine restriction prevents onset of type 2 diabetes in NZO mice
JF - The FASEB journal : the official journal of the Federation of American Societies for Experimental Biology
N2 - Dietary methionine restriction (MR) is well known to reduce body weight by increasing energy expenditure (EE) and insulin sensitivity. An elevated concentration of circulating fibroblast growth factor 21 (FGF21) has been implicated as a potential underlying mechanism. The aims of our study were to test whether dietary MR in the context of a high-fat regimen protects against type 2 diabetes in mice and to investigate whether vegan and vegetarian diets, which have naturally low methionine levels, modulate circulating FGF21 in humans. New Zealand obese (NZO) mice, a model for polygenic obesity and type 2 diabetes, were placed on isocaloric high-fat diets (protein, 16 kcal%; carbohydrate, 52 kcal%; fat, 32 kcal%) that provided methionine at control (Con; 0.86% methionine) or low levels (0.17%) for 9 wk. Markers of glucose homeostasis and insulin sensitivity were analyzed. Among humans, low methionine intake and circulating FGF21 levels were investigated by comparing a vegan and a vegetarian diet to an omnivore diet and evaluating the effect of a short-term vegetarian diet on FGF21 induction. In comparison with the Con group, MR led to elevated plasma FGF21 levels and prevented the onset of hyperglycemia in NZO mice. MR-fed mice exhibited increased insulin sensitivity, higher plasma adiponectin levels, increased EE, and up-regulated expression of thermogenic genes in subcutaneous white adipose tissue. Food intake and fat mass did not change. Plasma FGF21 levels were markedly higher in vegan humans compared with omnivores, and circulating FGF21 levels increased significantly in omnivores after 4 d on a vegetarian diet. These data suggest that MR induces FGF21 and protects NZO mice from high-fat diet-induced glucose intolerance and type 2 diabetes. The normoglycemic phenotype in vegans and vegetarians may be caused by induced FGF21. MR akin to vegan and vegetarian diets in humans may offer metabolic benefits via increased circulating levels of FGF21 and merits further investigation.-Castano-Martinez, T., Schumacher, F., Schumacher, S., Kochlik, B., Weber, D., Grune, T., Biemann, R., McCann, A., Abraham, K., Weikert, C., Kleuser, B., Schurmann, A., Laeger, T. Methionine restriction prevents onset of type 2 diabetes in NZO mice.
KW - energy expenditure
KW - hyperglycemia
KW - obesity
KW - vegan
KW - vegetarian
Y1 - 2019
U6 - https://doi.org/10.1096/fj.201900150R
SN - 0892-6638
SN - 1530-6860
VL - 33
IS - 6
SP - 7092
EP - 7102
PB - Federation of American Societies for Experimental Biology
CY - Bethesda
ER -
TY - JOUR
A1 - John, Cathleen
A1 - Grune, Jana
A1 - Ott, Christiane
A1 - Nowotny, Kerstin
A1 - Deubel, Stefanie
A1 - Kühne, Arne
A1 - Schubert, Carola
A1 - Kintscher, Ulrich
A1 - Regitz-Zagrosek, Vera
A1 - Grune, Tilman
T1 - Sex Differences in Cardiac Mitochondria in the New Zealand Obese Mouse
JF - Frontiers in Endocrinology
N2 - Background: Obesity is a risk factor for diseases including type 2 diabetes mellitus (T2DM) and cardiovascular disorders. Diabetes itself contributes to cardiac damage. Thus, studying cardiovascular events and establishing therapeutic intervention in the period of type T2DM onset and manifestation are of highest importance. Mitochondrial dysfunction is one of the pathophysiological mechanisms leading to impaired cardiac function. Methods: An adequate animal model for studying pathophysiology of T2DM is the New Zealand Obese (NZO) mouse. These mice were maintained on a high-fat diet (HFD) without carbohydrates for 13 weeks followed by 4 week HFD with carbohydrates. NZO mice developed severe obesity and only male mice developed manifest T2DM. We determined cardiac phenotypes and mitochondrial function as well as cardiomyocyte signaling in this model. Results: The development of an obese phenotype and T2DM in male mice was accompanied by an impaired systolic function as judged by echocardiography and MyH6/7 expression. Moreover, the mitochondrial function only in male NZO hearts was significantly reduced and ERK1/2 and AMPK protein levels were altered. Conclusions: This is the first report demonstrating that the cardiac phenotype in male diabetic NZO mice is associated with impaired cardiac energy function and signaling events.
KW - NZO
KW - heart
KW - obesity
KW - mitochondrial function
KW - echocardiography
KW - systolic function
Y1 - 2018
U6 - https://doi.org/10.3389/fendo.2018.00732
SN - 1664-2392
VL - 9
PB - Frontiers Research Foundation
CY - Lausanne
ER -
TY - GEN
A1 - Castro, José Pedro
A1 - Wardelmann, Kristina
A1 - Grune, Tilman
A1 - Kleinridders, André
T1 - Mitochondrial chaperones in the brain
BT - safeguarding brain health and metabolism?
T2 - Postprints der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe
N2 - The brain orchestrates organ function and regulates whole body metabolism by the concerted action of neurons and glia cells in the central nervous system. To do so, the brain has tremendously high energy consumption and relies mainly on glucose utilization and mitochondrial function in order to exert its function. As a consequence of high rate metabolism, mitochondria in the brain accumulate errors over time, such as mitochondrial DNA (mtDNA) mutations, reactive oxygen species, and misfolded and aggregated proteins. Thus, mitochondria need to employ specific mechanisms to avoid or ameliorate the rise of damaged proteins that contribute to aberrant mitochondrial function and oxidative stress. To maintain mitochondria homeostasis (mitostasis), cells evolved molecular chaperones that shuttle, refold, or in coordination with proteolytic systems, help to maintain a low steady-state level of misfolded/aggregated proteins. Their importance is exemplified by the occurrence of various brain diseases which exhibit reduced action of chaperones. Chaperone loss (expression and/or function) has been observed during aging, metabolic diseases such as type 2 diabetes and in neurode-generative diseases such as Alzheimer's (AD), Parkinson's (PD) or even Huntington's (HD) diseases, where the accumulation of damage proteins is evidenced. Within this perspective, we propose that proper brain function is maintained by the joint action of mitochondrial chaperones to ensure and maintain mitostasis contributing to brain health, and that upon failure, alter brain function which can cause metabolic diseases.
T3 - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 1031
KW - insulin signaling
KW - brain
KW - chaperones
KW - mitochondria homeostasis
KW - mitochondrial dysfunction
KW - neurodegeneration
Y1 - 2020
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-460650
SN - 1866-8372
IS - 1031
ER -
TY - JOUR
A1 - König, Jeannette
A1 - Grune, Tilman
A1 - Ott, Christiane
T1 - Assessing autophagy in murine skeletal muscle: current findings to modulate and quantify the autophagic flux
JF - Current opinion in clinical nutrition and metabolic care
N2 - Purpose of review In addition to the currently available lysosomotropic drugs and autophagy whole-body knockout mouse models, we provide alternative methods that enable the modulation and detection of autophagic flux in vivo, discussing advantages and disadvantages of each method. Recent findings With the autophagosome-lysosome fusion inhibitor colchicine in skeletal muscle and temporal downregulation of autophagy using a novel Autophagy related 5-short hairpin RNA (Atg5-shRNA) mouse model we mention two models that directly modulate autophagy flux in vivo. Furthermore, methods to quantify autophagy flux, such as mitophagy transgenic reporters, in situ immunofluorescent staining and multispectral imaging flow cytometry, in mature skeletal muscle and cells are addressed. To achieve clinical benefit, less toxic, temporary and cell-type-specific modulation of autophagy should be pursued further. A temporary knockdown as described for the Atg5-shRNA mice could provide a first insight into possible implications of autophagy inhibition. However, it is also important to take a closer look into the methods to evaluate autophagy after harvesting the tissue. In particular caution is required when experimental conditions can influence the final measurement and this should be pretested carefully.
KW - autophagy flux
KW - in vivo
KW - skeletal muscle
Y1 - 2019
U6 - https://doi.org/10.1097/MCO.0000000000000579
SN - 1363-1950
SN - 1473-6519
VL - 22
IS - 5
SP - 355
EP - 362
PB - Lippincott Williams & Wilkins
CY - Philadelphia
ER -
TY - JOUR
A1 - Speckmann, Bodo
A1 - Schulz, Sarah
A1 - Hiller, Franziska
A1 - Hesse, Deike
A1 - Schumacher, Fabian
A1 - Kleuser, Burkhard
A1 - Geisel, Juergen
A1 - Obeid, Rima
A1 - Grune, Tilman
A1 - Kipp, Anna Patricia
T1 - Selenium increases hepatic DNA methylation and modulates one-carbon metabolism in the liver of mice
JF - The journal of nutritional biochemistry
N2 - The average intake of the essential trace element selenium (Se) is below the recommendation in most European countries, possibly causing sub-optimal expression of selenoproteins. It is still unclear how a suboptimal Se status may affect health. To mimic this situation, mice were fed one of three physiologically relevant amounts of Se. We focused on the liver, the organ most sensitive to changes in the Se supply indicated by hepatic glutathione peroxidase activity. In addition, liver is the main organ for synthesis of methyl groups and glutathione via one-carbon metabolism. Accordingly, the impact of Se on global DNA methylation, methylation capacity, and gene expression was assessed. We observed higher global DNA methylation indicated by LINE1 methylation, and an increase of the methylation potential as indicated by higher S-adenosylmethionine (SAM)/S-adenosylhomocysteine (SAH) ratio and by elevated mRNA expression of serine hydroxymethyltransferase in both or either of the Se groups. Furthermore, increasing the Se supply resulted in higher plasma concentrations of triglycerides. Hepatic expression of glycolytic and lipogenic genes revealed consistent Se dependent up-regulation of glucokinase. The sterol regulatory element-binding transcription factor 1 (Srebf1) was also up-regulated by Se. Both effects were confirmed in primary hepatocytes. In contrast to the overall Se-dependent increase of methylation capacity, the up-regulation of Srebf1 expression was paralleled by reduced local methylation of a specific CpG site within the Srebf1 gene. Thus, we provided evidence that Se-dependent effects on lipogenesis involve epigenetic mechanisms. (C) 2017 The Authors. Published by Elsevier Inc.
KW - Selenium
KW - DNA methylation
KW - Liver
KW - Lipogenesis
KW - Srebf1
Y1 - 2017
U6 - https://doi.org/10.1016/j.jnutbio.2017.07.002
SN - 0955-2863
SN - 1873-4847
VL - 48
SP - 112
EP - 119
PB - Elsevier
CY - New York
ER -
TY - JOUR
A1 - Castro, José Pedro
A1 - Grune, Tilman
A1 - Speckmann, Bodo
T1 - The two faces of reactive oxygen species (ROS) in adipocyte function and dysfunction
JF - Biological chemistry
N2 - White adipose tissue (WAT) is actively involved in the regulation of whole-body energy homeostasis via storage/ release of lipids and adipokine secretion. Current research links WAT dysfunction to the development of metabolic syndrome (MetS) and type 2 diabetes (T2D). The expansion of WAT during oversupply of nutrients prevents ectopic fat accumulation and requires proper preadipocyte-to-adipocyte differentiation. An assumed link between excess levels of reactive oxygen species (ROS), WAT dysfunction and T2D has been discussed controversially. While oxidative stress conditions have conclusively been detected in WAT of T2D patients and related animal models, clinical trials with antioxidants failed to prevent T2D or to improve glucose homeostasis. Furthermore, animal studies yielded inconsistent results regarding the role of oxidative stress in the development of diabetes. Here, we discuss the contribution of ROS to the (patho) physiology of adipocyte function and differentiation, with particular emphasis on sources and nutritional modulators of adipocyte ROS and their functions in signaling mechanisms controlling adipogenesis and functions of mature fat cells. We propose a concept of ROS balance that is required for normal functioning of WAT. We explain how both excessive and diminished levels of ROS, e. g. resulting from over supplementation with antioxidants, contribute to WAT dysfunction and subsequently insulin resistance.
KW - adipogenesis
KW - adipose tissue dysregulation
KW - antioxidants
KW - metabolic disorders
KW - oxidative stress
Y1 - 2016
U6 - https://doi.org/10.1515/hsz-2015-0305
SN - 1431-6730
SN - 1437-4315
VL - 397
SP - 709
EP - 724
PB - De Gruyter
CY - Berlin
ER -
TY - JOUR
A1 - Reeg, Sandra
A1 - Jung, Tobias
A1 - Castro, José Pedro
A1 - Davies, Kelvin J. A.
A1 - Henze, Andrea
A1 - Grune, Tilman
T1 - The molecular chaperone Hsp70 promotes the proteolytic removal of oxidatively damaged proteins by the proteasome
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 - One hallmark of aging is the accumulation of protein aggregates, promoted by the unfolding of oxidized proteins. Unraveling the mechanism by which oxidized proteins are degraded may provide a basis to delay the early onset of features, such as protein aggregate formation, that contribute to the aging phenotype. In order to prevent aggregation of oxidized proteins, cells recur to the 20S proteasome, an efficient turnover proteolysis complex. It has previously been shown that upon oxidative stress the 26S proteasome, another form, dissociates into the 20S form. A critical player implicated in its dissociation is the Heat Shock Protein 70 (Hsp70), which promotes an increase in free 20S proteasome and, therefore, an increased capability to degrade oxidized proteins. The aim of this study was to test whether or not Hsp70 is involved in cooperating with the 20S proteasome for a selective degradation of oxidatively damaged proteins. Our results demonstrate that Hsp70 expression is induced in HT22 cells as a result of mild oxidative stress conditions. Furthermore, Hsp70 prevents the accumulation of oxidized proteins and directly promotes their degradation by the 20S proteasome. In contrast the expression of the Heat shock cognate protein 70 (Hsc70) was not changed in recovery after oxidative stress and Hsc70 has no influence on the removal of oxidatively damaged proteins. We were able to demonstrate in HT22 cells, in brain homogenates from 129/SV mice and in vitro, that there is an increased interaction of Hsp70 with oxidized proteins, but also with the 20S proteasome, indicating a role of Hsp70 in mediating the interaction of oxidized proteins with the 20S proteasome. Thus, our data clearly implicate an involvement of Hsp70 oxidatively damaged protein degradation by the 20S proteasome. c) 2016 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
KW - Protein oxidation
KW - Proteasome
KW - Chaperone
KW - HSP70
Y1 - 2016
U6 - https://doi.org/10.1016/j.freeradbiomed.2016.08.002
SN - 0891-5849
SN - 1873-4596
VL - 99
SP - 153
EP - 166
PB - Elsevier
CY - New York
ER -
TY - GEN
A1 - Stuetz, Wolfgang
A1 - Weber, Daniela
A1 - Dollé, Martijn E. T.
A1 - Jansen, Eugène
A1 - Grubeck-Loebenstein, Beatrix
A1 - Fiegl, Simone
A1 - Toussaint, Olivier
A1 - Bernhardt, Juergen
A1 - Gonos, Efstathios S.
A1 - Franceschi, Claudio
A1 - Sikora, Ewa
A1 - Moreno-Villanueva, María
A1 - Breusing, Nicolle
A1 - Grune, Tilman
A1 - Bürkle, Alexander
T1 - Plasma carotenoids, tocopherols, and retinol in the age-stratified (35–74 years) general population
BT - a cross-sectional study in six European countries
T2 - Nutrients
N2 - Blood micronutrient status may change with age. We analyzed plasma carotenoids, α-/γ-tocopherol, and retinol and their associations with age, demographic characteristics, and dietary habits (assessed by a short food frequency questionnaire) in a cross-sectional study of 2118 women and men (age-stratified from 35 to 74 years) of the general population from six European countries. Higher age was associated with lower lycopene and α-/β-carotene and higher β-cryptoxanthin, lutein, zeaxanthin, α-/γ-tocopherol, and retinol levels. Significant correlations with age were observed for lycopene (r = −0.248), α-tocopherol (r = 0.208), α-carotene (r = −0.112), and β-cryptoxanthin (r = 0.125; all p < 0.001). Age was inversely associated with lycopene (−6.5% per five-year age increase) and this association remained in the multiple regression model with the significant predictors (covariables) being country, season, cholesterol, gender, smoking status, body mass index (BMI (kg/m2)), and dietary habits. The positive association of α-tocopherol with age remained when all covariates including cholesterol and use of vitamin supplements were included (1.7% vs. 2.4% per five-year age increase). The association of higher β-cryptoxanthin with higher age was no longer statistically significant after adjustment for fruit consumption, whereas the inverse association of α-carotene with age remained in the fully adjusted multivariable model (−4.8% vs. −3.8% per five-year age increase). We conclude from our study that age is an independent predictor of plasma lycopene, α-tocopherol, and α-carotene.
T3 - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 449
KW - carotenoids
KW - plasma
KW - age
KW - Europe
KW - micronutrient
KW - lycopene
KW - retinol
KW - tocopherols
Y1 - 2018
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-407659
ER -
TY - GEN
A1 - Castro, José Pedro
A1 - Grune, Tilman
A1 - Speckmann, Bodo
T1 - The two faces of reactive oxygen species (ROS) in adipocyte function and dysfunction
N2 - White adipose tissue (WAT) is actively involved in the regulation of whole-body energy homeostasis via storage/release of lipids and adipokine secretion. Current research links WAT dysfunction to the development of metabolic syndrome (MetS) and type 2 diabetes (T2D). The expansion of WAT during oversupply of nutrients prevents ectopic fat accumulation and requires proper preadipocyte-to-adipocyte differentiation. An assumed link between excess levels of reactive oxygen species (ROS), WAT dysfunction and T2D has been discussed controversially. While oxidative stress conditions have conclusively been detected in WAT of T2D patients and related animal models, clinical trials with antioxidants failed to prevent T2D or to improve glucose homeostasis. Furthermore, animal studies yielded inconsistent results regarding the role of oxidative stress in the development of diabetes. Here, we discuss the contribution of ROS to the (patho)physiology of adipocyte function and differentiation, with particular emphasis on sources and nutritional modulators of adipocyte ROS and their functions in signaling mechanisms controlling adipogenesis and functions of mature fat cells. We propose a concept of ROS balance that is required for normal functioning of WAT. We explain how both excessive and diminished levels of ROS, e.g. resulting from over supplementation with antioxidants, contribute to WAT dysfunction and subsequently insulin resistance.
T3 - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 339
KW - adipogenesis
KW - adipose tissue dysregulation
KW - antioxidants
KW - metabolic disorders
KW - oxidative stress
Y1 - 2017
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-398039
ER -