@article{FreyHenzeNagletal.2009, author = {Frey, Simone K. and Henze, Andrea and Nagl, Britta and Raila, Jens and Scholze, Alexandra and Tepel, Martin and Schweigert, Florian J. and Zidek, Walter}, title = {Effect of renal replacement therapy on retinol-binding protein 4 isoforms}, issn = {0009-8981}, doi = {10.1016/j.cca.2008.11.008}, year = {2009}, abstract = {Background: Retinol-binding protein 4 (RBP4) levels are elevated in the serum of patients with kidney dysfunction. We recently showed that RBP4 isoforms including apo-RBP4 (RBP4 not bound to retinol) and RBP4 truncated at the C-terminus (RBP4-L, RBP4-LL) are increased in the serum of patients with kidney diseases but not in serum of patients with various liver diseases. The aim of this study was to investigate the effect of renal replacement therapy on RBP4 isoforms. Methods: We investigated serum levels of RBP4, apo-RBP4, holo-RBP4, RBP4-L, RBP4-LL, retinol and transthyretin (TTR) in 18 hemodialysis (HD) patients, 30 patients after renal transplantation (RTx) and in 35 healthy controls. RBP4 and TTR levels were measured by enzyme-linked immunosorbent assay, apo- and holo-RBP4 by native electrophoresis, retinol by high performance liquid chromatography and RBP4-L and RBP4-LL were analyzed by mass spectrometry. Results: HD and RTx patients had elevated RBP4, apo-RBP4 and RBP4-LL levels compared to controls. RTx patients had elevated amounts of RBP4-L compared to controls and elevated RBP4 and apo-RBP4 levels compared to HD patients. Conclusion: The results demonstrate a strong correlation between kidney function and RBP4 isoforms and provide data for investigating the relation of RBP4 and insulin resistance in these patients.}, language = {en} } @article{FreySprangerHenzeetal.2009, author = {Frey, Simone K. and Spranger, Joachim and Henze, Andrea and Pfeiffer, Andreas F. H. and Schweigert, Florian J. and Raila, Jens}, title = {Factors that influence retinol-binding protein 4-transthyretin interaction are not altered in overweight subjects and overweight subjects with type 2 diabetes mellitus}, issn = {0026-0495}, doi = {10.1016/j.metabol.2009.05.003}, year = {2009}, abstract = {Retinol-binding protein 4 (RBP4) is an adipokine bound in plasma to transthyretin (TTR), which prevents its glomerular filtration and subsequent catabolism in the kidney. Alterations of this interaction have been Suggested to be implicated in the elevation of RBP4 that are thought to contribute to the development Of insulin resistance associated with obesity and type 2 diabetes mellitus (T2DM). However, the factors linking RBP4 to TTR in humans are not clear. Therefore, this Study evaluated parameters influencing the RBP4-TTR interaction and their relation to obesity and T2DM. The RBP4 and TTR levels were quantified in plasma of 16 lean controls, 28 overweight controls, and 14 overweight T2DM patients by enzyme-linked immunosorbent assay. Transthyretin isoforms involved in RBP4 binding were determined by linear matrix-assisted laser desorption/ionization-time of flight-mass spectrometry after RBP4 coimmunoprecipitation. Holo-RBP4 (retinol-bound) and apo-RBP4 (retinol-free) were assessed by immunoblotting using nondenaturating polyacrylamide gel electrophoresis. Plasma levels of both RBP4 and TTR did not differ among the groups of lean controls, overweight controls, and overweight T2DM subjects. Using RBP4 immunoprecipitation, 4 mass signals were observed for TTR representing native, S-cysteinylated, S-cysteinglycinylated, and S-glutathionylated TTR. No differences in peak intensity of TTR isoforms were observed among the groups. Moreover, no differences in the ratio of holo- and apo-RBP4 were evident. The results suggest that circulating RBP4 and TTR were not affected by human obesity or T2DM, which might be attributed to the absence of alterations of TTR isoforms and the ratio of holo- and apo-RBP4 that might modify the TTR-RBP4 interaction.}, language = {en} } @phdthesis{Henze2009, author = {Henze, Andrea}, title = {Chronic kidney disease and type 2 diabetes mellitus as factors influencing retinol-binding protein 4}, address = {Potsdam}, pages = {XI, 143 S. : Ill., graph. Darst.}, year = {2009}, language = {en} } @article{BobbertRailaSchwarzetal.2010, author = {Bobbert, Thomas and Raila, Jens and Schwarz, Franziska and Mai, Knut and Henze, Andrea and Pfeiffer, Andreas F. H. and Schweigert, Florian J. and Spranger, Joachim}, title = {Relation between retinol, retinol-binding protein 4, transthyretin and carotid intima media thickness}, issn = {0021-9150}, doi = {10.1016/j.atherosclerosis.2010.07.063}, year = {2010}, abstract = {Objective: Retinol is transported in a complex with retinol-binding protein 4 (RBP4) and transthyretin (TTR) in the circulation. While retinol is associated with various cardiovascular risk factors, the relation between retinol, RBP4, TTR and carotid intima media thickness (IMT) has not been analysed yet. Methods: Retinol, RBP4 and TTR were measured in 96 individuals and their relation to mean and maximal IMT was determined. Results: Mean IMT correlated with RBP4 (r = 0.335, p < 0.001), retinol (r = -0.241, p = 0.043), RBP/TTR ratio (r = 0.254, p = 0.025) and retinol/RBP4 ratio (r = -0.549, p < 0.001). Adjustment for age, sex, BMI, blood pressure, HDL/total cholesterol ratio, triglyceride, diabetes and smoking revealed that the retinol/RBP4 ratio was strongly and independently associated with mean IMT. Similar results were found for maximal IMT, which included the measurement of plaques. Conclusion: The data support that the transport complex of vitamin A is associated with the IMT, an established parameter of atherosclerosis. Changes in RBP4 saturation with retinol may link renal dysfunction and insulin resistance to atherosclerosis.}, language = {en} } @article{HenzeFreyRailaetal.2010, author = {Henze, Andrea and Frey, Simone K. and Raila, Jens and Scholze, Alexandra and Spranger, Joachim and Weickert, Martin O. and Tepel, Martin and Zidek, Walter and Schweigert, Florian J.}, title = {Alterations of retinol-binding protein 4 species in patients with different stages of chronic kidney disease and their relation to lipid parameters}, issn = {0006-291X}, doi = {10.1016/j.bbrc.2010.01.082}, year = {2010}, abstract = {Retinol-binding protein 4 (RBP4) is elevated in patients with chronic kidney disease (CKD) and has been discussed as marker of kidney function. In addition to an elevated concentration, the existence of truncated RBP4 species, RBP4-L (truncated at last C-terminal leucine) and RBP4-LL (truncated at both C-terminal leucines), has been reported in serum of hemodialysis patients. Since little is known about the occurrence of RBP4 species during the progression of CKD it was the aim of this study to analyse this possible association. The presence of RBP4, RBP4-L, RBP4- LL and transthyretin (TTR) was assessed in serum of 45 healthy controls and 52 patients with stage 2-5 of CKD using ELISA and RBP4 immunoprecipitation with subsequent MALDI-TOF-MS analysis. A reduction of glomerular filtration rate was accompanied by a gradual elevation of RBP4 serum levels and relative amounts of RBP4-LL. Correlation analysis revealed a strong association of the RBP4-TTR ratio with parameters of lipid metabolism and with diabetes-related factors. In conclusion, RBP4 serum concentration and the appearance of RBP4-LL seem to be influenced by kidney function. Furthermore, the RBP4-TTR ratio may provide diagnostic potential with regard to metabolic complications in CKD patients.}, language = {en} } @misc{AlterOttvonWebskyetal.2011, author = {Alter, Markus L. and Ott, Ina and von Websky, Karoline and Tsuprykov, Oleg and Sharkovska, Yuliya and Krause-Relle, Katharina and Raila, Jens and Henze, Andrea and Kretschmer, Axel and Stasch, Johannes-Peter and Hocher, Berthold}, title = {Additional stimulation of sGC on top of standard treatment with ARB`s may offer a new therapeutic approach for the treatment of diabetic nephropathy resistant to ARB treatment alone}, series = {Postprints der Universit{\"a}t Potsdam : Mathematisch-Naturwissenschaftliche Reihe}, journal = {Postprints der Universit{\"a}t Potsdam : Mathematisch-Naturwissenschaftliche Reihe}, number = {855}, issn = {1866-8372}, doi = {10.25932/publishup-42825}, url = {http://nbn-resolving.de/urn:nbn:de:kobv:517-opus4-428250}, pages = {4}, year = {2011}, abstract = {Background Riociguat is the first of a new class of drugs, the soluble guanylate cyclase (sGC) stimulators. Riociguat has a dual mode of action: it sensitizes sGC to the body's own NO and can also increase sGC activity in the absence of NO. The NO-sGC-pathway is impaired in many cardiovascular diseases such as heart failure, pulmonary hypertension and diabetic nephropathy (DN). DN leads to high cardiovascular morbidity and mortality. There is still a high unmet medical need. The urinary albumin excretion rate is a predictive biomarker for these clinical events. Therefore, we investigated the effect of riociguat, alone and in combination with the angiotensin II receptor antagonist (ARB) telmisartan on the progression of DN in diabetic eNOS knock out mice, a new model closely resembling human pathology. Methods Seventy-six male eNOS knockout C57BL/6J mice were divided into 4 groups after receiving intraperitoneal high-dose streptozotocin: telmisartan (1 mg/kg), riociguat (3 mg/kg), riociguat+telmisartan (3 and 1 mg/kg), and vehicle. Fourteen mice were used as non-diabetic controls. After 12 weeks, urine and blood were obtained and blood pressure measured. Glucose concentrations were highly increased and similar in all diabetic groups. Results Riociguat, alone (105.2 ± 2.5 mmHg; mean±SEM; n = 14) and in combination with telmisartan (105.0 ± 3.2 mmHg; n = 12), significantly reduced blood pressure versus diabetic controls (117.1 ± 2.2 mmHg; n = 14; p = 0.002 and p = 0.004, respectively), whereas telmisartan alone (111.2 ± 2.6 mmHg) showed a modest blood pressure lowering trend (p = 0.071; n = 14). The effects of single treatment with either riociguat (97.1 ± 15.7 µg/d; n = 13) or telmisartan (97.8 ± 26.4 µg/d; n = 14) did not significantly lower albumin excretion on its own (p = 0.067 and p = 0.101, respectively). However, the combined treatment led to significantly lower urinary albumin excretion (47.3 ± 9.6 µg/d; n = 12) compared to diabetic controls (170.8 ± 34.2 µg/d; n = 13; p = 0.004), and reached levels similar to non-diabetic controls (31.4 ± 10.1 µg/d, n = 12). Conclusion Riociguat significantly reduced urinary albumin excretion in diabetic eNOS knock out mice that were refractory to treatment with ARB's alone. Patients with diabetic nephropathy refractory to treatment with ARB's have the worst prognosis among all patients with diabetic nephropathy. Our data indicate that additional stimulation of sGC on top of standard treatment with ARB`s may offer a new therapeutic approach for patients with diabetic nephropathy resistant to ARB treatment.}, language = {en} } @article{ThawnashomTungtrongchitrChanchayetal.2011, author = {Thawnashom, Kittisak and Tungtrongchitr, Rungsunn and Chanchay, Siriporn and Tungtrongchitr, Anchalee and Raila, Jens and Henze, Andrea and Schweigert, Florian J.}, title = {Association between Retinol-Binding protein and renal function among Asian subjects with type 2 diabetes mellitus a cross-sectiona{\"o} study}, series = {The Southeast Asian journal of tropical medicine and public health : official publication of the SEAMEO Regional Tropical Medicine and Public Health Project (TROPMED)}, volume = {42}, journal = {The Southeast Asian journal of tropical medicine and public health : official publication of the SEAMEO Regional Tropical Medicine and Public Health Project (TROPMED)}, number = {4}, publisher = {SEAMEO}, address = {Bangkok}, issn = {0125-1562}, pages = {936 -- 945}, year = {2011}, abstract = {Retinol-binding protein 4 (RBP4) has been suggested as new adipokine, possibly linking obesity to type 2 diabetes mellitus (T2DM). Since the kidneys are the main site of RBP4 degradation and since renal failure is a frequent co-morbid condition with diabetes mellitus, we evaluated the association among RBP4, renal function and T2DM in an Asian population. RBP4 serum levels were analyzed in 110 subjects (50 with T2DM) using an enzyme-linked immunosorbent assay (ELISA). Based on a cut-off estimated glomerular filtration rate (eGFR) of 60 ml/min per 1.73 m(2) (calculated according the abbreviated MDRD formula which uses serum creatinine level, age and gender) and on the T2DM status, subjects were assigned to four subgroups: Group A - controls with an eGFR > 60 ml/min per 1.73 m(2), Group B - controls with an eGFR < 60 ml/min per 1.73 m(2), Group C- T2DM subjects with an eGFR>60 ml/min per 1.73 m(2), and Group D - T2DM subjects with an eGFR <60 ml/ mm per 1.73 m(2). In both the T2DM and control groups, RBP4 levels were higher in subjects with an eGFR < 60 ml/min per 1.73 m(2) than in subjects with an eGFR >60 ml/min per 1.73 m(2). However, the difference was only significant between the control groups (p <0.05). After adjusting for age, gender, BMI, eGFR and the presence of T2DM, eGFR, not T2DM, was associated with plasma RBP4 levels (p<0.05). These results suggest among Asians the eGFR, but not the presence of T2DM, is a major determinant of RBP4 serum levels. The eGFR should be taken into account when evaluating the role of RBP4 in the pathogenesis of insulin resistance and T2DM.}, language = {en} } @article{HenzeRailaKempfetal.2011, author = {Henze, Andrea and Raila, Jens and Kempf, Caroline and Reinke, Petra and Sefrin, Anett and Querfeld, Uwe and Schweigert, Florian J.}, title = {Vitamin A metabolism is changed in donors after living-kidney transplantation an observational study}, series = {Lipids in health and disease}, volume = {10}, journal = {Lipids in health and disease}, number = {23}, publisher = {BioMed Central}, address = {London}, issn = {1476-511X}, doi = {10.1186/1476-511X-10-231}, pages = {7}, year = {2011}, abstract = {Background: The kidneys are essential for the metabolism of vitamin A (retinol) and its transport proteins retinol-binding protein 4 (RBP4) and transthyretin. Little is known about changes in serum concentration after living donor kidney transplantation (LDKT) as a consequence of unilateral nephrectomy; although an association of these parameters with the risk of cardiovascular diseases and insulin resistance has been suggested. Therefore we analyzed the concentration of retinol, RBP4, apoRBP4 and transthyretin in serum of 20 living-kidney donors and respective recipients at baseline as well as 6 weeks and 6 months after LDKT. Results: As a consequence of LDKT, the kidney function of recipients was improved while the kidney function of donors was moderately reduced within 6 weeks after LDKT. With regard to vitamin A metabolism, the recipients revealed higher levels of retinol, RBP4, transthyretin and apoRBP4 before LDKT in comparison to donors. After LDKT, the levels of all four parameters decreased in serum of the recipients, while retinol, RBP4 as well as apoRBP4 serum levels of donors increased and remained increased during the follow-up period of 6 months. Conclusion: LDKT is generally regarded as beneficial for allograft recipients and not particularly detrimental for the donors. However, it could be demonstrated in this study that a moderate reduction of kidney function by unilateral nephrectomy, resulted in an imbalance of components of vitamin A metabolism with a significant increase of retinol and RBP4 and apoRBP4 concentration in serum of donors.}, language = {en} } @article{EspeRailaHenzeetal.2011, author = {Espe, Katharina M. and Raila, Jens and Henze, Andrea and Krane, Vera and Schweigert, Florian J. and Hocher, Berthold and Wanner, Christoph and Drechsler, Christiane}, title = {Impact of vitamin A on clinical outcomes in haemodialysis patients}, series = {Nephrology, dialysis, transplantation}, volume = {26}, journal = {Nephrology, dialysis, transplantation}, number = {12}, publisher = {Oxford Univ. Press}, address = {Oxford}, organization = {German Diabetes \& Dialysis Study I}, issn = {0931-0509}, doi = {10.1093/ndt/gfr171}, pages = {4054 -- U583}, year = {2011}, abstract = {Background. Patients on maintenance haemodialysis treatment experience an excessive risk of cardiovascular disease and mortality. The vitamin A concentration is known to be higher in these patients compared to the general population where elevated vitamin A concentrations are associated with adverse outcome. The impact of vitamin A on morbidity and mortality in end-stage renal disease patients is controversial and is the topic of this study. Methods. We analysed plasma retinol and retinol-binding protein 4 (RBP4) in 1177 diabetic haemodialysis patients, who participated in the German Diabetes and Dialysis Study (median follow-up 4 years). By Cox regression analyses hazard ratios (HRs) were determined for pre-specified, adjudicated end points according to baseline concentrations. Results. Patients had a mean age of 66 +/- 8 years, mean retinol and RBP4 concentrations of 3.28 (0.71-7.44) and 4.02 (1.28-10.1) mu mol/L, respectively. Patients with retinol concentrations in the first quartile (<2.6 mu mol/L) had an almost 2-fold increased risk of all-cause mortality compared to patients of the fourth quartile [>3.9 mu mol/L; HR 1.81, 95\% confidence interval (CI) 1.43-2.30]. There was a strong association between low retinol and the risk of sudden cardiac death (SCD, HR 2.22, 95\% CI 1.41-3.50) and fatal infection (HR 2.19, 95\% CI 1.26-3.82). Patients with RBP4 concentrations in the lowest quartile (<3.0 mu mol/L) were more likely to die of any cause (HR 1.43, 95\% CI 1.14-1.80), experience SCD (HR 1.97, 95\% CI 1.28-3.03) and cardiovascular events (HR 1.43, 95\% CI 1.10-1.85). Conclusion. This large cohort study shows a strong association of low retinol and RBP4 concentrations with SCD and all-cause mortality in diabetic haemodialysis patients.}, language = {en} } @article{HenzeAumerGrabneretal.2011, author = {Henze, Andrea and Aumer, Franziska and Grabner, Arthur and Raila, Jens and Schweigert, Florian J.}, title = {Genetic differences in the serum proteome of horses, donkeys and mules are detectable by protein profiling}, series = {The British journal of nutrition : an international journal devoted to the science of human and animal nutrition}, volume = {106}, journal = {The British journal of nutrition : an international journal devoted to the science of human and animal nutrition}, publisher = {Cambridge Univ. Press}, address = {Cambridge}, issn = {0007-1145}, doi = {10.1017/S0007114511000845}, pages = {S170 -- S173}, year = {2011}, abstract = {Although horses and donkeys belong to the same genus, their genetic characteristics probably result in specific proteomes and post-translational modifications (PTM) of proteins. Since PTM can alter protein properties, specific PTM may contribute to species-specific characteristics. Therefore, the aim of the present study was to analyse differences in serum protein profiles of horses and donkeys as well as mules, which combine the genetic backgrounds of both species. Additionally, changes in PTM of the protein transthyretin (TTR) were analysed. Serum protein profiles of each species (five animals per species) were determined using strong anion exchanger ProteinChips (R) (Bio-Rad, Munich, Germany) in combination with surface-enhanced laser desorption ionisation-time of flight MS. The PTM of TTR were analysed subsequently by immunoprecipitation in combination with matrix-assisted laser desorption ionisation-time of flight MS. Protein profiling revealed species-specific differences in the proteome, with some protein peaks present in all three species as well as protein peaks that were unique for donkeys and mules, horses and mules or for horses alone. The molecular weight of TTR of horses and donkeys differed by 30Da, and both species revealed several modified forms of TTR besides the native form. The mass spectra of mules represented a merging of TTR spectra of horses and donkeys. In summary, the present study indicated that there are substantial differences in the proteome of horses and donkeys. Additionally, the results probably indicate that the proteome of mules reveal a higher similarity to donkeys than to horses.}, language = {en} } @misc{HenzeAumerGrabneretal.2011, author = {Henze, Andrea and Aumer, Franziska and Grabner, Arthur and Raila, Jens and Schweigert, Florian J.}, title = {Genetic differences in the serum proteome of horses, donkeys and mules are detectable by protein profiling}, series = {Postprints der Universit{\"a}t Potsdam : Mathematisch-Naturwissenschaftliche Reihe}, journal = {Postprints der Universit{\"a}t Potsdam : Mathematisch-Naturwissenschaftliche Reihe}, number = {567}, issn = {1866-8372}, doi = {10.25932/publishup-41288}, url = {http://nbn-resolving.de/urn:nbn:de:kobv:517-opus4-412886}, pages = {4}, year = {2011}, abstract = {Although horses and donkeys belong to the same genus, their genetic characteristics probably result in specific proteomes and post-translational modifications (PTM) of proteins. Since PTM can alter protein properties, specific PTM may contribute to species-specific characteristics. Therefore, the aim of the present study was to analyse differences in serum protein profiles of horses and donkeys as well as mules, which combine the genetic backgrounds of both species. Additionally, changes in PTM of the protein transthyretin (TTR) were analysed. Serum protein profiles of each species (five animals per species) were determined using strong anion exchanger ProteinChips (R) (Bio-Rad, Munich, Germany) in combination with surface-enhanced laser desorption ionisation-time of flight MS. The PTM of TTR were analysed subsequently by immunoprecipitation in combination with matrix-assisted laser desorption ionisation-time of flight MS. Protein profiling revealed species-specific differences in the proteome, with some protein peaks present in all three species as well as protein peaks that were unique for donkeys and mules, horses and mules or for horses alone. The molecular weight of TTR of horses and donkeys differed by 30Da, and both species revealed several modified forms of TTR besides the native form. The mass spectra of mules represented a merging of TTR spectra of horses and donkeys. In summary, the present study indicated that there are substantial differences in the proteome of horses and donkeys. Additionally, the results probably indicate that the proteome of mules reveal a higher similarity to donkeys than to horses.}, language = {en} } @article{OttAltervonWebskyetal.2012, author = {Ott, Ina M. and Alter, Markus L. and von Websky, Karoline and Kretschmer, Axel and Tsuprykov, Oleg and Sharkovska, Yuliya and Krause-Relle, Katharina and Raila, Jens and Henze, Andrea and Stasch, Johannes-Peter and Hocher, Berthold}, title = {Effects of Stimulation of Soluble Guanylate Cyclase on Diabetic Nephropathy in Diabetic eNOS Knockout Mice on Top of Angiotensin II Receptor Blockade}, series = {PLOS ONE}, volume = {7}, journal = {PLOS ONE}, number = {8}, publisher = {PUBLIC LIBRARY SCIENCE}, address = {SAN FRANCISCO}, issn = {1932-6203}, doi = {10.1371/journal.pone.0042623}, pages = {9}, year = {2012}, abstract = {The prevalence of diabetes mellitus and its complications, such as diabetic nephropathy (DN), is rising worldwide and prevention and treatment are therefore becoming increasingly important. Therapy of DN is particularly important for patients who do not adequately respond to angiotensin receptor blocker (ARB) treatment. Novel approaches include the stimulation of soluble guanylate cyclase (sGC) as it is reported to have beneficial effects on cardiac and renal damage. We aimed to investigate the effects of the sGC stimulator riociguat and ARB telmisartan on kidney function and structure in a hypertensive model of diabetic nephropathy. Seventy-six diabetic male eNOS knockout C57BL/6J mice were randomly divided after having received streptozotocin: telmisartan (1 mg/kg/d), riociguat (3 mg/kg/d), riociguat+telmisartan (3+1 mg/kg/d), and vehicle. Fourteen mice were used as non-diabetic controls. Treatment duration was 11 weeks. Glucose concentrations were increased and similar in all diabetic groups. Telmisartan insignificantly reduced blood pressure by 5.9 mmHg compared with diabetic controls (111.2 +/- 2.3 mmHg vs. 117.1 +/- 2.2 mmHg; p = 0.071). Treatment with riociguat both alone and in combination with telmisartan led to a significant reduction of blood pressure towards diabetic vehicle (105.2 +/- 2.5 mmHg and 105.0 +/- 3.2 mmHg, respectively, vs. 117.1 +/- 2.2 mmHg). Combined treatment also significantly decreased albuminuria compared with diabetic controls (47.3 +/- 9.6 mu g/24 h vs. 170.8 +/- 34.2 mu g/24 h; p = 0.002) reaching levels similar to those of non-diabetic controls (34.4 +/- 10.6 mu g/24 h), whereas the reduction by single treatment with either telmisartan (97.8 +/- 26.4 mu g/24 h) or riociguat (97.1 +/- 15.7 mu g/24 h) was not statistically significant. The combination treatment led to a significant (p < 0.01) decrease of tissue immunoreactivity of malondialdehyde, as consequence of reduced oxidative stress. In conclusion, stimulation of sGC significantly reduced urinary albumin excretion in diabetic eNOS knockout mice treated already with ARB. Thus, this new drug class on top of standard ARBs administration may offer a new therapeutic approach for patients resistant to ARB treatment.}, language = {en} } @inproceedings{EspeRailaHenzeetal.2012, author = {Espe, Katharina M. and Raila, Jens and Henze, Andrea and Blouin, Katja and Schneider, A. and Schmiedeke, D. and Krane, Vera and Schweigert, Florian J. and Hocher, Berthold and Wanner, Christoph and Drechsler, Christiane}, title = {Low vitamin E plasma levels are associated with cerebrovascular events and mortality in hemodialysis patients}, series = {Annals of nutrition \& metabolism : journal of nutrition, metabolic diseases and dietetics ; an official journal of International Union of Nutritional Sciences (IUNS)}, volume = {60}, booktitle = {Annals of nutrition \& metabolism : journal of nutrition, metabolic diseases and dietetics ; an official journal of International Union of Nutritional Sciences (IUNS)}, number = {2}, publisher = {Karger}, address = {Basel}, issn = {0250-6807}, pages = {137 -- 137}, year = {2012}, language = {en} } @article{HenzeEspeWanneretal.2012, author = {Henze, Andrea and Espe, Katharina M. and Wanner, Christoph and Krane, Vera and Raila, Jens and Hocher, Berthold and Schweigert, Florian J. and Drechsler, Christiane}, title = {Transthyretin predicts cardiovascular outcome in hemodialysis patients with type 2 diabetes}, series = {Diabetes care}, volume = {35}, journal = {Diabetes care}, number = {11}, publisher = {American Diabetes Association}, address = {Alexandria}, issn = {0149-5992}, doi = {10.2337/dc12-0455}, pages = {2365 -- 2372}, year = {2012}, abstract = {OBJECTIVE-BMI and albumin are commonly accepted parameters to recognize wasting in dialysis patients and are powerful predictors of morbidity and mortality. However, both parameters reveal limitations and may not cover the entire range of patients with wasting. The visceral protein transthyretin (TTR) may be helpful in overcoming the diagnostic and prognostic gap. Therefore, the aim of this study was to assess the association of TTR with morbidity and mortality in hemodialysis patients. RESEARCH DESIGN AND METHODS-The TTR concentration was determined in plasma samples of 1,177 hemodialysis patients with type 2 diabetes. Cox regression analyses were used to determine hazard ratios (HRs) for the risk of cardiovascular end points (CVEs) and mortality according to quartiles of TTR concentration for the total study cohort and the subgroups BMI >= 23 kg/m(2), albumin concentration >= 3.8 g/dL, and a combination of both. RESULTS-A low TTR concentration was associated with an increased risk for CVE for the total study cohort (HR 1.65 [95\% CI 1.27-2.14]), patients with BMI >= 23 kg/m(2) (1.70 [1.22-2.37]), albumin >= 3.8 g/dL (1.68 [1.17-2.42]), and the combination of both (1.69 [1.13-2.53]). Additionally, a low TTR concentration predicted mortality for the total study cohort (1.79 [1.43-2.24]) and patients with BMI >= 23 kg/m(2) (1.46 [1.09-1.95]). CONCLUSIONS-The current study demonstrated that TTR is a useful predictor for cardiovascular outcome and mortality in diabetic hemodialysis patients. TTR was particularly useful in patients who were not identified to be at risk by BMI or albumin status.}, language = {en} } @article{AlterOttvonWebskyetal.2012, author = {Alter, Markus L. and Ott, Ina M. and von Websky, Karoline and Tsuprykov, Oleg and Sharkovska, Yuliya and Krause-Relle, Katharina and Raila, Jens and Henze, Andrea and Klein, Thomas and Hocher, Berthold}, title = {DPP-4 Inhibition on top of angiotensin receptor blockade offers a new therapeutic approach for diabetic nephropathy}, series = {Kidney \& blood pressure research : official organ of the Gesellschaft f{\"u}r Nephrologie}, volume = {36}, journal = {Kidney \& blood pressure research : official organ of the Gesellschaft f{\"u}r Nephrologie}, number = {1}, publisher = {Karger}, address = {Basel}, issn = {1420-4096}, doi = {10.1159/000341487}, pages = {119 -- 130}, year = {2012}, abstract = {Background: The need for an improved treatment for diabetic nephropathy is greatest in patients who do not adequately respond to angiotensin II receptor blockers (ARBs). This study investigated the effect of the novel dipeptidyl peptidase-4 inhibitor linagliptin alone and in combination with the ARB telmisartan on the progression of diabetic nephropathy in diabetic endothelial nitric oxide synthase (eNOS) knockout mice. Methods: Sixty male eNOS knockout C57BL/6J mice were divided into four groups after receiving intraperitoneal high-dose streptozotocin: telmisartan (1 mg/kg), linagliptin (3 mg/kg), linagliptin + telmisartan (3 mg/kg + 1 mg/kg) and vehicle. Fourteen mice were used as non-diabetic controls. Results: After 12 weeks, urine and blood were obtained and blood pressure measured. Glucose concentrations were increased and similar in all diabetic groups. Telmisartan alone reduced systolic blood pressure by 5.9 mmHg versus diabetic controls (111.2 +/- 2.3 mmHg vs 117.1 +/- 2.2 mmHg; mean +/- SEM; P = 0.071). Combined treatment significantly reduced albuminuria compared with diabetic controls (71.7 +/- 15.3 mu g/24 h vs 170.8 +/- 34.2 mu g/24 h; P = 0.017), whereas the effects of single treatment with either telmisartan (97.8 +/- 26.4 mu g/24 h) or linagliptin (120.8 +/- 37.7 mu g/24 h) were not statistically significant. DPP-4 inhibition, alone and in combination, led to significantly lower plasma osteopontin levels compared with telmisartan alone. Histological analysis revealed reduced glomerulosclerosis after Linagliptin alone and in combination with telmisartan in comparison to non treated diabetic animals (p < 0.01 and p < 0.05). Kidney malonaldehyde immune-reactivity, a marker of oxidative stress, was significantly lower in animals treated with linagliptin. Conclusions: DPP-4 inhibition on top of ARB treatment significantly reduced urinary albumin excretion and oxidative stress in diabetic eNOS knockout mice. Linagliptin on top of an angiotensin II receptor blocker may offer a new therapeutic approach for patients with diabetic nephropathy.}, language = {en} } @article{EspeRailaHenzeetal.2013, author = {Espe, Katharina M. and Raila, Jens and Henze, Andrea and Blouin, Katja and Schneider, Andreas and Schmiedeke, Daniel and Krane, Vera and Pilz, Stefan and Schweigert, Florian J. and Hocher, Berthold and Wanner, Christoph and Drechsler, Christiane}, title = {Low plasma alpha-tocopherol concentrations and adverse clinical outcomes in diabetic hemodialysis patients}, series = {Clinical journal of the American Society of Nephrology}, volume = {8}, journal = {Clinical journal of the American Society of Nephrology}, number = {3}, publisher = {American Society of Nephrology}, address = {Washington}, organization = {German Diabet \& Dialysis Study Inv}, issn = {1555-9041}, doi = {10.2215/CJN.04880511}, pages = {452 -- 458}, year = {2013}, abstract = {Background and objectives Trials with the antioxidant vitamin E have failed to show benefit in the general population. Considering the different causes of death in ESRD, this study investigated the association between plasma concentrations of alpha-tocopherol and specific clinical outcomes in diabetic hemodialysis patients. Design, settings, participants, \& measurements In 1046 diabetic hemodialysis patients (participants of the German Diabetes and Dialysis Study), alpha-tocopherol was measured in plasma by reversed-phase HPLC. By Cox regression analyses, hazard ratios were determined for prespecified end points according to baseline plasma alpha-tocopherol levels: sudden death (n=134), myocardial infarction (n=172), stroke (n=89), combined cardiovascular events (n=398), fatal infection (n=107), and all-cause mortality (n=508). Results Patients had a mean age of 66 8 years, and mean plasma alpha-tocopherol level was 22.8+/-9.6 mu mol/L. Levels of alpha-tocopherol were highly correlated to triglycerides (r=0.63, P<0.001). Patients in the lowest alpha-tocopherol quartile had (in unadjusted analyses) a 79\% higher risk of stroke and a 31\% higher risk of all-cause mortality compared with patients in the highest quartile. The associations were attenuated after adjustment for confounders (hazard ratio(stroke)=1.56, 95\% confidence interval=0.75-3.25; hazard ratio(mortality)=1.22, 95\% confidence interval=0.89-1.69, respectively). There was no association between alpha-tocopherol and myocardial infarction, sudden death, or infectious death. Conclusions Plasma alpha-tocopherol concentrations were not independently associated with cardiovascular outcomes, infectious deaths, or all-cause mortality in diabetic hemodialysis patients. The lack of association can partly be explained by a confounding influence of malnutrition, which should be considered in the planning of trials to reduce cardiovascular risk in dialysis patients.}, language = {en} } @article{HenzeRailaScholzeetal.2013, author = {Henze, Andrea and Raila, Jens and Scholze, Alexandra and Zidek, Walter and Tepel, Martin and Schweigert, Florian J.}, title = {Does N-Acetylcysteine modulate post-translational modifications of transthyretin in hemodialysis patients?}, series = {Antioxidants \& redox signaling}, volume = {19}, journal = {Antioxidants \& redox signaling}, number = {11}, publisher = {Liebert}, address = {New Rochelle}, issn = {1523-0864}, doi = {10.1089/ars.2012.5125}, pages = {1166 -- 1172}, year = {2013}, abstract = {It is assumed that effects of the thiol antioxidant N-acetylcysteine (NAC) are mediated by interaction with protein-associated cysteine residues, however, information on protein level in vivo are missing. Therefore, we analyzed NAC-induced modifications of the protein transthyretin (TTR) in plasma of hemodialysis patients in a randomized, placebo-controlled study. TTR was selected due to its low molecular weight and the free cysteine residue in the polypeptide chain, which is known to be extensively modified by formation of mixed disulfides. The intravenous application of NAC during a hemodialysis session resulted in a substantial increase of native TTR from median 15\% (range 8.8\%-30\%) to median 40\% (37-50) and reduction of S-cysteinylated TTR [51\% (44-60) vs. 6.6\% (2.4-10)]. Additionally the pronounced formation of a TTR-NAC adduct was detected. However, all these modifications seemed to be reversible. Additionally, in vitro incubation of plasma with NAC confirmed the in vivo results and indicated that changes in post-translational modification pattern of TTR were a function of NAC concentration. Based on these observations and the essential metabolic and biochemical role of protein-associated cysteine residues we hypothesize that the interaction of NAC with proteins may explain altered protein functions due to modification of cysteine residues. Antioxid. Redox Signal. 19, 1166-1172.}, language = {en} } @article{MuenznerTuviaDeutschmannetal.2013, author = {M{\"u}nzner, Matthias and Tuvia, Neta and Deutschmann, Claudia and Witte, Nicole and Tolkachov, Alexander and Valai, Atijeh and Henze, Andrea and Sander, Leif E. and Raila, Jens and Schupp, Michael}, title = {Retinol-binding protein 4 and its membrane receptor STRA6 control adipogenesis by regulating cellular retinoid homeostasis and retinoic acid receptor alpha activity}, series = {Molecular and cellular biology}, volume = {33}, journal = {Molecular and cellular biology}, number = {20}, publisher = {American Society for Microbiology}, address = {Washington}, issn = {0270-7306}, doi = {10.1128/MCB.00221-13}, pages = {4068 -- 4082}, year = {2013}, abstract = {Retinoids are vitamin A (retinol) derivatives and complex regulators of adipogenesis by activating specific nuclear receptors, including the retinoic acid receptor (RAR) and retinoid X receptor (RXR). Circulating retinol-binding protein 4 (RBP4) and its membrane receptor STRA6 coordinate cellular retinol uptake. It is unknown whether retinol levels and the activity of RAR and RXR in adipocyte precursors are linked via RBP4/STRA6. Here, we show that STRA6 is expressed in precursor cells and, dictated by the apo-and holo-RBP4 isoforms, mediates bidirectional retinol transport that controls RAR alpha activity and subsequent adipocyte differentiation. Mobilization of retinoid stores in mice by inducing RBP4 secretion from the liver activated RAR alpha signaling in the precursor cell containing the stromal-vascular fraction of adipose tissue. Retinol-loaded holo-RBP4 blocked adipocyte differentiation of cultured precursors by activating RAR alpha. Remarkably, retinol-free apo-RBP4 triggered retinol efflux that reduced cellular retinoids, RAR alpha activity, and target gene expression and enhanced adipogenesis synergistically with ectopic STRA6. Thus, STRA6 in adipocyte precursor cells links nuclear RAR alpha activity to the circulating RBP4 isoforms, whose ratio in obese mice was shifted toward limiting the adipogenic potential of their precursors. This novel cross talk identifies a retinoldependent metabolic function of RBP4 that may have important implications for the treatment of obesity.}, language = {en} } @inproceedings{HenzeRailaScholzeetal.2013, author = {Henze, Andrea and Raila, Jens and Scholze, Alexandra and Schweigert, Florian J. and Tepel, Martin}, title = {Administration of N-Acetylcyteine causes beneficial posttranslationalmodifications of transthyretin in hemodialysis patients}, series = {Nephrology, dialysis, transplantation}, volume = {28}, booktitle = {Nephrology, dialysis, transplantation}, number = {2}, publisher = {Oxford Univ. Press}, address = {Oxford}, issn = {0931-0509}, pages = {164 -- 164}, year = {2013}, language = {en} } @article{FredeHenzeKhaliletal.2014, author = {Frede, Katja and Henze, Andrea and Khalil, Mahmoud and Baldermann, Susanne and Schweigert, Florian J. and Rawel, Harshadrai Manilal}, title = {Stability and cellular uptake of lutein-loaded emulsions}, series = {Journal of functional food}, volume = {8}, journal = {Journal of functional food}, publisher = {Elsevier}, address = {Amsterdam}, issn = {1756-4646}, doi = {10.1016/j.jff.2014.03.011}, pages = {118 -- 127}, year = {2014}, abstract = {The carotenoid lutein can improve human health. Since only a fraction is absorbed from food, lutein supplementation might be recommended. Emulsions could be good carrier systems to improve the bioavailability of lutein. Six different emulsifier compositions were used in this study to prepare lutein-loaded emulsions: beta-lactoglobulin, beta-lactoglobulin/lecithin, Biozate 1, Biozate 1/lecithin, Been 20 and Tween 20/lecithin. The droplet size, resistance to creaming, lutein stability, cytotoxicity and lutein uptake by HT29 cells were investigated. The whey protein beta-lactoglobulin, the whey protein hydrolysate Biozate 1 and the combination with lecithin brought the most promising results. The small droplet sizes and resistance to creaming were an indication of physical stable emulsions. Furthermore, these emulsifiers prevented oxidation of lutein. The choice of emulsifier had a strong impact on the uptake by HT29 cells. The highest lutein absorption was observed with the combination of Biozate 1 and lecithin.}, language = {en} } @article{DanquahDobruckyFranketal.2015, author = {Danquah, Ina and Dobrucky, C. Lydia and Frank, Laura K. and Henze, Andrea and Amoako, Yaw A. and Bedu-Addo, George and Raila, Jens and Schulze, Matthias Bernd and Mockenhaupt, Frank P. and Schweigert, Florian J.}, title = {Vitamin A: potential misclassification of vitamin A status among patients with type 2 diabetes and hypertension in urban Ghana}, series = {The American journal of clinical nutrition : a publication of the American Society for Nutrition, Inc.}, volume = {102}, journal = {The American journal of clinical nutrition : a publication of the American Society for Nutrition, Inc.}, number = {1}, publisher = {American Society for Nutrition, Inc.}, address = {Bethesda}, issn = {0002-9165}, doi = {10.3945/ajcn.114.101345}, pages = {207 -- 214}, year = {2015}, abstract = {Background: Sub-Saharan Africa is facing a double burden of malnutrition: vitamin A deficiency (VAD) prevails, whereas the nutrition-related chronic conditions type 2 diabetes (T2D) and hypertension are emerging. Serum retinol a VAD marker increases in kidney disease and decreases in inflammation, which can partly be attributed to alterations in the vitamin A transport proteins retinol-binding protein 4 (RBP4) and prealbumin. Kidney dysfunction and inflammation commonly accompany T2D and hypertension. Objective: Among urban Ghanaians, we investigated the associations of T2D and hypertension with serum retinol as well as the importance of kidney function and inflammation in this regard. Design: A hospital-based, case-control study in individuals for risk factors of T2D, hypertension, or both was conducted in Kumasi, Ghana (328 controls, 197 with T2D, 354 with hypertension, and 340 with T2D plus hypertension). In 1219 blood samples, serum retinol, RBP4, and prealbumin were measured. Urinary albumin and estimated glomerular filtration rate (eGFR) defined kidney function. C-reactive protein (CRP) >5 mg/L indicated inflammation. We identified associations of T2D and hypertension with retinol by linear regression and calculated the contribution of RBP4, prealbumin, urinary albumin, eGFR, and CRP to these associations as the percentages of the explained variance of retinol. Results: VAD (retinol <1.05 mu mol/L) was present in 10\% of this predominantly female, middle-aged, overweight, and deprived population. Hypertension, but not T2D, was positively associated with retinol (beta: 0.12; 95\% CI: 0.08, 0,17), adjusted for age, sex, socioeconomic factors, anthropometric measurements, and lifestyle. In addition to RBP4 (72\%) and prealbumin (22\%), the effect of increased retinol on individuals with hypertension was mainly attributed to impaired kidney function (eGFR: 30\%; urinary albumin: 5\%) but not to inflammation. Conclusions: In patients with hypertension, VAD might be underestimated because of increased serum retinol in the context of kidney dysfunction. Thus, the interpretation of serum retinol in sub-Saharan Africa should account for hypertension status.}, language = {en} } @article{FruscalzoLonderoDriuletal.2015, author = {Fruscalzo, Arrigo and Londero, Ambrogio P. and Driul, Lorenza and Henze, Andrea and Tonutti, Laura and Ceraudo, Maria and Zanotti, Giuseppe and Berni, Rodolfo and Schweigert, Florian J. and Raila, Jens}, title = {First trimester concentrations of the TTR-RBP4-retinol complex components as early markers of insulin-treated gestational diabetes mellitus}, series = {Clinical chemistry and laboratory medicine : journal of the Forum of the European Societies of Clinical Chemistry - the European Branch of the International Federation of Clinical Chemistry and Laboratory Medicine}, volume = {53}, journal = {Clinical chemistry and laboratory medicine : journal of the Forum of the European Societies of Clinical Chemistry - the European Branch of the International Federation of Clinical Chemistry and Laboratory Medicine}, number = {10}, publisher = {De Gruyter}, address = {Berlin}, issn = {1434-6621}, doi = {10.1515/cclm-2014-0929}, pages = {1643 -- 1651}, year = {2015}, abstract = {Background: The objective of the study was to investigate the relationship between first trimester maternal serum levels of the TTR-RBP4-ROH complex components and the later insurgence of an altered glucose metabolism during pregnancy. Methods: Retrospective case control study including 96 patients between the 12th and 14th week of gestation, 32 that developed gestational diabetes mellitus (GDM), respectively, 21 non-insulin-treated (dGDM) and 11 insulin-treated (iGDM), 20 large for gestational age fetuses (LGA) without GDM and 44 patients with normal outcome as control. Serum concentrations of RBP4 and TTR were assessed by ELISA; serum concentration of ROH by reverse-phase high performance liquid chromatography (rpHPLC). The molecular heterogeneity of TTR and RBP4 was analyzed after immunoprecipitation by matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF-MS). Results: iGDM patients were characterized by reduced TTR, RBP4 and ROH compared to controls (respectively, iGDM vs. controls, mean +/- SD: TTR 3.96 +/- 0.89 mu mol/L vs. 4.68 +/- 1.21 mu mol/L, RBP4 1.13 +/- 0.25 mu mol/L vs. 1.33 +/- 0.38 mu mol/L and ROH 1.33 +/- 0.17 mu mol/L vs. 1.62 +/- 0.29 mu mol/L, p < 0.05). TTR containing Gly10 in place of Cys10 was lower in the iGDM group (p < 0.05) compared to controls. In the final logistic regression model ROH significantly predicted the diagnosis of iGDM (OR 0.93, 95\% CI 0.87-0.98, p < 0.05). Conclusions: First trimester maternal serum ROH, RBP4 and TTR represent potential biomarkers associated with the development of iGDM.}, language = {en} } @article{HenzeHomannRohnetal.2016, author = {Henze, Andrea and Homann, Thomas and Rohn, Isabelle and Aschner, Michael A. and Link, Christopher D. and Kleuser, Burkhard and Schweigert, Florian J. and Schwerdtle, Tanja and Bornhorst, Julia}, title = {Caenorhabditis elegans as a model system to study post-translational modifications of human transthyretin}, series = {Scientific reports}, volume = {6}, journal = {Scientific reports}, publisher = {Nature Publishing Group}, address = {London}, issn = {2045-2322}, doi = {10.1038/srep37346}, pages = {12}, year = {2016}, abstract = {The visceral protein transthyretin (TTR) is frequently affected by oxidative post-translational protein modifications (PTPMs) in various diseases. Thus, better insight into structure-function relationships due to oxidative PTPMs of TTR should contribute to the understanding of pathophysiologic mechanisms. While the in vivo analysis of TTR in mammalian models is complex, time- and resource-consuming, transgenic Caenorhabditis elegans expressing hTTR provide an optimal model for the in vivo identification and characterization of drug-mediated oxidative PTPMs of hTTR by means of matrix assisted laser desorption/ionization - time of flight - mass spectrometry (MALDI-TOF-MS). Herein, we demonstrated that hTTR is expressed in all developmental stages of Caenorhabditis elegans, enabling the analysis of hTTR metabolism during the whole life-cycle. The suitability of the applied model was verified by exposing worms to D-penicillamine and menadione. Both drugs induced substantial changes in the oxidative PTPM pattern of hTTR. Additionally, for the first time a covalent binding of both drugs with hTTR was identified and verified by molecular modelling.}, language = {en} } @misc{HenzeHomannRohnetal.2016, author = {Henze, Andrea and Homann, Thomas and Rohn, Isabelle and Aschner, Michael A. and Link, Christopher D. and Kleuser, Burkhard and Schweigert, Florian J. and Schwerdtle, Tanja and Bornhorst, Julia}, title = {Caenorhabditis elegans as a model system to study post-translational modifications of human transthyretin}, url = {http://nbn-resolving.de/urn:nbn:de:kobv:517-opus4-103674}, pages = {12}, year = {2016}, abstract = {The visceral protein transthyretin (TTR) is frequently affected by oxidative post-translational protein modifications (PTPMs) in various diseases. Thus, better insight into structure-function relationships due to oxidative PTPMs of TTR should contribute to the understanding of pathophysiologic mechanisms. While the in vivo analysis of TTR in mammalian models is complex, time- and resource-consuming, transgenic Caenorhabditis elegans expressing hTTR provide an optimal model for the in vivo identification and characterization of drug-mediated oxidative PTPMs of hTTR by means of matrix assisted laser desorption/ionization - time of flight - mass spectrometry (MALDI-TOF-MS). Herein, we demonstrated that hTTR is expressed in all developmental stages of Caenorhabditis elegans, enabling the analysis of hTTR metabolism during the whole life-cycle. The suitability of the applied model was verified by exposing worms to D-penicillamine and menadione. Both drugs induced substantial changes in the oxidative PTPM pattern of hTTR. Additionally, for the first time a covalent binding of both drugs with hTTR was identified and verified by molecular modelling.}, language = {en} } @article{HenzeHomannRohnetal.2016, author = {Henze, Andrea and Homann, Thomas and Rohn, Isabelle and Aschner, Michael A. and Link, Christopher D. and Kleuser, Burkhard and Schweigert, Florian J. and Schwerdtle, Tanja and Bornhorst, Julia}, title = {Caenorhabditis elegans as a model system to study post-translational modifications of human transthyretin}, series = {Scientific reports}, volume = {6}, journal = {Scientific reports}, publisher = {Nature Publ. Group}, address = {London}, issn = {2045-2322}, doi = {10.1038/srep37346}, pages = {12}, year = {2016}, abstract = {The visceral protein transthyretin (TTR) is frequently affected by oxidative post-translational protein modifications (PTPMs) in various diseases. Thus, better insight into structure-function relationships due to oxidative PTPMs of TTR should contribute to the understanding of pathophysiologic mechanisms. While the in vivo analysis of TTR in mammalian models is complex, time-and resource-consuming, transgenic Caenorhabditis elegans expressing hTTR provide an optimal model for the in vivo identification and characterization of drug-mediated oxidative PTPMs of hTTR by means of matrix assisted laser desorption/ionization - time of flight - mass spectrometry (MALDI-TOF-MS). Herein, we demonstrated that hTTR is expressed in all developmental stages of Caenorhabditis elegans, enabling the analysis of hTTR metabolism during the whole life-cycle. The suitability of the applied model was verified by exposing worms to D-penicillamine and menadione. Both drugs induced substantial changes in the oxidative PTPM pattern of hTTR. Additionally, for the first time a covalent binding of both drugs with hTTR was identified and verified by molecular modelling.}, language = {en} } @article{ReegJungCastroetal.2016, author = {Reeg, Sandra and Jung, Tobias and Castro, Jos{\´e} Pedro and Davies, Kelvin J. A. and Henze, Andrea and Grune, Tilman}, title = {The molecular chaperone Hsp70 promotes the proteolytic removal of oxidatively damaged proteins by the proteasome}, series = {Free radical biology and medicine : the official journal of the Oxygen Society, a constituent member of the International Society for Free Radical Research}, volume = {99}, journal = {Free radical biology and medicine : the official journal of the Oxygen Society, a constituent member of the International Society for Free Radical Research}, publisher = {Elsevier}, address = {New York}, issn = {0891-5849}, doi = {10.1016/j.freeradbiomed.2016.08.002}, pages = {153 -- 166}, year = {2016}, abstract = {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/).}, language = {en} } @article{AuyyuenyongHenzeUngruetal.2017, author = {Auyyuenyong, Ratchada and Henze, Andrea and Ungru, Julia and Schweigert, Florian Johannes and Raila, Jens and Vervuert, Ingrid}, title = {Determination of lipid profiles in serum of obese ponies before and after weight reduction by using multi-one-dimensional thin-layer chromatography}, series = {Research in veterinary science}, volume = {117}, journal = {Research in veterinary science}, publisher = {Elsevier}, address = {Oxford}, issn = {0034-5288}, doi = {10.1016/j.rvsc.2017.11.013}, pages = {111 -- 117}, year = {2017}, abstract = {Obesity is a key component of equine metabolic syndrome, which is highly associated with laminitis. Feed restriction and/or exercise are known to alleviate the detrimental effects of insulin resistance in obese ponies. However, little is known about changes in the serum lipid patterns due to weight reduction and its association with disease outcomes. Therefore, the lipid patterns in the serum of 14 mature ponies before and after a 14-week body weight reduction program (BWRP) were investigated by multi-one-dimensional thin-layer chromatography (MOD-TLC). Additionally, sensitivity to insulin (SI), body condition scores (BCS) and cresty neck scores (CNS) were measured. A BWRP resulted in a significant loss of body weight (P < 0.001), which was associated with beneficial decreases in BCS and CNS (both, P < 0.001). Serum lipid compositions revealed significantly increased free fatty acid (FFA), sphingomyelin (SM; both P < 0.001), total cholesterol (C) and cholesterol ester (CE) (both P < 0.01) and triacylglycerol (TG; P < 0.05) densities. Improvement of SI after the BWRP was associated with increases in neutral lipids (C, CE and TG, all P < 0.01), FFA and the phospholipid SM (both, P < 0.001). The results show that a BWRP in obese ponies was effective and associated with changes in the concentrations of neutral lipids and the phospholipid SM, indicating that SM may play a role in insulin signaling pathways and thus in the pathogenesis of insulin resistance and the progression of metabolic syndrome in obese ponies.}, language = {en} } @article{FruscalzoFrommerLonderoetal.2017, author = {Fruscalzo, Arrigo and Frommer, Julia-Marie and Londero, Ambrogio P. and Henze, Andrea and Schweigert, Florian J. and Nofer, Jerzy-Roch and Steinhard, Johannes and Klockenbusch, Walter and Schmitz, Ralf and Raila, Jens}, title = {First trimester TTR-RBP4-ROH complex and angiogenic factors in the prediction of small for gestational age infant's outcome}, series = {Archives of gynecology and obstetrics}, volume = {295}, journal = {Archives of gynecology and obstetrics}, publisher = {Springer}, address = {Heidelberg}, issn = {0932-0067}, doi = {10.1007/s00404-017-4338-4}, pages = {1157 -- 1165}, year = {2017}, abstract = {To study the role of the TTR-RBP4-ROH complex components (transthyretin, serum retinol binding protein, retinol) and of angiogenic factors PlGF (placental growth factor) and sFlt-1 (soluble fms-like tyrosine kinase-1) in pregnancies complicated by small for gestational age infants (SGA). Case control study conducted on maternal serum collected between 11 + 0 to 13 + 6 weeks of gestation. TTR, RBP4, ROH, PlGF and sFlt-1 were measured in SGA patients (birth weight < 10\%) who delivered at term (n = 37) and before 37 weeks of gestation (n = 17) and in a matched control group with uneventful pregnancies (n = 37). We found decreased RBP4 in SGA patients that delivered fetuses < 3\% and in fetuses delivered after the 37 weeks of gestation compared to controls [1.50 (95\% CI 1.40-1.75) vs 1.62 (95\% CI 1.47-1.98), p < 0.05]. Further, we found lower PlGF and sFlt-1 concentrations in SGA that delivered before 37 weeks of gestation compared to controls (respectively, PIGF and sFlt-1: 39.7 pg/ml (95\% CI 32.3-66.3) vs 62.9 pg/ml (95\% CI 45.2-78.4) and 906 pg/ml (95\% CI 727-1626) vs 1610 pg/ml (95\% CI 1088-212), p < 0.05). First trimester maternal serum RBP4 and angiogenic factors PlGF and sFlt-1 can differently predict the timing of delivery of pregnancies complicated by SGA fetuses.}, language = {en} } @misc{HenzeRailaKempfetal.2017, author = {Henze, Andrea and Raila, Jens and Kempf, Caroline and Reinke, Petra and Sefrin, Anett and Querfeld, Uwe and Schweigert, Florian J.}, title = {Vitamin A metabolism is changed in donors after living-kidney transplantation}, url = {http://nbn-resolving.de/urn:nbn:de:kobv:517-opus4-400942}, pages = {7}, year = {2017}, abstract = {Background The kidneys are essential for the metabolism of vitamin A (retinol) and its transport proteins retinol-binding protein 4 (RBP4) and transthyretin. Little is known about changes in serum concentration after living donor kidney transplantation (LDKT) as a consequence of unilateral nephrectomy; although an association of these parameters with the risk of cardiovascular diseases and insulin resistance has been suggested. Therefore we analyzed the concentration of retinol, RBP4, apoRBP4 and transthyretin in serum of 20 living-kidney donors and respective recipients at baseline as well as 6 weeks and 6 months after LDKT. Results As a consequence of LDKT, the kidney function of recipients was improved while the kidney function of donors was moderately reduced within 6 weeks after LDKT. With regard to vitamin A metabolism, the recipients revealed higher levels of retinol, RBP4, transthyretin and apoRBP4 before LDKT in comparison to donors. After LDKT, the levels of all four parameters decreased in serum of the recipients, while retinol, RBP4 as well as apoRBP4 serum levels of donors increased and remained increased during the follow-up period of 6 months. Conclusion LDKT is generally regarded as beneficial for allograft recipients and not particularly detrimental for the donors. However, it could be demonstrated in this study that a moderate reduction of kidney function by unilateral nephrectomy, resulted in an imbalance of components of vitamin A metabolism with a significant increase of retinol and RBP4 and apoRBP4 concentration in serum of donors.}, language = {en} } @article{AlickeBoakyeAppiahAbdulJaliletal.2017, author = {Alicke, Marie and Boakye-Appiah, Justice K. and Abdul-Jalil, Inusah and Henze, Andrea and van der Giet, Markus and Schulze, Matthias Bernd and Schweigert, Florian J. and Mockenhaupt, Frank P. and Bedu-Addo, George and Danquah, Ina}, title = {eAdolescent health in rural Ghana: A crosssectional study on the co-occurrence of infectious diseases, malnutrition and cardiometabolic risk factors}, series = {PLoS one}, volume = {12}, journal = {PLoS one}, publisher = {PLoS}, address = {San Fransisco}, issn = {1932-6203}, doi = {10.1371/journal.pone.0180436}, pages = {4463 -- 4477}, year = {2017}, abstract = {In sub-Saharan Africa, infectious diseases and malnutrition constitute the main health problems in children, while adolescents and adults are increasingly facing cardio-metabolic conditions. Among adolescents as the largest population group in this region, we investigated the co-occurrence of infectious diseases, malnutrition and cardio-metabolic risk factors (CRFs), and evaluated demographic, socio-economic and medical risk factors for these entities. In a cross-sectional study among 188 adolescents in rural Ghana, malarial infection, common infectious diseases and Body Mass Index were assessed. We measured ferritin, C-reactive protein, retinol, fasting glucose and blood pressure. Socio-demographic data were documented. We analyzed the proportions (95\% confidence interval, CI) and the cooccurrence of infectious diseases (malaria, other common diseases), malnutrition (underweight, stunting, iron deficiency, vitamin A deficiency [VAD]), and CRFs (overweight, obesity, impaired fasting glucose, hypertension). In logistic regression, odds ratios (OR) and 95\% CIs were calculated for the associations with socio-demographic factors. In this Ghanaian population (age range, 14.4-15.5 years; males, 50\%), the proportions were for infectious diseases 45\% (95\% CI: 38-52\%), for malnutrition 50\% (43-57\%) and for CRFs 16\% (11- 21\%). Infectious diseases and malnutrition frequently co-existed (28\%; 21-34\%). Specifically, VAD increased the odds of non-malarial infectious diseases 3-fold (95\% CI: 1.03, 10.19). Overlap of CRFs with infectious diseases (6\%; 2-9\%) or with malnutrition (7\%; 3-11\%) was also present. Male gender and low socio-economic status increased the odds of infectious diseases and malnutrition, respectively. Malarial infection, chronic malnutrition and VAD remain the predominant health problems among these Ghanaian adolescents. Investigating the relationships with evolving CRFs is warranted.}, language = {en} } @misc{Henze2018, author = {Henze, Andrea}, title = {Proteinoxidation als Indikator des Alterungsph{\"a}notyps und Target einer individualisierten Ern{\"a}hrungsintervention (ProAID)}, series = {Ern{\"a}hrungs-Umschau : Forschung \& Praxis}, volume = {65}, journal = {Ern{\"a}hrungs-Umschau : Forschung \& Praxis}, number = {10}, publisher = {Umschau-Zeitschriftenverl.}, address = {Frankfurt, Main}, issn = {0174-0008}, pages = {M566 -- M567}, year = {2018}, abstract = {Oxidative posttranslationale Modifikationen endogener Proteine werden v. a. durch reaktive Sauerstoff- und Stickstoffspezies (engl:. Reactive Oxygen Species, ROS, reactive nitrogen species, RNS) hervorgerufen und k{\"o}nnen sowohl reversibel (z. B. Disulfidbindungen) als auch irreversibel (z. B. Proteincarbonyle) erfolgen [1-3]. Lange wurde angenommen, dass oxidative posttranslationale Proteinmodifikationen (oxPTPM) nur von untergeordneter Bedeutung f{\"u}r den Metabolismus sind. Tats{\"a}chlich handelt es sich jedoch um einen physiologischen Prozess, der {\"u}ber die Modulation der Proteinstruktur auch die Proteinfunktion (z. B. Enzymaktivit{\"a}t, Stabilit{\"a}t) und somit zahlreiche Stoffwechselwege wie den Energiestoffwechsel, die Immunfunktion, die vaskul{\"a}re Funktion sowie Apoptose und Genexpression beeinflussen kann. Die Bildung von oxPTPM ist dabei hochreguliert und h{\"a}ngt u. a. von der Proteinstruktur, der Verf{\"u}gbarkeit von ROS und RNS sowie dem lokalen Mikromilieu der Zelle ab [2, 4].}, language = {de} } @article{SchutkowskiKoenigKlugeetal.2019, author = {Schutkowski, Alexandra and K{\"o}nig, Bettina and Kluge, Holger and Hirche, Frank and Henze, Andrea and Schwerdtle, Tanja and Lorkowski, Stefan and Dawczynski, Christine and Gabel, Alexander and Grosse, Ivo and Stangl, Gabriele I.}, title = {Metabolic footprint and intestinal microbial changes in response to dietary proteins in a pig model}, series = {The journal of nutritional biochemistry}, volume = {67}, journal = {The journal of nutritional biochemistry}, publisher = {Elsevier}, address = {New York}, issn = {0955-2863}, doi = {10.1016/j.jnutbio.2019.02.004}, pages = {149 -- 160}, year = {2019}, abstract = {Epidemiological studies revealed that dietary proteins can contribute to the modulation of the cardiovascular disease risk. Still, direct effects of dietary proteins on serum metabolites and other health-modulating factors have not been fully explored. Here, we compared the effects of dietary lupin protein with the effects of beef protein and casein on the serum metabolite profile, cardiovascular risk markers and the fecal microbiome. Pigs were fed diets containing 15\% of the respective proteins for 4 weeks. A classification analysis of the serum metabolites revealed six biomarker sets of two metabolites each that discriminated between the intake of lupin protein, lean beef or casein. These biomarker sets included 1- and 3-methylhistidine, betaine, carnitine, homoarginine and methionine. The study revealed differences in the serum levels of the metabolites 1- and 3- methylhistidine, homoarginine, methionine and homocysteine, which are involved in the one-carbon cycle. However, these changes were not associated with differences in the methylation capacity or the histone methylation pattern. With the exception of serum homocysteine and homoarginine levels, other cardiovascular risk markers, such as the homeostatic model assessment index, trimethylamine-N-oxide and lipids, were not influenced by the dietary protein source. However, the composition of the fecal microorganisms was markedly changed by the dietary protein source. Lupin-protein-fed pigs exhibited more species from the phyla Bacteroidetes and Firmicutes than the other two groups. In conclusion, different dietary protein sources induce distinct serum metabolic fingerprints, have an impact on the cardiovascular risk and modulate the composition of the fecal microbiome. (C) 2019 Elsevier Inc. All rights reserved.}, language = {en} } @article{FeddersMuenznerWeberetal.2021, author = {Fedders, Ronja and Muenzner, Matthias and Weber, Pamela and Sommerfeld, Manuela and Knauer, Miriam and Kedziora, Sarah and Kast, Naomi and Heidenreich, Steffi and Raila, Jens and Weger, Stefan and Henze, Andrea and Schupp, Michael}, title = {Liver-secreted RBP4 does not impair glucose homeostasis in mice}, series = {The journal of biological chemistry}, volume = {293}, journal = {The journal of biological chemistry}, number = {39}, publisher = {American Society for Biochemistry and Molecular Biology}, address = {Bethesda}, issn = {1083-351X}, doi = {10.1074/jbc.RA118.004294}, pages = {15269 -- 15276}, year = {2021}, abstract = {Retinol-binding protein 4 (RBP4) is the major transport protein for retinol in blood. Recent evidence from genetic mouse models shows that circulating RBP4 derives exclusively from hepatocytes. Because RBP4 is elevated in obesity and associates with the development of glucose intolerance and insulin resistance, we tested whether a liver-specific overexpression of RBP4 in mice impairs glucose homeostasis. We used adeno-associated viruses (AAV) that contain a highly liver-specific promoter to drive expression of murine RBP4 in livers of adult mice. The resulting increase in serum RBP4 levels in these mice was comparable with elevated levels that were reported in obesity. Surprisingly, we found that increasing circulating RBP4 had no effect on glucose homeostasis. Also during a high-fat diet challenge, elevated levels of RBP4 in the circulation failed to aggravate the worsening of systemic parameters of glucose and energy homeostasis. These findings show that liver-secreted RBP4 does not impair glucose homeostasis. We conclude that a modest increase of its circulating levels in mice, as observed in the obese, insulin-resistant state, is unlikely to be a causative factor for impaired glucose homeostasis.}, language = {en} }