S R Bornstein

King's College London, Londinium, England, United Kingdom

Are you S R Bornstein?

Claim your profile

Publications (384)1326.44 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Aims: Endothelial dysfunction is an early step in the development of atherosclerosis. Increased formation of superoxide anions by NADPH oxidase Nox1, 2, and 5 reduces nitric oxide availability and can promote endothelial dysfunction. In contrast, recent evidence supports a vasoprotective role of H2O2 produced by main endothelial isoform Nox4. Therefore, we analysed the impact of genetic deletion of Nox4 on endothelial dysfunction and atherosclerosis in the low-density lipoprotein receptor (Ldlr) knockout model. Methods and results: Ex vivo analysis of endothelial function by Mulvany myograph showed impaired endothelial function in thoracic aorta of Nox4(-/-)/Ldlr(-/-) mice. Further progression of endothelial dysfunction due to high-fat diet increased atherosclerotic plaque burden and galectin-3 staining in Nox4(-/-)/Ldlr(-/-) mice compared with Ldlr(-/-) mice. Under physiological conditions, loss of Nox4 does not influence aortic vascular function. In this setting, loss of Nox4-derived H2O2 production could be partially compensated for by nNOS upregulation. Using an innovative optical coherence tomography approach, we were able to analyse endothelial function by flow-mediated vasodilation in the murine saphenous artery in vivo. This new approach revealed an altered flow-mediated dilation in Nox4(-/-) mice, indicating a role for Nox4 under physiological conditions in peripheral arteries in vivo. Conclusions: Nox4 plays an important role in maintaining endothelial function under physiological and pathological conditions. Loss of Nox4-derived H2O2 could be partially compensated for by nNOS upregulation, but severe endothelial dysfunction is not reversible. This leads to increased atherosclerosis under atherosclerotic prone conditions.
    European Heart Journal 11/2015; DOI:10.1093/eurheartj/ehv564 · 15.20 Impact Factor
  • M Hanefeld · S Bornstein · A Barthel ·

    Diabetes aktuell 11/2015; 13(06):248-254. DOI:10.1055/s-0041-107293
  • E Ullmann · A Barthel · S Taché · A Bornstein · J Licinio · S R Bornstein ·
    [Show abstract] [Hide abstract]
    ABSTRACT: Molecular Psychiatry publishes work aimed at elucidating biological mechanisms underlying psychiatric disorders and their treatment
    Molecular Psychiatry 11/2015; 20(12). DOI:10.1038/mp.2015.164 · 14.50 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Background: Randomised controlled trials have shown that bariatric surgery is more effective than conventional treatment for the short-term control of type-2 diabetes. However, published studies are characterised by a relatively short follow-up. We aimed to assess 5 year outcomes from our randomised trial designed to compare surgery with conventional medical treatment for the treatment of type 2 diabetes in obese patients. Methods: We did our open-label, randomised controlled trial at one diabetes centre in Italy. Patients aged 30-60 years with a body-mass index of 35 kg/m(2) or more and a history of type 2 diabetes lasting at least 5 years were randomly assigned (1:1:1), via a computer-generated randomisation procedure, to receive either medical treatment or surgery by Roux-en-Y gastric bypass or biliopancreatic diversion. Participants were aware of treatment allocation before the operation and study investigators were aware from the point of randomisation. The primary endpoint was the rate of diabetes remission at 2 years, defined as a glycated haemaglobin A1c (HbA1c) concentration of 6·5% or less (≤47·5 mmol/mol) and a fasting glucose concentration of 5·6 mmol/L or less without active pharmacological treatment for 1 year. Here we analyse glycaemic and metabolic control, cardiovascular risk, medication use, quality of life, and long-term complications 5 years after randomisation. Analysis was by intention to treat for the primary endpoint and by per protocol for the 5 year follow-up. This study is registered with ClinicalTrials.gov, number NCT00888836. Findings: Between April 27, 2009, and Oct 31, 2009, we randomly assigned 60 patients to receive either medical treatment (n=20) or surgery by gastric bypass (n=20) or biliopancreatic diversion (n=20); 53 (88%) patients completed 5 years' follow-up. Overall, 19 (50%) of the 38 surgical patients (seven [37%] of 19 in the gastric bypass group and 12 [63%] of 19 in the bilipancreatic diversion group) maintained diabetes remission at 5 years, compared with none of the 15 medically treated patients (p=0·0007). We recorded relapse of hyperglycaemia in eight (53%) of the 15 patients who achieved 2 year remission in the gastric bypass group and seven (37%) of the 19 patients who achieved 2 year remission in the biliopancreatic diversion group. Eight (42%) patients who underwent gastric bypass and 13 (68%) patients who underwent biliopancreatic diversion had an HbA1c concentration of 6·5% or less (≤47·5 mmol/mol) with or without medication, compared with four (27%) medically treated patients (p=0·0457). Surgical patients lost more weight than medically treated patients, but weight changes did not predict diabetes remission or relapse after surgery. Both surgical procedures were associated with significantly lower plasma lipids, cardiovascular risk, and medication use. Five major complications of diabetes (including one fatal myocardial infarction) arose in four (27%) patients in the medical group compared with only one complication in the gastric bypass group and no complications in the biliopancreatic diversion group. No late complications or deaths occurred in the surgery groups. Nutritional side-effects were noted mainly after biliopancreatic diversion. Interpretation: Surgery is more effective than medical treatment for the long-term control of obese patients with type 2 diabetes and should be considered in the treatment algorithm of this disease. However, continued monitoring of glycaemic control is warranted because of potential relapse of hyperglycaemia. Funding: Catholic University of Rome.
    The Lancet 09/2015; 386(9997):964-73. DOI:10.1016/S0140-6736(15)00075-6 · 45.22 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Background: Obesity is characterized by increased adipocyte number and size as well as white adipose tissue (WAT) inflammation, which is fundamental for the development of insulin resistance and type-2 diabetes. These processes, regulated by various endocrine, paracrine and autocrine factors, are extensively studied with the hope to interfere and to inhibit weight gain and related complications in obese patients. Recent data suggest an important role of bone morphogenic protein 4 (BMP4) in the regulation of adipogenesis and development of obesity. BMP4 is a growth factor of the transforming growth factor-β superfamily. Initially, BMPs were identified as inducers of ectopic bone formation. It is now apparent, however, that these proteins have different pleiotropic developmental actions and including playing a role in white adipogenesis. Methods and results: Here, we demonstrate that the expression of BMP4 in human WAT is negatively correlated to body mass index and to the expression of pro-inflammatory cytokines. In vitro, BMP4 expression in cultured human adipocytes is upregulated after induction of differentiation. Cells treated with exogenous BMP4 increased peroxisome proliferator-activated receptor γ (PPARγ) expression and significantly reduced the expression of pro-inflammatory cytokines including tumor necrosis factor α (TNF-α) and monocyte chemoattractant protein 1. TNF-α treatment of fully differentiated adipocytes resulted in downregulation of the expression of adipogenic genes and elevated expression of pro-inflammatory cytokines. Exogenous BMP4 addition significantly reduced the negative effect of TNF-α on the expression profile of adipocytes. Finally, treatment of human adipocytes with exogenous BMP4 reduced the adipocytes' chemoattractant potential and the migration of monocytes toward adipocyte-conditioned medium. Conclusions: These results indicate that BMP4 is an important anti-inflammatory molecule, which may act through PPARγ and reduces TNF-α-mediated pro-inflammatory cytokine production in human adipocytes. Through its anti-inflammatory potential, BMP4 may serve as a protective factor for inflammation-related diseases such as insulin-tolerance or type-2 diabetes.International Journal of Obesity advance online publication, 25 August 2015; doi:10.1038/ijo.2015.141.
    International journal of obesity (2005) 07/2015; DOI:10.1038/ijo.2015.141 · 5.00 Impact Factor
  • A Barthel · S R Bornstein ·

    Hormone and Metabolic Research 06/2015; 47(6):470-1. DOI:10.1055/s-0035-1548874 · 2.12 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Iron deficiency (ID) and iron deficiency anemia (IDA) are common findings in patients undergoing lipoprotein apheresis (LA). Different intravenous (iv) formulations are used to treat ID in LA patients, however guidelines and data on ID/IDA management in LA patients are lacking. We therefore performed a prospective observational multi-center cohort study of ID/IDA in LA patients, comparing two approved i.v. iron formulations, ferric gluconate (FG) and ferric carboxymaltose (FCM). Inclusion criteria were a) serum ferritin <100 μg/L or b) serum ferritin <300 μg/L and transferrin saturation <20%. Patients received either FG (62.5 mg weekly) or FCM (500 mg once in ID or up to 1000 mg if IDA was present) i.v. until iron deficiency was resolved. Efficacy and safety were determined by repeated laboratory and clinical assessment. Iron parameters pre and post apheresis were measured to better understand the pathogenesis of ID/IDA in LA patients. 80% of LA patients treated at the three participating centers presented with ID/IDA; 129 patients were included in the study. Serum ferritin and transferrin levels were reduced following apheresis (by 18% (p < 0.0001) and by 13% (p < 0.0001) respectively). Both FG and FCM were effective and well tolerated in the treatment of ID/IDA in LA patients. FCM led to a quicker repletion of iron stores (p < 0.05), while improvement of ID/IDA symptoms was not different. Number and severity of adverse events did not differ between FG and FCM, no severe adverse events occurred. Our results suggest that FG and FCM are equally safe, well-tolerated and effective in treating ID/IDA in LA patients. These data form the basis for follow-up randomized controlled trials to establish clinical guidelines. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
    Atherosclerosis. Supplements 05/2015; 18. DOI:10.1016/j.atherosclerosissup.2015.02.030 · 2.29 Impact Factor
  • Barbara Ludwig · Stefan Bornstein ·

    Diabetes aktuell 05/2015; 13(02):81-82. DOI:10.1055/s-0035-1552951

  • Experimental and Clinical Endocrinology & Diabetes 03/2015; 122(03). DOI:10.1055/s-0035-1547699 · 1.56 Impact Factor

  • Experimental and Clinical Endocrinology & Diabetes 03/2015; 122(03). DOI:10.1055/s-0035-1549081 · 1.56 Impact Factor
  • C Jennewein · N Tran · W Kanczkowski · SR Bornstein · K Zacharowski ·

    Experimental and Clinical Endocrinology & Diabetes; 03/2015
  • J Gräßler · S Sales · M Bickle · R Al-Atrip · SR Bornstein · A Shevchenko ·

    Experimental and Clinical Endocrinology & Diabetes 03/2015; 122(03). DOI:10.1055/s-0035-1547686 · 1.56 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The antiepileptic drug valproic acid (VPA) has been shown to influence the neural differentiation and neurite outgrowth of neural stem cells. Sympathoadrenal progenitor cells share properties with neural stem cells and are considered a potential cell source in the treatment of neurodegenerative diseases. The present study therefore aims at modulating the neural differentiation potential of these cells by treatment with the histone deacetylase inhibitor VPA. We studied the epigenetic effects of VPA in two culture conditions: suspension conditions aimed to expand adrenomedullary sympathoadrenal progenitors within free-floating chromospheres and adherent cell cultures optimized to derive neurons. Treatment of chromospheres with VPA may launch neuronal differentiation mechanisms and improve their neurogenic potential upon transplantation. However, also transplantation of differentiated functional neurons could be beneficial. Treating chromospheres for 7 days with clinically relevant concentrations of VPA (2 mm) revealed a decrease of neural progenitor markers Nestin, Notch2 and Sox10. Furthermore, VPA initiated catecholaminergic neuronal differentiation indicated by upregulation of the neuronal marker β-III-tubulin, the dopaminergic transcription factor Pitx3 and the catecholaminergic enzymes TH and GTPCH. In adherent neural differentiation conditions, VPA treatment improved the differentiation of sympathoadrenal progenitor cells into catecholaminergic neurons with significantly elevated levels of nor- and epinephrine. In conclusion, similar to neural stem cells, VPA launches differentiation mechanisms in sympathoadrenal progenitor cells that result in increased generation of functional neurons. Thus, data from this study will be relevant to the potential use of chromaffin progenitors in transplantation therapies of neurodegenerative diseases.Molecular Psychiatry advance online publication, 24 February 2015; doi:10.1038/mp.2015.3.
    Molecular Psychiatry 02/2015; 20(8). DOI:10.1038/mp.2015.3 · 14.50 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Background: Adrenocortical cancer (ACC) is a rare malignant endocrine tumor. Previously we found that erlotinib (inhibitor of EGFR) had an additive cytotoxic effect to standard therapy with mitotane in H295R cell line, especially after EGF stimulation. Primary cultures of ACC have been proven to be challenging to establish and maintain for further experiments, especially for assessing their steroid profile. Design: The aim of this study was to test the effect in the use of Erlotinib on primary ACC cultures. We successfully cultured 3 ACCs. In 2 ACC cases radical surgery was a treatment of choice, whereas in the last case - surgery was after neo-adjuvant chemotherapy. Because last tumour was very heterogeneous, we cultured 2 samples from macroscopically different areas. Cell proliferation rate and the effect of the drugs were assessed by AlamarBlue assay. We used LCMS/MS to assess tumour steroids production from primary cultures derived from metastatic ACC cases. Results: Treatment with mitotane resulted in the decrease of cell proliferation (9%±2%) in all cases at 10uM and total death at 50μM. In one of radically operated ACCs, erlotinib (10μM) decreased proliferation by 24%, whereas in another it was not effective. Surprisingly, erlotinib has opposite effect on cell proliferation in two samples from metastatic ACC, however its combination with low dose of mitotane (10μM) was sufficient to induce total death. Furthermore the basal steroid production was different in those samples and it changed in a different manner after treatment with mitotane and/or erlotinib (with or without EGF stimulation). Conclusion: Erlotinib can have an anti-proliferative effect in primary ACC cultures and can reduce mitotane effective concentration. For cases pre-treated with neo-adjuvant therapy, erlotinib may cause opposite responses in different parts of the same tumour; hence its clinical use needs further careful consideration. Different responses in steroidogenesis from different parts of the same ACC tumour has not been previously described underlines ACC heterogeneity.
    Modern Pathology 02/2015; 28(2 (Suppl 2)):133. DOI:10.1038/modpathol.2015.14 · 6.19 Impact Factor
  • S Saha · S R Bornstein · J Graessler · S Kopprasch ·
    [Show abstract] [Hide abstract]
    ABSTRACT: Low-density lipoprotein (LDL) is considered to be a risk factor for atherosclerosis. In the presence of hyperglycemia, LDL undergoes glycoxidative modification and this glycoxidized (glycox) LDL promotes atherosclerosis in type 2 diabetic (T2D) individuals. Moreover, because of its cholesterol content, LDL contributes to aldosterone biosynthesis, which is modulated by angiotensin II (AngII) and has been implicated in cardiovascular complications of T2D. However, the molecular mechanism of the crosstalk between glycoxLDL, AngII, and aldosterone has not been explained clearly. Therefore, this study has been aimed to investigate the impact of in vitro modified glycoxLDL on aldosterone release in an AngII-sensitized adrenocortical carcinoma cell line (NCI H295R). Native LDL (natLDL), isolated from healthy volunteers by sequential density gradient ultracentrifugation, was subjected to d-glucose (200 mmol/l), for glycoxidative modification, at 37°C for 6 days. The AngII-sensitized H295R cells were treated with natLDL and glycoxLDL for 24 h and the supernatant was used for aldosterone measurement. The treated cells were utilized for protein isolation and mRNA quantification. Compared to natLDL, glycoxLDL produced a significantly greater effect on aldosterone release from AngII-sensitized cells. The treatment with specific pharmacological inhibitors suggests that modified LDL recruits ERK1/2 and janus kinase-2 for transcriptional regulation of aldosterone synthase. Moreover, glycoxLDL modulates aldosterone release via cAMP-dependent protein kinase A (PKA) pathway. However, glycoxLDL induces ERK phosphorylation independent of PKA activation and this novel mechanism could be targeted for therapeutic trials. In conclusion, this in vitro study emphasizes a possible causal relationship between LDL glycoxidative modification, AngII-sensitization, and adrenocortical steroid hormone release. © Georg Thieme Verlag KG Stuttgart · New York.
    Hormone and Metabolic Research 01/2015; 47(11). DOI:10.1055/s-0034-1395568 · 2.12 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Solid organ and cell transplantation, including pancreatic islets constitute the treatment of choice for chronic terminal diseases. However, the clinical use of allogeneic transplantation is limited by the growing shortage of human organs. This has prompted us to initiate a unique multi-center and multi-team effort to promote translational research in xenotransplantation to bring xenotransplantation to the clinical setting. Supported by the German Research Foundation, an interdisciplinary group of surgeons, internal medicine doctors, diabetologists, material sciences experts, immunologists, cell biologists, virologists, veterinarians, and geneticists have established a collaborative research center (CRC) focusing on the biology of xenogeneic cell, tissue, and organ transplantation. A major strength of this consortium is the inclusion of members of the regulatory bodies, including the Paul-Ehrlich Institute (PEI), infection specialists from the Robert Koch Institute and PEI, veterinarians from the German Primate Center, and representatives of influential ethical and religious institutions. A major goal of this consortium is to promote islet xenotransplantation, based on the extensive expertise and experience of the existing clinical islet transplantation program. Besides comprehensive approaches to understand and prevent inflammation-mediated islet xenotransplant dysfunction [immediate blood-mediated inflammatory reaction (IBMIR)], we also take advantage of the availability of and experience with islet macroencapsulation, with the goal to improve graft survival and function. This consortium harbors a unique group of scientists with complementary expertise under a cohesive program aiming at developing new therapeutic approaches for islet replacement and solid organ xenotransplantation. © Georg Thieme Verlag KG Stuttgart · New York.
    Hormone and Metabolic Research 12/2014; 47(01). DOI:10.1055/s-0034-1395518 · 2.12 Impact Factor

  • Hormone and Metabolic Research 12/2014; 47(01). DOI:10.1055/s-0034-1394453 · 2.12 Impact Factor
  • M Hanefeld · S R Bornstein · A Barthel ·

    DMW - Deutsche Medizinische Wochenschrift 12/2014; 139(49):2494-7. DOI:10.1055/s-0034-1387406 · 0.54 Impact Factor
  • V Kamvissi · A Salerno · S R Bornstein · G Mingrone · F Rubino ·
    [Show abstract] [Hide abstract]
    ABSTRACT: The role of incretins in glucose homeostasis is well known. Yet, in recent years, the sustained weight loss and rapid glycemic control following bariatric surgery has challenged our understanding of the intestinal-pancreatic interaction. This in turn led to the introduction of metabolic surgery, an innovative medical discipline in which a surgical manipulation of the gastrointestinal tract (e. g., through a Roux-en-Y gastric bypass, RYGB, or Bilio-Pancreatic-Diversion, BPD) yields a sustained remission of diabetes mellitus. The pathophysiological background of this metabolic effect is, amongst other things, based on the anti-incretin theory. This theory postulates that in addition to the well-known incretin effect, nutrient passage through the GI-tract could also activate negative feedback mechanisms (anti-incretins) to balance the effects of incretins and other postprandial glucose-lowering mechanisms (i. e., suppression of ghrelin, glucagon, and hepatic glucose production via activation of nutrient sensing). This in turn prevents postprandial hyperinsulinemic hypoglycemia. The bypass of the duodenum, the entire jejunum and the first portion of the ileum by BPD induce normalization of peripheral insulin sensitivity, while the bypass of a shorter intestinal tract by RYGB mainly improves the hepatic insulin sensitivity. In addition, RYGB greatly increases insulin secretion. Therefore, metabolic surgery highlights the important role of the small intestine in glucose homeostasis, while until few years ago, it was only the pancreas and the liver that were thought to represent the regulatory organs for glucose disposal.
    Hormone and Metabolic Research 11/2014; 47(01). DOI:10.1055/s-0034-1394374 · 2.12 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Inflammation in the central nervous system (CNS) and disruption of its immune privilege are major contributors to the pathogenesis of multiple sclerosis (MS) and of its rodent counterpart, experimental autoimmune encephalomyelitis (EAE). We have previously identified developmental endothelial locus-1 (Del-1) as an endogenous anti-inflammatory factor, which inhibits integrin-dependent leukocyte adhesion. Here we show that Del-1 contributes to the immune privilege status of the CNS. Intriguingly, Del-1 expression decreased in chronic-active MS lesions and in the inflamed CNS in the course of EAE. Del-1-deficiency was associated with increased EAE severity, accompanied by increased demyelination and axonal loss. As compared with control mice, Del-1(-/-) mice displayed enhanced disruption of the blood-brain barrier and increased infiltration of neutrophil granulocytes in the spinal cord in the course of EAE, accompanied by elevated levels of inflammatory cytokines, including interleukin-17 (IL-17). The augmented levels of IL-17 in Del-1-deficiency derived predominantly from infiltrated CD8(+) T cells. Increased EAE severity and neutrophil infiltration because of Del-1-deficiency was reversed in mice lacking both Del-1 and IL-17 receptor, indicating a crucial role for the IL-17/neutrophil inflammatory axis in EAE pathogenesis in Del-1(-/-) mice. Strikingly, systemic administration of Del-1-Fc ameliorated clinical relapse in relapsing-remitting EAE. Therefore, Del-1 is an endogenous homeostatic factor in the CNS protecting from neuroinflammation and demyelination. Our findings provide mechanistic underpinnings for the previous implication of Del-1 as a candidate MS susceptibility gene and suggest that Del-1-centered therapeutic approaches may be beneficial in neuroinflammatory and demyelinating disorders.Molecular Psychiatry advance online publication, 11 November 2014; doi:10.1038/mp.2014.146.
    Molecular Psychiatry 11/2014; 20(7). DOI:10.1038/mp.2014.146 · 14.50 Impact Factor

Publication Stats

8k Citations
1,326.44 Total Impact Points


  • 2014-2015
    • King's College London
      • Division of Diabetes and Nutritional Sciences
      Londinium, England, United Kingdom
    • ICL
      Londinium, England, United Kingdom
  • 1998-2015
    • Technische Universität Dresden
      • • Center for Internal Medicine
      • • Medical Clinic III
      • • Medical Clinic III, Department General Medicine
      Dresden, Saxony, Germany
  • 2011-2014
    • Center for Regenerative Therapies, Dresden
      Dresden, Saxony, Germany
    • University of Texas Health Science Center at San Antonio
      • Division of Diabetes
      San Antonio, TX, United States
  • 1999-2014
    • Carl Gustav Carus-Institut
      Pforzheim, Baden-Württemberg, Germany
    • University of Gothenburg
      Goeteborg, Västra Götaland, Sweden
  • 2012
    • Institut für klinische Pharmakologie
      Stuttgart, Baden-Württemberg, Germany
  • 2007-2012
    • Universitätsklinikum Dresden
      • Medizinische Klinik und Poliklinik III
      Dresden, Saxony, Germany
    • Universitätsklinikum Düsseldorf
      • Klinik für Endokrinologie und Diabetologie
      Düsseldorf, North Rhine-Westphalia, Germany
  • 1998-2009
    • National Institute of Child Health and Human Development
      Maryland, United States
  • 2008
    • Garki Hospital Abuja
      Abuja, Abuja Federal Capital Territory, Nigeria
  • 2001-2006
    • Heinrich-Heine-Universität Düsseldorf
      Düsseldorf, North Rhine-Westphalia, Germany
  • 2002
    • Evangelic Hospital Bielefeld
      Bielefeld, North Rhine-Westphalia, Germany
    • Rambam Medical Center
      • Department of Pediatrics
      H̱efa, Haifa, Israel
  • 1995-2001
    • University of Leipzig
      • Institute of Immunology
      Leipzig, Saxony, Germany
  • 2000
    • Northern Inyo Hospital
      BIH, California, United States
  • 1999-2000
    • Eunice Kennedy Shriver National Institute of Child Health and Human Development
      Роквилл, Maryland, United States
  • 1998-1999
    • National Institutes of Health
      • Section on Reproductive Endocrinology
      베서스다, Maryland, United States
  • 1991-1994
    • Universität Ulm
      • • Clinic of Internal Medicine I
      • • Clinic of Gynecology and Obstetrics
      Ulm, Baden-Wuerttemberg, Germany