Publications by authors named "Stefan R Bornstein"

380 Publications

Rivaroxaban compared with low-dose aspirin in individuals with type 2 diabetes and high cardiovascular risk: a randomised trial to assess effects on endothelial function, platelet activation and vascular biomarkers.

Diabetologia 2021 Sep 8. Epub 2021 Sep 8.

Medical Clinic III, Universitätsklinikum 'Carl Gustav Carus', Dresden, Germany.

Aims/hypothesis: Individuals with type 2 diabetes mellitus and subclinical inflammation have stimulated coagulation, activated platelets and endothelial dysfunction. Recent studies with the direct factor Xa inhibitor rivaroxaban in combination with low-dose aspirin demonstrated a significant reduction of major cardiovascular events, especially in individuals with type 2 diabetes and proven cardiovascular disease. Therefore, we asked the question of whether treatment with rivaroxaban could influence endothelial function, arterial stiffness and platelet activation.

Methods: We conducted a multi-centre, prospective, randomised, open-label trial in 179 participants with type 2 diabetes (duration 2-20 years), subclinical inflammation (high-sensitivity C-reactive protein 2-10 mg/l) and at least two traits of the metabolic syndrome to compare the effects of the direct factor Xa inhibitor rivaroxaban (5 mg twice daily) vs aspirin (100 mg every day) on endothelial function (assessed by forearm occlusion plethysmography), skin blood flow (assessed by laser-Doppler fluxmetry), arterial stiffness (assessed by pulse wave velocity) and serum biomarkers of endothelial function and inflammation. Furthermore, we investigated phosphorylation of vasodilator-stimulated phosphoprotein (VASP) in platelets, the concentration of platelet-derived microparticles (PMPs) and the effects of isolated PMPs on HUVEC proliferation in vitro.

Results: Rivaroxaban treatment for 20 weeks (n = 89) resulted in a significant improvement of post-ischaemic forearm blood flow (3.6 ± 4.7 vs 1.0 ± 5.2 ml/100 ml, p = 0.004), a numerically increased skin blood flow and reduced soluble P-Selectin plasma level vs aspirin. We did not find significant differences of arterial stiffness or further biomarkers. Neither rivaroxaban nor aspirin influenced VASP phosphorylation of platelets. The number of PMPs increased significantly with both rivaroxaban (365.2 ± 372.1 vs 237.4 ± 157.1 μl, p = 0.005) and aspirin (266.0 ± 212.7 vs 201.7 ± 162.7 μl, p = 0.021). PMPs of rivaroxaban-treated participants stimulated HUVEC proliferation in vitro compared with aspirin. Rivaroxaban was associated with a higher number of bleeding events.

Conclusions/interpretation: Our findings indicate that the direct factor Xa inhibitor rivaroxaban improved endothelial function in participants with type 2 diabetes and subclinical inflammation but also increased the risk of bleeding.

Trial Registration: ClinicalTrials.gov NCT02164578.

Funding: The study was supported by a research grant from Bayer Vital AG, Germany.
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http://dx.doi.org/10.1007/s00125-021-05562-9DOI Listing
September 2021

Dysfunction of the key ferroptosis-surveilling systems hypersensitizes mice to tubular necrosis during acute kidney injury.

Nat Commun 2021 07 20;12(1):4402. Epub 2021 Jul 20.

Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, Bonn, Germany.

Acute kidney injury (AKI) is morphologically characterized by a synchronized plasma membrane rupture of cells in a specific section of a nephron, referred to as acute tubular necrosis (ATN). Whereas the involvement of necroptosis is well characterized, genetic evidence supporting the contribution of ferroptosis is lacking. Here, we demonstrate that the loss of ferroptosis suppressor protein 1 (Fsp1) or the targeted manipulation of the active center of the selenoprotein glutathione peroxidase 4 (Gpx4) sensitize kidneys to tubular ferroptosis, resulting in a unique morphological pattern of tubular necrosis. Given the unmet medical need to clinically inhibit AKI, we generated a combined small molecule inhibitor (Nec-1f) that simultaneously targets receptor interacting protein kinase 1 (RIPK1) and ferroptosis in cell lines, in freshly isolated primary kidney tubules and in mouse models of cardiac transplantation and of AKI and improved survival in models of ischemia-reperfusion injury. Based on genetic and pharmacological evidence, we conclude that GPX4 dysfunction hypersensitizes mice to ATN during AKI. Additionally, we introduce Nec-1f, a solid inhibitor of RIPK1 and weak inhibitor of ferroptosis.
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http://dx.doi.org/10.1038/s41467-021-24712-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8292346PMC
July 2021

Optimized procedures for testing plasma metanephrines in patients on hemodialysis.

Sci Rep 2021 Jul 19;11(1):14706. Epub 2021 Jul 19.

Department of Medicine ΙΙI, University Hospital Carl Gustav Carus at the TU Dresden, Fetscherstraße 74, 01307, Dresden, Germany.

Diagnosis of pheochromocytomas and paragangliomas in patients receiving hemodialysis is troublesome. The aim of the study was to establish optimal conditions for blood sampling for mass spectrometric measurements of normetanephrine, metanephrine and 3-methoxytyramine in patients on hemodialysis and specific reference intervals for plasma metanephrines under the most optimal sampling conditions. Blood was sampled before and near the end of dialysis, including different sampling sites in 170 patients on hemodialysis. Plasma normetanephrine concentrations were lower (P < 0.0001) and metanephrine concentrations higher (P < 0.0001) in shunt than in venous blood, with no differences for 3-methoxytyramine. Normetanephrine, metanephrine and 3-methoxytyramine concentrations in shunt and venous blood were lower (P < 0.0001) near the end than before hemodialysis. Upper cut-offs for normetanephrine were 34% lower when the blood was drawn from the shunt and near the end of hemodialysis compared to blood drawn before hemodialysis. This study establishes optimal sampling conditions using blood from the dialysis shunt near the end of hemodialysis with optimal reference intervals for plasma metanephrines for the diagnosis of pheochromocytomas/paragangliomas among patients on hemodialysis.
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http://dx.doi.org/10.1038/s41598-021-94104-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8290036PMC
July 2021

Hepatic-Metabolite-Based Intermittent Fasting Enables a Sustained Reduction in Insulin Resistance in Type 2 Diabetes and Metabolic Syndrome.

Horm Metab Res 2021 Aug 30;53(8):529-540. Epub 2021 Jun 30.

Department of Medicine, Technische Universität Dresden, Dresden, Germany.

Insulin resistance is the hallmark of Type 2 Diabetes and is still an unmet medical need. Insulin resistance lies at the crossroads of non-alcoholic fatty liver disease, obesity, weight loss and exercise resistance, heart disease, stroke, depression, and brain health. Insulin resistance is purely nutrition related, with a typical molecular disease food intake pattern. The insulin resistant state is accessible by TyG as the appropriate surrogate marker, which is found to lead the personalized molecular hepatic nutrition system for highly efficient insulin resistance remission. Treating insulin resistance with a molecular nutrition-centered approach shifts the treatment paradigm of Type 2 Diabetes from management to cure. This allows remission within five months, with a high efficiency rate of 85%. With molecular intermittent fasting a very efficient treatment for prediabetes and metabolic syndrome is possible, improving the non-alcoholic fatty liver disease (NAFL) state and enabling the body to lose weight in a sustainable manner.
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http://dx.doi.org/10.1055/a-1510-8896DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8360708PMC
August 2021

Chronic post-COVID-19 syndrome and chronic fatigue syndrome: Is there a role for extracorporeal apheresis?

Mol Psychiatry 2021 Jun 17. Epub 2021 Jun 17.

Zentrums für Apherese- und Hämofiltration am INUS Tagesklinikum, Cham, Germany.

As millions of patients have been infected by SARS-CoV-2 virus a vast number of individuals complain about continuing breathlessness and fatigue even months after the onset of the disease. This overwhelming phenomenon has not been well defined and has been called "post-COVID syndrome" or "long-COVID" [1]. There are striking similarities to myalgic encephalomyelitis also called chronic fatigue syndrome linked to a viral and autoimmune pathogenesis. In both disorders neurotransmitter receptor antibodies against ß-adrenergic and muscarinic receptors may play a key role. We found similar elevation of these autoantibodies in both patient groups. Extracorporeal apheresis using a special filter seems to be effective in reducing these antibodies in a significant way clearly improving the debilitating symptoms of patients with chronic fatigue syndrome. Therefore, such a form of neuropheresis may provide a promising therapeutic option for patients with post-COVID-19 syndrome. This method will also be effective when other hitherto unknown antibodies and inflammatory mediators are involved.
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http://dx.doi.org/10.1038/s41380-021-01148-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8209771PMC
June 2021

The role of regulated necrosis in endocrine diseases.

Nat Rev Endocrinol 2021 08 16;17(8):497-510. Epub 2021 Jun 16.

Clinic of Internal Medicine III, Division of Nephrology, University Hospital Carl Gustav Carus at the Technische Universität Dresden, Dresden, Germany.

The death of endocrine cells is involved in type 1 diabetes mellitus, autoimmunity, adrenopause and hypogonadotropism. Insights from research on basic cell death have revealed that most pathophysiologically important cell death is necrotic in nature, whereas regular metabolism is maintained by apoptosis programmes. Necrosis is defined as cell death by plasma membrane rupture, which allows the release of damage-associated molecular patterns that trigger an immune response referred to as necroinflammation. Regulated necrosis comes in different forms, such as necroptosis, pyroptosis and ferroptosis. In this Perspective, with a focus on the endocrine environment, we introduce these cell death pathways and discuss the specific consequences of regulated necrosis. Given that clinical trials of necrostatins for the treatment of autoimmune conditions have already been initiated, we highlight the therapeutic potential of such novel therapeutic approaches that, in our opinion, should be tested in endocrine disorders in the future.
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http://dx.doi.org/10.1038/s41574-021-00499-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8207819PMC
August 2021

Viral infiltration of pancreatic islets in patients with COVID-19.

Nat Commun 2021 06 10;12(1):3534. Epub 2021 Jun 10.

Department of Internal Medicine III, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.

Metabolic diseases are associated with an increased risk of severe COVID-19 and conversely, new-onset hyperglycemia and complications of preexisting diabetes have been observed in COVID-19 patients. Here, we performed a comprehensive analysis of pancreatic autopsy tissue from COVID-19 patients using immunofluorescence, immunohistochemistry, RNA scope and electron microscopy and detected SARS-CoV-2 viral infiltration of beta-cells in all patients. Using SARS-CoV-2 pseudoviruses, we confirmed that isolated human islet cells are permissive to infection. In eleven COVID-19 patients, we examined the expression of ACE2, TMPRSS and other receptors and factors, such as DPP4, HMBG1 and NRP1, that might facilitate virus entry. Whereas 70% of the COVID-19 patients expressed ACE2 in the vasculature, only 30% displayed ACE2-expression in beta-cells. Even in the absence of manifest new-onset diabetes, necroptotic cell death, immune cell infiltration and SARS-CoV-2 viral infection of pancreatic beta-cells may contribute to varying degrees of metabolic dysregulation in patients with COVID-19.
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http://dx.doi.org/10.1038/s41467-021-23886-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8192507PMC
June 2021

SARS-CoV-2 RNAemia and proteomic trajectories inform prognostication in COVID-19 patients admitted to intensive care.

Nat Commun 2021 06 7;12(1):3406. Epub 2021 Jun 7.

Peter Gorer Department of Immunobiology, School of Immunology and Microbial Sciences, King's College London, London, UK.

Prognostic characteristics inform risk stratification in intensive care unit (ICU) patients with coronavirus disease 2019 (COVID-19). We obtained blood samples (n = 474) from hospitalized COVID-19 patients (n = 123), non-COVID-19 ICU sepsis patients (n = 25) and healthy controls (n = 30). Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA was detected in plasma or serum (RNAemia) of COVID-19 ICU patients when neutralizing antibody response was low. RNAemia is associated with higher 28-day ICU mortality (hazard ratio [HR], 1.84 [95% CI, 1.22-2.77] adjusted for age and sex). RNAemia is comparable in performance to the best protein predictors. Mannose binding lectin 2 and pentraxin-3 (PTX3), two activators of the complement pathway of the innate immune system, are positively associated with mortality. Machine learning identified 'Age, RNAemia' and 'Age, PTX3' as the best binary signatures associated with 28-day ICU mortality. In longitudinal comparisons, COVID-19 ICU patients have a distinct proteomic trajectory associated with mortality, with recovery of many liver-derived proteins indicating survival. Finally, proteins of the complement system and galectin-3-binding protein (LGALS3BP) are identified as interaction partners of SARS-CoV-2 spike glycoprotein. LGALS3BP overexpression inhibits spike-pseudoparticle uptake and spike-induced cell-cell fusion in vitro.
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http://dx.doi.org/10.1038/s41467-021-23494-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8184784PMC
June 2021

Heparan sulfate proteoglycans in beta cells provide a critical link between endoplasmic reticulum stress, oxidative stress and type 2 diabetes.

PLoS One 2021 4;16(6):e0252607. Epub 2021 Jun 4.

Department of Immunology and Infectious Disease, The John Curtin School of Medical Research, The Australian National University, Canberra, Australian Capital Territory, Australia.

Heparan sulfate proteoglycans (HSPGs) consist of a core protein with side chains of the glycosaminoglycan heparan sulfate (HS). We have previously identified (i) the HSPGs syndecan-1 (SDC1), and collagen type XVIII (COL18) inside mouse and human islet beta cells, and (ii) a critical role for HS in beta cell survival and protection from reactive oxygen species (ROS). The objective of this study was to investigate whether endoplasmic reticulum (ER) stress contributes to oxidative stress and type 2 diabetes (T2D) by depleting beta cell HSPGs/HS. A rapid loss of intra-islet/beta cell HSPGs, HS and heparanase (HPSE, an HS-degrading enzyme) accompanied upregulation of islet ER stress gene expression in both young T2D-prone db/db and Akita Ins2WT/C96Y mice. In MIN6 beta cells, HSPGs, HS and HPSE were reduced following treatment with pharmacological inducers of ER stress (thapsigargin or tunicamycin). Treatment of young db/db mice with Tauroursodeoxycholic acid (TUDCA), a chemical protein folding chaperone that relieves ER stress, improved glycemic control and increased intra-islet HSPG/HS. In vitro, HS replacement with heparin (a highly sulfated HS analogue) significantly increased the survival of wild-type and db/db beta cells and restored their resistance to hydrogen peroxide-induced death. We conclude that ER stress inhibits the synthesis/maturation of HSPG core proteins which are essential for HS assembly, thereby exacerbating oxidative stress and promoting beta cell failure. Diminished intracellular HSPGs/HS represent a previously unrecognized critical link bridging ER stress, oxidative stress and beta cell failure in T2D.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0252607PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8177513PMC
June 2021

The trans-ancestral genomic architecture of glycemic traits.

Nat Genet 2021 06 31;53(6):840-860. Epub 2021 May 31.

Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.

Glycemic traits are used to diagnose and monitor type 2 diabetes and cardiometabolic health. To date, most genetic studies of glycemic traits have focused on individuals of European ancestry. Here we aggregated genome-wide association studies comprising up to 281,416 individuals without diabetes (30% non-European ancestry) for whom fasting glucose, 2-h glucose after an oral glucose challenge, glycated hemoglobin and fasting insulin data were available. Trans-ancestry and single-ancestry meta-analyses identified 242 loci (99 novel; P < 5 × 10), 80% of which had no significant evidence of between-ancestry heterogeneity. Analyses restricted to individuals of European ancestry with equivalent sample size would have led to 24 fewer new loci. Compared with single-ancestry analyses, equivalent-sized trans-ancestry fine-mapping reduced the number of estimated variants in 99% credible sets by a median of 37.5%. Genomic-feature, gene-expression and gene-set analyses revealed distinct biological signatures for each trait, highlighting different underlying biological pathways. Our results increase our understanding of diabetes pathophysiology by using trans-ancestry studies for improved power and resolution.
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http://dx.doi.org/10.1038/s41588-021-00852-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610958PMC
June 2021

Gain in survival after metabolic-bariatric surgery.

Lancet 2021 May 6;397(10287):1785-1787. Epub 2021 May 6.

Division of Diabetes & Nutritional Sciences, Faculty of Life Sciences & Medicine, King's College London, London, UK; Department of Medicine III, Universitätsklinikum Carl Gustav Carus an der Technischen Universität Dresden, Dresden, Germany.

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http://dx.doi.org/10.1016/S0140-6736(21)00952-1DOI Listing
May 2021

Adrenal Hormone Interactions and Metabolism: A Single Sample Multi-Omics Approach.

Horm Metab Res 2021 May 26;53(5):326-334. Epub 2021 Apr 26.

Institute of Clinical Chemistry and Laboratory Medicine, Technische Universität Dresden, Dresden, Germany.

The adrenal gland is important for many physiological and pathophysiological processes, but studies are often restricted by limited availability of sample material. Improved methods for sample preparation are needed to facilitate analyses of multiple classes of adrenal metabolites and macromolecules in a single sample. A procedure was developed for preparation of chromaffin cells, mouse adrenals, and human chromaffin tumors that allows for multi-omics analyses of different metabolites and preservation of native proteins. To evaluate the new procedure, aliquots of samples were also prepared using conventional procedures. Metabolites were analyzed by liquid-chromatography with mass spectrometry or electrochemical detection. Metabolite contents of chromaffin cells and tissues analyzed with the new procedure were similar or even higher than with conventional methods. Catecholamine contents were comparable between both procedures. The TCA cycle metabolites, -aconitate, isocitate, and α-ketoglutarate were detected at higher concentrations in cells, while in tumor tissue only isocitrate and potentially fumarate were measured at higher contents. In contrast, in a broad untargeted metabolomics approach, a methanol-based preparation procedure of adrenals led to a 1.3-fold higher number of detected metabolites. The established procedure also allows for simultaneous investigation of adrenal hormones and related enzyme activities as well as proteins within a single sample. This novel multi-omics approach not only minimizes the amount of sample required and overcomes problems associated with tissue heterogeneity, but also provides a more complete picture of adrenal function and intra-adrenal interactions than previously possible.
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http://dx.doi.org/10.1055/a-1440-0278DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8105089PMC
May 2021

Comparative efficacy of different weight loss treatments on knee osteoarthritis: A network meta-analysis.

Obes Rev 2021 Aug 15;22(8):e13230. Epub 2021 Apr 15.

Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy.

The lifetime risk of developing symptomatic knee osteoarthritis is 60% in subjects with obesity. It is unclear which is the best weight loss interventions leading to a meaningful improvement of osteoarthritis symptoms and clinical conditions in subjects with obesity. Our network meta-analysis compares different weight loss interventions on the improvement of osteoarthritis symptoms and clinical conditions in subjects affected by obesity. PubMed, Embase, and Cochrane databases were systematically searched for eligible studies until November 2020. Thirty eligible studies comprising 4651 adults (74.6% women) were included. The most effective interventions reducing pain were bariatric surgery, low-calorie diet and exercise, and intensive weight loss and exercise (-62.7 [95% CrI: -74.6, -50.6]; -34.4 [95% CrI: -48.1, -19.5]; -27.1 [95% CrI: -40.4, -13.6] respectively). For every 1% weight loss Western Ontario and McMaster Universities Osteoarthritis (WOMAC) pain, function, and stiffness scores decreased by about 2% points. In conclusion, our meta-analysis shows that a substantial weight loss is necessary to reduce significantly knee pain and joint stiffness and to improve physical function: 25% weight reduction from baseline is necessary to obtain a 50% reduction of each subscale of the WOMAC score. However, performing physical exercise is essential to preserve the lean body mass and to avoid sarcopenia. Our results apply to a large spectrum of body mass index (BMI), from overweight to severe obesity.
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http://dx.doi.org/10.1111/obr.13230DOI Listing
August 2021

Adrenal medulla development and medullary-cortical interactions.

Mol Cell Endocrinol 2021 05 30;528:111258. Epub 2021 Mar 30.

Department of Internal Medicine III, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany. Electronic address:

The mammalian adrenal gland is composed of two distinct tissue types in a bidirectional connection, the catecholamine-producing medulla derived from the neural crest and the mesoderm-derived cortex producing steroids. The medulla mainly consists of chromaffin cells derived from multipotent nerve-associated descendants of Schwann cell precursors. Already during adrenal organogenesis, close interactions between cortex and medulla are necessary for proper differentiation and morphogenesis of the gland. Moreover, communication between the cortex and the medulla ensures a regular function of the adult adrenal. In tumor development, interfaces between the two parts are also common. Here, we summarize the development of the mammalian adrenal medulla and the current understanding of the cortical-medullary interactions under development and in health and disease.
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http://dx.doi.org/10.1016/j.mce.2021.111258DOI Listing
May 2021

Low-fat hypocaloric diet reduces neprilysin in overweight and obese human subjects.

ESC Heart Fail 2021 04 27;8(2):938-942. Epub 2021 Feb 27.

Section of Metabolic and Vascular Medicine, Medical Clinic III, University Hospital Carl Gustav Carus, TU Dresden, Dresden, Germany.

Aims: Neprilysin (NEP), a zinc metallopeptidase, degrades a variety of bioactive peptides including natriuretic peptides terminating their biological action on arterial blood pressure and natriuresis. Pharmacological inhibition of NEP reduces mortality in patients with heart failure with reduced ejection fraction. Physiological interventions reducing NEP levels are unknown in humans. Because obesity leads to increased NEP levels and increases the risk for heart failure, we hypothesized that weight loss reduces NEP concentrations in plasma and tissue.

Methods And Results: We randomized overweight to obese human subjects to a low-fat or low-carbohydrate hypocaloric 6 month weight loss intervention. Soluble NEP was determined in plasma, and NEP mRNA was analysed from subcutaneous adipose tissue before and after diet. Low-fat diet-induced weight loss reduced soluble NEP levels from 0.83 ± 0.18 to 0.72 ± 0.18 μg/L (P = 0.038), while subcutaneous adipose tissue NEP mRNA expression was reduced by both dietary interventions [21% (P = 0.0057) by low-fat diet and 16% (P = 0.048) by low-carbohydrate diet]. We also analysed the polymorphisms of the gene coding for NEP, rs9827586 and rs701109, known to be associated with plasma NEP levels. For both single-nucleotide polymorphisms, minor allele carriers (A/A) had higher baseline plasma NEP levels (rs9827586: β = 0.53 ± 0.23, P < 0.0001; rs701109: β = 0.43 ± 0.22, P = 0.0016), and minor allele carriers of rs9827586 responded to weight loss with a larger NEP reduction (rs9827586: P = 0.0048).

Conclusions: Our study identifies weight loss via a hypocaloric low-fat diet as the first physiological intervention in humans to reduce NEP in plasma and adipose tissue. Specific single-nucleotide polymorphisms further contribute to the decrease. Our findings may help to explain the beneficial effect of weight loss on cardiac function in patients with heart failure.
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http://dx.doi.org/10.1002/ehf2.13220DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8006681PMC
April 2021

Scoping review of COVID-19-related systematic reviews and meta-analyses: can we really have confidence in their results?

Postgrad Med J 2021 Feb 26. Epub 2021 Feb 26.

NICHD, National Institutes of Health, Bethesda, Maryland, USA

Aim: The aim of this study was to systematically appraise the quality of a sample of COVID-19-related systematic reviews (SRs) and discuss internal validity threats affecting the COVID-19 body of evidence.

Design: We conducted a scoping review of the literature. SRs with or without meta-analysis (MA) that evaluated clinical data, outcomes or treatments for patients with COVID-19 were included.

Main Outcome Measures: We extracted quality characteristics guided by A Measurement Tool to Assess Systematic Reviews-2 to calculate a qualitative score. Complementary evaluation of the most prominent published limitations affecting the COVID-19 body of evidence was performed.

Results: A total of 63 SRs were included. The majority were judged as a critically low methodological quality. Most of the studies were not guided by a pre-established protocol (39, 62%). More than half (39, 62%) failed to address risk of bias when interpreting their results. A comprehensive literature search strategy was reported in most SRs (54, 86%). Appropriate use of statistical methods was evident in nearly all SRs with MAs (39, 95%). Only 16 (33%) studies recognised heterogeneity in the definition of severe COVID-19 as a limitation of the study, and 15 (24%) recognised repeated patient populations as a limitation.

Conclusion: The methodological and reporting quality of current COVID-19 SR is far from optimal. In addition, most of the current SRs fail to address relevant threats to their internal validity, including repeated patients and heterogeneity in the definition of severe COVID-19. Adherence to proper study design and peer-review practices must remain to mitigate current limitations.
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http://dx.doi.org/10.1136/postgradmedj-2020-139392DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7918809PMC
February 2021

Involvement of Pattern Recognition Receptors in the Direct Influence of Bacterial Components and Standard Antiacne Compounds on Human Sebaceous Gland Cells.

Skin Pharmacol Physiol 2021 18;34(1):19-29. Epub 2021 Feb 18.

Department of Internal Medicine III, University Hospital Carl Gustav Carus, University of Dresden, Dresden, Germany.

Introduction: Pattern recognition receptors are involved in innate and adaptive immunity by detecting microbial components. Bacteria have been accused to play a role in inflammatory acne. We investigated the potential involvement of Toll-like receptor (TLR)2, TLR4, TLR6, and CD14 in the direct influence of bacterial components and standard antiacne compounds on human sebocytes.

Methods: mRNA and protein expression of TLR2, TLR4, TLR6, and CD14 in SZ95 sebocytes was evaluated by real-time qRT-PCR and immunocytochemistry. The effects of lipopolysaccharides (LPS) and lipoteichoic acid on TLR2, TLR4, and CD14 expression and of cytokine/chemokine secretion by 13-cis-retinoic acid, all-trans-retinoic acid, retinol, and hydrocortisone at the mRNA and protein levels were assessed by real-time qRT-PCR and ELISA and verified by cocultivation with neutralizing antibodies.

Results: The constitutive expression of TLR2, TLR4, and CD14 in SZ95 sebocytes was augmented by exposure to LPS. Hydrocortisone induced TLR2, but markedly reduced TLR4 expression. 13-cis-retinoic acid and all-trans-retinoic acid regulated IL-6 release. LPS enhanced and hydrocortisone reduced cytokine and chemokine release. Anti-TLR4 and anti-CD14 mAb blocked LPS-induced IL-8 and IL-6 release.

Conclusions: Microbial components use pattern recognition receptors to directly activate sebocytes to express a wide range of proinflammatory molecules and especially IL-8 and IL-6 in a TLR4- and CD14-specific manner. Retinoids, but mostly corticosteroids, also use this pathway to exhibit anti-inflammatory effects.
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http://dx.doi.org/10.1159/000513259DOI Listing
February 2021

Hormonal responsiveness in the Trier Social Stress Test and the dexamethasone-corticotropin releasing hormone test in healthy individuals.

Psych J 2021 Apr 28;10(2):305-317. Epub 2021 Jan 28.

Department of Internal Medicine III, University Hospital Carl Gustav Carus Dresden, Technische Universitaet Dresden, Dresden, Germany.

A number of different laboratory procedures investigate the hormonal response in a standardized pharmacological challenge test (dexamethasone-corticotropin releasing hormone; DEX-CRH) or in a psychosocial stress induction on the hypothalamic-pituitary-adrenocortical axis by the Trier Social Stress Test (TSST). However, the magnitude of the response related to the different stressors and the interaction of the responsiveness between the two tests is still unclear. Fifty-two participants underwent both the DEX-CRH test and the TSST on two separate days. The cortisol and the plasma adrenocorticotropic hormone (ACTH) release were assessed before and after the stress tests. For a specification of the cortisol response to both conditions, subgroups of high- and low-cortisol responders to the TSST and the DEX-CRH test were formed. The healthy participants showed a substantial increase in the ACTH and the cortisol concentration after the two tests. This increase was 3 times greater in the TSST than the DEX-CRH test. High responders in both tests demonstrated a higher factor of the cortisol reactivity ratio (TSST/DEX-CRH test). Psychosocial stress as induced by the TSST was associated with a significantly greater increase in cortisol compared to the DEX-CRH test, even though the ACTH response displayed no differences. Our findings indicate an interaction of the hormonal responsiveness between the two tests with regard to the cortisol patterns.
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http://dx.doi.org/10.1002/pchj.424DOI Listing
April 2021

Metabolic surgery versus conventional medical therapy in patients with type 2 diabetes: 10-year follow-up of an open-label, single-centre, randomised controlled trial.

Lancet 2021 01;397(10271):293-304

Division of Diabetes and Nutritional Sciences, Faculty of Life Sciences and Medicine, King's College London, London, UK; Department of Diabetes, Bariatric and Metabolic Surgery, King's College Hospital, London, UK.

Background: No data from randomised controlled trials of metabolic surgery for diabetes are available beyond 5 years of follow-up. We aimed to assess 10-year follow-up after surgery compared with medical therapy for the treatment of type 2 diabetes.

Methods: We did a 10-year follow-up study of an open-label, single-centre (tertiary hospital in Rome, Italy), randomised controlled trial, in which patients with type 2 diabetes (baseline duration >5 years; glycated haemoglobin [HbA] >7·0%, and body-mass index ≥35 kg/m) were randomly assigned (1:1:1) to medical therapy, Roux-en-Y gastric bypass (RYGB), or biliopancreatic diversion (BPD) by a computerised system. The primary endpoint of the study was diabetes remission at 2 years (HbA <6·5% and fasting glycaemia <5·55 mmol/L without ongoing medication for at least 1 year). In the 10-year analysis, durability of diabetes remission was analysed by intention to treat (ITT). This study is registered with ClinicalTrials.gov, NCT00888836.

Findings: Between April 30, 2009, and Oct 31, 2011, of 72 patients assessed for eligibility, 60 were included. The 10-year follow-up rate was 95·0% (57 of 60). Of all patients who were surgically treated, 15 (37·5%) maintained diabetes remission throughout the 10-year period. Specifically, 10-year remission rates in the ITT population were 5·5% for medical therapy (95% CI 1·0-25·7; one participant went into remission after crossover to surgery), 50·0% for BPD (29·9-70·1), and 25·0% for RYGB (11·2-46·9; p=0·0082). 20 (58·8%) of 34 participants who were observed to be in remission at 2 years had a relapse of hyperglycaemia during the follow-up period (BPD 52·6% [95% CI 31·7-72·7]; RYGB 66·7% [41·7-84·8]). All individuals with relapse, however, maintained adequate glycaemic control at 10 years (mean HbA 6·7% [SD 0·2]). Participants in the RYGB and BPD groups had fewer diabetes-related complications than those in the medical therapy group (relative risk 0·07 [95% CI 0·01-0·48] for both comparisons). Serious adverse events occurred more frequently among participants in the BPD group (odds ratio [OR] for BPD vs medical therapy 2·7 [95% CI 1·3-5·6]; OR for RYGB vs medical therapy 0·7 [0·3-1·9]).

Interpretation: Metabolic surgery is more effective than conventional medical therapy in the long-term control of type 2 diabetes. Clinicians and policy makers should ensure that metabolic surgery is appropriately considered in the management of patients with obesity and type 2 diabetes.

Funding: Fondazione Policlinico Universitario Agostino Gemelli IRCCS.
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http://dx.doi.org/10.1016/S0140-6736(20)32649-0DOI Listing
January 2021

Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability.

Nat Commun 2021 01 5;12(1):24. Epub 2021 Jan 5.

Department of Biostatistics and Data Science, Division of Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, NC, USA.

Differences between sexes contribute to variation in the levels of fasting glucose and insulin. Epidemiological studies established a higher prevalence of impaired fasting glucose in men and impaired glucose tolerance in women, however, the genetic component underlying this phenomenon is not established. We assess sex-dimorphic (73,089/50,404 women and 67,506/47,806 men) and sex-combined (151,188/105,056 individuals) fasting glucose/fasting insulin genetic effects via genome-wide association study meta-analyses in individuals of European descent without diabetes. Here we report sex dimorphism in allelic effects on fasting insulin at IRS1 and ZNF12 loci, the latter showing higher RNA expression in whole blood in women compared to men. We also observe sex-homogeneous effects on fasting glucose at seven novel loci. Fasting insulin in women shows stronger genetic correlations than in men with waist-to-hip ratio and anorexia nervosa. Furthermore, waist-to-hip ratio is causally related to insulin resistance in women, but not in men. These results position dissection of metabolic and glycemic health sex dimorphism as a steppingstone for understanding differences in genetic effects between women and men in related phenotypes.
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http://dx.doi.org/10.1038/s41467-020-19366-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7785747PMC
January 2021

Pioglitazone and bariatric surgery are the most effective treatments for non-alcoholic steatohepatitis: A hierarchical network meta-analysis.

Diabetes Obes Metab 2021 04 15;23(4):980-990. Epub 2021 Jan 15.

Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy.

Aims: To compare different treatments for non-alcoholic steatohepatitis (NASH) and to determine an effectiveness hierarchy.

Materials And Methods: We conducted a systematic review and Bayesian network meta-analysis including randomized controlled trials or prospective trials with at least 6 months' follow-up and histologically proven NASH in adult participants. Monte Carlo simulations were performed, each generating 10 000 data points, and results are reported as medians and 95% credibility intervals (CrIs). A meta-regression was conducted to find the effects of body mass index (BMI) decrement or reduction of homeostatic model assessment of insulin resistance (HOMA-IR) index on non-alcoholic fatty liver disease activity score (NAS) change.

Results: The review identified 48 eligible trials comprising 2356 adults (55.6% men). Data were pooled using a random-effects model. The most effective treatments in terms of NAS reduction per semester were pioglitazone and Roux-en-Y gastric bypass (RYGB; -1.50 [95% CrI -2.08, -1.00] for pioglitazione and -1.00 [95% CrI -1.70, -0.32] for RYGB). Pioglitazone was also the best therapy for steatosis and lobular inflammation reduction. RYGB was the best treatment for hepatocellular ballooning reduction, whereas antioxidants appeared to be best for fibrosis improvement. For each 1% decrement in BMI, NAS was reduced by 1.3% (β = 1.28%, P = 0.01). Conversely, a 1% reduction of HOMA-IR index reduced NAS by 0.3% (β = 0.31%, P < 0.001). Treatments that were regarded as promising, such as elafibranor, simtuzumab, selonsertib, cenicriviroc, obeticholic acid and liraglutide, did not reduce either NAS or liver fibrosis significantly.

Conclusions: Pioglitazione and RYGB are the most effective therapies for NASH. Antioxidants may be effective in reducing liver fibrosis. Weight loss and improvement of hepatic insulin resistance are promising approaches in the treatment of NASH.
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http://dx.doi.org/10.1111/dom.14304DOI Listing
April 2021

Insulin Resistance Is Central to Long-Term Reversal of Histologic Nonalcoholic Steatohepatitis After Metabolic Surgery.

J Clin Endocrinol Metab 2021 03;106(3):750-761

Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy.

Context: Nonalcoholic steatohepatitis (NASH) is considered the hepatic counterpart of metabolic syndrome.

Objective: This work aimed to investigate the determinants of NASH reversal in patients undergoing biliopancreatic diversion (BPD) in a 5-year follow-up study.

Methods: This prospective study was conducted at Policlinico Universitario Agostino Gemelli. A total of 37 patients underwent fine-needle liver biopsy during BPD. Ultrasonography-guided percutaneous liver biopsy was obtained 5 years after the operation. The primary outcome of our study was histologic NASH reversal at 5-year follow-up. To better characterize the clinical variables involved in the resolution of NASH, we also compared patients without histologic NASH resolution at 5 years with those in whom NASH had disappeared.

Results: At follow-up, NASH had reversed in 56.5% of the patients. The NAFLD activity score (NAS) improved from 3.7 ± 0.93 to 2 ± 1.11 (P < .001). Fibrosis reversed in 16% patients (P = .022), and 32% improved (95% CI, 0.05-0.54). No significant differences in body mass index or clinical parameters changes explained the effect of surgery on NASH, apart from the measure of insulin sensitivity post surgery. The Homeostasis Model Assessment of Insulin Resistance decreased from 3.31 ± 1.72 at baseline to 1.73 ± 1.08 (P < .001) after BPD, and the Matsuda index improved from 2.66 ± 1.79 to 4.73 ± 3.05 (P < .001). The lipid profile normalized (total cholesterol from 4.75 ± 1.18 to 3.32 ± 0.77 mmol/L, P < .001; low-density lipoprotein cholesterol from 2.92 ± 0.91 to 1.60 ± 0.51 mmol/L, P = .0001; high-density lipoprotein cholesterol from 0.97 ± 0.33 to 1.10 ± 0.35 mmol/L, P = .023; triglycerides from 2.52 ± 1.6 to 1.47 ± 0.67 mmol/L, P = .003). Neural network analysis showed that the end-study Matsuda index discriminated between responders and nonresponders with high accuracy (receiver operating characteristic area under the curve = 0.98%).

Conclusion: Remission of NASH is driven by reversal of whole-body insulin resistance post intervention.
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http://dx.doi.org/10.1210/clinem/dgaa892DOI Listing
March 2021

Insulin and obesity transform hypothalamic-pituitary-adrenal axis stemness and function in a hyperactive state.

Mol Metab 2021 01 4;43:101112. Epub 2020 Nov 4.

Department of Internal Medicine III, University Hospital Carl Gustav Carus, Dresden University of Technology, Fetscherstraße 74, Dresden, 01307, Germany. Electronic address:

Objective: Metabolic diseases are an increasing problem in society with the brain-metabolic axis as a master regulator of the human body for sustaining homeostasis under metabolic stress. However, metabolic inflammation and disease will trigger sustained activation of the hypothalamic-pituitary-adrenal axis. In this study, we investigated the role of metabolic stress on progenitor cells in the hypothalamic-pituitary-adrenal axis.

Methods: In vitro, we applied insulin and leptin to murine progenitor cells isolated from the pituitary and adrenal cortex and examined the role of these hormones on proliferation and differentiation. In vivo, we investigated two different mouse models of metabolic disease, obesity in leptin-deficient ob/ob mice and obesity achieved via feeding with a high-fat diet.

Results: Insulin was shown to lead to enhanced proliferation and differentiation of both pituitary and adrenocortical progenitors. No alterations in the progenitors were noted in our chronic metabolic stress models. However, hyperactivation of the hypothalamic-pituitary-adrenal axis was observed and the expression of the appetite-regulating genes Npy and Agrp changed in both the hypothalamus and adrenal.

Conclusions: It is well-known that chronic stress and stress hormones such as glucocorticoids can induce metabolic changes including obesity and diabetes. In this article, we show for the first time that this might be based on an early sensitization of stem cells of the hypothalamic-pituitary-adrenal axis. Thus, pituitary and adrenal progenitor cells exposed to high levels of insulin are metabolically primed to a hyper-functional state leading to enhanced hormone production. Likewise, obese animals exhibit a hyperactive hypothalamic-pituitary-adrenal axis leading to adrenal hyperplasia. This might explain how stress in early life can increase the risk for developing metabolic syndrome in adulthood.
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http://dx.doi.org/10.1016/j.molmet.2020.101112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7691554PMC
January 2021

Rare Functional Variants Associated with Antidepressant Remission in Mexican-Americans: Short title: Antidepressant remission and pharmacogenetics in Mexican-Americans.

J Affect Disord 2021 01 17;279:491-500. Epub 2020 Oct 17.

Department of Psychiatry and Behavioral Sciences, State University of New York, Upstate Medical University, Syracuse, NY, USA; Department of Neuroscience and Physiology, State University of New York, Upstate Medical University, Syracuse, NY, USA; Mind & Brain Theme, South Australian Health and Medical Research Institute Adelaide, South Australia, Australia; Department of Psychiatry, Flinders University College of Medicine and Public Health, Bedford Park, South Australia, Australia. Electronic address:

Introduction: Rare genetic functional variants can contribute to 30-40% of functional variability in genes relevant to drug action. Therefore, we investigated the role of rare functional variants in antidepressant response.

Method: Mexican-American individuals meeting the Diagnostic and Statistical Manual-IV criteria for major depressive disorder (MDD) participated in a prospective randomized, double-blind study with desipramine or fluoxetine. The rare variant analysis was performed using whole-exome genotyping data. Network and pathway analyses were carried out with the list of significant genes.

Results: The Kernel-Based Adaptive Cluster method identified functional rare variants in 35 genes significantly associated with treatment remission (False discovery rate, FDR <0.01). Pathway analysis of these genes supports the involvement of the following gene ontology processes: olfactory/sensory transduction, regulation of response to cytokine stimulus, and meiotic cell cycleprocess.

Limitations: Our study did not have a placebo arm. We were not able to use antidepressant blood level as a covariate. Our study is based on a small sample size of only 65 Mexican-American individuals. Further studies using larger cohorts are warranted.

Conclusion: Our data identified several rare functional variants in antidepressant drug response in MDD patients. These have the potential to serve as genetic markers for predicting drug response.

Trial Registration: ClinicalTrials.gov NCT00265291.
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http://dx.doi.org/10.1016/j.jad.2020.10.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7953425PMC
January 2021

HIF2α supports pro-metastatic behavior in pheochromocytomas/paragangliomas.

Endocr Relat Cancer 2020 11;27(11):625-640

Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Carl Gustav Carus, Medical Faculty Carl Gustav Carus, Technische Universität Dresden, Fetscherstrasse, Dresden, Germany.

Mutations that drive the stabilization of hypoxia inducible factor 2α (HIF2α) and downstream pseudohypoxic signaling are known to predispose to the development of pheochromocytomas and paragangliomas (PPGLs). However, any role of HIF2α in predisposition to metastatic disease remains unclear. To assess such a role we combined gene-manipulations in pheochromocytoma cell lines with retrospective analyses of patient data and gene expression profiling in tumor specimens. Among 425 patients with PPGLs identified with mutations in tumor-susceptibility genes, those with tumors due to activation of pseudohypoxic pathways had a higher frequency of metastatic disease than those with tumors due to activation of kinase-signaling pathways, even without inclusion of patients with mutations in SDHB (18.6% vs 4.3% in, P < 0.0001). Three out of nine (33%) patients with gain-of-function mutations in HIF2α had metastatic disease. In cell line studies, elevated expression of HIF2α enhanced cell proliferation and led to increased migration and invasion capacity. Moreover, HIF2α expression in HIF2α-deficient cells resulted in increased cell motility, diffuse cluster formation and emergence of pseudopodia indicating changes in cell adhesion and cytoskeletal remodeling. In a mouse liver metastasis model, Hif2a enhanced the metastatic load. Transcriptomics data revealed alterations in focal adhesion and extracellular matrix-receptor interactions in HIF2α-mutated PPGLs. Our translational findings demonstrate that HIF2α supports pro-metastatic behavior in PPGLs, though other factors remain critical for subsequent transition to metastasis. We identified LAMB1 and COL4A2 as new potential therapeutic targets for HIF2α-driven PPGLs. Identified HIF2α downstream targets might open a new therapeutic window for aggressive HIF2α-expressing tumors.
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http://dx.doi.org/10.1530/ERC-20-0205DOI Listing
November 2020

Offensive Behavior, Striatal Glutamate Metabolites, and Limbic-Hypothalamic-Pituitary-Adrenal Responses to Stress in Chronic Anxiety.

Int J Mol Sci 2020 Oct 9;21(20). Epub 2020 Oct 9.

Traumatic Stress Studies Division, ICAHN School of Medicine at Mount Sinai, New York, NY 10029-6574, USA.

Variations in anxiety-related behavior are associated with individual allostatic set-points in chronically stressed rats. Actively offensive rats with the externalizing indicators of sniffling and climbing the stimulus and material tearing during 10 days of predator scent stress had reduced plasma corticosterone, increased striatal glutamate metabolites, and increased adrenal 11-dehydrocorticosterone content compared to passively defensive rats with the internalizing indicators of freezing and grooming, as well as to controls without any behavioral changes. These findings suggest that rats that display active offensive activity in response to stress develop anxiety associated with decreased allostatic set-points and increased resistance to stress.
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http://dx.doi.org/10.3390/ijms21207440DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7589759PMC
October 2020
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