Publications by authors named "Ravichandran Ramasamy"

121 Publications

Macrophage-adipocyte communication and cardiac remodeling.

J Exp Med 2021 Sep 20;218(9). Epub 2021 Jul 20.

Diabetes Research Program, New York University Grossman Medical Center, New York, NY.

In obesity complicated by hypertension, multicellular processes integrate to orchestrate cardiac fibrosis; the underlying mechanisms, however, remain elusive. In this issue of JEM, Cheng et al. (2021. J. Exp. Med. https://doi.org/10.1084/jem.20210252) describe adipocyte-macrophage collaboration to foster cardiac fibrosis through the actions of angiotensin II in obesity.
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http://dx.doi.org/10.1084/jem.20211098DOI Listing
September 2021

Inflammation Meets Metabolism: Roles for the Receptor for Advanced Glycation End Products Axis in Cardiovascular Disease.

Immunometabolism 2021 2;3(3). Epub 2021 Jun 2.

Diabetes Research Program, Department of Medicine, New York University Grossman School of Medicine, New York, NY 10016, USA.

Fundamental modulation of energy metabolism in immune cells is increasingly being recognized for the ability to impart important changes in cellular properties. In homeostasis, cells of the innate immune system, such as monocytes, macrophages and dendritic cells (DCs), are enabled to respond rapidly to various forms of acute cellular and environmental stress, such as pathogens. In chronic stress milieus, these cells may undergo a re-programming, thereby triggering processes that may instigate tissue damage and failure of resolution. In settings of metabolic dysfunction, moieties such as excess sugars (glucose, fructose and sucrose) accumulate in the tissues and may form advanced glycation end products (AGEs), which are signaling ligands for the receptor for advanced glycation end products (RAGE). In addition, cellular accumulation of cholesterol species such as that occurring upon macrophage engulfment of dead/dying cells, presents these cells with a major challenge to metabolize/efflux excess cholesterol. RAGE contributes to reduced expression and activities of molecules mediating cholesterol efflux. This Review chronicles examples of the roles that sugars and cholesterol, via RAGE, play in immune cells in instigation of maladaptive cellular signaling and the mediation of chronic cellular stress. At this time, emerging roles for the ligand-RAGE axis in metabolism-mediated modulation of inflammatory signaling in immune cells are being unearthed and add to the growing body of factors underlying pathological immunometabolism.
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http://dx.doi.org/10.20900/immunometab20210024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8232874PMC
June 2021

Diabetes and Cardiovascular Complications: The Epidemics Continue.

Curr Cardiol Rep 2021 06 3;23(7):74. Epub 2021 Jun 3.

Diabetes Research Program, Department of Medicine, New York University Grossman School of Medicine, 435 East 30th Street, Science Building, Room 615, New York, NY, 10016, USA.

Purpose Of Review: The cardiovascular complications of type 1 and 2 diabetes are major causes of morbidity and mortality. Extensive efforts have been made to maximize glycemic control; this strategy reduces certain manifestations of cardiovascular complications. There are drawbacks, however, as intensive glycemic control does not impart perennial protective benefits, and these efforts are not without potential adverse sequelae, such as hypoglycemic events.

Recent Findings: Here, the authors have focused on updates into key areas under study for mechanisms driving these cardiovascular disorders in diabetes, including roles for epigenetics and gene expression, interferon networks, and mitochondrial dysfunction. Updates on the cardioprotective roles of the new classes of hyperglycemia-targeting therapies, the sodium glucose transport protein 2 inhibitors and the agonists of the glucagon-like peptide 1 receptor system, are reviewed. In summary, insights from ongoing research and the cardioprotective benefits of the newer type 2 diabetes therapies are providing novel areas for therapeutic opportunities in diabetes and CVD.
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http://dx.doi.org/10.1007/s11886-021-01504-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8173334PMC
June 2021

Aldose Reductase: An Emerging Target for Development of Interventions for Diabetic Cardiovascular Complications.

Front Endocrinol (Lausanne) 2021 11;12:636267. Epub 2021 Mar 11.

Diabetes Research Program, Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, NYU Grossman School of Medicine, New York, NY, United States.

Diabetes is a leading cause of cardiovascular morbidity and mortality. Despite numerous treatments for cardiovascular disease (CVD), for patients with diabetes, these therapies provide less benefit for protection from CVD. These considerations spur the concept that diabetes-specific, disease-modifying therapies are essential to identify especially as the diabetes epidemic continues to expand. In this context, high levels of blood glucose stimulate the flux aldose reductase (AR) pathway leading to metabolic and signaling changes in cells of the cardiovascular system. In animal models flux AR in hearts is increased by diabetes and ischemia and its inhibition protects diabetic and non-diabetic hearts from ischemia-reperfusion injury. In mouse models of diabetic atherosclerosis, human AR expression accelerates progression and impairs regression of atherosclerotic plaques. Genetic studies have revealed that single nucleotide polymorphisms (SNPs) of the () is associated with diabetic complications, including cardiorenal complications. This Review presents current knowledge regarding the roles for AR in the causes and consequences of diabetic cardiovascular disease and the status of AR inhibitors in clinical trials. Studies from both human subjects and animal models are presented to highlight the breadth of evidence linking AR to the cardiovascular consequences of diabetes.
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http://dx.doi.org/10.3389/fendo.2021.636267DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7992003PMC
March 2021

Heme & RAGE: A new opportunistic relationship?

FEBS J 2021 06 10;288(11):3424-3427. Epub 2021 Feb 10.

Diabetes Research Program, Department of Medicine, New York University Grossman Medical Center, NY, USA.

Heme is an iron-containing complex involved in fundamental cellular functions including oxygen transport. Free heme accumulation in blood, during intravascular hemolysis and other pathological conditions, triggers vascular dysfunction, pro-inflammatory, and prothrombotic cascade. Studies by May et al present a novel finding that heme is a ligand for RAGE and that heme binds to the V domain of RAGE and induces RAGE oligomerization. Furthermore, they show that the in vivo consequences of heme-RAGE interaction lead to a pro-inflammatory and procoagulant phenotype in the lungs. This discovery of heme as a ligand for RAGE sets the stage for probing the role of RAGE in heme homeostasis and the pathogenic role of heme-RAGE interaction in hemolytic diseases.
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http://dx.doi.org/10.1111/febs.15723DOI Listing
June 2021

Journey to a Receptor for Advanced Glycation End Products Connection in Severe Acute Respiratory Syndrome Coronavirus 2 Infection: With Stops Along the Way in the Lung, Heart, Blood Vessels, and Adipose Tissue.

Arterioscler Thromb Vasc Biol 2021 02 17;41(2):614-627. Epub 2020 Dec 17.

Diabetes Research Program, Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, NYU Grossman School of Medicine (D.R., R.R., A.M.S.).

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has affected millions of people worldwide and the pandemic has yet to wane. Despite its associated significant morbidity and mortality, there are no definitive cures and no fully preventative measures to combat SARS-CoV-2. Hence, the urgency to identify the pathobiological mechanisms underlying increased risk for and the severity of SARS-CoV-2 infection is mounting. One contributing factor, the accumulation of damage-associated molecular pattern molecules, is a leading trigger for the activation of nuclear factor-kB and the IRF (interferon regulatory factors), such as IRF7. Activation of these pathways, particularly in the lung and other organs, such as the heart, contributes to a burst of cytokine release, which predisposes to significant tissue damage, loss of function, and mortality. The receptor for advanced glycation end products (RAGE) binds damage-associated molecular patterns is expressed in the lung and heart, and in priming organs, such as the blood vessels (in diabetes) and adipose tissue (in obesity), and transduces the pathological signals emitted by damage-associated molecular patterns. It is proposed that damage-associated molecular pattern-RAGE enrichment in these priming tissues, and in the lungs and heart during active infection, contributes to the widespread tissue damage induced by SARS-CoV-2. Accordingly, the RAGE axis might play seminal roles in and be a target for therapeutic intervention in SARS-CoV-2 infection.
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http://dx.doi.org/10.1161/ATVBAHA.120.315527DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7837689PMC
February 2021

Chronic low-dose rapamycin treatment fine tunes cardioprotective signalling in ischaemia-reperfused diabetic hearts.

Cardiovasc Res 2020 11;116(13):2038-2039

Diabetes Research Program, New York University Grossman Medical Center, 430 East 30th Street, New York, NY, 10016, USA.

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http://dx.doi.org/10.1093/cvr/cvaa304DOI Listing
November 2020

COVID-19 and the Heart and Vasculature: Novel Approaches to Reduce Virus-Induced Inflammation in Patients With Cardiovascular Disease.

Arterioscler Thromb Vasc Biol 2020 09 20;40(9):2045-2053. Epub 2020 Jul 20.

From the Department of Medicine, Leon H. Charney Division of Cardiology, New York University Grossman School of Medicine (B.S.K., M.S.G., K.J.M., J.D.N., R.R., H.R.R., J.H., G.I.F., S.D.K.).

The coronavirus disease 2019 (COVID-19) pandemic presents an unprecedented challenge and opportunity for translational investigators to rapidly develop safe and effective therapeutic interventions. Greater risk of severe disease in COVID-19 patients with comorbid diabetes mellitus, obesity, and heart disease may be attributable to synergistic activation of vascular inflammation pathways associated with both COVID-19 and cardiometabolic disease. This mechanistic link provides a scientific framework for translational studies of drugs developed for treatment of cardiometabolic disease as novel therapeutic interventions to mitigate inflammation and improve outcomes in patients with COVID-19.
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http://dx.doi.org/10.1161/ATVBAHA.120.314513DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7446967PMC
September 2020

RAGE impairs murine diabetic atherosclerosis regression and implicates IRF7 in macrophage inflammation and cholesterol metabolism.

JCI Insight 2020 07 9;5(13). Epub 2020 Jul 9.

Diabetes Research Program, Division of Endocrinology, Diabetes and Metabolism, Department of Medicine.

Despite advances in lipid-lowering therapies, people with diabetes continue to experience more limited cardiovascular benefits. In diabetes, hyperglycemia sustains inflammation and preempts vascular repair. We tested the hypothesis that the receptor for advanced glycation end-products (RAGE) contributes to these maladaptive processes. We report that transplantation of aortic arches from diabetic, Western diet-fed Ldlr-/- mice into diabetic Ager-/- (Ager, the gene encoding RAGE) versus WT diabetic recipient mice accelerated regression of atherosclerosis. RNA-sequencing experiments traced RAGE-dependent mechanisms principally to the recipient macrophages and linked RAGE to interferon signaling. Specifically, deletion of Ager in the regressing diabetic plaques downregulated interferon regulatory factor 7 (Irf7) in macrophages. Immunohistochemistry studies colocalized IRF7 and macrophages in both murine and human atherosclerotic plaques. In bone marrow-derived macrophages (BMDMs), RAGE ligands upregulated expression of Irf7, and in BMDMs immersed in a cholesterol-rich environment, knockdown of Irf7 triggered a switch from pro- to antiinflammatory gene expression and regulated a host of genes linked to cholesterol efflux and homeostasis. Collectively, this work adds a new dimension to the immunometabolic sphere of perturbations that impair regression of established diabetic atherosclerosis and suggests that targeting RAGE and IRF7 may facilitate vascular repair in diabetes.
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http://dx.doi.org/10.1172/jci.insight.137289DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7406264PMC
July 2020

An Eclectic Cast of Cellular Actors Orchestrates Innate Immune Responses in the Mechanisms Driving Obesity and Metabolic Perturbation.

Circ Res 2020 05 21;126(11):1565-1589. Epub 2020 May 21.

From the Diabetes Research Program, Division of Endocrinology, Diabetes and Metabolism, Department of Medicine (L.A., H.H.R., R.A.W., M.B.M., P.F.G., R.R., A.M.S.), NYU Grossman School of Medicine, New York.

The escalating problem of obesity and its multiple metabolic and cardiovascular complications threatens the health and longevity of humans throughout the world. The cause of obesity and one of its chief complications, insulin resistance, involves the participation of multiple distinct organs and cell types. From the brain to the periphery, cell-intrinsic and intercellular networks converge to stimulate and propagate increases in body mass and adiposity, as well as disturbances of insulin sensitivity. This review focuses on the roles of the cadre of innate immune cells, both those that are resident in metabolic organs and those that are recruited into these organs in response to cues elicited by stressors such as overnutrition and reduced physical activity. Beyond the typical cast of innate immune characters invoked in the mechanisms of metabolic perturbation in these settings, such as neutrophils and monocytes/macrophages, these actors are joined by bone marrow-derived cells, such as eosinophils and mast cells and the intriguing innate lymphoid cells, which are present in the circulation and in metabolic organ depots. Upon high-fat feeding or reduced physical activity, phenotypic modulation of the cast of plastic innate immune cells ensues, leading to the production of mediators that affect inflammation, lipid handling, and metabolic signaling. Furthermore, their consequent interactions with adaptive immune cells, including myriad T-cell and B-cell subsets, compound these complexities. Notably, many of these innate immune cell-elicited signals in overnutrition may be modulated by weight loss, such as that induced by bariatric surgery. Recently, exciting insights into the biology and pathobiology of these cell type-specific niches are being uncovered by state-of-the-art techniques such as single-cell RNA-sequencing. This review considers the evolution of this field of research on innate immunity in obesity and metabolic perturbation, as well as future directions.
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http://dx.doi.org/10.1161/CIRCRESAHA.120.315900DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7250004PMC
May 2020

Enhanced glycolysis and HIF-1α activation in adipose tissue macrophages sustains local and systemic interleukin-1β production in obesity.

Sci Rep 2020 03 27;10(1):5555. Epub 2020 Mar 27.

Department of Medicine, Marc and Ruti Bell Program for Vascular Biology and Disease, The Leon H. Charney Division of Cardiology, New York University Langone Health, New York, NY, USA.

During obesity, macrophages infiltrate the visceral adipose tissue and promote inflammation that contributes to type II diabetes. Evidence suggests that the rewiring of cellular metabolism can regulate macrophage function. However, the metabolic programs that characterize adipose tissue macrophages (ATM) in obesity are poorly defined. Here, we demonstrate that ATM from obese mice exhibit metabolic profiles characterized by elevated glycolysis and oxidative phosphorylation, distinct from ATM from lean mice. Increased activation of HIF-1α in ATM of obese visceral adipose tissue resulted in induction of IL-1β and genes in the glycolytic pathway. Using a hypoxia-tracer, we show that HIF-1α nuclear translocation occurred both in hypoxic and non-hypoxic ATM suggesting that both hypoxic and pseudohypoxic stimuli activate HIF-1α and its target genes in ATM during diet-induced obesity. Exposure of macrophages to the saturated fatty acid palmitate increased glycolysis and HIF-1α expression, which culminated in IL-1β induction thereby simulating pseudohypoxia. Using mice with macrophage-specific targeted deletion of HIF-1α, we demonstrate the critical role of HIF-1α-derived from macrophages in regulating ATM accumulation, and local and systemic IL-1β production, but not in modulating systemic metabolic responses. Collectively, our data identify enhanced glycolysis and HIF-1α activation as drivers of low-grade inflammation in obesity.
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http://dx.doi.org/10.1038/s41598-020-62272-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7101445PMC
March 2020

Receptor for Advanced Glycation End Products (RAGE) and Mechanisms and Therapeutic Opportunities in Diabetes and Cardiovascular Disease: Insights From Human Subjects and Animal Models.

Front Cardiovasc Med 2020 10;7:37. Epub 2020 Mar 10.

Diabetes Research Program, Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, New York University School of Medicine, New York, NY, United States.

Obesity and diabetes are leading causes of cardiovascular morbidity and mortality. Although extensive strides have been made in the treatments for non-diabetic atherosclerosis and its complications, for patients with diabetes, these therapies provide less benefit for protection from cardiovascular disease (CVD). These considerations spur the concept that diabetes-specific, disease-modifying therapies are essential to identify, especially as the epidemics of obesity and diabetes continue to expand. Hence, as hyperglycemia is a defining feature of diabetes, it is logical to probe the impact of the specific consequences of hyperglycemia on the vessel wall, immune cell perturbation, and endothelial dysfunction-all harbingers to the development of CVD. In this context, high levels of blood glucose stimulate the formation of the irreversible advanced glycation end products, the products of non-enzymatic glycation and oxidation of proteins and lipids. AGEs accumulate in diabetic circulation and tissues and the interaction of AGEs with their chief cellular receptor, receptor for AGE or RAGE, contributes to vascular and immune cell perturbation. The cytoplasmic domain of RAGE lacks endogenous kinase activity; the discovery that this intracellular domain of RAGE binds to the formin, DIAPH1, and that DIAPH1 is essential for RAGE ligand-mediated signal transduction, identifies the specific cellular means by which RAGE functions and highlights a new target for therapeutic interruption of RAGE signaling. In human subjects, prominent signals for RAGE activity include the presence and levels of two forms of soluble RAGE, sRAGE, and endogenous secretory (es) RAGE. Further, genetic studies have revealed single nucleotide polymorphisms (SNPs) of the gene ( is the gene encoding RAGE) and , which display associations with CVD. This Review presents current knowledge regarding the roles for RAGE and DIAPH1 in the causes and consequences of diabetes, from obesity to CVD. Studies both from human subjects and animal models are presented to highlight the breadth of evidence linking RAGE and DIAPH1 to the cardiovascular consequences of these metabolic disorders.
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http://dx.doi.org/10.3389/fcvm.2020.00037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7076074PMC
March 2020

Advanced Glycation End Products: Building on the Concept of the "Common Soil" in Metabolic Disease.

Endocrinology 2020 01;161(1)

Diabetes Research Program, Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, NYU School of Medicine, New York, NY, USA.

The role of advanced glycation end products (AGEs) in promoting and/or exacerbating metabolic dysregulation is being increasingly recognized. AGEs are formed when reducing sugars nonenzymatically bind to proteins or lipids, a process that is enhanced by hyperglycemic and hyperlipidemic environments characteristic of numerous metabolic disorders including obesity, diabetes, and its complications. In this mini-review, we put forth the notion that AGEs span the spectrum from cause to consequence of insulin resistance and diabetes, and represent a "common soil" underlying the pathophysiology of these metabolic disorders. Collectively, the surveyed literature suggests that AGEs, both those that form endogenously as well as exogenous AGEs derived from environmental factors such as pollution, smoking, and "Western"-style diets, contribute to the pathogenesis of obesity and diabetes. Specifically, AGE accumulation in key metabolically relevant organs induces insulin resistance, inflammation, and oxidative stress, which in turn provide substrates for excess AGE formation, thus creating a feed-forward-fueled pathological loop mediating metabolic dysfunction.
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http://dx.doi.org/10.1210/endocr/bqz006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7188081PMC
January 2020

Netrin-1 Alters Adipose Tissue Macrophage Fate and Function in Obesity.

Immunometabolism 2019 7;1(2). Epub 2019 Aug 7.

Department of Medicine, New York University School of Medicine, New York, NY 10016, USA.

Macrophages accumulate prominently in the visceral adipose tissue (VAT) of obese humans and high fat diet (HFD) fed mice, and this is linked to insulin resistance and type II diabetes. While the mechanisms regulating macrophage recruitment in obesity have been delineated, the signals directing macrophage persistence in VAT are poorly understood. We previously showed that the neuroimmune guidance cue netrin-1 is expressed in the VAT of obese mice and humans, where it promotes macrophage accumulation. To better understand the source of netrin-1 and its effects on adipose tissue macrophage (ATM) fate and function in obesity, we generated mice with myeloid-specific deletion of netrin-1 ( ; Ntn1). Interestingly, Ntn1 mice showed a modest decrease in HFD-induced adiposity and adipocyte size, in the absence of changes in food intake or leptin, that was accompanied by an increase in markers of adipocyte beiging (, UCP-1). Using single cell RNA-seq, combined with conventional histological and flow cytometry techniques, we show that myeloid-specific deletion of netrin-1 caused a 50% attrition of ATMs in HFD-fed mice, particularly of the resident macrophage subset, and altered the phenotype of residual ATMs to enhance lipid handling. Pseudotime analysis of single cell transcriptomes showed that in the absence of netrin-1, macrophages in the obese VAT underwent a phenotypic switch with the majority of ATMs activating a program of genes specialized in lipid handling, including fatty acid uptake and intracellular transport, lipid droplet formation and lipolysis, and regulation of lipid localization. Furthermore, Ntn1 macrophages had reduced expression of genes involved in arachidonic acid metabolism, and targeted LCMS/MS metabololipidomics analysis revealed decreases in proinflammatory eicosanoids (5-HETE, 6- LTB, TXB, PGD) in the obese VAT. Collectively, our data show that targeted deletion of netrin-1 in macrophages reprograms the ATM phenotype in obesity, leading to reduced adipose inflammation, and improved lipid handling and metabolic function.
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http://dx.doi.org/10.20900/immunometab20190010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6699780PMC
August 2019

A Receptor of the Immunoglobulin Superfamily Regulates Adaptive Thermogenesis.

Cell Rep 2019 07;28(3):773-791.e7

Diabetes Research Program, Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, NYU School of Medicine, 435 East 30(th) Street, New York, NY 10016, USA. Electronic address:

Exquisite regulation of energy homeostasis protects from nutrient deprivation but causes metabolic dysfunction upon nutrient excess. In human and murine adipose tissue, the accumulation of ligands of the receptor for advanced glycation end products (RAGE) accompanies obesity, implicating this receptor in energy metabolism. Here, we demonstrate that mice bearing global- or adipocyte-specific deletion of Ager, the gene encoding RAGE, display superior metabolic recovery after fasting, a cold challenge, or high-fat feeding. The RAGE-dependent mechanisms were traced to suppression of protein kinase A (PKA)-mediated phosphorylation of its key targets, hormone-sensitive lipase and p38 mitogen-activated protein kinase, upon β-adrenergic receptor stimulation-processes that dampen the expression and activity of uncoupling protein 1 (UCP1) and thermogenic programs. This work identifies the innate role of RAGE as a key node in the immunometabolic networks that control responses to nutrient supply and cold challenges, and it unveils opportunities to harness energy expenditure in environmental and metabolic stress.
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http://dx.doi.org/10.1016/j.celrep.2019.06.061DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6686683PMC
July 2019

Incense Burning is Associated with Human Oral Microbiota Composition.

Sci Rep 2019 07 11;9(1):10039. Epub 2019 Jul 11.

Department of Population Health, New York University School of Medicine, New York, USA.

Incense burning is common worldwide and produces environmental toxicants that may influence health; however, biologic effects have been little studied. In 303 Emirati adults, we tested the hypothesis that incense use is linked to compositional changes in the oral microbiota that can be potentially significant for health. The oral microbiota was assessed by amplification of the bacterial 16S rRNA gene from mouthwash samples. Frequency of incense use was ascertained through a questionnaire and examined in relation to overall oral microbiota composition (PERMANOVA analysis), and to specific taxon abundances, by negative binomial generalized linear models. We found that exposure to incense burning was associated with higher microbial diversity (p < 0.013) and overall microbial compositional changes (PERMANOVA, p = 0.003). Our study also revealed that incense use was associated with significant changes in bacterial abundances (i.e. depletion of the dominant taxon Streptococcus), even in occasional users (once/week or less) implying that incense use impacts the oral microbiota even at low exposure levels. In summary, this first study suggests that incense burning alters the oral microbiota, potentially serving as an early biomarker of incense-related toxicities and related health consequences. Although a common indoor air pollutant, guidelines for control of incense use have yet to be developed.
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http://dx.doi.org/10.1038/s41598-019-46353-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6624419PMC
July 2019

Metabolism, Obesity, and Diabetes Mellitus.

Arterioscler Thromb Vasc Biol 2019 07 26;39(7):e166-e174. Epub 2019 Jun 26.

From the Diabetes Research Program, Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, New York University School of Medicine, NY.

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http://dx.doi.org/10.1161/ATVBAHA.119.312005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6693645PMC
July 2019

Metabolic dysfunction in Emirati subjects in Abu Dhabi: Relationship to levels of soluble RAGEs.

J Clin Transl Endocrinol 2019 Jun 23;16:100192. Epub 2019 Apr 23.

Department of Medicine, Sheikh Khalifa Medical City, United Arab Emirates.

Background: The United Arab Emirates is experiencing increasing rates of type 2 diabetes (T2D) and its complications. As soluble levels of the receptor for advanced glycation end products, (sRAGE), and endogenous secretory RAGE (esRAGE), the latter an alternatively spliced form of (the gene encoding RAGE), have been reported to be associated with T2D and its complications, we tested for potential relationships between these factors and T2D status in Emirati subjects.

Methods: In a case-control study, we recruited Emirati subjects with T2D and controls from the Sheikh Khalifa Medical City in Abu Dhabi. Anthropomorphic characteristics, levels of plasma sRAGE and esRAGE, and routine chemistry variables were measured.

Results: Two hundred and sixteen T2D subjects and 215 control subjects (mean age, 57.4 ± 12.1 50.7 ± 15.4 years;  < 0.0001, respectively) were enrolled. Univariate analyses showed that levels of sRAGE were significantly lower in the T2D control subjects (1033.9 ± 545.3 1169.2 ± 664.1 pg/ml, respectively;  = 0.02). Multivariate analyses adjusting for age, sex, systolic blood pressure, pulse, body mass index, Waist/Hip circumference ratio, fasting blood glucose, HDL, LDL, insulin, triglycerides, Vitamin D and urea levels revealed that the difference in sRAGE levels between T2D and control subjects remained statistically-significant,  = 0.03, but not after including estimated glomerular filtration rate in the model,  = 0.14. There were no significant differences in levels of esRAGE. Levels of plasma insulin were significantly higher in the control the T2D subjects (133.6 ± 149.9 107.6 ± 93.3 pg/L. respectively;  = 0.01, after adjustment for age and sex).

Conclusion/discussion: Levels of sRAGE, but not esRAGE, were associated with T2D status in Abu Dhabi, but not after correction for eGFR. Elevated levels of plasma insulin in both control and T2D subjects suggests the presence of metabolic dysfunction, even in subjects without diabetes.
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http://dx.doi.org/10.1016/j.jcte.2019.100192DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6503160PMC
June 2019

Significance and Mechanistic Relevance of SIRT6-Mediated Endothelial Dysfunction in Cardiovascular Disease Progression.

Circ Res 2019 05;124(10):1408-1410

From the Diabetes Research Program, Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, New York University School of Medicine, New York.

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http://dx.doi.org/10.1161/CIRCRESAHA.119.315098DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6510269PMC
May 2019

The Receptor for Advanced Glycation End Products (RAGE) and DIAPH1: Implications for vascular and neuroinflammatory dysfunction in disorders of the central nervous system.

Neurochem Int 2019 06 20;126:154-164. Epub 2019 Mar 20.

Diabetes Research Program, Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, New York University School of Medicine, New York, NY, 10016, USA. Electronic address:

The Receptor for Advanced Glycation End Products (RAGE) is expressed by multiple cell types in the brain and spinal cord that are linked to the pathogenesis of neurovascular and neurodegenerative disorders, including neurons, glia (microglia and astrocytes) and vascular cells (endothelial cells, smooth muscle cells and pericytes). Mounting structural and functional evidence implicates the interaction of the RAGE cytoplasmic domain with the formin, Diaphanous1 (DIAPH1), as the key cytoplasmic hub for RAGE ligand-mediated activation of cellular signaling. In aging and diabetes, the ligands of the receptor abound, both in the central nervous system (CNS) and in the periphery. Such accumulation of RAGE ligands triggers multiple downstream events, including upregulation of RAGE itself. Once set in motion, cell intrinsic and cell-cell communication mechanisms, at least in part via RAGE, trigger dysfunction in the CNS. A key outcome of endothelial dysfunction is reduction in cerebral blood flow and increased permeability of the blood brain barrier, conditions that facilitate entry of activated leukocytes into the CNS, thereby amplifying primary nodes of CNS cellular stress. This contribution details a review of the ligands of RAGE, the mechanisms and consequences of RAGE signal transduction, and cites multiple examples of published work in which RAGE contributes to the pathogenesis of neurovascular perturbation. Insights into potential therapeutic modalities targeting the RAGE signal transduction axis for disorders of CNS vascular dysfunction and neurodegeneration are also discussed.
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http://dx.doi.org/10.1016/j.neuint.2019.03.012DOI Listing
June 2019

The receptor for advanced glycation end products (RAGE) and DIAPH1: unique mechanisms and healing the wounded vascular system.

Expert Rev Proteomics 2019 06 13;16(6):471-474. Epub 2019 Jan 13.

a Diabetes Research Program, Division of Endocrinology, Diabetes and Metabolism, Department of Medicine , New York University School of Medicine , New York , NY , USA.

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http://dx.doi.org/10.1080/14789450.2018.1536551DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6467738PMC
June 2019

Deletion of the formin Diaph1 protects from structural and functional abnormalities in the murine diabetic kidney.

Am J Physiol Renal Physiol 2018 12 22;315(6):F1601-F1612. Epub 2018 Aug 22.

Diabetes Research Program, Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, New York University School of Medicine , New York, New York.

Diaphanous 1 (DIAPH1), a member of the formin family, binds to the cytoplasmic domain of the receptor for advanced glycation end products (RAGE) and is required for RAGE signal transduction. Experiments employing genetic overexpression or deletion of Ager (the gene encoding RAGE) or its pharmacological antagonism implicate RAGE in the pathogenesis of diabetes-associated nephropathy. We hypothesized that DIAPH1 contributes to pathological and functional derangements in the kidneys of diabetic mice. We show that DIAPH1 is expressed in the human and murine diabetic kidney, at least in part in the tubulointerstitium and glomerular epithelial cells or podocytes. To test the premise that DIAPH1 is linked to diabetes-associated derangements in the kidney, we rendered male mice globally devoid of Diaph1 ( Diaph1) or wild-type controls (C57BL/6 background) diabetic with streptozotocin. Control mice received equal volumes of citrate buffer. After 6 mo of hyperglycemia, diabetic Diaph1 mice displayed significantly reduced mesangial sclerosis, podocyte effacement, glomerular basement thickening, and urinary albumin-to-creatinine ratio compared with diabetic mice expressing Diaph1. Analysis of whole kidney cortex revealed that deletion of Diaph1 in diabetic mice significantly reduced expression of genes linked to fibrosis and inflammation. In glomerular isolates, expression of two genes linked to podocyte stress, growth arrest-specific 1 ( Gas1) and cluster of differentiation 36 ( Cd36), was significantly attenuated in diabetic Diaph1 mice compared with controls, in parallel with significantly higher levels of nestin (Nes) mRNA, a podocyte marker. Collectively, these data implicate DIAPH1 in the pathogenesis of diabetes-associated nephropathy and suggest that the RAGE-DIAPH1 axis is a logical target for therapeutic intervention in this disorder.
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http://dx.doi.org/10.1152/ajprenal.00075.2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6336994PMC
December 2018

Types of tobacco consumption and the oral microbiome in the United Arab Emirates Healthy Future (UAEHFS) Pilot Study.

Sci Rep 2018 07 27;8(1):11327. Epub 2018 Jul 27.

Department of Population Health, New York University School of Medicine, New York, USA.

Cigarette smoking alters the oral microbiome; however, the effect of alternative tobacco products remains unclear. Middle Eastern tobacco products like dokha and shisha, are becoming globally widespread. We tested for the first time in a Middle Eastern population the hypothesis that different tobacco products impact the oral microbiome. The oral microbiome of 330 subjects from the United Arab Emirates Healthy Future Study was assessed by amplifying the bacterial 16S rRNA gene from mouthwash samples. Tobacco consumption was assessed using a structured questionnaire and further validated by urine cotinine levels. Oral microbiome overall structure and specific taxon abundances were compared, using PERMANOVA and DESeq analyses respectively. Our results show that overall microbial composition differs between smokers and nonsmokers (p = 0.0001). Use of cigarettes (p = 0.001) and dokha (p = 0.042) were associated with overall microbiome structure, while shisha use was not (p = 0.62). The abundance of multiple genera were significantly altered (enriched/depleted) in cigarette smokers; however, only Actinobacillus, Porphyromonas, Lautropia and Bifidobacterium abundances were significantly changed in dokha users whereas no genera were significantly altered in shisha smokers. For the first time, we show that smoking dokha is associated to oral microbiome dysbiosis, suggesting that it could have similar effects as smoking cigarettes on oral health.
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http://dx.doi.org/10.1038/s41598-018-29730-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6063860PMC
July 2018

Human Aldose Reductase Expression Prevents Atherosclerosis Regression in Diabetic Mice.

Diabetes 2018 09 11;67(9):1880-1891. Epub 2018 Jun 11.

Marc and Ruti Bell Vascular Biology Program, Leon Charney Division of Cardiology, New York University School of Medicine, New York, NY

Guidelines to reduce cardiovascular risk in diabetes include aggressive LDL lowering, but benefits are attenuated compared with those in patients without diabetes. Consistent with this, we have reported in mice that hyperglycemia impaired atherosclerosis regression. Aldose reductase (AR) is thought to contribute to clinical complications of diabetes by directing glucose into pathways producing inflammatory metabolites. Mice have low levels of AR, thus raising them to human levels would be a more clinically relevant model to study changes in diabetes under atherosclerosis regression conditions. Donor aortae from Western diet-fed mice were transplanted into normolipidemic wild-type, Ins2Akita ( , insulin deficient), human AR (hAR) transgenic, or /hAR mice. mice had impaired plaque regression as measured by changes in plaque size and the contents of CD68 cells (macrophages), lipids, and collagen. Supporting synergy between hyperglycemia and hAR were the even more pronounced changes in these parameters in /hAR mice, which had atherosclerosis progression in spite of normolipidemia. Plaque CD68 cells from the /hAR mice had increased oxidant stress and expression of inflammation-associated genes but decreased expression of anti-inflammatory genes. In summary, hAR expression amplifies impaired atherosclerosis regression in diabetic mice, likely by interfering with the expected reduction in plaque macrophage inflammation.
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http://dx.doi.org/10.2337/db18-0156DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6110315PMC
September 2018

Patterns of tobacco use in the United Arab Emirates Healthy Future (UAEHFS) pilot study.

PLoS One 2018 30;13(5):e0198119. Epub 2018 May 30.

Public Health Research Center, New York University Abu Dhabi, Abu Dhabi, United Arab Emirates.

Introduction: Self-reported tobacco use in the United Arab Emirates is among the highest in the region. Use of tobacco products other than cigarettes is widespread, but little is known about specific behavior use patterns. There have been no studies that have biochemically verified smoking status.

Methods: The UAE Healthy Future Study (UAEHFS) seeks to understand the causes of non-communicable diseases through a 20,000-person cohort study. During the study pilot, 517 Emirati nationals were recruited to complete a questionnaire, provide clinical measurements and biological samples. Complete smoking data were available for 428 participants. Validation of smoking status via cotinine testing was conducted based on complete questionnaire data and matching urine samples for 399 participants, using a cut-off of 200ng/ml to indicate active smoking status.

Results: Self-reported tobacco use was 36% among men and 3% among women in the sample. However, biochemical verification of smoking status revealed that 42% men and 9% of women were positive for cotinine indicating possible recent tobacco use. Dual and poly-use of tobacco products was fairly common with 32% and 6% of the sample reporting respectively.

Conclusions: This is the first study in the region to biochemically verify tobacco use self-report data. Tobacco use in this study population was found to be higher than previously thought, especially among women. Misclassification of smoking status was more common than expected. Poly-tobacco use was also very common. Additional studies are needed to understand tobacco use behaviors and the extent to which people may be exposed to passive tobacco smoke.

Implications: This study is the first in the region to biochemically verify self-reported smoking status.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0198119PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5976156PMC
November 2018

Targeted drug discovery and development, from molecular signaling to the global market: an educational program at New York University, 5-year metrics.

J Transl Sci 2018 16;4(2):1-9. Epub 2018 Feb 16.

Department of Pediatrics, PI NIDDK R25, New York University School of Medicine, New York, NY, USA.

Drug discovery and development (DDD) is a collaborative, dynamic process of great interest to researchers, but an area where there is a lack of formal training. The Drug Development Educational Program (DDEP) at New York University was created in 2012 to stimulate an improved, multidisciplinary DDD workforce by educating early stage scientists as well as a variety of other like-minded students. The first course of the program emphasizes post-compounding aspects of DDD; the second course focuses on molecular signaling pathways. In five years, 196 students (candidates for PhD, MD, Master's degree, and post-doctoral MD/PhD) from different schools (Medicine, Biomedical Sciences, Dentistry, Engineering, Business, and Education) completed the course(s). Pre/post surveys demonstrate knowledge gain across all course topics. 26 students were granted career development awards (73% women, 23% underrepresented minorities). Some graduates of their respective degree-granting/post-doctoral programs embarked on DDD related careers. This program serves as a framework for other academic institutions to develop compatible programs designed to train a more informed DDD workforce.
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http://dx.doi.org/10.15761/JTS.1000215DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5898375PMC
February 2018

Training scientists as future industry leaders: teaching translational science from an industry executive's perspective.

J Transl Sci 2018 13;4(2). Epub 2018 Feb 13.

Department of Pediatrics, PI NIDDK R25, New York University School of Medicine, New York, NY, USA.

PhDs and post-doctoral biomedical graduates, in greater numbers, are choosing industry based careers. However, most scientists do not have formal training in business strategies and venture creation and may find senior management positions untenable. To fill this training gap, "Biotechnology Industry: Structure and Strategy" was offered at New York University School of Medicine (NYUSOM). The course focuses on the business aspects of translational medicine and research translation and incorporates the practice of business case discussions, mock negotiation, and direct interactions into the didactic. The goal is to teach scientists at an early career stage how to create solutions, whether at the molecular level or via the creation of devices or software, to benefit those with disease. In doing so, young, talented scientists can develop a congruent mindset with biotechnology/industry executives. Our data demonstrates that the course enhances students' knowledge of the biotechnology industry. In turn, these learned skills may further encourage scientists to seek leadership positions in the field. Implementation of similar courses and educational programs will enhance scientists' training and inspire them to become innovative leaders in the discovery and development of therapeutics.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5898379PMC
http://dx.doi.org/10.15761/JTS.1000214DOI Listing
February 2018

The UAE healthy future study: a pilot for a prospective cohort study of 20,000 United Arab Emirates nationals.

BMC Public Health 2018 01 5;18(1):101. Epub 2018 Jan 5.

University of Oxford, Oxford, UK.

Background: The United Arab Emirates (UAE) is faced with a rapidly increasing burden of non-communicable diseases including obesity, diabetes, and cardiovascular disease. The UAE Healthy Future study is a prospective cohort designed to identify associations between risk factors and these diseases amongst Emiratis. The study will enroll 20,000 UAE nationals aged ≥18 years. Environmental and genetic risk factors will be characterized and participants will be followed for future disease events. As this was the first time a prospective cohort study was being planned in the UAE, a pilot study was conducted in 2015 with the primary aim of establishing the feasibility of conducting the study. Other objectives were to evaluate the implementation of the main study protocols, and to build adequate capacity to conduct advanced clinical laboratory analyses.

Methods: Seven hundred sixty nine UAE nationals aged ≥18 years were invited to participate voluntarily in the pilot study. Participants signed an informed consent, completed a detailed questionnaire, provided random blood, urine, and mouthwash samples and were assessed for a series of clinical measures. All specimens were transported to the New York University Abu Dhabi laboratories where samples were processed and analyzed for routine chemistry and hematology. Plasma, serum, and a small whole blood sample for DNA extraction were aliquoted and stored at -80 °C for future analyses.

Results: Overall, 517 Emirati men and women agreed to participate (68% response rate). Of the total participants, 495 (95.0%), 430 (82.2%), and 492 (94.4%), completed the questionnaire, physical measurements, and provided biological samples, respectively.

Conclusions: The pilot study demonstrated the feasibility of recruitment and completion of the study protocols for the first large-scale cohort study designed to identify emerging risk factors for the major non-communicable diseases in the region.
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http://dx.doi.org/10.1186/s12889-017-5012-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5755402PMC
January 2018

The Formin, DIAPH1, is a Key Modulator of Myocardial Ischemia/Reperfusion Injury.

EBioMedicine 2017 Dec 21;26:165-174. Epub 2017 Nov 21.

Diabetes Research Program, Department of Medicine, New York University Langone Medical Center, New York, NY 10016, USA. Electronic address:

The biochemical, ionic, and signaling changes that occur within cardiomyocytes subjected to ischemia are exacerbated by reperfusion; however, the precise mechanisms mediating myocardial ischemia/reperfusion (I/R) injury have not been fully elucidated. The receptor for advanced glycation end-products (RAGE) regulates the cellular response to cardiac tissue damage in I/R, an effect potentially mediated by the binding of the RAGE cytoplasmic domain to the diaphanous-related formin, DIAPH1. The aim of this study was to investigate the role of DIAPH1 in the physiological response to experimental myocardial I/R in mice. After subjecting wild-type mice to experimental I/R, myocardial DIAPH1 expression was increased, an effect that was echoed following hypoxia/reoxygenation (H/R) in H9C2 and AC16 cells. Further, compared to wild-type mice, genetic deletion of Diaph1 reduced infarct size and improved contractile function after I/R. Silencing Diaph1 in H9C2 cells subjected to H/R downregulated actin polymerization and serum response factor-regulated gene expression. Importantly, these changes led to increased expression of sarcoplasmic reticulum Ca ATPase and reduced expression of the sodium calcium exchanger. This work demonstrates that DIAPH1 is required for the myocardial response to I/R, and that targeting DIAPH1 may represent an adjunctive approach for myocardial salvage after acute infarction.
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http://dx.doi.org/10.1016/j.ebiom.2017.11.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5832565PMC
December 2017

The AGE-RAGE axis in an Arab population: The United Arab Emirates Healthy Futures (UAEHFS) pilot study.

J Clin Transl Endocrinol 2017 Dec 14;10:1-8. Epub 2017 Aug 14.

Diabetes Research Program, Division of Endocrinology, Diabetes and Metabolism, Department of Medicine New York University School of Medicine, New York, NY, USA.

Aims: The transformation of the United Arab Emirates (UAE) from a semi-nomadic to a high income society has been accompanied by increasing rates of obesity and Type 2 diabetes mellitus. We examined if the AGE-RAGE (receptor for advanced glycation endproducts) axis is associated with obesity and diabetes mellitus in the pilot phase of the UAE Healthy Futures Study (UAEHFS).

Methods: 517 Emirati subjects were enrolled and plasma/serum levels of AGE, carboxy methyl lysine (CML)-AGE, soluble (s)RAGE and endogenous secretory (es)RAGE were measured along with weight, height, waist and hip circumference (WC/HC), blood pressure, HbA1c, Vitamin D levels and routine chemistries. The relationship between the AGE-RAGE axis and obesity and diabetes mellitus was tested using proportional odds models and linear regression.

Results: After covariate adjustment, AGE levels were significantly associated with diabetes status. Levels of sRAGE and esRAGE were associated with BMI and levels of sRAGE were associated with WC/HC.

Conclusions: The AGE-RAGE axis is associated with diabetes status and obesity in this Arab population. Prospective serial analysis of this axis may identify predictive biomarkers of obesity and cardiometabolic dysfunction in the UAEHFS.
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http://dx.doi.org/10.1016/j.jcte.2017.08.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5691216PMC
December 2017
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