A5074568892- Advanced Glycation End Products research
- Aldose Reductase and Taurine
- Cardiac Ischemia and Reperfusion
- Cardiovascular Function and Risk Factors
- Adipose Tissue and Metabolism
- Cardiac Arrest and Resuscitation
- Adenosine and Purinergic Signaling
- Biochemical effects in animals
- Diabetes Management and Research
- Diabetes and associated disorders
- Hormonal Regulation and Hypertension
- Cardiac Fibrosis and Remodeling
- Heme Oxygenase-1 and Carbon Monoxide
- Pharmacological Effects of Natural Compounds
- Electron Spin Resonance Studies
- RNA modifications and cancer
- Genomics, phytochemicals, and oxidative stress
- Chronic Kidney Disease and Diabetes
- Retinoids in leukemia and cellular processes
- Hemoglobin structure and function
- Apelin-related biomedical research
- Endoplasmic Reticulum Stress and Disease
- Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Eicosanoids and Hypertension Pharmacology
- Genetics and Neurodevelopmental Disorders
New York University
2013-2024
Diabetes & Endocrine Associates
2021
NYU Langone Health
2016-2020
New York Proton Center
2020
Hinge Health
2020
Columbia University Irving Medical Center
2010-2016
Columbia University
2006-2010
Previous studies showed that genetic deletion or pharmacological blockade of the receptor for advanced glycation end products (RAGE) prevents early structural changes in glomerulus associated with diabetic nephropathy. To overcome limitations mouse models lack progressive glomerulosclerosis observed humans, we studied contribution RAGE to nephropathy OVE26 type 1 mouse, a model and decline renal function.We bred mice homozygous knockout (RKO) examined used inulin clearance albumin:creatinine...
Abstract The receptor for advanced glycation endproducts (RAGE) binds diverse ligands linked to chronic inflammation and disease. NMR spectroscopy x-ray crystallization studies of the extracellular domains RAGE indicate that bind by distinct charge- hydrophobicity-dependent mechanisms. cytoplasmic tail (ct) is essential ligand-mediated signal transduction consequent modulation gene expression cellular properties. signaling requires interaction ctRAGE with intracellular effector, mammalian...
Background Advanced glycation end-products (AGEs) have been implicated in diverse pathological settings including diabetes, inflammation and acute ischemia/reperfusion injury the heart. AGEs interact with receptor for (RAGE) transduce signals through activation of MAPKs proapoptotic pathways. In current study, adult cardiomyocytes were studied an vitro (I/R) model to delineate molecular mechanisms underlying RAGE-mediated due hypoxia/reoxygenation (H/R). Methodology/Principal Findings...
Small-molecule antagonism of RAGE-DIAPH1 reduces diabetes-related complications in mice.
Inter-organelle contact and communication between mitochondria sarco/endoplasmic reticulum (SR/ER) maintain cellular homeostasis are profoundly disturbed during tissue ischemia. We tested the hypothesis that formin Diaphanous-1 (DIAPH1), which regulates actin dynamics, signal transduction metabolic functions, contributes to these processes. demonstrate DIAPH1 interacts directly with Mitofusin-2 (MFN2) shorten mitochondria-SR/ER distance, thereby enhancing mitochondria-ER in cells including...
We investigated the pre-clinical utility of carbon monoxide form PEGylated hemoglobin (PEG-Hb also named SANGUINATE™) in myocardial infarction (MI) and particular response diabetic tissues to superimposed ischemia/reperfusion injury. SANGUINATE™ was evaluated normal mice subjected 30 min coronary artery ligation followed by either 48 h or 28 days reperfusion. Our results demonstrate that effective reducing infarct size when administered prior left anterior descending (LAD) occlusion during...
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. receptor for advanced glycation end-products (RAGE) regulates cellular response cardiac tissue damage in I/R, an effect potentially mediated binding of RAGE cytoplasmic domain diaphanous-related formin, DIAPH1. aim this study was investigate...
Aldose reductase (AR), a member of the aldo-keto family, has been demonstrated to play central role in mediating myocardial ischemia-reperfusion (I/R) injury. Recently, using transgenic mice broadly overexpressing human AR (ARTg), we that is an important component I/R injury and inhibition this enzyme protects heart from (20-22, 48, 49, 56). To rigorously delineate mechanisms by which pathway influences ischemic injury, investigated played reactive oxygen species (ROS), antioxidant enzymes,...
Abstract Exaggerated inflammatory responses and the resultant increases in alveolar-capillary permeability underlie pathogenesis of acute lung injury during sepsis. This study examined functions aldose reductase (AR) mediating inflammation. Transgenic mice expressing human AR (ARTg) were used to since have low intrinsic activity. In a mild cecal ligation puncture model, ARTg demonstrated an enhanced activity greater response as evaluated by circulating cytokine levels, neutrophil...
Dietary n-3 fatty acids (FAs) may reduce cardiovascular disease risk. We questioned whether acute administration of rich triglyceride (TG) emulsions could preserve cardiac function and decrease injury after ischemia/reperfusion (I/R) insult. used two different experimental models: in vivo, C57BL/6 mice were exposed to occlusion the left anterior descending coronary artery (LAD), ex-vivo, murine hearts perfused using Langendorff technique (LT). In LAD model, treated with TG emulsion (1.5g/kg...
Histone deacetylase 3 (HDAC3), a chromatin-modifying enzyme, requires association with the deacetylase-containing domain (DAD) of nuclear receptor corepressors NCOR1 and SMRT for its stability activity. Here, we show that aldose reductase (AR), rate-limiting enzyme polyol pathway, competes HDAC3 to bind NCOR1/SMRT DAD. Increased AR expression leads degradation followed by increased PPARγ signaling, resulting in lipid accumulation heart. also downregulates corepressor complex cofactors...
The aim of our project was to study the effect streptozotocin (STZ)-induced hyperglycemia on sciatic nerve morphology, blood plasma markers and immunohistochemical expression RAGE (the Receptor for Advanced Glycation End-products), its ligands-S100B Carboxymethyl Lysine (CML)-advanced glycation endproduct (AGE) in laboratory pig. Six months after STZ-injections, measurements, morphometric analysis fiber density, immunofluorescent distribution potential molecular neuropathy contributors,...
Abstract Objective Aldose reductase ( AKR1B1 in humans; Akr1b3 mice), a key enzyme of the polyol pathway, mediates lipid accumulation murine heart and liver. The study objective was to explore potential roles for AKR1B1/Akr1b3 pathogenesis obesity its complications. Methods employed mice treated with an inhibitor aldose or devoid were used determine their response high‐fat diet. subcutaneous adipose tissue‐derived adipocytes investigate mechanisms by which promotes diet‐induced obesity....
Diabetic Cardiomyopathy (DbCM) leading to overt heart failure is a common sequelae of both type 1 and 2 diabetes. Prior attempts develop treatments for DbCM via inhibition Aldose Reductase (AR) were unsuccessful, due low AR binding affinity off-target with Aldehyde (AldR), an enzyme critical detoxification aldehydes in the liver normal hepatocyte function. This resulted liver-related safety tolerability issues first generation ARIs. We report on selectivity specificity AT-001, novel small...
Aldose reductase (AR: human, AKR1B1; mouse, AKR1B3), the first enzyme in polyol pathway, plays a key role mediating myocardial ischemia/reperfusion (I/R) injury. In earlier studies, using transgenic mice broadly expressing human AKR1B1 to human-relevant levels, devoid of Akr1b3, and pharmacological inhibitors AR, we demonstrated that AR is an important component I/R injury inhibition this protects heart from study, our objective was investigate if modulates β-catenin pathway consequent...
Abstract Diabetes affects metabolism and metabolite concentrations in multiple organs. Previous preclinical studies have shown that receptor for advanced glycation end products (RAGE, gene symbol Ager ) its cytoplasmic domain binding partner, Diaphanous‐1 (DIAPH1), are key mediators of diabetic micro‐ macro‐vascular complications. In this study, we used 1 H‐Magnetic Resonance Spectroscopy (MRS) chemical shift encoded (CSE) Magnetic Imaging (MRI) to investigate the water‐fat fraction heart...
The generation of Reactive Oxygen Species (ROS) and Advanced Glycation Endproducts (AGE’s) resulting from chronic tissue exposure to elevated levels glucose has been identified as a key modulator diabetic complications including cardiomyopathy. Abnormal activation the polyol pathway converts excess sorbitol, generating ROS AGEs. This conversion is catalyzed by enzyme Aldose Reductase. Inhibition Reductase, rate limiting in pathway, reduces production attenuates increases NADH, down-regulates...
Omega‐3 fatty acids (n‐3 FA) are bioactive nutrients exerting cardioprotective effects. In our previous study, we showed that acute n‐3 FA emulsion administration after myocardial ischemia/reperfusion (I/R) injury provides cardioprotection by preserving cardiac function and decreasing infarct size. To address molecular mechanisms responsible for their effects focused on two main pathways: lipid metabolism pathways Ca 2+ signaling, both playing a crucial role during early reperfusion in the...
mDia1, a member of the formin family and an effector Rho GTPases, has emerged as downstream RAGE signaling. been shown to stimulate deleterious effects ischemia/reperfusion injury. The goal this study was elucidate role mDia1 in heart after In mouse hearts subjected left anterior coronary artery occlusion (LAD) for 30 minutes followed by 48 hours reperfusion, there is ten-fold increase protein expression compared sham. We thus tested deletion mDia1; adult male mDia1-/- mice wild type...
n‐3 fatty acids may decrease cardiovascular disease risk. We questioned if acute intervention of triglyceride (TG) emulsion (48% = EPA+DHA) is protective and improves cardiac function after ischemia/reperfusion (I/R). TG were administered I/R in two models: a) hearts (C57BL/6 mice) perfused ex‐vivo using the Langendorff technique (LT); b) with occlusion left anterior descending coronary artery (LAD) vivo . After LAD (1.5g/kg body weight) was injected intraperitoneally at end ischemia 1h...
Cardiac injury remains a major cause of death worldwide. Previous studies have demonstrated that chronic unchecked inflammation, during post ischemic reperfusion, adversely affects adaptive repair and augments tissue damage. Nature the infiltrating immune cells determines extent vs exacerbation damage myocardial ischemia. Understanding mechanisms by which ischemia-mediated inflammatory responses exacerbate mitigate pathways are vital to discover therapeutics for infarction. Our earlier...
Our previous work has shown that the cytoplasmic tail (ct) of RAGE is essential for ligand‐mediated signal transduction and consequent modulation gene expression cellular properties. signaling requires interaction ctRAGE with intracellular effector, mammalian diaphanous 1, or DIAPH1. Given complex, multi‐ligand nature ligands binding to extracellular domains RAGE, we sought discover small molecule inhibitors Prompted by our identification 13 molecules block ctRAGE‐DIAPH1, pursued...