Huy Ong

• B.Pharm, PhD
• Professor (Full) at Université de Montréal

Macrophage mitochondrial dysfunction, caused by oxidative stress, has been proposed as an essential event in the progression of chronic inflammation diseases, such as atherosclerosis. The cluster of differentiation-36 (CD36) and lectin-like oxLDL receptor-1 (LOX-1) scavenger receptors mediate macrophage uptake of oxidized low-density lipoprotein (o...

Reperfusion of ischemic skeletal muscle triggers oxidative stress and an immediate inflammatory reaction, leading to damage of distant organs such as the lungs. The inflammatory process implicates numerous mediators, including cytokines, chemokines, and arachidonic acid metabolites. In the orchestration of the inflammatory cascade, a critical role...

Background Abdominal aortic aneurysm (AAA) is a detrimental disease with no effective pharmacological therapy. While inflammation is recognized as one of the key regulators of AAA, targeting inflammatory pathways once the disease is established does not impact the outcomes. However, understanding the earliest molecular indicators could shed light o...

Atherosclerosis is a chronic inflammatory disease of the arterial walls that develops at predisposed sites. As a major risk factor for adverse cardiovascular pathology, atherosclerosis can progress to myocardial infarction and stroke, due to the rupture of unstable atherosclerotic lesions. Macrophage uptake of modified lipoproteins and metabolic dy...

Growth hormone-releasing peptide-6 (GHRP-6) is part of a group of small synthetic peptides with potent GH-releasing activity that have gained attention in the last two decades by virtue of their cyto- and cardioprotective effects. Despite numerous preclinical studies highlighting the potential cardiovascular benefits of GHRP-6, confirmation of clin...

Fifteen N-aminoimidazolone (Nai) dipeptides having a variety of 5-position side-chain groups were synthesized by regioselective proline-catalyzed reactions of azopeptide and aldehyde components followed by acid-mediated dehydration of an aza-aspartate semialdehyde intermediate. The introduction of 5-aryl-Nai dipeptides into cluster of differentiati...

The retinal pigment epithelium (RPE) performs many functions that maintain photoreceptor health. Oxidative damage to the RPE is a critical component in the pathogenesis of eye diseases such as age-related macular degeneration (AMD). Ligands of the cluster of differentiation 36 (CD36) have previously preserved photoreceptor integrity in mouse models...

Extracellular vesicles (EVs) are implicated in the crosstalk between adipocytes and other metabolic organs, and an altered biological cargo has been observed in EVs from human obese adipose tissue (AT). Yet, the role of adipocyte-derived EVs in pancreatic β-cells remains to be determined. Here, we explored the effects of EVs, released from both rod...

The innovative development of azapeptide analogues of growth hormone releasing peptide-6 (GHRP-6) has produced selective modulators of the cluster of differentiation 36 receptor (CD36). The azapeptide CD36 modulators curb macrophage-driven inflammation and mitigate atherosclerotic and angiogenic pathology. In macrophages activated with Toll-like re...

Background and aims Scavenger receptor class B member 3, also known as cluster of differentiation-36 (CD36) receptor, is involved in the uptake and accumulation of modified lipoprotein in macrophages, driving atherosclerosis progression. Azapeptide analogs of growth hormone-releasing peptide-6 (GHRP-6) have been developed as selective CD36 ligands...

Aim: Diabetes is a conventional risk factor for atherosclerotic cardiovascular disease and myocardial infarction (MI) is the most common cause of death among these patients. Mesenchymal stromal cells (MSCs) in patients with type 2 diabetes (T2DM) and atherosclerosis have impaired ability to suppress activated T-cells (i.e. reduced immunopotency)....

Background: CD36, a member of the class B scavenger receptor family, participates in Toll-like receptor signaling on mononuclear phagocytes (MP) and can promote sterile pathogenic inflammation. We here analyzed the effect of CD36 deficiency on retinal inflammation and photoreceptor degeneration, the hallmarks of age-related macular degeneration (AM...

Dynamic chirality influences numerous processes in nature from protein folding to catalysis. Azapeptides are peptidomimetics possessing semicarbazide residues that can interconvert between sp2 and sp3 hybridization, resulting in stereo-dynamic interconversions of pseudo-R and -S-configurations by way of a planar intermediate. Cyclic azapeptides hav...

Purpose: Targeting β-adrenergic receptor signaling with propranolol has emerged as a potential candidate to counteract choroidal neovascularization (CNV). Little is known of its effect on macrophages, which play a critical role in CNV. We investigated the effect of propranolol on angiogenic response of mononuclear phagocytes (MPs). Methods: The...

In subretinal inflammation, activated mononuclear phagocytes (MP) play a key role in the progression of retinopathies. Little is known about the mechanism involved in the loss of photoreceptors leading to vision impairment. Studying retinal damage induced by photo-oxidative stress, we observed that cluster of differentiation 36 (CD36)-deficient mic...

Solid-phase chemistry for the synthesis and Diels-Alder reaction of Fmoc-protected azopeptides has been developed and used to construct aza-pipecolyl (azaPip) peptides. Considering their ability to induce electronic and structural constraints that favour cis-amide isomer geometry and type VI β-turn conformation in model peptides, azaPip residues ha...

Over 1 million cases of scorpion stings are estimated every year, whereas current treatment is limited to antivenom serum combined with supportive therapy. Tityus serrulatus scorpion venom (TsV) is composed of diverse molecules, including toxins that induce a catecholamine storm and mediate classical symptoms of scorpion envenomation. However, the...

Unacylated ghrelin (UAG), the most abundant form of ghrelin in circulation, has been shown to exert cardioprotective effect in experimental cardiopathies. The present study aimed to investigate the cardioprotective effect of a linear bioactive fragment of UAG against myocardial ischemia-induced injury and dysfunction in C57BL/6 wild type mice and t...

Modulation of the cluster of differentiation-36 receptor (CD36) has proven promising for dampening pro-inflammatory macrophage signaling. For example, azapeptides (e.g., 1 and 2) bind CD36 selectively with high affinity, mitigate Toll-like receptor (TLR) agonist-induced overproduction of nitric oxide (NO), and reduce pro-inflammatory cytokine and c...

The retention of lipoprotein particles in the intima, in particular to glycosaminoglycan side chains of proteoglycans, is a critical step in atherosclerosis initiation. Administration of chP3R99, a chimeric mouse/human monoclonal antibody inducing an anti-idiotypic network response against glycosaminoglycans was previously shown to prevent atherosc...

Azapeptide analogs of growth hormone releasing peptide-6 (GHRP-6) exhibit promising affinity, selectivity and modulator activity on the cluster of differentiation 36 receptor (CD36). For example, [A¹, azaF⁴]- and [azaY⁴]-GHRP-6 (1a and 2b) were previously shown to bind selectively to CD36, and exhibited respectively significant antiangiogenic and s...

CD36 is a multiligand receptor involved in lipid metabolism. We investigated the mechanisms underlying the cardioprotective effect of CP-3(iv), an azapeptide belonging to a new class of selective CD36 ligands. The role of CP-3(iv) in mediating cardioprotection was investigated because CD36 signaling leads to activation of peroxisome proliferator-ac...

Macrocyclization has enabled the use of peptides in drug discovery creating a need for methods to synthesize diverse peptide macrocycles. Azapeptides have advanced to clinically used drugs, however, few cyclic azapeptides have been studied. A multiple component “A³-macrocyclization” strategy is described for the preparation of diverse cyclic azapep...

Macrocyclization has enabled the use of peptides in drug discovery creating a need for methods to synthesize diverse peptide macrocycles. Azapeptides have advanced to clinically used drugs, however, few cyclic azapeptides have been studied. A multiple component "A(3) -macrocyclization" strategy is described for the preparation of diverse cyclic aza...

CD36 transmembrane proteins have diverse roles in lipid uptake, cell adhesion and pathogen sensing. Despite numerous in vitro studies, how they act in native cellular contexts is poorly understood. A Drosophila CD36 homologue, sensory neuron membrane protein 1 (SNMP1), was previously shown to facilitate detection of lipid-derived pheromones by thei...

Supplementary Figures 1-7 and Supplementary Tables 1-2

SNMP1 ectodomain protein homology model

Objective: Proprotein convertase subtilisin/kexin type 9 (PCSK9) promotes the degradation of the low-density lipoprotein receptor thereby elevating plasma low-density lipoprotein cholesterol levels and the risk of coronary heart disease. Thus, the use of PCSK9 inhibitors holds great promise to prevent heart disease. Previous work found that PCSK9...

Objective Ghrelin can be found in the circulation under two different forms: acylated ghrelin (AG) and unacylated ghrelin (UAG). UAG, while being the predominant ghrelin isoform in circulation, is devoid of endocrine activity. Despite its inability to activate the classical ghrelin receptor, some studies have shown that UAG possesses cardiotropic p...

QRFP (RFamide) peptides are neuropeptides involved in food intake and adiposity regulation in rodents. We have previously shown that QRFP-43 (43RFa) and QRFP-26 (26RFa) inhibited isoproterenol (ISO)-induced lipolysis in adipocytes. However, the antilipolytic signaling pathways activated by QRFP peptides have not been investigated. In the present st...

Atherosclerosis is the main underlying cause of ischemic heart disease and related acute cardiovascular complications, including myocardial infarction and stroke. In view of the failure of statins to demonstrate a beneficial effect in all patients, exhaustive research efforts have unfold into different research avenues, in close relation to the inc...

RFamide peptides 43RFa and 26RFa have been shown to promote food intake and to exert different peripheral actions through GPR103 receptor binding. Moreover, 26RFa was found to inhibit pancreatic insulin secretion, whereas the role of 43RFa on β-cell function is unknown, as well as the effects of both peptides on β-cell survival. Herein, we investig...

Pyroglutamylated RF-amide peptide (QRFP) is involved in the regulation of food intake, thermogenesis, adipogenesis and lipolysis. The expression of QRFP in adipose tissue is reduced in diet-induced obesity, a mouse model in which plasma concentrations of endotoxins are slightly elevated. The present study investigated the role of metabolic endotoxe...

Aims: The CD36 selective ligand, EP 80317, features potent anti-atherosclerotic and hypocholesterolemic effects that are associated with an increase in macrophage cholesterol efflux through the activation of the peroxisome proliferator-activated receptor γ-liver X receptor α (LXRα)-ATP-binding cassette (ABC) transporter pathway. Cholesterol efflux...

Objective: The pathogenesis of atherosclerosis is associated with the early retention of low-density lipoproteins that are trapped in the extracellular matrix of the arterial intima by interaction with glycosaminoglycan side chains of proteoglycans. Mutant mouse/human chimeric antibodies of the murine monoclonal antibody P3, which react with N-gly...

The CD36 receptor plays an important role in facilitating fatty acid transport to the heart. The present study aimed to assess whether EP 80317, a selective synthetic peptide ligand of CD36, is cardioprotective in a murine model of myocardial ischaemia and reperfusion (MI/R) injury. Mice were pretreated with daily subcutaneous injections of EP 8031...

The synthetic hexapeptide growth hormone releasing peptide-6 (GHRP-6) exhibits dual affinity for the growth hormone secretagogue receptor 1a (GHS-R1a) and the cluster of differentiation 36 (CD36) receptor. Azapeptide GHRP-6 analogues have been synthesized, exhibiting micromolar affinity to the CD36 receptor with reduced affinity toward the GHS-R1a....

The metabolic actions of the ghrelin gene-derived peptide obestatin are still unclear. We investigated obestatin effects in vitro, on adipocyte function, and in vivo, on insulin resistance and inflammation in mice fed a high-fat diet (HFD). Obestatin effects on apoptosis, differentiation, lipolysis, and glucose uptake were determined in vitro in mo...

A peptide self-assembled monolayer (SAM) was designed to bind His-tagged biomolecules for surface plasmon resonance (SPR) bioanalysis, which was applied for the determination of K(d) for small ligand screening against CD36. Nonspecific adsorption could be minimized using penta- and hexa-peptide monolayers. In particular, monolayers consisting of 3-...

The cluster of differentiation 36 (CD36) class B scavenger receptor binds a variety of biologically endogenous ligands in addition to synthetic peptides (i.e., growth hormone-releasing peptides, GHRPs), which modulate biological function related to anti-angiogenic and anti-atherosclerotic activities. Affinity labeling had previously shown that GHRP...

Vascular degeneration and the ensuing abnormal vascular proliferation are central to proliferative retinopathies. Given the metabolic discordance associated with these diseases, the authors explored the role of ghrelin and its growth hormone secretagogue receptor 1a (GHSR-1a) in proliferative retinopathy. In a rat model of oxygen-induced retinopath...

Age-related macular degeneration (AMD) represents the major cause of vision loss in industrialized nations. Laminar deposits in Bruch's membrane (BM) are among the first prominent histopathologic features, along with drusen formation, and have been found to contain oxidized lipids. Increases in concentrations of oxidized LDL (oxLDL) in plasma are o...

In clinical studies, postnatal weight gain is strongly associated with retinopathy of prematurity (ROP). However, animal studies are needed to investigate the pathophysiological mechanisms of how postnatal weight gain affects the severity of ROP. In the present study, we identify nutritional supply as one potent parameter that affects the extent of...

The activation of G protein-coupled receptor 103 (GPR103) by its endogenous peptidic ligands, QRFPs, is involved in the central regulation of feeding by increasing food intake, body weight, and fat mass after intracerebroventricular injection in mice. However, the role of GPR103 in regulating peripheral metabolic pathways has not yet been explored....

Incorporation of amino lactams into biologically active peptides restricts conformational mobility and may enhance selectivity and increase potency. alpha- and beta-amino gamma-lactams (Agl and Bgl), in both S and R configurations, were introduced into the growth hormone secretagogue GHRP-6 using a Fmoc-compatible solid-phase protocol relying on N-...

The peroxisome proliferator-activator receptor PPARgamma plays an essential role in vascular biology, modulating macrophage function and atherosclerosis progression. Recently, we have described the beneficial effect of combined activation of the ghrelin/GHS-R1a receptor and the scavenger receptor CD36 to induce macrophage cholesterol release throug...

Submonomer synthesis of aza-peptides featuring regioselective alkylation of peptide-bound aza-Gly residues provided ten aza-analogues of the Growth Hormone Releasing Peptide-6 (GHRP-6) in 15-42% yield and purity generally >or=90%. Circular dichroism demonstrated that azaPhe-peptide 7a induced a beta-turn conformation which may be responsible for it...

Incorporation of amino lactams into biologically active peptides has been commonly used to restrict conformational mobility, enhance selectivity, and increase potency. A solid-phase method using a Fmoc-protection strategy has been developed for the systematic synthesis of peptides containing configurationally defined alpha- and beta-amino gamma-lac...

Growth hormone-releasing peptides (GHRPs) as CD36 selective ligands feature potent anti-atherosclerotic activity that is associated with an upregulation of the peroxisome proliferator-activated receptor gamma (PPARgamma)-liver X receptor alpha (LXRalpha)-ATP-binding cassette (ABC) transporter pathway. However, the mechanism involved in PPARgamma ac...

CD36 has been shown to associate with non-receptor Src kinases to activate mitogen-activated protein kinases and trigger cytoskeletal remodelling, important events in foam cell formation and macrophage migration. Yet, its role in regulating circulating mononuclear phagocyte trafficking to atherosclerotic lesions has not been investigated. The aim o...

Neovascularization (NV) of the normally avascular cornea arises from various causes including inflammation, infection, trauma, and contact lens wear. Corneal NV, whatever the cause, impairs vision and threatens the survival of corneal allografts, thus representing a serious clinical problem for which treatment is limited. Recent interest has focuse...

Corneal avascularity is tightly regulated by a balance between angiogenic and antiangiogenic factors (angiogenic privilege). In the current study, we tested the hypothesis that the CD36+/+ antiangiogenic receptor contributes toward the maintenance of corneal avascularity. Corneas of CD36 wild-type (CD36) and knockout (CD36) mice aged 4, 16, 52, and...

In the Western world, a major cause of blindness is age-related macular degeneration (AMD). Recent research in angiogenesis has furthered the understanding of choroidal neovascularization, which occurs in the "wet" form of AMD. In contrast, very little is known about the mechanisms of the predominant, "dry" form of AMD, which is characterized by re...

The etiology of type 2 diabetes often involves diet-induced obesity (DIO), which is associated with elevated plasma fatty acids and lipoprotein associated triglycerides. Since aberrant hepatic fatty acid uptake may contribute to this, we investigated whether increased expression of a fatty acid transport protein (CD36) in the liver during DIO contr...

To assess the effect of short-term treatment with GH on left ventricular contractility and remodeling, after the development of heart failure in cardiomyopathic hamsters (CMH). Two groups of 200-day-old UM-X7.1 CMH received daily subcutaneous injections of recombinant bovine (rb) GH (1mg/kg/day) or 0.9% NaCl for 40 days. Golden Syrian hamsters (GSH...

Whereas the uptake of oxidized lipoproteins by scavenger receptor CD36 in macrophages has been associated with foam cell formation and atherogenesis, little is known about the role of CD36 in regulating lipid metabolism in adipocytes. Here we report that treatment of 3T3-L1 adipocytes with hexarelin, a GH-releasing peptide that interacts with CD36,...

Macrophages play a central role in the pathogenesis of atherosclerosis by accumulating cholesterol through increased uptake of oxidized low-density lipoproteins by scavenger receptor CD36, leading to foam cell formation. Here we demonstrate the ability of hexarelin, a GH-releasing peptide, to enhance the expression of ATP-binding cassette A1 and G1...

A bidimensional HPLC system combining steric gel exclusion and reverse phase ODS columns for determination of theophylline in serum is reported. Factors involved in the development of the method and its performance are discussed. This technique is a practical alternative for the determination of theophylline levels in serum without any clean up pro...

This study was undertaken to investigate the role of the antiangiogenic receptor CD36 during inflammatory corneal neovascularization (CNV). In a murine model of inflammatory CNV, CD36 expression was evaluated by RT-PCR and immunofluorescence. Mice subjected to CNV were treated topically (thrice daily) with CD36 functionally neutralizing antibodies...

Ischemic and nonischemic cardiomyopathies are associated with significant morbidity and mortality in industrialized countries. Cardiomyopathies of primary origin, and more specifically the dilated form of the disease, have been associated with a number of gene defects in cytoskeletal, membrane, and sarcomeric proteins. Cardiomyopathies of secondary...

Ghrelin, a newly discovered endogenous hormone that is produced by the stomach, and synthetic peptides have been identified recently as potent growth-hormone secretagogues. This effect is exerted through interaction with a specific G-protein-coupled receptor, GHS-R1a, which is expressed mainly in the hypothalamus-pituitary complex. A study of the p...

Nitrative stress has an important role in microvascular degeneration leading to ischemia in conditions such as diabetic retinopathy and retinopathy of prematurity. Thus far, mediators of nitrative stress have been poorly characterized. We recently described that trans-arachidonic acids are major products of NO(2)(*)-mediated isomerization of arachi...

The recent advent of biotechnologies has led to the development of labile macromolecular therapeutic agents that require complex formulations for their efficient administration. This work reports a novel concept for the systemic, sustained delivery of such agents. The proposed approach is based on the spontaneous self-assembly of low-molecular weig...

CD36, a type B scavenger receptor expressed on macrophages, appears to play a major role in fatty streak formation through scavenging oxidatively modified lipoproteins in the arterial wall. We tested the hypothesis that EP 80317, a novel CD36 ligand derived from the growth hormone (GH)-releasing peptide family but devoided of any GH releasing activ...

The GHRPs (growth hormone-releasing peptides) are a class of small synthetic peptides known to stimulate GH release through binding of a G-protein-coupled receptor (designated GHS-R). We have found that hexarelin, a hexapeptide member of the GHRPs, binds to another protein identified as CD36, a scavenger receptor that is expressed in various tissue...

Background: Intravitreal neovascular diseases, as in ischemic retinopathies, are a major cause of blindness. Because inflammatory mechanisms influence vitreal neovascularization and cyclooxygenase (COX)-2 promotes tumor angiogenesis, we investigated the role of COX-2 in ischemic proliferative retinopathy. Methods and results: We describe here th...

In view of the potentially beneficial effect of GH on ventricular function of humans suffering from idiopathic dilated cardiomyopathy, we undertook a study to evaluate the optimal time to initiate treatment with GH and its duration in UM-X7.1 cardiomyopathic hamsters (CMH). GH (1 mg/kg.d) therapy was initiated either in the early or late (30 and 16...

Growth hormone secretagogues (GHS) consist of a series of small enkephalin derived peptides identified as growth hormone-releasing peptides (GHRPs) (Bowers, 1993) and non-peptidyl derivatives modeled from GHRPs (Smith et al., 1997). To this class of compounds is recently added a new member, ghrelin, an endogenous 28 amino acid polypeptide isolated...

Growth hormone-releasing peptides (GHRPs) are known as potent growth hormone secretagogues whose actions are mediated by the ghrelin receptor, a G protein-coupled receptor cloned from pituitary libraries. Hexarelin, a hexapeptide of the GHRP family, has reported cardiovascular activity. To identify the molecular target mediating this activity, rat...

The intestinal permeability of hexarelin and EP 51389, two growth hormone releasing hexa- and tri- peptide analogues, was assessed in vitro with side-by-side diffusion chambers in the apical-to-basolateral (AP-to-BL) and in the basolateral-to-apical (BL-to-AP) direction using excised rat jejunal segments. The effect of EP 51389 on P-glycoprotein (P...