The Positive Regulation of eNOS Signaling by PPAR Agonists in Cardiovascular Diseases

Maccallini, Cristina; Mollica, Adriano; Amoroso, Rosa

doi:10.1007/s40256-017-0220-9

Cited by 55 publications

(36 citation statements)

References 84 publications

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“…There is increasing evidence showing that the cardiovascular benefits of PPAR agonists are attributed, at least in part, to the activation of the endothelial nitric oxide synthase (eNOS) [19]. Under physiological conditions, nitric oxide produced by eNOS acts as a vasodilator and anti-thrombotic agent to safeguard endothelial functions.…”

Section: Mechanistic Rationales For Targeting Ppars In Various Human mentioning

confidence: 99%

Exploration and Development of PPAR Modulators in Health and Disease: An Update of Clinical Evidence

Cheng

Tan

Low

et al. 2019

IJMS

177

152

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Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that govern the expression of genes responsible for energy metabolism, cellular development, and differentiation. Their crucial biological roles dictate the significance of PPAR-targeting synthetic ligands in medical research and drug discovery. Clinical implications of PPAR agonists span across a wide range of health conditions, including metabolic diseases, chronic inflammatory diseases, infections, autoimmune diseases, neurological and psychiatric disorders, and malignancies. In this review we aim to consolidate existing clinical evidence of PPAR modulators, highlighting their clinical prospects and challenges. Findings from clinical trials revealed that different agonists of the same PPAR subtype could present different safety profiles and clinical outcomes in a disease-dependent manner. Pemafibrate, due to its high selectivity, is likely to replace other PPARα agonists for dyslipidemia and cardiovascular diseases. PPARγ agonist pioglitazone showed tremendous promises in many non-metabolic disorders like chronic kidney disease, depression, inflammation, and autoimmune diseases. The clinical niche of PPARβ/δ agonists is less well-explored. Interestingly, dual- or pan-PPAR agonists, namely chiglitazar, saroglitazar, elafibranor, and lanifibranor, are gaining momentum with their optimistic outcomes in many diseases including type 2 diabetes, dyslipidemia, non-alcoholic fatty liver disease, and primary biliary cholangitis. Notably, the preclinical and clinical development for PPAR antagonists remains unacceptably deficient. We anticipate the future design of better PPAR modulators with minimal off-target effects, high selectivity, superior bioavailability, and pharmacokinetics. This will open new possibilities for PPAR ligands in medicine.

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Section: Mechanistic Rationales For Targeting Ppars In Various Human mentioning

confidence: 99%

Exploration and Development of PPAR Modulators in Health and Disease: An Update of Clinical Evidence

Cheng

Tan

Low

et al. 2019

IJMS

177

152

View full text Add to dashboard Cite

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“…Therefore, based on cell localization and the enzyme isoform by which is produced, NO has numerous molecular targets and pathophysiological functions (Figure ). For example, it controls neurotransmission and neurodegeneration, vascular tone (by stimulating NO‐sensitive guanylyl cyclase) in the health and failing cardiovascular system, regulates gene transcription and mRNA translation, and produces post‐translational modifications of proteins . Moreover, from the reaction with the superoxide anion (O 2 − ), NO generates the potent oxidant peroxynitrite (ONOO − ) which is responsible for oxidative damage, nitration, and S‐nitrosylation of biomolecules including proteins, lipids, and DNA.…”

Section: Introductionmentioning

confidence: 99%

Targeting iNOS As a Valuable Strategy for the Therapy of Glioma

et al. 2020

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Gliomas are the most prevalent primary tumors of the brain and spinal cord. Histologically, they share features of normal glial cells, but whether gliomas originate from normal glial cells, glial or neural precursors, stem cells, or other cell types remains a topic of investigation. The enhanced expression of inducible nitric oxide synthase (iNOS) has been reported as a hallmark of chemoresistance in gliomas, and several lines of evidence have reported that a decreased proliferation of glioma cells could be related to the selective inhibition of iNOS. This review aims to summarize the current understanding of iNOS expression and activity modulation in the regulation of glioma pathogenesis, along with compounds that could act as therapeutic agents against glioma.

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“…Indeed, NO activates it, with the consequent increase of cyclic guanosine‐3′,5′‐monophosphate (cGMP) level, which subsequently activates intracellular effector molecules, cGMP‐dependent protein kinases, cGMP‐gated ion channels, and cGMP‐regulated phosphodiesterases . The eNOS‐derived NO relaxes vasculature, inhibits platelet and white cell adhesion, prevents smooth muscle cell replication, promotes angiogenesis, and controls the expression of vascular endothelium growth factor (VEGF) . The nNOS‐derived NO is responsible for neuronal signaling in central nervous system (CNS), and relaxation of vascular and nonvascular smooth muscles in peripheral nervous system .…”

Section: Introductionmentioning

confidence: 99%

Inducible nitric oxide synthase inhibitors: A comprehensive update

Minhas

Bansal

2019

Medicinal Research Reviews

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Inducible nitric oxide synthase (iNOS), which is expressed in response to bacterial/proinflammatory stimuli, generates nitric oxide (NO) that provides cytoprotection. Overexpression of iNOS increases the levels of NO, and this increased NO level is implicated in pathophysiology of complex multifactorial diseases like Parkinson's disease, Alzheimer's disease, multiple sclerosis, rheumatoid arthritis, and inflammatory bowel disease. Selective inhibition of iNOS is an effective approach in treatment of such complex diseases. L-Arginine, being a substrate for iNOS, is the natural lead to develop iNOS inhibitors. More than 200 research reports on development of nitric oxide synthase inhibitors by different research groups across the globe have appeared in literature so far. The first review on iNOS, in 2002, discussed the iNOS inhibitors under two classes that is, amino acid and non-amino acid derivatives. Other review articles discussing specific chemical classes of iNOS inhibitors also appeared during last decade. In the present review, all reports on both natural and synthetic iNOS inhibitors, published 2002 onwards, are studied, classified, and discussed to provide comprehensive information on iNOS inhibitors. The synthetic inhibitors are broadly classified into two categories that is, arginine and non-arginine analogs. The latter are further classified into amidines, five-or six-membered heterocyclics, fused cyclics, steroidal type, and chalcones analogs. Structures of the most/significantly potent compounds from each report are provided to know the functional groups important for incurring iNOS inhibitory activity and selectivity. This review is aimed to provide a comprehensive view to the medicinal chemists for rational designing of novel and potent iNOS inhibitors. K E Y W O R D S arginine, inflammation, inhibitors, multifactorial disease, nitric oxide 1 | INTRODUCTION Nitric oxide (NO) is a relaxing factor derived from endothelium, which is responsible for neuronal transmission, cardiovascular, gastrointestinal, genitourinary, respiratory, antipathogenic, and antitumor responses. The production of NO is effected by nitric oxide synthase (NOS) through catalysis of NADPH-dependent oxidation of L-arginine (the substrate). 1NOS exists in three distinct isoforms, depending on the site of its existence that is, neuronal NOS (nNOS, type I), inducible or inflammatory NOS (iNOS, type II) and endothelial NOS (eNOS, type III). Constitutive NOS are regulated by the binding of calcium-calmodulin protein, whereas iNOS is transcriptionally regulated and calcium-calmodulin independent. NO plays both physiological and pathological roles depending on the magnitude and duration of its production. 2 The physiological roles of NO are executed by soluble guanylate cyclase. Indeed, NO activates it, with the consequent increase of cyclic guanosine-3′,5′-monophosphate (cGMP) level, which subsequently activates intracellular effector molecules, cGMPdependent protein kinases, cGMP-gated ion channels, and cGMP-regulated phosphodiesteras...

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The Positive Regulation of eNOS Signaling by PPAR Agonists in Cardiovascular Diseases

Cited by 55 publications

References 84 publications

Exploration and Development of PPAR Modulators in Health and Disease: An Update of Clinical Evidence

Exploration and Development of PPAR Modulators in Health and Disease: An Update of Clinical Evidence

Targeting iNOS As a Valuable Strategy for the Therapy of Glioma

Inducible nitric oxide synthase inhibitors: A comprehensive update

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