scholarly journals PPAR-Mediated Toxicology and Applied Pharmacology

Cells ◽  
2020 ◽  
Vol 9 (2) ◽  
pp. 352 ◽  
Author(s):  
Yue Xi ◽  
Yunhui Zhang ◽  
Sirui Zhu ◽  
Yuping Luo ◽  
Pengfei Xu ◽  
...  
Keyword(s):  
Multiple Organ ◽  
Nuclear Hormone Receptor ◽  
Peroxisome Proliferator ◽  
Protective Effects ◽  
Pharmacological Agents ◽  
Peroxisome Proliferator Activated Receptors ◽  
Systematic Understanding ◽  
Approved Drugs ◽  
Receptor Family

Peroxisome proliferator-activated receptors (PPARs), members of the nuclear hormone receptor family, attract wide attention as promising therapeutic targets for the treatment of multiple diseases, and their target selective ligands were also intensively developed for pharmacological agents such as the approved drugs fibrates and thiazolidinediones (TZDs). Despite their potent pharmacological activities, PPARs are reported to be involved in agent- and pollutant-induced multiple organ toxicity or protective effects against toxicity. A better understanding of the protective and the detrimental role of PPARs will help to preserve efficacy of the PPAR modulators but diminish adverse effects. The present review summarizes and critiques current findings related to PPAR-mediated types of toxicity and protective effects against toxicity for a systematic understanding of PPARs in toxicology and applied pharmacology.

scholarly journals Emerging PPARγ-Independent Role of PPARγLigands in Lung Diseases

PPAR Research ◽  
2012 ◽  
Vol 2012 ◽  
pp. 1-13 ◽  
Author(s):  
Ajit A. Kulkarni ◽  
Collynn F. Woeller ◽  
Thomas H. Thatcher ◽  
Sesquile Ramon ◽  
Richard P. Phipps ◽  
...  
Keyword(s):  
Transcriptional Control ◽  
Nuclear Hormone Receptor ◽  
Great Promise ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Novel Proteins ◽  
Therapeutic Uses ◽  
Independent Effects ◽  
Approved Drugs

Peroxisome proliferator activated receptor (PPAR)-γis a nuclear hormone receptor that is activated by multiple agonists including thiazolidinediones, prostaglandins, and synthetic oleanolic acids. Many PPARγligands are under investigation as potential therapies for human diseases. These ligands modulate multiple cellular pathways via both PPARγ-dependent and PPARγ-independent mechanisms. Here, we review the role of PPARγand PPARγligands in lung disease, with emphasis on PPARγ-independent effects. PPARγligands show great promise in moderating lung inflammation, as antiproliferative agents in combination to enhance standard chemotherapy in lung cancer and as treatments for pulmonary fibrosis, a progressive fatal disease with no effective therapy. Some of these effects occur when PPARγis pharmaceutically antagonized or genetically PPARγand are thus independent of classical PPARγ-dependent transcriptional control. Many PPARγligands demonstrate direct binding to transcription factors and other proteins, altering their function and contributing to PPARγ-independent inhibition of disease phenotypes. These PPARγ-independent mechanisms are of significant interest because they suggest new therapeutic uses for currently approved drugs and because they can be used as probes to identify novel proteins and pathways involved in the pathogenesis or treatment of disease, which can then be targeted for further investigation and drug development.

scholarly journals Peroxisome Proliferator-Activated Receptors and Progression of Colorectal Cancer

PPAR Research ◽  
2008 ◽  
Vol 2008 ◽  
pp. 1-7 ◽  
Author(s):  
Dingzhi Wang ◽  
Raymond N. DuBois
Keyword(s):  
Colorectal Cancer ◽  
Tumor Suppressors ◽  
Drug Targets ◽  
Cancer Chemoprevention ◽  
Nuclear Hormone Receptor ◽  
Lipid Homeostasis ◽  
Peroxisome Proliferator ◽  
Cellular Events ◽  
Peroxisome Proliferator Activated Receptors

The peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily. These receptors are also ligand-dependent transcription factors responsible for the regulation of cellular events that range from glucose and lipid homeostases to cell differentiation and apoptosis. The importance of these receptors in lipid homeostasis and energy balance is well established. In addition to these metabolic and anti-inflammatory properties, emerging evidence indicates that PPARs can function as either tumor suppressors or accelerators, suggesting that these receptors are potential candidates as drug targets for cancer prevention and treatment. However, conflicting results have emerged regarding the role of PPARs on colon carcinogenesis. Therefore, further investigation is warranted prior to considering modulation of PPARs as an efficacious therapy for colorectal cancer chemoprevention and treatment.

scholarly journals The Role of PPARs in Cancer

PPAR Research ◽  
2008 ◽  
Vol 2008 ◽  
pp. 1-15 ◽  
Author(s):  
Keisuke Tachibana ◽  
Daisuke Yamasaki ◽  
Kenji Ishimoto ◽  
Takefumi Doi
Keyword(s):  
Fatty Acid ◽  
Density Lipoprotein ◽  
Nuclear Hormone Receptor ◽  
Keratinocyte Differentiation ◽  
Acid Oxidation ◽  
Peroxisome Proliferator ◽  
Cancer Cell Growth ◽  
Peroxisome Proliferator Activated Receptors

Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors that belong to the nuclear hormone receptor superfamily. PPAR is mainly expressed in the liver, where it activates fatty acid catabolism. PPAR activators have been used to treat dyslipidemia, causing a reduction in plasma triglyceride and elevation of high-density lipoprotein cholesterol. PPAR is expressed ubiquitously and is implicated in fatty acid oxidation and keratinocyte differentiation. PPAR activators have been proposed for the treatment of metabolic disease. PPAR2 is expressed exclusively in adipose tissue and plays a pivotal role in adipocyte differentiation. PPAR is involved in glucose metabolism through the improvement of insulin sensitivity and represents a potential therapeutic target of type 2 diabetes. Thus PPARs are molecular targets for the development of drugs treating metabolic syndrome. However, PPARs also play a role in the regulation of cancer cell growth. Here, we review the function of PPARs in tumor growth.

New trends in the pharmacological intervention of PPARs in obesity: Role of natural and synthetic compounds_

2020 ◽  
Vol 28 ◽  
Author(s):  
Seyed Mohammad Nabavi ◽  
Kasi Pandima Devi ◽  
Sethuraman Sathya ◽  
Ana Sanches-Silva ◽  
Listos Joanna ◽  
...  
Keyword(s):  
Tissue Expression ◽  
Health Concern ◽  
Pharmacological Intervention ◽  
Peroxisome Proliferator ◽  
Expression Of Genes ◽  
Ppar Agonists ◽  
Prevalence Of Obesity ◽  
Peroxisome Proliferator Activated Receptors ◽  
Natural And Synthetic

: Obesity is a major health concern for a growing fraction of the population, with the prevalence of obesity and its related metabolic disorders not being fully understood. Over the last decade, many attempts have been undertaken to understand the mechanisms at the basis of this condition, in which the accumulation of fat occurring in adipose tissue, leads to the pathogenesis of obesity related disorders. Among the most recent studies, those on Peroxisome Proliferator Activated Receptors (PPARs) revealed that these nuclear receptor proteins acting as transcription factors, among others, regulate the expression of genes involved in energy, lipid, and glucose metabolisms, and chronic inflammation. The three different isotypes of PPARs, with different tissue expression and ligand binding specificity, exert similar or overlapping functions directly or indirectly linked to obesity. In this study, we reviewed the available scientific reports concerning the PPARs structure and functions, especially in obesity, considering both natural and synthetic ligands and their role in the therapy of obesity and obesity-associated disorders. In the whole, the collected data show that there are both natural and synthetic compounds that show beneficial promising activity as PPAR agonists in chronic diseases related to obesity.

scholarly journals Molecular Mechanisms of Obesity-Linked Cardiac Dysfunction: An Up-Date on Current Knowledge

Cells ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 629
Author(s):  
Jorge Gutiérrez-Cuevas ◽  
Ana Sandoval-Rodriguez ◽  
Alejandra Meza-Rios ◽  
Hugo Christian Monroy-Ramírez ◽  
Marina Galicia-Moreno ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cardiac Dysfunction ◽  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Peroxisome Proliferator ◽  
White Adipocyte ◽  
Peroxisome Proliferator Activated Receptors ◽  
And Oxidative Stress

Obesity is defined as excessive body fat accumulation, and worldwide obesity has nearly tripled since 1975. Excess of free fatty acids (FFAs) and triglycerides in obese individuals promote ectopic lipid accumulation in the liver, skeletal muscle tissue, and heart, among others, inducing insulin resistance, hypertension, metabolic syndrome, type 2 diabetes (T2D), atherosclerosis, and cardiovascular disease (CVD). These diseases are promoted by visceral white adipocyte tissue (WAT) dysfunction through an increase in pro-inflammatory adipokines, oxidative stress, activation of the renin-angiotensin-aldosterone system (RAAS), and adverse changes in the gut microbiome. In the heart, obesity and T2D induce changes in substrate utilization, tissue metabolism, oxidative stress, and inflammation, leading to myocardial fibrosis and ultimately cardiac dysfunction. Peroxisome proliferator-activated receptors (PPARs) are involved in the regulation of carbohydrate and lipid metabolism, also improve insulin sensitivity, triglyceride levels, inflammation, and oxidative stress. The purpose of this review is to provide an update on the molecular mechanisms involved in obesity-linked CVD pathophysiology, considering pro-inflammatory cytokines, adipokines, and hormones, as well as the role of oxidative stress, inflammation, and PPARs. In addition, cell lines and animal models, biomarkers, gut microbiota dysbiosis, epigenetic modifications, and current therapeutic treatments in CVD associated with obesity are outlined in this paper.

scholarly journals Protective Effects of PGC-1α Activators on Ischemic Stroke in a Rat Model of Photochemically Induced Thrombosis

2021 ◽  
Vol 11 (3) ◽  
pp. 325
Author(s):  
Fatima M. Shakova ◽  
Yuliya I. Kirova ◽  
Denis N. Silachev ◽  
Galina A. Romanova ◽  
Sergey G. Morozov
Keyword(s):  
Rat Model ◽  
Nuclear Translocation ◽  
Peroxisome Proliferator ◽  
Protective Effects ◽  
Protein Markers ◽  
Peroxisome Proliferator Activated Receptor ◽  
Pharmacological Agents ◽  
Ischemic Brain ◽  
Neuroprotective Therapy ◽  
Dependent Protein

The pharmacological induction and activation of peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α), a key regulator of ischemic brain tolerance, is a promising direction in neuroprotective therapy. Pharmacological agents with known abilities to modulate cerebral PGC-1α are scarce. This study focused on the potential PGC-1α-modulating activity of Mexidol (2-ethyl-6-methyl-3-hydroxypyridine succinate) and Semax (ACTH(4–7) analog) in a rat model of photochemical-induced thrombosis (PT) in the prefrontal cortex. Mexidol (100 mg/kg) was administered intraperitoneally, and Semax (25 μg/kg) was administered intranasally, for 7 days each. The expression of PGC-1α and PGC-1α-dependent protein markers of mitochondriogenesis, angiogenesis, and synaptogenesis was measured in the penumbra via immunoblotting at Days 1, 3, 7, and 21 after PT. The nuclear content of PGC-1α was measured immunohistochemically. The suppression of PGC-1α expression was observed in the penumbra from 24 h to 21 days following PT and reflected decreases in both the number of neurons and PGC-1α expression in individual neurons. Administration of Mexidol or Semax was associated with preservation of the neuron number and neuronal expression of PGC-1α, stimulation of the nuclear translocation of PGC-1α, and increased contents of protein markers for PGC-1α activation. This study opens new prospects for the pharmacological modulation of PGC-1α in the ischemic brain.

scholarly journals Elucidating the Beneficial Role of PPAR Agonists in Cardiac Diseases

2018 ◽  
Vol 19 (11) ◽  
pp. 3464 ◽  
Author(s):  
Zaza Khuchua ◽  
Aleksandr I. Glukhov ◽  
Arnold W. Strauss ◽  
Sabzali Javadov
Keyword(s):  
Animal Models ◽  
Hormone Receptors ◽  
Lipid Lowering ◽  
Acid Oxidation ◽  
Peroxisome Proliferator ◽  
Pharmacological Agents ◽  
Beneficial Effects ◽  
Ppar Agonists ◽  
Energy Deprivation

Peroxisome proliferator-activated receptors (PPARs) are nuclear hormone receptors that bind to DNA and regulate transcription of genes involved in lipid and glucose metabolism. A growing number of studies provide strong evidence that PPARs are the promising pharmacological targets for therapeutic intervention in various diseases including cardiovascular disorders caused by compromised energy metabolism. PPAR agonists have been widely used for decades as lipid-lowering and anti-inflammatory drugs. Existing studies are mainly focused on the anti-atherosclerotic effects of PPAR agonists; however, their role in the maintenance of cellular bioenergetics remains unclear. Recent studies on animal models and patients suggest that PPAR agonists can normalize lipid metabolism by stimulating fatty acid oxidation. These studies indicate the importance of elucidation of PPAR agonists as potential pharmacological agents for protection of the heart from energy deprivation. Here, we summarize and provide a comprehensive analysis of previous studies on the role of PPARs in the heart under normal and pathological conditions. In addition, the review discusses the PPARs as a therapeutic target and the beneficial effects of PPAR agonists, particularly bezafibrate, to attenuate cardiomyopathy and heart failure in patients and animal models.

scholarly journals Estrogen Receptor and Vascular Aging

2021 ◽  
Vol 2 ◽  
Author(s):  
Morgane Davezac ◽  
Melissa Buscato ◽  
Rana Zahreddine ◽  
Patrick Lacolley ◽  
Daniel Henrion ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Cardiovascular Diseases ◽  
Experimental Studies ◽  
Hormonal Treatment ◽  
Protective Effects ◽  
Age Related ◽  
Nuclear Receptor Family ◽  
The Impact ◽  
Receptor Family

Cardiovascular diseases remain an age-related pathology in both men and women. These pathologies are 3-fold more frequent in men than in women before menopause, although this difference progressively decreases after menopause. The vasculoprotective role of estrogens are well established before menopause, but the consequences of their abrupt decline on the cardiovascular risk at menopause remain debated. In this review, we will attempt to summarize the main clinical and experimental studies reporting the protective effects of estrogens against cardiovascular diseases, with a particular focus on atherosclerosis, and the impact of aging and estrogen deprivation on their endothelial actions. The arterial actions of estrogens, but also part of that of androgens through their aromatization into estrogens, are mediated by the estrogen receptor (ER)α and ERβ. ERs belong to the nuclear receptor family and act by transcriptional regulation in the nucleus, but also exert non-genomic/extranuclear actions. Beside the decline of estrogens at menopause, abnormalities in the expression and/or function of ERs in the tissues, and particularly in arteries, could contribute to the failure of classic estrogens to protect arteries during aging. Finally, we will discuss how recent insights in the mechanisms of action of ERα could contribute to optimize the hormonal treatment of the menopause.

scholarly journals Exploring Ligand Binding to Calcitonin Gene-Related Peptide Receptors

2021 ◽  
Vol 8 ◽  
Author(s):  
Giuseppe Deganutti ◽  
Silvia Atanasio ◽  
Roxana-Maria Rujan ◽  
Patrick M. Sexton ◽  
Denise Wootten ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Ligand Binding ◽  
Calcitonin Gene Related Peptide ◽  
Related Peptide ◽  
Calcitonin Gene ◽  
Approved Drugs ◽  
G Protein Coupled ◽  
Dynamic Docking ◽  
Receptor Family

Class B1 G protein-coupled receptors (GPCRs) are important targets for many diseases, including cancer, diabetes, and heart disease. All the approved drugs for this receptor family are peptides that mimic the endogenous activating hormones. An understanding of how agonists bind and activate class B1 GPCRs is fundamental for the development of therapeutic small molecules. We combined supervised molecular dynamics (SuMD) and classic molecular dynamics (cMD) simulations to study the binding of the calcitonin gene-related peptide (CGRP) to the CGRP receptor (CGRPR). We also evaluated the association and dissociation of the antagonist telcagepant from the extracellular domain (ECD) of CGRPR and the water network perturbation upon binding. This study, which represents the first example of dynamic docking of a class B1 GPCR peptide, delivers insights on several aspects of ligand binding to CGRPR, expanding understanding of the role of the ECD and the receptor-activity modifying protein 1 (RAMP1) on agonist selectivity.

scholarly journals Peroxisome Proliferator-Activated Receptors (PPARs) Activation as Therapeutic Targets in Skin Inflammation

2020 ◽  
Vol 4 (2) ◽  
pp. 9
Author(s):  
Akihiro Aioi
Keyword(s):  
Skin Diseases ◽  
Skin Barrier ◽  
Skin Inflammation ◽  
Cell Types ◽  
Immune Dysregulation ◽  
Nuclear Hormone Receptor ◽  
Peroxisome Proliferator ◽  
Barrier Dysfunction ◽  
Cytokine Network ◽  
Peroxisome Proliferator Activated Receptors

Peroxisome proliferator-activated receptors (PPARs) are fatty acid activated transcription factors that belong to the nuclear hormone receptor family. They are initially known as transcriptional regulators of lipid and glucose metabolism, although further evidence has also been accumulated for other functions. Due to the nature of all PPAR isotypes which are expressed and exert effects by regulating the functions of cell types residing and infiltrating in the skin, PPARs represent a major research target for the understanding and treatment of many skin diseases. Atopic dermatitis (AD) is a chronic and relapsing disease characterized by skin barrier dysfunction and immune dysregulation. Skin barrier disturbance is one of the exacerbation factors of AD, due to facile penetration of molecules such as antigens. From the aspect of immune dysregulation, innate and acquired immunity including cell proliferation, cell differentiation, and cytokine network are involved in the pathogenesis. In this review, the role of PPAR in AD and the possibility of its agonist for the treatment of AD are discussed.

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