scholarly journals Treatment of Obesity-Related Complications with Novel Classes of Naturally Occurring PPAR Agonists

2011 ◽  
Vol 2011 ◽  
pp. 1-7 ◽  
Author(s):  
Josep Bassaganya-Riera ◽  
Amir J. Guri ◽  
Raquel Hontecillas
Keyword(s):  
Metabolic Diseases ◽  
Inflammatory Diseases ◽  
Peroxisome Proliferator ◽  
Punicic Acid ◽  
Ppar Γ ◽  
Naturally Occurring ◽  
Wide Range ◽  
Ppar Agonists ◽  
Peroxisome Proliferator Activated Receptors ◽  
Treatment Of Obesity

The prevalence of obesity and its associated comorbidities has grown to epidemic proportions in the US and worldwide. Thus, developing safe and effective therapeutic approaches against these widespread and debilitating diseases is important and timely. Activation of peroxisome proliferator-activated receptors (PPARs) α, γ, and δ through several classes of pharmaceuticals can prevent or treat a variety of metabolic and inflammatory diseases, including type II diabetes (T2D). Thus, PPARs represent important molecular targets for developing novel and better treatments for a wide range of debilitating and widespread obesity-related diseases and disorders. However, available PPAR γ agonistic drugs such as Avandia have significant adverse side effects, including weight gain, fluid retention, hepatotoxicity, and congestive heart failure. An alternative to synthetic agonists of PPAR γ is the discovery and development of naturally occurring and safer nutraceuticals that may be dual or pan PPAR agonists. The purpose of this paper is to summarize the health effects of three plant-derived PPAR agonists: abscisic acid (ABA), punicic acid (PUA), and catalpic acid (CAA) in the prevention and treatment of chronic inflammatory and metabolic diseases and disorders.

scholarly journals Minireview: Challenges and Opportunities in Development of PPAR Agonists

2014 ◽  
Vol 28 (11) ◽  
pp. 1756-1768 ◽  
Author(s):  
Matthew B. Wright ◽  
Michele Bortolini ◽  
Moh Tadayyon ◽  
Martin Bopst
Keyword(s):  
Peroxisome Proliferator ◽  
Gene Promoters ◽  
Ppar Γ ◽  
Specific Target Gene ◽  
Challenges And Opportunities ◽  
Ppar Agonists ◽  
Peroxisome Proliferator Activated Receptors ◽  
Transcriptional Complex ◽  
Ppar Ligands ◽  
Coregulatory Proteins

The clinical impact of the fibrate and thiazolidinedione drugs on dyslipidemia and diabetes is driven mainly through activation of two transcription factors, peroxisome proliferator-activated receptors (PPAR)-α and PPAR-γ. However, substantial differences exist in the therapeutic and side-effect profiles of specific drugs. This has been attributed primarily to the complexity of drug-target complexes that involve many coregulatory proteins in the context of specific target gene promoters. Recent data have revealed that some PPAR ligands interact with other non-PPAR targets. Here we review concepts used to develop new agents that preferentially modulate transcriptional complex assembly, target more than one PPAR receptor simultaneously, or act as partial agonists. We highlight newly described on-target mechanisms of PPAR regulation including phosphorylation and nongenomic regulation. We briefly describe the recently discovered non-PPAR protein targets of thiazolidinediones, mitoNEET, and mTOT. Finally, we summarize the contributions of on- and off-target actions to select therapeutic and side effects of PPAR ligands including insulin sensitivity, cardiovascular actions, inflammation, and carcinogenicity.

scholarly journals Parsing the Role of PPARs in Macrophage Processes

2021 ◽  
Vol 12 ◽  
Author(s):  
Daniel Toobian ◽  
Pradipta Ghosh ◽  
Gajanan D. Katkar
Keyword(s):  
Cell Function ◽  
Immune Cell ◽  
Inflammatory Diseases ◽  
Chronic Inflammatory Disease ◽  
Peroxisome Proliferator ◽  
Microbial Infection ◽  
Ppar Agonists ◽  
Peroxisome Proliferator Activated Receptors ◽  
Nuclear Receptor Family

Cells are richly equipped with nuclear receptors, which act as ligand-regulated transcription factors. Peroxisome proliferator activated receptors (PPARs), members of the nuclear receptor family, have been extensively studied for their roles in development, differentiation, and homeostatic processes. In the recent past, there has been substantial interest in understanding and defining the functions of PPARs and their agonists in regulating innate and adaptive immune responses as well as their pharmacologic potential in combating acute and chronic inflammatory disease. In this review, we focus on emerging evidence of the potential roles of the PPAR subtypes in macrophage biology. We also discuss the roles of dual and pan PPAR agonists as modulators of immune cell function, microbial infection, and inflammatory diseases.

scholarly journals Activation of PPARs Modulates Signalling Pathways and Expression of Regulatory Genes in Osteoclasts Derived from Human CD14+ Monocytes

2019 ◽  
Vol 20 (7) ◽  
pp. 1798 ◽  
Author(s):  
Abe Kasonga ◽  
Marlena C. Kruger ◽  
Magdalena Coetzee
Keyword(s):  
Fatty Acids ◽  
Unsaturated Fatty Acids ◽  
Monounsaturated Fatty Acids ◽  
Nuclear Factor Κb ◽  
The Body ◽  
Signalling Pathways ◽  
Peroxisome Proliferator ◽  
Ppar Γ ◽  
Ppar Agonists ◽  
Peroxisome Proliferator Activated Receptors

Osteoclasts are the sole bone resorbing cell in the body and their over activity is key in the development of osteoporosis. Osteoclastogenesis is mediated by receptor activator of nuclear factor κB ligand (RANKL) signalling pathways. Unsaturated fatty acids (UFA) are known to inhibit osteoclastogenesis by targeting RANKL signalling. However, the mechanisms of action remain unclear. Peroxisome proliferator activated receptors (PPARs) are a family of nuclear receptors, with three known isoforms (PPAR-α, PPAR-β/δ and PPAR-γ), that are known to bind UFAs and are expressed in osteoclasts. In this study, we aimed to determine how different families of UFAs activate PPARs and how PPAR activation influences osteoclast signalling. Human CD14+ monocytes were seeded into cluster plates with RANKL and macrophage colony stimulating factor (M-CSF) in the presence of PPAR agonists or different types of UFAs. All the PPAR agonists were shown to upregulate the activity of their respective receptors. Polyunsaturated fatty acids increased PPAR-α to a greater extent than monounsaturated fatty acids (MUFAs), which favoured PPAR-β/δ activation. All PPAR agonists inhibited osteoclastogenesis. The activation of RANKL signalling pathways and expression of key osteoclast genes were downregulated by PPAR agonists. This study reveals that PPAR activation can inhibit osteoclastogenesis through modulation of RANKL signalling.

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 PPARs in Liver Diseases and Cancer: Epigenetic Regulation by MicroRNAs

PPAR Research ◽  
2012 ◽  
Vol 2012 ◽  
pp. 1-16 ◽  
Author(s):  
Marion Peyrou ◽  
Pierluigi Ramadori ◽  
Lucie Bourgoin ◽  
Michelangelo Foti
Keyword(s):  
Liver Diseases ◽  
Metabolic Diseases ◽  
Viral Infections ◽  
Inflammatory Responses ◽  
Current Knowledge ◽  
Hepatocellular Adenoma ◽  
Peroxisome Proliferator ◽  
Cancer Therapies ◽  
Ppar Agonists ◽  
Expression And Activity

Peroxisome-proliferator-activated receptors (PPARs) are ligand-activated nuclear receptors that exert in the liver a transcriptional activity regulating a whole spectrum of physiological functions, including cholesterol and bile acid homeostasis, lipid/glucose metabolism, inflammatory responses, regenerative mechanisms, and cell differentiation/proliferation. Dysregulations of the expression, or activity, of specific PPAR isoforms in the liver are therefore believed to represent critical mechanisms contributing to the development of hepatic metabolic diseases, disorders induced by hepatic viral infections, and hepatocellular adenoma and carcinoma. In this regard, specific PPAR agonists have proven to be useful to treat these metabolic diseases, but for cancer therapies, the use of PPAR agonists is still debated. Interestingly, in addition to previously described mechanisms regulating PPARs expression and activity, microRNAs are emerging as new important regulators of PPAR expression and activity in pathophysiological conditions and therefore may represent future therapeutic targets to treat hepatic metabolic disorders and cancers. Here, we reviewed the current knowledge about the general roles of the different PPAR isoforms in common chronic metabolic and infectious liver diseases, as well as in the development of hepatic cancers. Recent works highlighting the regulation of PPARs by microRNAs in both physiological and pathological situations with a focus on the liver are also discussed.

Enrichment of IGF-1R and PPARγ signalling pathways in orbital inflammatory diseases: steps toward understanding pathogenesis

2021 ◽  
pp. bjophthalmol-2020-318330
Author(s):  
Rohan Verma ◽  
Dongseok Choi ◽  
Allison J Chen ◽  
Christina A Harrington ◽  
David J Wilson ◽  
...  
Keyword(s):  
Gene Expression ◽  
Inflammatory Diseases ◽  
Target Therapy ◽  
Signalling Pathways ◽  
Peroxisome Proliferator ◽  
Healthy Controls ◽  
Gene Expressions ◽  
Peroxisome Proliferator Activated Receptor ◽  
Orbital Inflammation ◽  
Wide Range

BackgroundOrbital inflammatory disease (OID) encompasses a wide range of pathology including thyroid-associated orbitopathy (TAO), granulomatosis with polyangiitis (GPA), sarcoidosis and non-specific orbital inflammation (NSOI), accounting for up to 6% of orbital diseases. Understanding the underlying pathophysiology of OID can improve diagnosis and help target therapy.AimsTo test the hypothesis that shared signalling pathways are activated in different forms of OID.MethodsIn this secondary analysis, pathway analysis was performed on the previously reported differentially expressed genes from orbital adipose tissue using patients with OID and healthy controls who were characterised by microarray. For the original publications, tissue specimens were collected from oculoplastic surgeons at 10 international centres representing four countries (USA, Canada, Australia and Saudi Arabia). Diagnoses were independently confirmed by two masked ocular pathologists (DJW, HEG). Gene expression profiling analysis was performed at the Oregon Health & Science University. Eighty-three participants were included: 25 with TAO, 6 with orbital GPA, 7 with orbital sarcoidosis, 25 with NSOI and 20 healthy controls.ResultsAmong the 83 subjects (mean (SD) age, 52.8 (18.3) years; 70% (n=58) female), those with OID demonstrated perturbation of the downstream gene expressions of the IGF-1R (MAPK/RAS/RAF/MEK/ERK and PI3K/Akt/mTOR pathways), peroxisome proliferator-activated receptor-γ (PPARγ), adipocytokine and AMPK signalling pathways compared with healthy controls. Specifically, GPA samples differed from controls in gene expression within the insulin-like growth factor-1 receptor (IGF-1R, PI3K-Akt (p=0.001), RAS (p=0.005)), PPARγ (p=0.002), adipocytokine (p=0.004) or AMPK (p=<0.001) pathways. TAO, sarcoidosis and NSOI samples were also found to have statistically significant differential gene expression in these pathways.ConclusionsAlthough OID includes a heterogenous group of pathologies, TAO, GPA, sarcoidosis and NSOI share enrichment of common gene signalling pathways, namely IGF-1R, PPARγ, adipocytokine and AMPK. Pathway analyses of gene expression suggest that other forms of orbital inflammation in addition to TAO may benefit from blockade of IGF-1R signalling pathways.

scholarly journals Effects of peroxisome proliferator activated receptors (PPAR)-γ and -α agonists on cochlear protection from oxidative stress

PLoS ONE ◽  
2017 ◽  
Vol 12 (11) ◽  
pp. e0188596 ◽  
Author(s):  
Marijana Sekulic-Jablanovic ◽  
Vesna Petkovic ◽  
Matthew B. Wright ◽  
Krystsina Kucharava ◽  
Nathan Huerzeler ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Peroxisome Proliferator ◽  
Ppar Γ ◽  
Peroxisome Proliferator Activated Receptors

scholarly journals Neuroprotective Mechanisms of PPARδ: Modulation of Oxidative Stress and Inflammatory Processes

PPAR Research ◽  
2011 ◽  
Vol 2011 ◽  
pp. 1-10 ◽  
Author(s):  
Caroline I. Schnegg ◽  
Mike E. Robbins
Keyword(s):  
Energy Homeostasis ◽  
Peroxisome Proliferator ◽  
Cellular Processes ◽  
Wide Range ◽  
Inflammatory Processes ◽  
The Central Nervous System ◽  
Chronic Injuries ◽  
Neuroprotective Efficacy ◽  
Anti Inflammatory ◽  
Peroxisome Proliferator Activated Receptors

Peroxisome proliferator-activated receptors (PPARα,δ, andγ) are ligand-activated transcription factors that regulate a wide range of cellular processes, including inflammation, proliferation, differentiation, metabolism, and energy homeostasis. All three PPAR subtypes have been identified in the central nervous system (CNS) of rodents. While PPARαand PPARγare expressed in more restricted areas of the CNS, PPARδis ubiquitously expressed and is the predominant subtype. Although data regarding PPARδare limited, studies have demonstrated that administration of PPARδagonists confers neuroprotection following various acute and chronic injuries to the CNS, such as stroke, multiple sclerosis, and Alzheimer's disease. The antioxidant and anti-inflammatory properties of PPARδagonists are thought to underly their neuroprotective efficacy. This review will focus on the putative neuroprotective benefits of therapeutically targeting PPARδin the CNS, and specifically, highlight the antioxidant and anti-inflammatory functions of PPARδagonists.

scholarly journals The Renoprotective Actions of Peroxisome Proliferator-Activated Receptors Agonists in Diabetes

PPAR Research ◽  
2012 ◽  
Vol 2012 ◽  
pp. 1-10 ◽  
Author(s):  
M. C. Thomas ◽  
K. A. Jandeleit-Dahm ◽  
C. Tikellis
Keyword(s):  
Cardiovascular Effects ◽  
Lipid Lowering ◽  
Peroxisome Proliferator ◽  
Oral Hypoglycaemic Agents ◽  
Diabetic Kidney ◽  
Critical Pathways ◽  
Patients With Diabetes ◽  
Ppar Agonists ◽  
Peroxisome Proliferator Activated Receptors ◽  
In The Diabetic Kidney

Pharmaceutical agonists of peroxisome proliferator-activated receptors (PPARs) are widely used in the management of type 2 diabetes, chiefly as lipid-lowering agents and oral hypoglycaemic agents. Although most of the focus has been placed on their cardiovascular effects, both positive and negative, these agents also have significant renoprotective actions in the diabetic kidney. Over and above action on metabolic control and effects on blood pressure, PPAR agonists also appear to have independent effects on a number of critical pathways that are implicated in the development and progression of diabetic kidney disease, including oxidative stress, inflammation, hypertrophy, and podocyte function. This review will examine these direct and indirect actions of PPAR agonists in the diabetic kidney and explore recent findings of clinical trials of PPAR agonists in patients with diabetes.

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