scholarly journals PPAR Ligands Function as Suppressors That Target Biological Actions of HMGB1

PPAR Research ◽  
2016 ◽  
Vol 2016 ◽  
pp. 1-10 ◽  
Author(s):  
Shibo Ying ◽  
Xiang Xiao ◽  
Tianhui Chen ◽  
Jianlin Lou
Keyword(s):  
High Mobility ◽  
Peroxisome Proliferator ◽  
Inflammatory Disorders ◽  
Extracellular Secretion ◽  
Anticancer Effects ◽  
Therapeutic Value ◽  
Intracellular Expression ◽  
Peroxisome Proliferator Activated Receptors ◽  
Ppar Ligands ◽  
Biological Actions

High mobility group box 1 (HMGB1), which has become one of the most intriguing molecules in inflammatory disorders and cancers and with which ligand-activated peroxisome proliferator-activated receptors (PPARs) are highly associated, is considered as a therapeutic target. Of particular interest is the fact that certain PPAR ligands have demonstrated their potent anti-inflammatory activities and potential anticancer effects. In this review article we summarize recent experimental evidence that PPAR ligands function as suppressors that target biological actions of HMGB1, including intracellular expression, receptor signaling cascades, and extracellular secretion of HMGB1 in cell lines and/or animal models. We also propose the possible mechanisms underlying PPAR involvement in inflammatory disorders and discuss the future therapeutic value of PPAR ligands targeting HMGB1 molecule for cancer prevention and treatment.

GLP-1-mediated delivery of the PPAR𝛼/𝛾 dual-agonist Tesaglitazar improves obesity and glucose metabolism in mice

2021 ◽  
Author(s):  
Carmelo Quarta ◽  
Kerstin Stemmer ◽  
Aaron Novikoff ◽  
Bin Yang ◽  
Felix Klingelhuber ◽  
...  
Keyword(s):  
Body Weight ◽  
Glucose Metabolism ◽  
Peroxisome Proliferator ◽  
Protein Targets ◽  
Beneficial Effects ◽  
Glucose And Lipid Metabolism ◽  
Therapeutic Value ◽  
Affect Body Weight ◽  
Peroxisome Proliferator Activated Receptors ◽  
Dual Agonist

Abstract Dual-agonists activating the peroxisome proliferator-activated receptors alpha and gamma (PPAR𝛼/𝛾) have shown beneficial effects on glucose and lipid metabolism in patients with type 2 diabetes, but their development was discontinued due to unfavorable cardiovascular and/or renal effects. Here we report the design and preclinical evaluation of a molecule that covalently links the PPAR𝛼/𝛾 dual-agonist Tesaglitazar to GLP-1 to allow for the GLP-1 receptor-dependent delivery of Tesaglitazar. GLP-1/Tesaglitazar does not differ from matched GLP-1 in GLP-1R signaling, but shows GLP-1R-dependent PPAR𝛾-RXR heterodimerization with enhanced efficacy to improve body weight, food intake, and glucose metabolism relative to GLP-1 or Tesaglitazar in mice with diet- and genetically-induced obesity. The conjugate fails to affect body weight and glucose metabolism in GLP-1R knockout (ko) mice and shows preserved effects in DIO mice at doses subthreshold for GLP-1 and Tesaglitazar to improve metabolism. Consistent with the GLP-1R expression pattern, LC/MS-based proteomics identified a series of novel PPAR protein targets in the hypothalamus that are acutely upregulated by Tesaglitazar and by GLP-1/Tesaglitazar, but not by treatment with GLP-1. Collectively, our data show that GLP-1/Tesaglitazar improves energy and glucose metabolism with superior efficacy to GLP-1 or Tesaglitazar alone and suggest that this conjugate holds therapeutic value to treat hyperglycemia and insulin resistance.

scholarly journals Peroxisome-proliferator-activated receptors and the control of levels of prostaglandin-endoperoxide synthase 2 by arachidonic acid in the bovine uterus

2007 ◽  
Vol 406 (1) ◽  
pp. 175-183 ◽  
Author(s):  
E. Linda R. Sheldrick ◽  
Kamila Derecka ◽  
Elaine Marshall ◽  
Evonne C. Chin ◽  
Louise Hodges ◽  
...  
Keyword(s):  
Arachidonic Acid ◽  
Stromal Cells ◽  
Time Course ◽  
Nuclear Factor Κb ◽  
Peroxisome Proliferator ◽  
Endometrial Stromal Cells ◽  
Prostaglandin Endoperoxide ◽  
Prostaglandin Endoperoxide Synthase ◽  
Peroxisome Proliferator Activated Receptors ◽  
Ppar Ligands

Arachidonic acid is a potential paracrine agent released by the uterine endometrial epithelium to induce PTGS2 [PG (prostaglandin)-endoperoxide synthase 2] in the stroma. In the present study, bovine endometrial stromal cells were used to determine whether PTGS2 is induced by arachidonic acid in stromal cells, and to investigate the potential role of PPARs (peroxisome-proliferator-activated receptors) in this effect. Arachidonic acid increased PTGS2 levels up to 7.5-fold within 6 h. The cells expressed PPARα and PPARδ (also known as PPARβ) (but not PPARγ). PTGS2 protein level was increased by PPAR agonists, including polyunsaturated fatty acids, synthetic PPAR ligands, PGA1 and NSAIDs (non-steroidal anti-inflammatory drugs) with a time course resembling that of arachidonic acid. Use of agonists and antagonists indicated PPARα (but not PPARδ or PPARγ) was responsible for PTGS2 induction. PTGS2 induction by arachidonic acid did not require PG synthesis. PTGS2 levels were increased by the PKC (protein kinase C) activators 4β-PMA and PGF2α, and the effects of arachidonic acid, NSAIDs, synthetic PPAR ligands and 4β-PMA were blocked by PKC inhibitors. This is consistent with PPAR phosphorylation by PKC. Induction of PTGS2 protein by 4β-PMA in the absence of a PPAR ligand was decreased by the NF-κB (nuclear factor κB) inhibitors MG132 and parthenolide, suggesting that PKC acted through NF-κB in addition to PPAR phosphorylation. Use of NF-κB inhibitors allowed the action of arachidonic acid as a PPAR agonist to be dissociated from an effect through PKC. The results are consistent with the hypothesis that arachidonic acid acts via PPARα to increase PTGS2 levels in bovine endometrial stromal cells.

scholarly journals Activation of Peroxisome Proliferator-Activated Receptorγby Rosiglitazone Inhibits Lipopolysaccharide-Induced Release of High Mobility Group Box 1

2012 ◽  
Vol 2012 ◽  
pp. 1-9 ◽  
Author(s):  
Jung Seok Hwang ◽  
Eun Sil Kang ◽  
Sun Ah Ham ◽  
Taesik Yoo ◽  
Hanna Lee ◽  
...  
Keyword(s):  
Cellular Response ◽  
Survival Rates ◽  
High Mobility ◽  
Inhibitory Effect ◽  
High Mobility Group ◽  
Raw 264.7 Cells ◽  
Signal Molecules ◽  
Peroxisome Proliferator ◽  
Treatment And Prevention ◽  
Peroxisome Proliferator Activated Receptors

Peroxisome proliferator-activated receptors (PPARs) are shown to modulate the pathological status of sepsis by regulating the release of high mobility group box 1 (HMGB1), a well-known late proinflammatory mediator of sepsis. Ligand-activated PPARs markedly inhibited lipopolysaccharide- (LPS) induced release of HMGB1 in RAW 264.7 cells. Among the ligands of PPAR, the effect of rosiglitazone, a specific ligand for PPARγ, was superior in the inhibition of HMGB1 release induced by LPS. This effect was observed in cells that received rosiglitazone before LPS or after LPS treatment, indicating that rosiglitazone is effective in both treatment and prevention. Ablation of PPARγwith small interfering RNA or GW9662-mediated inhibition of PPARγabolished the effect of rosiglitazone on HMGB1 release. Furthermore, the overexpression of PPARγmarkedly potentiated the inhibitory effect of rosiglitazone on HMGB1 release. In addition, rosiglitazone inhibited LPS-induced expression of Toll-like receptor 4 signal molecules, suggesting a possible mechanism by which rosiglitazone modulates HMGB1 release. Notably, the administration of rosiglitazone to mice improved survival rates in an LPS-induced animal model of endotoxemia, where reduced levels of circulating HMGB1 were demonstrated. Taken together, these results suggest that PPARs play an important role in the cellular response to inflammation by inhibiting HMGB1 release.

The Journey of Thiazolidinediones as Modulators of PPARs for the Management of Diabetes: A Current Perspective

2019 ◽  
Vol 25 (23) ◽  
pp. 2540-2554 ◽  
Author(s):  
Waquar Ahsan
Keyword(s):  
Peroxisome Proliferator ◽  
Expression Of Genes ◽  
Current Perspective ◽  
Drug Designing ◽  
Peroxisome Proliferator Activated Receptors ◽  
To Come ◽  
Ppar Ligands ◽  
A Current

Peroxisome Proliferator-Activated Receptors (PPARs) also known as glitazone receptors are a family of receptors that regulate the expression of genes and have an essential role in carbohydrate, lipid and protein metabolism apart from other functions. PPARs come in 3 sub-types: PPAR-α, PPAR-β/δ and PPAR-γ - with PPAR-γ having 2 isoforms - γ1 and γ2. Upon activation, the PPARs regulate the transcription of various genes involved in lipid and glucose metabolism, adipocyte differentiation, increasing insulin sensitivity, prevention of oxidative stress and to a certain extent, modulation of immune responses via macrophages that have been implicated in the pathogenesis of insulin resistance. Hence, PPARs are an attractive molecular target for designing new anti-diabetic drugs. This has led to a boost in the research efforts directed towards designing of PPAR ligands - particularly ones that can selectively and specifically activate one or more of the PPAR subtypes. Though, PPAR- γ full agonists such as Thiazolidinediones (TZDs) are well established agents for dyslipidemia and type 2 diabetes mellitus (T2D), the side effect profile associated with TZDs has potentiated an imminent need to come up with newer agents that act through this pathway. Several newer derivatives having TZD scaffold have been designed using structure based drug designing technique and computational tools and tested for their PPAR binding affinity and efficacy in combating T2D and some have shown promising activities. This review would focus on the role of PPARs in the management of T2D; recently reported TZD derivatives which acted as agonists of PPAR- γ and its subtypes and are potentially useful in the new drug discovery for the disease.

PPAR Ligands Containing Stilbene Scaffold

2019 ◽  
Vol 19 (19) ◽  
pp. 1599-1610 ◽  
Author(s):  
Marialuigia Fantacuzzi ◽  
Barbara De Filippis ◽  
Rosa Amoroso ◽  
Letizia Giampietro
Keyword(s):  
The Body ◽  
Peroxisome Proliferator ◽  
Signaling Proteins ◽  
Health Promoting ◽  
Pparγ Agonists ◽  
Anti Inflammatory ◽  
Peroxisome Proliferator Activated Receptors ◽  
Pharmacological Potential ◽  
Ppar Ligands ◽  
New Generation

: Peroxisome proliferator-activated receptors (PPARs) are transcriptional factors which belong to the ligand-activated nuclear receptor superfamily. They are ubiquitously expressed throughout the body. So far, three major subtypes have been identified, PPARα, PPARβ/δ and PPARγ. They are crucial for lipid and glucose metabolism and are also involved in the regulation of several types of tumors, inflammation, cardiovascular diseases and infertility. The importance of these transcription factors in physiology and pathophysiology has been largely investigated. : Synthetic PPAR ligands are widely used in the treatment of dyslipidemia (e.g. fibrates - PPARα activators) or in diabetes mellitus (e.g. thiazolidinediones - PPARγ agonists) while a new generation of dual agonists reveals hypolipemic, hypotensive, antiatherogenic, anti-inflammatory and anticoagulant action. Many natural ligands, including polyphenolic compounds, influence the expression of these receptors. They have several health-promoting properties, including antioxidant, anti-inflammatory, and antineoplastic activities. Resveratrol, a stilbene polyphenol, is a biological active modulator of several signaling proteins, including PPARs. Given the enormous pharmacological potential of resveratrol, stilbene-based medicinal chemistry had a rapid increase covering various areas of research. : The present review discusses ligands of PPARs that contain stilbene scaffold and summarises the different types of compounds on the basis of chemical structure.

A Mechanistic approach of Peroxisome Proliferator-Activated Receptors and its subtypes on Clinical and preclinical model of Neurodegenerative disorders

2021 ◽  
pp. 3967-3975
Author(s):  
Jinu Avarachan ◽  
Anitta Augustine ◽  
Pallavi Mahadev Shinde ◽  
Venkatesh Gunasekaran
Keyword(s):  
Neurodegenerative Disorders ◽  
Symptomatic Relief ◽  
Preclinical Model ◽  
Peroxisome Proliferator ◽  
Mechanistic Approach ◽  
Peroxisome Proliferator Activated Receptors ◽  
Nuclear Receptor Family ◽  
Preclinical And Clinical Studies ◽  
Ppar Ligands

Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors, belonging to the nuclear receptor family, which has high expression of three structurally homologous PPARs isotypes (PPARα, PPARβ/δ, and PPARγ) in brain. Several studies have discovered role of PPARs in oxidative stress, mitochondrial dysfunction, neuroinflammation and production of the toxic proteins in various neurodegenerative disorders such as Parkinson disease, Alzheimer’s disease, Huntington disease, Amyotrophic Lateral Sclerosis, Multiple sclerosis etc. Currently available drugs provide symptomatic relief, but disease progression cannot be stopped, because of their unclear molecular approach. The ability of PPAR to modulate the pathways involved in these conditions paved a path for future studies. Due to increasing challenges to treat central nervous system related disorders, hence PPARs have attracted much attention nowadays. In this review, we discussed various mechanisms of PPARs subtypes in neurodegenerative disorders. We congregate the molecular evidences which support PPARs as a therapeutic target to treat neurodegenerative disorders from preclinical and clinical studies and provide a basis for the potential therapeutic use of PPAR ligands in human diseases.

scholarly journals Mitochondria, PPARs, and Cancer: Is Receptor-Independent Action of PPAR Agonists a Key?

PPAR Research ◽  
2008 ◽  
Vol 2008 ◽  
pp. 1-10 ◽  
Author(s):  
Roberto Scatena ◽  
Patrizia Bottoni ◽  
Bruno Giardina
Keyword(s):  
Cell Differentiation ◽  
Side Effects ◽  
Nuclear Receptors ◽  
Cancer Biology ◽  
Experimental Models ◽  
Peroxisome Proliferator ◽  
Ppar Agonists ◽  
Peroxisome Proliferator Activated Receptors ◽  
Reciprocal Influences ◽  
Ppar Ligands

Before the discovery of peroxisome proliferator activated receptors (PPARs), it was well known that certain drugs considered as classical PPAR-alpha agonists induced hepatocarcinoma or peroxisome proliferation in rodents. These drugs were derivatives of fibric acid, and they included clofibrate, bezafibrate, and fenofibrate. However, such toxicity has never been observed in human patients treated with these hypolipidemic drugs. Thiazolidinediones are a new class of PPAR activators showing greater specificity for the isoform of PPARs. These drugs are used as insulin sensitizers in the treatment of type II diabetes. In addition, they have been shown to induce cell differentiation or apoptosis in various experimental models of cancer. PPAR- ligands have also been shown to induce cancer cell differentiation and, paradoxically, PPAR- drug activators have been reported to act as carcinogens. The confusing picture that emerges from these data is further complicated by the series of intriguing side effects observed following administration of pharmacological PPAR ligands (rhabdomyolysis, liver and heart toxicity, anemia, leucopenia). These side effects cannot be easily explained by simple interactions between the drug and nuclear receptors. Rather, these side effects seem to indicate that the ligands have biological activity independent of the nuclear receptors. Considering the emerging role of mitochondria in cancer and the potential metabolic connections between this organelle and PPAR physiology, characterization of the reciprocal influences is fundamental not only for a better understanding of cancer biology, but also for more defined pharmacotoxicological profiles of drugs that modulate PPARs.

scholarly journals Nuclear Control of the Inflammatory Response in Mammals by Peroxisome Proliferator-Activated Receptors

PPAR Research ◽  
2013 ◽  
Vol 2013 ◽  
pp. 1-23 ◽  
Author(s):  
Stéphane Mandard ◽  
David Patsouris
Keyword(s):  
Inflammatory Response ◽  
Protective Role ◽  
Peroxisome Proliferator ◽  
Nuclear Control ◽  
Inflammatory Bowel ◽  
Peroxisome Proliferator Activated Receptors ◽  
Ppar Ligands ◽  
The Impact

Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors that play pivotal roles in the regulation of a very large number of biological processes including inflammation. Using specific examples, this paper focuses on the interplay between PPARs and innate immunity/inflammation and, when possible, compares it among species. We focus on recent discoveries establishing how inflammation and PPARs interact in the context of obesity-induced inflammation and type 2 diabetes, mostly in mouse and humans. We illustrate that PPARγability to alleviate obesity-associated inflammation raises an interesting pharmacologic potential. In the light of recent findings, the protective role of PPARαand PPARβ/δagainst the hepatic inflammatory response is also addressed. While PPARs agonists are well-established agents that can treat numerous inflammatory issues in rodents and humans, surprisingly very little has been described in other species. We therefore also review the implication of PPARs in inflammatory bowel disease; acute-phase response; and central, cardiac, and endothelial inflammation and compare it along different species (mainly mouse, rat, human, and pig). In the light of the data available in the literature, there is no doubt that more studies concerning the impact of PPAR ligands in livestock should be undertaken because it may finally raise unconsidered health and sanitary benefits.

scholarly journals The Role of Peroxisome Proliferator-Activated Receptors in the Development and Physiology of Gametes and Preimplantation Embryos

PPAR Research ◽  
2008 ◽  
Vol 2008 ◽  
pp. 1-7 ◽  
Author(s):  
Jaou-Chen Huang
Keyword(s):  
Germ Cells ◽  
Current Knowledge ◽  
Polycystic Ovary ◽  
Preimplantation Embryos ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptors ◽  
X Receptors ◽  
Ppar Ligands

In several species, a family of nuclear receptors, the peroxisome proliferator-activated receptors (PPARs) composed of three isotypes, is expressed in somatic cells and germ cells of the ovary as well as the testis. Invalidation of these receptors in mice or stimulation of these receptors in vivo or in vitro showed that each receptor has physiological roles in the gamete maturation or the embryo development. In addition, synthetic PPARγligands are recently used to induce ovulation in women with polycystic ovary disease. These results reveal the positive actions of PPAR in reproduction. On the other hand, xenobiotics molecules (in herbicides, plasticizers, or components of personal care products), capable of activating PPAR, may disrupt normal PPAR functions in the ovary or the testis and have consequences on the quality of the gametes and the embryos. Despite the recent data obtained on the biological actions of PPARs in reproduction, relatively little is known about PPARs in gametes and embryos. This review summarizes the current knowledge on the expression and the function of PPARs as well as their partners, retinoid X receptors (RXRs), in germ cells and preimplantation embryos. The effects of natural and synthetic PPAR ligands will also be discussed from the perspectives of reproductive toxicology and assisted reproductive technology.

scholarly journals PPARαLigands as Antitumorigenic and Antiangiogenic Agents

PPAR Research ◽  
2008 ◽  
Vol 2008 ◽  
pp. 1-8 ◽  
Author(s):  
Ambra Pozzi ◽  
Jorge H. Capdevila
Keyword(s):  
Target Genes ◽  
Suppressor Gene ◽  
Migration And Invasion ◽  
Antiangiogenic Agents ◽  
Peroxisome Proliferator ◽  
Cell Functions ◽  
Obesity And Diabetes ◽  
Brown Adipose ◽  
Peroxisome Proliferator Activated Receptors ◽  
Ppar Ligands

Peroxisome proliferator-activated receptors (PPARs) belong to the nuclear receptor family of ligand-activated transcription factors. This subfamily is composed of three members—PPARα, PPARδ, and PPARγ—that differ in their cell and tissue distribution as well as in their target genes. PPARαis abundantly expressed in liver, brown adipose tissue, kidney, intestine, heart, and skeletal muscle; and its ligands have been used to treat diseases such as obesity and diabetes. The recent finding that members of the PPAR family, including the PPARα, are expressed by tumor and endothelial cells together with the observation that PPAR ligands regulate cell growth, survival, migration, and invasion, suggested that PPARs also play a role in cancer. In this review, we focus on the contribution of PPARαto tumor and endothelial cell functions and provide compelling evidence that PPARαcan be viewed as a new class of ligand activated tumor “suppressor” gene with antiangiogenic and antitumorigenic activities. Given that PPAR ligands are currently used in medicine as hypolipidemic drugs with excellent tolerance and limited toxicity, PPARαactivation might offer a novel and potentially low-toxic approach for the treatment of tumor-associated angiogenesis and cancer.

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