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 Beyond the Canonical Endocannabinoid System. A Screening of PPAR Ligands as FAAH Inhibitors

2020 ◽  
Vol 21 (19) ◽  
pp. 7026
Author(s):  
Leonardo Brunetti ◽  
Antonio Carrieri ◽  
Luca Piemontese ◽  
Paolo Tortorella ◽  
Fulvio Loiodice ◽  
...  
Keyword(s):  
Endocannabinoid System ◽  
Docking Study ◽  
Binding Mode ◽  
Peroxisome Proliferator ◽  
System A ◽  
Ppar Agonists ◽  
Peroxisome Proliferator Activated Receptors ◽  
Ppar Ligands ◽  
Faah Inhibitors ◽  
Further Development

In recent years, Peroxisome Proliferator-Activated Receptors (PPARs) have been connected to the endocannabinoid system. These nuclear receptors indeed mediate the effects of anandamide and similar substances such as oleoyl-ethanolamide and palmitoyl-ethanolamide. An increasing body of literature describing the interactions between the endocannabinoid system and PPARs has slowly but surely been accumulating over the past decade, and a multitarget approach involving these receptors and endocannabinoid degrading enzyme FAAH has been proposed for the treatment of inflammatory states, cancer, and Alzheimer’s disease. The lack of knowledge about compounds endowed with such an activity profile therefore led us to investigate a library of readily available, well-characterized PPAR agonists that we had synthesized over the years in order to find a plausible lead compound for further development. Moreover, we propose a rationalization of our results via a docking study, which sheds some light on the binding mode of these PPAR agonists to FAAH and opens the way for further research in this field.

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 PPARs as Nuclear Receptors for Nutrient and Energy Metabolism

Molecules ◽  
2019 ◽  
Vol 24 (14) ◽  
pp. 2545 ◽  
Author(s):  
Fan Hong ◽  
Shijia Pan ◽  
Yuan Guo ◽  
Pengfei Xu ◽  
Yonggong Zhai
Keyword(s):  
Energy Metabolism ◽  
Nuclear Receptors ◽  
Metabolic Networks ◽  
Energy Homeostasis ◽  
Whole Body ◽  
Therapeutic Effects ◽  
Peroxisome Proliferator ◽  
Metabolic States ◽  
Ppar Agonists ◽  
Peroxisome Proliferator Activated Receptors

It has been more than 36 years since peroxisome proliferator-activated receptors (PPARs) were first recognized as enhancers of peroxisome proliferation. Consequently, many studies in different fields have illustrated that PPARs are nuclear receptors that participate in nutrient and energy metabolism and regulate cellular and whole-body energy homeostasis during lipid and carbohydrate metabolism, cell growth, cancer development, and so on. With increasing challenges to human health, PPARs have attracted much attention for their ability to ameliorate metabolic syndromes. In our previous studies, we found that the complex functions of PPARs may be used as future targets in obesity and atherosclerosis treatments. Here, we review three types of PPARs that play overlapping but distinct roles in nutrient and energy metabolism during different metabolic states and in different organs. Furthermore, research has emerged showing that PPARs also play many other roles in inflammation, central nervous system-related diseases, and cancer. Increasingly, drug development has been based on the use of several selective PPARs as modulators to diminish the adverse effects of the PPAR agonists previously used in clinical practice. In conclusion, the complex roles of PPARs in metabolic networks keep these factors in the forefront of research because it is hoped that they will have potential therapeutic effects in future applications.

scholarly journals Nuclear Receptors in Myocardial and Cerebral Ischemia—Mechanisms of Action and Therapeutic Strategies

2021 ◽  
Vol 22 (22) ◽  
pp. 12326
Author(s):  
Joanna Rzemieniec ◽  
Laura Castiglioni ◽  
Paolo Gelosa ◽  
Majeda Muluhie ◽  
Benedetta Mercuriali ◽  
...  
Keyword(s):  
Cardiovascular Diseases ◽  
Nuclear Receptors ◽  
Mechanisms Of Action ◽  
Experimental Models ◽  
Therapeutic Window ◽  
Peroxisome Proliferator ◽  
Aryl Hydrocarbon ◽  
Heart Ischemia ◽  
Peroxisome Proliferator Activated Receptors ◽  
The Brain

Nearly 18 million people died from cardiovascular diseases in 2019, of these 85% were due to heart attack and stroke. The available therapies although efficacious, have narrow therapeutic window and long list of contraindications. Therefore, there is still an urgent need to find novel molecular targets that could protect the brain and heart against ischemia without evoking major side effects. Nuclear receptors are one of the promising targets for anti-ischemic drugs. Modulation of estrogen receptors (ERs) and peroxisome proliferator-activated receptors (PPARs) by their ligands is known to exert neuro-, and cardioprotective effects through anti-apoptotic, anti-inflammatory or anti-oxidant action. Recently, it has been shown that the expression of aryl hydrocarbon receptor (AhR) is strongly increased after brain or heart ischemia and evokes an activation of apoptosis or inflammation in injury site. We hypothesize that activation of ERs and PPARs and inhibition of AhR signaling pathways could be a promising strategy to protect the heart and the brain against ischemia. In this Review, we will discuss currently available knowledge on the mechanisms of action of ERs, PPARs and AhR in experimental models of stroke and myocardial infarction and future perspectives to use them as novel targets in cardiovascular diseases.

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 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.

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 PPAR: The Portrait of a Target Ally to Cancer Chemopreventive Agents

PPAR Research ◽  
2008 ◽  
Vol 2008 ◽  
pp. 1-10 ◽  
Author(s):  
Ioannis Sainis ◽  
Katerina Vareli ◽  
Vasilios Karavasilis ◽  
Evangelos Briasoulis
Keyword(s):  
Cell Differentiation ◽  
Adipocyte Differentiation ◽  
Peroxisome Proliferator ◽  
Biological Processes ◽  
Peroxisome Proliferator Activated Receptor ◽  
Chemopreventive Agents ◽  
Bioactive Natural Products ◽  
Great Relevance ◽  
Ppar Ligands ◽  
Tumor Types

Peroxisome proliferator-activated receptor-gamma (PPAR), one of three ligand-activated transcription factors named PPAR, has been identified as a molecular target for cancer chemopreventive agents. PPAR was initially understood as a regulator of adipocyte differentiation and glucose homeostasis while later on, it became evident that it is also involved in cell differentiation, apoptosis, and angiogenesis, biological processes which are deregulated in cancer. It is now established that PPAR ligands can induce cell differentiation and yield early antineoplastic effects in several tumor types. Moreover, several bioactive natural products with cancer protecting potential are shown to operate through activation of PPAR. Overall, PPAR appears to be a prevalent target ally to cancer chemopreventive agents and therefore pursuing research in this area is of great relevance.

scholarly journals PPARs in Calorie Restricted and Genetically Long-Lived Mice

PPAR Research ◽  
2007 ◽  
Vol 2007 ◽  
pp. 1-7 ◽  
Author(s):  
Michal M. Masternak ◽  
Andrzej Bartke
Keyword(s):  
Transcription Factors ◽  
Energy Metabolism ◽  
Nuclear Receptors ◽  
Calorie Restriction ◽  
Insulin Action ◽  
Peroxisome Proliferator ◽  
Physiological Functions ◽  
Multiple Organs ◽  
Longevity Genes ◽  
Peroxisome Proliferator Activated Receptors

Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear receptors superfamily. The three subtypes, PPARα, PPARγ, and PPARβ/δ, are expressed in multiple organs. These transcription factors regulate different physiological functions such as energy metabolism (including lipid and carbohydrate metabolism), insulin action, and immunity and inflammation, and apparently also act as important mediators of longevity and aging. Calorie restriction (CR) is the most effective intervention known to delay aging and increase lifespan. Calorie restriction affects the same physiological functions as PPARs. This review summarizes recent findings on the effects of CR and aging on the expression of PPARγ,α, andβ/δin mice and discusses possible involvement of PPARs in mediating the effects of murine longevity genes. The levels of PPARs change with age and CR appears to prevent these alterations which make “PPARs-CR-AGING” dependence of considerable interest.

scholarly journals Regulation of Glial Cell Functions by PPAR- Natural and Synthetic Agonists

PPAR Research ◽  
2008 ◽  
Vol 2008 ◽  
pp. 1-10 ◽  
Author(s):  
Antonietta Bernardo ◽  
Luisa Minghetti
Keyword(s):  
Therapeutic Potential ◽  
Experimental Models ◽  
Brain Inflammation ◽  
Peroxisome Proliferator ◽  
Protective Effects ◽  
Peroxisome Proliferator Activated Receptor ◽  
Cell Functions ◽  
Parkinson’S Diseases ◽  
Ppar Agonists ◽  
Anti Inflammatory

In the recent years, the peroxisome proliferator-activated receptor- (PPAR-), a well known target for type II diabetes treatment, has received an increasing attention for its therapeutic potential in inflammatory and degenerative brain disorders. PPAR- agonists, which include naturally occurring compounds (such as long chain fatty acids and the cyclopentenone prostaglandin 15-deoxy prostaglandin ), and synthetic agonists (among which the thiazolidinediones and few nonsteroidal anti-inflammatory drugs) have shown anti-inflammatory and protective effects in several experimental models of Alzheimer's and Parkinson's diseases, amyotrophic lateral sclerosis, multiple sclerosis and stroke, as well as in few clinical studies. The pleiotropic effects of PPAR- agonists are likely to be mediated by several mechanisms involving anti-inflammatory activities on peripheral immune cells (macrophages and lymphocytes), as well as direct effects on neural cells including cerebral vascular endothelial cells, neurons, and glia. In the present article, we will review the recent findings supporting a major role for PPAR- agonists in controlling neuroinflammation and neurodegeneration through their activities on glial cells, with a particular emphasis on microglial cells as major macrophage population of the brain parenchyma and main actors in brain inflammation.

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