scholarly journals Peroxisome Proliferator-Activated Receptor -β/δ, -γAgonists and Resveratrol Modulate Hypoxia Induced Changes in Nuclear Receptor Activators of Muscle Oxidative Metabolism

PPAR Research ◽  
2010 ◽  
Vol 2010 ◽  
pp. 1-13 ◽  
Author(s):  
Timothy R. H. Regnault ◽  
Lin Zhao ◽  
Jacky S. S. Chiu ◽  
Stephanie K. Gottheil ◽  
Allison Foran ◽  
...  
Keyword(s):  
Insulin Sensitivity ◽  
Oxidative Metabolism ◽  
Intrauterine Growth Restriction ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Ppar Γ ◽  
Hypoxia Adaptation ◽  
Induced Changes ◽  
Ppar Pathway

PPAR-α, PPAR-β, and PPAR-γ, and RXR in conjunction with PGC-1α and SIRT1, activate oxidative metabolism genes determining insulin sensitivity. In utero, hypoxia is commonly observed in Intrauterine Growth Restriction (IUGR), and reduced insulin sensitivity is often observed in these infants as adults. We sought to investigate how changes in oxygen tension might directly impact muscle PPAR regulation of oxidative genes. Following eight days in culture at 1% oxygen, C2C12muscle myoblasts displayed a reduction of PGC-1α, PPAR-α, and RXR-α mRNA, as well as CPT-1b and UCP-2 mRNA. SIRT1 and PGC-1α protein was reduced, and PPAR-γ protein increased. The addition of a PPAR-β agonist (L165,041) for the final 24 hours of 1% treatment resulted in increased levels of UCP-2 mRNA and protein whereas Rosiglitazone induced SIRT1, PGC-1α, RXR-α, PPAR-α, CPT-1b, and UCP-2 mRNA and SIRT1 protein. Under hypoxia, Resveratrol induced SIRT1, RXR-α, PPAR-α mRNA, and PPAR-γ and UCP-2 protein. These findings demonstrate that hypoxia alters the components of the PPAR pathway involved in muscle fatty acid oxidative gene transcription and translation. These results have implications for understanding selective hypoxia adaptation and how it might impact long-term muscle oxidative metabolism and insulin sensitivity.

Evolution of Peroxisome Proliferator-Activated Receptor Agonists

2007 ◽  
Vol 41 (6) ◽  
pp. 973-983 ◽  
Author(s):  
Feng Chang ◽  
Linda A Jaber ◽  
Helen D Berlie ◽  
Mary Beth O'Connell
Keyword(s):  
Metabolic Syndrome ◽  
Insulin Sensitivity ◽  
Adverse Effects ◽  
Phase Ii ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Metabolism Regulation ◽  
Ppar Γ ◽  
The Metabolic Syndrome ◽  
Phase Ii And Iii

OBJECTIVE: To discuss the evolution of peroxisome proliferator-activated receptor (PPAR) agonists from single site to multiple subtype or partial agonists for the treatment of type 2 diabetes, dyslipidemia, obesity, and the metabolic syndrome. DATA SOURCES: Information was obtained from MEDLINE (1966-March 2007) using search terms peroxisome proliferator-activated receptor agonist, PPAR dual agonist, PPAR α/γ agonist, PPAR pan agonist, partial PPAR, and the specific compound names. Other sources included pharmaceutical companies, the Internet, and the American Diabetes Association 64th-66th Scientific Sessions abstract books. STUDY SELECTION AND DATA EXTRACTION: Animal data, abstracts, clinical trials, and review articles were reviewed and summarized. DATA SYNTHESIS: PPAR α, γ, and δ receptors play an important role in lipid metabolism, regulation of adipocyte proliferation and differentiation, and insulin sensitivity. The PPAR dual agonists were developed to combine the triglyceride lowering and high-density lipoprotein cholesterol elevation from the PPAR-α agonists (fibrates) with the insulin sensitivity improvement from the PPAR-γ agonists (thiazolidinediones). Although the dual agonists reduced hemoglobin A1C(A1C) and improved the lipid profile, adverse effects led to discontinued development. Currently, PPAR-γ agonists (GW501516 in Phase I trials), partial PPAR-γ agonists (metaglidasen in Phase II and III trials), and pan agonists (α, γ, δ netoglitazone in Phase II and III trials) with improved cell and tissue selectivity are undergoing investigation to address multiple aspects of the metabolic syndrome with a single medication. By decreasing both A1C and triglycerides, metaglidasen did improve multiple aspects of the metabolic syndrome with fewer adverse effects than compared with placebo. Metaglidasen is now being compared with pioglitazone. CONCLUSIONS: Influencing the various PPARs results in improved glucose, lipid, and weight management, with effects dependent on full or partial agonist activity at single or multiple receptors. Although the dual PPAR compounds have been associated with unacceptable toxicities, new PPAR agonist medications continue to be developed and investigated to discover a safe drug with benefits in multiple disease states.

scholarly journals Identification of Novel Drug-Like Compounds from Momordica cymbalaria as PPAR-γ Agonists: A Molecular Docking Study

2019 ◽  
Vol 8 (2) ◽  
pp. 71-74
Author(s):  
E. Abbirami ◽  
M. Selvakumar
Keyword(s):  
Molecular Docking ◽  
Insulin Sensitivity ◽  
Binding Affinity ◽  
Docking Study ◽  
Peroxisome Proliferator ◽  
Molecular Docking Study ◽  
Peroxisome Proliferator Activated Receptor ◽  
Ppar Γ ◽  
Proliferation And Differentiation ◽  
Novel Drug

Peroxisome Proliferator-Activated Receptor – γ (PPARγ) is a ligand-activated transcription factor, has become a main target for the treatment of diabetes. It is a member of the nuclear receptor superfamily that regulate the gene expression of proteins involved in glucose, lipid metabolism, adipocyte proliferation and differentiation and insulin sensitivity. Thiazolidinediones (TZDs) are one important class of synthetic agonists of PPAR-γ. TZDs are antidiabetic agents that target adipose tissue and improve insulin sensitivity, and they are currently being used in the treatment of type 2 diabetes. This work was designed to find out the bioactive compounds from Momordica cymbalaria that have the ability to stimulate the PPAR-γ using molecular docking procedure. Six metabolites namely 2-Methoxy-4-vinylphenol, Guaiacol, Carbinoxamine maleate, Azulene, 4N Ethylcytosine and Methyl cinnamate were docked with PPAR-γ using AutoDock and the results were determined using binding affinity. Among the six compounds three compounds (Carbinoxamine maleate, 2-Methoxy-4-vinylphenol and 4N Ethylcytosine) showed significant binding affinity towards the PPAR-γ. Based on the findings of this study these phytochemicals can serve as source of anti-diabetic drugs via agonizing PPAR-γ.

scholarly journals In silico molecular docking studies of some phytochemicals against peroxisome-proliferator activated receptor gamma (PPAR-γ)

2018 ◽  
Vol 5 (2) ◽  
pp. 001-005
Author(s):  
H. A. Ahmed ◽  
I. Y. Alkali
Keyword(s):  
Molecular Docking ◽  
Insulin Sensitivity ◽  
Binding Affinity ◽  
Docking Studies ◽  
Peroxisome Proliferator ◽  
Autodock Vina ◽  
Peroxisome Proliferator Activated Receptor ◽  
Standard Drug ◽  
Molecular Docking Studies ◽  
Ppar Γ

Peroxisome Proliferator-Activated Receptor-γ (PPAR-γ) is a ligand-activated transcription factor and a member of the nuclear receptor superfamily that regulate the gene expression of proteins involved in glucose, lipid metabolism, adipocyte proliferation and differentiation and insulin sensitivity. Thiazolidinediones (TZDs) are one important class of synthetic agonists of PPAR-γ. TZDs are antidiabetic agents that target adipose tissue and improve insulin sensitivity, and they are currently being used in the treatment of type 2 diabetes. The study was carried out in order to discover new phytochemicals that have the ability to stimulate the PPAR-γ using molecular docking studies. AutoDock vina was used as molecular-docking tool in order to carry out the docking simulations. Nine phytochemicals namely plumbagin, quercetin, isovitexin, mangiferin, syringin, lupe-20-ene-3-one, purine 2, 6-dione, diosmetin and β sitosterol and pioglitazone a standard drug were docked against PPAR-γ using AutoDock vina and the results were analyzed using binding affinity. The results revealed that the compounds have significant binding affinity towards the PPAR-γ comparable to pioglitazone the standard drug. Based on the findings of this study these phytochemicals can serve as source of antidiabetic drugs via the mechanism of inhibition of PPAR-γ.

Dual PPARα/γ activation provides enhanced improvement of insulin sensitivity and glycemic control in ZDF rats

2003 ◽  
Vol 284 (4) ◽  
pp. E841-E854 ◽  
Author(s):  
Christian L. Brand ◽  
Jeppe Sturis ◽  
Carsten F. Gotfredsen ◽  
Jan Fleckner ◽  
Christian Fledelius ◽  
...  
Keyword(s):  
Insulin Sensitivity ◽  
Glycemic Control ◽  
Whole Body ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Beneficial Effects ◽  
Ppar Γ ◽  
Late Intervention ◽  
Beneficial Impact ◽  
Zdf Rats

Improvement of insulin sensitivity and lipid and glucose metabolism by coactivation of both nuclear peroxisome proliferator-activated receptor (PPAR)γ and PPARα potentially provides beneficial effects over existing PPARγ and α preferential drugs, respectively, in treatment of type 2 diabetes. We examined the effects of the dual PPARα/γ agonist ragaglitazar on hyperglycemia and whole body insulin sensitivity in early and late diabetes stages in Zucker diabetic fatty (ZDF) rats and compared them with treatment with the PPARγ preferential agonist rosiglitazone. Despite normalization of hyperglycemia and Hb A1c and reduction of plasma triglycerides by both compounds in both prevention and early intervention studies, ragaglitazar treatment resulted in overall reduced circulating insulin and improved insulin sensitivity to a greater extent than after treatment with rosiglitazone. In late-intervention therapy, ragaglitazar reduced Hb A1c by 2.3% compared with 1.1% by rosiglitazone. Improvement of insulin sensitivity caused by the dual PPARα/γ agonist ragaglitazar seemed to have beneficial impact over that of the PPARγ-preferential activator rosiglitazone on glycemic control in frankly diabetic ZDF rats.

scholarly journals Long-term outcomes of monascin – a novel dual peroxisome proliferator-activated receptor γ/nuclear factor-erythroid 2 related factor-2 agonist in experimental intracerebral hemorrhage

2020 ◽  
Vol 13 ◽  
pp. 175628642092108
Author(s):  
Pengcheng Fu ◽  
Jiachen Liu ◽  
Qinqin Bai ◽  
Xingang Sun ◽  
Zhenjia Yao ◽  
...  
Keyword(s):  
Brain Injury ◽  
Iron Overload ◽  
Peroxisome Proliferator ◽  
Related Factor ◽  
Nuclear Factor ◽  
Long Term Outcomes ◽  
Hematoma Volume ◽  
Peroxisome Proliferator Activated Receptor ◽  
Ppar Γ

Background: Hematoma is the chief culprit in brain injury following intracranial cerebral hemorrhage (ICH). Noninvasive hematoma clearance could be an option to prevent and alleviate early brain injury after ICH. Peroxisome proliferator-activated receptor γ (PPAR-γ) and nuclear factor-erythroid 2 related factor-2 (Nrf2) facilitate removal of hematoma in ICH. Monascin acts as the natural Nrf2 activator with PPAR-γ agonist, and the long-term effects of monascin following ICH have not been elucidated. Methods: ICH in rats was induced by stereotactic, intrastriatal injection of type IV collagenase. Monascin was administered twice daily by gastric perfusion for 14 days after ICH induction. Long-term neurological scores (T maze, Garcia scales, rotor rod test, and Morris water maze), hematoma volume, as well as iron overload around hematoma and brain atrophy were evaluated at 7, 14, and 28 days after ICH. Results: The results showed that monascin improved long-term neurological deficits, spatial memory performance, learning ability, and brain shrinkage after ICH. Monascin also reduced hematoma volume at 7 days and iron content at 7 and 14 days after ICH. Conclusion: PPAR γ and Nrf2 play a crucial role in hematoma clearance after ICH in rat. As a dual agonist of PPAR γ and Nrf2, monascin improved long-term outcomes by facilitating hematoma clearance, and by attenuating iron overload and brain atrophy after experimental ICH.

scholarly journals Andrographis paniculata and Its Main Bioactive Ingredient Andrographolide Decrease Alcohol Drinking and Seeking in Rats Through Activation of Nuclear PPARγ Pathway

2021 ◽  
Author(s):  
Serena Stopponi ◽  
Yannick Fotio ◽  
Carlo Cifani ◽  
Hongwu Li ◽  
Carolina L Haass-Koffler ◽  
...  
Keyword(s):  
Oral Administration ◽  
Alcohol Drinking ◽  
Andrographis Paniculata ◽  
Peroxisome Proliferator ◽  
Herbaceous Plant ◽  
Dependent Manner ◽  
Peroxisome Proliferator Activated Receptor ◽  
Ppar Γ ◽  
Treatment Administration ◽  
Dried Extract

Abstract Background and aims Andrographis paniculata is an annual herbaceous plant which belongs to the Acanthaceae family. Extracts from this plant have shown hepatoprotective, anti-inflammatory and antidiabetic properties, at least in part, through activation of the nuclear receptor Peroxisome Proliferator-Activated Receptor-gamma (PPAR γ). Recent evidence has demonstrated that activation of PPARγ reduces alcohol drinking and seeking in Marchigian Sardinian (msP) alcohol-preferring rats. Methods The present study evaluated whether A. paniculata reduces alcohol drinking and relapse in msP rats by activating PPARγ. Results Oral administration of an A. paniculata dried extract (0, 15, 150 mg/kg) lowered voluntary alcohol consumption in a dose-dependent manner and achieved ~65% reduction at the dose of 450 mg/kg. Water and food consumption were not affected by the treatment. Administration of Andrographolide (5 and 10 mg/kg), the main active component of A. paniculata, also reduced alcohol drinking. This effect was suppressed by the selective PPARγ antagonist GW9662. Subsequently, we showed that oral administration of A. paniculata (0, 150, 450 mg/kg) prevented yohimbine- but not cues-induced reinstatement of alcohol seeking. Conclusions Results point to A. paniculata-mediated PPARγactivation as a possible therapeutic strategy to treat alcohol use disorder.

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