PPAR dual agonists: are they opening Pandora's Box?
ABSTRACT Cardiovascular disorders are the major cause of mortality in patients of diabetes mellitus. Peroxisome proliferator activated receptors (PPARs) are ligand-activated transcription factors of nuclear hormone receptor superfamily comprising of three subtypes such as PPARalpha, PPARgamma and PPARdelta/beta. Activation of PPARalpha reduces triglycerides and involves in regulation of energy homeostasis. Activation of PPARgamma causes insulin sensitization and enhances glucose metabolism, whereas activation of PPARdelta enhances fatty acid metabolism. Current therapeutic strategies available for the treatment of diabetes do not inhibit the associated secondary cardiovascular complications. Hence, the development of multimodal drugs which can reduce hyperglycemia and concomitantly inhibit the progression of secondary cardiovascular complications may offer valuable therapeutic option. Several basic and clinical studies have exemplified the beneficial effects of PPARalpha and PPARgamma ligands in preventing the cardiovascular risks. The PPARalpha/gamma dual agonists are developed to increase insulin sensitivity and simultaneously prevent diabetic cardiovascular complications. Such compounds are under clinical trials and proposed for treatment of Type II diabetes with secondary cardiovascular complications. However, PPARalpha/gamma dual agonists such as muraglitazar, tesaglitazar and ragaglitazar have been noted to produce several cardiovascular risks and carcinogenicity, which raised number of questions about the clinical applications of dual agonists in diabetes and its associated complications. The ongoing basic studies have elucidated the cardio protective role of PPARdelta. Therefore, further studies are on the track to develop PPARalpha/delta and PPAR gamma/delta dual agonists and PPARalpha/gamma/delta pan agonists for the treatment of diabetic cardiovascular complications. The present review critically analyzes the protective and detrimental effect of PPAR agonists in diabetic cardiovascular complications. Moreover, the newly developed PPARalpha/delta and PPAR gamma/delta dual agonists and PPARalpha/gamma/delta pan agonists have also been discussed which may open a new vista in the management of diabetic cardiovascular complications in near future.
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ABSTRACT: Described since long as a member of the nuclear receptor super family, peroxisome proliferator-activated receptors (PPARs) regulate the gene expression of proteins involved in glucose and lipid metabolism. PPARs indeed regulate several physiologic processes, including lipid homeostasis, adipogenesis, inflammation, and wound healing. PPARs bind natural or synthetic PPAR ligands do function as cellular sensors to regulate the gene transcription. Dyslipidemia, and type 2 diabetes mellitus (T2DM) with insulin resistance are treated using agonists of PPARα and PPARγ, respectively. The PPARγ is a key regulator of insulin sensitization and glucose metabolism, and therefore is considered as an imperative pharmacological target to combat diabetic metabolic disease and insulin resistance. Of note, currently available PPARγ full agonists like rosiglitazone display serious adverse effects such as fluid retention/oedema, weight gain, and increased incidence of cardiovascular events. On the other hand, PPARγ partial agonists are being suggested to devoid or having less incidence of these undesirable events, and are under developmental stages. Current research is on the way for the development of novel PPARγ partial agonists with enhanced therapeutic efficacy and reduced adverse effects. This review sheds lights on the current status of development of PPARγ partial agonists, for the management of T2DM, having comparatively less or no adverse effects to that of PPARγ full agonists. Copyright © 2015. Published by Elsevier B.V.European Journal of Pharmacology 03/2015; 755. DOI:10.1016/j.ejphar.2015.02.043 · 2.68 Impact Factor
Advances in Predictive, Preventive and Personalised Medicine - New Strategies to Advance Pre-Diabetes Care: Integrative Approach by PPPM, 01/2013: pages 29-87; Springer Netherlands., ISBN: 978-94-007-5970-1
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ABSTRACT: In Tibet, the flower of Edgeworthia gardneri (Wall.) Meisn., locally named "Lvluohua, ", has been traditionally used to treat diabetes mellitus for many years. To evaluate the activity of dual agonists for PPARγ/β from the flower of E.gardneri in vitro. HeLa cells were transiently co-transfected with the re-constructed plasmids of pBIND-PPARγ-LBD or pBIND-PPARβ-LBD and rL4.35. The activities of crude extracts, secondary fractions and compounds from the flower of E.gardneri were evaluated with the transfected cells. Rosiglitazone (at 0.5μg/mL) and L-165041 (at 0.5μg/mL) were used as the positive controls for PPARγ and PPARβ respectively. The results demonstrated that n-hexane, ethyl acetate and n-butanol extracts from the flower of E.gardneri were able to significantly activate PPARγ and PPARβ respectively, and the activity of ethyl acetate extract was much better. We further observed that, among the 11 secondary fractions of ethyl acetate extract, the fr. 9 could activate PPARγ and PPARβ significantly. Moreover, umbelliferone (from fr.9) and pentadecanoic acid could activate PPARγ and PPARβ at the same time. The extracts from the flower of E.gardneri could significantly activate PPARγ and PPARβ. Besides, umbelliferone and pentadecanoic acid isolated from the flower of E.gardneri were the new agonists for PPARγ and PPARβ. Copyright © 2015. Published by Elsevier Ireland Ltd.Journal of Ethnopharmacology 12/2014; DOI:10.1016/j.jep.2014.12.034 · 2.94 Impact Factor