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Natural product agonists of peroxisome proliferator-activated receptor gamma (PPARγ): a review

a , 1 , b , 1 , c , c , c , a , a , b , b , a , d , a , c , b , a , a , *

Biochemical Pharmacology

Elsevier Science

PPAR gamma, Nuclear receptor, Natural product, Nutrition, Diabetes, 9-(S)-HODE, (9S,10E,12Z)-9-hydroxyoctadeca-10,12-dienoic acid, AF-2, activation function-2, CAP, c-Cbl-associated protein, Cdk5, cyclin-dependent kinase 5, DCM, dichloromethane, DIO, diet-induced obesity, DPP-4, dipeptidylpeptidase 4, EMA, European Medicines Agency, FDA, Food and Drug Administration, Glut4, glucose transporter type 4, HDL, high-density lipoprotein, HUVEC, human umbilical vein endothelial cells, LBD, ligand-binding domain, LDL, low-density lipoprotein, MAPK, mitogen-activated protein kinase, MeOH, methanol, NF-κB, nuclear factor-kappaB, PPAR, peroxisome proliferator-activated receptor, RXR, retinoid X receptor, PDB, protein data bank, PPRE, peroxisome proliferator response element, SPPARMs, selective PPARγ modulators, TCM, traditional Chinese medicine, TNF-α, tumor necrosis factor alpha

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      Graphical abstract

      Abstract

      Agonists of the nuclear receptor PPARγ are therapeutically used to combat hyperglycaemia associated with the metabolic syndrome and type 2 diabetes. In spite of being effective in normalization of blood glucose levels, the currently used PPARγ agonists from the thiazolidinedione type have serious side effects, making the discovery of novel ligands highly relevant.

      Natural products have proven historically to be a promising pool of structures for drug discovery, and a significant research effort has recently been undertaken to explore the PPARγ-activating potential of a wide range of natural products originating from traditionally used medicinal plants or dietary sources. The majority of identified compounds are selective PPARγ modulators (SPPARMs), transactivating the expression of PPARγ-dependent reporter genes as partial agonists. Those natural PPARγ ligands have different binding modes to the receptor in comparison to the full thiazolidinedione agonists, and on some occasions activate in addition PPARα (e.g. genistein, biochanin A, sargaquinoic acid, sargahydroquinoic acid, resveratrol, amorphastilbol) or the PPARγ-dimer partner retinoid X receptor (RXR; e.g. the neolignans magnolol and honokiol). A number of in vivo studies suggest that some of the natural product activators of PPARγ (e.g. honokiol, amorfrutin 1, amorfrutin B, amorphastilbol) improve metabolic parameters in diabetic animal models, partly with reduced side effects in comparison to full thiazolidinedione agonists. The bioactivity pattern as well as the dietary use of several of the identified active compounds and plant extracts warrants future research regarding their therapeutic potential and the possibility to modulate PPARγ activation by dietary interventions or food supplements.

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          Rosiglitazone is widely used to treat patients with type 2 diabetes mellitus, but its effect on cardiovascular morbidity and mortality has not been determined. We conducted searches of the published literature, the Web site of the Food and Drug Administration, and a clinical-trials registry maintained by the drug manufacturer (GlaxoSmithKline). Criteria for inclusion in our meta-analysis included a study duration of more than 24 weeks, the use of a randomized control group not receiving rosiglitazone, and the availability of outcome data for myocardial infarction and death from cardiovascular causes. Of 116 potentially relevant studies, 42 trials met the inclusion criteria. We tabulated all occurrences of myocardial infarction and death from cardiovascular causes. Data were combined by means of a fixed-effects model. In the 42 trials, the mean age of the subjects was approximately 56 years, and the mean baseline glycated hemoglobin level was approximately 8.2%. In the rosiglitazone group, as compared with the control group, the odds ratio for myocardial infarction was 1.43 (95% confidence interval [CI], 1.03 to 1.98; P=0.03), and the odds ratio for death from cardiovascular causes was 1.64 (95% CI, 0.98 to 2.74; P=0.06). Rosiglitazone was associated with a significant increase in the risk of myocardial infarction and with an increase in the risk of death from cardiovascular causes that had borderline significance. Our study was limited by a lack of access to original source data, which would have enabled time-to-event analysis. Despite these limitations, patients and providers should consider the potential for serious adverse cardiovascular effects of treatment with rosiglitazone for type 2 diabetes. Copyright 2007 Massachusetts Medical Society.
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            Author and article information

            Affiliations
            [a ]Department of Pharmacognosy, University of Vienna, Austria
            [b ]Institute of Pharmacy/Pharmacognosy and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, Austria
            [c ]Institute of Pharmaceutical Sciences, Department of Pharmacognosy, University of Graz, Austria
            [d ]Institute of Pharmacy/Pharmaceutical Chemistry and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, Austria
            Author notes
            [* ]Corresponding author. Department of Pharmacognosy, University of Vienna, Althanstrasse 14, A-1090 Vienna, Austria, Tel.: +43 1 4277 55226; fax: +43 1 4277 9552. atanas.atanasov@ 123456univie.ac.at
            [1]

            These authors contributed equally to this work.

            Contributors
            Journal
            Biochem Pharmacol
            Biochem. Pharmacol
            Biochemical Pharmacology
            Elsevier Science
            0006-2952
            1873-2968
            01 November 2014
            01 November 2014
            : 92
            : 1
            : 73-89
            25083916
            4212005
            S0006-2952(14)00424-9
            10.1016/j.bcp.2014.07.018
            © 2014 The Authors
            Categories
            Part of the Special Issue: Metabolism 2014 – Alterations of metabolic pathways as therapeutic targets

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