Li Feng1,2, Huan Luo3, Zhijian Xu4, Zhuo Yang4, Guoxin Du1, Yu Zhang2, Lijing Yu2, Kaifeng Hu3, Weiliang Zhu4, Qingchun Tong5, Kaixian Chen1,4, Fujiang Guo6, Cheng Huang7, Yiming Li8. 1. Department of TCM Chemistry, School of Pharmacy, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai, 201203, People's Republic of China. 2. Laboratory of Drug Discovery, School of Pharmacy, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai, 201203, People's Republic of China. 3. State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, People's Republic of China. 4. CAS Key Laboratory for Membrane Research, Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, People's Republic of China. 5. The Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX, USA. 6. Department of TCM Chemistry, School of Pharmacy, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai, 201203, People's Republic of China. gfj@shutcm.edu.cn. 7. Laboratory of Drug Discovery, School of Pharmacy, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai, 201203, People's Republic of China. chuang@shutcm.edu.cn. 8. Department of TCM Chemistry, School of Pharmacy, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai, 201203, People's Republic of China. ymli@shutcm.edu.cn.
Abstract
AIMS/HYPOTHESIS: Pan-peroxisome proliferator-activated receptor (PPAR) agonists have long been sought as therapeutics against the metabolic syndrome, but current PPAR agonists show limited efficacy and adverse effects. Natural herbs provide a structurally untapped resource to prevent and treat complicated metabolic syndrome. METHODS: Natural PPAR agonists were screened using reporter gene, competitive binding and 3T3-L1 pre-adipocyte differentiation assays in vitro. The effects on metabolic phenotypes were verified in db/db and diet-induced obese mice. In addition, potentially synergistic actions of bavachinin (BVC, a novel natural pan-PPAR agonist from the fruit of the traditional Chinese glucose-lowering herb malaytea scurfpea) and synthetic PPAR agonists were studied through nuclear magnetic resonance, molecular docking, reporter gene assays and mouse studies. RESULTS: BVC exhibited glucose-lowering properties without inducing weight gain and hepatotoxicity. Importantly, BVC synergised with thiazolidinediones, which are synthetic PPAR-γ agonists, and fibrates, which are PPAR-α agonists, to induce PPAR transcriptional activity, as well as to lower glucose and triacylglycerol levels in db/db mice. We further found that BVC occupies a novel alternative binding site in addition to the canonical site of synthetic agonists of PPAR, and that the synthetic PPAR-γ agonist rosiglitazone can block BVC binding to this canonical site but not to the alternative site. CONCLUSIONS/ INTERPRETATION: This is the first report of a synergistic glucose- and lipid-lowering effect of BVC and synthetic agonists induced by unique binding with PPAR-γ or -α. This combination may improve the efficacy and decrease the toxicity of marketed drugs for use as adjunctive therapy to treat the metabolic syndrome.
AIMS/HYPOTHESIS: Pan-peroxisome proliferator-activated receptor (PPAR) agonists have long been sought as therapeutics against the metabolic syndrome, but current PPAR agonists show limited efficacy and adverse effects. Natural herbs provide a structurally untapped resource to prevent and treat complicated metabolic syndrome. METHODS: Natural PPAR agonists were screened using reporter gene, competitive binding and 3T3-L1 pre-adipocyte differentiation assays in vitro. The effects on metabolic phenotypes were verified in db/db and diet-induced obese mice. In addition, potentially synergistic actions of bavachinin (BVC, a novel natural pan-PPAR agonist from the fruit of the traditional Chinese glucose-lowering herb malaytea scurfpea) and synthetic PPAR agonists were studied through nuclear magnetic resonance, molecular docking, reporter gene assays and mouse studies. RESULTS: BVC exhibited glucose-lowering properties without inducing weight gain and hepatotoxicity. Importantly, BVC synergised with thiazolidinediones, which are synthetic PPAR-γ agonists, and fibrates, which are PPAR-α agonists, to induce PPAR transcriptional activity, as well as to lower glucose and triacylglycerol levels in db/db mice. We further found that BVC occupies a novel alternative binding site in addition to the canonical site of synthetic agonists of PPAR, and that the synthetic PPAR-γ agonist rosiglitazone can block BVC binding to this canonical site but not to the alternative site. CONCLUSIONS/ INTERPRETATION: This is the first report of a synergistic glucose- and lipid-lowering effect of BVC and synthetic agonists induced by unique binding with PPAR-γ or -α. This combination may improve the efficacy and decrease the toxicity of marketed drugs for use as adjunctive therapy to treat the metabolic syndrome.
Authors: B Brunmair; K Staniek; J Dörig; Z Szöcs; K Stadlbauer; V Marian; F Gras; C Anderwald; H Nohl; W Waldhäusl; C Fürnsinn Journal: Diabetologia Date: 2006-09-08 Impact factor: 10.122
Authors: Mark A Deeg; John B Buse; Ronald B Goldberg; David M Kendall; Anthony J Zagar; Scott J Jacober; Mehmood A Khan; Alfonzo T Perez; Meng H Tan Journal: Diabetes Care Date: 2007-06-26 Impact factor: 19.112
Authors: Jang Hyun Choi; Alexander S Banks; Theodore M Kamenecka; Scott A Busby; Michael J Chalmers; Naresh Kumar; Dana S Kuruvilla; Youseung Shin; Yuanjun He; John B Bruning; David P Marciano; Michael D Cameron; Dina Laznik; Michael J Jurczak; Stephan C Schürer; Dušica Vidović; Gerald I Shulman; Bruce M Spiegelman; Patrick R Griffin Journal: Nature Date: 2011-09-04 Impact factor: 49.962