title: Bavachinin, as a novel natural pan-PPAR agonist, exhibits unique synergistic effects with synthetic PPAR-γ and PPAR-α agonists on carbohydrate and lipid metabolism in db/db and diet-induced obese mice.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.affiliation: Department of TCM Chemistry, School of Pharmacy, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai, 201203, People's Republic of China.|Laboratory of Drug Discovery, School of Pharmacy, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai, 201203, People's Republic of China.
authors.forename: Li
authors.initials: L
authors.lastname: Feng
authors.affiliation: 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.
authors.forename: Huan
authors.initials: H
authors.lastname: Luo
authors.affiliation: 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.
authors.forename: Zhijian
authors.initials: Z
authors.lastname: Xu
authors.affiliation: 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.
authors.forename: Zhuo
authors.initials: Z
authors.lastname: Yang
authors.affiliation: Department of TCM Chemistry, School of Pharmacy, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai, 201203, People's Republic of China.
authors.forename: Guoxin
authors.initials: G
authors.lastname: Du
authors.affiliation: Laboratory of Drug Discovery, School of Pharmacy, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai, 201203, People's Republic of China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Laboratory of Drug Discovery, School of Pharmacy, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai, 201203, People's Republic of China.
authors.forename: Lijing
authors.initials: L
authors.lastname: Yu
authors.affiliation: 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.
authors.forename: Kaifeng
authors.initials: K
authors.lastname: Hu
authors.affiliation: 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.
authors.forename: Weiliang
authors.initials: W
authors.lastname: Zhu
authors.affiliation: The Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX, USA.
authors.forename: Qingchun
authors.initials: Q
authors.lastname: Tong
authors.affiliation: Department of TCM Chemistry, School of Pharmacy, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai, 201203, People's Republic of China.|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.
authors.forename: Kaixian
authors.initials: K
authors.lastname: Chen
authors.affiliation: 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.
authors.forename: Fujiang
authors.initials: F
authors.lastname: Guo
authors.affiliation: 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.
authors.forename: Cheng
authors.initials: C
authors.lastname: Huang
authors.affiliation: 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.
authors.forename: Yiming
authors.initials: Y
authors.lastname: Li
mesh_terms: D041721:3T3-L1 Cells; D000818:Animals; D001665:Binding Sites; D001786:Blood Glucose / Q000187:drug effects; D004357:Drug Synergism; D005260:Female; D005419:Flavonoids / Q000008:administration & dosage / Q000627:therapeutic use*; D050356:Lipid Metabolism / Q000187:drug effects; D051379:Mice; D009765:Obesity / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism*; D047493:PPAR alpha / Q000819:agonists*; D047495:PPAR gamma; D045162:Thiazolidinediones / Q000627:therapeutic use; D014280:Triglycerides / Q000097:blood; D047309:Flavones
chemical_list: D001786:Blood Glucose; D005419:Flavonoids; D047493:PPAR alpha; D047495:PPAR gamma; D045162:Thiazolidinediones; D014280:Triglycerides; C468752:bavachinin; D047309:Flavones
keywords: Alternative binding site; Bavachinin; Canonical ligand-binding pocket; Carbohydrate metabolism; Lipid metabolism; Pan-PPAR agonist; Synergistic effects