title: Marine natural product des-O-methyllasiodiplodin effectively lowers the blood glucose level in db/db mice via ameliorating inflammation.
abstract: OBJECTIVE
  des-O-methyllasiodiplodin (DML) from Cerbera manghas has shown antagonistic activity against mineralocorticoid receptor (MR). Considering the involvement of MR in the insulin tolerance, we attempted to investigate the potential of DML in the treatment of type 2 diabetes mellitus (T2DM).
  
  
  METHODS
  Surface plasmon resonance (SPR) technology and reporter gene-based assays were used to study protein-small molecule interactions. HepG2 and 3T3-L1 cells were treated with H2O2 (0.2 mmol/L) or aldosterone (10 nmol/L) for 24 h. The expression of MR in the cells was downregulated with siRNA. The anti-inflammatory effect of the compound was evaluated, respectively. db/db mice were administered DML (30 mg·kg(-1)·d(-1)) for 4 weeks. Serum biochemical parameters and insulin sensitivity were examined. The expression levels of pro-inflammatory cytokines (MCP-1, TNF-α and IL-6) and ROS-related genes (NADPH p47 subunit and transcriptional factor PU.1) in adipose tissues and livers were analyzed using real-time RT-PCR.
  
  
  RESULTS
  In HepG2 and 3T3-L1 cells, both H2O2 and aldosterone markedly stimulates the expression of MCP-1, TNFα, IL-6, p47 and PU.1 genes. Co-treatment with DML (10 μmol/L) significantly reduced the H2O2- or aldosterone-induced expression of these genes. SPR-based assay confirmed the antagonistic activity of DML against the interaction between SRC-1 and MR-LBD. Furthermore, DML decreased aldosterone-induced MR transcriptional activity in a dose-dependent manner. Downregulation of MR with siRNA in the cells prevented or significantly attenuated aldosterone-stimulated expression of these genes, whereas DML did no longer affect the expression of these genes except that of IL-6. Oral administration of DML effectively reduced the levels of blood glucose and glycosylated hemoglobin (HbA1c) in db/db mice. The treatment also rectified the expression of pro-inflammatory factor and ROS-related genes in db/db mice.
  
  
  CONCLUSIONS
  DML effectively lowers the blood glucose level in db/db mice possibly via ameliorating the expression of obesity-related pro-inflammatory cytokines, highlighting the potential of the marine natural product as a drug lead for the treatment of metabolic disorders.
authors.affiliation: School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China.
authors.forename: Rong
authors.initials: R
authors.lastname: Zhou
authors.forename: Zhong-Hui
authors.initials: ZH
authors.lastname: Lin
authors.forename: Cheng-Shi
authors.initials: CS
authors.lastname: Jiang
authors.forename: Jing-Xu
authors.initials: JX
authors.lastname: Gong
authors.forename: Li-Li
authors.initials: LL
authors.lastname: Chen
authors.forename: Yue-Wei
authors.initials: YW
authors.lastname: Guo
authors.forename: Xu
authors.initials: X
authors.lastname: Shen
mesh_terms: D041721:3T3-L1 Cells; D000450:Aldosterone / Q000494:pharmacology; D000818:Animals; D029062:Apocynaceae / Q000737:chemistry*; D001786:Blood Glucose / Q000187:drug effects*; D016207:Cytokines / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D004305:Dose-Response Relationship, Drug; D017930:Genes, Reporter; D006442:Glycated Hemoglobin / Q000378:metabolism; D056945:Hep G2 Cells; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007249:Inflammation / Q000188:drug therapy* / Q000473:pathology; D018942:Macrolides / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D051379:Mice; D009765:Obesity / Q000188:drug therapy / Q000503:physiopathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020349:Surface Plasmon Resonance
chemical_list: D000450:Aldosterone; D001786:Blood Glucose; D016207:Cytokines; D006442:Glycated Hemoglobin; D006861:Hydrogen Peroxide; D018942:Macrolides; C558290:de-O-methyllasiodiplodin