Marine natural product des-O-methyllasiodiplodin effectively lowers the blood glucose level in db/db mice via ameliorating inflammation

Abstract

Aim: 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 H 2 O 2 (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 H 2 O 2 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 H 2 O 2 -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. Conclusion: 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.

Chemistry and Pharmacognosy of the Genus Durio

“…The macrolides hypothemycin and aigialomycin D that were obtained from the mangrove fungus Aigialus parvus exhibited in vitro antimalarial activity with IC 50 values of 2.2 and 6.6 g/mL, respectively [60]. The compound also inhibited prostaglandin biosynthesis with an IC 50 value of 71.9 M [43][44], and exhibited antagonistic activity against the mineralocorticoid receptor (MR) with an IC 50 value of 8.93 M [51][52], and may have potential in the treatment of type 2 diabetes mellitus [53].…”

“…Moreover, Huang et al[50] also completed the formal synthesis of (R)-(+)-lasiodiplodin(31) and (R)-(+)-de-O-methyl congener 32 by using catalytic asymmetric allylic substitution, sp 3 -sp3 Suzuki coupling and ringclosing metathesis (RCM). The biological activities of 31 and related resorcylic acid lactones (RALs) are of considerable interest given the recent reports of their biological activity[51][52][53][54][55][56][57][58][59][60], as described below.Bioactivities: Cytotoxic activity. Maslinic acid (1) prevents tumor cell proliferation in SK-OV-3 (ovary), SK-MEL-2 (melanoma), HCT15 (colon), A549 (non small cell lung), and XF498 (central nerve system) cell lines with ED 50 values of 18.4, 19.8, 15.3, 19.4 and >30 μg/mL, respectively [61].…”

Design, synthesis, and characterization of rhein analogs as novel inhibitors of scavenger receptor A

“…Compound 1 was known as a natural product, namely danthron. Danthron was also isolated from the traditional Chinese medicinal plant, rhubarb [21]. The other two compounds (compound 2 and 3 , Fig.…”