It is a great challenge to develop drugs for treatment of metabolic syndrome. With ganomycin I as a leading compound, 14 meroterpene derivatives were synthesized and screened for their α-glucosidase and HMG-CoA reductase inhibitory activities. As a result, a α-glucosidase and HMG-CoA reductase dual inhibitor (( R, E)-5-(4-( tert-butyl)phenyl)-3-(4,8-dimethylnona-3,7-dien-1-yl)furan-2(5 H)-one, 7d) with improved chemical stability and long-term safety was obtained. Compound 7d showed multiple and strong in vivo efficacies in reducing weight gain, lowering HbAlc level, and improving insulin resistance and lipid dysfunction in both ob/ob and diet-induced obesity (DIO) mice models. Compound 7d was also found to reduce hepatic steatosis in ob/ob model. 16S rRNA gene sequencing, SCFA, and intestinal mucosal barrier function analysis indicated that gut microbiota plays a central and causative role in mediating the multiple efficacies of 7d. Our results demonstrate that 7d is a promising drug candidate for metabolic syndrome.

Cultivation and characterization of symbiotic bacteria from the gut of Reticulitermes chinensis.

Previous study on refolding of sulfur oxygenase reductase (SOR) inclusion bodies from recombinantEscherichia coli showed that iron was critical to the activity of the SOR from Acidianus ambivalens. In this study, enzymatic assays showed that 2,2′-Dipyridyl, Tiron and 8-hydroxyquinoline, which are specific for chelating ferrous or ferric ions, strongly inhibited the activity of SOR from A. tengchongensis, suggesting that iron atom is essential for SOR activity. Alignment of several functionally identified SORs and SOR-like sequences from genome database revealed a conserved, putative iron binding motif, H 86 -X 3 -H 90 -X n -E 114 -X n -E 129 (numbering according to the Acidianus tengchongensis SOR sequence). Three mutants of SOR were generated by site-directed mutagenesis of H 86 , H 90 and E 129 into phenylalanine or alanine residue in this study. Circular dichroism spectrum determination indicated that there was no change of the secondary structures of mutant SORs, H 86 F, H 90 F and E 129A, but all mutants were completely inactive. Through determination of iron contents we found that SOR mutants of H 86 F, H 90 F and E 129 A completely or partially lost iron, while mutants of C 31 S, C 101 S, and C 104 S (generated in a previous study) did not. This result indicated that H 86 , H 90 and E 129 but not C 31 , C 101 , and C 104 were involved in binding to iron atom. Based on this and previous studies, it is proposed that the conserved motifs,