Alginate oligosaccharide assimilation by gut microorganisms and the potential role in gut inflammation alleviation.

Dietary fiber metabolism by gut microorganisms plays important roles in host physiology and health. Alginate, the major dietary fiber of daily diet seaweeds, is drawing more attention because of multiple biological activities. To advance the understanding of alginate assimilation mechanism in the gut, we show the presence of unsaturated alginate oligosaccharides (uAOS)-specific alginate utilization loci (AUL) in human gut microbiome. As a representative example, a working model of the AUL from the gut microorganism Bacteroides clarus was reconstructed from biochemistry and transcriptome data. The fermentation of resulting monosaccharides through Entner-Doudoroff pathway tunes the metabolism of short-chain fatty acids and amino acids. Furthermore, we show that uAOS feeding protects the mice against dextran sulfate sodium-induced acute colitis probably by remodeling gut microbiota and metabolome. IMPORTANCE: Alginate has been included in traditional Chinese medicine and daily diet for centuries. Recently discovered biological activities suggested that alginate-derived alginate oligosaccharides (AOS) might be an active ingredient in traditional Chinese medicine, but how these AOS are metabolized in the gut and how it affects health need more information. The study on the working mechanism of alginate utilization loci (AUL) by the gut microorganism uncovers the role of unsaturated alginate oligosaccharides (uAOS) assimilation in tuning short-chain fatty acids and amino acids metabolism and demonstrates that uAOS metabolism by gut microorganisms results in a variation of cell metabolites, which potentially contributes to the physiology and health of gut.

Virtual Screening Based on Ensemble Docking Targeting Wild-Type p53 for Anticancer Drug Discovery.

The tumor-suppressor function of p53 makes it an attractive drug target. Efforts were mostly put on stabilization of the functional p53 or reactivation of mutated p53. Previous studies have shown that small molecules targeting Loop1/Sheet3 (L1/S3) can reactivate the R175H-p53 and stabilize p53 in vitro. Since the L1/S3 pocket is shared by the mutate and the wild type (WT) p53, virtual screening is introduced to identify natural products targeting the L1/S3 of WT p53. Considering the high flexibility of Loop1, ensemble docking method is utilized for different clusters of the L1/S3. Seven conformations were chosen for docking. As one of the 181 selected candidates, torilin not only improved p53 activity, but also increased p21 protein expression level, which lies downstream of p53, therefore suppressing HCT116 cancer cell growth. Torilin may covalently bind to Cys124 of p53 by 2-methyl-2-butenal (2M2B) group, as torilin derivatives, which do not contain the 2M2B group, were not able to increase the p53 transcription activity. In conclusion, this study demonstrated that L1/S3 of WT-p53 is a druggable pocket, and torilin has a potential cytotoxicity through activating the p53 pathway.