Selenite Inhibits Notch Signaling in Cells and Mice.

Selenium is an essential micronutrient with a wide range of biological effects in mammals. The inorganic form of selenium, selenite, is supplemented to relieve individuals with selenium deficiency and to alleviate associated symptoms. Additionally, physiological and supranutritional selenite have shown selectively higher affinity and toxicity towards cancer cells, highlighting their potential to serve as chemotherapeutic agents or adjuvants. At varying doses, selenite extensively regulates cellular signaling and modulates many cellular processes. In this study, we report the identification of Delta-Notch signaling as a previously uncharacterized selenite inhibited target. Our transcriptomic results in selenite treated primary mouse hepatocytes revealed that the transcription of Notch1, Notch2, Hes1, Maml1, Furin and c-Myc were all decreased following selenite treatment. We further showed that selenite can inhibit Notch1 expression in cultured MCF7 breast adenocarcinoma cells and HEPG2 liver carcinoma cells. In mice acutely treated with 2.5 mg/kg selenite via intraperitoneal injection, we found that Notch1 expression was drastically lowered in liver and kidney tissues by 90% and 70%, respectively. Combined, these results support selenite as a novel inhibitor of Notch signaling, and a plausible mechanism of inhibition has been proposed. This discovery highlights the potential value of selenite applied in a pathological context where Notch is a key drug target in diseases such as cancer, fibrosis, and neurodegenerative disorders.

The branching ratio of enzymatically synthesized α-glucans impacts microbiome and metabolic outcomes of in vitro fecal fermentation.

The aim of this study was to evaluate the impacts of enzymatically synthesized α-glucans possessing α-1,4- and α-1,6-glucose linkages, and varying in branching ratio, on colonic microbiota composition and metabolic function. Four different α-glucans varying in branching ratio were synthesized by amylosucrase from Neisseria polysaccharea and glycogen branching enzyme from Rhodothermus obamensis. The branching ratios were found to range from 0 % to 2.8 % using GC/MS. In vitro fecal fermentation analyses (n = 8) revealed that the branching ratio dictates the short-chain fatty acid (SCFA) generation by fecal microbiota. Specifically, slightly branched (0.49 %) α-glucan resulted in generation of significantly (P < 0.05) higher amounts of propionate, compared to more-branched counterparts. In addition, the amount of butyrate generated from this α-glucan was statistically (P > 0.05) indistinguishable than those observed in resistant starches. 16S rRNA sequencing revealed that enzymatically synthesized α-glucans stimulated Lachnospiraceae and Ruminococcus related OTUs. Overall, the results demonstrated metabolic function of colonic microbiota can be manipulated by altering the branching ratio of enzymatically synthesized α-glucans, providing insights into specific structure-function relationships between dietary fibers and the colonic microbiome. Furthermore, the slightly branched α-glucans could be used as functional carbohydrates to stimulate the beneficial microbiota and SCFAs in the colon.

Dietary Fibers of Tree Nuts Differ in Composition and Distinctly Impact the Fecal Microbiota and Metabolic Outcomes In Vitro.

This study aimed to evaluate and compare the effects of dietary fibers (DFs) of commercially important tree nuts (almond, cashew, hazelnut, pistachio, and walnut) on gut microbiota in vitro. Microbial compositions and short-chain fatty acids were determined using 16S rRNA sequencing and gas chromatography (GC), respectively. Neutral and acidic monosaccharides were analyzed using GC/MS and spectrophotometry, respectively. Our results revealed that cashew fibers exhibit higher butyrate formation compared to others. Accordingly, cashew fiber promoted butyric acid-producing bacteria-related operational taxonomic units (OTUs; Butyricimonas and Collinsella) at higher relative abundances. The higher butyrogenic capacity of cashew fiber is mainly attributed to its higher soluble/total DF ratio and remarkably distinct monosaccharide composition. Additionally, nut fibers stimulated family Lachnospiraceae- and Ruminococcaceae-related OTUs. These findings show that although the degree of promotion is nut type-dependent, nut fibers are generally capable of promoting beneficial microbes in the colon, further suggesting that DFs of tree nuts are contributing factors to their health-promoting effects.

Differences in fine arabinoxylan structures govern microbial selection and competition among human gut microbiota.

Dietary fibers are known to modulate microbiome composition, but it is unclear to what extent minor fiber structural differences impact community assembly, microbial division of labor, and organismal metabolic responses. To test the hypothesis that fine linkage variations afford different ecological niches for distinct communities and metabolism, we employed a 7-day in vitro sequential batch fecal fermentation with four fecal inocula and measured responses using an integrated multi-omics approach. Two sorghum arabinoxylans (SAXs) were fermented, with one (RSAX) having slightly more complex branch linkages than the other (WSAX). Although there were minor glycoysl linkage differences, consortia on RSAX retained much higher species diversity (42 members) than on WSAX (18-23 members) with distinct species-level genomes and metabolic outcomes (e.g., higher short chain fatty acid production from RSAX and more lactic acid produced from WSAX). The major SAX-selected members were from genera of Bacteroides and Bifidobacterium and family Lachnospiraceae. Carbohydrate active enzyme (CAZyme) genes in metagenomes revealed broad AX-related hydrolytic potentials among key members; however, CAZyme genes enriched in different consortia displayed various catabolic domain fusions with diverse accessory motifs that differ among the two SAX types. These results suggest that fine polysaccharide structure exerts deterministic selection effect for distinct fermenting consortia.