Metabolic syndrome (MetS), characterized as obesity, insulin resistance, and non-alcoholic fatty liver diseases (NAFLD), is associated with vitamin D insufficiency/deficiency in epidemiological studies, while the underlying mechanism is poorly addressed. On the other hand, disorder of gut microbiota, namely dysbiosis, is known to cause MetS and NAFLD. It is also known that systemic inflammation blocks insulin signaling pathways, leading to insulin resistance and glucose intolerance, which are the driving force for hepatic steatosis. Vitamin D receptor (VDR) is highly expressed in the ileum of the small intestine, which prompted us to test a hypothesis that vitamin D signaling may determine the enterotype of gut microbiota through regulating the intestinal interface. Here, we demonstrate that high-fat-diet feeding (HFD) is necessary but not sufficient, while additional vitamin D deficiency (VDD) as a second hit is needed, to induce robust insulin resistance and fatty liver. Under the two hits (HFD+VDD), the Paneth cell-specific alpha-defensins including α-defensin 5 (DEFA5), MMP7 which activates the pro-defensins, as well as tight junction genes, and MUC2 are all suppressed in the ileum, resulting in mucosal collapse, increased gut permeability, dysbiosis, endotoxemia, systemic inflammation which underlie insulin resistance and hepatic steatosis. Moreover, under the vitamin D deficient high fat feeding (HFD+VDD), Helicobacter hepaticus, a known murine hepatic-pathogen, is substantially amplified in the ileum, while Akkermansia muciniphila, a beneficial symbiotic, is diminished. Likewise, the VD receptor (VDR) knockout mice exhibit similar phenotypes, showing down regulation of alpha-defensins and MMP7 in the ileum, increased Helicobacter hepaticus and suppressed Akkermansia muciniphila. Remarkably, oral administration of DEFA5 restored eubiosys, showing suppression of Helicobacter hepaticus and increase of Akkermansia muciniphila in association with resolving metabolic disorders and fatty liver in the HFD+VDD mice. An in vitro analysis showed that DEFA5 peptide could directly suppress Helicobacter hepaticus. Thus, the results of this study reveal critical roles of a vitamin D/VDR axis in optimal expression of defensins and tight junction genes in support of intestinal integrity and eubiosis to suppress NAFLD and metabolic disorders.
Monitoring the in situ growth of Mn-doped ZnS quantum dots is shown to be a route to selectively detect H2S, an important endogenously produced signalling molecule. The use of Mn(2+) as a dopant resulted in orange phosphorescence, making it possible to avoid the background fluorescence from biological surroundings that can occur at other wavelengths. The choice of ZnS QDs as the host material ensured selectivity, since only sulfide can precipitate Zn(2+) and Mn(2+) from aqueous solution.
A pandemic of metabolic diseases, consisting of type 2 diabetes, nonalcoholic fatty liver disease, and obesity, has imposed critical challenges for societies worldwide, prompting investigation of underlying mechanisms and exploration of low-cost and effective treatment. In this report, we demonstrate that metabolic disorders in mice generated by feeding with a high-fat diet without dietary vitamin D can be prevented by oral administration of polycationic amine resin. Oral administration of cholestyramine, but not the control uncharged polystyrene, was able to sequester negatively charged bacterial endotoxin in the gut, leading to 1) reduced plasma endotoxin levels, 2) resolved systemic inflammation and hepatic steatohepatitis, and 3) improved insulin sensitivity. Gut dysbiosis, characterized as an increase of the phylum Firmicutes and a decrease of Bacteroidetes and Akkermansia muciniphila, was fully corrected by cholestyramine, indicating that the negatively charged components in the gut are critical for the dysbiosis. Furthermore, fecal bacteria transplant, derived from cholestyramine-treated animals, was sufficient to antagonize the metabolic disorders of the recipient mice. These results indicate that the negatively charged components produced by dysbiosis are critical for biogenesis of metabolic disorders and also show a potential application of cationic polystyrene to treat metabolic disorders through promoting gut eubiosis.
Protein-directed synthesis of quantum dots (QDs) is a ''greener'' alternative to the current hightemperature and aqueous synthetic protocols, which provide water-soluble, biocompatible proteinfunctionalized QDs in one-pot. However, the protein activity in such synthetic schemes is a critical issue, since the synthetic conditions (for instance, high pH of the precursors, long time of synthesis, and disruption of disulfide bonds) are not suitable for retaining the activity (especially for enzymes). Herein, we present a facile and instant glucose oxidase (GOD)-directed strategy for the preparation of highly luminescent, phosphorescent Mn-doped ZnS (Mn-ZnS) QDs in one-step at room temperature and in neutral aqueous media. With such mild synthetic conditions, the enzymatic activity of GOD was totally retained. Furthermore, we also carried out GOD-directed synthesis of QDs with several other conditions that are reported in the literature. It turned out that the GOD enzymatic activity under these synthetic conditions was lower than that of the proposed protocol, indicating that mild synthetic conditions are the prerequisite for retaining the enzymatic activity. Importantly, the as-prepared GOD-mediated Mn-ZnS QDs exhibited high photostability, high salt tolerance and colloidal stability, and can be stored for months at 4 1C or 25 1C without changing their phosphorescent intensity and enzymatic activity. Via selective chemical modification, the exact functional groups (amino acid residues) of GOD in directing the synthesis of Mn-ZnS QDs were studied in detail. It turned out to be imidazole in histidine residues but not thiol in cysteine residues that directed the formation of Mn-ZnS QDs, and this was further confirmed with several other proteins for synthesis of Mn-ZnS QDs. The as-prepared GOD-capped Mn-ZnS QDs were employed as phosphorescent probes for background-free sensing of glucose in serum samples.
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