Vitamin D Signaling through Induction of Paneth Cell Defensins Maintains Gut Microbiota and Improves Metabolic Disorders and Hepatic Steatosis in Animal Models.

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

Cationic Polystyrene Resolves Nonalcoholic Steatohepatitis, Obesity, and Metabolic Disorders by Promoting Eubiosis of Gut Microbiota and Decreasing Endotoxemia.

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

A Novel P53/POMC/Gas/SASH1 Autoregulatory Feedback Loop and Pathologic Hyperpigmentation

P53-regulated proteins in transcriptional level are associated with many signal transduction pathways and p53 plays a pivotal role in a number of positive and negative autoregulatory feedback loops. Although POMC/α-MSH productions induced by ultraviolet (UV) are directly mediated by p53, p53 is related to UV-independent pathological pigmentation. In the process of identifying the causative gene of dyschromatosis universalis hereditaria (DUH), three mutations encoding amino acid substitutions were found in the gene SAM and SH3 domain containing 1 (SASH1). SASH1 was identified to interact with guanine nucleotide-binding protein subunit-alpha isoforms short (Gαs). However, for about 90 years, the pathological gene and the pathological mechanism of DUH are unclear. Our study indicates that SASH1 is physiologically medicated by p53 upon UV stimulation and a reciprocal SASH-p53 inducement is existed physiologically and pathophysiologically. A novel p53/POMC/α-MSH/Gαs/SASH1 signal cascade regulates SASH1 to foster melanogenesis. SASH1 mutations control a novel p53/POMC/Gαs/SASH1 autoregulatory positive feedback loop to promote pathological hyperpigmentation phenotype in DUH-affected individuals. Our work illustrates a novel p53/POMC/Gαs/SASH1 autoregulatory positive feedback loop that is mediated by SASH1 mutations to foster pathological hyperpigmentation phenotype

Novel prognostic signature for hepatocellular carcinoma using a comprehensive machine learning framework to predict prognosis and guide treatment

BackgroundHepatocellular carcinoma (HCC) is highly aggressive, with delayed diagnosis, poor prognosis, and a lack of comprehensive and accurate prognostic models to assist clinicians. This study aimed to construct an HCC prognosis-related gene signature (HPRGS) and explore its clinical application value.MethodsTCGA-LIHC cohort was used for training, and the LIRI-JP cohort and HCC cDNA microarray were used for validation. Machine learning algorithms constructed a prognostic gene label for HCC. Kaplan–Meier (K-M), ROC curve, multiple analyses, algorithms, and online databases were used to analyze differences between high- and low-risk populations. A nomogram was constructed to facilitate clinical application.ResultsWe identified 119 differential genes based on transcriptome sequencing data from five independent HCC cohorts, and 53 of these genes were associated with overall survival (OS). Using 101 machine learning algorithms, the 10 most prognostic genes were selected. We constructed an HCC HPRGS with four genes (SOCS2, LCAT, ECT2, and TMEM106C). Good predictive performance of the HPRGS was confirmed by ROC, C-index, and K-M curves. Mutation analysis showed significant differences between the low- and high-risk patients. The low-risk group had a higher response to transcatheter arterial chemoembolization (TACE) and immunotherapy. Treatment response of high- and low-risk groups to small-molecule drugs was predicted. Linifanib was a potential drug for high-risk populations. Multivariate analysis confirmed that HPRGS were independent prognostic factors in TCGA-LIHC. A nomogram provided a clinical practice reference.ConclusionWe constructed an HPRGS for HCC, which can accurately predict OS and guide the treatment decisions for patients with HCC

Dynamic changes of soil microorganisms in rotation farmland at the western foot of the Greater Khingan range

Crop rotation and other tillage systems can affect soil microbial communities and functions. Few studies have reported the response of soil spatial microbial communities to rotation under drought stress. Therefore, the purpose of our study was to explore the dynamic changes of the soil space microbial community under different drought stress-rotation patterns. In this study, two water treatments were set up, control W1 (mass water content 25%–28%), and drought W2 (mass water content 9%–12%). Four crop rotation patterns were set in each water content, spring wheat continuous (R1), spring wheat-potato (R2), spring wheat-potato-rape (R3) and spring wheat-rape (R4), for a total of eight treatments (W1R1, W1R2, W1R3, W1R4, W2R1, W2R2, W2R3, W2R4). Endosphere, rhizosphere and bulk soil of spring wheat in each treatment were collected, and root space microbial community data were generated. The soil microbial community changed under different treatments and their relationship with soil factors were analyzed using a co-occurrence network, mantel test, and other methods. The results revealed that the alpha diversity of microorganisms in the rhizosphere and bulk soil did not differ significantly, but it was significantly greater than in the endosphere. The bacteria community structure was more stable, fungi alpha-diversity significant changes (p < 0.05), that were more sensitive to the response of various treatments than bacteria. The co-occurrence network between fungal species was stable under rotation patterns (R2, R3, R4), while the community stability was poor under continuous cropping pattern (R1), and interactions were strengthened. Soil organic matter (SOM), microbial biomass carbon (MBC), and pH value were the most important factors dominating the bacteria community structural changed in the endosphere, rhizosphere, and bulk soil. The dominant factor that affected the fungal community structural changed in the endosphere, rhizosphere, and bulk soil was SOM. Therefore, we conclude that soil microbial community changes under the drought stress-rotation patterns are mainly influenced by soil SOM and microbial biomass content

Experiment Research on the Mechanical Performance of Alkali-activated Slag Cementitious Material

Abstract The influence of three different kinds of alkali (sodium hydroxide, sodium sulfate and water glass) excitation agents on the mechanical properties of slag cement materials has been studied by compressive test. The results show that the effect of excitation of sodium silicate is better than that of sodium hydroxide and sodium sulfate, with the increase of alkali equivalent excitation agent, compressive strength of mortar specimens remarkably, compared with alkali equivalent of 3.1% of the sodium sulfate, the 28d compressive strength of mortar specimens with alkali equivalent of 4.65% and 6.2%, has been increased by 140% and 31.5% respectively.</jats:p