Gut bacteria alleviate smoking-related NASH by degrading gut nicotine.

Tobacco smoking is positively correlated with non-alcoholic fatty liver disease (NAFLD)1-5, but the underlying mechanism for this association is unclear. Here we report that nicotine accumulates in the intestine during tobacco smoking and activates intestinal AMPKα. We identify the gut bacterium Bacteroides xylanisolvens as an effective nicotine degrader. Colonization of B. xylanisolvens reduces intestinal nicotine concentrations in nicotine-exposed mice, and it improves nicotine-exacerbated NAFLD progression. Mechanistically, AMPKα promotes the phosphorylation of sphingomyelin phosphodiesterase 3 (SMPD3), stabilizing the latter and therefore increasing intestinal ceramide formation, which contributes to NAFLD progression to non-alcoholic steatohepatitis (NASH). Our results establish a role for intestinal nicotine accumulation in NAFLD progression and reveal an endogenous bacterium in the human intestine with the ability to metabolize nicotine. These findings suggest a possible route to reduce tobacco smoking-exacerbated NAFLD progression.

SETDB2 interacts with BUBR1 to induce accurate chromosome segregation independently of its histone methyltransferase activity.

SETDB2 is a H3K9 histone methyltransferase required for accurate chromosome segregation. Its H3K9 histone methyltransferase activity was reported to be associated with chromosomes during metaphase. Here, we confirm that SETDB2 is required for mitosis and accurate chromosome segregation. However, these functions are independent of its histone methyltransferase activity. Further analysis showed that SETDB2 can interact with BUBR1, and is required for CDC20 binding to BUBR1 and APC/C complex and CYCLIN B1 degradation. The ability of SETDB2 to regulate the binding of CDC20 to BUBR1 or APC/C complex, and stabilization of CYCLIN B1 are also independent of its histone methyltransferase activity. These results suggest that SETDB2 interacts with BUBR1 to promote binding of CDC20 to BUBR1 and APC3, then degrades CYCLIN B1 to ensure accurate chromosome segregation and mitosis, independently of its histone methyltransferase activity.

Sphingosine d18:1 promotes nonalcoholic steatohepatitis by inhibiting macrophage HIF-2α.

Non-alcoholic steatohepatitis (NASH) is a severe type of the non-alcoholic fatty liver disease (NAFLD). NASH is a growing global health concern due to its increasing morbidity, lack of well-defined biomarkers and lack of clinically effective treatments. Using metabolomic analysis, the most significantly changed active lipid sphingosine d18:1 [So(d18:1)] is selected from NASH patients. So(d18:1) inhibits macrophage HIF-2α as a direct inhibitor and promotes the inflammatory factors secretion. Male macrophage-specific HIF-2α knockout and overexpression mice verified the protective effect of HIF-2α on NASH progression. Importantly, the HIF-2α stabilizer FG-4592 alleviates liver inflammation and fibrosis in NASH, which indicated that macrophage HIF-2α is a potential drug target for NASH treatment. Overall, this study confirms that So(d18:1) promotes NASH and clarifies that So(d18:1) inhibits the transcriptional activity of HIF-2α in liver macrophages by suppressing the interaction of HIF-2α with ARNT, suggesting that macrophage HIF-2α may be a potential target for the treatment of NASH.

[Psychological intervention for negative emotion and quality of life of patients with head and neck cancer (HNC): a meta-analysis].

PURPOSE: To systematically assess the efficacy of psychological intervention for patients with head and neck cancer (HNC) in easing negative emotion and improving quality of life, so as to provide evidence-based reference for clinical psycho-intervention of HNC patients. METHODS: PubMed, Central, Embase, clinicaltrials.gov, ICTRP, Web of science, CBM, CNKI, VIP, and Wan Fang database were searched from inception to 15th, May for randomized controlled trails conducted to assess psychological intervention for HNC patients. The retrieval, screening, quality evaluation, and data extraction were elaborately proceeded by two reviewers independently. Meta analysis was performed using RevMan 5.4 software. RESULTS: Eighteen RCTs were included with 2 097 participants. Meta analysis showed that compared to control group, psychological intervention group manifested greater decrease in anxiety scores [SMD=-2.33, 95%CI（-2.96，-1.70）, P＜0.000 01] and depression scores [SMD=-2.26, 95%CI（-2.78，-1.74）, P＜0.000 01], and better increase in QOL scores [SMD=6.04, 95%CI（1.53，10.56）, P=0.009] and SQL-90 scores [MD=29.99, 95%CI（-36.22, -23.76），P＜0.000 01]. CONCLUSIONS: The anxiety and depression of HNC patients can be effectively relieved through psychological intervention, so that their quality of life and metal health status can be improved. Due to the limitation of quality of included RCT , the result remains to be further validated by more well-designed and better-qualified study.

Lithocholic acid promotes rosacea-like skin inflammation via G protein-coupled bile acid receptor 1.

BACKGROUND: Rosacea is a chronic inflammatory skin disorder with unclear etiology. Evidence showed that immunoinflammatory dysregulation was involved in the pathogenesis. Bile acids, as important participants of hepatoenteric circulation, play a vital role in immunoinflammatory regulation through peripheral blood circulation. However, whether it has effects on rosacea remains unknown. METHODS: Here, we performed a bile acid analysis on the serum samples of rosacea patients and healthy controls. Then we gavage G protein-coupled bile acid receptor 1 (TGR5) knockout mice with lithocholic acid (LCA) based on a LL37-induced rosacea-like model. We further overexpress TGR5 in HaCaT keratinocytes to figure out the downstream pathway. RESULTS: We found varied bile acid profile in the peripheral blood circulation of patients, especially the most significant increase in LCA. LCA promoted skin inflammation in LL37-induced rosacea-like mouse model. Our in vivo and in vitro results further demonstrated that LCA induced inflammatory cytokines and chemokines, thus exacerbated rosacea-like skin inflammation, via TGR5 in keratinocytes and LL37-induced rosacea-like mouse model. CONCLUSIONS: Therefore, we conclude that LCA promotes skin inflammation of rosacea via TGR5, and LCA-TGR5 axis may be a novel therapeutic target for rosacea.

Transcutaneous electrical acupoint stimulation (TEAS) for cancer-related fatigue: study protocol for a systematic review and meta-analysis.

INTRODUCTION: Cancer-related fatigue (CRF) is a prevalent symptom in cancer survivors. Transcutaneous electrical acupoint stimulation (TEAS) has been reported as a promising therapy for CRF. This protocol is proposed for a systematic review that aims to assess the efficacy and safety of TEAS for CRF. METHODS AND ANALYSIS: Cochrane Central Register of Controlled Trials, PubMed, Medline, Embase, Chinese National Knowledge Infrastructure, VIP, Wanfang database, Chinese Biomedical Literature Database, Chinese Clinical Trial Registry System, ClinicalTrials.gov and WHO International Clinical Trial Registry Platform will be searched from inception to 31 January 2021 without language limitations. The eligible randomised controlled trials will be included. The primary outcomes include changes in the revised Piper fatigue scale, the Brief fatigue inventory, the Multidimensional fatigue inventory and the Functional assessment of chronic illness therapy fatigue. The secondary outcomes are the quality-of-life measurement index, the Hamilton anxiety scale, the Hamilton depression scale and adverse events. The selection of studies, data extraction and assessment of risk of bias will be conducted independently by two reviewers. Data synthesis will be performed using RevMan V.5.4.1. The quality of evidence will be evaluated with the Grading of Recommendations, Assessment, Development and Evaluation system. This study will strictly adhere to the Preferred Reporting Items for Systematic Review and Meta-Analysis guidelines. ETHICS AND DISSEMINATION: Ethical approval is not required as this is a systematic review and meta-analysis based on previously published studies involving no private information of patients. The results of this study will be disseminated in a peer-reviewed journal. PROSPERO REGISTRATION NUMBER: CRD42020220282.

Human Microbiome and Its Medical Applications.

The commensal microbiome is essential for human health and is involved in many processes in the human body, such as the metabolism process and immune system activation. Emerging evidence implies that specific changes in the microbiome participate in the development of various diseases, including diabetes, liver diseases, tumors, and pathogen infections. Thus, intervention on the microbiome is becoming a novel and effective method to treat such diseases. Synthetic biology empowers researchers to create strains with unique and complex functions, making the use of engineered microbes for clinical applications attainable. The aim of this review is to summarize recent advances about the roles of the microbiome in certain diseases and the underlying mechanisms, as well as the use of engineered microbes in the prevention, detection, and treatment of various diseases.

Flow-diverting device versus coil embolization for unruptured intracranial aneurysm: A meta-analysis.

BACKGROUND: Both coil embolization (CE) and flow-diverting device (FDD) placement are widely used for treatment of intracranial aneurysms (IAs). The aim of this meta-analysis is to compare the relative clinical safety and efficacy of FDD and CE for the treatment of unruptured IAs. METHODS: The PubMed, Embase, and Cochrane Library databases were searched for relevant studies from the date of inception through April 2020. The primary endpoint for this meta-analysis was the 6-month rate of complete occlusion, while secondary endpoints included rates of retreatment, complications, and parental arterial patency. RESULTS: This meta-analysis includes 8 studies, which included 839 total patients that underwent FDD and 2734 that underwent CE. FDD group exhibited a significantly higher pooled 6-month complete occlusion rate (P = .02). The subgroup analysis demonstrated that FDD treatment was associated with significantly higher pooled 6-month complete occlusion rates in patients with large or giant IAs (P < .00001), whereas no differences in 6-month complete occlusion rates were observed between the FDD and CE groups of patients with non-large/giant IAs (P = .83). The pooled retreatment (P = .16) and complication (P = .15) rates were comparable between 2 groups. The CE group exhibited significantly higher pooled parent artery patency rate (P = .01). The funnel plots did not reveal any evidence of publication bias. CONCLUSIONS: FDDs can be used to effectively and safely treat large and giant IAs, achieving higher rates of complete occlusion than CE treatment. For non-large/giant IAs, we observed comparable efficacy between FDD and CE treatments.

Natural Products in Modulating Methamphetamine-Induced Neuronal Apoptosis.

Methamphetamine (METH), an amphetamine-type psychostimulant, is highly abused worldwide. Chronic abuse of METH causes neurodegenerative changes in central dopaminergic neurons with numerous neuropsychiatric consequences. Neuronal apoptosis plays a critical role in METH-induced neurotoxicity and may provide promising pharmacological targets for preventing and treating METH addiction. In recent years, accumulating evidence has revealed that natural products may possess significant potentials to inhibit METH-evoked neuronal apoptosis. In this review, we summarized and analyzed the improvement effect of natural products on METH-induced neuronal apoptosis and their potential molecular mechanisms on modulating dopamine release, oxidative stress, mitochondrial-dependent apoptotic pathway, endoplasmic reticulum stress-mediated apoptotic pathway, and neuroinflammation. Hopefully, this review may highlight the potential value of natural products in modulating METH-caused neuronal apoptosis and provide useful information for future research and developments of novel and efficacious pharmacotherapies in this field.

Macrophage HIF-2α suppresses NLRP3 inflammasome activation and alleviates insulin resistance.

The interrelation between hypoxia and immune response has pivotal roles in the pathogenesis of chronic metabolic diseases. However, the role of macrophage HIF-2α in NLRP3 inflammasome activation remains unclear. Here, we show that deficiency of HIF-2α in macrophages results in excessive activation of the NLRP3 inflammasome in a manner dependent on CPT1A-mediated enhancement of fatty acid oxidation (FAO). Mechanistically, HIF-2α binds directly to the Cpt1a promoter and is involved in the regulation of H3K27me3 methylation during NLRP3 inflammasome activation. Myeloid-specific Hif2α knockout mice exhibit exacerbated insulin resistance and increased activation of NLRP3 inflammasome in macrophages. Overexpression of the Hif2α gene or stabilization of the protein by FG-4592 ameliorates insulin resistance and reduces NLRP3 inflammasome activation in macrophages. Taken together, our results suggest that macrophage HIF-2α inhibits FAO-mediated activation of the NLRP3 inflammasome and alleviates insulin resistance.

Suppressing the intestinal farnesoid X receptor/sphingomyelin phosphodiesterase 3 axis decreases atherosclerosis.

Intestinal farnesoid X receptor (FXR) signaling is involved in the development of obesity, fatty liver disease, and type 2 diabetes. However, the role of intestinal FXR in atherosclerosis and its potential as a target for clinical treatment have not been explored. The serum levels of fibroblast growth factor 19 (FGF19), which is encoded by an FXR target gene, were much higher in patients with hypercholesterolemia than in control subjects and were positively related to circulating ceramide levels, indicating a link between intestinal FXR, ceramide metabolism, and atherosclerosis. Among ApoE-/- mice fed a high-cholesterol diet (HCD), intestinal FXR deficiency (in FxrΔIE ApoE-/- mice) or direct FXR inhibition (via treatment with the FXR antagonist glycoursodeoxycholic acid [GUDCA]) decreased atherosclerosis and reduced the levels of circulating ceramides and cholesterol. Sphingomyelin phosphodiesterase 3 (SMPD3), which is involved in ceramide synthesis in the intestine, was identified as an FXR target gene. SMPD3 overexpression or C16:0 ceramide supplementation eliminated the improvements in atherosclerosis in FxrΔIE ApoE-/- mice. Administration of GUDCA or GW4869, an SMPD3 inhibitor, elicited therapeutic effects on established atherosclerosis in ApoE-/- mice by decreasing circulating ceramide levels. This study identified an intestinal FXR/SMPD3 axis that is a potential target for atherosclerosis therapy.

Hyocholic acid species improve glucose homeostasis through a distinct TGR5 and FXR signaling mechanism.

Hyocholic acid (HCA) and its derivatives are found in trace amounts in human blood but constitute approximately 76% of the bile acid (BA) pool in pigs, a species known for its exceptional resistance to type 2 diabetes. Here, we show that BA depletion in pigs suppressed secretion of glucagon-like peptide-1 (GLP-1) and increased blood glucose levels. HCA administration in diabetic mouse models improved serum fasting GLP-1 secretion and glucose homeostasis to a greater extent than tauroursodeoxycholic acid. HCA upregulated GLP-1 production and secretion in enteroendocrine cells via simultaneously activating G-protein-coupled BA receptor, TGR5, and inhibiting farnesoid X receptor (FXR), a unique mechanism that is not found in other BA species. We verified the findings in TGR5 knockout, intestinal FXR activation, and GLP-1 receptor inhibition mouse models. Finally, we confirmed in a clinical cohort, that lower serum concentrations of HCA species were associated with diabetes and closely related to glycemic markers.

TMEM16A Ca2+-activated Cl- channel inhibition ameliorates acute pancreatitis via the IP3R/Ca2+/NFκB/IL-6 signaling pathway.

TMEM16A Ca2+-activated Cl- channels are expressed in pancreatic acinar cells and participate in inflammation-associated diseases. Whether TMEM16A contributes to the pathogenesis of acute pancreatitis (AP) remains unknown. Here, we found that increased TMEM16A expression in the pancreatic tissue was correlated with the interleukin-6 (IL-6) level in the pancreatic tissue and in the serum of a cerulein-induced AP mouse model. IL-6 treatment promoted TMEM16A expression in AR42J pancreatic acinar cells via the IL-6 receptor (IL-6R)/signal transducers and activators of transcription 3 (STAT3) signaling pathway. In addition, TMEM16A was co-immunoprecipitated with the inositol 1,4,5-trisphosphate receptor (IP3R) and was activated by IP3R-mediated Ca2+ release. TMEM16A inhibition reduced the IP3R-mediated Ca2+ release induced by cerulein. Furthermore, TMEM16A overexpression activated nuclear factor-κB (NFκB) and increased IL-6 release by increasing intracellular Ca2+. TMEM16A knockdown by shRNAs reduced the cerulein-induced NFκB activation by Ca2+. TMEM16A inhibitors inhibited NFκB activation by decreasing channel activity and reducing TMEM16A protein levels in AR42J cells, and it ameliorated pancreatic damage in cerulein-induced AP mice. This study identifies a novel mechanism underlying the pathogenesis of AP by which IL-6 promotes TMEM16A expression via IL-6R/STAT3 signaling activation, and TMEM16A overexpression increases IL-6 secretion via IP3R/Ca2+/NFκB signaling activation in pancreatic acinar cells. TMEM16A inhibition may be a new potential strategy for treating AP.

Gut microbiota-bile acid-interleukin-22 axis orchestrates polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is characterized by androgen excess, ovulatory dysfunction and polycystic ovaries1, and is often accompanied by insulin resistance2. The mechanism of ovulatory dysfunction and insulin resistance in PCOS remains elusive, thus limiting the development of therapeutics. Improved metabolic health is associated with a relatively high microbiota gene content and increased microbial diversity3,4. This study aimed to investigate the impact of the gut microbiota and its metabolites on the regulation of PCOS-associated ovarian dysfunction and insulin resistance. Here, we report that Bacteroides vulgatus was markedly elevated in the gut microbiota of individuals with PCOS, accompanied by reduced glycodeoxycholic acid and tauroursodeoxycholic acid levels. Transplantation of fecal microbiota from women with PCOS or B. vulgatus-colonized recipient mice resulted in increased disruption of ovarian functions, insulin resistance, altered bile acid metabolism, reduced interleukin-22 secretion and infertility. Mechanistically, glycodeoxycholic acid induced intestinal group 3 innate lymphoid cell IL-22 secretion through GATA binding protein 3, and IL-22 in turn improved the PCOS phenotype. This finding is consistent with the reduced levels of IL-22 in individuals with PCOS. This study suggests that modifying the gut microbiota, altering bile acid metabolism and/or increasing IL-22 levels may be of value for the treatment of PCOS.

Publisher Correction: Gut microbiota-bile acid-interleukin-22 axis orchestrates polycystic ovary syndrome.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Gut microbiota and intestinal FXR mediate the clinical benefits of metformin.

The anti-hyperglycemic effect of metformin is believed to be caused by its direct action on signaling processes in hepatocytes, leading to lower hepatic gluconeogenesis. Recently, metformin was reported to alter the gut microbiota community in humans, suggesting that the hyperglycemia-lowering action of the drug could be the result of modulating the population of gut microbiota. However, the critical microbial signaling metabolites and the host targets associated with the metabolic benefits of metformin remained elusive. Here, we performed metagenomic and metabolomic analysis of samples from individuals with newly diagnosed type 2 diabetes (T2D) naively treated with metformin for 3 d, which revealed that Bacteroides fragilis was decreased and the bile acid glycoursodeoxycholic acid (GUDCA) was increased in the gut. These changes were accompanied by inhibition of intestinal farnesoid X receptor (FXR) signaling. We further found that high-fat-diet (HFD)-fed mice colonized with B. fragilis were predisposed to more severe glucose intolerance, and the metabolic benefits of metformin treatment on glucose intolerance were abrogated. GUDCA was further identified as an intestinal FXR antagonist that improved various metabolic endpoints in mice with established obesity. Thus, we conclude that metformin acts in part through a B. fragilis-GUDCA-intestinal FXR axis to improve metabolic dysfunction, including hyperglycemia.