Intestinal IL-33 promotes microbiota-derived trimethylamine N -oxide synthesis and drives metabolic dysfunction-associated steatotic liver disease progression by exerting dual regulation on HIF-1α.

BACKGROUND AND AIMS: Gut microbiota plays a prominent role in the pathogenesis of metabolic dysfunction-associated steatotic liver disease (MASLD). IL-33 is highly expressed at mucosal barrier sites and regulates intestinal homeostasis. Herein, we aimed to investigate the role and mechanism of intestinal IL-33 in MASLD. APPROACH AND RESULTS: In both humans and mice with MASLD, hepatic expression of IL-33 and its receptor suppression of tumorigenicity 2 (ST2) showed no significant change compared to controls, while serum soluble ST2 levels in humans, as well as intestinal IL-33 and ST2 expression in mice were significantly increased in MASLD. Deletion of global or intestinal IL-33 in mice alleviated metabolic disorders, inflammation, and fibrosis associated with MASLD by reducing intestinal barrier permeability and rectifying gut microbiota dysbiosis. Transplantation of gut microbiota from IL-33 deficiency mice prevented MASLD progression in wild-type mice. Moreover, IL-33 deficiency resulted in a decrease in the abundance of trimethylamine N -oxide-producing bacteria. Inhibition of trimethylamine N -oxide synthesis by 3,3-dimethyl-1-butanol mitigated hepatic oxidative stress in mice with MASLD. Nuclear IL-33 bound to hypoxia-inducible factor-1α and suppressed its activation, directly damaging the integrity of the intestinal barrier. Extracellular IL-33 destroyed the balance of intestinal Th1/Th17 and facilitated Th1 differentiation through the ST2- Hif1a - Tbx21 axis. Knockout of ST2 resulted in a diminished MASLD phenotype resembling that observed in IL-33 deficiency mice. CONCLUSIONS: Intestinal IL-33 enhanced gut microbiota-derived trimethylamine N -oxide synthesis and aggravated MASLD progression through dual regulation on hypoxia-inducible factor-1α. Targeting IL-33 and its associated microbiota may provide a potential therapeutic strategy for managing MASLD.

Evaluation of the Efficacy and Safety of Chinese Herbal Injection Combined With Trimetazidine for Viral Myocarditis: A Network Meta-Analysis.

Background: Viral myocarditis (VMC) is a common emergency of cardiovascular disease. Current treatment for VMC includes the prohibition of exercise plus supportive and symptomatic treatment, given the lack of specific antiviral therapeutic options and insufficient evidence for the use of novel immunosuppressive therapies. Trimetazidine, a drug used to improve myocardial energy metabolism, is frequently used for the treatment of viral myocarditis. In China, Chinese herbal injections (CHIs) are often used in combination with trimetazidine. Therefore, we evaluate the efficacy and safety of CHI combined with trimetazidine in the treatment of VMC through the method of network meta-analysis. Methods: We searched PubMed, the Cochrane Library, Embase, China National Knowledge Infrastructure (CNKI), Wanfang Database, Chinese Scientific Journals Full-text Database (VIP), and China Biology Medicine Database (CBM) databases from inception to September 1, 2020, to identify eligible randomized controlled trials. The Cochrane risk of bias tool was used to assess the risk of bias among selected studies and the Stata 16.0 software was used to perform the network meta-analysis. Results: A total of 29 studies were included, representing data from 2,687 patients. The effectiveness rate, level of myocardial injury marker, and the adverse reaction rate were evaluated. Compared with conventional treatment or conventional treatment combined with trimetazidine, CHIs combined with trimetazidine appeared to have a better therapeutic effect, with higher effectiveness rate and better reduction of the levels of creatine kinase, creatine kinase-MB, and lactate dehydrogenase. Based on surface under the cumulative ranking, Shenmai injection combined with trimetazidine appeared to be superior in terms of effective rate, while Astragalus injection or Salviae miltiorrhizae and ligustrazine hydrochloride injection combined with trimetazidine appeared most effective in reducing myocardial injury markers. There was no significant difference in safety between the interventions. However, a lack of safety monitoring in some selected studies meant that the safety of some interventions could not be fully evaluated. Conclusion: CHIs combined with trimetazidine may have therapeutic value in the treatment of viral myocarditis, and Shenmai injection, Astragalus injection, and Salviae miltiorrhizae and ligustrazine hydrochloride injection may represent the most effective CHIs. Further clinical investigation is required to confirm these results.

[A dynamic study on titer of EB virus VCA/IgA and EA/IgA in nasopharygeal carcinoma patients].

OBJECTIVE: To analyze the change of EB virus VCA/IgA and EA/IgA titer during the development of nasopharyngeal carcinoma (NPC), and the role in screening for NPC. METHODS: VCA/IgA and EA/IgA were monitored in a period of 12 years by immunoenzymatic titration from the sera of 54 NPC patients after primary serological screening. RESULTS: VCA/IgA and EA/IgA titer had shown gradual increment 1 - 7 years before NPC was pathologically diagnosed. The mean titer of VCA/IgA was 1:21.04, 7 - 4 years before diagnosis. VCA/IgA titer ascended quickly within 3 years before diagnosis. The geometric mean titer (GMT) of VCA/IgA and EA/IgA were 1:76.86 and 1:6.49 when NPC was diagnosed, which descended quickly after radiotherapy and, in 4 years, approached the average titer of VCA/IgA positive population. CONCLUSION: VCA/IgA titer rises uninterruptedly 3 years before NPC is diagnosed pathologically in most patients but their EA/IgA titer rises slowly. The detection of VCA/IgA titer can be used to find early NPC, whereas EA/IgA can not. The pre-clinical phase of NPC is 3 years according to this dynamic study.

Epidemiological trends of nasopharyngeal carcinoma in China.

Research papers and data concerning NPC epidemiology in China available worldwide were reviewed. It was found that although the results of three national all death-causes sampling surveys in China showed mortality rates in most sampling areas and all as overall to be declining continuously and remarkably, figures for 1987-2000 in some selected areas of China released by the World Health Organization were relatively stable, and the NPC incidence and mortality rates reported by Zhongshan and Sihui cities of Guangdong Province in China had shown ascending or stable trends, respectively. Differences with regard to change in NPC incidence and mortality rates over time may be caused by variation in the data quality from divergent sources, but the exact reasons clearly warrant further analysis.