A rat HIRI model was constructed and treated with an intraperitoneal injection of agomir-miR-494 or agomir-NC (negative control) for 7 days after the surgery. The pathophysiological changes in sham-operated rats, HIRI, HIRI + agomir-miR-494, and HIRI + agomir-NC were compared. The effect of miR-494 was also assessed in an H2O2-induced apoptosis model. Hepatic AML12 cells were transfected with mimics NC or miR-494 mimics, followed by 6-h H2O2 treatment. Cell proliferation and apoptosis were detected by CCK8 assay and flow cytometry, respectively. Further, the miR-494 target gene was identified by luciferase reporter assay, and verified both in vitro and in vivo experiments. The activity of AKT pathway was further analyzed in vivo by Western blot. HIRI + agomir-miR-494 rats exhibited significantly higher miR-494 expression, lower serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), and glutamate dehydrogenase (GLDH) level, lower hepatic MDA, TOA, and OSI, alleviated hepatic necrosis, reduced hepatocyte apoptosis, and decreased expression of apoptosis-related proteins, when compared with HIRI + agomir-NC rats (P<0.05 or 0.01). After H2O2 treatment, AML-12 cells transfected with miR-494 mimics had significantly higher proliferation and lower apoptosis rate compared with mimics NC group (P<0.01). PTEN was identified as an miR-494 target gene. PTEN expression was significantly down-regulated in AML12 cells transfected with miR-494 mimics, and was up-regulated by treatment of miR-494 inhibitor (P<0.01). Moreover, HIRI + agomir-miR-494 rats exhibited significantly lower PTEN expression, and higher p-AKT, p-mTOR, and p-p70S6K levels compared with HIRI + agomir-NC rats. Therefore, miR-494 protected rats against hepatic ischemia/reperfusion (I/R) injury through down-regulating its downstream target gene PTEN, leading to the activation of PI3K/AKT signaling pathway.
Background and aims Chronic liver disease (CLD) patients and liver transplant (LT) recipients have an increased risk of morbidity and mortality from coronavirus disease 2019 (COVID‐19). The immunogenicity of COVID‐19 vaccines in CLD patients and LT recipients is poorly understood. The present study aimed to evaluate the immunogenicity of COVID‐19 vaccines in CLD patients and LT recipients. Methods We searched electronic databases for eligible studies. Two reviewers independently conducted the literature search, extracted the data and assessed the risk of bias of included studies. The rates of detectable immune response were pooled from single‐arm studies. For comparative studies, we compared the rates of detectable immune response between patients and healthy controls. The meta‐analysis was conducted using the Stata software with a random‐effects model. Results In total, 19 observational studies involving 4191 participants met the inclusion criteria. The pooled rates of detectable humoral immune response after two doses of COVID‐19 vaccination in CLD patients and LT recipients were 95% (95% confidence interval [CI] = 88%–99%) and 66% (95% CI = 57%–74%) respectively. After two doses of vaccination, the humoral immune response rate was similar in CLD patients and healthy controls (risk ratio [RR] = 0.96; 95% CI = 0.90–1.02; p = .14). In contrast, LT recipients had a lower humoral immune response rate after two doses of vaccination than healthy controls (RR = 0.68; 95% CI = 0.59–0.77; p < .01). Our meta‐analysis demonstrated that COVID‐19 vaccination induced strong humoral immune responses in CLD patients but poor humoral immune responses in LT recipients.
Background Some genetic association studies tried to investigate potential associations of transmembrane 6 superfamily member 2 (TM6SF2) polymorphisms with chronic liver disease. However, the results of these studies were not consistent. Thus, we performed the present meta‐analysis to explore associations between TM6SF2 polymorphisms and chronic liver disease in a larger pooled population. Methods Systematic literature research of PubMed, Web of Science, Embase, and CNKI was performed to identify eligible studies for pooled analyses. I2 statistics were employed to assess between‐study heterogeneities. If I2 was greater than 50%, random‐effect models (REMs) would be used to pool the data. Otherwise, fixed‐effect models (FEMs) would be applied for synthetic analyses. Results Totally 28 studies were included for analyses (13,137 cases and 11,010 controls). The pooled analyses showed that rs58542926 polymorphism was significantly associated with chronic liver disease in overall population (dominant model: p < 0.0001, OR = 0.70, 95% CI = 0.64–0.76, I2 = 47%; recessive model: p < 0.0001, OR = 2.94, 95% CI = 2.05–4.20, I2 = 0%; over‐dominant model: p < 0.0001, OR = 1.34, 95% CI = 1.23–1.47, I2 = 0%; allele model: p < 0.0001, OR = 0.68, 95% CI = 0.63–0.73, I2 = 47%), and these significant findings were further confirmed in both Asians and Caucasians. Stratified analyses by type of disease revealed similar positive results in hepatocellular carcinoma (HCC), cirrhosis, alcoholic liver disease (ALD) and NAFLD (Nonalcoholic fatty liver disease), but not in chronic hepatitis B infection (CHB) and chronic hepatitis C infection (CHC). Conclusions These results suggested that TM6SF2 rs58542926 could be used to identify individuals at higher susceptibility to chronic liver disease, especially for HCC, cirrhosis, ALD, and NAFLD.
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