MicroRNAs (miRNAs) have been demonstrated to modulate cellular processes in the liver. However, the role of miRNAs in liver fibrosis is poorly understood. Because the activation of hepatic stellate cells (HSCs) is a pivotal event in the initiation and progression of hepatic fibrosis, we investigate the differential expression of miRNAs in activated and quiescent rat HSCs by microarray analysis and find that miR-214 (miR-214-3p) is significantly upregulated during HSC activation. Moreover, the robust induction of miR-214 is correlated with liver fibrogenesis in carbon tetrachloride (CCl4)-treated rats and mice, high-fat diet-induced non-alcoholic steatohepatitis in mice, and cirrhosis in humans. We identify that miR-214 expression is driven by the helix–loop–helix transcription factor Twist1 via the E-box element. The increased miR-214 inhibits the expression of suppressor-of-fused homolog (Sufu), a negative regulator of the Hedgehog signaling pathway, thereby contributing to HSC activation to promote the accumulation of fibrous extracellular matrix and the expression of profibrotic genes in HSCs and LX2 cells. Furthermore, miR-214 expression is inversely correlated with the expression of Sufu in clinical cirrhosis samples. To explore the clinical potential of miR-214, we inject antagomiR-214 oligos into mice to induce hepatic fibrosis. The knockdown of miR-214 in vivo enhances Sufu expression and reduces fibrosis marker expression, which ameliorates liver fibrosis in mice. In conclusions, the Twist1-regulated miR-214 promotes the activation of HSC cells through targeting Sufu involved in the Hedgehog pathway and participates in the development of hepatic fibrosis. Hence, the knockdown of miR-214 expression may be a promising therapeutic strategy for liver fibrosis.

Background/Aims: Autoimmune hepatitis (AIH) is a chronic necroinflammatory disease of the liver whose pathogenic mechanisms have not yet been elucidated. Moreover, the current treatment used for the vast majority of AIH patients is largely dependent on immunosuppressant administration and liver transplantation. However, research on the pathogenesis of AIH and effective new treatments for AIH have been hampered by a lack of animal models that accurately reproduce the human condition. Methods: AIH models created by concanavalin A (ConA) injections at different times and doses. The levels of ALT, AST, LDH and inflammatory cytokines were examined at various times after 20 mg/kg ConA was administered by ELISA using commercially available kits. Moreover, liver pathological changes were observed by flow cytometry (FCM) and H&E staining. Results: Our experiments demonstrated that the levels of ALT, AST, LDH and several inflammatory cytokines, including TNF-α, IFN-γ, and IL-6, were higher in the 20 mg/kg 12 h ConA group than in the other groups. Importantly, the numbers of activated CD4⁺ and CD8⁺ T lymphocytes in the blood, spleen and liver were calculated. These results showed that ConA (20 mg/kg for 12 h)-induced hepatitis was similar to that in clinical AIH patients. Furthermore, we found that the number of MDSCs in the blood was significantly increased in the ConA (20 mg/kg for 12 h) group compared with controls. Our findings indicated that ConA (20 mg/kg for 12 h)-induced hepatitis could be used as an experimental murine model that mirrors most of the pathogenic properties of human type I AIH. Conclusion: This model [ConA (20 mg/kg for 12 h)] provides a valuable tool for studying AIH immunopathogenesis and rapidly assessing novel therapeutic approaches.

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Circulating Nogo-B may be an effective indicator for liver cirrhosis. Nogo-B inhibition could diminish HSC activation, in which alleviating ER stress may be one of the mechanisms, suggesting a potential approach to interference Nogo-B in liver fibrosis.

The effectiveness of standard triple therapy (STT) for the eradication of Helicobacter pylori has decreased recently. Sequential therapy (SQT) is a new regimen proposed to address this problem. The aim of this study was to compare the efficacy of SQT versus STT for H. pylori eradication. We searched The Cochrane Library, MEDLINE, Web of Science, and EMBASE databases up to July 2014. The risk ratios (RRs) of eradication rate were pooled, with a 95% confidence interval (CI). Thirty-six randomized clinical trials including a total of 10,316 patients met the inclusion criteria. The RR for eradication of H. pylori with SQT compared with STT was 1.14 (95% CI: 1.09-1.17), the eradication rates were 84.1% and 75.1%, respectively. There was significant heterogeneity between trial results (I = 73%; P < 0.00001). Subgroup analyses showed that SQT was superior to both 7- and 10-day STT, but not significantly better than 14-day STT. This superiority existed when patients were treated with either metronidazole or tinidazole. Patients with single clarithromycin-resistant strain showed a greater benefit of SQT over STT (eradication rates 80.9% vs. 40.7%), RR = 1.98 (95% CI: 1.33-2.94). There was no significant difference between groups in terms of the risk of adverse effects. In conclusion, SQT is more efficacious than STT (7 days and 10 days) in the eradication of HP, but the pooled rate seemed suboptimal. Further research is needed to develop more effective therapeutic approaches. Surveillance of resistance rates should be performed to guide treatment.

The aim of this study was to investigate the influence of NUDT15 R139C and thiopurine S-methyltransferase ( TPMT ) on azathioprine (AZA) induced leukopenia in patients with autoimmune hepatitis (AIH) and related cirrhosis. A total of 149 Chinese AIH patients with a history of AZA treatment were retrospectively evaluated. The clinical and epidemiological characteristics of the patients were obtained from an electronic database and reviewed. NUDT15 (rs116855232) and TPMT ∗ 3C (rs1142345) SNPs were genotyped using a PCR method. Twelve patients developed leukopenia, and this adverse drug reaction was significantly associated with the T risk allele in NUDT15 [ P < 0.00001, odds ratio = 20.41; 95% confidence interval (CI) (7.84, 53.13)], with the sensitivity and specificity of 91.67 and 89.05%, respectively. The median maintenance dosages for patients with the rs116855232 CC and CT genotypes were 1.23 (0.95, 1.53) mg ⋅ kg −1 ⋅ d −1 and 0.96 (0.83, 1.19) mg ⋅ kg −1 ⋅ d −1 , respectively ( P = 0.028). In contrast, no significant association was observed for TPMT ∗ 3C genotypes. Notably, subgroup analysis of the 13 patients with leukopenia before therapy, these white blood cell (WBC) counts did not show further reduction after AZA treatment and maintenance dosage was 1.13 (0.94, 1.60) mg ⋅ kg −1 ⋅ d −1 . Therefore, NUDT15 polymorphism is significantly associated with thiopurine-induced leukopenia in Chinese patients with AIH and related cirrhosis. Adjusting the AZA dosage should be considered in patients according to the NUDT15 R139C genotypes.

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