Maoyao Wen

Sequential Therapy or Standard Triple Therapy for Helicobacter pylori Infection: An Updated Systematic Review.

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 (I2 = 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.

Nogo‐B: A potential indicator for hepatic cirrhosis and regulator in hepatic stellate cell activation

To evaluate plasma Nogo‐B levels in liver cirrhotic patients and declare a novel molecular basis by which Nogo‐B modulates hepatic stellate cell (HSC) activation.

Involvement of miR-30c in hepatic stellate cell activation through the repression of plasminogen activator inhibitor-1

AIMS This study aimed to determine the role of miR-30c in the process of hepatic stellate cells (HSCs) activation and liver fibrosis/cirrhosis and to explore the underlying mechanism. MAIN METHODS A microarray analysis of miRNAs in HSCs was performed, and quantitative RT-PCR analyses were conducted to validate the results in HSCs, cirrhotic liver tissues and plasma. Rat HSCs were stimulated with angiotensin II (AngII) and transfected with miR-30c mimics/inhibitor to elucidate the underlying mechanism. KEY FINDINGS miR-30c was down-regulated during HSCs activation and in cirrhotic liver tissues and plasma. This miRNA was found to be involved in HSCs activation by repressing the expression of one of its target genes-plasminogen activator inhibitor-1 (PAI-1), and AngII stimulation decreased the expression of miR-30c. However, the up-regulation of miR-30c by specific mimics could down-regulate the mRNA and protein expression of α-SMA, a marker of HSCs activation, in AngII-stimulated HSCs and attenuate the AngII-induced activation of HSCs. SIGNIFICANCE miR-30c is involved in HSCs activation and might be a novel biomarker of liver fibrosis/cirrhosis.

MircoRNA-145 promotes activation of hepatic stellate cells via targeting krüppel-like factor 4

Krüppel-like Factor 4 (KLF4), a target gene of miR-145, can negatively regulate lung fibrosis. However, the potential role of KLF4 and miR-145 in hepatic stellate cells (HSCs) activation or in hepatic fibrosis keeps unclear. This study aims to characterize miR-145 and KLF4 in activated HSCs and liver cirrhotic, and the underlying molecular basis. miR-145 was significantly up-regulated, while KLF4 was dramatically down-regulated during the activation of rat primary HSCs and TGF-βtreated HSCs. Furthermore, miR-145 mimics induced and inhibition of miR-145 reduced α-SMA and COL-I expression in primary HSCs. Additionally, the mRNA and protein levels of KLF4 in the liver of cirrhotic patients and rats were significantly down-regulated. α-SMA and COL-I were increased after inhibition of KLF4 by specific shRNA in primary HSCs. Forced KLF4 expression led to a reduction of α-SMA and COL-I expression in HSCs. miR-145 promotes HSC activation and liver fibrosis by targeting KLF4.

MiR-142-3p blocks TGF-β-induced activation of hepatic stellate cells through targeting TGFβRI

Aim: To understand the contribution of miR‐142‐3p in the activation of hepatic stellate cells (HSCs) and liver fibrosis, and the underlying mechanism. Materials and methods: We detected microRNAs expression profiles in quiescent and activated HSCs by microRNA‐array, and performed qRT‐PCR to validate these data in HSCs and plasma of cirrhosis patients. In vitro, the 3rd–5th passage HSCs was transfected with mir‐142‐3p mimics or stimulated with TGF &bgr;. The markers of HSCs activation (i.e. FN and &agr;‐SMA) were examined by qRT‐PCR and western blotting, and cell viability was detected by MTT, colony formation assays respectively. Key finding: In our study, we identified miR‐142‐3p as a novel regulator of HSCs activation and indicator of hepatic cirrhosis. We found that miR‐142‐3p was significantly reduced in activated HSCs, while TGF&bgr;RI was distinctly up‐regulated in activated HSCs. Ectopic expression of miR‐142‐3p in activated HSCs inhibited cell viability as well as cell growth, and blocked HSCs activation, concomitant with decreased transdifferentiation markers (i.e. FN and &agr;‐SMA). Further, we confirmed that miR‐142‐3p was reduced upon TGF‐&bgr; exposure, while diminishing TGF‐&bgr;‐Smad signaling pathway in turn by reducing TGF&bgr;RI expression in HSCs. Besides, the plasma level of miR‐142‐3p declined significantly in patients with hepatic cirrhosis. Significance: In conclusion, we demonstrated that miR‐142‐3p repressed TGF‐&bgr;‐Smad signaling pathway to prevent HSCs activation through directly targeting TGF&bgr;RI in HSCs.

Comparison of Concanavalin a-Induced Murine Autoimmune Hepatitis Models

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.

MicroRNA-214 promotes hepatic stellate cell activation and liver fibrosis by suppressing Sufu expression

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.

Efficacy and Safety of Immunosuppressive Therapy for PBC-AIH Overlap Syndrome Accompanied by Decompensated Cirrhosis: A Real-World Study.

Aim To explore the efficacy and safety of immunosuppressive therapy for the treatment of primary biliary cirrhosis-autoimmune hepatitis (PBC-AIH) overlap syndrome accompanied by decompensated cirrhosis. Methods A cohort study was performed to evaluate the usefulness of immunosuppressive therapy in this unique group. This cohort study was performed between October 2013 and June 2017 and included 28 biopsy-proven patients diagnosed according to the Paris criteria. The therapies included ursodeoxycholic acid (UDCA) alone (N=14) or in combination with immunosuppression (IS) therapy (N=14). The primary endpoints were biochemical remission, liver-related adverse events, transplant-free survival, and drug side-effects. Results The frequency of biochemical remission for the AIH features was significantly higher in the UDCA+IS group than in the UDCA-only group (60.0 versus 9.1%, P=0.024) after 12 months of therapy but not after 3 and 6 months (28.6 versus 0%, P=0.165; 35.7 versus 7.1%, P=0.098). The rates of liver-related adverse events were lower in the combined group (2/14 versus 9/14, P=0.018). The Kaplan-Meier estimate showed that the transplant-free survival was distinct between the two groups (P=0.019). In the UDCA+IS group, mild and transient leukopenia occurred in two patients receiving azathioprine (AZA), and an infection was observed in one patient receiving mycophenolate mofetil (MMF). Conclusions PBC-AIH patients with decompensated cirrhosis receiving a combination of UDCA and immunosuppressors presented with higher biochemical remission rates and experienced fewer liver-related adverse events, implying that the combined treatment might be a better therapeutic option for strictly defined decompensated PBC-AIH overlap syndrome.

Does adding variceal status to the Child-Turcotte-Pugh score improve its performance in predicting mortality in cirrhosis?

AbstractThe Child–Turcotte–Pugh (CTP) score is widely used worldwide to predict outcomes across a broad spectrum of liver diseases, mainly cirrhosis. Portal hypertension and variceal bleed are significant causes of morbidity and mortality in cirrhotic patients, although the variceal status is not incorporated into the classical CTP score. We sought to determine whether the inclusion of variceal status, specifically the Child–Turcotte–Pugh–Kumar (CTPK) score, would improve the utility of the classical CTP score to predict the clinical outcomes of cirrhotic patients in a single but high-volume center in China.We retrospectively analyzed the records of 253 patients from January 1, 2014 to December 31, 2014 and performed follow-up for at least 12 months. The CTPK score and the CTP score were obtained as soon as possible after the patients admission. Telephone follow-up was performed to assess survival situations.At 3 and 12 months, the cumulative number of deaths was 9.1% (n = 23) and 13.8% (n = 35), respectively. In the multivariate Cox proportional hazards models, the CTPK score was independently associated with death within 3 and 12 months after adjusting for potential confounders. The predictive ability related to the 2 scores was evaluated by the area under the receiver operating characteristic curve (AUC-ROC) respectively. At 3 months of enrollment, the AUCs of CTPK and CTP were 0.814 and 0.838, respectively. At 12 months of enrollment, the AUCs of CTPK and CTP were 0.825 and 0.840, respectively. No significant difference between time points was observed. Both the CTPK score and the CTP score displayed prognostic value in cirrhotic patients, as the Kaplan–Meier analysis showed that the CTPK score could clearly discriminate patients in the intermediate term (P < 0.001).The CTPK score provides reliable prediction of mortality in Chinese cirrhotic patients for both short-term and medium-term prognoses, although it is not superior to the CTP score. Therefore, the CTP score remains an excellent tool for outcome prediction in patients with cirrhosis, and greater attention to variceal status may be in veins, even for patients with a history of variceal bleed or medium/large varices.

Infections in hospitalized patients with decompensated cirrhosis should be used in determining prognosis: a validation on a large Chinese cohort.

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