CB2R agonist GW405833 alleviates acute liver failure in mice via inhibiting HIF-1α-mediated reprogramming of glycometabolism and macrophage proliferation.

The inflammatory responses involving infiltration and activation of liver macrophages play a vital role in acute liver failure (ALF). In the liver of ALF mice, cannabinoid receptor 2 (CB2R) is significantly upregulated on macrophages, while CB2R agonist GW405833 (GW) could protect against cell death in acute liver damage. In this study, we investigated the molecular mechanisms underlying the protective effects of GW against ALF in vivo and in vitro from a perspective of macrophage glycometabolism. Mice were pretreated with GW (10 mg/kg, i.p.), then were injected with D-GalN (750 mg/kg, i.p.) and LPS (10 mg/kg, i.p.) to induce ALF. We verified the protective effects of GW pretreatment in ALF mice. Furthermore, GW pretreatment significantly reduced liver macrophage infiltration and M1 polarization, and inhibited the release of inflammatory factors TNF-α and IL-1ß in ALF mice. These protective effects were eliminated by CB2R antagonist SR144528 or in CB2R-/- ALF mice. We used LPS-stimulated RAW264.7 cells as an in vitro M1 macrophage-centered model of inflammatory response, and demonstrated that pretreatment with GW (10 µM) significantly reduced glucose metabolism by inhibiting glycolysis, which inhibited LPS-induced macrophage proliferation and inflammatory cytokines release. We verified these results in a stable CB2R-/- RAW264.7 cell line. Moreover, we found that GW significantly inhibited the expression of hypoxia inducible factor 1α (HIF-1α). Using a stable HIF-1α-/- RAW264.7 cell line, we confirmed that GW reduced the release of inflammatory cytokines from macrophages and inhibited glycolysis by downregulating HIF-1α expression. In conclusion, activation of CB2Rs inhibits the proliferation of hepatic macrophages and release of inflammatory factors in ALF mice through downregulating HIF-1α to inhibit glycolysis.

Protective effects of specific cannabinoid receptor 2 agonist GW405833 on concanavalin A-induced acute liver injury in mice.

Cannabinoid receptor 2 (CB2R) is highly expressed in immune cells and plays an important role in regulating immune responses. In the current study, we investigated the effects of GW405833 (GW), a specific CB2R agonist, on acute liver injury induced by concanavalin A (Con A). In animal experiments, acute liver injury was induced in mice by injection of Con A (20 mg/kg, i.v.). The mice were treated with GW (20 mg/kg, i.p., 30 min after Con A injection) or GW plus the selective CB2R antagonist AM630 (2 mg/kg, i.p., 15 min after Con A injection). We found that Con A caused severe acute liver injury evidenced by significantly increased serum aminotransferase levels, massive hepatocyte apoptosis, and necrosis, as well as lymphocyte infiltration in liver tissues. Treatment with GW significantly ameliorated Con A-induced pathological injury in liver tissue, decreased serum aminotransferase levels, and decreased hepatocyte apoptosis. The therapeutic effects of GW were prevented by AM630. In cell experiments, we showed that CB2Rs were highly expressed in Jurkat T cells, but little expression in L02 liver cells. Treatment with GW (10-40 µg/mL) dose-dependently decreased the viability of Jurkat T cells and induced cell apoptosis, which was reversed by AM630. In the coculture of Jurkat T cells with L02 liver cells, GW dose-dependently protected L02 cells from apoptosis induced by Con A (5 µg/mL). The protective effect of GW was reversed by AM630 (1 µg/mL). Our results suggest that GW protects against Con A-induced acute liver injury in mice by inhibiting Jurkat T-cell proliferation through the CB2Rs.

The benefit of statins in chronic hepatitis C patients: a systematic review and meta-analysis.

BACKGROUND AND AIM: Besides regulating lipid metabolism, statins have garnered considerable interest because of their antiviral and antineoplastic properties. The potential benefit of statins using in chronic hepatitis C (CHC) patients is not well described. This meta-analysis was carried out to quantitatively assess the efficacy of statins in improving the therapeutic effect and prognosis of patients with CHC. PATIENTS AND METHODS: We searched electronic databases for relevant studies comparing the course of benefit in CHC patients with statins versus without statins. Risk estimates were pooled to assess the association of statins use with sustained virological response and the prognosis of CHC patients. RESULTS: Twenty-three studies fulfilled the inclusion criteria. Meta-analysis of 16 homogeneous studies showed that the sustained virological response rate increased by 31% [relative risk (RR)=1.31; 95% confidence interval (CI): 1.23-1.39] in 12 791 CHC patients with statins as an adjuvant under the general antiviral therapy compared with those without this adjuvant therapy. Moreover, meta-analysis of seven studies suggested that statins was beneficial on several specific poor outcomes of CHC patients (RR=0.49; 95% CI: 0.42-0.56). CHC patients with statin use were found to be inversely associated with a 55% reduced risk of hepatocellular carcinoma (RR=0.45; 95% CI: 0.36-0.57) and 53% reduced risk of cirrhosis (RR=0.47; 95% CI: 0.33-0.67) as well as 44% reduced risk of mortality (RR=0.56; 95% CI: 0.46-0.69). However, significant heterogeneity and publication bias were present in some of our analyses. CONCLUSION: Beneficial effects of statins use were found in the therapy and the prognosis of CHC patients. Further prospective studies are still needed to confirm these benefits.

Metformin use improves survival of diabetic liver cancer patients: systematic review and meta-analysis.

Metformin has garnered considerable interest as a chemo-preventive and chemo-therapeutic agent given the increased risk of liver cancer among diabetic patients. This work was performed to illustrate the association between metformin use and survival of diabetic liver cancer patients. We conducted a comprehensive literature search of PubMed, Web of Science, Embase, BIOSIS Previews, Cochrane Library from inception to 12 May 2016. Meta-analyses were performed using Stata (version 12.0), with hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) as effect measures. Eleven cohort studies involving 3452 liver cancer patients fulfilled the inclusion criteria. Meta-analyses showed that metformin use was associated with better survival (HR = 0.59; 95% CI, 0.42-0.83; p = 0.002) of liver cancer patients, and the beneficial effect persisted (HR = 0.64; 95% CI, 0.42-0.97; p = 0.035) when the population was restricted to diabetic liver cancer patients. After adjusting for age, etiology, index of tumor severity and treatment of liver cancer, the association between metformin use and better survival of liver cancer patients was stable, pooled HR ranged from 0.47 to 0.57. The results indicated that metformin use improved survival of diabetic liver cancer patients. However, the results should be interpreted with caution given the possibility of residual confounding. Further prospective studies are still needed to confirm the prognostic benefit of metformin use.

Helicobacter pylori infection may increase the risk of progression of chronic hepatitis B disease among the Chinese population: a meta-analysis.

OBJECTIVES: Helicobacter pylori is a bacterium that infects over 50% of the human population worldwide. An increasing number of studies have demonstrated that H. pylori may cause liver diseases, and the underlying relationship between H. pylori infection and chronic hepatitis B has attracted much attention. This study aimed to examine the association between H. pylori infection and the progression of chronic hepatitis B in the Chinese population. METHODS: A search was performed of the PubMed/MEDLINE, Web of Science, and Cochrane Central Register of Controlled Trials (CENTRAL) databases, as well as the Chinese databases, China National Knowledge Infrastructure and Wanfang Data, for studies published between January 1, 1994 and November 1, 2015. RESULTS: In total, 2977 patients were included in the chronic hepatitis B group, while 1668 participants were included in the healthy control group. The prevalence of H. pylori among patients with chronic hepatitis B was significantly higher than that among those without chronic hepatitis B. The pooled odds ratio was 3.17. In the subgroup analysis, the odds ratio was 4.28 for hepatitis B virus (HBV)-related cirrhosis and 6.02 for hepatocellular carcinoma. CONCLUSION: These results indicate a strong relationship between H. pylori and chronic hepatitis B, particularly during HBV progression.

The Association between Helicobacter pylori Infection and Chronic Hepatitis C: A Meta-Analysis and Trial Sequential Analysis.

Purpose. Helicobacter pylori is a common gastric disease-inducing pathogen. Although an increasing number of recent studies have shown that H. pylori is a risk factor for liver disease, the potential association between H. pylori infection and chronic hepatitis C still remains controversial. The aim of our meta-analysis was to evaluate a potential association between H. pylori infection and chronic hepatitis C. Methods. We searched the PubMed, Embase, CNKI, Web of Science, and the Cochrane Central Register of Controlled Trials (CENTRAL) databases between January 1, 1994, and May 1, 2015. Results. This study included a total of 1449 patients with chronic hepatitis C and 2377 control cases. The prevalence of H. pylori was significantly higher in patients with chronic hepatitis C than in those without chronic hepatitis C. The pooled odds ratio was 2.93. In a subgroup analysis, the odds ratios were 4.48 for hepatitis C virus- (HCV-) related cirrhosis and 5.45 for hepatocellular carcinoma. Conclusion. Our study found a strong association between H. pylori and chronic hepatitis C, particularly during the HCV progression stage; thus, we recommend active screening for H. pylori in patients with chronic hepatitis C.

A comprehensive long-term prognosis of chronic hepatitis C patients with antiviral therapy: a meta-analysis of studies from 2008 to 2014.

CONTEXT: Attaining a sustained virological response with antiviral therapy is a sign of clinical cure for chronic hepatitis C patients. The aim of this meta-analysis was to evaluate the long-term efficiency and outcome of antiviral therapy in patients with hepatitis C who attained a sustained virological response. EVIDENCE ACQUISITION: A literature search was performed on published articles between January 2008 and February 2014. Patients with Hepatitis C who received interferon with or without ribavirin therapy were enrolled. Relative risks were estimated using either fixed or random effect models. RESULTS: Patients who attained sustained virological response had a less risk (85%) for all-cause mortality and about 63% reduced risk of hepatocellular carcinoma incidence than those who did not achieve sustained virological response. Based on deeply analysis, the stage of liver fibrosis was a risk factor at baseline for the incidence of hepatocellular carcinoma. CONCLUSIONS: Sustained virological response can reduce all-cause mortality and the incidence of hepatocellular carcinoma of patients with hepatitis C. Advanced liver fibrosis is still a risk factor for the incidence of hepatocellular carcinoma, in spite of hepatitis C patients attained a sustained virological response.