The herbal medicine berberine (BBR) has been recently shown to be an AMP-activated protein kinase (AMPK) productive activator with various properties that induce anti-inflammatory responses. We investigated the effects of BBR on the mechanisms of mucosal CD4 + T cell activation in vitro and on the inflammatory responses in T cell transfer mouse models of inflammatory bowel disease (IBD). We examined the favorable effects of BBR in vitro , using lamina propria (LP) CD4 + T cells in T cell transfer IBD models in which SCID mice had been injected with CD4 + CD45RB high T cells. BBR suppressed the frequency of IFN-γ- and Il-17A-producing LP CD4 + T cells. This effect was found to be regulated by AMPK activation possibly induced by oxidative phosphorylation inhibition. We then examined the effects of BBR on the same IBD models in vivo . BBR-fed mice showed AMPK activation in the LPCD4 + T cells and an improvement of colitis. Our study newly showed that the BBR-induced AMPK activation of mucosal CD4 + T cells resulted in an improvement of IBD and underscored the importance of AMPK activity in colonic inflammation.

Chronic viral hepatitis B and C and non-alcoholic fatty liver disease (NAFLD) have been widely acknowledged to be the leading causes of liver cirrhosis and hepatocellular carcinoma. As anti-viral treatment progresses, the impact of NAFLD is increasing. NAFLD can coexist with chronic viral hepatitis and exacerbate its progression. Oxidative stress has been recognized as a chronic liver disease progression-related and cancer-initiating stress response. However, there are still many unresolved issues concerning oxidative stress, such as the correlation between the natural history of the disease and promising treatment protocols. Recent findings indicate that oxidative stress is also an anti-cancer response that is necessary to kill cancer cells. Oxidative stress might therefore be a cancer-initiating response that should be down regulated in the pre-cancerous stage in patients with risk factors for cancer, while it is an anti-cancer cell response that should not be down regulated in the post-cancerous stage, especially in patients using anti-cancer agents. Antioxidant nutrients should be administered carefully according to the patients’ disease status. In this review, we will highlight these paradoxical effects of oxidative stress in chronic liver diseases, pre- and post-carcinogenesis.

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Background andAim: Human telomerase reverse transcriptase (TERT) promoter mutations were the most prevalent mutations in patients with hepatocellular carcinoma (HCC). We tried to detect the mutations with plasma circulating tumor DNA (ctDNA) in patients with advanced HCC and elucidated their clinical utility. Methods: Circulating tumor DNA in plasma was extracted from 130 patients with advanced HCC who were treated with systemic chemotherapy (n = 86) or transcatheter arterial chemoembolization (n = 44), and TERT promoter mutations were examined with digital droplet polymerase chain reaction. The correlations between these mutations and the clinical outcome of patients were analyzed. Results: Of the 130 patients examined, 71 patients (54.6%) were positive for TERT promoter mutations in ctDNA, of which 64 patients were À124bp G > A and 10 were À146bp G > A. The presence of TERT promoter mutations was correlated with large intrahepatic tumor size (P = 0.05) and high des-gamma carboxyprothrombin (P = 0.005). Overall survival of the patients with the mutations was significantly shorter than those without them (P < 0.001), and the patients with high (≥ 1%) fractional abundance of the mutant alleles showed shorter survival than those with low (< 1%) fractional abundance. Multivariate analysis revealed that TERT promoter mutation (hazard ratio [HR]: 1.94; 95% confidence interval [CI], 1.18-3.24; P < 0.01), systemic chemotherapy (HR: 2.38; 95% CI, 1.29-4.57; P < 0.01), and vascular invasion (HR: 2.16; 95% CI, 1.22-3.76; P < 0.01) were significant factors for poor overall survival. Conclusions: TERT promoter mutations in ctDNA were associated with short survival and could be a valuable biomarker for predicting the prognosis of patients with advanced HCC.

Background: Mutations in the human telomerase reverse transcriptase (hTERT) gene promoter have been reported in hepatocellular carcinoma (HCC); however, analyses of these mutations in liquid biopsies have been technically difficult because of the high GC content of the regions of interest within this promoter. We evaluated the feasibility and prognostic value of hTERT promoter mutations identified in circulating cell-free DNA (cfDNA) from the serum of patients with HCC. Objective: A cohort of HCC patients (n = 36) who were curatively treated by surgical resection between June 2003 and September 2014 were enrolled in this study. Methods: The presence of hTERT promoter mutations in cfDNA from the patients' serum was analyzed via modified droplet digital polymerase chain reaction, and associations were sought between specific promoter mutations and patients' diseasefree survival (DFS). Results: The G>A hTERT mutation at -124 bp was detected in the serum of 25 patients (69%). Although no marked differences were observed between the characteristics of the serum mutation-positive and serum mutation-negative patient groups, the DFS of patients with the mutation was significantly shorter than that of the serum mutation-negative patients (p = 0.02). Among 18 clinicopathologic and background liver factors examined, the presence of the -124 bp G>A mutation was an independent and significant predictor of patients' DFS (hazard ratio = 3.01, 95% confidence interval 1.11-10.5, p = 0.03) in multivariate analyses. Conclusions: The -124 bp G>A hTERT promoter mutation was observed in the serum of 69% of HCC patients who underwent surgical resection and was an independent predictor of disease progression in HCC.