Hepatocellular carcinoma (HCC), which is a common malignancy worldwide, usually develops in a cirrhotic liver due to hepatitis virus infection. Metabolic syndrome, which is frequently complicated by obesity and diabetes mellitus, is also a critical risk factor for liver carcinogenesis. Green tea catechins (GTCs) may possess potent anticancer and chemopreventive properties for a number of different malignancies, including liver cancer. Antioxidant and anti-inflammatory activities are key mechanisms through which GTCs prevent the development of neoplasms, and they also exert cancer chemopreventive effects by modulating several signaling transduction and metabolic pathways. Furthermore, GTCs are considered to be useful for the prevention of obesity- and metabolic syndrome-related carcinogenesis by improving metabolic disorders. Several interventional trials in humans have shown that GTCs may ameliorate metabolic abnormalities and prevent the development of precancerous lesions. The purpose of this article is to review the key mechanisms by which GTCs exert chemopreventive effects in liver carcinogenesis, focusing especially on their ability to inhibit receptor tyrosine kinases and improve metabolic abnormalities. We also review the evidence for GTCs acting to prevent metabolic syndrome-associated liver carcinogenesis.

Non-alcoholic fatty liver disease (NAFLD), which is strongly associated with metabolic syndrome, is increasingly a major cause of hepatic disorder. Dipeptidyl peptidase (DPP)-4 inhibitors, anti-diabetic agents, are expected to be effective for the treatment of NAFLD. In the present study, we established a novel NAFLD model mouse using monosodium glutamate (MSG) and a high-fat diet (HFD) and investigated the effects of a DPP-4 inhibitor, teneligliptin, on the progression of NAFLD. Male MSG/HFD-treated mice were divided into two groups, one of which received teneligliptin in drinking water. Administration of MSG and HFD caused mice to develop severe fatty changes in the liver, but teneligliptin treatment improved hepatic steatosis and inflammation, as evaluated by the NAFLD activity score. Serum alanine aminotransferase and intrahepatic triglyceride levels were significantly decreased in teneligliptin-treated mice (p < 0.05). Hepatic mRNA levels of the genes involved in de novo lipogenesis were significantly downregulated by teneligliptin (p < 0.05). Moreover, teneligliptin increased hepatic expression levels of phosphorylated AMP-activated protein kinase (AMPK) protein. These findings suggest that teneligliptin attenuates lipogenesis in the liver by activating AMPK and downregulating the expression of genes involved in lipogenesis. DPP-4 inhibitors may be effective for the treatment of NAFLD and may be able to prevent its progression to non-alcoholic steatohepatitis.

Recently, treatments for chronic hepatitis C virus (HCV) infection have significantly improved by the development of direct‑acting antiviral agents (DAAs) and almost all patients with HCV can complete antiviral treatment without apparent adverse events. Malignant lymphoma, particularly B‑cell non‑Hodgkin's lymphoma, is one of the extrahepatic manifestations associated with chronic HCV infection. The effectiveness of anti‑HCV therapy with DAAs for B‑cell non‑Hodgkin's lymphoma has been demonstrated in recent reports, whereas late‑onset B‑cell non‑Hodgkin's lymphoma after HCV eradication with DAAs has occasionally been reported. In the present study, a 77‑year‑old man with chronic hepatitis C and intermediate liver cancer risk received sofosbuvir‑ledipasvir treatment for 12 weeks. Two months following the end of antiviral therapy, he had achieved sustained virologic response for 8 weeks. However, the patient occasionally found swelling of the right cervical lymph nodes without any subjective symptoms. Lymph node biopsy revealed diffuse large B‑cell lymphoma and whole‑body 18F‑fluorodeoxyglucose (FDG) positron emission tomography with computed tomography showed increased FDG uptake in the right cervical, right submandibular, mediastinal and mesenteric lymph nodes. The patient received six courses of rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone chemotherapy and achieved complete response at 8 months after chemotherapy initiation. Thus, the development of lymphoid malignancies may arise, even after HCV eradication with DAAs. Therefore, clinicians should be aware of such risks during and after antiviral treatment with DAAs.

Obesity and its related metabolic disorders are serious health problems worldwide, and lead to various health-related complications, including cancer. Among human cancers, hepatocellular carcinoma (HCC) is one of the most common malignancies affected by obesity. Therefore, obesity and its related disorders might be a key target for the prevention of HCC. Recently, new research indicates that the molecular abnormalities associated with obesity, including insulin resistance/hyperinsulinemia, chronic inflammation, adipokine imbalance, and oxidative stress, are possible molecular mechanisms underlying the pathogenesis of obesity-related hepatocarcinogenesis. Green tea catechins and branched-chain amino acids, both of which are classified as nutraceutical agents, have been reported to prevent obesity-related HCC development by improving metabolic abnormalities. The administration of acyclic retinoid, a pharmaceutical agent, reduced the incidence of HCC in obese and diabetic mice, and was also associated with improvements in insulin resistance and chronic inflammation. In this article, we review the detailed molecular mechanisms that link obesity to the development of HCC in obese individuals. We also summarize recent evidence from experimental and clinical studies using either nutraceutical or pharmaceutical agents, and suggest that nutraceutical and pharmaceutical approaches targeting metabolic abnormalities might be a promising strategy to prevent the development of obesity-related HCC.

Background: This study aimed to investigate the usefulness of the psoas muscle index (PMI) as an independent predictor of survival after systemic targeted therapy initiation in patients with hepatocellular carcinoma (HCC). Method: In total, 214 patients with HCC who underwent systemic targeted therapy at the Gifu University Hospital were enrolled. The correlation between the PMI and the skeletal muscle index (SMI) was assessed using Pearson’s correlation coefficient (PCC). The Cox proportional hazards model was employed to determine whether the PMI, along with the α-fetoprotein (AFP) level and the ALBI score, influenced survival; these variables were considered time-dependent covariates. The optimal PMI cut-off value that yielded the most significant differences in survival was determined using maximally selected statistics. Results: The PMI was significantly correlated with the SMI (PCC = 0.38 and p < 0.001 for women; PCC = 0.62 and p < 0.001 for men). The PMI independently influenced survival (hazard ratio: 0.852; 95% confidence interval: 0.755–0.962; and p < 0.001), along with established prognostic factors such as the AFP and the ALBI score. The optimal PMI cut-off values that yielded the most significant differences in survival were 2.86 cm²/m² for women and 3.55 cm²/m² for men, and these values significantly stratified patient outcomes for both sexes (p < 0.001). Conclusions: The PMI serves as a reliable surrogate for the SMI in assessing skeletal muscle mass and predicting survival.

Colorectal cancer represents one of the most serious complications of inflammatory bowel disease. The NLRP3 inflammasome plays a pivotal role in the onset and progression of inflammatory bowel disease and is also implicated in colorectal cancer. This study aimed to investigate whether NLRP3 deficiency or glyburide, a sulfonylurea used for diabetes management and known as an NLRP3 inhibitor, could suppress colitis and its related colorectal tumorigenesis. Mice were divided into three groups: a control group, a glyburide group, and an NLRP3-deficient group. We investigated acute colitis and inflammation-related tumor models using azoxymethane and dextran sodium sulfate. In the colitis model, the colonic inflammation grade was significantly increased in NLRP3-deficient mice but not in mice administered glyburide. In the colorectal carcinogenesis model, fewer colorectal tumors were observed in both NLRP3-deficient and glyburide-treated groups. Additionally, a reduction in the expression levels of inflammatory cytokine genes was detected in the colonic mucosa of the mice of these groups. These findings suggest that NLRP3 deficiency may exacerbate acute colitis, while pharmacological inhibition, as well as deficiency of NLRP3, suppresses colitis-related tumorigenesis, presumably due to the attenuation of chronic inflammation in the colorectum. Glyburide holds promise as a potential chemopreventive agent for colitis-related colorectal cancer.