Enhanced Intracellular Delivery and Improved Antitumor Efficacy of Menaquinone-4

Hepatocellular carcinoma (HCC) is a major malignant tumor type that occurs globally. HCC incidence is increasing, especially in Asian countries. Despite many therapeutic approaches, the long-term prognosis of HCC remains poor because of frequent recurrence due to intrahepatic metastasis or multicentric carcinogenesis. Therefore, it is necessary to develop effective and safe chemopreventive agents to improve the prognosis of HCC. Menaquinone-4 (MK-4) has a suppressive effect on HCC, but cellular delivery is poor. We hypothesized that effective cellular delivery of menahydroquinone-4 (MKH), a fully reduced form of MK-4, would regulate HCC growth and metastasis. We developed a bioreductive activation-independent delivery system with the N,N-dimethylglycine ester of MKH (MKH-bis-DMG) to deliver MKH to HCC cells without any bioreductive processing of MK-4. MKH-bis-DMG inhibited the proliferation of both DCP-positive and DCP-negative HCC cell lines in a time- and dose-dependent manner via G1/S cell-cycle arrest. We assessed the effect of MKH-derivatives on HCC metastasis using a mouse model of spleen-liver metastasis. The mean tumor hepatic replacement area of MKH-bis-DMG treated mice was significantly less than that of untreated mice. In conclusion, MKH-bis-DMG may be beneficial as a chemopreventive agent for recurrent HCC

Nutrition and Nonalcoholic Fatty Liver Disease: The Significance of Cholesterol

Nonalcoholic fatty liver disease (NAFLD) is a common chronic liver disease that ranges in severity from simple steatosis to cirrhosis. NAFLD is considered to be associated with hepatic metabolic disorders, resulting in overaccumulation of fatty acids/triglycerides and cholesterol. The pathogenesis and progression of NAFLD are generally explained by the “two-hit theory.” Most studies of lipid metabolism in the NAFLD liver have focused on the metabolism of fatty acids/triglycerides; therefore, the impact of cholesterol metabolism is still ambiguous. In this paper, we review recent studies on NAFLD from the viewpoint of hepatic lipid metabolism-associated factors and discuss the impact of disordered cholesterol metabolism in the etiology of NAFLD. The clinical significance of managing cholesterol metabolism, an option for the treatment of NAFLD, is also discussed

Metabolic Disorders and Steatosis in Patients with Chronic Hepatitis C: Metabolic Strategies for Antiviral Treatments

It has been reported that hepatitis C virus (HCV) infection is closely associated with hepatic metabolic disorders. Hepatic steatosis and insulin resistance are both relatively common in patients with chronic hepatitis C. Recent investigations suggest that HCV infection changes the expression profile of lipid-metabolism-associated factors in the liver, conferring advantages to the life cycle of HCV. Moreover, insulin resistance and steatosis are independent predictors of impaired response to antiviral treatment in chronic hepatitis C. In this paper, we summarize our current knowledge of hepatic metabolic disorders and describe how HCV leads to and exploits these hepatic disorders. We also discuss the clinical significance of insulin sensitizers used to improve insulin resistance and lipid modulators used to manage lipid metabolism as potential treatment options for chronic hepatitis C

Comparison of tissue pressure and ablation time between the LeVeen and cool-tip needle methods

BACKGROUND: Radio frequency ablation (RFA) has been accepted clinically as a useful local treatment for hepatocellular carcinoma (HCC). However, intrahepatic recurrence after RFA has been reported which might be attributable to increase in intra-tumor pressure during RFA. To reduce the pressure and ablation time, we developed a novel method of RFA, a multi-step method in which a LeVeen needle, an expansion-type electrode, is incrementally and stepwise expanded. We compared the maximal pressure during ablation and the total ablation time among the multi-step method, single-step method (a standard single-step full expansion with a LeVeen needle), and the method with a cool-tip electrode. Finally, we performed a preliminary comparison of the ablation times for these methods in HCC cases. RESULTS: A block of pig liver sealed in a rigid plastic case was used as a model of an HCC tumor with a capsule. The multi-step method with the LeVeen electrode resulted in the lowest pressure as compared with the single-step or cool-tip methods. There was no significant difference in the ablation time between the multi-step and cool-tip ablation methods, although the single-step methods had longer ablation times than the other ablation procedures. In HCC cases, the multi-step method had a significantly shorter ablation time than the single-step or cool-tip methods. CONCLUSION: We demonstrated that the multi-step method was useful to reduce the ablation time and to suppress the increase in pressure. The multi-step method using a LeVeen needle may be a clinically applicable procedure for RFA

NPC1L1 inhibitor ezetimibe is a reliable therapeutic agent for non-obese patients with nonalcoholic fatty liver disease

<p>Abstract</p> <p>Background</p> <p>We recently examined the distribution of abdominal fat, dietary intake and biochemical data in patients with nonalcoholic fatty liver disease (NAFLD) and found that non-obese NAFLD patients did not necessarily exhibit insulin resistance and/or dysregulated secretion of adipocytokines. However, dietary cholesterol intake was superabundant in non-obese patients compared with obese patients, although total energy and carbohydrate intake was not excessive. Therefore, excess cholesterol intake appears to be one of the main factors associated with NAFLD development and liver injury.</p> <p>Methods</p> <p>We reviewed a year of follow-up data of non-obese NAFLD patients treated with Niemann-Pick C1 like 1 inhibitor ezetimibe to evaluate its therapeutic effect on clinical parameters related to NAFLD. Without any dietary or exercise modification, 10 mg/day of ezetimibe was given to 8 patients. In 4 of 8 patients, ezetimibe was administered initially. In the remaining 4 patients, medication was switched from ursodeoxycholic acid to ezetimibe.</p> <p>Results</p> <p>In each patient, body mass index was maintained under 25 kg/m²during the observation period. Serum ALT levels significantly decreased within 6 months and in 4 patients levels reached the normal range (<30 U/L), which was accompanied with at least a 10% decrease in serum total cholesterol and LDL-cholesterol. However, ultrasonographic findings of fatty liver did not show obvious improvement for a year.</p> <p>Conclusion</p> <p>We conclude that the cholesterol absorption inhibitor ezetimibe can suppress hepatic injury in non-obese patients with NAFLD and that ezetimibe may offer a novel treatment for NAFLD.</p

Menahydroquinone-4 Prodrug: A Promising Candidate Anti-Hepatocellular Carcinoma Agent

Recently, new therapeutics have been developed for hepatocellular carcinoma (HCC). However, the overall survival rate of HCC patients is still unsatisfactory; one of the reasons for this is the high frequency of recurrence after radical treatment. Consequently, to improve prognosis, it will be important to develop a novel anti-tumor agent that is especially effective against HCC recurrence. For clinical application, long-term safety, together with high anti-tumor efficacy, is desirable. Recent studies have proposed menahydroquinone-4 1,4-bis-N,N-dimethylglycinate hydrochloride (MKH-DMG), a prodrug of menahydroquinone-4 (MKH), as a promising candidate for HCC treatment including the inhibition of recurrence; MKH-DMG has been shown to achieve good selective accumulation of MKH in tumor cells, resulting in satisfactory inhibition of cell proliferation in des-γ-carboxyl prothrombin (DCP)-positive and DCP-negative HCC cell lines. In a spleen-liver metastasis mouse model, MKH-DMG has been demonstrated to have anti-proliferation and anti-metastatic effects in vivo. The characteristics of MKH-DMG as a novel anti-HCC agent are presented in this review article