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The gut‑liver‑muscle axis is associated with the development of sarcopenia in liver cirrhosis. The present study aimed to illustrate the combined effects of rifaximin and L‑carnitine on skeletal muscle atrophy in cirrhotic rats with steatohepatitis. For this purpose, a total of 344 Fischer rats were fed a choline‑deficient L‑amino acid‑defined (CDAA) diet with the daily oral administration of rifaximin (100 mg/kg) and/or L‑carnitine (200 mg/kg), and measurements of psoas muscle mass index and forelimb grip strength were performed. After feeding for 12 weeks, blood samples, and liver, ileum and gastrocnemius muscle tissues were harvested. The effects of L‑carnitine on rat myocytes were assessed using

L-carnitine (4-N-trimethylammonium-3-hydroxybutyric acid) is the physiologically active form of carnitine and is a natural compound that has been shown to exhibit antioxidant activity. L-carnitine is used as a supplementary treatment in patients with cirrhosis with hepatic encephalopathy, hyperammonemia or muscle cramps. In the present study, the effect of L-carnitine supplementation on health-related quality of life in 30 patients with cirrhosis was prospectively examined. L-carnitine (1,800 mg/day) was administered orally for 6 months. To assess the effects of L-carnitine on chronic fatigue, patients filled out a self-report questionnaire regarding their physical and mental health. The levels of total and free carnitine, and acylcarnitine were found to be significantly higher 1, 3 and 6 months after therapy initiation compared with before treatment. Serum albumin levels were significantly increased 3 and 6 months after initiation of therapy. L-carnitine supplementation significantly increased the BAP/d-ROM ratio, a marker of antioxidant status in patients with cirrhosis. Changes in serum carnitine concentrations were positively correlated with changes in serum albumin levels (R2=0.369; P=0.012), but not with changes in serum ammonia levels (R2= 0.005; P=0.78). Total and mental health scores improved significantly, and physical scores improved marginally 3 and 6 months after initiation of L-carnitine. These findings may be attributed to the enhanced serum albumin levels and oxidative stress rather than the reduced serum ammonia levels. Based on these results, it is suggested that L-carnitine can potentially alleviate chronic fatigue, along with the increased BAP/d-ROM ratio, which were involved in increased oxidative stress in patients with cirrhosis. The specific mechanisms by which L-carnitine ameliorates chronic fatigue is not fully understood and requires further investigation.

Depression is a major reason for interferon (IFN) therapy cessation. IFN-free direct-acting antiviral (DAA) therapy for depression is not well-documented. Thus, four different IFN-free regimens were assessed in genotype-1 hepatitis C virus (HCV) patients with depression. Overall, 287 HCV genotype-1 patients who received combination therapies with IFN-free DAAs of daclatasvir/asunaprevir (DCV/ASV) (n=84), sofosbuvir/ledipasvir (SOF/LDV) (n=95), ombitasvir/paritaprevir/ritonavir (OBV/PTV/r) (n=74), and elbasvir/grazoprevir (EBR/GZR) (n=34) were included. Treatment-induced depression as a complication of HCV therapy in IFN-free DAA regimens was assessed. The severity of depression was evaluated using the Beck Depression Inventory-II (BDI-II) questionnaire. It was demonstrated that all four DAA regimens achieved similar high efficacy in Japanese patients with HCV genotype-1 infection. Moreover, in seven patients with depression who received the 24-week DCV/ASV treatment regimen, the BDI-II scores significantly increased at week 4 as compared with pretreatment values; furthermore, they decreased below baseline at week 12 despite the rapid decline of serum HCV levels after the initiation of DCV/ASV therapy. The BDI-II scores gradually decreased during therapy in the remaining 77 DCV/ASV-treated patients without depression. The BDI-II scores showed a significant decrease from baseline to the end of treatment with 12-week regimens, including SOF/LDV and EBR/GZR. The 12-week DAA regimen of SOF/LDV and EBR/GZR can be safely used with high efficacy in patients with genotype-1 HCV infection, including those with depression.

Interferon (IFN) is known as a multifunctional cytokine. The aim of this study was to examine the different effects of IFN subclass; namely, IFN-alpha and IFN-beta, on hepatocellular carcinoma (HCC) growth especially in conjunction with angiogenesis that is known to play a pivotal role in the tumor growth. Furthermore, we also examined whether the p53 status in the tumor would alter the anti-tumoral effect of IFN against HCC growth since the p53 status reportedly affected the therapeutic effect of anti-angiogenic agents against cancer. When compared with IFN-alpha, IFN-beta exerted a more potent inhibitory effect on HCC growth, even after the tumor was established, along with suppression of neovascularization in the tumor. A single treatment with clinically comparable low doses of IFN-beta significantly inhibited HCC growth whereas the same dose of IFN-alpha did not. IFN-beta also significantly suppressed the tumor growth both in the p53-wild and p53-mutant HCC cells. Our in vitro study revealed that IFN-beta showed a more potent inhibitory effect on the endothelial cell proliferation than IFN-alpha as in the in vivo study. Collectively, IFN may be an alternative anti-angiogenic agent against HCC since it exerted a significant tumoricidal effect regardless of the host p53 status even at a low dose. A cautious approach may be also required in the clinical practice since even in a same IFN subclass (class-I), IFN-alpha and IFN-beta exert tumoricidal effects of different magnitudes on HCC.

Therapies aimed at destruction of the tumor vasculature are now recognized as a promising approach against cancer, and it has been reported that the combination treatment with an angiogenic inhibitor and conventional chemotherapeutic drug exerted synergistic anti-cancerous effects. We previously reported that the clinically used angiotensin-converting enzyme inhibitor (ACE-I) exerted potent-anti-angiogenic activities. The aim of our current study was to examine the combined effect of ACE-I and 5-fluorouracil (5-FU), which is widely used for hepatogastrointestinal tumors, on hepatocellular carcinoma (HCC) growth and hepatocarcinogenesis. When used individually at low doses, neither 5-FU nor ACE-I exerted significant inhibitory effects on the HCC growth. However, the combination treatment of 5-FU and ACE-I showed a potent inhibitory effect on HCC growth along with suppression of neovascularization in the tumor. The expression level of the vascular endothelial growth factor, a potent angiogenic factor, was also suppressed, almost in conjunction with tumor growth inhibition. Furthermore, 5-FU and ACE-I treatment resulted in a marked increase of apoptosis in the tumor. In the hepatocarcinogenesis model, the combination treatment with 5-FU and ACE-I also showed a marked inhibitory effect on the development of preneoplastic lesions. The in vitro study demonstrated that this combination treatment inhibited endothelial cell tubular formation. Collectively, the combination treatment of 5-FU and ACE-I exerted a marked synergistic inhibitory effect on HCC growth via suppression of angiogenesis. This regimen also showed a chemopreventive effect against hepatocarcinogenesis. Since both 5-FU and ACE-I are widely used in clinical practice, this combination therapy may be an effective new therapeutic strategy against HCC in the future.

Both platelet-derived growth factor (PDGF) and transforming growth factor-beta (TGF-beta) are known to be pivotal cytokines in liver fibrosis development. The aim of our current study was to elucidate the effects of dual inhibition of PDGF and TGF-beta by combination of the clinically used imatinib mesylate (STI-571) and perindopril (an ACE-inhibitor; ACE-I), respectively, on ongoing liver fibrosis development in rats. The effects of STI-571 and ACE-I at clinically comparable low doses were examined in a rat model of CCl4-induced liver fibrogenesis. Treatment with both STI-571 and ACE-I inhibited liver fibrogenesis and suppressed activation of hepatic stellate cells (HSCs). Administration of both agents exerted a more potent inhibitory effect than administration of either single agent. Our in vitro study demonstrated that STI-571 and ACE-I suppressed PDGF receptor (PDGFR) phosphorylation and TGF-beta expression in activated HSCs, respectively. Dual suppression of PDGF and TGF-beta with a combination of clinically comparable low doses of STI-571 and ACE-I exerted a significant inhibitory effect on ongoing liver fibrosis development. Since both agents are widely used in clinical practice, this combination therapy may provide a new strategy against liver fibrosis in the future.