Catechins, a major component of green tea extract, have anti-hyperlipidemic effects. The present study investigated the effects of consumption of green tea with high-density catechins in non-alcoholic fatty liver disease (NAFLD) patients. Seventeen patients with NAFLD consumed green tea with high-density catechins, low-density catechins or a placebo for 12 weeks in a randomized double-blind study. Ultrasonography and computed tomography (CT) were performed at baseline and after 12 weeks. Serum alanine aminotransferase (ALT) levels and urine 8-isoprostane were monitored and compared to baseline at 4, 8 and 12 weeks. Body fat was significantly decreased in the high-density catechin group compared with the placebo and low-density catechin groups after 12 weeks of consumption. All the patients in the high-density catechin group showed a significantly improved liver-to-spleen CT attenuation ratio compared with the placebo and low-density catechin groups after 12 weeks of consumption. The high-density catechin group significantly decreased serum ALT levels and reduced urinary 8-isoprostane excretion compared with the placebo and low-density catechin group after 12 weeks of consumption. Based on a reduced proportion of body fat as estimated by bioimpedance measurement, increased liver-to-spleen CT attenuation ratio, decreased serum ALT levels and reduced urinary 8-isoprostane excretion, we concluded that 12 weeks of 700 ml per day of green tea containing >1 g catechin improved liver fat content and inflammation by reducing oxidative stress in patients with NAFLD.

Background & Aims: We investigated whether endothelial progenitor cell (EPC) transplantation could reduce established liver fibrosis and promote hepatic regeneration by isolating rat EPCs from bone marrow cells. Methods: Recipient rats were injected intraperitoneally with carbon tetrachloride (CCl₄) twice weekly for 6 weeks before initial administration of EPCs. CCl₄ was then readministered twice weekly for 4 more weeks, and EPC transplantation was carried out for these same 4 weeks. Results: At 7 days in culture, the cells expressed Thy-1, CD31, CD133, Flt-1, Flk-1, and Tie-2, suggesting an immature endothelial lineage. Immunohistochemical analyses showed fluorescent-labeled, transplantation EPCs were incorporated into the portal tracts and fibrous septa. Single and multiple EPC transplantation rats had reduced liver fibrosis, with decreased α2-(I)-procollagen, fibronectin, transforming growth factor-β, and α-smooth muscle actin-positive cells. Film in situ zymographic analysis revealed strong gelatinolytic activity in the periportal area, in accordance with EPC location. Real-time polymerase chain reaction analysis of multiple EPC-transplantation livers showed significantly increased messenger RNA levels of matrix metalloproteinase (MMP)-2, -9 and -13, whereas tissue inhibitor of metalloproteinase-1 expression was significantly reduced. Expression of hepatocyte growth factor, transforming growth factor-α, epidermal growth factor, and vascular endothelial growth factor was increased in multiple EPC-transplantation livers, while hepatocyte proliferation increased. Transaminase, total bilirubin, total protein, and albumin levels were maintained in EPC-transplantation rats, significantly improving survival rates. Conclusions: We conclude that single or repeated EPC transplantation halts established liver fibrosis in rats by suppressing activated hepatic stellate cells, increasing matrix metalloproteinase activity, and regulating hepatocyte proliferation.

Background: Although lenvatinib has become the standard therapy for hepatocellular carcinoma (HCC), the high incidence rate of adverse events (AEs) is an issue. This study aimed to clarify the AEs of lenvatinib and the therapeutic impact of five days-on/two days-off administration (i.e., weekends-off strategy) for lenvatinib. Methods: We retrospectively assessed the therapeutic effects and AEs of 135 patients treated with lenvatinib, and the improvement of tolerability and therapeutic efficacy of 30 patients treated with the weekends-off strategy. We also evaluated lenvatinib-induced vascular changes in tumors and healthy organs using a mouse hepatoma model. Results: The incidence rates of any grade and grade ≥ 3 AEs were 82.1% and 49.6%. Fatigue was the most important AE since it resulted in dose reduction and discontinuation. Of the 30 patients who received weekends-off lenvatinib, 66.7% tolerated the AEs. Although 80.8% of the patients showed progression after dose reduction, the therapeutic response improved in 61.5% of the patients by weekends-off lenvatinib. Notably, weekends-off administration significantly prolonged the administration period and survival (p < 0.001 and p < 0.05). The mouse hepatoma model showed that weekends-off administration contributed to recovery of vascularity in the organs. Conclusion: Weekends-off administration of lenvatinib was useful to recover the therapeutic response and tolerability toward AEs.

Hepatocellular carcinoma (HCC) is the sixth most common cancer and the third leading cause of cancer deaths worldwide. The etiology of HCC has now dramatically changed from viral hepatitis to metabolic dysfunction-associated steatotic liver disease (MASLD). The main pathogenesis of MASLD-related HCC is the hepatic lipid accumulation of hepatocytes, which causes chronic inflammation and the subsequent progression of hepatic fibrosis. Chronic hepatic inflammation generates oxidative stress and DNA damage in hepatocytes, which contribute to genomic instability, resulting in the development of HCC. Several metabolic and molecular pathways are also linked to chronic inflammation and HCC in MASLD. In particular, the MAPK and PI3K-Akt-mTOR pathways are upregulated in MASLD, promoting the survival and proliferation of HCC cells. In addition, MASLD has been reported to enhance the development of HCC in patients with chronic viral hepatitis infection. Although there is no approved medication for MASLD besides resmetirom in the USA, there are some preventive strategies for the onset and progression of HCC. Sodium-glucose cotransporter-2 (SGLT2) inhibitor, a class of medications, has been reported to exert anti-tumor effects on HCC by regulating metabolic reprogramming. Moreover, CD34-positive cell transplantation improves hepatic fibrosis by promoting intrahepatic angiogenesis and supplying various growth factors. Furthermore, exercise improves MASLD through an increase in energy consumption as well as changes in chemokines and myokines. In this review, we summarize the recent progress made in the pathogenic mechanisms of MASLD-associated HCC. Furthermore, we introduced new therapeutic strategies for preventing the development of HCC based on the pathogenesis of MASLD.

The cytokine transforming growth factor‑β (TGF‑β) serves a key role in hepatic fibrosis and has cytostatic effects on hepatocytes. The present study investigated the anti‑fibrogenic and regenerative effects of the TGF‑β receptor type I kinase inhibitor galunisertib (LY2157299) in mice with carbon tetrachloride (CCl4)‑induced liver cirrhosis and in vitro. Mice were intraperitoneally treated with CCl4 for 8 weeks. At week 5, the mice were divided randomly into four treatment groups: Vehicle‑treated; and treated with low‑; middle‑; and high‑dose galunisertib, which was administered from weeks 5‑8. The mice were sacrificed after 8 weeks of CCl4 treatment. Liver fibrosis, as evaluated by histology and determination of hydroxyproline content, progressed during week 4‑8 of CCl4 treatment in the vehicle‑treated mice. Galunisertib treatment dose‑dependently prevented liver fibrosis, as demonstrated by the direct inhibition of α‑smooth muscle actin‑positive activated hepatic stellate cells (HSCs) after 8 weeks of CCl4 treatment. The levels of active matrix metalloproteinase (MMP)‑9 in galunisertib‑treated livers were significantly increased compared with the vehicle‑treated livers. In the high‑dose group, the number of PCNA‑positive hepatocytes and endothelial cells markedly increased compared with the vehicle group. Reverse transcription‑quantitative PCR analysis verified that interleukin‑6 and epiregulin expression levels were significantly increased in livers from the group treated with high‑dose galunisertib compared with the vehicle‑treated group. Galunisertib inhibited the proliferation of activated HSCs and collagen synthesis in addition to restoring MMP activity. Moreover, galunisertib promoted liver remodeling by proliferating hepatocytes and vascular endothelial cells, while significantly increasing liver weight. These results are consistent with the cytostatic action of TGF‑β that negatively regulates liver regeneration, and demonstrated that galunisertib inhibited TGF‑β signaling, halted liver fibrosis progression and promoted hepatic regeneration. The results of the present study suggest that galunisertib may be an effective treatment for liver cirrhosis.