Matrine promotes hepatic oval cells differentiation into hepatocytes and alleviates liver injury by suppression of Notch signalling pathway.

AIMS: Recent studies have shown that the hyperactive Notch pathway is involved in cirrhosis and hepatocellular carcinoma (HCC) development by regulating differentiation of hepatic oval cells (HOCs) into cancer cells. The aim of this study was to investigate whether matrine can alleviate liver injury and promote HOC differentiation into hepatocytes by suppression of Notch pathway. MAIN METHODS: We evaluated the expression of Notch-1, Jagged-1, and Hes-1 in HCC tissue by immunohistochemistry. Stem cell characteristics of HOCs were evaluated by CCK-8, cell cycle, and apoptosis. The expression of Notch pathway, HOC markers and albumin (ALB) was detected by immunohistochemistry, QRT-PCR and western blotting. The effects of matrine in protecting liver in vivo were investigated in a rat Solt-Farber precancerous model. KEY FINDINGS: We found an abnormal activated Notch pathway in HCC tissue, and the hyperactive Notch pathway was strongly associated with poor liver function in patients with cirrhosis with HCC. Using siNotch-1 to inhibit Notch pathway confirmed that Notch pathway could maintain stem cell characteristics of HOCs. Matrine inhibited stem cell characteristics of HOCs, the expression of Notch pathway and HOC markers but upregulated ALB. Matrine in combined with siNotch-1 RNA decreased the more potently inhibited HOC markers and Notch pathway. In rat Solt-Farber precancerous model, prophylactic application of matrine alleviated liver injury, downregulated Notch pathway and HOC markers, and upregulated ALB in a dose-dependent manner. SIGNIFICANCE: Matrine could promote the differentiation of HOCs into hepatocytes by inhibiting the Notch signalling pathway and alleviate liver injury.

Matrine prevents the early development of hepatocellular carcinoma like lesions in rat liver.

Matrine (C15H24N2O) is an alkaloid extracted from the Chinese herb Sophora flavescens that has anti-fibrotic and anti-cancer properties. The aim of the present study was to determine the chemopreventive effect of matrine on the development of primary hepatocellular carcinoma (HCC) and its possible association with the suppression of the Notch signaling pathway. The rats were randomly divided into four groups: Control, model, low-dose matrine and high-dose matrine groups. The model was established by combining a partial hepatectomy with diethylnitrosamine (DEN) + 2-acetylaminofluorene (2-AAF). Low- and high-dose matrine groups received intragastric administration of matrine (0.25 and 2.5 g/l of matrine, respectively). DEN + 2-AAF injections and hepatectomy were not performed in the control group. All rats were sacrificed 2, 4 and 7 weeks after hepatectomy. HCC-like histopathological lesions were detected using hematoxylin and eosin staining. The expression levels of α-1-fetoprotein (AFP), albumin (ALB), Notch1 and Hes1 were analyzed using immunohistochemistry. Hepatic lobule structure loss, liver tissue necrosis and inflammatory cell infiltration, and edema degeneration were observed in the model group. By contrast, hepatocyte cord structure was restored and hepatocyte edema degeneration was significantly reduced after 7 weeks of treatment with matrine. In addition, compared with the model group, matrine reduced the expression of AFP, increased the expression of ALB and reduced the expression of Notch1 and Hes1 (only for high-dose matrine; all P<0.05). The findings suggested that matrine could prevent the early development of HCC-like lesions in a rat model, possibly by modulating Notch pathway activation.

Clinical efficacy and safety of paclitaxel liposomes as first-line chemotherapy in advanced gastric cancer.

Aim: To compare the performance of first-line paclitaxel liposome + oxaliplatin and SOX (tegafur/gimeracil/oteracil + oxaliplatin) in advanced gastric cancer patients. Materials & methods: Stage IIb-IV gastric cancer patients underwent either first-line paclitaxel liposome + oxaliplatin (n = 52) or SOX (n = 69) between 2010-2013, and followed up until 2015 or death. Results: Both groups had similar objective response rate (p = 0.48) and disease control rate (p = 0.992) after two chemotherapy cycles, median progression-free survival (p = 0.495) and median overall survival (p = 0.208). Liposome group had significantly lower rate of grade I-II platelet decline and liver function damage (p = 0.04 and 0.019). Multivariate COX regression identified pre-treatment neutrophil-to-lymphocyte ratio as an independent prognostic factor. Conclusion: First-line paclitaxel liposome + oxaliplatin has comparable efficacy, but causes reduced adverse reactions in advanced gastric cancer as compared with SOX.

Combined intra-arterial and intravenous chemotherapy for unresectable, advanced gastric cancer has an improved curative effect compared with intravenous chemotherapy only.

The aim of the present study was to evaluate the efficacy and safety of a combination of intra-arterial and intravenous chemotherapy in the treatment of unresectable, advanced gastric cancer, and assess which patients are likely to benefit from combined treatment. The clinical data of 128 patients diagnosed with unresectable, advanced gastric cancer at The Fourth Hospital of Hebei Medical University (Shijiazhuang, China) from January 2009 to September 2012 were retrospectively analyzed. The patients were divided into two groups as follows: Those who received regional intra-arterial chemoembolization plus systemic chemotherapy (combined group; n=62) and those who received systemic chemotherapy only (venous group; n=66). The clinical response, overall survival (OS) and toxic effects in the two groups were compared. Univariate and multivariate analyses were performed to identify the primary factors affecting the survival time of patients in the combined group. The overall response rate was significantly increased (35.5%) in the combined group compared with the venous group (19.7%; P=0.045). The median OS was 14 months in the combined group and 13 months in the venous group, and the 1-year and 2-year survival rates in the two groups were 45.2 and 9.7%, and 40.9 and 6.1%, respectively. There were significant differences between the survival curves (P=0.044). The median time to progression in the combined group and the venous group was 10 months and 6 months, respectively, and the difference was statistically significant (P=0.003). Multivariate analysis revealed that tumor-node-metastasis (TNM)-stage and the degree of tumor staining were independent factors affecting OS. No differences in adverse reactions between the two groups were observed (P>0.05). The combination of intra-arterial and intravenous chemotherapy may effectively improve the rate of clinical response, prolong OS and time to symptomatic progression in patients with unresectable, advanced gastric cancer, in particular those with an earlier TNM stage and distinct tumor staining.