Nonsurgical Secondary Prophylaxis of Esophageal Variceal Bleeding in Cirrhotic Patients: A Systematic Review and Network Meta-analysis.

INTRODUCTION: The aim of this study was to evaluate the effectiveness of nonsurgical secondary prophylaxis interventions for esophageal varices (EV) rebleeding in cirrhotic patients using network meta-analysis. MATERIALS AND METHODS: Secondary prophylaxis of EV rebleeding in cirrhosis is searched on PubMed, Embase, and the Cochrane Library databases. The quality of literatures was extracted by 2 independent investigators according to the requirements of Cochrane Handbook for Systematic Reviews of Interventions, Version 5.0.0. Meta-analysis was performed on Review Manager 5.3 software for the incidence of cirrhosis EV rebleeding, rebleeding-related mortality, and overall mortality; and STATA 15.1 software was used for network meta-analysis. RESULTS: In all, 57 randomized controlled trials were reviewed. Endoscopic band ligation (EBL)+argon plasma coagulation has not been recommended by guidelines, and it is rarely used; the number of existing studies and the sample size are small. Considering poor stability of the combined results, these studies were excluded; 55 literatures were included. In terms of reducing the incidence of rebleeding, transjugular intrahepatic portosystemic shunt (TIPS) surface under the cumulative ranking curve (SUCRA) (94.3%) was superior to EBL+endoscopic injection sclerotherapy (EIS) (84.4%), EIS+ß-blockers (77.9%), EBL (59.8%), EBL+ß-blockers+isosorbide-5-mononitrate (52.7%), EBL+ß-blockers (51.4%), EIS (34.2%), ß-blockers+isosorbide-5-mononitrate (23.7%), ß-blockers (20.8%), and placebo (0.8%). In reducing rebleeding-related mortality, TIPS SUCRA (87.2%) was more efficacious than EBL+EIS (83.5%), EIS (47.9%), EBL+ß-blockers (47.4%), ß-blockers (41.8%), EBL (34.5%), and placebo (7.6%). In reducing overall mortality, TIPS SUCRA (81.1%) was superior to EBL+EIS (68.9%), EIS+ß-blockers (59.2%), EBL+ß-blockers (55.4%), EIS (48.8%), EBL (48.7%), ß-blockers (34.2%), placebo (3.6%). CONCLUSIONS: TIPS was more effective in reducing the incidence of cirrhosis EV rebleeding, rebleeding-related mortality, and overall mortality in cirrhosis. Combined with the above results, TIPS is more likely to be recommended as a secondary prophylaxis intervention for EV in cirrhosis.

Erinacine Facilitates the Opening of the Mitochondrial Permeability Transition Pore Through the Inhibition of the PI3K/ Akt/GSK-3ß Signaling Pathway in Human Hepatocellular Carcinoma.

BACKGROUND/AIMS: Erinacine, which is extracted from the medicinal mushroom Hericium erinaceus, is known to play anticancer roles in human cancers. The following study aims to investigate the role of erinacine in the opening of the mitochondrial permeability transition pore (MPTP) in hepatocellular carcinoma (HCC) through the PI3K/Akt/GSK-3ß signaling pathway and highlights the applicability of erinacine in HCC treatments. METHODS: HCC and paracancerous tissues were obtained from 85 HCC patients who've undergone surgical resection. Immunohistochemistry was adopted to detect positive expression of PI3K, Akt, and GSK-3ß. Treatment of HepG-2 with LY294002 (an inhibitor of the PI3K/Akt/GSK-3ß signaling pathway) and different concentration of erinacine was performed to determine the involvement of LY294002 in erinacine action. The expressions of PI3K, Akt, GSK-3ß, CyclinD1, Vimentin, ß-catenin, Bcl-2, E-cadherin, Bax, and caspase-9 were determined by RT-qPCR and Western blot analysis. Cell viability, colony formation rate, migration, invasion, cycle, and apoptosis were detected by MTT, colony formation, wound healing assay, Transwell assay, and flow cytometry, respectively. The size and weight of xenograft tumors were observed in nude mice. Mitochondrial membrane potential in HepG-2 was determined using laser scanning confocal microscopy following JC-1 staining. Mitochondrial Ca2+ indicator Rhod-2, AM was used to detect the changes of mitochondrial Ca2+, while western blot analysis was employed to detect the presence levels of cytochrome C (cyt-C). RESULTS: The results revealed that PI3K, Akt, and GSK-3ß were up-regulated in HCC tissues. Erinacine or LY294002 led to a decrease in mitochondrial membrane potential, increase in intracellular mitochondrial Ca2+, and the release of cyt-C in mitochondria. In addition, Erinacine was found to decrease the mitochondrial membrane potential, expression of PI3K, Akt, GSK-3ß, CyclinD1, Vimentin, ß-catenin, and Bcl-2, cell proliferation, colony formation ability, migration, invasion, and xenograft tumor size, while E-cadherin, Bax, and caspase-9 expression, and cell apoptosis were elevated in a dose-dependent manner. Erinacine also stimulated the effects of LY294002 on the HCC. Following the addition of 500 µM Erinacine and MPTP opening inhibitor CsA, we found that the mitochondrial membrane potential level increased, while mitochondrial Ca2+ and Cyt-C decreased from the mitochondria. CONCLUSION: The results from the study demonstrated that erinacine induced MPTP opening, facilitates the release of cyt-C, and inhibited cell proliferation, migration, and invasion, while it promotes apoptosis by inactivating the PI3K/Akt/GSK-3ß signaling pathway, preventing the progression of HCC.

Let-7b contributes to hepatocellular cancer progression through Wnt/ß-catenin signaling.

Elevated evidences show that microRNAs (miRNAs) play vital roles in tumor progression regulation. However, the functional role of let-7b in hepatocellular carcinoma (HCC) is still largely unknown. In this study, we try to investigate the biological activity of let-7b in human HCC cells and try to find the potential regulatory signaling pathway. Our results indicate that let- 7b was remarkably down-regulated in human HCC tissues by qRT-PCR. In addition, let-7b overexpression decreased the expression of ß-catenin and c-Myc, while upregulated E-cadherin expression in HCC cells which was verified by quantitative real-time PCR (qRT-PCR) and western blotting. Furthermore, Wnt/ß-catenin was involved in let-7b biological activity which was revealed by luciferase assay. Moreover, Wnt/ß-catenin signaling inhibitor blocks HCC cell proliferation which is as the same pattern as let-7b overexpression inhibits in HCC cells proliferation. In conclusion, down-regulated let-7b promotes HCC cell proliferation through Wnt/ß-catenin signaling in HCC cells. These results suggested that appropriate manipulation of let-7b might be a new treatment of human HCC in the future.

[The mechanisms of inhibitory effect of adenovirus-mediated wild-type PTEN gene on the proliferation in activated hepatic stellate cells in vitro].

OBJECTIVE: Using an adenoviral vector, the wild-type PTEN gene was transduced into activated hepatic stellate cell (HSC) cultured in vitro and cell cycle markers and were detect. Thereby, the potential mechanisms of inhibitory effect of the wild-type PTEN overexpression on the proliferation in activated HSC was investigated. METHODS: The wild type PTEN gene was transduced into activated HSC (HSC-T6 ) cultured in vitro mediated by adenoviral vector. PTEN expression in HSC was measured by Western blot and Real-time fluorescent quantitation PCR. Flow cytometry (FCM) was then used to detect cell cycle phase of activated HSC. And the expressions of cyclinD1 and cyclin dependent kinase 4 (CDK4) in HSC were determined by Western blot. RESULTS: The data showed that exogenous wild type PTEN gene was successfully transduced and expressed in activated HSC cultured in vitro. The over-expression of wild type PTEN resulted in the increased number of HSC at G0/G1 phase ( P less than 0.01), and the number of HSC at S phase and G2/M phase were decreased significantly, P less than 0.01. Furthermore, there were decreased cyclinD1 and CDK4 expression in HSC infected with Ad-PTEN, P less than 0.01. CONCLUSION: The over-expression of wild type PTEN inhibit transition of activated HSC in vitro from G1 to S phase and arrest cell cycle of them at G0/G1 phase via the down-regulated expressions of cyclinD1 and CDK4, and then inhibit HSC proliferation.