Givinostat inhibition of hepatic stellate cell proliferation and protein acetylation

AIM: To explore the effect of the histone deacetylase inhibitor givinostat on proteins related to regulation of hepatic stellate cell proliferation.METHODS: The cell counting kit-8 assay and flow cytometry were used to observe changes in proliferation, apoptosis, and cell cycle in hepatic stellate cells treated with givinostat. Western blot was used to observe expression changes in p21, p57, CDK4, CDK6, cyclin D1, caspase-3, and caspase-9 in hepatic stellate cells exposed to givinostat. The scratch assay was used to analyze the effect of givinostat on cell migration. Effects of givinostat on the reactive oxygen species profile, mitochondrial membrane potential, and mitochondrial permeability transition pore opening in JS-1 cells were observed by laser confocal microscopy.RESULTS: Givinostat significantly inhibited JS-1 cell proliferation and promoted cell apoptosis, leading to cell cycle arrest in G0/G1 phases. Treatment with givinostat downregulated protein expression of CDK4, CDK6, and cyclin D1, whereas expression of p21 and p57 was significantly increased. The givinostat-induced apoptosis of hepatic stellate cells was mainly mediatedthrough p38 and extracellular signal-regulated kinase 1/2. Givinostat treatment increased intracellular reactive oxygen species production, decreased mitochondrial membrane potential, and promoted mitochondrial permeability transition pore opening. Acetylation of superoxide dismutase(acetyl K68) and nuclear factor-κB p65(acetyl K310) was upregulated, while there was no change in protein expression. Moreover, the notable beneficial effect of givinostat on liver fibrosis was also confirmed in the mouse models.CONCLUSION: Givinostat has antifibrotic activities via regulating the acetylation of nuclear factor-κB and superoxide dismutase 2, thus inhibiting hepatic stellate cell proliferation and inducing apoptosis.

Long-term prognosis in patients continuing taking antithrombotics after peptic ulcer bleeding

AIM To investigate the long-term prognosis in peptic ulcer patients continuing taking antithrombotics after ulcer bleeding, and to determine the risk factors that influence the prognosis. METHODS All clinical data of peptic ulcer patients treated from January 1, 2009 to January 1, 2014 were retrospectively collected and analyzed. Patients were divided into either a continuing group to continue taking antithrombotic drugs after ulcer bleeding or a discontinuing group to discontinue antithrombotic drugs. The primary outcome of follow-up in peptic ulcer bleeding patients was recurrent bleeding, and secondary outcome was death or acute cardiovascular disease occurrence. The final date of follow-up was December 31, 2014. Basic demographic data, complications, and disease classifications were analyzed and compared by t- or χ2-test. The number of patients that achieved various outcomes was counted and analyzed statistically. A survival curve was drawn using the Kaplan-Meier method, and the differencewas compared using the log-rank test. COX regression multivariate analysis was applied to analyze risk factors for the prognosis of peptic ulcer patients. RESULTS A total of 167 patients were enrolled into this study. As for the baseline information, differences in age, smoking, alcohol abuse, and acute cardiovascular diseases were statistically significant between the continuing and discontinuing groups(70.8 ± 11.4 vs 62.4 ± 12.0, P < 0.001; 8(8.2%) vs 15(21.7%), P < 0.05; 65(66.3%) vs 13(18.8%), P < 0.001). At the end of the study, 18 patients had recurrent bleeding and three patients died or had acute cardiovascular disease in the continuing group, while four patients had recurrent bleeding and 15 patients died or had acute cardiovascular disease in the discontinuing group. The differences in these results were statistically significant(P = 0.022, P = 0.000). The Kaplan-Meier survival curve indicated that the incidence of recurrent bleeding was higher in patients in the continuing group, and the risk of death and developing acute cardiovascular disease was higher in patients in the discontinuing group(log-rank test, P = 0.000 for both). Furthermore, COX regression multivariate analysis revealed that the hazard ratio(HR) for recurrent bleeding was 2.986(95%CI: 067-8.356, P = 0.015) in the continuing group, while HR for death or acute cardiovascular disease was 5.216(95%CI: 1.035-26.278, P = 0.028).CONCLUSION After the occurrence of peptic ulcer bleeding, continuing antithrombotics increases the risk of recurrent bleeding events, while discontinuing antithrombotics would increase the risk of death and developing cardiovascular disease. This suggests that clinicians should comprehensively consider the use of antithrombotics after peptic ulcer bleeding.

The Gut Microbiome and Ferroptosis in MAFLD

Metabolic-associated fatty liver disease(MAFLD)is a new disease definition,and is proposed to replace the previous name,nonalcoholic fatty liver disease(NAFLD).Globally,MAFLD/NAFLD is the most common liver disease,with an incidence rate ranging from 6%to 35%in adult populations.The pathogenesis of MAFLD/NAFLD is closely related to insulin resistance(IR),and the genetic susceptibility to acquired metabolic stress-associated liver injury.Similarly,the gut microbiota in MAFLD/NAFLD is being revaluated by scientists,as the gut and liver influence each other via the gut-liver axis.Ferroptosis is a novel form of programmed cell death caused by iron-dependent lipid peroxidation.Emerging evidence suggests that ferroptosis has a key role in the pathological progression of MAFLD/NAFLD,and inhibition of ferroptosis may become a novel therapeutic strategy for the treatment of NAFLD.This review focuses on the main mechanisms behind the promotion of MAFLD/NAFLD occurrence and development by the intestinal microbiota and ferroptosis.It outlines new strategies to target the intestinal microbiota and ferroptosis to facilitate future MAFLD/NAFLD therapies.