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.

Value of fasting plasma glucose to screen gestational diabetes mellitus before the 24th gestational week in women with different pre-pregnancy body mass index

Background:Gestational diabetes mellitus(GDM)is usually diagnosed between 24th and 28th gestational week using the 75-g oral glucose tolerance test(OGTT).It is difficult to predict GDM before 24th gestational week because fast plasma glucose(FPG)decreases as the gestational age increases.It is controversial that if FPG≥5.1 mmol/L before 24th gestational week should be intervened or not.The aim of this study was to evaluate the value of FPG to screen GDM before 24th gestational week in women with different pre-pregnancy body mass index(BMI).Methods:This was a multi-region retrospective cohort study in China.Women who had a singleton live birth between June 20,2013 and November 30,2014,resided in Beijing,Guangzhou and Chengdu,and received prenatal care in 21 selected hospitals,were included in this study.Pre-pregnancy BMI,FPG before the 24th gestational week,and one-step GDM screening with 75 g-OGTT at the 24th to 28th gestational weeks were extracted from medical charts and analyzed.The pregnant women were classified into four groups based on pre-pregnancy BMI:Group A(underweight,BMI<18.5 kg/m^2),Group B(normal,BMI 18.5-23.9 kg/m^2),Group C(overweight,BMI 24.0-27.9 kg/m^2)and Group D(obesity,BMI≥28.0 kg/m^2).The trend of FPG before 24th week of gestation was described,and the sensitivity and specificity of using FPG before the 24th gestational week to diagnose GDM among different pre-pregnancy BMI groups were reported.Differences in the means between groups were evaluated using independent sample t-test and analysis of variance.Pearson Chi-square test was used for categorical variables.Results:The prevalence of GDM was 20.0%(6806/34,087)in the study population.FPG decreased gradually as the gestational age increased in all pre-pregnancy BMI groups until the 19th gestational week.FPG was higher in women with higher pre-pregnancy BMI.FPG before the 24th gestational week and pre-pregnancy BMI could be used to predict GDM.The incidence of GDM in women with FPG≥5.10 mmol/L in the 19th to 24th gestational weeks and pre-pregnancy overweight or obesity was significantly higher than that in women with FPG≥5.10 mmol/L and pre-pregnancy BMI<24.0 kg/m^2(78.5%[62/79]vs.52.9%[64/121],χ^2=13.425,P<0.001).Conclusions:FPG decreased gradually as the gestational age increased in all pre-pregnancy BMI groups until the 19th gestational week.Pre-pregnancy overweight or obesity was associated with an increased FPG value before the 24th gestational week.FPG≥5.10 mmol/L between 19 and 24 gestational weeks should be treated as GDM in women with pre-pregnancy overweight and obesity.