Bing-Zhu Yan

Hepatitis C virus core protein induces hepatic metabolism disorders through down-regulation of the SIRT1-AMPK signaling pathway.

BACKGROUND Steatosis and insulin resistance induced by hepatitis C virus (HCV) infection are, at least in part, critical factors for the progression of chronic hepatitis C (CHC) and can influence the outcome of antiviral treatment. Silent information regulator 1 (SIRT1) and adenosine monophosphate-activated protein kinase (AMPK) play a key role in the regulation of hepatic glucose and lipid metabolism. The aim of this study was to investigate the possible effect of HCV core protein on energy, glucose, and lipid metabolism of hepatocytes and expression of SIRT1 and AMPK. METHODS HCV core protein expression plasmid was transfected into HepG2 cells. The level of reactive oxygen species (ROS) and values of NAD(+)/NADH and ATP/ADP were detected. Intracellular levels of triacylglycerol (TG), cholesterol, glucose uptake by hepatocytes, and glucose production were measured. The expression levels of mRNA and protein of SIRT1 and AMPK were detected. The mRNA levels of SIRT1 and AMPK downstream glucose and lipid metabolism genes were measured. RESULTS In HepG2 cells expressing HCV core protein, the level of ROS increased, the value of NAD(+)/NADH decreased, the activity and expression levels of mRNA and protein of SIRT1 and AMPK decreased, glucose uptake and its regulator gene GLUT2 mRNA levels decreased, glucose production and its regulator genes PEPCK and G6Pase mRNA levels increased, intracellular TG and cholesterol contents and their regulator gene (SREBP-1c, FAS, ACC, HMGR, and HMGS) mRNA levels increased, the glycolytic gene GK and fatty acid oxidation genes PPARα and CPT1A mRNA levels decreased. CONCLUSIONS HCV core protein induces alterations in cellular redox state (decrease in the NAD(+)/NADH ratio), which could influence the activity of SIRT1 and secondarily AMPK, then change the expression profile of glucose and lipid metabolism-related genes, thereby causing metabolism disorders of hepatocytes.

Lamivudine treatment is associated with improved survival in fulminant hepatitis B.

Objective: Fulminant hepatitis B is a clinical syndrome that results from massive necrosis of liver cells leading to the development of hepatic encephalopathy. The aim of this study was to evaluate the efficacy of lamivudine in patients with fulminant hepatitis B and study the prognostic factors.

Efficacy and factors influencing treatment with peginterferon alpha-2a and ribavirin in elderly patients with chronic hepatitis C

BACKGROUND In China, hepatitis C virus (HCV) infection is characterized by an increasing prevalence during aging. This study was undertaken to evaluate the efficacy of treatment with peginterferon alpha-2a and ribavirin in elderly chronic hepatitis C (CHC) patients and study the factors related to the sustained virologic response (SVR). METHODS The medical records of 417 patients treated with peginterferon and ribavirin were retrospectively analyzed. These patients were divided into two groups according to age: patients aged ≥ 65 years (n=140) and patients aged <65 years (n=277). The rate of ribavirin reduction or discontinuation and virologic response rates of the two groups were compared. The factors influencing SVR were studied by multivariate analysis. RESULTS Ribavirin reduction or discontinuation was more frequent in patients aged ≥ 65 years than patients aged <65 years (37.1%, 52/140 vs 20.2%, 56/277; X2=13.883, P<0.001). For genotype 1, patients aged ≥ 65 years had a higher relapse rate (50.0%, 42/84 vs 29.2%, 52/178; X2=10.718, P=0.001) and a lower SVR rate (40.0%, 42/105 vs 60.0%, 126/210; X2=11.250, P=0.001) than patients aged <65 years. There were no significant differences in virologic response rates between the two groups for patients with genotype 2. For genotype 1, in patients aged ≥ 65 years, the SVR rate of females was lower than that of males (28.6%, 12/42 vs 47.6%, 30/63; X2=8.150, P=0.004); in the high viral load group, patients aged ≥ 65 years had a lower SVR rate than patients aged <65 years (30.0%, 18/60 vs 54.8%, 69/126; X2=10.010, P=0.002). In multivariate logistic regression analysis, the independent factors associated with SVR in patients aged ≥ 65 years were sex (P=0.020), genotype (P=0.005), ribavirin reduction or discontinuation (P=0.009) and presence of rapid virologic response (RVR) (P=0.001). CONCLUSIONS The rate of ribavirin reduction or discontinuation and relapse rate of patients aged ≥ 65 years with genotype 1 are high, and the SVR rate is low. Age has no impact on virologic responses rates for genotype 2. Among patients ≥ 65 years old, genotype 2 patients and genotype 1 patients with a low baseline viral load or achieving RVR or male may benefit from combination therapy.

The effect of metformin on the efficacy of antiviral therapy in patients with genotype 1 chronic hepatitis C and insulin resistance

OBJECTIVES Insulin resistance (IR) affects sustained virological response (SVR) in chronic hepatitis C (CHC). The aim of this study was to investigate the effect of adding metformin to peginterferon alfa-2a and ribavirin on the efficacy in patients with genotype 1 CHC and IR. METHODS Ninety-eight patients with genotype 1 CHC and IR were randomized into the treatment group (n=49) and the control group (n=49). Patients in the control group received peginterferon alfa-2a and ribavirin, and patients in the treatment group received metformin in addition to peginterferon alfa-2a and ribavirin. The rate of virological response, changes in the homeostasis model assessment of insulin resistance (HOMA-IR) index, and the incidence of side effects were compared between the two groups. Factors influencing the SVR were studied by multivariate analysis. RESULTS The SVR rate of the treatment group was significantly higher than that of the control group (59.2%, 29/49 vs. 38.8%, 19/49; Chi-square=4.083, p=0.043). The HOMA-IR index of patients in the treatment group was lower than that of patients in the control group at weeks 12, 24, and 48 of the treatment period, and at week 24 of follow-up (3.00±0.65 vs. 3.50±0.72, 1.90±0.45 vs. 2.90±0.64, 1.75±0.40 vs. 2.74±0.48, and 1.60±0.35 vs. 2.60±0.55, respectively; t=3.610, 8.947, 11.091, and 10.738, respectively; p<0.01). Diarrhea was more often seen in the treatment group (28.6%, 14/49 vs. 10.2%, 5/49; Chi-square=5.288, p=0.021). In the multivariate logistic regression analysis, the independent factors associated with SVR were treatment method (p=0.009) and HOMA-IR <2 at week 24 (p=0.011). CONCLUSIONS A combination of metformin, peginterferon alfa-2a, and ribavirin improved insulin sensitivity and increased the SVR rate of patients with hepatitis C genotype 1 and IR, with a good safety profile.

Impact of sex on virologic response rates in genotype 1 chronic hepatitis C patients with peginterferon alpha-2a and ribavirin treatment

OBJECTIVES The relationship between patient sex and the effectiveness of peginterferon alpha-2a and ribavirin treatment in chronic hepatitis C (CHC) patients remains unclear. The aim of this study was to investigate the impact of sex on virologic responses rates in genotype 1 CHC patients. METHODS A matched retrospective cohort study of 630 genotype 1 patients treated with peginterferon and ribavirin derived from our hospital database was conducted. These patients were divided into three groups according to age: patients aged <40 years (n=200), patients aged 40-50 years (n=210), and patients aged 51-60 years (n=220). The rate of patients receiving ≥ 80% of the planned drug dose and virologic response rates were compared between males and females in the three groups. Factors influencing the sustained virologic response (SVR) were studied by multivariate analysis. RESULTS In patients aged 51-60 years, the rate of female patients receiving ≥ 80% of the planned ribavirin dose was significantly lower than that of males (42.7%, 47/110 vs. 61.8%, 68/110; Chi-square=8.035, p=0.005). In patients aged <40 years, the SVR rate of females was significantly higher than that of males (75%, 75/100 vs. 54%, 54/100; Chi-square=9.630, p=0.002); in patients aged 40-50 years, there was no significant difference in the SVR rate between males and females (50.5%, 53/105 vs. 54.3%, 57/105; Chi-square=0.305, p=0.580); in patients aged 51-60 years, the SVR rate of females was significantly lower than that of males (33.6%, 37/110 vs. 48.2%, 53/110; Chi-square=4.814, p=0.028). In multivariate logistic regression analysis, the independent factors associated with SVR in patients aged 51-60 years were sex (p=0.013), ≥ 80% of the planned ribavirin dose (p=0.008), and the presence of a rapid virologic response (p=0.001). CONCLUSIONS In the group of patients aged <40 years, the SVR rate of females was higher than that of males; in the group of patients aged 40-50 years, females and males shared similar SVR rates; in the group of patients aged 51-60 years, the SVR rate of females was lower than that of males.

Silent information regulator 1 inhibition induces lipid metabolism disorders of hepatocytes and enhances hepatitis C virus replication

Hepatic steatosis is an important histopathological feature of chronic hepatitis C virus (HCV) infection. Silent information regulator 1 (SIRT1) plays key role in regulation of hepatic lipid metabolism. We investigated the possible effect of HCV replication on lipid metabolism of hepatocytes and expression of SIRT1 using Huh‐7.5 cells harboring HCV replicon.

Hepatoprotective effects of cathepsin B inhibitor on acute hepatic failure induced by lipopolysaccharide/D-galactosamine in mice.

BACKGROUND Increasing evidence suggests that the inactivation of cathepsin B attenuates hepatocyte apoptosis and liver damage. This study aimed to investigate the protective effects of a cathepsin B inhibitor (CA-074me) on lipopolysaccharide (LPS)/D-galactosamine (D-GalN)-induced acute hepatic failure (AHF) in mice. METHODS Mice were intraperitoneally injected with a combination of LPS/D-GalN to induce AHF with or without CA-074me pretreatment. The cumulative survival rates were calculated 48 hours after the induction of AHF. As well as changes in biochemical indicators and liver histology, hepatocyte apoptosis was assessed using a TUNEL method. Serum tumor necrosis factor-alpha (TNF-alpha) production, caspase-3, caspase-8, and caspase-9 activity was evaluated. Cytosolic cytochrome c and Bcl-2 expression were measured by Western blotting. RESULTS The marked elevation in serum aminotransferase activity and prothrombin time found in LPS/D-GalN-treated mice was significantly improved by pretreatment with CA-074me. The efficacy of CA-074me was also confirmed by histological analysis and TUNEL assay. The survival rate significantly improved in LPS/D-GalN-induced mice given CA-074me compared with untreated mice. LPS/D-GalN-induced caspase-3 and caspase-9 activation was remarkably suppressed by CA-074me. However, the increased levels of serum TNF-alpha and elevated caspase-8 activity in AHF mice were not significantly reduced by CA-074me. Moreover, CA-074me sharply reduced the increased expression of cytosolic cytochrome c and markedly augmented Bcl-2 expression. CONCLUSION These results suggest that CA-074me has a protective effect in acute hepatic failure induced by LPS/D-GalN.

The study of relationship between neutropenia and infection during treatment with peginterferon α and ribavirin for chronic hepatitis C

Objective Neutropenia is frequent during treatment of chronic hepatitis C (CHC) with peginterferon and ribavirin. It remains unclear whether neutropenia is associated with infection in CHC. The aim was to study the relationship between neutropenia and infection during treatment with peginterferon and ribavirin for CHC. Methods A retrospective cohort on 399 patients treated with peginterferon &agr; and ribavirin derived from our hospital database was conducted. The occurrence of infections and their relationship to neutropenia were investigated. Potential risk factors for infection were identified by multivariate analysis. Results During treatment, neutropenia [absolute neutrophil counts (ANC) <1.5×109/l] occurred in 251 patients, mild neutropenia [ANC (0.75–1.5)×109/l] occurred in 132 patients, moderate neutropenia [ANC (0.50–0.75)×109/l] occurred in 103 patients, and severe neutropenia (ANC<0.50×109/l) occurred in 16 patients. Eighty infections (20.1%) occurred, 14 infections (17.5%) were defined as severe. There was no significant difference in infection rate between patients with and without moderate and severe neutropenia (21.0%, 25/119 vs. 19.6%, 55/280; &khgr;2=0.097, P=0.755). There was no significant difference in infection rate between patients with and without peginterferon dose modifications (21.5%, 31/144 vs. 19.2%, 49/255; &khgr;2=0.307, P=0.580). In multivariate logistic regression analysis, the independent factors associated with infection were age (P=0.021), diabetes (P=0.004), and cirrhosis (P=0.012). Conclusion Infections during treatment with peginterferon &agr; and ribavirin for CHC are not associated with neutropenia. The independent factors associated with infection are age, diabetes, and cirrhosis.

The therapeutic effect of CORM-3 on acute liver failure induced by lipopolysaccharide/D-galactosamine in mice.

BACKGROUND Acute liver failure (ALF) is a severe and life-threatening clinical syndrome resulting in a high mortality and extremely poor prognosis. Recently, a water-soluble CO-releasing molecule (CORM-3) has been shown to have anti-inflammatory effect. The present study was to investigate the effect of CORM-3 on ALF and elucidate its underlying mechanism. METHODS ALF was induced by a combination of LPS/D-GalN in mice which were treated with CORM-3 or inactive CORM-3 (iCORM-3). The efficacy of CORM-3 was evaluated based on survival, liver histopathology, serum aminotransferase activities (ALT and AST) and total bilirubin (TBiL). Serum levels of inflammatory cytokines (TNF-alpha, IL-6, IL-1beta and IL-10) and liver immunohistochemistry of NF-kappaB-p65 were determined; the expression of inflammatory mediators such as iNOS, COX-2 and TLR4 was measured using Western blotting. RESULTS The pretreatment with CORM-3 significantly improved the liver histology and the survival rate of mice compared with the controls; CORM-3 also decreased the levels of ALT, AST and TBiL. Furthermore, CORM-3 significantly inhibited the increased concentration of pro-inflammatory cytokines (TNF-alpha, IL-6 and IL-1beta) and increased the anti-inflammatory cytokine (IL-10) productions in ALF mice. Moreover, CORM-3 significantly reduced the increased expression of iNOS and TLR4 in liver tissues and inhibited the nuclear expression of NF-kappaB-p65. CORM-3 had no effect on the increased expression of COX-2 in the ALF mice. An iCORM-3 failed to prevent acute liver damage induced by LPS/D-GalN. CONCLUSION These findings provided evidence that CORM-3 may offer a novel alternative approach for the management of ALF through anti-inflammatory functions.

Inhibition of silent information regulator 1 induces glucose metabolism disorders of hepatocytes and enhances hepatitis C virus replication

Background and objectiveGlucose metabolism disorders including insulin resistance (IR) and type 2 diabetes are frequent and important cofactors of chronic hepatitis C (CHC). Silent information regulator 1 (SIRT1) plays a key role in the regulation of hepatic glucose metabolism. We investigated the possible effect of HCV replication on glucose metabolism of hepatocytes and expression of SIRT1 using Huh-7.5 cells harboring the HCV replicon.MethodsThe level of reactive oxygen species (ROS) and value of NAD+/NADH and ATP/ADP were detected. Glucose uptake by hepatocytes and glucose production were measured. The activity and expression levels of SIRT1 and expression of its downstream glucose-metabolism genes were measured.ResultsIn replicon cells, the level of ROS increased and the value of nicotinamide adenine dinucleotide (NAD+)/NADH decreased, then the activity and expression level of mRNA and protein of SIRT1 decreased. Inhibition of SIRT1 not only increased insulin receptor substrate-1 phosphorylation and decreased Akt phosphorylation, inhibited cell surface expression of glucose transporter 2 and suppressed cellular glucose uptake, but it also decreased phosphorylation of forkhead box O1, then upregulated phosphoenolpyruvate carboxykinase and glucose 6-phosphatase genes and downregulated the glucokinase gene, thus promoting glucose production. Interferon treatment restored the aforementioned changes. SIRT1 activator improved glucose metabolism disorders by an increase in glucose uptake and a decrease in glucose production, and it inhibited HCV replication.ConclusionsHCV replication decreasing the NAD+/NADH ratio may downregulate the activity and expression of SIRT1, then change the expression profile of glucose metabolism-related genes, thereby causing glucose metabolism disorders of hepatocytes and promoting HCV replication. Treatment with SIRT1 activator improves glucose metabolic disorders and inhibits HCV replication, suggesting that restoration of SIRT1 activity may be a promising new therapeutic approach for CHC patients with IR.