Hepatitis C virus core protein induces dysfunction of liver sinusoidal endothelial cell by down-regulation of silent information regulator 1.

Hepatic fibrosis is a frequent feature of chronic hepatitis C virus (HCV) infection. Some evidence has suggested the potential role of silent information regulator 1 (SIRT1) in organ fibrosis. The aim of this study was to investigate the effect of HCV core protein on expression of SIRT1 of liver sinusoidal endothelial cell (LSEC) and function of LSEC. LSECs were co-cultured with HepG2 cells or HepG2 cells expressing HCV core protein and LSECs cultured alone were used as controls. After co-culture, the activity and expression levels of mRNA and protein of SIRT1 in LSEC were detected by a SIRT1 fluorometric assay kit, real time-PCR (RT-PCR), Western blot, respectively. The levels of adiponectin receptor 2 (AdipoR2), endothelial nitric oxide synthase (eNOS) and vascular endothelial growth factor (VEGF) were measured by Western blot. Cluster of differentiation 31 (CD31), CD14, and von Willebrand factor (vWf) of LSECs was performed by flow cytometry. The level of reactive oxygen species (ROS) was assayed. Malondialdehyde (MDA), superoxide dismutase (SOD), adiponectin, nitric oxide (NO), and endothelin-1 (ET-1) levels in the co-culture supernatant were measured. The co-culture supernatant was then used to cultivate LX-2 cells. The levels of α-smooth muscle actin (ASMA) and transforming growth factor-ß1 (TGF-ß1) protein in LX-2 cells were measured by Western blot. Compared with LSEC co-cultured with HepG2 cells group, in LSEC co-cultured with HepG2-core cells group, the activity and expression level of mRNA and protein of SIRT1 reduced; the level of adiponectin reduced and the expression level of AdipoR2 protein decreased; ROS levels increased; the expression level of eNOS, VEGF protein decreased; and the expression level of CD14 decreased; the expression level of vWf and CD31 increased; NO and SOD levels decreased; whereas ET-1 and MDA levels increased; the levels of ASMA and TGF-ß1 protein in LX-2 cells increased. SIRT1 activator improved the above-mentioned changes. HCV core protein may down-regulate the activity and the expression of SIRT1 of LSEC, then decreasing synthesis of adiponectin and the expression of AdipoR2, thus inducing contraction of LSEC and hepatic sinusoidal capillarization and increasing oxidative stress, ultimately cause hepatic stellate cell (HSC) activation. Treatment with SIRT1 activator restored the function of LSEC and inhibited the activation of HSC.

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

AIM: 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. METHODS: The level of reactive oxygen species (ROS) and malondialdehyde (MDA), the activity of superoxide dismutase (SOD), and the value of nicotinamide adenine dinucleotide (NAD(+) )/NADH was detected. The level of triacylglycerol (TG), total cholesterol (TC) and fatty acid ß-oxidation rate was detected. The activity and expression levels of SIRT1 and expression of its downstream lipid-metabolism genes were measured. RESULTS: In replicon cells, the level of ROS and MDA increased, SOD activity and the value of NAD(+) /NADH decreased, then the activity and expression level of mRNA and protein of SIRT1 reduced. Inhibition of SIRT1 decreased phosphorylation of forkhead box O1 (FoxO1), which not only upregulated SREBP-1c, FAS, ACC, SREBP-2, HMGR and HMGS genes and increased fatty acid synthesis; but also downregulated PPAR-α and CPT1A genes and decreased fatty acid ß-oxidation. Interferon treatment restored aforementioned changes. SIRT1 activator improved lipid metabolism disorders by an increase in fatty acid ß-oxidation and a decrease in TG and TC synthesis and inhibited HCV replication. CONCLUSION: HCV replication decreasing NAD(+) /NADH ratio may downregulate the activity and the expression of SIRT1, then change the expression profile of lipid metabolism-related genes, thereby cause lipid metabolism disorders of hepatocytes and promote HCV replication. Treatment with SIRT1 activator ameliorates lipid metabolic disorders and inhibits HCV replication.

[Inhibition of silent information regulator-1 in hepatocytes induces lipid metabolism disorders and enhances hepatitis C virus replication].

OBJECTIVE: To investigate the role of the host-encoded silent information regulator 1 (SIRT1) on hepatocytes' lipid metabolism under conditions of hepatitis C virus (HCV) infection and assess its potential effects on virus replication in vitro. METHODS: The Huh-7.5 human hepatocyte cell line was used as the control group and Huh-7.5 cells stably expressing the HCV replicon (Huh7.5-HCV) were used as the experimental group. Effects of interferon (IFN) treatment and activation of SIRT1 by resveratrol were also observed. The mRNA and protein expression levels of SIRT1 were detected by real time (q)PCR and western blotting. Effects on SIRT1 protein activity were tested by measuring the levels of reactive oxygen species (ROS) and the nicotinamide adenine dinucleotide (NAD+)/beta-nicotinamide adenine dinucleotide, reduced (NADH) by flow cytometry and chromatometry, and the levels of triacylglycerol (TG), total cholesterol (TC), and fatty acid beta oxidation rate by enzymatic analysis and liquid scintillation counting. Effects on mRNA expression of SIRT1 downstream lipid-metabolism genes were measured by qPCR. RESULTS: The Huh7.5-HCV cells had a significantly higher level of ROS (3.8+/-0.5 vs. Huh-7.5: 1.0+/-0.2; t = 12.736, P less than 0.01) but significantly lower levels of NAD+/NADH (0.03+/-0.01 vs. 0.12+/-0.03; t = 6.971, P less than 0.01), SIRT1 activity (0.3+/-0.1 vs. 1.0+/-0.2, 0.9+/-0.2, F = 6.766, P less than 0.01), SIRT1 mRNA (0.4+/-0.1 vs. 1.0+/-0.3, 0.9+/-0.2, F = 5.864, P less than 0.01), and SIRT1 protein (0.3+/-0.1 vs. 0.8+/-0.2, 0.9+/-0.2, F = 5.419, P less than 0.01). The lower levels of SIRT1 in Huh7.5-HCV cells accompanied decreased phosphorylation of the forkhead box O1 (FoxO1), which not only up-regulated the downstream genes of SREBP-1c, FAS, ACC, SREBP-2, HMGR and HMGS (which increased fatty acid synthesis) but also down-regulated the downstream genes of PPAR and CPT1A genes (which decreased fatty acid beta oxidation). IFN treatment restored all of the aforementioned changes. Resveratrol-induced SIRT activation improved the perturbations in lipid metabolism pathways, as evidenced by an increase in fatty acid beta oxidation and a decrease in TG and TC synthesis, as well as inhibited HCV replication. CONCLUSION: HCV may decrease the NAD+/NADH ratio in hepatocytes, leading to a down-regulation of SIRT1 activity and expression and perturbing the downstream expression profile of lipid metabolism-related factors, ultimately causing lipid metabolism disorders and establishing a permissive intracellular environment for HCV replication.

Effects of vitamin D supplementation on glucose and lipid metabolism in patients with type 2 diabetes mellitus and risk factors for insulin resistance.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is a chronic metabolic disease featured by insulin resistance (IR) and decreased insulin secretion. Currently, vitamin D deficiency is found in most patients with T2DM, but the relationship between vitamin D and IR in T2DM patients requires further investigation. AIM: To explore the risk factors of IR and the effects of vitamin D supplementation on glucose and lipid metabolism in patients with T2DM. METHODS: Clinical data of 162 T2DM patients treated in First Affiliated Hospital of Harbin Medical University between January 2019 and February 2022 were retrospectively analyzed. Based on the diagnostic criteria of IR, the patients were divided into a resistance group (n = 100) and a non-resistance group (n = 62). Subsequently, patients in the resistance group were subdivided to a conventional group (n = 44) or a joint group (n = 56) according to the treatment regimens. Logistic regression was carried out to analyze the risk factors of IR in T2DM patients. The changes in glucose and lipid metabolism indexes in T2DM patients with vitamin D deficiency were evaluated after the treatment. RESULTS: Notable differences were observed in age and body mass index (BMI) between the resistance group and the non-resistance group (both P < 0.05). The resistance group exhibited a lower 25-hydroxyvitamin D3 (25(OH)D3) level, as well as notably higher levels of 2-h postprandial blood glucose (2hPG), fasting blood glucose (FBG), and glycosylated hemoglobin (HbA1c) than the non-resistance group (all P < 0.0001). Additionally, the resistance group demonstrated a higher triglyceride (TG) level but a lower high-density lipoprotein-cholesterol (HDL-C) level than the non-resistance group (all P < 0.0001). The BMI, TG, HDL-C, 25(OH)D3, 2hPG, and HbA1c were found to be risk factors of IR. Moreover, the post-treatment changes in levels of 25(OH)D3, 2hPG, FBG and HbA1c, as well as TG, total cholesterol, and HDL-C in the joint group were more significant than those in the conventional group (all P < 0.05). CONCLUSION: Patients with IR exhibit significant abnormalities in glucose and lipid metabolism parameters compared to the non-insulin resistant group. Logistic regression analysis revealed that 25(OH)D3 is an independent risk factor influencing IR. Supplementation of vitamin D has been shown to improve glucose and lipid metabolism in patients with IR and T2DM.

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 impact of serum total bilirubin level on long-term prognosis in patients with chronic heart failure].

OBJECTIVE: To analyze the relationship between serum total bilirubin coincident with congestive heart failure (CHF) exacerbation and subsequent long-term mortality in patients with CHF. METHODS: The study population consisted of 140 consecutive patients admitted for CHF exacerbation with left ventricular ejection fraction ≤ 45%. They were divided into 2 groups according to whether death attacked or not in the following 28.5 months. Binary logistic regression analysis was used to investigate independent predictors of death from clinical parameters on admission or within 24 hours. RESULTS: Serum TBil and B-type natriuretic peptide (BNP) levels on admission were independent predictors of subsequent death after hospital discharge. According to increasing textiles of TBil stratified by the level of 12.8 and 18.2 mmol/L, the patients were divided into 3 groups: lower-level group (TBil ≤ 12.8 mmol/L), moderate-level group(TBil > 12.8 ∼ 18.2 mmol/L) and higher-level group (TBil > 18.2 mmol/L), with the death rates after 28.5 months of 12.2%, 17.9% and 38.9%, respectively(P = 0.002). Meanwhile, the pulse pressure decreased to (55.5 ± 17.3) mm Hg (1 mm Hg = 0.133 kPa), (48.9 ± 13.1) mm Hg and (46.1 ± 13.7) mm Hg, respectively (P = 0.008). TBil on admission had significant correlation with echocardiography-measured left ventricular endo-diastolic diameter (r = 0.34, P = 0.000) and right ventricular diastolic diameter (r = 0.23, P = 0.011). CONCLUSIONS: Increased TBil coincident with cardiac decompensation predicts a worse long-term death of CHF, presumably through the potential liability to both decompensated RV function and lower cardiac output syndrome occurred simultaneously when HF deteriorates.

[A study of the relationship between neutropenia and clinical infection risk during treatment with peginterferon alfa-2a and ribavirin for chronic hepatitis C].

OBJECTIVE: To investigate the correlation between neutropenia (ANC) incidence and infection during treatment with peginterferon alfa and ribavirin for chronic hepatitis C. METHODS: A retrospective cohort study of 399 patients treated with peginterferon and ribavirin derived from database of Department of Infectious Diseases, the Second Affiliated Hospital, Harbin Medical University was conducted. The incidence of infections and their relation with ANC were investigated. Potential risk factors for infection were identified by multivariate analysis. RESULTS: During treatment, neutropenia (ANC < 1.50 × 10(9)/L) occurred in 251 patients. Among which, mild neutropenia [ANC: (> 0.75 - < 1.50) × 10(9)/L], moderate neutropenia [ANC: (0.50 - 0.75) × 10(9)/L] and severe neutropenia (ANC < 0.50 × 10(9)/L) occurred in 132 patients, 103 patients and 16 patients, respectively. A total of 80 infections (20.1%) occurred, among which, 14 infections were defined as severe. There was no significant difference in infection rate between patients with and without neutropenia (19.9%, 50/251 vs 20.3%, 50/251; χ(2) = 0.007, P = 0.933). There was no significant difference in infection rate between patients with and without peginterferon dose reduction (21.5%, 31/144 vs 19.2%, 49/255; χ(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). CONCLUSIONS: Infections during treatment with peginterferon alfa and ribavirin for chronic hepatitis C are irrelevant to neutropenia. The independent factors associated with infection are age, diabetes and cirrhosis.

[Association between fractional flow reserve and quantitative coronary angiography parameters in intermediate coronary artery stenosis].

OBJECTIVE: To explore the relationship between quantitative coronary angiography (QCA) parameters and fractional flow reserve (FFR) for identifying ideal angiographic parameters predictive of myocardial ischemia. METHODS: The study included 121 lesions with QCA and FFR data from 106 patients [mean age: (63 ± 10) years]. The lesions were grouped into FFR > 0.75 group and FFR ≤ 0.75 group. Assessed parameters by QCA included percentage diameter stenosis, minimum luminal diameter (MLD), percentage area stenosis, minimum luminal area (MLA), reference vessel diameter (RVD) and lesion length (LL). Correlation analysis was used to identify the relationship between QCA parameters and FFR value, and receiver operating characteristic (ROC) curve was used to determine parameters predictive of FFR ≤ 0.75. RESULTS: LL was significantly higher [(14.8 ± 7.9) mm vs. (10.7 ± 5.4) mm, P = 0.024] while MLD [(1.47 ± 0.31) mm vs. (1.82 ± 0.51) mm, P = 0.028], RVD [(2.30 ± 0.50) mm vs. (2.81 ± 0.64) mm, P = 0.036], and MLA [(2.30 ± 1.50) mm(2) vs. (3.60 ± 2.30) mm(2), P = 0.038] were significantly lower in FFR ≤ 0.75 group than in FFR > 0.75 group. LL (r = -0.209, P = 0.040) was negatively correlated with FFR, and MLD (r = 0.414, P = 0.040), RVD (r = 0.303, P = 0.000) and MLA (r = 0.315, P = 0.002) were positively correlated with FFR. ROC analysis showed that MLD ≥ 1.6 mm was the best cut-off value to predict FFR > 0.75 with sensitivity 63%, specificity 82%, and positive predictive value 96%. CONCLUSIONS: QCA derived anatomic parameters of intermediate coronary lesions correlate to FFR value in some extent. MLD ≥ 1.6 mm is the best cut-off value to predict FFR > 0.75 in patients with intermediate coronary lesions.

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. METHODS: A matched retrospective cohort study using data on fulminant hepatitis B patients derived from our hospital database was conducted. Forty patients receiving lamivudine treatment were selected into the lamivudine treatment group with another 40 without lamivudine treatment studied as control. They were matched for sex, age and HBeAg status with lamivudine treatment group. The mortality of patients in two groups was compared. The influential factors on the mortality were studied by Cox proportional hazards model. RESULTS: The mortality of patients in the lamivudine group (n=38) was significantly lower than that of the control group (n=39) (63.2 vs. 84.6%; χ(2) =4.609, P=0.032). For patients without systemic inflammatory response syndrome (SIRS), the mortality of patients in the lamivudine group (n=25) was significantly lower than that of the control group (n=26) (52.0 vs. 80.8%; χ(2) =4.747, P=0.029). In multivariate Cox proportional hazards analyses, for patients without SIRS, age (P=0.037), ratio of total to direct bilirubin (P=0.008), treatment method (P=0.005) and the decline of hepatitis B virus (HBV) DNA load during therapy (P=0.019) were independent predictors of prognosis. CONCLUSIONS: Treatment with lamivudine significantly decreases the mortality of fulminant hepatitis B patients without SIRS, and a rapid decline of HBV DNA load is one of the good predictors for the treatment outcome.

[Impact of age and sex on virologic responses of peginterferon alfa-2a and ribavirin treatment in chronic hepatitis C].

OBJECTIVE: To investigate the impact of age and sex on virologic responses rates to peginterferon alfa-2a and ribavirin treatment in patients with chronic hepatitis C. METHODS: The medical records of 449 chronic hepatitis C patients, treated with peginterferon and ribavirin in Department of Infectious Diseases, the Second Affiliated Hospital, Harbin Medical University, were retrospectively analyzed. These patients were divided into three groups according to age: patients < 40 years (n = 131), patients 40 - 50 years (n = 131) and patients > 50 years (n = 187). The virologic response rates, the incidences of side events, and the rates of patients receiving ≥ 80% of planned peginterferon alfa-2a or ribavirin dose were compared between male and female patients in the three groups. The influential factors on sustained virologic response (SVR) of patients were studied by multivariate analysis. RESULTS: For genotype 1, in patients < 40 years group, the SVR rate of female was significantly higher than that of male (75.0%, 30/40 vs 54.0%, 27/50; P < 0.05); in patients 40-50 years group, there was no significant difference in the SVR rate between male and female (51.0%, 25/49 vs 53.7%, 22/41; P > 0.05); in patients > 50 years group, the SVR rate of female was significantly lower than that of male (31.1%, 19/61 vs 50.7%, 34/67; P < 0.05). For genotype 2, there were no significant differences in virologic response rates between male and female in the three groups. The incidence of adverse events of patients aged < 40 years group, 40 - 50 years group, > 50 years group, were 51.1% (67/131), 51.1% (67/131), and 70.6% (132/187), respectively, and the incidence of adverse events of patients aged > 50 years was significantly higher than those of other groups (P < 0.001). For genotype 1, in patients > 50 years group, the rate of patients receiving ≥ 80% of planned ribavirin dose of female was significantly lower than that of male (42.6%, 26/61 vs 62.7%, 42/67; P < 0.05). In multivariate analysis, the independent factors associated with SVR of patients aged > 50 years were sex (P = 0.013), genotypes (P = 0.002), cirrhosis (P = 0.004), ≥ 80% of planned ribavirin dose (P = 0.008) and presence of rapid virologic response (RVR) (P = 0.001). CONCLUSIONS: For genotype 1 patients, in patients < 40 years group the SVR rate of female is higher than that of male; in patients 40 - 50 years group, male and female share similar SVR rates; in patients > 50 years group the SVR rate of female is lower than that of male. Age and sex has no impact on virologic responses rates for genotype 2 patients.

Influential factors of prognosis in lamivudine treatment for patients with acute-on-chronic hepatitis B liver failure.

BACKGROUND AND AIMS: Chronic hepatitis B virus (HBV) infection is a major global health issue, and the prognosis of patients with HBV-associated acute-on-chronic hepatic failure (ACLF) is extremely poor. In this study, the efficacy of lamivudine was investigated in patients with ACLF. The effects of HBV DNA load and its related factors on the prognosis were also further explored. METHODS: A matched retrospective cohort study using data on ACLF patients derived from our hospital database was conducted. One hundred and thirty patients receiving lamivudine were selected into the lamivudine treatment group with another 130 without lamivudine treatment studied as control. They were matched for sex, age and imaging finding with the lamivudine treatment group. All the patients were followed up for 3 months and the survival rates were compared. The influential factors on the mortality were studied by the Cox proportional hazards model. RESULTS: The cumulative survival rates of patients in the lamivudine group were higher than those of the control group (chi(2) = 9.50, P = 0.0021). The mortality of patients in the high virus load group (71/95, 74.7%) was higher than that of those in the low virus load group (15/29, 51.7%) (chi(2) = 5.536, P = 0.019). For patients with a Model for End-Stage Liver Disease (MELD) score of 20-30 by week 4, the mortality of those with HBV DNA that was undetectable or declined for more than 2 log(10) (2/12, 16.7%; 18/40, 45.0%) was lower than that of those with a less than 2 log(10) decline (18/23, 78.3%) (chi(2) = 10.106, P = 0.001). In the Cox proportional hazards model, for patients with a MELD score of 20-30, treatment method (P = 0.002), pretreatment HBV DNA load (P = 0.007) and decline of HBV DNA load during therapy (P = 0.003) were independent predictors; for those with a MELD score of above 30, MELD score (P = 0.008) was the only independent predictor. CONCLUSION: Lamivudine can significantly decrease the 3-month mortality of patients with a MELD score of 20-30, and a low pretreatment viral load and rapid decline of HBV DNA load are good predictors for the outcome of the treatment.

The study of efficacy of lamivudine in patients with severe acute hepatitis B.

BACKGROUND AND AIM: Severe acute hepatitis B is a rapid deterioration of liver function, which carries a high mortality rate. The aim of this study is to evaluate the efficacy of lamivudine in patients with severe acute hepatitis B. METHODS: In this study, 80 patients with severe acute hepatitis B were randomly divided into lamivudine and the control group. For the two groups, we compared HBsAg, HBeAg seroconversion rates, serum HBV DNA-negative rate, biochemical indicators, the incidence of liver failure, and mortality. The influential factors on the mortality were studied by Cox proportional hazards model. RESULTS: The improvement in serum TBiL, INR, and HBV DNA levels of the lamivudine group was significantly greater than that of the control group. The mortality of lamivudine group (7.5%, 3/40) was significantly lower than that of the control group (25.0%, 10/40) (p = 0.034). The incidence of liver failure (8.7%, 2/23) of patients receiving lamivudine within a week was significantly lower than that (35.3%, 6/17) of those who received it after a week (p = 0.038). In multivariate Cox proportional hazards analyses, age (p = 0.043), ratio of total to direct bilirubin (p = 0.009), treatment method (p = 0.006), and the decline of HBV DNA load during therapy (p = 0.017) were independent predictors of mortality. The HBsAg seroconversion rates (62.5%, 25/40) and HBeAg seroconversion rates (63.6%, 21/33) of the lamivudine group were significantly lower than those (85.0%, 34/40), (87.5%, 28/32) of the control group (p = 0.022, 0.026). CONCLUSIONS: Early treatment with lamivudine leads to a greater decrease in HBV DNA level, better clinical improvement and mortality improvement in patients with severe acute hepatitis B, but with a lower seroconversion rate. A rapid decline of HBV DNA load is a good predictor for the treatment outcome.

Analysis of the efficacy of treatment with peginterferon alpha-2a and ribavirin in patients coinfected with hepatitis B virus and hepatitis C virus.

OBJECTIVE: To study the virological features of patients coinfected with hepatitis B virus (HBV) and hepatitis C virus (HCV) and the efficacy of combination therapy with peginterferon alpha-2a and ribavirin in these patients. METHODS: The epidemiological and virological data of 50 patients coinfected with HBV and HCV were analysed. The virological response rates of patients treated with peginterferon alpha-2a and ribavirin between the HBV and HCV coinfection group and the HCV monoinfection group were compared. RESULTS: HCV-dominant virus strains accounted for 92.0% of the 50 coinfected individuals, and HCV- and HBV-dominant virus strains accounted for the remaining 8.0%. The HBV DNA level of the patients coinfected with HBV and HCV was 4.6+/-0.9 log(10) copies/ml, which was significantly lower than that in the HBV monoinfection group (5.9+/-1.2 log(10) copies/ml) (t=5.964, P<0.01). The HBeAg-positive rate (12.0%, 6/50) of the coinfection group was significantly lower than (45.3%, 19/42) that of the HBV monoinfection group (chi(2)=12.743, P<0.01). The partial early virological response (pEVR) rate and the end-of-treatment virological response (ETVR) rate (50.0%, 15/30; 90.0%, 27/30) of patients with genotype 1 in the coinfection group were significantly higher than those (16.0%, 4/25; 56.0%, 14/25) in the HCV monoinfection group (chi(2)=6.971, P=0.008; chi(2)=8.307, P=0.004). The relapse rate (55.6%, 15/27) of patients with genotype 1 in the coinfection group was significantly higher than that (21.4%, 3/14) in the HCV monoinfection group (chi(2)=4.360, P=0.037). The sustained virological response (SVR) rate (40.0%, 12/30) of patients with genotype 1 in the coinfection group was compared with that of the HCV monoinfection group (44.0%, 11/25) (chi(2)=0.090, P=0.765). There was no significant difference in the on-treatment virological response, ETVR, SVR and relapse rates between two groups for patients with genotype 2. The incidence of side effects (30%, 15/50) of patients in the coinfection group was significantly higher than that (13%, 6/46) in the HCV monoinfection group (chi(2)=4.031, P=0.045). The reactivation rate of HBV DNA (33.3%, 9/27) with HCV SVR was significantly higher than that of patients without SVR (8.7%, 2/23) (chi(2)=4.393, P=0.036). CONCLUSIONS: The replication of HBV was suppressed, and HCV was the dominant virus strain. Compared with HCV-monoinfected patients, pEVR, ETVR and relapse rates of patients with genotype 1 in the coinfection group were high, while they shared similar SVR rates. HBV and HCV coinfection had no impact on the rate of virological response for genotype 2.

Hyaluronic Acid Nanoparticles Based on a Conjugated Oligomer Photosensitizer: Target-Specific Two-Photon Imaging, Redox-Sensitive Drug Delivery, and Synergistic Chemo-Photodynamic Therapy.

Self-assembled hyaluronic acid (HA) nanoparticles have been extensively investigated as anticancer therapeutic agents due to the biocompatibility, biodegradability, and active targeting characteristics of HA. However, many HA nanoparticles are restricted to the applications in drug delivery for chemotherapy or lack effective imaging agents. Hence, we developed the camptothecin (CPT)-loaded HA-SS-BFVPBT nanoparticles (HSBNPs) as a multifunctional platform for two-photon imaging and synergistic chemo-photodynamic therapy at the same time. A novel conjugated oligomer photosensitizer, BFVPBT, which was conjugated onto HA through the redox-responsive disulfide linkage (SS), could not only provide a hydrophobic domain for the formation of nanoparticles and drug entrapment but also act as a two-photon photosensitizer that can be directly excited and simultaneously used in two-photon imaging and photodynamic therapy (PDT). HeLa cells overexpressing the HA receptor (CD44) were used for in vitro studies, which proved the specific cellular uptake of CPT-loaded HSBNPs and excellent two-photon PDT/chemotherapy synergistic effect. The nanoparticles have also been shown to realize tumor-targeting in vivo imaging in HeLa-tumor-bearing mice. Moreover, the fluorescence of CPT-loaded HSBNPs could be activated due to the degradation by the reductive glutathione (GSH) and overexpressed hyaluronidases (Hyal-1) in cancer cells, and the intracellular drug release rate was quickened, thus improving the probability of precise cancer diagnosis and therapy. Accordingly, this HSBNPs system is also anticipated to be a precise nanocarrier for other imaging and therapeutic agents besides CPT, offering a promising new avenue for imaging-guided efficient cancer therapy.

Prediction value of model for end-stage liver disease scoring system on prognosis in patients with acute-on-chronic hepatitis B liver failure after plasma exchange and lamivudine treatment.

BACKGROUND AND AIM: We used the model for end-stage liver disease (MELD) scoring system to predict the 3-month prognosis of patients with acute-on-chronic liver failure (ACLF) after plasma exchange (PE) and lamivudine treatment, and studied the predictive factors on the prognosis of patients. METHODS: A total of 280 patients treated with lamivudine were randomly divided into PE and control groups. The relationship between mortality and influential factors of patients was studied by univariate and multivariate analysis. RESULTS: The mortality (49.4%) of patients in the PE group with a MELD score from 30 to 40 was lower than that (86.1%) of the control group (chi(2) = 24.546, P < 0.01). The total bilirubin (TBIL) rebound rate of the dead group was significantly higher than that of the survival group (P < 0.01). Univariate analysis showed that mortality was significantly related to age (P = 0.003), treatment method (P = 0.000), TBIL (P = 0.010), MELD score (P = 0.001), international normalised ratio (P = 0.014), pretreatment HBV-DNA load (P = 0.000), decline of hepatitis B virus (HBV)-DNA load during therapy (P = 0.013), encephalopathy (P = 0.019), and hepatorenal syndrome (P = 0.026). In multivariate analysis, MELD scores of 30-40, treatment method (P = 0.003), pretreatment HBV-DNA load (P = 0.009), decline of HBV-DNA load during therapy (P = 0.016), and encephalopathy (P = 0.015) were independent predictors of mortality; for MELD scores above 40, only the MELD score (P = 0.012) was an independent predictive. CONCLUSIONS: PE significantly decreased the mortality of patients with a MELD score of 30-40. For ACLF patients with a MELD score of 30-40, a low viral load pretreatment and quick decline of HBV-DNA load are good predictors for the survival with PE and lamivudine treatment.

The MELD scoring system for predicting prognosis in patients with severe hepatitis after plasma exchange treatment.

BACKGROUND: Hepatic failure caused by severe hepatitis is a clinical syndrome where the major liver functions, particularly detoxification, synthetic functions, and metabolic regulation are impaired to different degrees, and may result in major life-threatening complications such as hepatic encephalopathy, ascites, jaundice, cholestasis, bleeding and hepatorenal syndrome. Plasma exchange (PE) has been found useful in treating patients with fulminant hepatic failure by removing hepatic toxins and replacement of clotting factors, so PE treatment has temporary supportive effects on liver failure caused by severe viral hepatitis. In this study, our aim was to predict the prognosis of patients with severe hepatitis after PE treatment using the end-stage liver disease (MELD) scoring system. METHODS: Two hundred and twenty patients were randomly divided into PE and control groups, and the MELD score was calculated for each patient according to the original formula. The efficacy of PE was assessed by mortality or improvement in biochemical parameters and MELD score. RESULTS: The levels of total bilirubin and international normalised ratio (INR) in patients whose MELD scores were between 30 and 39 were lower than those before PE treatment, as those in patients whose MELD scores were 40 or higher. The mortality of patients in the PE group with MELD scores from 30 to 39 was 50.0%, while it was 83.3% in the control group (P<0.01). The mortality of patients with MELD scores higher than 40 was 90.0% in the PE group and 98.0% in the control group (P>0.05). CONCLUSIONS: PE treatment can decrease the serum total bilirubin level and INR and MELD score of patients with severe hepatitis and improve liver function. Compared with the control group, PE can significantly decrease the mortality of patients with MELD scores from 30 to 39, but has no effect in patients with MELD scores of 40 or higher.

Factors influencing the functional significance in intermediate coronary stenosis.

OBJECTIVE: To analyze the influencing factors of the functional significance determined by fractional flow reserve (FFR) in intermediate coronary artery stenosis. METHODS: The study enrolled 143 patients with 203 intermediate coronary lesions. Pressure-derived FFR of these lesions was gained at maximal hyperemia induced by intravenous adenosine infusion. An FFR < 0.80 was considered as abnormal functional significance. Anatomic parameters at the lesion sites were obtained by off-line quantitative coronary angiography analysis (QCA). The predictive value of the demographic characteristics and anatomic parameters for FFR in these intermediate lesions was assessed using multiple linear and binary logistic regression analysis. RESULTS: Overall, FFR < 0.8 was found in 70 (34%) of the total 203 intermediate coronary lesions. FFR values were positively correlated with QCA-measured minimum lumen diameters (MLD, r = 0.372, P = 0.000) and the reference vessel diameters (RVD, r = 0.217, P = 0.002) were negatively correlated with percent area stenosis (AS, r = -0.251, P = 0.000) and percent diameter stenosis (DS, r = -0.210, P = 0.000). Age, MLD and the lesion location in different coronary arteries were the independent determinants of FFR < 0.8. CONCLUSIONS: MLD can predict the functional significance of intermediate coronary stenosis, while age and the lesion location in different coronary arteries should be taken into account as important influencing factors of FFR values.

Endocannabinoid system activation contributes to glucose metabolism disorders of hepatocytes and promotes hepatitis C virus replication.

BACKGROUND: Insulin resistance is highly prevalent in patients with chronic hepatitis C (CHC) and to some extent accounts for fibrosis and reducing viral eradication. Activated cannabinoid 1 receptor (CB1R) signaling has been implicated in the development of phenotypes associated with insulin resistance and steatosis. We investigated the role of the endocannabinoid system in glucose metabolism disorders induced by hepatitis C virus (HCV) replication. METHODS: Human hepatic stellate cells (HSC; LX-2 cells) were co-cultured with Huh-7.5 cells or Huh-7.5 cells harboring HCV replicon (replicon cells). Endocannabinoid levels were then measured by liquid chromatography/mass spectrometry. The expression of CB1R and its downstream glucose metabolism genes in hepatocytes were determined by real-time PCR and Western blot. Glucose uptake by hepatocytes and glucose production were measured. Glucose metabolism tests and measurements of HCV RNA levels and nonstructural protein 5A (NS5A) levels were taken after treatment with CB1R agonist arachidonyl-2-chloroethanolamide (ACEA) or antagonist AM251. RESULTS: Compared to the co-culture with Huh-7.5 cells, the level of 2-arachidonoylglycerol (2-AG) and the CB1R mRNA and protein levels increased in the co-culture of LX-2 cells with replicon cells. The activation of CB1R decreased AMP-activated protein kinase (AMPK) phosphorylation, inhibited cell surface expression of glucose transporter 2 (GLUT2), and suppressed cellular glucose uptake; furthermore, it increased cyclic AMP response element-binding protein H (CREBH), then up-regulated phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase) genes and down-regulated the glucokinase (GK) gene, thus promoting glucose production. Interferon treatment restored the aforementioned changes. CB1R antagonist improved glucose metabolism disorders by an increase in glucose uptake and a decrease in glucose production, and inhibited HCV replication. CONCLUSIONS: HCV replication may not only increase the 2-AG content, but may also up-regulate the expression of CB1R of hepatocytes, then change the expression profile of glucose metabolism-related genes, thereby causing glucose metabolism disorders of hepatocytes and promoting HCV replication. Treatment with CB1R antagonist improved glucose metabolism disorders and inhibited viral genome replication.

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

BACKGROUND AND OBJECTIVE: Glucose 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. METHODS: The 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. RESULTS: In 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. CONCLUSIONS: HCV 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.