Jidong Jia

Capital Medical University, Peping, Beijing, China

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Publications (33)105.17 Total impact

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    ABSTRACT: AimsTo compare the efficacy at week 104 of lamivudine monotherapy (MONO), lamivudine plus adefovir dipivoxil (ADV) combination therapy (COMBO), and lamivudine optimization strategy (OPTIMIZE).Methods Adult patients without antiviral therapy within 6 months before screening with HBV DNA ≥ 105 copies/mL, ALT 1.3 to 10 times upper limit of normal and compensated HBeAg positive chronic hepatitis B (CHB) were randomized into three groups with 1:1:1 ratio. Patients in OPTIMIZE group started with lamivudine 100 mg q.d., and ADV 10 mg q.d. was added to suboptimal responders (HBV DNA >1000 copies/mL at week 24) from week 30 to week 104, while patients with early virological response (HBV DNA ≤ 1000 copies/mL at week 24) continued lamivudine monotherapy untill week 104. For all the patients receiving lamivudine monotherapy, ADV would be added if virological breakthrough was confirmed.ResultsAt week 104, more patients in COMBO and OPTIMIZE groups achieved HBV DNA < 300 copies/mL (53.3% [64/120] and 48.3% [58/120]), with less lamivudine resistance (0.8% and 6.7%) compared with MONO group (HBV DNA < 300 copies/mL 34.8% [41/118], lamivudine resistance 58.47%). Patients under lamivudine monotherapy with early virological response showed superior efficacy at week 104 (HBV DNA < 300 copies/mL 73.1% [38/52], HBeAg seroconversion 40.4% [21/52]). All regimens were well tolerated.Conclusions Combination therapy of lamivudine plus ADV exhibited effective viral suppression and relatively low resistance in HBeAg positive CHB patients. In lamivudine treated patients with suboptimal virological response at week 24, promptly adding on ADV is necessary to prevent resistance development.
    Journal of Gastroenterology and Hepatology 10/2014; · 3.33 Impact Factor
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    ABSTRACT: Background and aimLiver stiffness measurement (LSM) using transient elastography (FibroScan®) is a useful tool to assess fibrosis in various chronic liver diseases. However, studies were mainly performed in Western countries and largely focused on chronic hepatitis C (CHC). We therefore carried out a multi-center study to validate the accuracy of LSM in the assessment of liver fibrosis in a large cohort of Chinese patients with chronic hepatitis B (CHB).Methods We compared LSM results to histological staging and serum fibrosis markers (5 direct markers, APRI and FIB-4) using Spearman correlation analysis and Area Under ROC Curves (AUROCs).Results469 patients were enrolled and eligible for statistical analysis. LSM in F0 to F4 was 5.5 ±1.7, 5.8 ±2.2, 7.6 ±3.4, 14.5 ±10.8, and 22.3 ±13.6 kPa, respectively (correlation with fibrosis stage r=0.522, p<0.001). AUROC for LSM to correctly allocate patients to histological fibrosis stage ≥F2, ≥F3 and F4 was 0.82, 0.88, and 0.90, respectively. LSM outperformed serum fibrosis markers for detection of fibrosis F≥2 and F4. Patients with ALT levels 1-5x and >5x the upper limit of normal values had significantly higher stiffness values than stage-matched patients with normal ALT.Conclusions Transient elastography is a reliable non-invasive technique to predict significant liver fibrosis in Chinese patients with CHB, being superior to current biomarker panels. However, enhanced inflammatory activity can lead to elevated stiffness values unrelated to histological fibrosis stage.
    Journal of Gastroenterology and Hepatology 10/2014; · 3.33 Impact Factor
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    ABSTRACT: The use of serum anti-hepatitis B core antibody (HBc)-positive/hepatitis B surface antigen (HBsAg)-negative liver donors for patients with hepatitis B virus (HBV)-related liver disease (HBRLD) is a promising means of expanding the organ donor pool and does not increase the risk of HBV recurrence. However, whether such donors will compromise the histology of the liver grafts is unclear.
    Clinics and research in hepatology and gastroenterology. 05/2014;
  • Clinical gastroenterology and hepatology: the official clinical practice journal of the American Gastroenterological Association 02/2014; · 5.64 Impact Factor
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    ABSTRACT: Optimization strategy based on ROADMAP concept is supposed to improve the clinical outcomes of patients with suboptimal antiviral response. The aim of this study is to prove the concept with a multicenter, open-label, randomized, controlled study. Six hundred and six Hepatitis B e antigen (HBeAg) -positive, nucleos(t)ide -naive chronic hepatitis B patients were randomized to OPTIMIZE or MONO group. Patients in OPTIMIZE group were treated with telbivudine for 24 weeks, after which those suboptimal responders with HBV DNA ≥ 300 copies/mL at week 24 received telbivudine plus adefovir until week 104, while the early virological responders continued telbivudine monotherapy. Patients in MONO group received telbivudine monotherapy. All patients with telbivudine monotherapy were added on adefovir if viral breakthrough developed. Sixty eight percent (204/300) patients in OPTIMIZE group were added on adefovir due to suboptimal response. At week 104, compared to MONO group, more patients in OPTIMIZE group achieved HBV DNA < 300 copies/ml (76.7% vs. 61.2%, p<0.001) with less genotypic resistance (2.7% vs. 25.8%, p<0.001). The rates of HBeAg seroconversion and ALT normalization were comparable between two groups (23.7% vs. 22.1%; 80.7% vs. 79.2%). For week 24 suboptimal responders, telbivudine plus adefovir showed additive antiviral potency with 71.1% achieving virological response at week 104 and only 0.5% developing genotypic resistance, compared with 46.6% who achieved virological response and 37.8% who developed genotypic resistance with telbivudine monotherapy. Both treatment regimens were well tolerated with observed persistent increase of glomerular filtration rate. Conclusion: For suboptimal virological responders to telbivudine at week 24, adjusting treatment strategy is recommended. Adding on adefovir can benefit these patients with additive antiviral potency and low resistance without increased side effect. (Hepatology 2013;).
    Hepatology 11/2013; · 12.00 Impact Factor
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    ABSTRACT: Chronic hepatitis C virus (HCV) infection is relatively frequent in China. This study investigated the clinical, demographic, and viral and host genetic characteristics that may influence disease manifestations and clinical management. In this cross-sectional observational study, treatment-naïve Han ethnic adults with recently confirmed chronic HCV infection were enrolled at 28 hospitals across China. HCV genotype and host IL28B genotypes were determined and compared with patient demographic parameters and medical status. Among the 997 HCV-positive patients analyzed, 56.8% were infected with HCV genotype 1b, followed in prevalence by genotypes 2, 3, and 6, with substantial regional variation. Overall 84.1% of patients were IL28B genotype CC (rs12979860), with little regional variation. Cirrhosis was reported in 10.1% of patients and was significantly associated with hepatitis B virus coinfection, low HCV viral load, low serum alanine aminotransferase, high serum aspartate aminotransferase, diabetes, and high pickled food consumption. Medical procedures were common transmission risk factors; however, lifestyle-associated risk factors, including intravenous drug abuse and tattoos or piercings, were more common in patients with HCV genotype 3 or 6. Most HCV-infected Han Chinese patients were IL28B genotype CC (rs12979860). HCV genotypes varied by geographic region, and disease characteristics differed according to HCV genotype. Relatively frequent detection of advanced liver disease may reflect limitations on access to antiviral therapy, and suggests that greater awareness of factors that influence HCV-associated disease may help avoid clinical complications and improve patient outcomes.
    Journal of Gastroenterology and Hepatology 10/2013; · 3.33 Impact Factor
  • Zheng Yu, Yu Wang, Lijuan Feng, Jidong Jia
    Digestive Diseases and Sciences 09/2013; · 2.26 Impact Factor
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    Yan Cui, Jidong Jia
    Journal of Gastroenterology and Hepatology 08/2013; 28(S1). · 3.33 Impact Factor
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    ABSTRACT: Objectives Health care decision makers are increasingly concerned about the value of chronic hepatitis B (CHB) treatments in China. This analysis aims at estimating the relative value of entecavir as a first-line option at treatment initiation and for different treatment durations from a holistic perspective.MethodsCHB was simulated by using a Markov disease transition model with disease states based on available natural history data. The model assumed 5-year treatment duration with entecavir, lamivudine, telbivudine, and adefovir based on published clinical data. The speed of disease progression varies by viral load and hepatitis B “e” antigen status. Direct medical costs included medication and management of liver complications. The primary output was the estimated cost savings of entecavir per patient per day versus the comparator.ResultsFor treatment duration of 5 years and a follow-up period of 30 years, entecavir treatment was translated into specific patient benefit of an estimated cost saving of $2.69 per day compared with no treatment. In addition, long-term usage of entecavir resulted in daily $2.33 and $1.73 cost saving compared with short-term usage (1-year and 2-year, respectively). Among available treatment options in China, entecavir treatment exhibited about $0.90 to $1.81 daily cost saving versus the comparators. The detailed daily cost saving of entecavir is summarized as follows—entecavir versus lamivudine: $1.81, entecavir versus telbivudine: $0.90, entecavir versus adefovir: $2.02, and entecavir versus generic adefovir: $1.37.Conclusions Long-term usage of entecavir exhibits the characteristics of a favorable CHB treatment, which translates into economic value as opposed to either no treatment or alternative strategies.
    Value in Health Regional Issues. 05/2013; 2(1):48–56.
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    ABSTRACT: Diethyldithiocarbamate (DDC) could block collagen synthesis in hepatic stellate cells through the inhibition of reactive oxygen species derived from hepatocyte cytochrome P450 2E1 (CYP2E1). However, the effect of DDC on matrix metalloproteinase-1 (MMP-1), which is the main collagen degrading matrix metalloproteinase, has not been reported. In co-culture experiments, we found that DDC significantly enhanced MMP-1 expression in human hepatic stellate cells (LX-2) that were cultured with hepatocyte C3A cells either expressing or not expressing CYP2E1. The levels of both proenzyme and active MMP-1 enzyme were upregulated in LX-2 cells, accompanied by elevated enzyme activity of MMP-1 and decreased collagen I, in both LX-2 cells and the culture medium. H2O2 treatment abrogated DDC-induced MMP-1 upregulation and collagen I decrease, while catalase treatment slightly upregulated MMP-1 expression. These data suggested that the decrease in ROS by DDC was partially responsible for the MMP-1 upregulation. ERK1/2, Akt and p38 were significantly activated by DDC. The ERK1/2 inhibitor (U0126) and Akt inhibitor (T3830) abrogated the DDC-induced MMP-1 upregulation. In addition, a p38 inhibitor (SB203580) improved MMP-1 upregulation through the stimulation of ERK1/2. Our data indicate that DDC significantly upregulates the expression of MMP-1 in LX-2 cells which results in greater MMP-1 enzyme activity and decreased collagen I. The enhancement of MMP-1 expression by DDC was associated with H2O2 inhibition and coordinated regulation by the ERK1/2 and Akt pathways. These data provide some new insights into treatment strategies for hepatic fibrosis.
    Bioscience Reports 04/2013; · 1.88 Impact Factor
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    ABSTRACT: Elevated tissue inhibitor of metalloproteinase 1 (TIMP-1) expression contributes to excess production of extracellular matrix in liver fibrosis. Herein, we constructed a recombinant adeno-associated virus (rAAV) carrying siRNA of the TIMP-1 gene (rAAV/siRNA-TIMP-1) and investigated its effects on liver fibrosis in rats. Two models of rat liver fibrosis, the carbon tetrachloride and bile duct ligation models, were treated with rAAV/siRNA-TIMP-1. In the carbon tetrachloride model, rAAV/siRNA-TIMP-1 administration attenuated fibrosis severity, as determined by histologic analysis of hepatic collagen accumulation, hydroxyproline content, and concentrations of types I and III collagen in livers and sera. Levels of mRNA and active matrix metalloproteinase (MMP) 13 were elevated, whereas levels of mRNA and active MMP-2 were decreased. Moreover, a marked decrease was noted in the expression of α-smooth muscle actin, a biomarker of activated hepatic stellate cells (HSCs), and transforming growth factor-β1, critical for the development of liver fibrosis. Similarly, rAAV/siRNA-TIMP-1 treatment significantly alleviated bile duct ligation-induced liver fibrosis. Furthermore, this treatment dramatically suppressed TIMP-1 expression in HSCs from both model rats. These data indicate that the administration of rAAV/siRNA-TIMP-1 attenuated liver fibrosis by directly elevating the function of MMP-13 and diminishing activated HSCs. It also resulted in indirect decreased expression of type I collagen, MMP-2, and transforming growth factor-β1. In conclusion, rAAV/siRNA-TIMP-1 may be an effective antifibrotic gene therapy agent.
    American Journal Of Pathology 03/2013; · 4.60 Impact Factor
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    Hong Ma, Jidong Jia
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    ABSTRACT: Chronic hepatitis B (CHB) is a worldwide public health problem which represents an enormous economic and social burden. Convincing evidence has shown that persistent active viral replication is an independent predictor of disease progression. Therefore, sustained suppression of HBV replication is the cornerstone for preventing the progression of disease and prolonging survival in patients with CHB. Pivotal clinical trials and real-world studies show that nucleos(t)ide analogues (NAs) are potent suppressors of HBV DNA replication with very good safety profiles. Although 1-year treatment with NAs only results in a modest rate of HBeAg seroconversion, extended treatment could increase this rate. Profound suppression of HBV DNA can result in histological improvement and a clinical benefit with a decrease in disease progression in patients with compensated or decompensated cirrhosis. Treatment must be begun with a highly potent and low resistant regimen to obtain long-term suppression of viral replication. An alternative solution may be a roadmap approach in which an inexpensive antiviral drug is started and another drug is added-on or switched-to if there is a suboptimal on-treatment decrease in HBV DNA. Clinical evidence has shown that once HBV DNA is suppressed and long-term HBeAg seroconversion is achieved, NAs can be stopped. In summary, high antiviral efficacy, excellent tolerance, extensive applicability, clearly proven histological improvement and long-term clinical benefit all make NAs the preferred choice for the management of CHB in most patients.
    Liver international: official journal of the International Association for the Study of the Liver 02/2013; 33(s1). · 3.87 Impact Factor
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    ABSTRACT: The activation of hepatic stellate cells (HSCs) is closely associated with liver fibrosis in chronic hepatitis B virus (HBV) infection. However, the molecular mechanisms leading to HSC activation remain unclear. It has been reported that the platelet-derived growth factor-B (PDGF-B)/PDGF receptor-β (PDGFR-β) signaling pathway is involved in this process. Thus, we investigated whether HBV and its protein contribute to HSC proliferation by the PDGF-B/PDGFR-β signaling pathway. HBV particles were purified from the supernatant of HepG2.2.15 cells by ultracentrifugation and the cell lines carrying HBV preS, e, c or x genes were obtained. After incubation with HBV particles or co-cultured with the cell lines expressed in the viral protein, the proliferation of LX-2 cells, an HSC cell line, were detected by flow cyto-metry and real-time PCR and the expression of molecules related to the PDGF-B/PDGFR-β signaling pathway were further measured. Our results indicated that HBV particles, c and x proteins promoted LX-2 proliferation and increased the mRNA levels of PDGF-B, PDGFR-β, collagen-I and α-smooth muscle actin (α-SMA), as well as the phosphorylation of PDGFR-β; however, the expression protein levels of PDGF-B and PDGFR-β remained unchanged. In conclusion, HBV particles and HBV c and x proteins promote HSC proliferation and fibrogenesis in vitro and the PDGF-B/PDGFR-β signaling pathway is important in this process.
    International Journal of Molecular Medicine 10/2012; · 1.96 Impact Factor
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    ABSTRACT: AIM: To compare the immunogenicity of two modified hepatitis B virus (HBV) vaccination schedules in liver transplant recipients. Hepatitis B immunoglobulin (HBIG) in combination with nucleoside/nucleotide analogs (NUCs) is the recommended prophylaxis for preventing HBV recurrence following liver transplantation (LT). However, HBIG treatment is expensive. Active immunization with hepatitis B vaccine would be a preferable alternative prophylaxis to replace HBIG treatment. However, the overall response rate to standard vaccination (given at months 0, 1 and 6) is relatively low in immune-compromised patients. METHODS: Two cohorts of 114 subjects were immunized with recombinant HBV vaccine containing S-antigen. The patients in the rapid schedule group were immunized with 40 μg HBV vaccine at months 0, 1, 2 and 3, and with 20 μg at months 4, 5 and 6. The patients in the accelerated schedule group were immunized with 40 μg of HBV vaccine at days 0, 7, 14 and 28, and 20 μg at months 2, 3 and 4. RESULTS: The overall response rate was 16.7% (19/114) and all responders discontinued HBIG injection and only one patient developed HBV recurrence. The response rate was 24.6% (14/57) and 8.8% (5/57) in the rapid vaccination and the accelerated vaccination schedules, respectively (P = 0.024). CONCLUSION: HBV vaccination may induce endogenous anti-HBs to replace HBIG in selected patients. Vaccination schedules may influence vaccine response, and individual optimization may improve response rate to HBV vaccination.
    Hepatology Research 09/2012; · 2.07 Impact Factor
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    ABSTRACT: Aim:  To investigate direct effects of hepatitis B virus (HBV) on collagen type I in vitro. Methods:  Collagen type I were measured after LX-2 cell cultured with purified or serum HBV for 12, 24 and 48 h. Furthermore, evidence of HBV infection to LX-2 were detected, and different inhibitors were used to identify pathways regulating collagen I expression. Results:  The 3 × 10(5)  IU/mL purified/serum HBV increased collagen type I mRNA expression by 2.2-/3.2- and 1.3-/1.5-fold at 24 and 48 h, respectively. Collagen type I protein in the supernatant of purified/serum HBV group also increased compared to the control group (408.0 ± 8.0/384.4 ± 6.8 vs 262.7 ± 15.7 ng/mL, P < 0.05). However, the 3 × 10(7)  IU/mL purified/serum HBV increased collagen type I expression similar to that of 3 × 10(5)  IU/mL, while 3 × 10(3)  IU/mL group showed no effect. Human HBV immunoglobulin alleviated HBV-induced collagen I expression, but no evidence of HBV infection was found. Neutralization of transforming growth factor beta, tumor necrosis factor alpha, platelet-derived growth factor, extracellular signal-regulated kinase and TGF-β receptor had no obvious inhibitory effects; only inhibition of p38 mitogen-activated protein kinase decreased collagen type I mRNA expression by 0.5-/0.4- and 0.4-/0.3-fold at 24 and 48 h, respectively. It reduced collagen type I protein in the purified/serum HBV group for 48 h (252.1 ± 14.1/251.7 ± 18.8 vs 403.9 ± 4.9/385.0 ± 4.2 ng/mL, P < 0.05). Conclusion:  HBV directly promotes collagen type I expression of LX-2 cells without infection in vitro.
    Hepatology Research 03/2012; 42(9):911-21. · 2.07 Impact Factor
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    ABSTRACT: In the GLOBE trial, telbivudine demonstrated superior efficacy to lamivudine at 2 years in patients with chronic hepatitis B (CHB). Aims: To investigate the long-term efficacy and safety of telbivudine in the telbivudine-treated cohort from the GLOBE trial. Virological and biochemical responses were assessed in 213 HBeAg-positive and 186 HBeAg-negative CHB patients who continued telbivudine treatment for 3 years. Undetectable hepatitis B virus DNA and HBeAg seroconversions were achieved by 77 and 37% of HBeAg-positive patients respectively. Cumulative HBeAg seroconversion rate was 46%. HBeAg seroconversion was sustained at 52 weeks off therapy in 84% of the patients enrolled in the off-treatment follow-up arm of the study. Undetectable viraemia and normal alanine aminotransferase (ALT) levels at 3 years were achieved by 85 and 83% of HBeAg-negative patients respectively. Genotypic resistance rates for the study population who continued therapy during the third year were 11.3 in HBeAg-positive and 6.5% in HBeAg-negative patients. Patients with undetectable viraemia at treatment week 24 had optimal outcomes at 3 years. In the HBeAg-positive population, cumulative HBeAg seroconversion occurred in 58%. Resistance rates for HBeAg-positive and HBeAg-negative patients were 3.6 and 6.2% respectively. The telbivudine safety profile during prolonged therapy was similar to that in the GLOBE trial. Three years of telbivudine treatment yielded high rates of viral suppression and ALT normalization with a favourable safety profile. High rates of HBeAg seroconversion were achieved with prolonged telbivudine therapy and were sustained in the majority of patients over 52 weeks off therapy.
    Liver international: official journal of the International Association for the Study of the Liver 05/2011; 31(5):676-84. · 3.87 Impact Factor
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    ABSTRACT: N-methyl-4-isoleucine cyclosporine (NIM811), a new analogue of cyclosporine A, can inhibit collagen deposition in vitro and reduce liver necrosis in a bile-duct-ligation animal model. However, whether NIM811 effects on CCl(4) -induced rat liver fibrosis, and the related mechanism has not been determined. A liver fibrosis model was induced in Wistar rats using CCl(4) for 6 weeks. Meanwhile, two different doses of NIM811 (low-dose 10 mg/kg and high-dose 20 mg/kg) were given to the CCl(4) -treated rats. Liver fibrosis was then evaluated according to histopathological scoring and liver hydroxyproline content. Serum alanine aminotransferase, aspartate aminotransferase and albumin levels, expression of matrix metalloproteinase-13, tissue inhibitor of metalloproteinase-1, α-smooth muscle actin and cyclophilin B and D in liver tissue were determined. Cyclophilin B and D were also studied in an hepatic stellate cell line. Hydroxyproline content was decreased in both NIM811 groups compared with the model (P < 0.05). Liver necrosis and fibrosis were also attenuated in the NIM811 groups. NIM811 suppressed the expression of tissue inhibitor of metalloproteinase-1, transforming growth factor beta mRNA and α-smooth muscle actin protein in liver tissue. Expression of cyclophilin B in the fibrosis model was increased compared with the normal group (P < 0.05), and was decreased significantly in the low-dose NIM811 treatment group (P < 0.05), which indicated that cyclophilin B might have a profibrotic effect. In vitro studies revealed that cyclophilin B and/or D knockout were associated with collagen inhibition. NIM811 attenuates liver fibrosis in a CCl(4)-induced rat liver fibrosis model, which may be related to binding with cyclophilin B and D.
    Journal of Gastroenterology and Hepatology 03/2011; 26(3):558-67. · 3.33 Impact Factor
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    ABSTRACT: Serum alanine aminotransferase (ALT) increase is a well-known phenomenon during interferon treatment for chronic hepatitis B. However, little is known about these increases during nucleoside/nucleotide treatment and the effects on long-term clinical outcomes. A total of 170 treatment-naive hepatitis B e antigen (HBeAg)-positive chronic hepatitis B patients were treated with a nucleoside/nucleotide analogue for at least 2 years and followed up for 1 more year post-treatment. Clinical characteristics were detected and analysed at baseline and at every 3-month interval. Two patterns of ALT increase, virus- and host-induced, were detected. Virus-induced increases were characterized by a rapid increase in serum ALT and HBV DNA typically after 2 years of treatment, and were more common than host-induced ALT increases (15.9% versus 6.5%; P<0.05) with a median ALT increase of 5.7-fold the upper limit of normal (ULN). Host-induced ALT increases were characterized by moderately increased ALT (median 2.5-fold ULN) with a slow decrease in HBV DNA that occurred mainly in the first year of treatment (63.6%). Most importantly, host-induced increases were associated with favourable long-term treatment outcomes in HBV DNA undetectable rate (82% versus 0%), HBeAg seroconversion (82% versus 7%) and histological improvement. Moreover, interferon-γ-expressing T-helper cells were increased in patients with host-induced ALT increases. Two patterns of ALT increases may occur during nucleoside/nucleotide analogue treatment. Host induced ALT increases, accompanied by decreased HBV DNA, lead to better long-term clinical outcomes.
    Antiviral therapy 01/2011; 16(3):299-307. · 3.07 Impact Factor
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    ABSTRACT: Hepatic stimulator substance (HSS) has been shown to protect liver cells from various toxins. However, the mechanism by which HSS protects hepatocytes remains unclear. In this study, we established BEL-7402 cells that stably express HSS and analyzed the protective ability of HSS on cells through mitochondrial permeability (MP). After administration of carbonyl cyanide m-chlorophenylhydrazone (CCCP), a specific agent that leads to depolarization of the mitochondrial transmembrane potential, the apoptosis rate of HSS-expressing cells was significantly reduced, as measured using Hoechst staining and flow cytometry. The mitochondrial membrane transition and cytochrome c leakage were significantly inhibited in the HSS-expressing cells as compared with the untransfected cells, and, as a consequence, the cellular ATP content in the HSS-expressing cells was relatively preserved. Additionally, decreased caspase-3 activity was observed in the HSS-expressing cells treated with CCCP as compared with the vector-transfected cells and cells expressing mutant HSS. Furthermore, silencing of HSS expression using small interfering RNA accelerated CCCP-induced apoptosis. In isolated mitochondria, recombinant HSS reduced the release of cytochrome c induced by CCCP, indicating a possible role for HSS in regulation of mitochondrial permeability transition (MPT). HSS-expressing BEL-7402 cells are resistant to CCCP injury, and HSS protection is identical to that observed with cyclosporin A, an inhibitor of MPT. Therefore, we propose that the protective effect of HSS may be associated with blockade of MPT.
    FEBS Journal 02/2010; 277(5):1297-309. · 4.25 Impact Factor
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    ABSTRACT: Elevated tissue inhibitor of metalloproteinase (TIMP)-1 expression contributes to excess production of extracellular matrix in liver fibrosis. However, there are few studies on sustained suppression of TIMP-1. We aimed to construct a recombinant adeno-associated virus (AAV) carrying small interfering RNAs (siRNAs) of TIMP-1 and investigate the long-term effects of RNA interference upon the TIMP-1 gene in rat hepatic stellate cells (HSCs). Five siRNA oligomers targeting rat TIMP-1 were designed and transfected into HSCs. A U6 promoter followed by the siRNA which had the strongest suppression effect was cloned into the AAV vector and packed into 293 cells to construct the recombinant AAV/siRNA-TIMP-1/neo. After infecting HSCs with this recombinant AAV, the transcription and expression levels of the TIMP-1 and matrix metalloproteinase-13 (MMP-13) genes were detected at 4 and 12 weeks. Three of the five designed siRNA oligomers had a suppressing effect on TIMP-1 expression in rat HSCs within 72 h. The transcription and expression levels of TIMP-1 were suppressed significantly (P<0.05) following recombinant AAV/siRNA1-TIMP-1/neo infection and lasted 12 weeks. TIMP-1 expression in rAAV/siRNA1-TIMP-1/neo-infected HSCs was suppressed by 60% after four weeks and 90% after twelve weeks when compared to the control recombinant AAV/neo and uninfected HSCs. Furthermore, the transcription and protein expression levels of MMP-13, the main substrate of TIMP-1, were elevated by approximately 40% at twelve weeks in rAAV/siRNA-TIMP-1/neo-infected HSCs. RNA interference exerts suppressive effect on the TIMP-1 gene in cultured HSCs for a longer time when a recombinant AAV is utilized as the gene delivery vector.
    International Journal of Molecular Medicine 11/2009; 24(5):685-92. · 1.96 Impact Factor