Eun Uk Jung

Heat Shock Protein 90 Inhibitor Induces Apoptosis and Attenuates Activation of Hepatic Stellate Cells

Activated hepatic stellate cells (HSCs) are major participants in hepatic fibrosis; thus, the induction of HSC apoptosis has been proposed as an antifibrotic treatment strategy. Heat shock protein (Hsp) 90 is a molecular chaperone that stabilizes major signal transduction proteins, and its inhibitors have antitumor activity. In this study, the susceptibility of HSCs to an Hsp90 inhibitor was evaluated. LX-2 cells, an immortalized human HSC line, 17-(allylamino)-17-demethoxygeldanamycin (17AAG), an Hsp90 inhibitor, and monensin, an acidic sphingomyelinase inhibitor, were used in this study. Cellular apoptosis was quantified by 4′,6-diamidino-2-phenylindole dihydrochloride staining, and signaling cascades were explored using immunoblotting and immunoprecipitation techniques. Nuclear factor (NF) κB activities were evaluated by immunofluorescent microscopy and enzyme-linked immunosorbent assay. Collagen α1 and α-smooth muscle actin expressions were determined by real-time reverse transcription-polymerase chain reaction and immunoblotting, respectively. It was found that 17AAG induced HSC apoptosis and that caspase 8 cleavage preceded the downstream activation of apoptotic signaling cascades. Furthermore, this caspase 8 activation was dependent on ceramide generation by acidic sphingomyelinase. In addition, 17AAG prevented NFκB nuclear translocation and activation, specifically by inducing complex formation between NFκB and the glucocorticoid receptor. In accordance, NFκB-dependent cellular FLICE-like inhibitory protein expression level was found to be reduced by 17AAG. Finally, 17AAG down-regulated collagen α1 and α-smooth muscle actin expression levels in HSCs before inducing apoptosis. These results demonstrate that the Hsp90 inhibitor induces HSC apoptosis via a sphingomyelinase- and NFκB-dependent mechanism. Because this inhibitor also reduces HSC activation before apoptosis, Hsp90 inhibitor treatment might be therapeutically useful as an antifibrotic strategy in a variety of liver diseases.

Accuracy of transient elastography in assessing liver fibrosis in chronic viral hepatitis: A multicentre, retrospective study

Transient elastography (TE) has become an alternative to liver biopsy (LB). This study investigated the diagnostic performance of liver stiffness (LS) measurement using TE in Korean patients with chronic hepatitis B and C (CHB and CHC).

Effects of pegylated interferon and ribavirin in Korean patients with chronic hepatitis C virus infection

BACKGROUND/AIMS We assessed the efficacy and safety of pegylated interferon (peginterferon) plus ribavirin and identified the predictors of a sustained virologic response (SVR) in Korean patients with chronic hepatitis C virus infection. METHODS A total of 192 patients with chronic hepatitis C, treated with both peginterferon (n=141) or conventional interferon (n=51) and ribavirin, were analyzed retrospectively. Peginterferon alfa-2a (180 microgram/week) or -2b (1.5 microgram/kg/week) or interferon alfa-2a (3 MIU thrice weekly) was administered in combination with ribavirin at 1,000-1,200 mg/day for 48 weeks for genotype 1 and at 800 mg/day for 24 weeks for genotypes 2 and 3. RESULTS The overall SVR rate was 80.9% (114/141) in the peginterferon group and 52.9% (27/51) in the interferon group (P=0.0001). The SVR rate in genotype 1 was 69.5% (41/59) in the peginterferon group and 31.6% (6/19) in the interferon group (P=0.0033), whereas in genotype 2 or 3 it was 89.0% (73/82) in the peginterferon group and 65.6% (21/32) in the interferon group (P=0.0032). The predictors of SVR in the peginterferon group were genotype, absence of cirrhosis, and early virologic response (P<0.05). CONCLUSIONS In Korean patients with chronic hepatitis C, a regimen of peginterferon and ribavirin was more effective than a regimen of conventional interferon and ribavirin. This result is comparable to those from studies on Western patients as an initial treatment for chronic hepatitis C.

Tenofovir Monotherapy versus Tenofovir plus Lamivudine or Telbivudine Combination Therapy in Treatment of Lamivudine-Resistant Chronic Hepatitis B

ABSTRACT Tenofovir disoproxil fumarate (TDF) monotherapy is a therapeutic option for chronic hepatitis B (CHB) patients infected with hepatitis B virus (HBV) variants resistant to lamivudine (LAM). We evaluated the antiviral efficacy and safety of TDF alone compared to those of TDF plus LAM or telbivudine (LdT) combination in patients harboring HBV variants with genotypic resistance to LAM. This multicenter retrospective study included consecutive patients who had LAM-resistant HBV variants and were treated with TDF alone (monotherapy group) or TDF combined with LAM or LdT (combination therapy group) for at least 6 months. Inverse probability of treatment weighting (IPTW) for the entire cohort was applied to control for treatment selection bias. Overall, 153 patients (33 in the monotherapy group and 120 in the combination therapy group) were analyzed. The overall probability of achieving complete virologic suppression at month 12 was 91.6%: 88.6% in the monotherapy group and 92.6% in the combination therapy group. Combination therapy was not superior to monotherapy in viral suppression before and after IPTW (P = 0.562 and P = 0.194, respectively). Hepatitis B e antigen (HBeAg) loss, biochemical response, and virologic breakthrough did not differ between treatment groups. The probabilities of complete virologic suppression were comparable between treatment groups in the subsets according to HBeAg status and HBV DNA levels at baseline. No patient experienced any significant renal dysfunction during the treatment period. In conclusion, TDF monotherapy has antiviral efficacy comparable to that of TDF plus LAM or LdT combination therapy, with a favorable safety profile in CHB patients with LAM-resistant HBV variants.

Efficacy of thymosin α-1 plus peginterferon α-2a combination therapy compared with peginterferon α-2a monotherapy in HBeAg-positive chronic hepatitis B: a prospective, multicenter, randomized, open-label study.

Abstract Objective. Thymosin α-1 plus interferon α-2a offers superior efficacy over interferon α-2a alone in patients with chronic hepatitis B. The aim was to compare the antiviral efficacy of thymosin α-1 plus peginterferon α-2a and peginterferon α-2a alone in HBeAg-positive chronic hepatitis B patients. Materials and methods. HBeAg-positive CHB patients were enrolled in this prospective, randomized, open-label study. Fifty-one patients were assigned to either combination (26 patients; 180 μg of peginterferon α-2a weekly for 48 weeks and 1.6 mg of thymosin α-1 twice a week for the first 12 weeks) or monotherapy (25 patients; 180 μg of peginterferon α-2a weekly for 48 weeks) groups. Results. The rates of the combined response, defined as HBeAg seroconversion, HBV DNA suppression, and normalization of serum ALT, were 4/26 (15.4%) and 3/25 (12.0%) for the combination group and the monotherapy group at the end of treatment (p = 0.725), and 6/26 (23.1%) and 5/25 (20.0%) at the end of follow-up (p = 0.789), respectively. Based on multiple logistic regression analysis, a >2 log10 IU/mL reduction of HBV DNA at week 12 was identified as an independent predictor for combined response (OR, 9.72; 95% CI, 1.33–71.06; p = 0.025) at the end of follow-up. A lower pretreatment HBV DNA level (≤7 log10 IU/mL) was another predictor for combined response (OR, 9.64; 95% CI, 1.23–75.32; p = 0.031). No significant differences in adverse events were observed. Conclusions. The short-term addition of thymosin α-1 was not superior to peginterferon α-2a alone in HBeAg-positive CHB patients on the basis of antiviral efficacy.

Prospective cohort study on the outcomes of hepatitis C virus‐related cirrhosis in South Korea

The outcomes of hepatitis C virus (HCV)‐related liver cirrhosis was limitedly studied in a hepatitis B virus‐endemic area. This multicenter, prospective cohort study was conducted to elucidate the incidence of hepatocellular carcinoma (HCC) and mortality in the Korean patients with HCV‐related cirrhosis.

Serum HBsAg levels during peginterferon α-2a treatment with or without thymosin α-1 in HBeAg-positive chronic hepatitis B patients.

The importance of serum hepatitis B surface antigen (HBsAg) level as a surrogate marker for viral load and a predictor of treatment response remains unclear. The aim of this study was to investigate whether serum HBsAg correlates with serum hepatitis B virus (HBV) DNA during peginterferon (PEG‐IFN) α‐2a treatment (with or without thymosin α‐1) in hepatitis B e antigen (HBeAg)‐positive chronic hepatitis B patients and whether it can predict treatment response. Sera from 37 HBeAg‐positive chronic hepatitis B patients receiving 48‐weeks PEG‐IFN α‐2a with (n = 20) or without (n = 17) an initial 12‐weeks thymosin α‐1 were obtained at baseline and at weeks 12, 24, 36, 48 (end of treatment), 56, 72, 84, and 96 (end of follow‐up). Taqman HBV DNA tests (Roche) and Architect HBsAg QT (Abbott) were performed. There was a moderate correlation between the HBsAg and HBV DNA levels (r = 0.452, P < 0.001). Median HBsAg levels at baseline and at week 96 were 6,218 IU/ml and 4,038 IU/ml, respectively. The mean HBV DNA and alanine aminotransferase (ALT) levels were 7.48 log10 IU/ml and 173 IU/L at baseline and 5.37 log10 IU/ml and 102 IU/L at week 96, respectively. A decrease to <60% of baseline levels of HBsAg at week 12 was identified as an independent predictive factor for HBeAg seroconversion (OR = 45.7, P < 0.05) at week 96. Serum HBsAg levels may be helpful for predicting the response to PEG‐IFN therapy in HBeAg‐positive chronic hepatitis B patients. J. Med. Virol. 83:88–94, 2011.

Guggulsterone attenuates activation and survival of hepatic stellate cell by inhibiting nuclear factor kappa B activation and inducing apoptosis

Liver fibrosis is associated with the deposition of the extracellular matrix, and hepatic stellate cells (HSCs) are the major source of these matrix proteins. Guggulsterone has recently been shown to induce apoptosis in several cell lines. Thus, the aim of this study was to evaluate whether guggulsterone has antifibrotic activities by reducing the activation and survival of HSCs.

Retinoic acid and its binding protein modulate apoptotic signals in hypoxic hepatocellular carcinoma cells

Hypoxia induces survival signals in hepatocellular carcinoma (HCC). We attempted to find a hypoxia-induced signal that could be used for modulating HCC cell death. Cellular retinoic acid binding protein-II (CRABP-II) expression was significantly increased in hypoxic HCC cells. Treatment with retinoic acid (RA), a ligand for CRABP-II, induced HCC cell apoptosis more effectively in hypoxia than in normoxia, whereas hypoxia-induced CRABP-II expression attenuated RA-induced apoptosis. Inhibition of CRABP-II enhanced RA-induced apoptosis and sensitized RA-resistant HCC cells to RA cytotoxicity by attenuating p42/44 MAPK and Akt activation. Therefore, RA/CRABP-II signal modulation is therapeutically implicated in infiltrative HCCs exposed to hypoxia.

Geographic differences in the epidemiological features of HCV infection in Korea

Background/Aims The prevalence of hepatitis C virus (HCV) infection in Korea exhibits significant geographic variation, with it being higher in Busan and Jeonam than in other areas. The reason for this intranational geographic difference was investigated in this study by conducting a comparative analysis of the risk factors related to HCV infection among three geographic areas: the capital (Seoul), Busan, and the province of Jeolla. Methods In total, 990 patients with chronic HCV infection were prospectively enrolled at 5 university hospitals located in Seoul (n=374), Busan (n=264), and Jeolla (n=352). A standardized questionnaire survey on the risk factors for HCV infection was administered to these three groups of patients, and a comparative analysis of the findings was performed. Results The analysis revealed significant regional differences in exposure to the risk factors of HCV infection. By comparison with patients in Seoul as a control group in the multivariate analysis, patients in Busan had significantly more experience of invasive medical procedures, acupuncture, cosmetic procedures, and multiple sex partners. In contrast, patients in Jeolla were significantly older, and they had a higher prevalence of hepatocellular carcinoma, a lower prevalence of multiple sex partners, and had experienced fewer invasive procedures. Conclusions There was a significant geographic difference in the exposure to potential risk factors of HCV infection between patients from the three studied regions. This may explain the regional variation of the prevalence of HCV infection in Korea, and should be taken into account when planning strategies for the prevention and management of HCV infection.