In Hee Kim

A prospective nationwide study of drug-induced liver injury in Korea.

OBJECTIVES:To address a growing concern about drug-induced liver injury (DILI), a nationwide study was performed to investigate the significance of DILI in Korea.METHODS:From May 2005 to May 2007, cases of DILI (alanine transferase >3 × upper normal limit or total bilirubin >2 × upper normal limit) from 17 referral university hospitals were prospectively enrolled. Adjudication by the seven review boards was considered for the confirmation of causality and the Roussel Uclaf Causality Assessment Method (RUCAM) scale was used.RESULTS:A total of 371 cases were diagnosed with DILI. The extrapolated incidence of hospitalization at university hospital in Korea was 12/100,000 persons/year. The causes included “herbal medications” (102, 27.5%), “prescription or non-prescription medications” (101, 27.3%), “health foods or dietary supplements” (51, 13.7%), “medicinal herbs or plants” (35, 9.4%), “folk remedies” (32, 8.6%), “combined” (30, 8.2%), “herbal preparations” (12, 3.2%), and others (8, 2.2%). Nine cases were linked to acetaminophen. The frequencies of hepatocellular, mixed, and cholestatic types were 76.3, 14.8, and 8.9%, respectively. A total of 234 cases met the criteria for Hys law. Five patients died or underwent transplantation. Twenty-five cases (21 herbs and 4 medications) did not meet the time-to-onset criteria of the RUCAM.CONCLUSIONS:DILI appears to be a highly relevant health problem in Korea. “Herbal medications” are the principal cause of DILI. A more objective and reproducible causality assessment tool is strongly desired as the RUCAM scale frequently undercounts the cases caused by herbs owing to a lack of previous information and incompatible time criteria.

Over-expression of the ribosomal protein L36a gene is associated with cellular proliferation in hepatocellular carcinoma.

Using messenger RNA (mRNA) differential display, we identified a single complementary DNA (cDNA) fragment (HG23T1) that was over‐expressed in a hepatocellular carcinoma (HCC) specimen. We cloned the full‐length HG23T1 gene by the rapid amplification of cDNA end (RACE) polymerase chain reaction (PCR) method. It perfectly matched the gene encoding human ribosomal protein L36a (RPL36A also referred to as RPL44). RPL36A mRNA was preferentially over‐expressed in 34 of 40 HCC cases (85%, P < .001) and in all of 8 HCC cell lines. Ectopically over‐expressed L36a ribosomal protein localized in the nucleoli of cells, and this localization seemed to be controlled by the N‐terminal or the internal tetrapeptide consensus with its adjacent N‐terminal domain. Over‐expression of L36a led to enhanced colony formation and cell proliferation, which may have resulted from rapid cell cycling, and an antisense cDNA effectively reversed these alterations. In conclusion, RPL36A plays a role in tumor cell proliferation and may be a potential target for anticancer therapy of HCC. (HEPATOLOGY 2004;39:129–138.)

Pentoxifylline vs. corticosteroid to treat severe alcoholic hepatitis: A randomised, non-inferiority, open trial

BACKGROUND & AIMS Both corticosteroid and pentoxifylline reduce short-term mortality in severe alcoholic hepatitis. However, few studies have directly compared the efficacy of pentoxifylline and corticosteroid in patients with this condition. METHODS In this multicentre, open-labelled, randomised non-inferiority trial, we assigned 121 patients with severe alcoholic hepatitis (Maddreys discriminant function ⩾32) to receive either pentoxifylline (400 mg, 3 times daily, in 62 subjects) or prednisolone (40 mg daily, in 59 subjects). The primary end point was non-inferiority in survival at the 1 month time point for the pentoxifylline treatment compared with prednisolone. RESULTS The 1-month survival rate of patients receiving pentoxifylline was 75.8% (15 deaths) compared with 88.1% (7 deaths) in those, taking prednisolone, for a treatment difference of 12.3% (95% confidence interval, -4.2% to 28.7%; p = 0.08). The 95% confidence interval for the observed difference exceeded the predefined margin of non-inferiority (Δ15%) and included zero. The 6-month survival rate was not significantly different between the pentoxifylline and prednisolone groups (64.5% vs. 72.9%; p = 0.23). At 7 days, the response to therapy assessed by the Lille model was significantly lower in the prednisolone group (n = 58) than in the pentoxifylline group (n = 5 9): 0.35 vs. 0.50 (p = 0.012). Hepatitis complications, including hepatorenal syndrome and side effects, such as infection and gastrointestinal bleeding, were similar in the two groups. CONCLUSIONS The findings demonstrate that the efficacy of the pentoxifylline is not statistically equivalent to the efficacy of prednisolone, supporting the use of prednisolone as a preferred treatment option in patients with severe alcoholic hepatitis.

A nationwide seroepidemiology of hepatitis C virus infection in South Korea

The aim of this study was to reveal nationwide seroprevalence of HCV infection in South Korea by a large‐scale survey.

A superoxide anion generator, pyrogallol, inhibits the growth of HeLa cells via cell cycle arrest and apoptosis

We investigated the in vitro effects of pyrogallol on cell growth, cell cycle regulation, and apoptosis in HeLa cells. Pyrogallol inhibited the growth of HeLa cells with an IC50 of approximately 45 µM. Pyrogallol induced arrest during all phases of the cell cycle and also very efficiently resulted in apoptosis in HeLa cells, as evidenced by flow cytometric detection of sub‐G1 DNA content, annexin V binding assay, and DAPI staining. This apoptotic process was accompanied by the loss of mitochondrial transmembrane potential (ΔΨm), Bcl‐2 decrease, caspase‐3 activation, and PARP cleavage. Pan‐caspase inhibitor (Z‐VAD) could rescue some HeLa cells from pyrogallol‐induced cell death, while caspase‐8 and ‐9 inhibitors unexpectedly enhanced the apoptosis. When we examined the changes of the ROS, H2O2 or O  2.− in pyrogallol‐treated cells, H2O2 was slightly increased and O  2.− significantly was increased. In addition, we detected a decreased GSH content in pyrogallol‐treated cells. Only pan‐caspase inhibitor showing recovery of GSH depletion and reduced intracellular O  2.− level decreased PI staining in pyrogallol‐treated HeLa cells, which indicates dead cells. In summary, we have demonstrated that pyrogallol as a generator of ROS, especially O  2.− , potently inhibited the growth of HeLa cells through arrests during all phases of the cell cycle and apoptosis.

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).

Incidence and risk factors of delayed postpolypectomy bleeding: a retrospective cohort study.

Background/Aim: Delayed bleeding is a serious complication that occurs after polypectomy. Many risk factors for delayed bleeding have been suggested, but there is little analysis of procedure-related risk factors. The purpose of this study is to identify a wide range of risk factors for delayed postpolypectomy bleeding (DPPB) and analyze the correlations of those potential DPPB risk factors. Materials and Methods: In this retrospective cohort study, 5981 polypectomies in 3788 patients were evaluated between January 2010 and February 2012. Patient-related, polyp-related, and procedure-related factors were evaluated as potential DPPB risk factors. Results: Delayed bleeding occurred in 42 patients (1.1%). Multivariate analysis revealed that polyp size >10 mm [odds ratio (OR), 2.785; 95% confidence interval (CI), 1.406-5.513; P=0.003], location in the right hemi-colon (OR, 2.289; 95% CI, 1.117-4.693; P=0.024), and endoscopist’s experience (<300 total cases of colonoscopy performed; OR, 4.803; 95% CI, 2.631-8.766; P=0.001) were significant risk factors for DPPB. Especially protruded type polyps (Ip, Isp) larger than 1 cm in the right-side colon were associated with increased risk. Right-side polypectomy by a nonexpert endoscopist was a significant risk factor for DPPB, especially with procedures in the cecum area. Taking the 1.5% DPPB incidence as cutoff value, the learning curve of colonoscopic polypectomy may be estimated as 400 cases of polypectomy. Conclusions: Polyp size, endoscopist’s experience, and right hemi-colon location were identified as potential risk factors for DPPB development.

Synergistic antitumor effect of 5-fluorouracil in combination with parthenolide in human colorectal cancer

Parthenolide (PT), a NF-κB inhibitor, has recently been demonstrated as a promising anticancer agent that promotes apoptosis of cancer cells. 5-fluorouracil (5-FU) has been a drug of choice for treatment of colorectal cancer (CRC). Unfortunately, many of the therapies that use 5-FU alone or in combination with other agents are likely to become ineffective due to drug resistance. In the present study, we investigated the antitumor effect of PT combined with 5-FU on a human CRC cell line, SW620. The results demonstrated that combination of PT and 5-FU induced apoptosis which was determined using MTT, cell cycle analysis, annexin-V assay, and Hoechst 33258 staining. Apoptosis through the mitochondrial pathway was confirmed by detecting regulation of Bcl-2 family members, cytochrome C release, and activation of caspase 3 and 9. Moreover, intra-peritoneal injection of PT and 5-FU showed significant inhibition of tumor growth in the xenograft model. These results demonstrate that PT exhibits anticancer activity in human colorectal cancer in vitro and in vivo. These findings provide an efficacious strategy to overcome 5-FU resistance in certain CRC.

Parthenolide-induced apoptosis of hepatic stellate cells and anti-fibrotic effects in an in vivo rat model

Parthenolide (PT), a sesquiterpene lactone derived from the plant feverfew, has pro-apoptotic activity in a number of cancer cell types. We assessed whether PT induces the apoptosis of hepatic stellate cells (HCSs) and examined its effects on hepatic fibrosis in an in vivo model. The effects of PT on rat HSCs were investigated in relation to cell growth inhibition, apoptosis, NF-κB binding activity, intracellular reactive oxygen species (ROS) generation, and glutathione (GSH) levels. In addition, the anti-fibrotic effects of PT were investigated in a thioacetamide-treated rat model. PT induced growth inhibition and apoptosis in HSCs, as evidenced by cell growth inhibition and apoptosis assays. PT increased the expression of Bax proteins during apoptosis, but decreased the expression of Bcl-2 and Bcl-XL proteins. PT also induced a reduction in mitochondrial membrane potential, poly(ADP-ribose) polymerase cleavage, and caspase-3 activation. PT inhibited TNF-α-stimulated NF-κB binding activity in HSCs. The pro-apoptotic activity of PT in HSCs was associated with increased intracellular oxidative stress as evidenced by increased intracellular ROS levels and depleted intracellular GSH levels. Furthermore, PT ameliorated hepatic fibrosis significantly in a thioacetamide-treated rat model. In conclusion, PT exhibited pro-apoptotic effects in rat HSCs and ameliorated hepatic fibrosis in a thioacetamide-induced rat model.

Parthenolide suppresses tumor growth in a xenograft model of colorectal cancer cells by inducing mitochondrial dysfunction and apoptosis

Parthenolide (PT), a principal active component in medicinal plants, has been used conventionally to treat migraine and inflammation. This component has recently been reported to induce apoptosis in cancer cells, through mitochondrial dysfunction. In the present study, we investigated PT-mediated cell death signaling pathway by focusing on the involvement of Bcl-2 family members in human colorectal cancer cells. We also investigated the inhibitory effect of PT on tumor growth in xenografts. Using the human colorectal cancer cell lines HT-29, SW620 and LS174T, we demonstrated that treatment of these cancer cells with PT induces apoptosis using MTT, Annexin V assay and Hoechst 33258 staining. Apoptosis through the mitochondrial pathway was confirmed by detecting regulation of Bcl-2 family members, cytochrome c release and caspase activation. Moreover, intraperitoneal injection of PT showed significant inhibition of tumor growth, angiogenesis in the xenograft model. These results demonstrate that PT exhibits anti-cancer activity in human colorectal cancer in vitro and in vivo. These findings may also provide a novel approach for the treatment of colorectal cancer.