• Toxicological Research
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• 제28권1호
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• pp.57-65
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• 2012

In this study, the 4-week oral toxicity and anti-cancer activity of the hexane layer of Melia azedarach L. var. japonica Makino's bark extract were investigated. We carried out a hollow fiber (HF) assay and 28-day repeated toxicity study to confirm the anti-cancer effect and safety of the hexane layer. The HF assay was carried out using an A549 human adenocarcinoma cell via intraperitoneal (IP) site with or without cisplatin. In the result, the 200 mg/kg b.w of hexane layer with 4 mg/kg b.w of cisplatin treated group, showed the highest cytotoxicity aginst A549 carcinoma cells. For the 28-day repeated toxicity study, 6 groups of 10 male and female mice were given by gavage 200, 100, or 50 mg/kg b.w hexane layer with or without 4 mg/kg b.w of cisplatin against body weight, and were then sacrificed for blood and tissue sampling. The subacute oral toxicity study in mice with doses of 200, 100, and 50 mg/kg b.w hexane layer showed no significant changes in body weight gain and general behavior. The cisplatin-treated group significantly decreased in body weight compared to the control group but regained weight with 100 and 200 mg/kg b.w of hexane layer. The biochemical analysis showed significant increase in several parameters (ALT, total billirubin, AST, creatinine, and BUN) in cisplatin-treated groups. However, in the group given a co-treatment of hexane layer (200 mg/kg b.w), levels of these parameters decreased. In hematological analysis, cisplatin induced the reduction of WBCs and neutrophils but co-treatment with hexane layer (100 and 200 mg/kg b.w) improved these toxicities caused by cisplatin. The histological profile of the livers showed eosinophilic cell foci in central vein and portal triad in cisplatin treated mice. These results show that hexane layer might have an anti-cancer activity and could improve the toxicity of cisplatin.

• Asian Pacific Journal of Cancer Prevention
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• 제16권9호
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• pp.3709-3713
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• 2015

Background: Many factors, including molecular ones, were demonstrated to be associated with long-term prognosis of hepatocellular carcinoma (HCC). Thus far, the expression and clinicopathologic and prognostic significance of the carboxyl terminus of Hsp70-interacting protein (CHIP) in B-type hepatitis virus (HBV)-related HCC remain unknown. Materials and Methods: CHIP expression was detected by immunohistochemical staining of surgical samples from 79 patients with HCC with HBsAg positivity. In addition, correlations with clinicopathologic parameters and patient survival were evaluated. Results: It was found that positive CHIP staining was observed in tumor, but not non-tumor, tissues. High expression of CHIP was significantly related to larger tumor size, with marginally significant associations noted for presence of portal vein invasion and higher serum a-fetoprotein level. In addition, univariate analysis showed that high CHIP expression was a powerful predictor for dismal overall and disease-free survival. However, independent prognostic implications of CHIP were not proven in multivariate Cox regression test. Conclusions: CHIP is overexpressed in HBV-related HCC and is associated with unfavorable biological behavior as well as poor prognosis. However, its prognostic role needs to be further validated.

• Asian Pacific Journal of Cancer Prevention
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• 제15권18호
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• pp.7563-7567
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• 2014

Background: Hepatocellular carcinoma (HCC) is the first cause of death in cirrhotic patients, mostly due to viral hepatitis with HCV or HBV infection. This study was performed to estimate the true prevalence of viral hepatitis-related HCC and the demographic and clinical-pathological associations with the two virus types. Materials and Methods: This cross sectional observational study enrolled clinical data base of 188 HCC patients and variables included from baseline were age, sex, area of residence, clinical-pathological features such as underlying co-morbidity, presence or absence of liver cirrhosis, macrovascular involvement, tumor extension and metastasis, liver lobes involved, serum alpha-fetoprotein level, and hepatitis serologies. Results: Overall prevalence of HCV- and HBV-related HCC was 66.0% and 34.0%, respectively. Patients with HCV were more likely to develop HCC at advanced age ($52.4{\pm}11.9$ vs. $40.7{\pm}12.09$ years), with highly raised serum AFP levels (${\geq}400ng/ml$) 78.2% (HBV 67.1%), large tumor size (HCV-66% >5 cm, HBV-59.3%), and presence of portal vein thrombosis (8.06%, HBV 1.56%). A binominal multivariate analysis showed that HCV-HCC group were more likely to be cirrhotic (OR=0.245, 95%CI: 0.117, 0.516) and had more than two times higher rate of solitary macrovascular involvement (OR=2.533, 95%CI: 1.162, 5.521) as compared with HBV associated HCC. Conclusions: Statistically significant variations were observed from baseline to clinical-pathological characteristics in HCV vs HBV associated HCC. Our study suggests prompt and early screening for high risk patients so that the rate of progression of these chronic viral diseases to cirrhosis and cancer can be decreased.

• Journal of Yeungnam Medical Science
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• 제29권1호
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• pp.48-53
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• 2012

Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related deaths in South Korea. To decrease its mortality rate, its early detection is very important. Screening for HCC detection has been accepted as the management modality for patients with chronic liver disease. Reported herein is a case involving the marked rapid growth of HCC detected at an advanced stage in a screening test with a 3 months interval. A 49-year-old male patient with chronic hepatitis B was admitted to the hospital due to a liver mass detected on CT scan. The patient underwent a first CT scan 3 months earlier, and no tumor was detected. Follow-up CT scan was performed and showed a 9.1 cm HCC with portal vein thrombosis. Percutaneous liver biopsy was performed, and the diagnosis of hepatocellular carcinoma was confirmed. In the pertinent guidelines, the recommended screening interval for HCC is 6-12 months, but the screening interval and additional diagnostic methods should be considered due to the variation in the HCC growth rate according to the patient's clinical characteristics.

• 한국임상수의학회지
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• 제30권4호
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• pp.273-277
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• 2013

This study was performed to compare clinical and diagnostic imaging features between asymptomatic and symptomatic extrahepatic portosystemic shunts in dogs. The data of thirty patients diagnosed with extrahepatic PSS by multi-detector CT were reviewed, and the dogs were divided into asymptomatic (9/30) and symptomatic (21/30) groups. Signalments, hematologic results, liver size, morphologic classifications and main portal vein to abdominal aortic ratio (PV/AO) at the porta hepatis level from CT images were evaluated in two groups. Shih-tzu (5/9) was the most frequent breed in asymptomatic group, and various breeds were presented in symptomatic group. Mean age of asymptomatic group ($9.2{\pm}3.2$ years) was significantly higher than that of symptomatic group ($4.5{\pm}3.2$ years). The most morphologic form of shunt vessel was the splenophrenic shunt (16/30). PV/AO of asymptomatic group ($1.1{\pm}0.19$) was significantly higher than the values of symptomatic group ($0.55{\pm}0.19$). Clinical signs, hematologic results and diagnostic imaging findings of asymptomatic PSS are too nonspecific to suspect PSS. Therefore, considering of patient's age and CT examination with application of PV/AO ratio could be useful for the diagnosis of asymptomatic PSS.

• 동의생리병리학회지
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• 제17권2호
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• pp.461-466
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• 2003

The primary mechanism of smooth muscle contraction is phosphorylation of the 20 kDa myosin light chains(LC20) by a myosin light chain kinase(MLCK). Relaxation, then, is generally the result of dephosphorylation of LC20 by myosin phosphatase(MP). Changes in MP activity is one of the important mechanisms in the regulation of Ca2+-sensitivity. Inhibition of MP activity is linked to an increase in phosphorylated myosin light chain(MLC) without an increase in [Ca/sup 2+/]i-levels. It is now generally accepted that Rho-kinase phosphorylates 130 kDa regulatory and myosin binding subunits(M130, MYPT) of MP, which results in an inhibition of MP activity. In addition Rho-kinase can also directly phosphorylate MLC. In the present study, LC20 phosphorylation and MP subunits translocation to the cell membrane were investigated in freshly isolated ferret portal vein smooth muscle single cells treated with PGF2α. We also examined the effect of Y27632(10-5mol/L), Rho-kinase inhibitor, in the MP subunits localization to compare with butanol fraction of Fructus Crataegi in its effect. Butanol fraction of Fructus Crataegi(BFFC; 1㎎/㎖) was more effective in PGF2α induced contraction than those of phenylephrine in its vasodilation effect. It significantly(P<0.05) dephosphorylated the LC20 at time indicated. In addition, the dissociation of subunits are inhibited by BFCF treatment. The results indicate that, in the smooth muscle cells, the relaxation effect of BFFC is associated with increase of MP activity based on inhibition of dissociation of the catalytic and targeting subunits of the phosphatase, and thus decrease the sensitivity of LC20 phosphorylation for Ca/sup 2+/.

• Toxicological Research
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• 제34권3호
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• pp.241-247
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• 2018

Lactobacillus (LAB) have been reported to exert both harmful and beneficial effects on human and animal health. Recently, it has been reported that dysbiosis and bacterial translocation contribute to liver fibrosis. However, the role of Gram-positive LAB in the situation of chronic liver diseases has not been yet elucidated. Liver injury was induced by bile duct ligation (BDL) in LAB or control-administered mice. Liver fibrosis was enhanced in LAB-administered mice compared with control-treated mice as demonstrated by quantification of Sirius-red positive area, hydroxyproline contents and fibrosis-related genes ($Col1{\alpha}1$, Acta2, Timp1, Tgfb1). Moreover, LAB-administered mice were more susceptible to BDL-induced liver injury as shown by increased ALT and AST level of LAB group compared with control group at 5 days post BDL. Consistent with serum level, inflammatory cytokines ($TNF-{\alpha}$, IL-6 and $IL-1{\beta}$) were also significantly increased in LAB-treated mice. Of note, LAB-treated liver showed increased lipoteichoic acid (LTA) expression compared with control-treated liver, indicating that LAB-derived LTA may translocate from intestine to liver via portal vein. Indeed, responsible receptor or inflammatory factor (PAFR and iNOS) for LTA were upregulated in LAB-administered group. The present findings demonstrate that administration of LAB increases LTA translocation to liver and induces profibrogenic inflammatory milieu, leading to aggravation of liver fibrosis. The current study provides new cautious information of LAB for liver fibrosis patients to prevent the detrimental effect of LAB supplements.

• 한국동물위생학회지
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• 제26권4호
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• pp.345-359
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• 2003

A number of toxicants have been incriminated as a causing hepatic disease. Among many detrimental injury, alcohol has been noted for hepatitis, fatty liver, fibrosis, and hepatic cirrhosis. The purpose of this study was to develop animal model for hepatic fibrosis in pigs fed ethanol, and to search for a new anti-fibrogenic agent via this model. Twelve male Landrace pigs were divided into 3 groups of 4 animals each. Group 1, 2 and 3 were fed with active ceramic water only, ceramic water + liquid diet containing 15% ethanol and normal tap water + liquid diet containing 15% ethanol for 12 weeks, respectively. At week 12, all pigs were immediately sacrificed for collection each tissue and blood. Serologically, serum ALT and AST levels were significantly reversed in group 2, as compared to group 3. They were normal range in pigs of group 1. Microscopically, macrovesicular lipid droplets and moderate hepatocellular necrosis were evident in the tap water + ethanol fed group 3. However, the active ceramic water treated group 1 showed normal architecture. Moreover, in group 2, mild fatty changes and necrosis were observed in hepatocytes. Collagen fibers were increased in spaces surrounding periportal and interlobular connective tissues in the group 3 of tap water + ethanol, but collagen synthesis and its thickness of fibrotic septa connecting portal tracts were markedly reduced in the group 2 of ceramic water + ethanol. Myofibroblasts were detected mainly in the interlobular connective tissues of pig liver of group 3 treated ethanol and tap water. Few to no myofibroblasts were observed in groups 1 and 2. CYP2E1 was not or rarely detected in group 1 fed ceramic water. However, group 2 showed slightly activation of CYP2E1 in the area of pericentral vein, while CYP2E1 was significantly activated in group 3 fed tap water and ethanol. Based on the above data, we believe that we have developed a unique alcohol induced fibrosis model in pig, which will be useful in developing anti-fibrotic agents and drugs. Furthermore, the active ceramic water used in our study had an inhibitory and may be protective against ethanol induced hepatic toxicity and fibrosis.

• Neonatal Medicine
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• 제17권1호
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• pp.136-140
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• 2010

신생아 선천성 대사이상 선별검사에서 갈락토스혈증이 의심되는 경우, 혈관내피종과 같은 간 실질 내 종양을 동반할 수 있으므로 갈락토스혈증 관련 효소검사와 함께 간초음파 검사와 같은 영상학적 진단법, 총담즙산, AFP등의 측정을 병행하여야 원인감별에 도움이 된다. 저자들은 신생아 선천성 대사이상 질환 선별검사에서 갈락토스혈증이 의심되었던 생후 13일된 영아에 대하여 원인을 조사하던 중 복부초음파 검사에서 간 내 혈관내피종을 발견된 1례를 경험하였기에 이에 보고하는 바이다.

• Journal of Pharmaceutical Investigation
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• 제28권2호
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• pp.73-80
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• 1998

In order to elucidate the effect of N-demethylation on the in vivo metabolite kinetics, especially hepatic first-pass effect of trimebutine(TMB), the N-demethylation of TMB to N-monodesmethyl trimebutine(N-TMB) was studied in rats. TMB(10 mg/kg) and N-TMB(10 mg/kg) were injected into the femoral and the portal vein, respectively. And the pharmacokinetic parameters were obtained from the plasma concentration-time profiles of TMB and N-TMB determined by the simultaneous analysis using high-performance liquid chromatography. It was supposed that these drugs were almost metabolized in vivo because the urinary and biliary excreated amounts of TMB and N-TMB were lower than 0.1% of the administered dose. According to the hepatic biotransformation model and metabolic pathways of TMB proposed, it was found that the fraction of systemic clearance of TMB which formed N-TMB in liver$(G_{mi})$ was 0.826, that of TMB which furnishes the available N-TMB to the systemic circulation$(F_{mi})$ was 0.083, and the absolute hepatic bioavailability of N-TMB formed trom TMB$(F_{mi.p})$ was 0.1. These results showed that TMB was suspected of the sequential hepatic first-pass metabolism and N-demethylated by 82.6%. Therefore, the residue would be hydrolyzed by the esterase in the liver. That is, the ability of N-demethylation of TMB was 4.75-fold larger than that of hydrolysis by the esterase in rats.