• Biomolecules & Therapeutics
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• v.26 no.6
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• pp.599-607
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• 2018

Fasiglifam (TAK-875) a G-protein coupled receptor 40 (GPR40) agonist, significantly improves hyperglycemia without hypoglycemia and weight gain, the major side effects of conventional anti-diabetics. Unfortunately, during multi-center Phase 3 clinical trials, unexpected liver toxicity resulted in premature termination of its development. Here, we investigated whether TAK-875 directly inflicts toxicity on hepatocytes and explored its underlying mechanism of toxicity. TAK-875 decreased viability of 2D and 3D cultures of HepG2, a human hepatocarcinoma cell line, in concentration-(>$50{\mu}M$) and time-dependent manners, both of which corresponded with ROS generation. An antioxidant, N-acetylcysteine, attenuated TAK-875-mediated hepatotoxicity, which confirmed the role of ROS generation. Of note, knockdown of GPR40 using siRNA abolished the hepatotoxicity of TAK-875 and attenuated ROS generation. In contrast, TAK-875 induced no cytotoxicity in fibroblasts up to $500{\mu}M$. Supporting the hepatotoxic potential of TAK-875, exposure to TAK-875 resulted in increased mortality of zebrafish larvae at$25{\mu}M$. Histopathological examination of zebrafish exposed to TAK-875 revealed severe hepatotoxicity as manifested by degenerated hypertrophic hepatocytes with cytoplasmic vacuolation and acentric nuclei, confirming that TAK-875 may induce direct hepatotoxicity and that ROS generation may be involved in a GPR40-dependent manner.

• Journal of Microbiology and Biotechnology
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• v.13 no.6
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• pp.919-925
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• 2003

Alcohol consumption has numerous health consequences for the human body. For example, heavy drinking on a daily basis causes liver diseases, and certain products such as acetaldehyde produced from alcohol metabolism are more toxic than alcohol itself. Accordingly, the current study evaluated the role of Lactobacillus fermentum MG590 to enhance the removal of the toxic effect of alcohol in alcohol metabolism. The maximum activities of the alcohol dehydrogenase (ADH) and acetaldehyde dehydrogenase (ALDH) by L. fermentum MG590 were observed after 6 h of culture. The production of ADH and ALDH by L. fermentum MG590 was also confirmed by SDS-PAGE. Six hours after the addition of alcohol to a culture broth of L. fermentum MG590, the alcohol concentration decreased from 7.5 to 2.7％. From an in vitro evaluation based on hepatocytes, the viability of hepatocytes in a medium containing alcohol and the cytosol of L. fermentum MG590 was higher than that in a medium containing only alcohol. From an in vivo test using SD rats fed a 22％ alcoholic drink, the blood alcohol concentration (BAC), glutamic-oxaloacetic transaminase (GOT), and glutamic-pyruvic transaminase (GPT) in the rats fed a medium containing L. fermentum MG590 were lower than those in the rats fed a medium containing only the alcohol drink. These results demonstrate that the ADH and ALDH produced by L. fermentum MG590 play an important role in detoxicating alcohol in vivo. Therefore, a fermentation broth of L. fermentum MG590 could be used as an effective alcohol detoxification drink.

• Korean Journal of Veterinary Pathology
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• v.2 no.2
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• pp.95-106
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• 1998

The prevalence of primary liver carcinoma (PLC) is relatively high in Clonorchis sinensis (CS) endemic areas in Korea. PLC is a malignant tumor which can be subclassified into hepatocellular carcinoma and cholangiocarcinoma(CC). CC has been associated with clonorchiasis, but it is unclear whether clonorchiasis is associated with hepatocarcinogenesis. This experiment was designed to investigate relationships between clonorchiasis and early changes of hepatocarcinogenesis. Sixteen Sprague-Dawley rats weighing 150g were divided into two groups of 8 rats in each. All rats were fed choline-devoid(CD) diet for 4 weeks. Group 1 was given 0.015-0.020% diethylnitrosamine(DEN) as drinking water for 1 week. After one week, the rats were treated orally with 1% N-acetylaminofluorene(AAF) (5 times per week for 2 weeks). Group 2 was treated equally to group 1 except for CS infection during AAF treatment. Two rats in each group were sacrificed at 4th, 5th, 6th and 7th week of the experiment. Livers were stained with OV -6, proliferating cell nuclear antigen(PCNA) and GST-p. Results were as follows: Group 2 livers showed more oval cell proliferation in parenchyma and portal areas at the 4th, 5th, 6th and 7th weeks than did livers of group 1 (p＜0.01). PCNA was mostly localized in oval cell populations, rather than hepatocytes and biliary cells. The ratio of oval cells to hepatocytes was much higher in group 2 than in group l(p＜0.01 The ratio of hepatocytes to biliary cells is higher in group 2 than in group 1 (p＜0.05), More group 2 acidophilic foci reacted to GST-p monoclonal antibody than in the noninfected group. It appeared that CS infection promoted potentially precancerous acidophilic foci and oval cell proliferation.

• Bulletin of the Korean Chemical Society
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• v.35 no.9
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• pp.2781-2786
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• 2014

Human ${\alpha}_1$-antitrypsin (${\alpha}_1$-AT) is a natural inhibitor of neutrophil elastases and has several dozens of genetic variants. Most of the deficient genetic variants of human ${\alpha}_1$-AT are unstable and cause pulmonary emphysema. However, the most clinically significant variant, Z-type ${\alpha}_1$-AT, exhibits retarded protein folding that leads to accumulation of folding intermediates. These aggregate within the endoplasmic reticulum (ER) of hepatocytes, subsequently causing liver cirrhosis as well as emphysema. Here, we studied the role of an ER folding assistant protein Cpr5p on Z-type ${\alpha}_1$-AT folding. Cpr5p was induced > 2-fold in Z-type ${\alpha}_1$-AT-expressing yeast cells compared with the wild type. Knockout of CPR5 exacerbated cytotoxicity of Z-type ${\alpha}_1$-AT, and re-introduction of CPR5 rescued the knockout cells from aggravated cytotoxicity caused by the ${\alpha}_1$-AT variant. Furthermore, Cpr5p co-immunoprecipitated with Z-type ${\alpha}_1$-AT and facilitated its protein folding. Our results suggest that protein-folding diseases may be suppressed by folding assistant proteins at the site of causal protein biosynthesis.

• Biotechnology and Bioprocess Engineering:BBE
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• v.8 no.5
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• pp.279-285
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• 2003

Lidocaine and galactose loading tests were performed on a bioartificial liver (BAL), an extracorporeal medical device incorporating living hepatocytes in a cartridge without a transport barrier across the membranes. The concentration changes were analyzed using pharmacokinetic equations to evaluate the efficacy and limitation of the proposed method. Lidocaine and galactose were found to be suitable drugs for a quantitative evaluation of the BAL functions, as they did not interact with the plasma proteins or blood vessels, making their concentrations easy to determine. The drug concentration changes after drug loading were easily analyzed using pharmacokinetic equations, and the BAL functions quantitatively expressed by pharmacokinetic parameters, such as the clearance (CL) and galactose elimination capacity (GEC). In addition, these two drugs have already been used in clinical tests to evaluate human liver functions over long periods, and lidocaine CL values and GEC values reported for a normal human liver. Thus, a comparison of the CL and GEC values for the BAL and a natural liver revealed what proportion of normal liver functions could be replaced by the BAL.

• 한국생물공학회:학술대회논문집
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• 2003.10a
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• pp.363-364
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• 2003

• Preventive Nutrition and Food Science
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• v.4 no.1
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• pp.75-78
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• 1999

Acetylcarnitine, a metabilite of carnitine, has been porven to be a potent inhibitor of ethanol oxidation in hepatocytes. It inhibits the activity of alcohol dehydrognase (ADH), but not the microsomal ethanol oxidizing system. which was significatly inhibited by acetylcarnitine at NAD ; acetylcarnitine $\leq$1. the main objectives of his study were to ascertain the interaction between acetylcarnitine and NAD on ADH activity and to elucidate whether different species have different effects. Tehpost-mocrosomal supernatant (PMS) was prepared from normal rat, guinea pig, mouse and broilers by differential centrifugation . Horse and yeast ADH were purchased from the Sigma Chemical Co. Prepared and purchased ADH are used for determination of ADH activity in the presence or absence of carnitine and acetylcar- nitine. Binding studies showed that acetylcarnitine did bind to ADH in a dose realted manner when low NAD ; acetylcar- nitine ratio was provided. It was found that the inhibitionof ADH activity occurred only when NAD concentration was less than the inhibitor concentration . Crystalline and crude ADH preparation from different vertebrate species wer inhibited by acetylcarnitine, whereas the yeast ADH was not affected by acetylcarnitine.

• The Korean Journal of Nuclear Medicine
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• v.32 no.4
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• pp.305-313
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• 1998

The reduction in the amount of asialoglycoprotein (ASGP) receptor, which resides exclusively on the plasma membrane of functioning mammalian hepatocytes, as a consequence of hepato-cellular damage has been demonstrated in various pathologic conditions of the liver. Galac-tosylated human serum albumin (GSA) is a newly developed receptor-binding agent, specific for the ASGP receptor. Tc-99m GSA binds quantitatively to liver ASGP receptors and the rate of accumulation in the liver is dependent on hepatic function represented as the amount of receptor, as well as the amount of ligand injected, its affinity to the receptor and the hepatic blood flow. The findings of Tc-99m GSA scintigraphy were reported to reflect the hepatic function of the patients with large hepatic tumors, obstructive jaundice, acute and chronic liver disease. Tc-99m GSA scintigraphy is an easy and reliable test and has the clinical potentials to evaluate the liver function in the patients with hepatic disorders.

• Proceedings of the PSK Conference
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• 2003.10b
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• pp.104.2-104.2
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• 2003

Cadmium is an environmental pollutant and exhibits nephrotoxicity, hepatotoxicity and immunotoxicity. Recently, cadmium was found to induce DNA fragmentation, a biochemical hallmark of apoptosis, in cultured renal cells, hepatocytes and neuroblastoma cell. Therefore, the various toxicities of cadmium are thought to be caused by the induction of apoptosis. Lipids-derived pro-apoptotic ceramide has emerged as an important intracellular signaling molecule that mediates diverse cellular effects, of which programmed cell death, or apoptosis, has attracted significant interest. (omitted)

• Molecular & Cellular Toxicology
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• v.2 no.3
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• pp.166-169
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• 2006

Accumulated evidences have established that aberrant regulation of histone deacetylases (HDACs) is one of major causes for development of human malignancies. Mammalian HDACs can be divided into three subclasses consisting of 11 homologous of HDACs and 7 of sirtuins, but little is known about HDAC2 causes for carcinogenesis in solid tumors. Here, in order to investigate the roles of HDAC2 in carcinogenesis of liver cancer progression, we analyzed the expression of HDAC2 in 62 human hepatocellular carcinomas by utilizing Immunohistochemistry. Moderate to strong expression of HDAC2 was found in 54 (87%) out of total 62 tumors. The majority of positive tumors were detected in nucleous, but normal hepatocytes did not express of HDAC2 or showed weak positive staining. Interestingly, we were also noted that HDAC2 expression was appeared to be associated with aggressiveness of the tumors by the fact that HDAC2 expression was observed with significances in high grade tumors (Edmonson grade II, III). Taken together, we found the aberrant expression of HDAC2 in hepatocellular carcinomas, and this suggests that HDAC2 may play an important role in the development of liver cancer.