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학술연구/단체지원/교육 등 연구자 활동을 지속하도록 DBpia가 지원하고 있어요.
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논문 기본 정보
- 자료유형
- 학술저널
- 저자정보
- 발행연도
- 2018.1
- 수록면
- 599 - 607 (9page)
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초록· 키워드
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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.
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참고문헌 (4)
참고문헌 신청
정지성 / 2017 / Low-Dose Bisphenol A Increases Bile Duct Proliferation in Juvenile Rats: A Possible Evidence for Risk of Liver Cancer in the Exposed Population? / Biomolecules & Therapeutics 25(5):545~552
정진우 / 2018 / Spermidine Protects against Oxidative Stress in Inflammation Models Using Macrophages and Zebrafish / Biomolecules & Therapeutics 26(2):146~156
김민정 / 2017 / Expression Levels of GABA-A Receptor Subunit Alpha 3, Gabra3 and Lipoprotein Lipase, Lpl Are Associated with the Susceptibility to Acetaminophen-Induced Hepatotoxicity / Biomolecules & Therapeutics 25(2):112~121
Abhijit Nirwane / 2016 / Neurobehavioural Changes and Brain Oxidative Stress Induced by Acute Exposure to GSM900 Mobile Phone Radiations in Zebrafish (Danio rerio) / 한국독성학회지 32(2):123~132
정진우 / 2018 / Spermidine Protects against Oxidative Stress in Inflammation Models Using Macrophages and Zebrafish / Biomolecules & Therapeutics 26(2):146~156
김민정 / 2017 / Expression Levels of GABA-A Receptor Subunit Alpha 3, Gabra3 and Lipoprotein Lipase, Lpl Are Associated with the Susceptibility to Acetaminophen-Induced Hepatotoxicity / Biomolecules & Therapeutics 25(2):112~121
Abhijit Nirwane / 2016 / Neurobehavioural Changes and Brain Oxidative Stress Induced by Acute Exposure to GSM900 Mobile Phone Radiations in Zebrafish (Danio rerio) / 한국독성학회지 32(2):123~132
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