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226 results on '"Leem, Jaechan"'

5. Efficacy of Trametinib in Alleviating Cisplatin-Induced Acute Kidney Injury: Inhibition of Inflammation, Oxidative Stress, and Tubular Cell Death in a Mouse Model.

Author

Lee, Joung Eun, Kim, Jung-Yeon, and Leem, Jaechan

Subjects
ACUTE kidney failure, OXIDATIVE stress, CELL death, MITOGEN-activated protein kinases, LABORATORY mice, ANIMAL disease models
Abstract

Cisplatin, a platinum-based chemotherapeutic, is effective against various solid tumors, but its use is often limited by its nephrotoxic effects. This study evaluated the protective effects of trametinib, an FDA-approved selective inhibitor of mitogen-activated protein kinase kinase 1/2 (MEK1/2), against cisplatin-induced acute kidney injury (AKI) in mice. The experimental design included four groups, control, trametinib, cisplatin, and a combination of cisplatin and trametinib, each consisting of eight mice. Cisplatin was administered intraperitoneally at a dose of 20 mg/kg to induce kidney injury, while trametinib was administered via oral gavage at 3 mg/kg daily for three days. Assessments were conducted 72 h after cisplatin administration. Our results demonstrate that trametinib significantly reduces the phosphorylation of MEK1/2 and extracellular signal-regulated kinase 1/2 (ERK1/2), mitigated renal dysfunction, and ameliorated histopathological abnormalities. Additionally, trametinib significantly decreased macrophage infiltration and the expression of pro-inflammatory cytokines in the kidneys. It also lowered lipid peroxidation by-products, restored the reduced glutathione/oxidized glutathione ratio, and downregulated NADPH oxidase 4. Furthermore, trametinib significantly inhibited both apoptosis and necroptosis in the kidneys. In conclusion, our data underscore the potential of trametinib as a therapeutic agent for cisplatin-induced AKI, highlighting its role in reducing inflammation, oxidative stress, and tubular cell death. [ABSTRACT FROM AUTHOR]

Published
2024
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13. Gemigliptin ameliorates western-diet-induced metabolic syndrome in mice

Author

Hee Choi, Seung, Leem, Jaechan, Park, Sungmi, Lee, Chong-Kee, Park, Keun-Gyu, and Lee, In-Kyu

Subjects
Proteases -- Health aspects, Hypoglycemic agents -- Dosage and administration, Metabolic diseases -- Prevention, Biological sciences
Abstract

Dipeptidyl peptidase 4 (DPP-4) inhibitors are widely used antihyperglycemic agents for type 2 diabetes mellitus. Recently, increasing attention has been focused on the pleiotropic actions of DPP-4 inhibitors. The aim of the present study was to examine whether gemigliptin, a recently developed DPP-4 inhibitor, could ameliorate features of metabolic syndrome. Mice were fed a Western diet (WD) for 12 weeks and were subsequently divided into 2 groups: mice fed a WD diet alone or mice fed a WD diet supplemented with gemigliptin for an additional 4 weeks. Gemigliptin treatment attenuated WD-induced body mass gain, hypercholesterolemia, adipocyte hypertrophy, and macrophage infiltration into adipose tissue, which were accompanied by an increased expression of uncoupling protein 1 in subcutaneous fat. These events contributed to improved insulin sensitivity, as assessed by the homeostasis model assessment of insulin resistance and intraperitoneal insulin tolerance test. Furthermore, gemigliptin reduced WD-induced hepatic triglyceride accumulation via inhibition of de novo lipogenesis and activation of fatty acid oxidation, which was accompanied by AMP-dependent protein kinase activation. Gemigliptin ameliorated WD induced hepatic inflammation and fibrosis through suppression of oxidative stress. These results suggest that DPP-4 inhibitors may represent promising therapeutic agents for metabolic syndrome beyond their current role as antihyperglycemic agents. Key words: DPP-4 inhibitor, metabolic syndrome, Western diet, adipocyte hypertrophy, adipose inflammation, nonalcoholic steatohepatitis, AMP-dependent protein kinase, oxidative stress. Les inhibiteurs de la dipeptidyl peptidase 4 (DPP-4) sont largement utilises comme agents anti-hyperglycemiques dans le diabete sucre de type 2. Recemment, une grande attention a ete portee aux actions pleiotropes des inhibiteurs de la DPP-4. Le but de la presente etude etait d'examiner si la gemigliptine, un inhibiteur de la DPP-4 recemment developpe, pouvait ameliorer les caracteristiques du syndrome metabolique. Des souris ont ete nourries avec un regime alimentaire occidental (RAO) pendant 12 semaines et subsequemment reparties en deux groupes : souris nourries avec un RAO seul ou souris nourries avec un RAO supplemente a la gemigliptine pendant 4 semaines de plus. Le traitement a la gemigliptine attenuait le gain de poids corporel, l'hypercholesterolemie, l'hypertrophie des adipocytes et l'infiltration du tissu adipeux par les macrophages resultant de le RAO, qui etaient accompagnes par une expression accrue de la thermogenine dans le gras sous-cutane. Ces evenements contribuaient a l'amelioration de la sensibilite a l'insuline, telle qu'estimee par revaluation du modele d'homeostasie de la resistance a l'insuline (HOMA;<< homeostasis model assessment of insuline resistance >>) et par le test de tolerance a l'insuline intraperitoneale. De plus, la gemigliptine reduisait l'accumulation de triglycerides hepatiques induite par le RAO par l'inhibition de la lipogenese de novo et l'activation de l'oxydation des acides gras, qui etait accompagnee par l'activation de la proteine kinase dependante de l'AMP. La gemigliptine ameliorait l'inflammation hepatique et la fibrose induites par le RAO par la suppression du stress oxydant. Ces resultats suggerent que les inhibiteurs de la DPP-4 peuvent constituer des agents therapeutiques prometteurs pour traiter le syndrome metabolique, au-dela de leurs roles actuels comme agents anti- hyperglycemiques. [Traduit par la Redaction] Mots-cles: inhibiteur de la DPP-4, syndrome metabolique, regime alimentaire occidental, hypertrophie des adipocytes, inflammation adipeuse, steatose hepatique non alcoolique, proteine kinase dependante de l'AMP, stress oxydant., Introduction Metabolic syndrome is a cluster of clinical features including central obesity, dyslipidemia, hypertension, and hyperglycemia (Eckel et al. 2005). The pathogenesis of metabolic syndrome is complex and poorly understood, [...]

Published
2017
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32. Sphingomyelin synthase 1 mediates hepatocyte pyroptosis to trigger non-alcoholic steatohepatitis

Author

National Research Foundation of Korea, Asan Institute for Life Sciences, National Institutes of Health (US), Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Instituto de Salud Carlos III, Fundación BBVA, Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (España), Fundació La Marató de TV3, Koh, Eun Hee, Yoon, Ji Eun, Ko, Myoung Seok, Leem, Jaechan, Yun, Ji-Young, Hong, Chung Hwan, Cho, Yun Kyung, Lee, Seung Eun, Jang, Jung Eun, Baek, Ji Yeon, Yoo, Hyun Ju, Kim, Su Jung, Sung, Chang Ohk, Lim, Joon Seo, Jeong, Won-Il, Back, Sung Hoon, Baek, In‐Jeoung, Torres, Sandra, Solsona-Vilarrasa, Estel, Conde de la Rosa, Laura, García-Ruiz, Carmen, Feldstein, Ariel E., Fernández-Checa, José C., Lee, Ki‐Up, National Research Foundation of Korea, Asan Institute for Life Sciences, National Institutes of Health (US), Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Instituto de Salud Carlos III, Fundación BBVA, Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (España), Fundació La Marató de TV3, Koh, Eun Hee, Yoon, Ji Eun, Ko, Myoung Seok, Leem, Jaechan, Yun, Ji-Young, Hong, Chung Hwan, Cho, Yun Kyung, Lee, Seung Eun, Jang, Jung Eun, Baek, Ji Yeon, Yoo, Hyun Ju, Kim, Su Jung, Sung, Chang Ohk, Lim, Joon Seo, Jeong, Won-Il, Back, Sung Hoon, Baek, In‐Jeoung, Torres, Sandra, Solsona-Vilarrasa, Estel, Conde de la Rosa, Laura, García-Ruiz, Carmen, Feldstein, Ariel E., Fernández-Checa, José C., and Lee, Ki‐Up

Abstract

Objective Lipotoxic hepatocyte injury is a primary event in non-alcoholic steatohepatitis (NASH), but the mechanisms of lipotoxicity are not fully defined. Sphingolipids and free cholesterol (FC) mediate hepatocyte injury, but their link in NASH has not been explored. We examined the role of free cholesterol and sphingomyelin synthases (SMSs) that generate sphingomyelin (SM) and diacylglycerol (DAG) in hepatocyte pyroptosis, a specific form of programmed cell death associated with inflammasome activation, and NASH. Design Wild-type C57BL/6J mice were fed a high fat and high cholesterol diet (HFHCD) to induce NASH. Hepatic SMS1 and SMS2 expressions were examined in various mouse models including HFHCD-fed mice and patients with NASH. Pyroptosis was estimated by the generation of the gasdermin-D N-terminal fragment. NASH susceptibility and pyroptosis were examined following knockdown of SMS1, protein kinase C¿ (PKC¿), or the NLR family CARD domain-containing protein 4 (NLRC4). Results HFHCD increased the hepatic levels of SM and DAG while decreasing the level of phosphatidylcholine. Hepatic expression of Sms1 but not Sms2 was higher in mouse models and patients with NASH. FC in hepatocytes induced Sms1 expression, and Sms1 knockdown prevented HFHCD-induced NASH. DAG produced by SMS1 activated PKC¿ and NLRC4 inflammasome to induce hepatocyte pyroptosis. Depletion of Nlrc4 prevented hepatocyte pyroptosis and the development of NASH. Conditioned media from pyroptotic hepatocytes activated the NOD-like receptor family pyrin domain containing 3 inflammasome (NLRP3) in Kupffer cells, but Nlrp3 knockout mice were not protected against HFHCD-induced hepatocyte pyroptosis. Conclusion SMS1 mediates hepatocyte pyroptosis through a novel DAG-PKC¿- NLRC4 axis and holds promise as a therapeutic target for NASH.

Published
2020

38. Sphingomyelin synthase 1 mediates hepatocyte pyroptosis to trigger non-alcoholic steatohepatitis

Author

Koh, Eun Hee, primary, Yoon, Ji Eun, additional, Ko, Myoung Seok, additional, Leem, Jaechan, additional, Yun, Ji-Young, additional, Hong, Chung Hwan, additional, Cho, Yun Kyung, additional, Lee, Seung Eun, additional, Jang, Jung Eun, additional, Baek, Ji Yeon, additional, Yoo, Hyun Ju, additional, Kim, Su Jung, additional, Sung, Chang Ohk, additional, Lim, Joon Seo, additional, Jeong, Won-Il, additional, Back, Sung Hoon, additional, Baek, In-Jeoung, additional, Torres, Sandra, additional, Solsona-Vilarrasa, Estel, additional, Conde de la Rosa, Laura, additional, Garcia-Ruiz, Carmen, additional, Feldstein, Ariel E, additional, Fernandez-Checa, Jose C, additional, and Lee, Ki-Up, additional

Published
2020
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46. Anti‐fibrotic effects of synthetic TGF‐β1 and Smad oligodeoxynucleotide on kidney fibrosis in vivo and in vitro through inhibition of both epithelial dedifferentiation and endothelial‐mesenchymal transitions

Author

Gwon, Mi‐Gyeong, primary, An, Hyun‐Jin, additional, Kim, Jung‐Yeon, additional, Kim, Woon‐Hae, additional, Gu, Hyemin, additional, Kim, Hyun‐Ju, additional, Leem, Jaechan, additional, Jung, Hyun Jin, additional, and Park, Kwan‐Kyu, additional

Published
2019
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48. Pharmacological Activation of Sirt1 Ameliorates Cisplatin-Induced Acute Kidney Injury by Suppressing Apoptosis, Oxidative Stress, and Inflammation in Mice

Author

Kim, Jung-Yeon, primary, Jo, Jungmin, additional, Kim, Kiryeong, additional, An, Hyun-Jin, additional, Gwon, Mi-Gyeong, additional, Gu, Hyemin, additional, Kim, Hyun-Ju, additional, Yang, A Young, additional, Kim, Sung-Woo, additional, Jeon, Eon Ju, additional, Park, Jae-Hyung, additional, Leem, Jaechan, additional, and Park, Kwan-Kyu, additional

Published
2019
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