Eletrophilic Chemistry of Tranilast Is Involved in Its Anti-Colitic Activity via Nrf2-HO-1 Pathway Activation

Tranilast (TRL), a synthetic derivative of a tryptophan metabolite, is an anti-allergic drug used to treat bronchial asthma. We investigated how TRL activated the nuclear factor-erythroid 2 p45-related factor 2 (Nrf2)-hemeoxygenase-1 (HO-1) pathway based on the electrophilic chemistry of the drug an...

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Autores principales:	Seongkeun Jeong, Changyu Kang, Sohee Park, Sanghyun Ju, Jin-Wook Yoo, In-Soo Yoon, Hwayoung Yun, Yunjin Jung
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	tranilast electrophile Nrf2 HO-1 colitis Medicine R Pharmacy and materia medica RS1-441
Acceso en línea:	https://doaj.org/article/d4c7830b0e65428d8b8d171c5bd527fb
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spelling	oai:doaj.org-article:d4c7830b0e65428d8b8d171c5bd527fb2021-11-25T18:39:16ZEletrophilic Chemistry of Tranilast Is Involved in Its Anti-Colitic Activity via Nrf2-HO-1 Pathway Activation10.3390/ph141110921424-8247https://doaj.org/article/d4c7830b0e65428d8b8d171c5bd527fb2021-10-01T00:00:00Zhttps://www.mdpi.com/1424-8247/14/11/1092https://doaj.org/toc/1424-8247Tranilast (TRL), a synthetic derivative of a tryptophan metabolite, is an anti-allergic drug used to treat bronchial asthma. We investigated how TRL activated the nuclear factor-erythroid 2 p45-related factor 2 (Nrf2)-hemeoxygenase-1 (HO-1) pathway based on the electrophilic chemistry of the drug and whether TRL activity contributed to the treatment of rat colitis. In human colon carcinoma cells, TRL activated Nrf2, as represented by an increase in nuclear Nrf2 and induction of Nrf2-dependent luciferase and, subsequently, HO-1, a target gene product of Nrf2. TRL activation of Nrf2 and induction of HO-1 were completely prevented by chemical reduction of the electrophilic functional group (α, β-unsaturated carbonyl group) in the drug. In parallel, TRL was reactive with the nucleophilic thiol group in <i>N</i>-acetylcysteine, forming a covalent adduct. Moreover, TRL, but not reduced TRL, binds to Kelch-like ECH-associated protein 1 (KEAP1), releasing Nrf2. TRL administration ameliorated colonic damage and inflammation in rats with dinitrobenzene sulfonic acid-induced colitis, which was partly compromised by the chemical reduction of TRL or co-treatment with an HO-1 inhibitor. Our results suggest that TRL activated the Nrf2-HO-1 pathway via covalent binding to KEAP1, partly contributing to TRL amelioration in rat colitis.Seongkeun JeongChangyu KangSohee ParkSanghyun JuJin-Wook YooIn-Soo YoonHwayoung YunYunjin JungMDPI AGarticletranilastelectrophileNrf2HO-1colitisMedicineRPharmacy and materia medicaRS1-441ENPharmaceuticals, Vol 14, Iss 1092, p 1092 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	tranilast electrophile Nrf2 HO-1 colitis Medicine R Pharmacy and materia medica RS1-441
spellingShingle	tranilast electrophile Nrf2 HO-1 colitis Medicine R Pharmacy and materia medica RS1-441 Seongkeun Jeong Changyu Kang Sohee Park Sanghyun Ju Jin-Wook Yoo In-Soo Yoon Hwayoung Yun Yunjin Jung Eletrophilic Chemistry of Tranilast Is Involved in Its Anti-Colitic Activity via Nrf2-HO-1 Pathway Activation
description	Tranilast (TRL), a synthetic derivative of a tryptophan metabolite, is an anti-allergic drug used to treat bronchial asthma. We investigated how TRL activated the nuclear factor-erythroid 2 p45-related factor 2 (Nrf2)-hemeoxygenase-1 (HO-1) pathway based on the electrophilic chemistry of the drug and whether TRL activity contributed to the treatment of rat colitis. In human colon carcinoma cells, TRL activated Nrf2, as represented by an increase in nuclear Nrf2 and induction of Nrf2-dependent luciferase and, subsequently, HO-1, a target gene product of Nrf2. TRL activation of Nrf2 and induction of HO-1 were completely prevented by chemical reduction of the electrophilic functional group (α, β-unsaturated carbonyl group) in the drug. In parallel, TRL was reactive with the nucleophilic thiol group in <i>N</i>-acetylcysteine, forming a covalent adduct. Moreover, TRL, but not reduced TRL, binds to Kelch-like ECH-associated protein 1 (KEAP1), releasing Nrf2. TRL administration ameliorated colonic damage and inflammation in rats with dinitrobenzene sulfonic acid-induced colitis, which was partly compromised by the chemical reduction of TRL or co-treatment with an HO-1 inhibitor. Our results suggest that TRL activated the Nrf2-HO-1 pathway via covalent binding to KEAP1, partly contributing to TRL amelioration in rat colitis.
format	article
author	Seongkeun Jeong Changyu Kang Sohee Park Sanghyun Ju Jin-Wook Yoo In-Soo Yoon Hwayoung Yun Yunjin Jung
author_facet	Seongkeun Jeong Changyu Kang Sohee Park Sanghyun Ju Jin-Wook Yoo In-Soo Yoon Hwayoung Yun Yunjin Jung
author_sort	Seongkeun Jeong
title	Eletrophilic Chemistry of Tranilast Is Involved in Its Anti-Colitic Activity via Nrf2-HO-1 Pathway Activation
title_short	Eletrophilic Chemistry of Tranilast Is Involved in Its Anti-Colitic Activity via Nrf2-HO-1 Pathway Activation
title_full	Eletrophilic Chemistry of Tranilast Is Involved in Its Anti-Colitic Activity via Nrf2-HO-1 Pathway Activation
title_fullStr	Eletrophilic Chemistry of Tranilast Is Involved in Its Anti-Colitic Activity via Nrf2-HO-1 Pathway Activation
title_full_unstemmed	Eletrophilic Chemistry of Tranilast Is Involved in Its Anti-Colitic Activity via Nrf2-HO-1 Pathway Activation
title_sort	eletrophilic chemistry of tranilast is involved in its anti-colitic activity via nrf2-ho-1 pathway activation
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/d4c7830b0e65428d8b8d171c5bd527fb
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Eletrophilic Chemistry of Tranilast Is Involved in Its Anti-Colitic Activity via Nrf2-HO-1 Pathway Activation

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