PMID- 34832874
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20211130
IS  - 1424-8247 (Print)
IS  - 1424-8247 (Electronic)
IS  - 1424-8247 (Linking)
VI  - 14
IP  - 11
DP  - 2021 Oct 28
TI  - Eletrophilic Chemistry of Tranilast Is Involved in Its Anti-Colitic Activity via 
      Nrf2-HO-1 Pathway Activation.
LID - 10.3390/ph14111092 [doi]
LID - 1092
AB  - 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 
      (alpha, beta-unsaturated carbonyl group) in the drug. In parallel, TRL was reactive with 
      the nucleophilic thiol group in N-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.
FAU - Jeong, Seongkeun
AU  - Jeong S
AD  - College of Pharmacy, Pusan National University, Busan 46241, Korea.
FAU - Kang, Changyu
AU  - Kang C
AD  - College of Pharmacy, Pusan National University, Busan 46241, Korea.
FAU - Park, Sohee
AU  - Park S
AD  - College of Pharmacy, Pusan National University, Busan 46241, Korea.
FAU - Ju, Sanghyun
AU  - Ju S
AD  - College of Pharmacy, Pusan National University, Busan 46241, Korea.
FAU - Yoo, Jin-Wook
AU  - Yoo JW
AUID- ORCID: 0000-0001-5216-5518
AD  - College of Pharmacy, Pusan National University, Busan 46241, Korea.
FAU - Yoon, In-Soo
AU  - Yoon IS
AUID- ORCID: 0000-0002-0997-5723
AD  - College of Pharmacy, Pusan National University, Busan 46241, Korea.
FAU - Yun, Hwayoung
AU  - Yun H
AUID- ORCID: 0000-0003-1414-6169
AD  - College of Pharmacy, Pusan National University, Busan 46241, Korea.
FAU - Jung, Yunjin
AU  - Jung Y
AD  - College of Pharmacy, Pusan National University, Busan 46241, Korea.
LA  - eng
GR  - 2021R1I1A3A0403710411/Ministry of Education/
PT  - Journal Article
DEP - 20211028
PL  - Switzerland
TA  - Pharmaceuticals (Basel)
JT  - Pharmaceuticals (Basel, Switzerland)
JID - 101238453
PMC - PMC8623426
OTO - NOTNLM
OT  - HO-1
OT  - Nrf2
OT  - colitis
OT  - electrophile
OT  - tranilast
COIS- The sponsors had no role in the design, execution, interpretation, or writing of 
      the study.
EDAT- 2021/11/28 06:00
MHDA- 2021/11/28 06:01
PMCR- 2021/10/28
CRDT- 2021/11/27 01:20
PHST- 2021/09/17 00:00 [received]
PHST- 2021/10/22 00:00 [revised]
PHST- 2021/10/26 00:00 [accepted]
PHST- 2021/11/27 01:20 [entrez]
PHST- 2021/11/28 06:00 [pubmed]
PHST- 2021/11/28 06:01 [medline]
PHST- 2021/10/28 00:00 [pmc-release]
AID - ph14111092 [pii]
AID - pharmaceuticals-14-01092 [pii]
AID - 10.3390/ph14111092 [doi]
PST - epublish
SO  - Pharmaceuticals (Basel). 2021 Oct 28;14(11):1092. doi: 10.3390/ph14111092.