PMID- 32334388 OWN - NLM STAT- MEDLINE DCOM- 20210310 LR - 20211204 IS - 1878-1705 (Electronic) IS - 1567-5769 (Linking) VI - 84 DP - 2020 Jul TI - Identification of 3',4',5'-trihydroxyflavone as an mammalian target of rapamycin inhibitor and its suppressive effects on dextran sulfate sodium-induced ulcerative colitis. PG - 106524 LID - S1567-5769(20)30436-7 [pii] LID - 10.1016/j.intimp.2020.106524 [doi] AB - Flavone derivatives have been shown to possess anti-inflammatory properties in various inflammation model systems; however, their underlying molecular mechanisms remain elusive. In this study, a flavone derivative 3',4',5'-trihydroxyflavone (THF; NJK16003) was synthesized, and its anti-inflammatory effects and molecular targets were investigated using in vitro systems and an in vivo colitis model. NJK16003 showed potent anti-inflammatory activities in cell-based assays using macrophages. In vitro enzyme activity assays using various inflammation-related kinases revealed the mammalian target of rapamycin (mTOR) as a possible molecular target. Treatment of RAW264.7 cells with NJK16003 resulted in an increase in light chain 3B protein lipidation and a decrease in p62 protein levels and ribosomal S6 kinase phosphorylation, indicating that NJK16003 induces autophagy through mTOR inhibition. NJK16003 treatment resulted in significant induction of autophagy and suppression of inflammatory responses in intestinal epithelial cells. Autophagy induction has been shown to alleviate colitis by suppressing inflammatory responses and apoptotic cell death of intestinal epithelial cells. Indeed, inflammatory responses and intestinal epithelial cell death in our DSS-induced colitis mouse model were significantly suppressed by NJK16003 treatment. Our results indicate that NJK16003 could suppress inflammation by inducing autophagy through its mTOR inhibitory activity. These results suggest that NJK16003 could be a possible therapeutic agent for the treatment of inflammatory bowel diseases including colitis. CI - Copyright (c) 2020 Elsevier B.V. All rights reserved. FAU - Kang, Sung-Bae AU - Kang SB AD - Department of Life and Nanopharmaceutical Science, College of Pharmacy, Kyung Hee University, Seoul 02447, Republic of Korea. FAU - Yoo, Hyung-Seok AU - Yoo HS AD - Department of Pharmacy, College of Pharmacy, Kyung Hee University, Seoul 02447, Republic of Korea. FAU - Jeon, Seung Ho AU - Jeon SH AD - Department of Fundamental Pharmaceutical Science, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea. FAU - Song, Chae Won AU - Song CW AD - Department of Life and Nanopharmaceutical Science, College of Pharmacy, Kyung Hee University, Seoul 02447, Republic of Korea. FAU - Lee, Na-Rae AU - Lee NR AD - Department of Life and Nanopharmaceutical Science, College of Pharmacy, Kyung Hee University, Seoul 02447, Republic of Korea. FAU - Kim, Nam-Jung AU - Kim NJ AD - Department of Life and Nanopharmaceutical Science, College of Pharmacy, Kyung Hee University, Seoul 02447, Republic of Korea; Department of Pharmacy, College of Pharmacy, Kyung Hee University, Seoul 02447, Republic of Korea. Electronic address: kimnj@khu.ac.kr. FAU - Lee, Jong Kil AU - Lee JK AD - Department of Pharmacy, College of Pharmacy, Kyung Hee University, Seoul 02447, Republic of Korea; Department of Fundamental Pharmaceutical Science, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea. Electronic address: jklee3984@khu.ac.kr. FAU - Inn, Kyung-Soo AU - Inn KS AD - Department of Life and Nanopharmaceutical Science, College of Pharmacy, Kyung Hee University, Seoul 02447, Republic of Korea. Electronic address: innks@khu.ac.kr. LA - eng PT - Journal Article DEP - 20200422 PL - Netherlands TA - Int Immunopharmacol JT - International immunopharmacology JID - 100965259 RN - 0 (Anti-Inflammatory Agents) RN - 0 (Flavones) RN - 0 (IL1B protein, mouse) RN - 0 (Interleukin-1beta) RN - 0 (Lipopolysaccharides) RN - 0 (Tnf protein, mouse) RN - 0 (Tumor Necrosis Factor-alpha) RN - 31C4KY9ESH (Nitric Oxide) RN - 9042-14-2 (Dextran Sulfate) RN - EC 1.14.13.39 (Nitric Oxide Synthase Type II) RN - EC 1.14.13.39 (Nos2 protein, mouse) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) SB - IM MH - Animals MH - Anti-Inflammatory Agents/pharmacology/*therapeutic use MH - Autophagy/drug effects MH - Cell Survival/drug effects MH - Colitis, Ulcerative/chemically induced/*drug therapy/immunology/pathology MH - Colon/drug effects/immunology/pathology MH - Dextran Sulfate MH - Flavones/pharmacology/*therapeutic use MH - HCT116 Cells MH - HT29 Cells MH - Humans MH - Interleukin-1beta/genetics MH - Lipopolysaccharides/pharmacology MH - Macrophage Activation/drug effects MH - Male MH - Mice MH - Mice, Inbred C57BL MH - Nitric Oxide/immunology MH - Nitric Oxide Synthase Type II/genetics MH - RAW 264.7 Cells MH - TOR Serine-Threonine Kinases/*antagonists & inhibitors MH - Tumor Necrosis Factor-alpha/genetics OTO - NOTNLM OT - 3',4',5'-Trihydroxyflavone OT - Autophagy OT - DSS-induced mouse colitis model OT - Inflammatory bowel disease OT - Mammalian target of rapamycin COIS- Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. EDAT- 2020/04/26 06:00 MHDA- 2021/03/11 06:00 CRDT- 2020/04/26 06:00 PHST- 2020/02/16 00:00 [received] PHST- 2020/03/29 00:00 [revised] PHST- 2020/04/15 00:00 [accepted] PHST- 2020/04/26 06:00 [pubmed] PHST- 2021/03/11 06:00 [medline] PHST- 2020/04/26 06:00 [entrez] AID - S1567-5769(20)30436-7 [pii] AID - 10.1016/j.intimp.2020.106524 [doi] PST - ppublish SO - Int Immunopharmacol. 2020 Jul;84:106524. doi: 10.1016/j.intimp.2020.106524. Epub 2020 Apr 22.