Full metadata record
DC Field | Value | Language |
---|---|---|
dc.contributor.author | 조성신 | - |
dc.date.accessioned | 2021-07-07T05:36:47Z | - |
dc.date.available | 2021-07-07T05:36:47Z | - |
dc.date.issued | 2020-03 | - |
dc.identifier.citation | SCIENTIFIC REPORTS, v. 10, no. 1, article no. 4570 | en_US |
dc.identifier.issn | 2045-2322 | - |
dc.identifier.uri | https://www.nature.com/articles/s41598-020-61630-x | - |
dc.identifier.uri | https://repository.hanyang.ac.kr/handle/20.500.11754/162706 | - |
dc.description.abstract | Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease linked to oxidative stress, which is associated with significant morbidity. The NADPH oxidase complex (NOX) produces reactive oxygen species (ROS) that are among the key markers for determining RA's pathophysiology. Therefore, understanding ROS-regulated molecular pathways and their interaction is necessary for developing novel therapeutic approaches for RA. Here, by combining mouse genetics and biochemistry with clinical tissue analysis, we reveal that in vivo Rubicon interacts with the p22phox subunit of NOX, which is necessary for increased ROS-mediated RA pathogenesis. Furthermore, we developed a series of new aryl propanamide derivatives consisting of tetrahydroindazole and thiadiazole as p22phox inhibitors and selected 2-(tetrahydroindazolyl)phenoxy-N-(thiadiazolyl)propanamide 2 (TIPTP, M.W. 437.44), which showed considerably improved potency, reaching an IC50 value up to 100-fold lower than an inhibitor that we previously synthesized reported N8 peptide-mimetic small molecule (blocking p22phox-Rubicon interaction). Notably, TIPTP treatment showed significant therapeutic effects a mouse model for RA. Furthermore, TIPTP had anti-inflammatory effects ex vivo in monocytes from healthy individuals and synovial fluid cells from RA patients. These findings may have clinical applications for the development of TIPTP as a small molecule inhibitor of the p22phox-Rubicon axis for the treatment of ROS-driven diseases such as RA. | en_US |
dc.description.sponsorship | This work was supported by the NRF grant funded by the Korea government (MSIP) (2016R1D1A1A02937312 and 2019R1I1A2A01064237); a grant from the KHIDI, funded by the Ministry of Health & Welfare, Republic of Korea (HI16C1653, HI16C1677, and HI17C0888) and a Health Fellowship Foundation. We would like to thank all members of the Infection Biology Lab for critical reading and discussion of the manuscript. | en_US |
dc.language.iso | en | en_US |
dc.publisher | NATURE PUBLISHING GROUP | en_US |
dc.subject | NLRP3 INFLAMMASOME | en_US |
dc.subject | LIPID-PEROXIDATION | en_US |
dc.subject | OXIDATIVE STRESS | en_US |
dc.subject | DISEASE-ACTIVITY | en_US |
dc.subject | REACTIVE OXYGEN | en_US |
dc.subject | SYNOVIAL-FLUID | en_US |
dc.subject | ANIMAL-MODELS | en_US |
dc.subject | KAPPA-B | en_US |
dc.subject | ACTIVATION | en_US |
dc.subject | MOUSE | en_US |
dc.title | Identification of highly potent and selective inhibitor, TIPTP, of the p22phox-Rubicon axis as a therapeutic agent for rheumatoid arthritis | en_US |
dc.type | Article | en_US |
dc.identifier.doi | 10.1038/s41598-020-61630-x | - |
dc.relation.page | 1-15 | - |
dc.relation.journal | SCIENTIFIC REPORTS | - |
dc.contributor.googleauthor | Kim, Ye-Ram | - |
dc.contributor.googleauthor | Kim, Jae-Sung | - |
dc.contributor.googleauthor | Gu, Su-Jin | - |
dc.contributor.googleauthor | Jo, Sungsin | - |
dc.contributor.googleauthor | Kim, Sojin | - |
dc.contributor.googleauthor | Kim, Sun Young | - |
dc.contributor.googleauthor | Lee, Daeun | - |
dc.contributor.googleauthor | Jang, Kiseok | - |
dc.contributor.googleauthor | Choo, Hyunah | - |
dc.contributor.googleauthor | Kim, Tae-Hwan | - |
dc.relation.code | 2020051242 | - |
dc.sector.campus | S | - |
dc.sector.daehak | RESEARCH INSTITUTE[S] | - |
dc.sector.department | RHEUMATISM CENTER | - |
dc.identifier.pid | joejo0517 | - |
dc.identifier.researcherID | AAL-3659-2021 | - |
dc.identifier.orcid | http://orcid.org/0000-0003-3034-5029 | - |
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