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Therapeutic effects of CKD-H059, a novel histone deacetylase 6 inhibitor, in rheumatoid arthritis
DC Field | Value | Language |
---|---|---|
dc.contributor.advisor | 송영욱 | - |
dc.contributor.author | 장유진 | - |
dc.date.accessioned | 2017-07-19T11:08:49Z | - |
dc.date.available | 2017-07-19T11:08:49Z | - |
dc.date.issued | 2016-02 | - |
dc.identifier.other | 000000132893 | - |
dc.identifier.uri | https://hdl.handle.net/10371/133393 | - |
dc.description | 학위논문 (석사)-- 서울대학교 융합과학기술대학원 : 융합과학기술대학원 분자의학 및 바이오제약학과, 2016. 2. 송영욱. | - |
dc.description.abstract | Background: Epigenetic changes including histone modification may play a role in development of rheumatoid arthritis (RA). Histone deacetylase inhibitor (HDACi) could increase transcription of numerous genes by rendering chromatin state more accessible for transcription factor and RNA-polymerase, leading to anti-proliferative and anti-inflammatory effects.
Objective: This study was aimed to investigate the effects of CKD-H059, a novel HDAC-6 inhibitor, on peripheral blood mononuclear cells (PBMCs), regulatory T (Treg) cells and fibroblast-like-synoviocytes (FLSs) of RA patients in vitro and on development of arthritis in animal model. Methods: After 24 hours activation with LPS in the increasing concentrations of CKD-H059, TNF-α, IL-1β, IL-6 and IL-10 production of RA PBMC were assessed. Regulatory T cells (iTreg) were induced from naive CD4+ T cells of RA patients. CFSE labeled effector T cells (Teff) from healthy subjects were co-cultured with iTreg in the increasing concentrations of CKD-H059 and Teff proliferation was analyzed by flow cytometry. After activation with IL-1β in the increasing concentrations of CKD-H059, MMP-1, MMP-3, IL-6 and IL-8 production of RA-FLS were assessed. Cytoplasmic acetylation of α-tubulin in the activated RA-FLS was visualized by confocal microscopy. Rats with adjuvant-induced arthritis (AIA) were treated with oral CKD-H059 (3, 10, 30, 50, 100 mg/kg) once a day and the severity of arthritis was assessed on 9, 13, and 16 days. Result: CKD-H059 decreased TNF-α and increased IL-10 of RA PBMCs without impact on cell viability. In the presence of CKD-H059, iTreg efficiently inhibited the proliferation of Teff in a dose dependent manner. CKD-H059 inhibited MMP-1, MMP-3, IL-6 and IL-8 and induced acetylation of α-tubulin in cytoskeleton with subsequent cell morphology change. In AIA rat, oral CKD-H059 was able to prevent the development of clinical arthritis in a dose-dependent manner. Conclusion: The novel HDAC6 inhibitor CKD-H059 inhibits the inflammatory response in PBMCs and FLS of RA and restores Treg cell function. CKD-H059 ameliorates arthritis severity in animal model. Therefore, CKD-H059 might offer a novel treatment option for RA. | - |
dc.description.tableofcontents | Introduction 7
Materials and methods 10 Results 16 Discussion 29 References 33 Abstract of Korean 39 | - |
dc.format | application/pdf | - |
dc.format.extent | 1055227 bytes | - |
dc.format.medium | application/pdf | - |
dc.language.iso | en | - |
dc.publisher | 서울대학교 융합과학기술대학원 | - |
dc.subject | RA | - |
dc.subject | HDAC inhibitor | - |
dc.subject | CKD-H059 | - |
dc.subject | PBMC | - |
dc.subject | Treg cells | - |
dc.subject | FLS | - |
dc.subject.ddc | 610 | - |
dc.title | Therapeutic effects of CKD-H059, a novel histone deacetylase 6 inhibitor, in rheumatoid arthritis | - |
dc.type | Thesis | - |
dc.description.degree | Master | - |
dc.citation.pages | 40 | - |
dc.contributor.affiliation | 융합과학기술대학원 분자의학 및 바이오제약학과 | - |
dc.date.awarded | 2016-02 | - |
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