Arthroprotective Effects of Cf-02 Sharing Structural Similarity with Quercetin

Autor: Hsu Shan Huang, Shiu Bii Lien, Chia Chung Lee, Jeng-Wei Lu, Min Chung Shen, Feng Cheng Liu, Yi Jung Ho, Liv Weichien Chen, Chiao Yun Chien, Jenn Haung Lai, Ling-Jun Ho, Leou Chyr Lin
Jazyk: angličtina
Rok vydání: 2018
Předmět:
0301 basic medicine
rheumatoid arthritis
Swine
chondrocytes
Arthritis
Nitric Oxide Synthase Type II
Pharmacology
Matrix metalloproteinase
Nitric Oxide
Protective Agents
Catalysis
Article
Inorganic Chemistry
Immunomodulation
03 medical and health sciences
chemistry.chemical_compound
Structure-Activity Relationship
0302 clinical medicine
In vivo
Matrix Metalloproteinase 13
medicine
Animals
Physical and Theoretical Chemistry
Cytotoxicity
Molecular Biology
Spectroscopy
Aggrecan
030203 arthritis & rheumatology
biology
Chemistry
Activator (genetics)
Tumor Necrosis Factor-alpha
Organic Chemistry
General Medicine
medicine.disease
Computer Science Applications
Nitric oxide synthase
osteoarthritis
030104 developmental biology
inflammation
biology.protein
Proteoglycans
Quercetin
Collagen
arthritis
small-molecule inhibitor
tumor necrosis factor-alpha
Transcription Factors
Zdroj: International Journal of Molecular Sciences; Volume 19; Issue 5; Pages: 1453
International Journal of Molecular Sciences
ISSN: 1422-0067
DOI: 10.3390/ijms19051453
Popis: In this study, we synthesized hundreds of analogues based on the structure of small-molecule inhibitors (SMIs) that were previously identified in our laboratory with the aim of identifying potent yet safe compounds for arthritis therapeutics. One of the analogues was shown to share structural similarity with quercetin, a potent anti-inflammatory flavonoid present in many different fruits and vegetables. We investigated the immunomodulatory effects of this compound, namely 6-(2,4-difluorophenyl)-3-(3-(trifluoromethyl)phenyl)-2H-benzo[e][1,3]oxazine-2,4(3H)-dione (Cf-02), in a side-by-side comparison with quercetin. Chondrocytes were isolated from pig joints or the joints of patients with osteoarthritis that had undergone total knee replacement surgery. Several measures were used to assess the immunomodulatory potency of these compounds in tumor necrosis factor (TNF-α)-stimulated chondrocytes. Characterization included the protein and mRNA levels of molecules associated with arthritis pathogenesis as well as the inducible nitric oxide synthase (iNOS)–nitric oxide (NO) system and matrix metalloproteinases (MMPs) in cultured chondrocytes and proteoglycan, and aggrecan degradation in cartilage explants. We also examined the activation of several important transcription factors, including nuclear factor-kappaB (NF-κB), interferon regulatory factor-1 (IRF-1), signal transducer and activator of transcription-3 (STAT-3), and activator protein-1 (AP-1). Our overall results indicate that the immunomodulatory potency of Cf-02 is fifty-fold more efficient than that of quercetin without any indication of cytotoxicity. When tested in vivo using the induced edema method, Cf-02 was shown to suppress inflammation and cartilage damage. The proposed method shows considerable promise for the identification of candidate disease-modifying immunomodulatory drugs and leads compounds for arthritis therapeutics.
Databáze: OpenAIRE
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