國家衛生研究院 NHRI:Item 3990099045/5973
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    Please use this identifier to cite or link to this item: http://ir.nhri.org.tw/handle/3990099045/5973


    Title: A benzamide-linked small molecule HS-Cf inhibits TNF-alpha-induced interferon regulatory factor-1 in porcine chondrocytes: A potential disease-modifying drug for osteoarthritis Therapeutics
    Other Titles: A benzamide-linked small molecule HS-Cf inhibits TNF-α-Induced interferon regulatory factor-1 in porcine chondrocytes: A potential disease-modifying drug for osteoarthritis Therapeutics
    Authors: Liu, FC;Huang, HS;Huang, CY;Yang, R;Chang, DM;Lai, JH;Ho, LJ
    Contributors: Institute of Cellular and Systems Medicine
    Abstract: Background: Using tumor necrosis factor-alpha (TNF-α)-activated porcine chondrocytes as a screening tool, we aim to synthesize and identify small-molecule inhibitors preserving immunomodulatory effects as therapeutics for osteoarthritis (OA). Methods: Chondrocytes were isolated from pig joints. A minilibrary of 300 benzamide-linked small molecules was established. The levels of inducible nitric oxide synthase (iNOS) and nitric oxide (NO) were measured by Western blot and Griess reaction, respectively. Proteoglycan degradation in cartilage explants was determined by histochemistry analysis. The activation of transcription factors and protein kinases was determined by electrophoretic mobility shift assays or Western blots. Zymography and real-time reverse transcriptase-polymerase chain reaction were used to determine enzyme activity and expression of matrix metalloproteinases (MMPs) and aggrecanases, respectively. Results: Bioassay screening of benzamide-linked small molecules revealed that 2-hydroxy-N-[3-(trifluoromethyl)phenyl]benzamide (HS-Cf) was a potent inhibitor of NO production and iNOS expression in TNF-α-stimulated porcine chondrocytes. HS-Cf suppressed TNF-α-induced activity of MMP-13 and expressions of several aggrecanases and prevented TNF-α-mediated reduction of collagen II. Histochemistry analysis confirmed that HS-Cf could prevent TNF-α-induced degradation and release of proteoglycan/aggrecan in cartilage explants. Such effects by HS-Cf were likely through suppressing TNF-α-induced interferon regulatory factor-1 (IRF-1) but not nuclear factor-kappaB signaling. The significance of IRF-1 was further confirmed by short hairpin knockdown studies. Conclusions: In a minilibrary containing 300 small molecules, we identified a benzamide-linked small molecule, HS-Cf, that through down-regulating TNF-α-induced IRF-1 activity suppressed chondrocyte activation and prevented cartilage destruction. HS-Cf might be a potential disease-modifying drug for OA therapeutics.
    Date: 2011-12
    Relation: Journal of Clinical Immunology. 2011 Dec;31(6):1131-1142.
    Link to: http://dx.doi.org/10.1007/s10875-011-9576-9
    JIF/Ranking 2023: http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=0271-9142&DestApp=IC2JCR
    Cited Times(WOS): https://www.webofscience.com/wos/woscc/full-record/WOS:000297522500023
    Cited Times(Scopus): http://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=84857054809
    Appears in Collections:[Ling-Jun Ho] Periodical Articles

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