Arthroprotective effects of Cf-02 sharing structural similarity with quercetin

Feng Cheng Liu, Jeng Wei Lu, Chiao Yun Chien, Hsu Shan Huang, Chia Chung Lee, Shiu Bii Lien, Leou Chyr Lin, Liv Weichien Chen, Yi Jung Ho, Min Chung Shen, Ling Jun Ho, Jenn Haung Lai

研究成果: 雜誌貢獻文章

3 引文 (Scopus)

摘要

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.
原文英語
文章編號1453
期刊International Journal of Molecular Sciences
19
發行號5
DOIs
出版狀態已發佈 - 五月 14 2018

指紋

Quercetin
Nitric oxide
Cartilage
Chondrocytes
arthritis
Arthritis
Knee prostheses
Lead compounds
Interferons
Proteins
Flavonoids
cartilage
Molecules
Transcription factors
Vegetables
Transcription
nitric oxide
Cytotoxicity
Fruits
Joints

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

引用此文

Arthroprotective effects of Cf-02 sharing structural similarity with quercetin. / Liu, Feng Cheng; Lu, Jeng Wei; Chien, Chiao Yun; Huang, Hsu Shan; Lee, Chia Chung; Lien, Shiu Bii; Lin, Leou Chyr; Chen, Liv Weichien; Ho, Yi Jung; Shen, Min Chung; Ho, Ling Jun; Lai, Jenn Haung.

於: International Journal of Molecular Sciences, 卷 19, 編號 5, 1453, 14.05.2018.

研究成果: 雜誌貢獻文章

Liu, FC, Lu, JW, Chien, CY, Huang, HS, Lee, CC, Lien, SB, Lin, LC, Chen, LW, Ho, YJ, Shen, MC, Ho, LJ & Lai, JH 2018, 'Arthroprotective effects of Cf-02 sharing structural similarity with quercetin', International Journal of Molecular Sciences, 卷 19, 編號 5, 1453. https://doi.org/10.3390/ijms19051453
Liu, Feng Cheng ; Lu, Jeng Wei ; Chien, Chiao Yun ; Huang, Hsu Shan ; Lee, Chia Chung ; Lien, Shiu Bii ; Lin, Leou Chyr ; Chen, Liv Weichien ; Ho, Yi Jung ; Shen, Min Chung ; Ho, Ling Jun ; Lai, Jenn Haung. / Arthroprotective effects of Cf-02 sharing structural similarity with quercetin. 於: International Journal of Molecular Sciences. 2018 ; 卷 19, 編號 5.
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abstract = "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.",
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AU - Liu, Feng Cheng

AU - Lu, Jeng Wei

AU - Chien, Chiao Yun

AU - Huang, Hsu Shan

AU - Lee, Chia Chung

AU - Lien, Shiu Bii

AU - Lin, Leou Chyr

AU - Chen, Liv Weichien

AU - Ho, Yi Jung

AU - Shen, Min Chung

AU - Ho, Ling Jun

AU - Lai, Jenn Haung

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N2 - 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.

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