The Experts below are selected from a list of 69 Experts worldwide ranked by ideXlab platform

Qiang Chen - One of the best experts on this subject based on the ideXlab platform.

  • structure of a Benzylidene Derivative of 9 10h anthracenone in complex with tubulin provides a rationale for drug design
    Biochemical and Biophysical Research Communications, 2018
    Co-Authors: Jie Cheng, Yangping Wu, Yuxi Wang, Chengdi Wang, Yanyan Wang, Chengyong Wu, Shaoxue Zeng, Yamei Yu, Qiang Chen
    Abstract:

    Abstract Microtubules are composed of αβ-tubulin heterodimers and have been treated as highly attractive targets for antitumor drugs. A broad range of agents bind to tubulin and interfere with microtubule assembly, including colchicine binding site inhibitors (CBSIs). Tubulin Polymerization Inhibitor I (TPI1), a Benzylidene Derivative of 9(10H)-anthracenone, is a CBSI that inhibits the assembly of microtubules. However, for a long time, the design and development of anthracenone family drugs have been hindered by the lack of structural information of the tubulin-agent complex. Here we report a 2.3 A crystal structure of tubulin complexed with TPI1, the first structure of anthracenone family agents. This complex structure reveals the interactions between TPI1 and tubulin, and thus provides insights into the development of new anthracenone Derivatives targeting the colchicine binding site.

Yo Mori - One of the best experts on this subject based on the ideXlab platform.

  • effect of a Benzylidene Derivative novel antirheumatic agent on the production of tissue inhibitor of metalloproteinases
    Biological & Pharmaceutical Bulletin, 1994
    Co-Authors: Koju Watanabe, Haruhisa Hayashi, Yo Mori
    Abstract:

    We investigated the effects of PAL (protocatechualdehyde), a metabolite of ACP (3, 4-diacetoxy Benzylidene diacetate) which is a candidate as a novel antirheumatic agent, on the production of a tissue inhibitor of metalloproteinases (TIMP) using a primary chondrocyte culture from bovine nasal septum cartilage.The addition of human recombinant interleukin-1α (hrIL-1α) induced proteoglycan (PG) depletion from a chondrocyte matrix. PAL significantly reduced the induction of PG depletion. HrIL-1α increased the casein-degrading activity, matrix metalloproteinase (MMP) activity, and the level of TIMP secretion in the culture media. PAL significantly reduced the casein-degrading activity and further increased TIMP secretion under hrIL-1α stimulation. Phorbol myristate acetate (PMA) also increased the level of TIMP secretion, and staurosporine, a specific inhibitor of protein kinase C (PKC), reduced the TIMP secretion to the control level under hrIL-1α or PMA stimulation. Furthermore, PAL showed a significant increase following treatment with a low concentration of PMA which alone did not increase TIMP production. These findings suggest that the activation of the PKC pathway plays an important role in TIMP production and that PAL increases the level of TIMP production through an additive or synergistic effect with the activation of the PKC pathway.In conclusion, these findings demonstrate that the inhibition of the MMP activity and the increase of TIMP production by PAL contribute to the inhibition of PG depletion in a primary chondrocyte culture from bovine nasal septum cartilage.

  • effect of a Benzylidene Derivative a novel antirheumatic agent on il 1 production
    Pharmacological Research, 1993
    Co-Authors: Koju Watanabe, Haruhisa Hayashi, Yo Mori
    Abstract:

    Abstract 3,4-Diacetoxy Benzylidene diacetate (ACP) is a prodrug of protocatechualdehyde (PAL). PAL significantly inhibited interleukin-1 (IL-1) production and release in human monocytes in a dose dependent fashion under lipopolysaccharide (LPS) stimulation. ACP showed inhibitory effects on cartilage destruction of the femoral condyles induced by adjuvant arthritis in vivo in a significant and dose dependent fashion. To clarify the mechanism of action of ACP on rat adjuvant arthritis, we investigated the effects of PAL, a metabolite of ACP, on IL-1 production using synovial cell cultures derived from patients with rheumatoid arthritis. PAL significantly inhibited the IL-1β production induced by IL-1α or PMA without inhibition of total protein synthesis and cytotoxicity. A protein kinase C (PKC) inhibitor, staurosporine, also suppressed the IL-1β production induced by IL-1 α or PMA, suggesting that the PKC pathway plays an important role in IL-1 α-induced IL-1β production. The calcium ionophore A23187 (A23187) potentiated the IL- 1β production induced by IL-1α. Whereas PAL slightly inhibited under these conditions, it was not statistically significant. These results suggest that PAL has a favourable action on cartilage destruction through the inhibition of IL-1 production induced by the modification of the PKC pathway.

Koju Watanabe - One of the best experts on this subject based on the ideXlab platform.

  • effect of a Benzylidene Derivative novel antirheumatic agent on the production of tissue inhibitor of metalloproteinases
    Biological & Pharmaceutical Bulletin, 1994
    Co-Authors: Koju Watanabe, Haruhisa Hayashi, Yo Mori
    Abstract:

    We investigated the effects of PAL (protocatechualdehyde), a metabolite of ACP (3, 4-diacetoxy Benzylidene diacetate) which is a candidate as a novel antirheumatic agent, on the production of a tissue inhibitor of metalloproteinases (TIMP) using a primary chondrocyte culture from bovine nasal septum cartilage.The addition of human recombinant interleukin-1α (hrIL-1α) induced proteoglycan (PG) depletion from a chondrocyte matrix. PAL significantly reduced the induction of PG depletion. HrIL-1α increased the casein-degrading activity, matrix metalloproteinase (MMP) activity, and the level of TIMP secretion in the culture media. PAL significantly reduced the casein-degrading activity and further increased TIMP secretion under hrIL-1α stimulation. Phorbol myristate acetate (PMA) also increased the level of TIMP secretion, and staurosporine, a specific inhibitor of protein kinase C (PKC), reduced the TIMP secretion to the control level under hrIL-1α or PMA stimulation. Furthermore, PAL showed a significant increase following treatment with a low concentration of PMA which alone did not increase TIMP production. These findings suggest that the activation of the PKC pathway plays an important role in TIMP production and that PAL increases the level of TIMP production through an additive or synergistic effect with the activation of the PKC pathway.In conclusion, these findings demonstrate that the inhibition of the MMP activity and the increase of TIMP production by PAL contribute to the inhibition of PG depletion in a primary chondrocyte culture from bovine nasal septum cartilage.

  • effect of a Benzylidene Derivative a novel antirheumatic agent on il 1 production
    Pharmacological Research, 1993
    Co-Authors: Koju Watanabe, Haruhisa Hayashi, Yo Mori
    Abstract:

    Abstract 3,4-Diacetoxy Benzylidene diacetate (ACP) is a prodrug of protocatechualdehyde (PAL). PAL significantly inhibited interleukin-1 (IL-1) production and release in human monocytes in a dose dependent fashion under lipopolysaccharide (LPS) stimulation. ACP showed inhibitory effects on cartilage destruction of the femoral condyles induced by adjuvant arthritis in vivo in a significant and dose dependent fashion. To clarify the mechanism of action of ACP on rat adjuvant arthritis, we investigated the effects of PAL, a metabolite of ACP, on IL-1 production using synovial cell cultures derived from patients with rheumatoid arthritis. PAL significantly inhibited the IL-1β production induced by IL-1α or PMA without inhibition of total protein synthesis and cytotoxicity. A protein kinase C (PKC) inhibitor, staurosporine, also suppressed the IL-1β production induced by IL-1 α or PMA, suggesting that the PKC pathway plays an important role in IL-1 α-induced IL-1β production. The calcium ionophore A23187 (A23187) potentiated the IL- 1β production induced by IL-1α. Whereas PAL slightly inhibited under these conditions, it was not statistically significant. These results suggest that PAL has a favourable action on cartilage destruction through the inhibition of IL-1 production induced by the modification of the PKC pathway.

  • effect of Benzylidene Derivative novel antirheumatic agent on chondrocyte metabolism
    Journal of pharmacobio-dynamics, 1992
    Co-Authors: Koju Watanabe, Fumihiko Kimura, Masayuki Shinmei
    Abstract:

    The effects of protocatechualdehyde (PAL), one of the metabolites of 3, 4-diacetoxy Benzylidene diacetate (ACP), on proteogylcan metabolism and secretion of interleukin 1 (IL-1) like activity (lymphocyte activating factor ; LAF activity) were studied using rabbit articular chondrocytes culture under phorbol myristate acetate (PMA) and Ca2+ ionophore A23187 (A23187) or IL-1α stimulation. In IL-1α (20 u/ml) or PMA (0.1 μg/ml) and A23187 (0.2 μg/ml) treated culture of rabbit articular chondrocytes, PAL significantly reduced the degradation of 35S-proteoglycan (35S-PG) from the cells and matrix layers into the culture media in a dose dependent fashion without affecting proteoglycan synthesis. Similarly, the secretion or production of matrix metalloproteinases which degrade proteoglycans was also inhibited to the same extent under IL-1α stimulated condition. However, PAL caused no effect on the secretion of IL-1 like activity by chondrocytes. These results suggest that an attractive candidate for an anti-inflammatory drug, ACP, which is a prodrug of PAL, has also a favorable action on chondrocyte metabolism in terms of proteoglycan degradation via inhibition of matrix metalloproteinases secretion or production.

Jie Cheng - One of the best experts on this subject based on the ideXlab platform.

  • structure of a Benzylidene Derivative of 9 10h anthracenone in complex with tubulin provides a rationale for drug design
    Biochemical and Biophysical Research Communications, 2018
    Co-Authors: Jie Cheng, Yangping Wu, Yuxi Wang, Chengdi Wang, Yanyan Wang, Chengyong Wu, Shaoxue Zeng, Yamei Yu, Qiang Chen
    Abstract:

    Abstract Microtubules are composed of αβ-tubulin heterodimers and have been treated as highly attractive targets for antitumor drugs. A broad range of agents bind to tubulin and interfere with microtubule assembly, including colchicine binding site inhibitors (CBSIs). Tubulin Polymerization Inhibitor I (TPI1), a Benzylidene Derivative of 9(10H)-anthracenone, is a CBSI that inhibits the assembly of microtubules. However, for a long time, the design and development of anthracenone family drugs have been hindered by the lack of structural information of the tubulin-agent complex. Here we report a 2.3 A crystal structure of tubulin complexed with TPI1, the first structure of anthracenone family agents. This complex structure reveals the interactions between TPI1 and tubulin, and thus provides insights into the development of new anthracenone Derivatives targeting the colchicine binding site.

Wing-hong Lo - One of the best experts on this subject based on the ideXlab platform.