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Potent anti-inflammatory activity of novel microtubule-modulating brominated noscapine analogs.

Zughaier S, Karna P, Stephens D, Aneja R - PLoS ONE (2010)

Bottom Line: Noscapine, a plant-derived, non-toxic, over-the-counter antitussive alkaloid has tubulin-binding properties.Brominated noscapine analogs were found to inhibit cytokine and chemokine release from macrophage cell lines but did not affect cell viability.This study is the first report to identify brominated noscapines as innate immune pathway anti-inflammatory molecules.

View Article: PubMed Central - PubMed

Affiliation: Division of Infectious Diseases, Emory University School of Medicine, Atlanta, Georgia, United States of America. szughai@emory.edu

ABSTRACT
Noscapine, a plant-derived, non-toxic, over-the-counter antitussive alkaloid has tubulin-binding properties. Based upon the structural resemblance of noscapine to colchicine, a tubulin-binding anti-inflammatory drug, noscapine and its semi-synthetic brominated analogs were examined for in vitro anti-inflammatory activity. Brominated noscapine analogs were found to inhibit cytokine and chemokine release from macrophage cell lines but did not affect cell viability. Brominated noscapine analogs demonstrated anti-inflammatory properties in both TLR- and non-TLR induced in vitro innate immune pathway inflammation models, mimicking septic and sterile infection respectively. In addition, electron microscopy and immunoblotting data indicated that these analogs induced robust autophagy in human macrophages. This study is the first report to identify brominated noscapines as innate immune pathway anti-inflammatory molecules.

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Related in: MedlinePlus

Schematic presentation of TLR4/MD-2 induced inflammation and hypothetical mode of action for the drug induced anti-inflammatory effect.Brominated noscapine analogs exert anti-inflammatory effect by interfering with targets either at 1-cell surface receptor ligation, 2- abrogating signal transduction by attenuating microtubule dynamics and/or by inducing autophagy, 3-inhibiting gene transcription in the nucleus. TLR4/MD-2 signaling model is adapted from Park et al., 2009 [36] and the embedded images are from the current study.
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pone-0009165-g009: Schematic presentation of TLR4/MD-2 induced inflammation and hypothetical mode of action for the drug induced anti-inflammatory effect.Brominated noscapine analogs exert anti-inflammatory effect by interfering with targets either at 1-cell surface receptor ligation, 2- abrogating signal transduction by attenuating microtubule dynamics and/or by inducing autophagy, 3-inhibiting gene transcription in the nucleus. TLR4/MD-2 signaling model is adapted from Park et al., 2009 [36] and the embedded images are from the current study.

Mentions: In summary, brominated noscapine analogs display innate anti-inflammatory activity without affecting cell viability. Our data suggest that non-toxic brominated noscapine analogs perhaps inhibit the pro-inflammatory responses by inducing autophagy that dampens inflammation by attenuating or recycling the inflammatory signaling complex. Brominated noscapine analogs attenuate microtubule dynamics without altering the monomer/polymer ratio of tubulin [6], [32]. Thus, the anti-inflammatory effect of these non-toxic brominated noscapine analogs may also be due to a direct affect on tubulin and the associated slow dynamics might consequently dampen signal transduction or delay/impede protein transcription. Our hypothetical mechanism for anti-inflammatory mode of action of the brominated noscapine analogs is illustrated in a schematic model (Figure 9). These novel drugs may serve as useful tools to study the involvement of the microtubular system in inflammatory signaling.


Potent anti-inflammatory activity of novel microtubule-modulating brominated noscapine analogs.

Zughaier S, Karna P, Stephens D, Aneja R - PLoS ONE (2010)

Schematic presentation of TLR4/MD-2 induced inflammation and hypothetical mode of action for the drug induced anti-inflammatory effect.Brominated noscapine analogs exert anti-inflammatory effect by interfering with targets either at 1-cell surface receptor ligation, 2- abrogating signal transduction by attenuating microtubule dynamics and/or by inducing autophagy, 3-inhibiting gene transcription in the nucleus. TLR4/MD-2 signaling model is adapted from Park et al., 2009 [36] and the embedded images are from the current study.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2820095&req=5

pone-0009165-g009: Schematic presentation of TLR4/MD-2 induced inflammation and hypothetical mode of action for the drug induced anti-inflammatory effect.Brominated noscapine analogs exert anti-inflammatory effect by interfering with targets either at 1-cell surface receptor ligation, 2- abrogating signal transduction by attenuating microtubule dynamics and/or by inducing autophagy, 3-inhibiting gene transcription in the nucleus. TLR4/MD-2 signaling model is adapted from Park et al., 2009 [36] and the embedded images are from the current study.
Mentions: In summary, brominated noscapine analogs display innate anti-inflammatory activity without affecting cell viability. Our data suggest that non-toxic brominated noscapine analogs perhaps inhibit the pro-inflammatory responses by inducing autophagy that dampens inflammation by attenuating or recycling the inflammatory signaling complex. Brominated noscapine analogs attenuate microtubule dynamics without altering the monomer/polymer ratio of tubulin [6], [32]. Thus, the anti-inflammatory effect of these non-toxic brominated noscapine analogs may also be due to a direct affect on tubulin and the associated slow dynamics might consequently dampen signal transduction or delay/impede protein transcription. Our hypothetical mechanism for anti-inflammatory mode of action of the brominated noscapine analogs is illustrated in a schematic model (Figure 9). These novel drugs may serve as useful tools to study the involvement of the microtubular system in inflammatory signaling.

Bottom Line: Noscapine, a plant-derived, non-toxic, over-the-counter antitussive alkaloid has tubulin-binding properties.Brominated noscapine analogs were found to inhibit cytokine and chemokine release from macrophage cell lines but did not affect cell viability.This study is the first report to identify brominated noscapines as innate immune pathway anti-inflammatory molecules.

View Article: PubMed Central - PubMed

Affiliation: Division of Infectious Diseases, Emory University School of Medicine, Atlanta, Georgia, United States of America. szughai@emory.edu

ABSTRACT
Noscapine, a plant-derived, non-toxic, over-the-counter antitussive alkaloid has tubulin-binding properties. Based upon the structural resemblance of noscapine to colchicine, a tubulin-binding anti-inflammatory drug, noscapine and its semi-synthetic brominated analogs were examined for in vitro anti-inflammatory activity. Brominated noscapine analogs were found to inhibit cytokine and chemokine release from macrophage cell lines but did not affect cell viability. Brominated noscapine analogs demonstrated anti-inflammatory properties in both TLR- and non-TLR induced in vitro innate immune pathway inflammation models, mimicking septic and sterile infection respectively. In addition, electron microscopy and immunoblotting data indicated that these analogs induced robust autophagy in human macrophages. This study is the first report to identify brominated noscapines as innate immune pathway anti-inflammatory molecules.

Show MeSH
Related in: MedlinePlus