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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

Noscapine analogs enhanced ROS release. ROS release from THP-1 macrophages primed with LPS (1 pM) overnight.Noscapine analogs (50 µM) were added just prior to a respiratory burst triggered with PMA (1 µM). ROS release was detected with the chemiluminescent probe lucigenin. p values were calculated with reference to no drug but LPS treated cells and were <0.002.
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pone-0009165-g008: Noscapine analogs enhanced ROS release. ROS release from THP-1 macrophages primed with LPS (1 pM) overnight.Noscapine analogs (50 µM) were added just prior to a respiratory burst triggered with PMA (1 µM). ROS release was detected with the chemiluminescent probe lucigenin. p values were calculated with reference to no drug but LPS treated cells and were <0.002.

Mentions: Oxidative and respiratory burst are vital cellular functions that play an important role in homeostasis and host defense. Oxidative burst leads to the release of highly reactive oxygen species (ROS) radicals. We have previously shown that brominated noscapine analog induces a mitochondrially-driven intrinsic apoptotic cascade by dissipation of the mitochondrial membrane potential [9], [10]. Since changes in mitochondrial membrane potential are usually associated with increases in ROS release [31], the effects of brominated noscapine analogs on ROS release from LPS-primed human macrophages were investigated using an enhanced chemiluminescence method [22]. The results showed that both noscapine and its brominated analogs enhanced ROS release in LPS primed cells when added just prior to triggering the respiratory burst, but not in unprimed macrophages (Figure 8). In contrast, no change in ROS release was seen when noscapine or its analogs were added to primed macrophages 2 hr prior to triggering the respiratory burst (data not shown). The data suggest that the enhanced ROS release from primed macrophages may perhaps be due to effects of the drug on mitochondrial membrane potential rather than cellular signaling and macrophage priming.


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

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

Noscapine analogs enhanced ROS release. ROS release from THP-1 macrophages primed with LPS (1 pM) overnight.Noscapine analogs (50 µM) were added just prior to a respiratory burst triggered with PMA (1 µM). ROS release was detected with the chemiluminescent probe lucigenin. p values were calculated with reference to no drug but LPS treated cells and were <0.002.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0009165-g008: Noscapine analogs enhanced ROS release. ROS release from THP-1 macrophages primed with LPS (1 pM) overnight.Noscapine analogs (50 µM) were added just prior to a respiratory burst triggered with PMA (1 µM). ROS release was detected with the chemiluminescent probe lucigenin. p values were calculated with reference to no drug but LPS treated cells and were <0.002.
Mentions: Oxidative and respiratory burst are vital cellular functions that play an important role in homeostasis and host defense. Oxidative burst leads to the release of highly reactive oxygen species (ROS) radicals. We have previously shown that brominated noscapine analog induces a mitochondrially-driven intrinsic apoptotic cascade by dissipation of the mitochondrial membrane potential [9], [10]. Since changes in mitochondrial membrane potential are usually associated with increases in ROS release [31], the effects of brominated noscapine analogs on ROS release from LPS-primed human macrophages were investigated using an enhanced chemiluminescence method [22]. The results showed that both noscapine and its brominated analogs enhanced ROS release in LPS primed cells when added just prior to triggering the respiratory burst, but not in unprimed macrophages (Figure 8). In contrast, no change in ROS release was seen when noscapine or its analogs were added to primed macrophages 2 hr prior to triggering the respiratory burst (data not shown). The data suggest that the enhanced ROS release from primed macrophages may perhaps be due to effects of the drug on mitochondrial membrane potential rather than cellular signaling and macrophage priming.

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