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Biochem Pharmacol. 2014 Sep 1;91(1):40-50. doi: 10.1016/j.bcp.2014.06.024. Epub 2014 Jul 3.

Andrographolide inhibits TNFα-induced ICAM-1 expression via suppression of NADPH oxidase activation and induction of HO-1 and GCLM expression through the PI3K/Akt/Nrf2 and PI3K/Akt/AP-1 pathways in human endothelial cells.

Author information

1
Department of Nutrition, China Medical University, Taichung 404, Taiwan.
2
Department of Health and Nutrition Biotechnology, Asia University, Taichung 413, Taiwan.
3
School of Nutrition, Chung Shan Medical University, Taichung 402, Taiwan; Department of Nutrition, Chung Shan Medical University Hospital, Taichung 402, Taiwan.
4
Department of Nutrition, China Medical University, Taichung 404, Taiwan; Department of Health and Nutrition Biotechnology, Asia University, Taichung 413, Taiwan. Electronic address: cklii@mail.cmu.edu.tw.
5
Department of Nutrition, China Medical University, Taichung 404, Taiwan. Electronic address: chenhw@mail.cmu.edu.tw.

Abstract

Andrographolide, the major bioactive component of Andrographis paniculata, has been demonstrated to have various biological properties including anti-inflammation, antioxidation, and anti-hepatotoxicity. Oxidative stress is considered a major risk factor in aging, inflammation, cancer, atherosclerosis, and diabetes mellitus. NADPH oxidase is a major source of endogenous reactive oxygen species (ROS). In this study, we used EA.hy926 endothelial-like cells to explore the anti-inflammatory activity of andrographolide. Andrographolide attenuated TNFα-induced ROS generation, Src phosphorylation, membrane translocation of the NADPH oxidase subunits p47(phox) and p67(phox), and ICAM-1 gene expression. In the small hairpin RNA interference assay, shp47(phox) abolished TNFα-induced p65 nuclear translocation, ICAM-1 gene expression, and adhesion of HL-60 cells. Andrographolide induced the gene expression of heme oxygenase 1 (HO-1) and glutamate cysteine ligase modifier subunit (GCLM) in a time-dependent manner. Cellular glutathione (GSH) content was increased by andrographolide. shGCLM attenuated the andrographolide-induced increase in GSH content and reversed the andrographolide inhibition of HL-60 adhesion. shHO-1 showed a similar effect on andrographolide inhibition of HL-60 adhesion to shGCLM. The mechanism underlying the up-regulation of HO-1 and GCLM by andrographolide was dependent on the PI3K/Akt pathway, and both the Nrf2 and AP-1 transcriptional factors were involved. Our results suggest that andrographolide attenuates TNFα-induced ICAM-1 expression at least partially through suppression of NADPH oxidase activation and induction of HO-1 and GCLM expression, which is PI3K/Akt pathway-dependent.

KEYWORDS:

Activator protein 1 (AP-1); Glutamate cysteine ligase modifier subunit (GCLM); Heme oxygenase 1 (HO-1); NADPH oxidase; Nuclear factor erythroid 2-related factor 2 (Nrf2)

PMID:
24998495
DOI:
10.1016/j.bcp.2014.06.024
[Indexed for MEDLINE]
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