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7‐Methoxy‐(9H‐β‐Carbolin‐1‐il)‐( E )‐1‐Propenoic Acid, a β‐Carboline Alkaloid From Eurycoma longifolia , Exhibits Anti‐Inflammatory Effects by Activating the Nrf2/Heme Oxygenase‐1 Pathway
Author(s) -
Hai Dang Nguyen,
Choo YoungYeon,
Tien Dat Nguyen,
Hoai Nam Nguyen,
Van Minh Chau,
Lee JeongHyung
Publication year - 2016
Publication title -
journal of cellular biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.028
H-Index - 165
eISSN - 1097-4644
pISSN - 0730-2312
DOI - 10.1002/jcb.25315
Subject(s) - heme oxygenase , p38 mitogen activated protein kinases , mcpa , nitric oxide synthase , chemistry , mapk/erk pathway , nitric oxide , pharmacology , gene knockdown , signal transduction , microbiology and biotechnology , biochemistry , biology , heme , apoptosis , enzyme , organic chemistry , pesticide , agronomy
ABSTRACT Eurycoma longifolia is an herbal medicinal plant popularly used in Southeast Asian countries. In the present study, we show that 7‐methoxy‐(9H‐β‐carbolin‐1‐il)‐( E )‐1‐propenoic acid (7‐MCPA), a β‐carboline alkaloid isolated from E. longifolia , exerted anti‐inflammatory effects by activating the nuclear factor‐E2‐related factor 2 (Nrf2)/heme oxygenase‐1 (HO‐1) pathway. 7‐MCPA inhibited lipopolysaccharide (LPS)‐induced production of nitric oxide (NO), prostaglandin E 2 (PGE 2 ), and interleukin‐6 (IL‐6) in RAW264.7 cells and rescued C57BL/6 mice from LPS‐induced lethality in vivo. LPS‐induced expression of inducible nitric oxide synthase (iNOS), cyclooxygenase‐2 (COX‐2), and IL‐6 was also significantly suppressed by treatment of 7‐MCPA in RAW264.7 cells. 7‐MCPA induced nuclear translocation of Nrf2 and increased transcription of its target genes, such as HO‐1. Treating RAW264.7 cells with 7‐MCPA increased the intracellular level of reactive oxygen species (ROS) and the phosphorylation level of p38 mitogen‐activated protein kinase (MAPK); however, co‐treatment with the antioxidant N‐acetyl‐cysteine (NAC) blocked 7‐MCPA‐induced p38 MAPK phosphorylation. Moreover, NAC or SB203580 (p38 MAPK inhibitor) blocked 7‐MCPA‐induced nuclear translocation of Nrf2, suggesting that 7‐MCPA activated Nrf2 via a ROS‐dependent p38 pathway. 7‐MCPA induced HO‐1 protein and mRNA expression and knockdown of Nrf2 with siRNA or SB203580 blocked 7‐MCPA‐mediated induction of HO‐1 expression. Inhibiting Nrf2 or HO‐1 abrogated the anti‐inflammatory effects of 7‐MCPA in LPS‐stimulated RAW264.7 cells. We also demonstrated that 7‐MCPA suppressed LPS‐induced nuclear factor κB (NF‐κB) activation. These results provide the first evidence that 7‐MCPA exerts its anti‐inflammatory effect by modulating the Nrf2 and NF‐κB pathways and may be a potential Nrf2 activator to prevent or treat inflammatory diseases. J. Cell. Biochem. 117: 659–670, 2016. © 2015 Wiley Periodicals, Inc.