title: Antagonistic effects of acetylshikonin on LPS-induced NO and PGE2 production in BV2 microglial cells via inhibition of ROS/PI3K/Akt-mediated NF-κB signaling and activation of Nrf2-dependent HO-1.
abstract: Although acetylshikonin (ACS) is known to have antioxidant and antitumor activities, whether ACS regulates the expression of proinflammatory mediators in lipopolysaccharide (LPS)-stimulated microglial cells remains unclear. In this study, it was found that ACS isolated from Lithospermum erythrorhizon inhibits LPS-induced nitric oxide (NO) and prostaglandin E2 (PGE2) release by suppressing the expression of inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2) in BV2 microglial cells. Furthermore, ACS reduced the LPS-induced DNA-binding activity of nuclear factor-κB (NF-κB) and subsequently suppressed iNOS and COX-2 expression. Consistent with these data, ACS attenuated the phosphorylation of PI3K and Akt and suppressed the DNA-binding activity of NF-κB by inducing the generation of reactive oxygen species (ROS) in LPS-stimulated cells. In addition, ACS enhanced heme oxygenase-1 (HO-1) expression via nuclear factor-erythroid 2-related factor 2 (Nrf2) activation. Zinc protoporphyrin, a specific HO-1 inhibitor, partially attenuated the antagonistic effects of ACS on LPS-induced NO and PGE2 production. By contrast, the presence of cobalt protoporphyrin, a specific HO-1 inducer, potently suppressed LPS-induced NO and PGE2 production. These data indicate that ACS downregulates proinflammatory mediators such as NO and PGE2 by suppressing PI3K/Akt-dependent NF-κB activity induced by ROS as well as inducing Nrf2-dependent HO-1 activity. Taken together, ACS might be a good candidate to regulate LPS-mediated inflammatory diseases.
authors.affiliation: Department of Marine Life Sciences, Jeju National University, Jeju, 690-756, Republic of Korea.
authors.forename: Rajapaksha Gedara Prasad Tharanga
authors.initials: RG
authors.lastname: Jayasooriya
authors.affiliation: Division of Wood Chemistry & Microbiology, Department of Forest Products, Korea Forest Research Institute, Seoul, 130-712, Republic of Korea. leekt999@gmail.com.
authors.forename: Kyoung-Tae
authors.initials: KT
authors.lastname: Lee
authors.affiliation: Department of Biochemistry, College of Oriental Medicine, Dongeui University, Busan, 614-051, Republic of Korea. choiyh@deu.ac.kr.
authors.forename: Yung Hyun
authors.initials: YH
authors.lastname: Choi
authors.affiliation: School of Food Science and Technology, Chung-Ang University, Ansung, 456-756, Republic of Korea. skmoon@cjnu.ac.kr.
authors.forename: Sung-Kwon
authors.initials: SK
authors.lastname: Moon
authors.affiliation: Department of Urology, College of Medicine, Chungbuk National University, Cheongju, Chungbuk, 361-763, Republic of Korea. wjkim@cbnu.ac.kr.
authors.forename: Wun-Jae
authors.initials: WJ
authors.lastname: Kim
authors.affiliation: Department of Marine Life Sciences, Jeju National University, Jeju, 690-756, Republic of Korea. immunkim@jejunu.ac.kr.
authors.forename: Gi-Young
authors.initials: GY
authors.lastname: Kim
mesh_terms: D000818:Animals; D000880:Anthraquinones / Q000737:chemistry / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D015232:Dinoprostone / Q000378:metabolism*; D051547:Heme Oxygenase-1 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D017628:Microglia / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000880:Anthraquinones; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D051267:NF-E2-Related Factor 2; D016328:NF-kappa B; C495636:Nfe2l2 protein, mouse; D017382:Reactive Oxygen Species; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D015232:Dinoprostone; C073944:acetylshikonin
keywords: Acetylshikonin; Heme oxygenase-1; Nitric oxide; Nuclear factor-erythroid 2-related factor 2; Nuclear factor-κB; Prostaglandin E2