title: Effective suppression of nitric oxide production by HX106N through transcriptional control of heme oxygenase-1.
abstract: Heme oxygenase-1 (HO-1) has been suggested to be a key neuroprotective enzyme because of its widespread distribution in the brain as well as its strong antioxidative effects. HX106N, a water-soluble botanical formulation, has previously been demonstrated to prevent amyloid β-induced memory impairment and oxidative stress in mice by upregulating HO-1 levels. In this study, the underlying molecular mechanisms of HX106N-induced HO-1 expression were investigated using BV-2 cells, a murine microglial cell line, and primary microglia. Treatment with HX106N induced the expression of HO-1 at the transcriptional level through the stress-responsive element-containing enhancer present in the ho-1 promoter. Nuclear factor E2-related factor 2 (Nrf2) was activated in cells treated with HX106N. The results from knockdown assay showed that small interfering RNA of Nrf2 attenuated HX106N-mediated HO-1 expression. Pharmacological inhibitors of p38 and JNK mitogen-activated protein kinases suppressed the HX106N-mediated induction of HO-1. The NF-κB signaling pathway was activated by HX106N and played a role in HX106N-induced HO-1 expression. Furthermore, HO-1 and one of its by-products during the enzymatic degradation of heme, CO, were found to be involved in HX106N-mediated suppression of NO production. Taken together, these data indicate that HX106N exerts potent antioxidative effects by increasing the expression of HO-1 through multiple signaling pathways, leading to the suppression of NO production.
authors.affiliation: School of Biological Sciences, Seoul National University, Seoul 151-742, Korea ViroMed Co., Ltd., Seoul 151-747, Korea.
authors.forename: Doo
authors.initials: D
authors.lastname: Suk Lee
authors.affiliation: Interdisciplinary Program in Neuroscience, College of Natural Sciences, Seoul National University, Seoul 151-742, Korea.
authors.forename: Binna N
authors.initials: BN
authors.lastname: Kim
authors.affiliation: School of Biological Sciences, Seoul National University, Seoul 151-742, Korea.
authors.forename: Seonung
authors.initials: S
authors.lastname: Lim
authors.affiliation: School of Biological Sciences, Seoul National University, Seoul 151-742, Korea.
authors.forename: Junsub
authors.initials: J
authors.lastname: Lee
authors.affiliation: School of Biological Sciences, Seoul National University, Seoul 151-742, Korea Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul 151-742, Korea.
authors.forename: Jiyoung
authors.initials: J
authors.lastname: Kim
authors.affiliation: ViroMed Co., Ltd., Seoul 151-747, Korea.
authors.forename: Jae-Gyun
authors.initials: JG
authors.lastname: Jeong
authors.affiliation: School of Biological Sciences, Seoul National University, Seoul 151-742, Korea ViroMed Co., Ltd., Seoul 151-747, Korea sunyoung@snu.ac.kr.
authors.forename: Sunyoung
authors.initials: S
authors.lastname: Kim
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D002248:Carbon Monoxide / Q000378:metabolism; D002460:Cell Line; D055785:Gene Knockdown Techniques; D051547:Heme Oxygenase-1 / Q000235:genetics*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D017628:Microglia / Q000187:drug effects / Q000378:metabolism; D008954:Models, Biological; D051267:NF-E2-Related Factor 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009569:Nitric Oxide / Q000096:biosynthesis*; D010936:Plant Extracts / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000975:Antioxidants; C000594602:HX106N; D051267:NF-E2-Related Factor 2; D016328:NF-kappa B; C495636:Nfe2l2 protein, mouse; D010936:Plant Extracts; D034741:RNA, Small Interfering; D018808:Transcription Factor AP-1; D009569:Nitric Oxide; D002248:Carbon Monoxide; D051547:Heme Oxygenase-1
keywords: HX106N; NF-κB; heme oxygenase-1; nitric oxide; nuclear factor E2-related factor 2