Effective suppression of nitric oxide production by HX106N through transcriptional control of heme oxygenase-1

• Published in: Experimental biology and medicine (Maywood, N.J.) N.J.), 2015-09, Vol.240 (9), p.1136-1146
• Main Authors: Suk Lee, Doo, Kim, Binna N., Lim, Seonung, Lee, Junsub, Kim, Jiyoung, Jeong, Jae-Gyun, Kim, Sunyoung
• Format: Article
• Language: English
• Subjects: Animals; Antioxidants - pharmacology; Carbon Monoxide - metabolism; Cell Line; Gene Knockdown Techniques; Heme Oxygenase-1 - genetics; MAP Kinase Signaling System - drug effects; Mice; Microglia - drug effects; Microglia - metabolism; Models, Biological; NF-E2-Related Factor 2 - antagonists & inhibitors; NF-E2-Related Factor 2 - genetics; NF-E2-Related Factor 2 - metabolism; NF-kappa B - metabolism; Nitric Oxide - biosynthesis; Original Research; Plant Extracts - pharmacology; RNA, Small Interfering - genetics; Signal Transduction - drug effects; Transcription Factor AP-1 - metabolism; Transcription, Genetic - drug effects; Up-Regulation - drug effects
• ISSN: 1535-3702; 1535-3699
• DOI: 10.1177/1535370214567612

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.