title: Mulberrofuran G Protects Ischemic Injury-induced Cell Death via Inhibition of NOX4-mediated ROS Generation and ER Stress.
abstract: The aim of this study was to investigate the neuroprotective effect of mulberrofuran G (MG) in in vitro and in vivo models of cerebral ischemia. MG was isolated from the root bark of Morus bombycis. MG inhibited nicotinamide adenine dinucleotide phosphate oxidase (NOX) enzyme activity and oxygen-glucose deprivation/reoxygenation (OGD/R)-induced NOX4 protein expression in SH-SY5Y cells. MG inhibited the expression of activated caspase-3 and caspase-9 and cleaved poly adenine dinucleotide phosphate-ribose polymerase in OGD/R-induced SH-SY5Y cells. In addition, MG protected OGD/R-induced neuronal cell death and inhibited OGD/R-induced reactive oxygen species generation in SH-SY5Y cells. In in vivo model, MG-treated groups (0.2, 1, and 5 mg/kg) reduced the infarct volume in middle cerebral artery occlusion/reperfusion-induced ischemic rats. The MG-treated groups also reduced NOX4 protein expression in middle cerebral artery occlusion/reperfusion-induced ischemic rats. Furthermore, protein expression of 78-kDa glucose-regulated protein/binding immunoglobulin protein, phosphorylated IRE1α, X-box-binding protein 1, and cytosine enhancer binding protein homologous protein, mediators of endoplasmic reticulum stress, were inhibited in MG-treated groups. Taken together, MG showed protective effect in in vitro and in vivo models of cerebral ischemia through inhibition of NOX4-mediated reactive oxygen species generation and endoplasmic reticulum stress. This finding will give an insight that inhibition of NOX enzyme activity and NOX4 protein expression could be a new potential therapeutic strategy for cerebral ischemia. Copyright © 2016 John Wiley & Sons, Ltd.
authors.affiliation: Natural Products Research Institute, College of Pharmacy, Seoul National University, Seoul, 08826, Korea.
authors.forename: Sungeun
authors.initials: S
authors.lastname: Hong
authors.affiliation: Department of Biosystems and Biotechnology, Korea University, Seoul, 02841, Korea.
authors.forename: Jaeyoung
authors.initials: J
authors.lastname: Kwon
authors.affiliation: Natural Products Research Institute, College of Pharmacy, Seoul National University, Seoul, 08826, Korea.
authors.forename: Dong-Woo
authors.initials: DW
authors.lastname: Kim
authors.affiliation: Division of Wood Chemistry and Microbiology, Department of Forest Products, Korea Forest Research Institute, Seoul, 02455, Korea.
authors.forename: Hak Ju
authors.initials: HJ
authors.lastname: Lee
authors.affiliation: Department of Biosystems and Biotechnology, Korea University, Seoul, 02841, Korea.
authors.forename: Dongho
authors.initials: D
authors.lastname: Lee
authors.affiliation: Natural Products Research Institute, College of Pharmacy, Seoul National University, Seoul, 08826, Korea.
authors.forename: Woongchon
authors.initials: W
authors.lastname: Mar
mesh_terms: D000818:Animals; D001572:Benzofurans / Q000737:chemistry* / Q000627:therapeutic use; D002545:Brain Ischemia / Q000188:drug therapy*; D016923:Cell Death; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D008297:Male; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species; D015398:Signal Transduction; D013729:Terpenes / Q000737:chemistry* / Q000627:therapeutic use
chemical_list: D001572:Benzofurans; D018696:Neuroprotective Agents; D017382:Reactive Oxygen Species; D013729:Terpenes; C047825:mulberrofuran G; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C498910:NOX4 protein, human
keywords: NADPH oxidase; endoplasmic reticulum stress; middle cerebral artery occlusion/reperfusion; mulberrofuran G; neuroprotection; oxygen-glucose deprivation/reoxygenation