PMID- 32654377 OWN - NLM STAT- MEDLINE DCOM- 20210923 LR - 20210923 IS - 1747-0285 (Electronic) IS - 1747-0277 (Linking) VI - 97 IP - 1 DP - 2021 Jan TI - Icaritin activates Nrf2/Keap1 signaling to protect neuronal cells from oxidative stress. PG - 111-120 LID - 10.1111/cbdd.13765 [doi] AB - Our earlier study indicated that icaritin (ICT) protected mice from cerebral ischemic injury by inhibiting oxidative stress, and this study aimed to investigate its mechanism using a H(2) O(2) -treated SH-SY5Y cells model. Cell viability was assessed by cell counting kit 8 (CCK-8). Oxidative stress parameters were detected by flow cytometry, and signaling pathways were analyzed by immunoblotting. We found that ICT alleviated apoptosis and intracellular and mitochondrial reactive oxygen species (ROS) levels, decreased the expressions of Bax and cleaved caspase-3, and increased the expressions of Bcl-2 compared to H(2) O(2) group. ICT increased mitochondrial membrane potential (DeltaPsim) and blocked the opening of mitochondrial membrane permeability transporter (MPT), and increased the activity of glutathione peroxidase (GSH-px), catalase (CAT), and superoxide dismutase (SOD), meanwhile, decreased the activity of malondialdehyde (MDA) compared to H(2) O(2) group. Further investigation revealed that ICT significantly up-regulated the expressions of nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase 1 (HO-1) and NAD(P)H-quinone oxidoreductase 1 (NQO-1). The anti-apoptosis and antioxidative effects of ICT were blocked bay ML385, a Nrf2/Keap1 signaling pathway inhibitor. These results indicate that ICT can play a neuroprotective role against oxidative stress injury by activating Nrf2/Keap1 signaling pathway. CI - (c) 2020 John Wiley & Sons A/S. FAU - Xu, Yuyu AU - Xu Y AD - State Key Laboratory of Generic Manufacture Technology of Chinese Traditional Medicine, Linyi, China. AD - Linyi Key Laboratory for Immunopharmacology and Immunotoxicology of Natural Medicine, Lunan Pharmaceutical Group Co. Ltd., Linyi, China. AD - Lunan Pharmaceutical Group Co. Ltd., Linyi, China. FAU - Lu, Xiaoyan AU - Lu X AD - State Key Laboratory of Generic Manufacture Technology of Chinese Traditional Medicine, Linyi, China. AD - Linyi Key Laboratory for Immunopharmacology and Immunotoxicology of Natural Medicine, Lunan Pharmaceutical Group Co. Ltd., Linyi, China. AD - Lunan Pharmaceutical Group Co. Ltd., Linyi, China. FAU - Zhang, Li AU - Zhang L AD - State Key Laboratory of Generic Manufacture Technology of Chinese Traditional Medicine, Linyi, China. AD - Lunan Pharmaceutical Group Co. Ltd., Linyi, China. FAU - Wang, Lijuan AU - Wang L AD - State Key Laboratory of Generic Manufacture Technology of Chinese Traditional Medicine, Linyi, China. AD - Linyi Key Laboratory for Immunopharmacology and Immunotoxicology of Natural Medicine, Lunan Pharmaceutical Group Co. Ltd., Linyi, China. AD - Lunan Pharmaceutical Group Co. Ltd., Linyi, China. FAU - Zhang, Guimin AU - Zhang G AD - State Key Laboratory of Generic Manufacture Technology of Chinese Traditional Medicine, Linyi, China. AD - Linyi Key Laboratory for Immunopharmacology and Immunotoxicology of Natural Medicine, Lunan Pharmaceutical Group Co. Ltd., Linyi, China. AD - Lunan Pharmaceutical Group Co. Ltd., Linyi, China. FAU - Yao, Jingchun AU - Yao J AD - State Key Laboratory of Generic Manufacture Technology of Chinese Traditional Medicine, Linyi, China. AD - Linyi Key Laboratory for Immunopharmacology and Immunotoxicology of Natural Medicine, Lunan Pharmaceutical Group Co. Ltd., Linyi, China. AD - Lunan Pharmaceutical Group Co. Ltd., Linyi, China. FAU - Sun, Chenghong AU - Sun C AUID- ORCID: 0000-0002-7579-5472 AD - State Key Laboratory of Generic Manufacture Technology of Chinese Traditional Medicine, Linyi, China. AD - Linyi Key Laboratory for Immunopharmacology and Immunotoxicology of Natural Medicine, Lunan Pharmaceutical Group Co. Ltd., Linyi, China. AD - Lunan Pharmaceutical Group Co. Ltd., Linyi, China. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20200726 PL - England TA - Chem Biol Drug Des JT - Chemical biology & drug design JID - 101262549 RN - 0 (Antioxidants) RN - 0 (Flavonoids) RN - 0 (KEAP1 protein, human) RN - 0 (Kelch-Like ECH-Associated Protein 1) RN - 0 (NF-E2-Related Factor 2) RN - 0 (NFE2L2 protein, human) RN - 0 (Reactive Oxygen Species) RN - 0 (bcl-2-Associated X Protein) RN - 4Y8F71G49Q (Malondialdehyde) RN - BBX060AN9V (Hydrogen Peroxide) RN - EC 1.14.14.18 (HMOX1 protein, human) RN - EC 1.14.14.18 (Heme Oxygenase-1) RN - EC 1.15.1.1 (Superoxide Dismutase) RN - EC 1.6.5.2 (NAD(P)H Dehydrogenase (Quinone)) RN - EC 1.6.5.2 (NQO1 protein, human) RN - UFE666UELY (icaritin) SB - IM MH - Antioxidants/chemistry MH - Apoptosis/*drug effects MH - Cell Line, Tumor MH - Cell Survival/drug effects MH - Flavonoids/*pharmacology MH - Heme Oxygenase-1/metabolism MH - Humans MH - Hydrogen Peroxide/pharmacology MH - Kelch-Like ECH-Associated Protein 1/metabolism MH - Malondialdehyde/metabolism MH - Membrane Potential, Mitochondrial/drug effects MH - Mitochondria/metabolism MH - NAD(P)H Dehydrogenase (Quinone)/metabolism MH - NF-E2-Related Factor 2/metabolism MH - Oxidative Stress/*drug effects MH - Reactive Oxygen Species/metabolism MH - Signal Transduction/*drug effects MH - Superoxide Dismutase/metabolism MH - Up-Regulation/drug effects MH - bcl-2-Associated X Protein/metabolism OTO - NOTNLM OT - Keap1 OT - Nrf2 OT - icaritin OT - neuronal cells OT - oxidative stress EDAT- 2020/07/13 06:00 MHDA- 2021/09/24 06:00 CRDT- 2020/07/13 06:00 PHST- 2020/03/04 00:00 [received] PHST- 2020/05/08 00:00 [revised] PHST- 2020/07/05 00:00 [accepted] PHST- 2020/07/13 06:00 [pubmed] PHST- 2021/09/24 06:00 [medline] PHST- 2020/07/13 06:00 [entrez] AID - 10.1111/cbdd.13765 [doi] PST - ppublish SO - Chem Biol Drug Des. 2021 Jan;97(1):111-120. doi: 10.1111/cbdd.13765. Epub 2020 Jul 26.