PMID- 33186701 OWN - NLM STAT- MEDLINE DCOM- 20210305 LR - 20210305 IS - 1872-7573 (Electronic) IS - 0378-8741 (Linking) VI - 268 DP - 2021 Mar 25 TI - Quercetin mitigates ethanol-induced hepatic steatosis in zebrafish via P2X7R-mediated PI3K/ Keap1/Nrf2 signaling pathway. PG - 113569 LID - S0378-8741(20)33457-7 [pii] LID - 10.1016/j.jep.2020.113569 [doi] AB - Ethnopharmacological relevanceQuercetin is the active component of the higher content in PCP, which exerts various biological activities such as anti-obesity effect, anti-inflammatory and anti-oxidant activities in alcoholic liver disease (ALD). AIM OF THE STUDY: P2X7 receptor (P2X7R) plays an important role in health and disease, which can be activated by extracellular ATP to induce a variety of downstream events, including lipid metabolism, inflammatory molecule release, oxidative stress. However, whether the mechanism of quercetin on ethanol-induced hepatic steatosis via P2X7R-mediated haven't been elucidated. MATERIAL AND METHODS: Zebrafish transgenic (fabp10: EGFP) larvae were treated with 100 muM, 50 muM, 25 muM quercetin for 48 h at 3 days post fertilization (dpf), then soaked in 350 mmol/L ethanol for 32 h, treated with 1 mM ATP (P2X7R activator) for 30min. Serum lipids, liver steatosis, oxidative stress factors were respectively detected. The mRNA levels in the related pathways were measured by quantitative Real-Time PCR (RT-qPCR) to investigate the mechanisms. RESULTS: Quercetin improved the liver function via decreasing ALT, AST and gamma-GT level of zebrafish with acute ethanol-induced hepatic steatosis and attenuated hepatic TG, TC accumulation. Additionally, quercetin significantly reduced the MDA content and suppressed the ethanol-induced reduction of hepatic oxidative stress biomarkers GSH, CAT and SOD and significantly down-regulated the expression of P2X7R, and up-regulated the expression of phosphatidylinositol 3-kinase (PI3K), Kelch like ECH associated protein1 (Keap1), Nuclear Factor E2 related factor 2 (Nrf2). Moreover, ATP stimulation activated P2X7R, which further mediated the mRNA expressions of PI3K, Keap1 and Nrf2. CONCLUSION: Quercetin exhibited hepatoprotective capacity in zebrafish model, via regulating P2X7R-mediated PI3K/Keap1/Nrf2 oxidative stress signaling pathway. CI - Copyright (c) 2020. Published by Elsevier B.V. FAU - Zhao, Xingtao AU - Zhao X AD - School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China; Key Laboratory of Standardization for Chinese Herbal Medicine, Ministry of Education, Chengdu, 611137, China; National Key Laboratory Breeding Base of Systematic Research, Development and Utilization of Chinese Medicine Resources, Chengdu, 611137, China. FAU - Gong, Lihong AU - Gong L AD - School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China; Key Laboratory of Standardization for Chinese Herbal Medicine, Ministry of Education, Chengdu, 611137, China; National Key Laboratory Breeding Base of Systematic Research, Development and Utilization of Chinese Medicine Resources, Chengdu, 611137, China. FAU - Wang, Cheng AU - Wang C AD - School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China; Key Laboratory of Standardization for Chinese Herbal Medicine, Ministry of Education, Chengdu, 611137, China; National Key Laboratory Breeding Base of Systematic Research, Development and Utilization of Chinese Medicine Resources, Chengdu, 611137, China. FAU - Liu, Meichen AU - Liu M AD - School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China; Key Laboratory of Standardization for Chinese Herbal Medicine, Ministry of Education, Chengdu, 611137, China; National Key Laboratory Breeding Base of Systematic Research, Development and Utilization of Chinese Medicine Resources, Chengdu, 611137, China. FAU - Hu, Naihua AU - Hu N AD - School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China; Key Laboratory of Standardization for Chinese Herbal Medicine, Ministry of Education, Chengdu, 611137, China; National Key Laboratory Breeding Base of Systematic Research, Development and Utilization of Chinese Medicine Resources, Chengdu, 611137, China. FAU - Dai, Xuyang AU - Dai X AD - School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China; Key Laboratory of Standardization for Chinese Herbal Medicine, Ministry of Education, Chengdu, 611137, China; National Key Laboratory Breeding Base of Systematic Research, Development and Utilization of Chinese Medicine Resources, Chengdu, 611137, China. FAU - Peng, Cheng AU - Peng C AD - School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China; Key Laboratory of Standardization for Chinese Herbal Medicine, Ministry of Education, Chengdu, 611137, China; National Key Laboratory Breeding Base of Systematic Research, Development and Utilization of Chinese Medicine Resources, Chengdu, 611137, China. Electronic address: Pengchengsub@126.com. FAU - Li, Yunxia AU - Li Y AD - School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China; Key Laboratory of Standardization for Chinese Herbal Medicine, Ministry of Education, Chengdu, 611137, China; National Key Laboratory Breeding Base of Systematic Research, Development and Utilization of Chinese Medicine Resources, Chengdu, 611137, China. Electronic address: lyxtgyxcdutcm@163.com. LA - eng PT - Journal Article DEP - 20201110 PL - Ireland TA - J Ethnopharmacol JT - Journal of ethnopharmacology JID - 7903310 RN - 0 (Antioxidants) RN - 0 (Carrier Proteins) RN - 0 (Keap1a protein, zebrafish) RN - 0 (NF-E2-Related Factor 2) RN - 0 (Purinergic P2X Receptor Antagonists) RN - 0 (Receptors, Purinergic P2X7) RN - 0 (Zebrafish Proteins) RN - 0 (nfe2l2a protein, zebrafish) RN - 3K9958V90M (Ethanol) RN - 9IKM0I5T1E (Quercetin) SB - IM MH - Animals MH - Animals, Genetically Modified MH - Antioxidants/pharmacology/therapeutic use MH - Carrier Proteins/*biosynthesis MH - Dose-Response Relationship, Drug MH - Ethanol/toxicity MH - Fatty Liver/chemically induced/*metabolism/prevention & control MH - NF-E2-Related Factor 2/*biosynthesis MH - Phosphatidylinositol 3-Kinases/*biosynthesis MH - Purinergic P2X Receptor Antagonists MH - Quercetin/pharmacology/*therapeutic use MH - Receptors, Purinergic P2X7/*biosynthesis MH - Signal Transduction/drug effects/physiology MH - Zebrafish MH - Zebrafish Proteins/*biosynthesis OTO - NOTNLM OT - Ethanol-induced hepatic steatosis OT - Keap l OT - Nrf2 OT - P2X7R OT - PI3K OT - Quercetin EDAT- 2020/11/14 06:00 MHDA- 2021/03/06 06:00 CRDT- 2020/11/13 20:09 PHST- 2020/09/13 00:00 [received] PHST- 2020/10/28 00:00 [revised] PHST- 2020/11/03 00:00 [accepted] PHST- 2020/11/14 06:00 [pubmed] PHST- 2021/03/06 06:00 [medline] PHST- 2020/11/13 20:09 [entrez] AID - S0378-8741(20)33457-7 [pii] AID - 10.1016/j.jep.2020.113569 [doi] PST - ppublish SO - J Ethnopharmacol. 2021 Mar 25;268:113569. doi: 10.1016/j.jep.2020.113569. Epub 2020 Nov 10.