槲皮素通过 P2X7R 介导的 PI3K/Keap1/Nrf2 信号通路减轻斑马鱼乙醇诱导的肝脂肪变性。
Quercetin mitigates ethanol-induced hepatic steatosis in zebrafish via P2X7R-mediated PI3K/ Keap1/Nrf2 signaling pathway.
机构信息
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.
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.
出版信息
J Ethnopharmacol. 2021 Mar 25;268:113569. doi: 10.1016/j.jep.2020.113569. Epub 2020 Nov 10.
UNLABELLED
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 μM, 50 μM, 25 μM 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 γ-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.
未加标签
植物血凝素是 PCP 中含量较高的活性成分，具有多种生物活性，如抗肥胖作用、抗炎和抗氧化活性，可用于治疗酒精性肝病（ALD）。
研究目的
P2X7 受体（P2X7R）在健康和疾病中起着重要作用，它可以被细胞外 ATP 激活，引发多种下游事件，包括脂质代谢、炎症分子释放、氧化应激。然而，槲皮素是否通过 P2X7R 介导的机制来减轻乙醇诱导的肝脂肪变性尚不清楚。
材料和方法
在受精后 3 天（dpf），用 100 μM、50 μM、25 μM 槲皮素处理斑马鱼转基因（fabp10: EGFP）幼虫 48 小时，然后在 350 mmol/L 乙醇中浸泡 32 小时，用 1 mM ATP（P2X7R 激活剂）处理 30 分钟。分别检测血清脂质、肝脂肪变性、氧化应激因子。用定量实时 PCR（RT-qPCR）测量相关通路中的 mRNA 水平，以探讨其机制。
结果
槲皮素通过降低急性乙醇诱导的肝脂肪变性斑马鱼的 ALT、AST 和 γ-GT 水平来改善肝功能，并减轻肝 TG、TC 积累。此外，槲皮素显著降低 MDA 含量，抑制乙醇诱导的肝氧化应激标志物 GSH、CAT 和 SOD 降低，并显著下调 P2X7R 的表达，上调磷脂酰肌醇 3-激酶（PI3K）、Kelch 样 ECH 相关蛋白 1（Keap1）、核因子 E2 相关因子 2（Nrf2）的表达。此外，ATP 刺激激活了 P2X7R，进一步介导了 PI3K、Keap1 和 Nrf2 的 mRNA 表达。
结论
槲皮素通过调节 P2X7R 介导的 PI3K/Keap1/Nrf2 氧化应激信号通路，在斑马鱼模型中表现出肝保护作用。
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