Vitamin C and Panceatitis
High-dose vitamin C alleviates pancreatic injury via the NRF2/NQO1/HO-1 pathway in a rat model of severe acute pancreatitis
Department of Emergency in Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
Background: Oxidative stress plays a pivotal role in the progress of severe acute pancreatitis (SAP). Vitamin C (VC) is the most important antioxidant in plasma. However, the effects of an intravenous administration of high-dose VC and the mechanisms by which it exerts its antioxidant function in an experimental model of SAP have not been determined.
Methods: Sodium taurocholate was used to induce rat pancreatic injury and AR42J cells injury. After the establishment of SAP model, SAP rat and injured AR42J cells were treated with VC. For the injured AR42J cells, small interfering RNA-mediated knockdown of NRF2 was conducted after VC treatment. The histopathological characteristics, the apoptosis of pancreatic acinar cells, oxidative stress markers and levels of enzymes, biochemical indicators, and inflammatory cytokines were examined in vivo and in vitro. Furthermore, the mortality of rats was assessed.
Results: In vivo and in vitro results demonstrated that VC treatment ameliorated apoptosis of pancreatic acinar cells, as evidenced by the increase in Bcl-2, Bcl-XL, and MCL-1 expressions and decrease in Bax and cleaved caspase-3 expression along with decreased TUNEL-positive cells. Also, we found that the elevation of MDA and decrease of SOD, GPx, GSH/GSSG, and T-AOC induced by SAP were reversed by VC treatment in vivo and in vitro, and VC treatment increased expressions of Nrf2, NQO1, and HO-1 in SAP model at protein and gene level, indicating that VC attenuated oxidative stress via the NRF2/NQO1/HO-1 pathway. Meanwhile, it was found that sodium taurocholate significantly induced the release of amylase, lipase, IL-1β, and IL-6 in rat plasma and AR42J cells, which were declined by VC treatment. In vitro results also revealed that these alterations in sodium taurocholate-injured AR42J cells due to VC treatment was attenuated by NRF2 knockdown. In addition, VC at a dose of 500 mg/kg decreased the levels of lactic acid, Cre, NGAL, AST, and ALT in the plasma of SAP rats, suggesting the improvement of renal and pancreatic injury and liver function of SAP rats. Furthermore, the mortality of SAP rats was 50%, which declined to 30% after VC treatment.
Conclusions: The present study suggests that high-dose of VC ameliorate pancreatic injury of SAP via the NRF2/NQO1/HO-1 pathway to inhibit oxidative stress.
Keywords: Severe acute pancreatitis (SAP); pancreatic acinar cells injury; vitamin C; oxidative stress; NRF2/NQO1/HO-1 pathway; inflammation
大剂量维生素C通过NRF2/NQO1/HO-1通路减轻急性重症胰腺炎大鼠胰腺损伤
上海交通大学医学院附属瑞金医院急诊科，中国上海
背景:氧化应激在重症急性胰腺炎(SAP)的发生过程中起着关键作用。维生素C (VC)是血浆中最重要的抗氧化剂。然而，静脉注射高剂量VC的作用及其在SAP实验模型中发挥抗氧化作用的机制尚未确定。
方法:采用牛磺胆酸钠诱导大鼠胰腺损伤和AR42J细胞损伤。建立SAP模型后，用VC处理SAP大鼠和受伤的AR42J细胞。对于损伤的AR42J细胞，VC处理后进行小干扰rna介导的NRF2敲低。研究了胰腺腺泡细胞凋亡、氧化应激标志物、酶、生化指标和炎性细胞因子的体内外组织病理学特征。此外，对大鼠的死亡率进行了评估。
结果:体内和体外结果表明，VC治疗可以改善胰腺腺泡细胞的凋亡，其表现为Bcl-2、Bcl-XL、mcl1表达增加，Bax和cleaved caspase-3表达减少，tunel阳性细胞减少。同时,我们发现SOD, MDA的升高和降低,GPx, GSH / GSSG,和T-AOC SAP被VC逆转治疗引起的体内和体外,和VC治疗增加Nrf2的表情,NQO1、并在SAP模型HO-1蛋白质和基因水平,表明VC减毒氧化应激通过Nrf2 / NQO1 / HO-1通路。同时，我们发现牛曲胆酸钠显著诱导大鼠血浆和AR42J细胞中淀粉酶、脂肪酶、IL-1蛋白和IL-6的释放，VC处理后，这些释放量下降。体外结果还显示，在牛磺酸钠损伤的AR42J细胞中，这些改变是由VC处理的NRF2敲低减弱。此外，500 mg/kg剂量的VC可降低SAP大鼠血浆中乳酸、Cre、NGAL、AST和ALT水平，提示改善SAP大鼠肾、胰腺损伤和肝功能。此外，SAP大鼠的死亡率为50%，VC治疗后下降到30%。
结论:本研究提示高剂量VC通过NRF2/NQO1/HO-1途径改善SAP的胰腺损伤，抑制氧化应激。
关键词:重症急性胰腺炎;胰腺腺泡细胞损伤;维生素C;氧化应激;NRF2 / NQO1 / HO-1通路;炎症
大剂量维生素C通过NRF2/NQO1/HO-1通路减轻大鼠重症急性胰腺炎胰腺损伤——徐-转化医学年报
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High-dose vitamin C alleviates pancreatic injury via the NRF2/NQO1/HO-1 pathway in a rat model of severe acute pancreatitis - Xu - Annals of Translational Medicine
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