茵陈蒿汤对重症急性胰腺炎大鼠相关急性肝损伤的作用及p62-keap1-Nrf2信号通路的影响Effects of Yinchenhao Decoction on Severe Acute Pancreatitis-related Acute Liver Injury and p62-keap1-Nrf2 Signaling Pathway in Rats
朱天红,陈本启,赵伟,鲍海琴
摘要(Abstract):
目的观察茵陈蒿汤对重症急性胰腺炎(SAP)大鼠相关急性肝损伤的作用及p62-keap1-Nrf2信号通路的影响。方法将雄性8周龄SD大鼠30只均分为3组:假手术组、模型组和茵陈蒿汤组。模型组与茵陈蒿汤组用逆行胰胆管注射5%牛磺胆酸钠建立SAP模型,以0.2 m L/min的均匀速度注射到胆管内。假手术组注射等量生理盐水。造模2 h后茵陈蒿汤组以5 g/kg进行灌胃,对照组和模型组给予等量生理盐水。24 h后处死大鼠后进行相关检测。结果假手术组未见病理损害,模型组和茵陈蒿汤组出现不同程度的小叶中心肝细胞坏死,肝细胞颗粒变性,炎性细胞浸润,但茵陈蒿汤组的病理损伤较模型组明显减轻。与假手术组比较,模型组和茵陈蒿汤组大鼠肝脏系数均增高、血清中血清淀粉酶(AMY)、丙氨酸氨基转移酶(ALT)和天冬氨酸氨基转移酶(GOT)、肿瘤坏死因子-α(TNF-α)和白细胞介素-1β(IL-1β)含量均增高,肝组织中p62、keap1和Nrf2蛋白表达均增高;与模型组比较,茵陈蒿汤组大鼠肝脏系数降低,血清中AMY、ALT、GOT、TNF-α和IL-1β含量均降低,肝组织中p62、keap1和Nrf2蛋白表达均降低。结论茵陈蒿汤能通过抑制p62-keap1-Nrf2信号通路从而减轻SAP大鼠急性肝损伤。
关键词(KeyWords): 重症急性胰腺炎;急性肝损伤;茵陈蒿汤;p62-keap1-Nrf2信号通路;大鼠
基金项目(Foundation): 湖北省卫计委指导项目(WJ2017F079)
作者(Author): 朱天红,陈本启,赵伟,鲍海琴
参考文献(References):
- [1]焦旭,卢云.中医药治疗急性胰腺炎的临床进展[J].中国中医急症,2016,25(10):1922-1925.
- [2] Pharmacokinetics and pharmacodynamics of Da-Cheng-Qi decoction in the liver of rats with severe acute pancreatitis[J].World Journal of GOTroenterology,2017,18(8):57-64.
- [3] Nawaz R,Zahid S,Idrees M,et al. HCV-induced regulatory alterations of IL-1β,IL-6,TNF-α,and IFN-γoperative,leading liver en-route to non-alcoholic steatohepatitis[J]. Inflammation research,2017,66(6):477-486.
- [4] Karampetsou MP,Comte D,Kistoth K,et al. Decreased SAP expression in T cells from patients with SLE contributes to early signaling abnormalities and reduced IL-2 production[J]. Journal of Immunology,2016,196(12):4915-4922.
- [5] Yan Y,Guo TM,Zhu C. Effects of Non-Steroidal Anti-Inflammatory drugs on serum proinflammatory cytokines in the treatment of ankylosing spondylitis[J]. Biochemistry&Cell Biology,2018,96(12):246-254.
- [6]侯旭东,朱琳,张国强,等.茵陈蒿汤及其不同组方提取物对雌激素诱导胆汁淤积大鼠的治疗作用及机制研究[J].中国医院药学杂志,2017,18(15):354-359.
- [7] Cheng D,Wu R,Guo Y,et al. Regulation of Keap1-Nrf2 signaling:The role of epigenetics[J]. Current Opinion in Toxicology,2016,1(5):134-138.
- [8]胡流芳,王迎,任汝静,等. Keap1-Nrf2/ARE信号通路的抗氧化应激作用及其调控机制[J].国际药学研究杂志,2016,43(1):146-152.
- [9] Sun X,Ou Z,Chen R,et al. Activation of the p62-Keap1-NRF2 pathway protects against ferroptosis in hepatocellular carcinoma cells[J]. Hepatology,2015,63(1):173-184.
- [10]李锦春,戴梅,刘荣,等.外周血炎症介质对重症急性胰腺炎继发肺部感染的辅助诊断价值[J].辽宁中医杂志,2017(8):124-126.
- [11] Miyaki E,Imamura M,Hiraga N,et al. Daclatasvir and asunaprevir treatment improves liver function parameters and reduces liver fibrosis markers in chronic hepatitis C patients[J]. Hepatology Research,2016,46(8):758-764.
- [12]邢志祥,沈世强.重症急性胰腺炎肝损伤的研究进展[J].腹部外科,2016,12(6):478-481.
- [13] Ying W,Mahata S,Bandyopadhyay GK,et al. Catestatin inhibits obesity-induced macrophage infiltration and inflammation in the liver and suppresses hepatic glucose production leading to improved insulin sensitivity[J]. Trace Elements in Medicine,2018,16(3):131-134.
- [14] Ilyas,Ghulam,Zhao,et al. Macrophage autophagy limits acute toxic liver injury in mice through down regulation of interleukin-1β[J]. Journal of Hepatology,2016,64(1):118-127.
- [15] Akram M,Shin I,Kim KA,et al. A newly synthesized macakurzin C-derivative attenuates acute and chronic skin inflammation:The Nrf2/heme oxygenase signaling as a potential target[J]. Toxicology and Applied Pharmacology,2016, 307(24):62-71.
- [16] An YW,Jhang KA,Woo SY,et al. Sulforaphane exerts its anti-inflammatory effect against amyloid-βpeptide via STAT-1dephosphorylation and activation of Nrf2/HO-1 cascade in human THP-1 macrophages[J]. Neurobiology of Aging,2016,38(5):1-10.
- [17] Lu MC,Ji JA,Jiang ZY,et al. The Keap1-Nrf2-ARE pathway as a potential preventive and therapeutic target:an update[J]. Medicinal Research Reviews,2016,12(4):132-139.
- [18] Zhang M,Wu J,Ding H,et al. Progesterone provides the pleiotropic neuroprotective effect on traumatic brain injury through the Nrf2/ARE signaling pathway[J]. Neurocritical Care,2017,26(2):292-300.
- [19] Sun X,Ou Z,Chen R,et al. Activation of the p62-Keap1-NRF2 pathway protects against ferroptosis in hepatocellular carcinoma cells[J]. Hepatology,2015,63(1):173-184.
- [20] Qiu P,Dong Y,Li B,et al. Dihydromyricetin modulates p62and autophagy crosstalk with the Keap-1/Nrf2 pathway to alleviate ethanol-induced hepatic injury[J]. Toxicology Letters,2017,274(6):31-41.
- [21] Chen Q,Zhou Y,Richards AM,et al. Up-regulation of miRNA-221 inhibits hypoxia/reoxygenation-in duced autophagy through the DDIT4/mTORC1 and Tp53inp1/p62 pathways.[J]. Biochemical&Biophysical Research Communications,2016,474(1):168-174.
- [22] Lee YJ,Chou TF,Pittman SK,et al. Keap1/Cullin3 modulates p62/SQSTM1 activity via UBA domain ubiquitination[J]. Cell Reports,2017,19(1):188-202.