The protective effect and mechanism of Astragalus polysaccharide on liver injury in the state of brain death_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

LIN Yi ¹ , LI Mingxia ¹ , WANG Yanfeng ¹ , FAN Xiaoli ¹ , ZHONG Zibiao ¹ , XIAO Qi ² , YE Qifa ^1,2 , LI Ling ¹ ,  PENG Guizhu ¹

1. Institute of Hepatobiliary Diseases of Wuhan University, Zhongnan Hospital of Wuhan University, Transplant Center of Wuhan University, Hubei Key Laboratory of Medical Technology on Transplantation, Wuhan 430071, P. R. China;
2. Research Center of National Health Ministry on Transplantation Medici-Engineering and Technology, The 3^rd Xiangya Hospital of Central South University, Changsha, Hunan 410013, P. R. China;

Corresponding author：

PENG Guizhu, Email: pengguizhu@139.com

Keywords：

brain death; Astragalus polysaccharide; liver damage; New Zealand rabbit

DOI：

10.7507/1007-9424.201606072

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Objective To explore the protective effect and mechanism of Astragalus polysaccharides (APS) on liver injury in the state of brain death in New Zealand rabbits. Methods Twenty-four New Zealand rabbits were randomly divided into 3 groups (n=8): the blank control group, the brain death group, and the APS group. We obtained blood and liver tissue specimens from rabbits of three groups at 4 h and 8 h after treatment respectively (n=4). The rabbits of blank control group simulated the procedures of anesthesia and surgery of the brain death, without the Foley balloon catheter being pressurized, and maintained anesthesia. The brain death group: brain-dead models were established. The APS group: injection of APS (12 mg/kg) via the femoral vein bolus immediately after anesthesia, brain-dead models were established as same as rabbits of brain death group. The blood and liver tissue samples were taken at 4 h and 8 h after treatment to detect aminotrans-ferase (AST), alanine amino-transferase (ALT) and tumor necrosis factor α (TNF-α), and to observe the change of liver tissue by HE staining and immunohistochemical staining〔expression level of nuclear transcription factor p65 protein (NF-κB p65) could be detected by immunohistochemical staining〕. Results ① ALT and AST. Compare with the blank control group at the same time (4 h and 8 h), levels of ALT and AST in brain death group and APS group were significantly increased (P<0.05), and the levels of ALT and AST in brain death group were higher than those of APS group at each time point (P<0.05). In the same group, compared with 4 h, there was no significant difference in the levels of ALT and AST in blank control group at 8 h (P>0.05); the levels of ALT and AST in brain death group at 8 h were both higher than those of 4 h (P<0.05); the levels of ALT at 8 h in APS group was higher than that of 4 h, but there was no significant difference in the level of AST between 4 h and 8 h (P>0.05). ② TNF-α. Compare with the blank control groups at same time (4 h and 8 h), levels of TNF-α in brain death group and APS group were significantly increased(P<0.05), and level of TNF-α in brain death group was higher than that of APS group at 4 h and 8 h (P<0.05). ③ The HE results. The liver tissue structure of blank control group, brain death group, and APS group at 4 h had no obvious change. The liver tissue structure of brain death group at 8 h showed the evident tissue damage: liver cells showed the balloon samples, disordered arrangement, cytoplasmic loose light dye net-like, and inflammatory cells infiltrated in portal area. The liver tissue structure of APS group at 8 h showed that, liver cells showed mild edema, normal arrangement, and a small amount of inflammatory cells infiltrated in portal area. The liver tissue structure damage of APS group at 8 h was milder than that of brain death group. ④ Immunohistochemical staining results. There was no significant difference in expression levels of NF-κB p65 protein among blank control group, brain death group, and APS group at 4 h (P>0.05). But at 8 h, the expression levels of NF-κB p65 protein in brain death group and APS group were higher than that of blank control group (P<0.05), and the expression level of NF-κB p65 protein in brain death group was higher than that of APS group (P<0.05). The expression levels of NF-κB p65 protein in brain death group and APS group at 8 h was higher than that of 4 h in the same group (P<0.05), but there was no significant difference between 4 h and 8 h in blank control group (P>0.05). Conclusions Brain death will cause liver damage and the injury degree may be related to the continuous time. The damage at 8 h was more serious than that of 4 h. APS has a protective effect on liver of brain-dead rabbits' and its mechanism may be closely related to inhibit TNF-α and NF-κB by diverse ways to reduce the inflammation of the liver injury.

Citation： LIN Yi, LI Mingxia, WANG Yanfeng, FAN Xiaoli, ZHONG Zibiao, XIAO Qi, YE Qifa, LI Ling, PENG Guizhu. The protective effect and mechanism of Astragalus polysaccharide on liver injury in the state of brain death. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2017, 24(3): 275-281. doi: 10.7507/1007-9424.201606072 Copy

1.	Kocaay AF, Celik SU, Eker T, et al. Brain death and organ donation: knowledge, awareness, and attitudes of medical, law, divinity, nursing, and communication students. Transplant Proc, 2015, 47(5): 1244-1248.
2.	Weiss S, Kotschb K, Francuski M, et al. Brain death activates donor organs and is associated with a worse I/R injury after liver transplantation. Am J Transplant, 2007, 7(6): 1584-1593.
3.	Li S, Loganathan S, Korkmaz S, et al. Transplantation of donor hearts after circulatory or brain death in a rat model. J Surg Res, 2015, 195(1): 315-324.
4.	陈克霏, 李波. 边缘供肝应用于肝脏移植的研究进展. 中国普外基础与临床杂志, 2004, 11(5): 413-415.
5.	Yin Y, Lu L, Wang D, et al. Astragalus polysaccharide inhibits autophagy and apoptosis from peroxide-induced injury in C2C12 myoblasts. Cell Biochem Biophys, 2015, 73(2): 433-439.
6.	Ren F, Qian XH, Qian XL. Astragalus polysaccharide upregulates hepcidin and reduces iron overload in mice via activation of p38 mitogen-activated protein kinase. Biochem Biophys Res Commun, 2016, 472(1): 163-168.
7.	Zhang J, Gu JY, Chen ZS, et al. Astragalus polysaccharide suppresses palmitate-induced apoptosis in human cardiac myocytes: the role of Nrf1 and antioxidant response. Int J Clin Exp Pathol, 2015, 8(3): 2515-2524.
8.	Zhang PP, Meng ZT, Wang LC, et al. Astragalus polysaccharide promotes the release of mature granulocytes through the L-selectin signaling pathway. Chin Med, 2015, 10(1): 1-17.
9.	Dai H, Jia G, Liu X, et al. Astragalus polysaccharide inhibits isoprenaline-induced cardiac hypertrophy via suppressing Ca²⁺-mediated calcineurin/NFATc3 and CaMKⅡ signaling cascades. Environ Toxicol Pharmacol, 2014, 38(1): 263-271.
10.	Liu W, Gao FF, Li Q, et al. Protective effect of astragalus polysaccharides on liver injury induced by several different chemotherapeutics in mice. Asian Pac J Cancer Prev, 2014, 15(23): 10413-10420.
11.	Li S, Zhang Y. Characterization and renal protective effect of a polysaccharide from Astragalus membranaceus. Carbohydr Polyme, 2009, 78(2): 343-348.
12.	Saat TC, Susa D, Kok NF, et al. Inflammatory genes in rat livers from cardiac- and brain death donors. J Surg Res, 2015, 198(1): 217-227.
13.	Fang H, Zhang S, Guo W, et al. Cobalt protoporphyrin protects the liver against apoptosis in rats of brain death. Clin Res Hepatol Gastroenterol, 2015, 39(4): 475-481.
14.	Schuurs TA, Morariu AM, Ottens PJ, et al. Time-dependent changes in donor brain death related processes. Am J Transplant, 2006, 6(12): 2903-2911.
15.	di Francesco F, Pagano D, Echeverri G, et al. Selective use of extended criteria deceased liver donors with anatomic variations. Ann Transplant, 2012, 17(4): 140-143.
16.	Bugge JF. Brain death and its implications for management of the potential organ donor. Acta Anaesthesiol Scand, 2009, 53(10): 1239-1250.
17.	范晓礼, 叶啟发, 钟自彪, 等. 无心跳脑死亡兔模型的建立及生命体征变化. 中华实验外科杂志, 2013, 30(9): 1906-1908.
18.	周志刚, 李超, 李立, 等. 2 例脑死亡无偿器官捐献供体的维护体会. 中国普外基础与临床杂志, 2012, 19(5): 486-489.
19.	Giannitti C, Lopalco G, Vitale A, et al. Long-term safety of anti-TNF agents on the liver of patients with spondyloarthritis and potential occult hepatitis B viral infection: an observational multicentre study. Clin Exp Rheumatol, 2017, 35(1): 93-97.
20.	Cui K, Zhang S, Jiang X, et al. Novel synergic antidiabetic effects of Astragalus polysaccharides combined with Crataegus flavonoids via improvement of islet function and liver metabolism. Mol Med Rep, 2016, 13(6): 4737-4744.
21.	Jiang X, Feng X, Huang H, et al. The effects of rotenone-induced toxicity via the NF-κB-iNOS pathway in rat liver. Toxicol Mech Methods, 2017, 26(22): 1-22.
22.	Van Der Hoeven JA, Moshage H, Schuurs T, et al. Brain death induces apoptosis in donor liver of the rat. Transplantation, 2003, 76(8): 1150-1154.
23.	Zhu HY, Gao YH, Wang ZY, et al. Astragalus polysaccharide suppresses the expression of adhesion molecules through the regulation of the p38 MAPK signaling pathway in human cardiac microvascular endothelial cells after ischemia-reperfusion injury. Evid Based Complement Alternat Med, 2013, 2013: 280493.
24.	李天一, 汪丽佩, 吴国林. 黄芪多糖对免疫性肝损伤小鼠免疫调节的影响. 中国中医急症, 2014, 23(1): 25-29.
25.	Xue H, Gan F, Zhang Z, et al. Astragalus polysaccharides inhibits PCV2 replication by inhibiting oxidative stress and blocking NF-κB pathway. Int J Biol Macromol, 2015, 81: 22-30.

1. Kocaay AF, Celik SU, Eker T, et al. Brain death and organ donation: knowledge, awareness, and attitudes of medical, law, divinity, nursing, and communication students. Transplant Proc, 2015, 47(5): 1244-1248.
2. Weiss S, Kotschb K, Francuski M, et al. Brain death activates donor organs and is associated with a worse I/R injury after liver transplantation. Am J Transplant, 2007, 7(6): 1584-1593.
3. Li S, Loganathan S, Korkmaz S, et al. Transplantation of donor hearts after circulatory or brain death in a rat model. J Surg Res, 2015, 195(1): 315-324.
4. 陈克霏, 李波. 边缘供肝应用于肝脏移植的研究进展. 中国普外基础与临床杂志, 2004, 11(5): 413-415.
5. Yin Y, Lu L, Wang D, et al. Astragalus polysaccharide inhibits autophagy and apoptosis from peroxide-induced injury in C2C12 myoblasts. Cell Biochem Biophys, 2015, 73(2): 433-439.
6. Ren F, Qian XH, Qian XL. Astragalus polysaccharide upregulates hepcidin and reduces iron overload in mice via activation of p38 mitogen-activated protein kinase. Biochem Biophys Res Commun, 2016, 472(1): 163-168.
7. Zhang J, Gu JY, Chen ZS, et al. Astragalus polysaccharide suppresses palmitate-induced apoptosis in human cardiac myocytes: the role of Nrf1 and antioxidant response. Int J Clin Exp Pathol, 2015, 8(3): 2515-2524.
8. Zhang PP, Meng ZT, Wang LC, et al. Astragalus polysaccharide promotes the release of mature granulocytes through the L-selectin signaling pathway. Chin Med, 2015, 10(1): 1-17.
9. Dai H, Jia G, Liu X, et al. Astragalus polysaccharide inhibits isoprenaline-induced cardiac hypertrophy via suppressing Ca²⁺-mediated calcineurin/NFATc3 and CaMKⅡ signaling cascades. Environ Toxicol Pharmacol, 2014, 38(1): 263-271.
10. Liu W, Gao FF, Li Q, et al. Protective effect of astragalus polysaccharides on liver injury induced by several different chemotherapeutics in mice. Asian Pac J Cancer Prev, 2014, 15(23): 10413-10420.
11. Li S, Zhang Y. Characterization and renal protective effect of a polysaccharide from Astragalus membranaceus. Carbohydr Polyme, 2009, 78(2): 343-348.
12. Saat TC, Susa D, Kok NF, et al. Inflammatory genes in rat livers from cardiac- and brain death donors. J Surg Res, 2015, 198(1): 217-227.
13. Fang H, Zhang S, Guo W, et al. Cobalt protoporphyrin protects the liver against apoptosis in rats of brain death. Clin Res Hepatol Gastroenterol, 2015, 39(4): 475-481.
14. Schuurs TA, Morariu AM, Ottens PJ, et al. Time-dependent changes in donor brain death related processes. Am J Transplant, 2006, 6(12): 2903-2911.
15. di Francesco F, Pagano D, Echeverri G, et al. Selective use of extended criteria deceased liver donors with anatomic variations. Ann Transplant, 2012, 17(4): 140-143.
16. Bugge JF. Brain death and its implications for management of the potential organ donor. Acta Anaesthesiol Scand, 2009, 53(10): 1239-1250.
17. 范晓礼, 叶啟发, 钟自彪, 等. 无心跳脑死亡兔模型的建立及生命体征变化. 中华实验外科杂志, 2013, 30(9): 1906-1908.
18. 周志刚, 李超, 李立, 等. 2 例脑死亡无偿器官捐献供体的维护体会. 中国普外基础与临床杂志, 2012, 19(5): 486-489.
19. Giannitti C, Lopalco G, Vitale A, et al. Long-term safety of anti-TNF agents on the liver of patients with spondyloarthritis and potential occult hepatitis B viral infection: an observational multicentre study. Clin Exp Rheumatol, 2017, 35(1): 93-97.
20. Cui K, Zhang S, Jiang X, et al. Novel synergic antidiabetic effects of Astragalus polysaccharides combined with Crataegus flavonoids via improvement of islet function and liver metabolism. Mol Med Rep, 2016, 13(6): 4737-4744.
21. Jiang X, Feng X, Huang H, et al. The effects of rotenone-induced toxicity via the NF-κB-iNOS pathway in rat liver. Toxicol Mech Methods, 2017, 26(22): 1-22.
22. Van Der Hoeven JA, Moshage H, Schuurs T, et al. Brain death induces apoptosis in donor liver of the rat. Transplantation, 2003, 76(8): 1150-1154.
23. Zhu HY, Gao YH, Wang ZY, et al. Astragalus polysaccharide suppresses the expression of adhesion molecules through the regulation of the p38 MAPK signaling pathway in human cardiac microvascular endothelial cells after ischemia-reperfusion injury. Evid Based Complement Alternat Med, 2013, 2013: 280493.
24. 李天一, 汪丽佩, 吴国林. 黄芪多糖对免疫性肝损伤小鼠免疫调节的影响. 中国中医急症, 2014, 23(1): 25-29.
25. Xue H, Gan F, Zhang Z, et al. Astragalus polysaccharides inhibits PCV2 replication by inhibiting oxidative stress and blocking NF-κB pathway. Int J Biol Macromol, 2015, 81: 22-30.

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The protective effect and mechanism of Astragalus polysaccharide on liver injury in the state of brain death

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