Mechanism research on protective effect of rapamycin on pancreatic brain tissues injury_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

JI Jiuwei , SONG Weidong ,  ZHAO Haiping

Department B of Abdominal Surgery, The Affiliated People’s Hospital of Inner Mongolia Medical University (Inner Mongolia Autonomous Region Cancer Hospital), Hohhot 010010, P. R. China;

Corresponding?author：

ZHAO Haiping, Email: zhaohaiping007@aliyun.com

Keywords：

severe acute pancreatitis; brain tissues injury; mTOR signaling pathway; rapamycin

DOI：

10.7507/1007-9424.202109088

Video：

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Objective To explore the protective effect of rapamycin on brain tissues injury in severe acute pancreatitis (SAP) and its possible mechanism in experimental rats. Methods Ninety SPF males SD rats were randomly divided into 3 groups by random envelope opening method: sham operation group (SO group), SAP group, and rapamycin group (RAPA group), then the rats of each group were divided into 24 h, 36 h, and 48 h 3 subgroups by random number table method. Rats in each group underwent laparotomy, the model was prepared by retrograde injection of solutions into biliopancreatic duct, rat of the SO group was injected with 0.9% normal saline (2 mL/kg), rats of the SAP group and the RAPA group were injected with 5% sodium taurocholate solution (2 mL/kg), but rat of the RAPA group was injected with rapamycin (1 mg/kg) at 30 min before narcosis. All survival rats in each subgroup were killed at 24 h, 36 h, and 48 h respectively, then the pancreas and brain tissues of rats were collected, pancreas and brain tissues were stained by hematoxylin-eosin staining, brain tissues were stained by Luxol fast blue additionally, pathological changes of brain tissues were scored under light microscope. The protective effect of rapamycin on brain tissues injury was determined by comparing the differences in the degree of brain tissues among 3 groups. The phosphorylated mammaliantarget of rapamycin (p-mTOR) and phosphorylated ribosomal 40S small subunitS6 protein kinase (p-S6K1) expression levels in brain tissues were detected by Western blot. In addition, the correlations between the expression levels of p-mTOR and p-S6K1 in brain tissues and the degree of brain tissues injury were analyzed to further explore the possible mechanism of rapamycin’s protective effect on brain tissues injury in SAP. Results ① At the point of 24 h, 36 h, and 48 h, the order of the relative expression levels of p-mTOR and p-S6K1 in brain tissues of three groups were all as follows: the SO group < the RAPA group < the SAP group (P<0.05). ② At the point of 24 h, 36 h, and 48 h, the order of brain histological score in three groups were all as follows: the SO group < the RAPA group < the SAP group (P<0.05). ③ The relative expression levels of p-mTOR and p-S6K1 in brain tissues were positively correlated with pathological scores of brain tissues (r=0.99, P<0.01; r=0.97, P<0.01). Conclusion Rapamycin plays a protective role in pancreatic brain tissues injure by down-regulating the expression levels of p-mTOR and p-S6K1 in mTOR signaling pathway.

Citation： JI Jiuwei, SONG Weidong, ZHAO Haiping. Mechanism research on protective effect of rapamycin on pancreatic brain tissues injury. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2022, 29(7): 869-874. doi: 10.7507/1007-9424.202109088 Copy

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2.	Gilsanz García V. Pancreatic encephalopathy. An R Acad Nac Med (Madr), 1982, 99(4): 567-586.
3.	Doghmi N, Benakrout A, Meskine A, et al. Pancreatic encephalopathy: about 2 cases and review of the literature. Pan Afr Med J, 2016, 25: 147. doi: 10.11604/pamj.2016.25.147.9324.
4.	Sharma V, Sharma R, Rana SS, et al Pancreatic encephalopathy: an unusual cause of asterixis. JOP, 2014, 15(4): 383-384.
5.	黃伯儒, 趙海平, 胡文秀. 髓鞘堿性蛋白、TNF-α和IL-6在實驗性大鼠胰性腦病中的水平變化及相關性研究. 中國普外基礎與臨床雜志, 2015, 22(7): 816-821.
6.	Bsibsi M, Peferoen LA, Holtman IR, et al. Demyelination during multiple sclerosis is associated with combined activation of microglia/macrophages by IFN-γ and alpha B-crystallin. Acta Neuropathol, 2014, 128(2): 215-229.
7.	Lallas M, Desai J. Wernicke encephalopathy in children and adolescents. World J Pediatr, 2014, 10(4): 293-298.
8.	Zou Z, Tao T, Li H, et al. mTOR signaling pathway and mTOR inhibitors in cancer: progress and challenges. Cell Biosci, 2020, 10: 31. doi: 10.1186/s13578-020-00396-1.
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11.	孔雷, 韓天權, 于穎彥, 等. 胰酶、細胞因子、高滲液和感染對大鼠腦損傷的形態學研究. 中華胰腺病雜志, 2004, 4(2): 98-101.
12.	Trikudanathan G, Wolbrink DRJ, van Santvoort HC, et al. Current concepts in severe acute and necrotizing pancreatitis: an evidence-based approach. Gastroenterology, 2019, 156(7): 1994-2007.
13.	Li M, Zhang X, Wang B, et al. Effect of JAK2/STAT3 signaling pathway on liver injury associated with severe acute pancreatitis in rats. Exp Ther Med, 2018, 16(3): 2013-2021.
14.	Yuan L, Zhu L, Zhang Y, et al. Effect of Da-Cheng-Qi decoction for treatment of acute kidney injury in rats with severe acute pancreatitis. Chin Med, 2018, 13: 38. doi: 10.1186/s13020-018-0195-8.
15.	Howard TJ. The role of antimicrobial therapy in severe acute pancreatitis. Surg Clin North Am, 2013, 93(3): 585-593.
16.	Lerch MM, Gorelick FS. Models of acute and chronic pancreatitis. Gastroenterology, 2013, 144(6): 1180-1193.
17.	Butt I, Ulloa N, Surapaneni BK, et al. Refeeding syndrome and non-alcoholic Wernicke’s encephalopathy in a middle-aged male initially presenting with gallstone pancreatitis: a clinical challenge. Cureus, 2019, 11(7): e5156. doi: 10.7759/cureus.5156.
18.	Yang YL, Li JP, Li KZ, et al Tumor necrosis factor alpha antibody prevents brain damage of rats with acute necrotizing pancreatitis. World J Gastroenterol, 2004, 10(19): 2898-2900.
19.	Wang XH, Chu L, Liu C, et al. Therapeutic effects of Saussurea involucrata injection against severe acute pancreatitis-induced brain injury in rats. Biomed Pharmacother, 2018, 100: 564-574.
20.	LI Z, MA B, LU M, et al. Construction of network for protein kinases that play a role in acute pancreatitis. Pancreas, 2013, 42(4): 607-613.
21.	Engelmann C, Weih F, Haenold R. Role of nuclear factor kappa B in central nervous system regeneration. Neural Regen Res, 2014, 9(7): 707-711.
22.	鄂偉國, 趙海平. p38mapk特異性抑制劑sb203580在胰性腦病中的作用. 世界最新醫學信息文摘, 2015, 15(81): 24-25.
23.	Yoon MS. The role of mammalian target of rapamycin (mTOR) in insulin signaling. Nutrients, 2017, 9(11): 1176. doi: 10.3390/nu9111176.

1. Rothermich NO, von Haam E . Pancreatic encephalopathy. J Clin Endocyinol, 1941, 1(11): 872-881.
2. Gilsanz García V. Pancreatic encephalopathy. An R Acad Nac Med (Madr), 1982, 99(4): 567-586.
3. Doghmi N, Benakrout A, Meskine A, et al. Pancreatic encephalopathy: about 2 cases and review of the literature. Pan Afr Med J, 2016, 25: 147. doi: 10.11604/pamj.2016.25.147.9324.
4. Sharma V, Sharma R, Rana SS, et al Pancreatic encephalopathy: an unusual cause of asterixis. JOP, 2014, 15(4): 383-384.
5. 黃伯儒, 趙海平, 胡文秀. 髓鞘堿性蛋白、TNF-α和IL-6在實驗性大鼠胰性腦病中的水平變化及相關性研究. 中國普外基礎與臨床雜志, 2015, 22(7): 816-821.
6. Bsibsi M, Peferoen LA, Holtman IR, et al. Demyelination during multiple sclerosis is associated with combined activation of microglia/macrophages by IFN-γ and alpha B-crystallin. Acta Neuropathol, 2014, 128(2): 215-229.
7. Lallas M, Desai J. Wernicke encephalopathy in children and adolescents. World J Pediatr, 2014, 10(4): 293-298.
8. Zou Z, Tao T, Li H, et al. mTOR signaling pathway and mTOR inhibitors in cancer: progress and challenges. Cell Biosci, 2020, 10: 31. doi: 10.1186/s13578-020-00396-1.
9. 吉九威, 趙海平, 胡文秀, 等. 亞甲藍+牛磺膽酸鈉聯合逆行胰膽管注射法制備重癥急性胰腺炎大鼠模型. 中國普外基礎與臨床雜志, 2018, 25(9): 1049-1054.
10. 吉九威, 趙海平, 胡文秀. 雷帕霉素對重癥急性胰腺炎胰腺損害的保護性作用. 中國普外基礎與臨床雜志, 2019, 26(4): 405-411.
11. 孔雷, 韓天權, 于穎彥, 等. 胰酶、細胞因子、高滲液和感染對大鼠腦損傷的形態學研究. 中華胰腺病雜志, 2004, 4(2): 98-101.
12. Trikudanathan G, Wolbrink DRJ, van Santvoort HC, et al. Current concepts in severe acute and necrotizing pancreatitis: an evidence-based approach. Gastroenterology, 2019, 156(7): 1994-2007.
13. Li M, Zhang X, Wang B, et al. Effect of JAK2/STAT3 signaling pathway on liver injury associated with severe acute pancreatitis in rats. Exp Ther Med, 2018, 16(3): 2013-2021.
14. Yuan L, Zhu L, Zhang Y, et al. Effect of Da-Cheng-Qi decoction for treatment of acute kidney injury in rats with severe acute pancreatitis. Chin Med, 2018, 13: 38. doi: 10.1186/s13020-018-0195-8.
15. Howard TJ. The role of antimicrobial therapy in severe acute pancreatitis. Surg Clin North Am, 2013, 93(3): 585-593.
16. Lerch MM, Gorelick FS. Models of acute and chronic pancreatitis. Gastroenterology, 2013, 144(6): 1180-1193.
17. Butt I, Ulloa N, Surapaneni BK, et al. Refeeding syndrome and non-alcoholic Wernicke’s encephalopathy in a middle-aged male initially presenting with gallstone pancreatitis: a clinical challenge. Cureus, 2019, 11(7): e5156. doi: 10.7759/cureus.5156.
18. Yang YL, Li JP, Li KZ, et al Tumor necrosis factor alpha antibody prevents brain damage of rats with acute necrotizing pancreatitis. World J Gastroenterol, 2004, 10(19): 2898-2900.
19. Wang XH, Chu L, Liu C, et al. Therapeutic effects of Saussurea involucrata injection against severe acute pancreatitis-induced brain injury in rats. Biomed Pharmacother, 2018, 100: 564-574.
20. LI Z, MA B, LU M, et al. Construction of network for protein kinases that play a role in acute pancreatitis. Pancreas, 2013, 42(4): 607-613.
21. Engelmann C, Weih F, Haenold R. Role of nuclear factor kappa B in central nervous system regeneration. Neural Regen Res, 2014, 9(7): 707-711.
22. 鄂偉國, 趙海平. p38mapk特異性抑制劑sb203580在胰性腦病中的作用. 世界最新醫學信息文摘, 2015, 15(81): 24-25.
23. Yoon MS. The role of mammalian target of rapamycin (mTOR) in insulin signaling. Nutrients, 2017, 9(11): 1176. doi: 10.3390/nu9111176.

CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Mechanism research on protective effect of rapamycin on pancreatic brain tissues injury

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