The effect of silymarin given before partial hepatectomy on liver regeneration in rats with ischemic preconditioning during liver resection

Background: The regeneration capacity of liver tissue after partial hepatectomy closely affects morbidity and mortality. We aimed to investigate the effect of silymarin and ischemic preconditioning (IPC) before partial hepatectomy on liver regeneration.Methods: Thirty rats were randomly divided into 5 groups (n=6). Serum AST, bilirubin, tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) values were studied 48 hours after hepatectomies. Mitotic count, congestion, necrosis, cytoplasmic vacuolization, and presence of neutrophils were evaluated histopathologically. Proliferating cell nuclear antigen (PCNA) antibody was studied immunohistochemically.Results: The AST value (2071.5±938.4) was the highest in the partial hepatectomy (PH) group. The Ischemic Preconditioning Partial Hepatectomy Group (IPC) (1535.5±204.8) and the Silymarin+Partial Hepatectomy Group (Silymarin group) (1192.3±526.3) had lower levels of AST values; however, the AST values were the lowest in the Silymarin+Ischemic Preconditioning+ Partial Hepatectomy Group (IPC+ Silymarin group) (1002.8±348.9). Likewise, the highest improvement in bilirubin levels was observed in the IPC+ Silymarin group (0.33±0.11). IL-6 (11.54±2.89) and TNF-α (39.2±22.73) values were the lowest in the IPC group, and interestingly, both were higher in the silymarin-treated groups. It was observed that these values increased in Silymarin group and IPC+ Silymarin group who received silymarin treatment compared to PH group and IPC group who did not receive silymarin. In histopathological analysis, it was found that the mitosis rate and PCNA percentage were higher in the Silymarin and IPC+ Silymarin groups.Conclusions: The use of silymarin before hepatectomy and IPC during partial hepatectomy increase liver regeneration.

Keywords:

Liver Resection, Silymarin, Ischemic Preconditioning, Liver Regeneration.,

PDF

___

1. Campana L, Esser H, Huch M, Forbes S. Liver regeneration and inflammation: from fundamental science to clinical applications. Nat Rev Mol Cell Biol. 2021 Sep;22(9):608-624.
2. Jiménez-Castro MB, Cornide-Petronio ME, Gracia-Sancho J, Peralta C. Inflammasome-Mediated Inflammation in Liver Ischemia-Reperfusion Injury. Cells. 2019 Sep 23;8(10):1131. doi: 10.3390/cells8101131.
3. Choi EK, Jung H, Jeon S, Lim JA, Lee J, Kim H, et al. Role of Remote Ischemic Preconditioning in Hepatic Ischemic Reperfusion Injury. Dose-Response. 2020;18(3):1559325820946923.
4. Rampes S, Ma D. Hepatic ischemia-reperfusion injury in liver transplant setting: mechanisms and protective strategies. J Biomed Res. 2019;33(4):221-34.
5. Rodríguez-Reynoso S, Leal-Cortés C, Portilla-de Buen E, López-De la Torre SP. Ischemic Preconditioning Preserves Liver Energy Charge and Function on Hepatic Ischemia/Reperfusion Injury in Rats. Arch Med Res. 2018 Aug;49(6):373-380.
6. Lin J, Huang H, Yang S, Duan J, Xu W, Zeng Z. Protective Effects of Ischemic Preconditioning Protocols on Ischemia-Reperfusion Injury in Rat Liver. J Invest Surg. 2020 Oct;33(9):876-883.
7. Khan H, Ullah H, Nabavi SM. Mechanistic insights of hepatoprotective effects of curcumin: Therapeutic updates and future prospects. Food Chem Toxicol. 2019 Feb;124:182-191.
8. Dwivedi PSR, Patil VS, Khanal P, Bhandare VV, Gurav S, Harish DR, Patil BM, Roy S. System biology-based investigation of Silymarin to trace hepatoprotective effect. Comput Biol Med. 2022 Mar;142:105223.
9. Xu GB, Xiao YH, Zhang QY, Zhou M, Liao SG. Hepatoprotective natural triterpenoids. Eur J Med Chem. 2018;145:691-716.
10. Rocha Hora Mendonça AK, de Jesus CVF, de Andrade de Carvalho FM, Ferrari YAC, Nardelli MJ, Leão SC, et al. Regenerative Hepatic Effect of Red Propolis Extract Administration After Partial Hepatectomy in Rats. Rev Bras Farmacogn. 2020;30(5):683-92.
11. Álvarez-Mercado AI, Caballeria-Casals A, Rojano-Alfonso C, Chávez- Reyes J, Micó-Carnero M, Sanchez-Gonzalez A, et al. Insights into Growth Factors in Liver Carcinogenesis and Regeneration: An Ongoing Debate on Minimizing Cancer Recurrence after Liver Resection. Biomedicines. 2021;9(9):1158.
12. Álvarez-Mercado AI, Bujaldon E, Gracia-Sancho J, Peralta C. The Role of Adipokines in Surgical Procedures Requiring Both Liver Regeneration and Vascular Occlusion. Int. J. Mol. Sci. 2018;19(11):3395.
13. Liu X, Cao L, Zhang T, Guo R, Lin W. Effect of Remote Ischemic Preconditioning in Patients Undergoing Hepatectomy With Portal Triad Clamping: A Randomized Controlled Trial. Anesthesia & Analgesia. 2019;129(6).
14. Kren V, Walterová D. Silybin and silymarin--new effects and applications. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2005;149(1):29-41.
15. Zholobenko A, Modriansky M. Silymarin and its constituents in cardiac preconditioning. Fitoterapia. 2014;97:122-32.
16. Nieuwenhuijs VB, De Bruijn MT, Padbury RT, Barritt GJ. Hepatic ischemia-reperfusion injury: roles of Ca2+ and other intracellular mediators of impaired bile flow and hepatocyte damage. Dig Dis Sci. 2006;51(6):1087-102.
17. Wang M, Shen J, Feng B, Gui L, Chen Q, Zhang B, et al. Remote ischemic preconditioning promotes early liver cell proliferation in a rat model of small-for-size liver transplantation. J Surg Res. 2013;179(1):e245-53.
18. Cescon M, Grazi GL, Grassi A, Ravaioli M, Vetrone G, Ercolani G, et al. Effect of ischemic preconditioning in whole liver transplantation from deceased donors. A pilot study. Liver Transpl. 2006;12(4):628-35.
19. Esin H KC, Emiroğlu M, et al. Dipyridamole: A New Liver Regeneration Agent. Tepecik Eğit ve Araşt Hast Dergisi. 2019;29(1):67-73.
20. Assy N, Minuk GY. Liver regeneration: methods for monitoring and their applications. J Hepatol. 1997;26(4):945-52.
21. Picard C, Lambotte L, Starkel P, Sempoux C, Saliez A, Van den Berge V, et al. Steatosis is not sufficient to cause an impaired regenerative response after partial hepatectomy in rats. J Hepatol. 2002;36(5):645-52.
22. Veteläinen R, van Vliet AK, van Gulik TM. Severe steatosis increases hepatocellular injury and impairs liver regeneration in a rat model of partial hepatectomy. Ann Surg. 2007;245(1):44-50.