The Potential Antifibrotic Effect of AMPK Activator(s) in Experimentally-Induced Hepatic Fibrosis: An Invivo Animal Study
Main Article Content
Keywords
Aspirin possesses a potential antifibrotic effect, which could be attributable – at least - to its antioxidant, anti-inflammatory, and AMPK activating properties.
Abstract
Liver fibrosis is a serious health problem that might cause liver cirrhosis and hepatocellular carcinoma. Unfortunately, successful antifibrotic treatment is not yet available in clinical use. Interestingly, activation of adenosine monophosphate-activated protein kinase by phosphorylation (p-AMPK) has been known to attenuate liver fibrosis. Aspirin has a well-known antipyretic, antioxidant, and anti-inflammatory properties. Newly, it has also been recognized as an AMPK activator. Therefore, aspirin is worth to be currently investigated by evaluating its potential antifibrotic activity in CCl4-induced hepatic fibrosis in mice besides the possible mechanisms such as oxidative stress, inflammation, and AMPK activation.
References
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14. Reanmongkol W, Itharat A, Bouking P. Evaluation of the anti-inflammatory, antinociceptive and antipyretic activities of the extracts from Smilax corbularia Kunth rhizomes in mice and rats (in vivo). Songklanakarin J Sci Technol. 2007;29(SUPPL. 1):59-67.
15. Scholten D, Trebicka J, Liedtke C, Weiskirchen R. The carbon tetrachloride model in mice. Lab Anim. 2015;49:4-11. doi:10.1177/0023677215571192
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17. Kim SH, Oh DS, Oh JY, Son TG, Yuk DY, Jung YS. Silymarin Prevents Restraint Stress-Induced Acute Liver Injury by Ameliorating Oxidative Stress and Reducing Inflammatory Response. Molecules. 2016;21(4). doi:10.3390/molecules21040443
18. Thackaberry EA, Kopytek S, Sherratt P, Trouba K, McIntyre B. Comprehensive Investigation of Hydroxypropyl Methylcellulose, Propylene Glycol, Polysorbate 80, and Hydroxypropyl-Beta-Cyclodextrin for use in General Toxicology Studies. Toxicol Sci. 2010;117(2):485-492. doi:10.1093/toxsci/kfq207
19. Gad SC, Spainhour CB, Shoemake C, et al. Tolerable Levels of Nonclinical Vehicles and Formulations Used in Studies by Multiple Routes in Multiple Species with Notes on Methods to Improve Utility. Int J Toxicol. 2016;35(2):95-178. doi:10.1177/1091581815622442
20. Sun M, Kisseleva T. Reversibility of liver fibrosis. Clin Res Hepatol Gastroenterol. 2015;39:S60-S63. doi:https://doi.org/10.1016/j.clinre.2015.06.015
21. Elsharkawy AM, Oakley F, Mann DA. The role and regulation of hepatic stellate cell apoptosis in reversal of liver fibrosis. Apoptosis. 2005;10(5):927-939. doi:10.1007/s10495-005-1055-4
22. Wang Y, Gao J, Zhang D, Zhang J, Ma J, Jiang H. New insights into the antifibrotic effects of sorafenib on hepatic stellate cells and liver fibrosis. J Hepatol. 2010;53(1):132-144. doi:10.1016/j.jhep.2010.02.027
23. Thompson AJ, Patel K. Antifibrotic therapies: Will we ever get there? Curr Gastroenterol Rep. 2010;12(1):23-29. doi:10.1007/s11894-009-0080-9
24. Sallam AM, Esmat A, Abdel-Naim AB. Cucurbitacin-B attenuates CCl 4 -induced hepatic fibrosis in mice through inhibition of STAT-3. Chem Biol Drug Des. 2018;91(4):933-941. doi:10.1111/cbdd.13160
25. Liu PP, Liu HH, Sun SH, et al. Aspirin alleviates cardiac fibrosis in mice by inhibiting autophagy. Acta Pharmacol Sin. 2017;38(4):488-497. doi:10.1038/aps.2016.143
26. Johnston DE, Kroening C. Mechanism of early carbon tetrachloride toxicity in cultured rat hepatocytes. Pharmacol Toxicol. 1998;83(6):231-239. doi:10.1111/j.1600-0773.1998.tb01475.x
27. Brattin WJ, Glende EA, Recknagel RO. Pathological mechanisms in carbon tetrachloride hepatotoxicity. J Free Radic Biol Med. 1985;1(1):27-38. doi:https://doi.org/10.1016/0748-5514(85)90026-1
28. Recknagel RO, Glende EA, Dolak JA, Waller RL. Mechanisms of carbon tetrachloride toxicity. Pharmacol Ther. 1989;43(1):139-154. doi:https://doi.org/10.1016/0163-7258(89)90050-8
29. Bahcecioglu IH, Koca SS, Poyrazoglu OK, et al. Hepatoprotective effect of infliximab, an anti-TNF-α agent, on carbon tetrachloride-induced hepatic fibrosis. Inflammation. 2008;31(4):215-221. doi:10.1007/s10753-008-9067-1
30. Yachi R, Igarashi O, Kiyose C. Protective effects of vitamin E analogs against carbon tetrachloride-induced fatty liver in rats. J Clin Biochem Nutr. 2010;47(2):148-154.
31. Subramanian V. Hepatoprotective activity of Brassica oleracea Italica against carbon tetrachloride induced in albino rats. J Pharm Res. 2011;4(4):1143.
32. KAWANO O, SAWABE T, MISAKI N, FUKAWA K. STUDIES ON COMBINATION DOSING (III) ASPIRIN AND ETHENZAMIDE. Jpn J Pharmacol. 1978;28(6):829-835. doi:10.1254/jjp.28.829
33. Carlson LM, Rasmuson A, Idborg H, et al. Low-dose aspirin delays an inflammatory tumor progression in vivo in a transgenic mouse model of neuroblastoma. Carcinogenesis. 2013;34(5):1081-1088. doi:10.1093/carcin/bgt009
34. Yoshida S, Ikenaga N, Liu SB, et al. Extrahepatic Platelet-Derived Growth Factor-β, Delivered by Platelets, Promotes Activation of Hepatic Stellate Cells and Biliary Fibrosis in Mice. Gastroenterology. 2014;147(6):1378-1392. doi:https://doi.org/10.1053/j.gastro.2014.08.038
35. Dabhi JK, Solanki JK, Mehta A. Antiatherosclerotic activity of ibuprofen, a non-selective COX inhibitor- An animal study. Indian J Exp Biol. 2008;46(6):476-481.
36. Hardie DG. AMP-activated protein kinase: A master switch in glucose and lipid metabolism. Rev Endocr Metab Disord. 2004;5(2):119-125. doi:10.1023/B:REMD.0000021433.63915.bb
37. Towler MC, Hardie DG. AMP-activated protein kinase in metabolic control and insulin signaling. Circ Res. 2007;100(3):328-341. doi:10.1161/01.RES.0000256090.42690.05
38. Jeon SM. Regulation and function of AMPK in physiology and diseases. Exp Mol Med. 2016;48(7):1-13. doi:10.1038/EMM.2016.81
39. Yang Y, Zhao Z, Liu Y, Kang X, Zhang H, Meng M. Suppression of oxidative stress and improvement of liver functions in mice by ursolic acid via LKB1-AMP-activated protein kinase signaling. J Gastroenterol Hepatol. 2015;30(3):609-618. doi:10.1111/jgh.12723
40. King JD, Lee J, Riemen CE, et al. Role of binding and nucleoside diphosphate kinase A in the regulation of the cystic fibrosis transmembrane conductance regulator by AMP-activated protein kinase. J Biol Chem. 2012;287(40):33389-33400. doi:10.1074/jbc.M112.396036
41. Hermida N, Markl A, Hamelet J, et al. HMGCoA reductase inhibition reverses myocardial fibrosis and diastolic dysfunction through AMP-activated protein kinase activation in a mouse model of metabolic syndrome. Cardiovasc Res. 2013;99(1):44-54. doi:10.1093/cvr/cvt070
42. Kim H, Moon SY, Kim JS, et al. Activation of AMP-activated protein kinase inhibits ER stress and renal fibrosis. Am J Physiol-Ren Physiol. 2015;308(3):F226-F236. doi:10.1152/ajprenal.00495.2014
43. Juban G, Saclier M, Yacoub-Youssef H, et al. AMPK Activation Regulates LTBP4-Dependent TGF-β1 Secretion by Pro-inflammatory Macrophages and Controls Fibrosis in Duchenne Muscular Dystrophy. Cell Rep. 2018;25(8):2163-2176.e6. doi:10.1016/j.celrep.2018.10.077
44. Hardie DG, Ross FA, Hawley SA. AMPK: A nutrient and energy sensor that maintains energy homeostasis. Nat Rev Mol Cell Biol. 2012;13(4):251-262. doi:10.1038/nrm3311
45. Kumar P, Smith T, Rahman K, Thorn NE, Anania FA. Adiponectin agonist ADP355 attenuates CCL4-induced liver fibrosis in mice. PLoS One. 2014;9(10). doi:10.1371/journal.pone.0110405
2. Akinyemiju T, Abera S, Ahmed M, et al. The burden of primary liver cancer and underlying etiologies from 1990 to 2015 at the global, regional, and national level: results from the global burden of disease study 2015. JAMA Oncol. 2017;3(12):1683-1691.
3. Shaheen FAM, Al-Attar B, Souqiyyeh MZ, et al. Liver donation and transplantation in Saudi Arabia. Exp Clin Transplant. 2014;12(SUPPL. 1):17-19. doi:10.6002/ect.25Liver.L16
4. Bataller R, Brenner D a. Science in medicine Liver fibrosis. J Clin Invest. 2005;115(2):209-218. doi:10.1172/JCI200524282.The
5. Liang Z, Li T, Jiang S, et al. AMPK: A novel target for treating hepatic fibrosis. Oncotarget. 2017;8(37):62780-62792. doi:10.18632/oncotarget.19376
6. IJsselmuiden CB, Faden RR. The New England Journal of Medicine Downloaded from nejm.org on January 31, 2011. For personal use only. No other uses without permission. Copyright © 1992 Massachusetts Medical Society. All rights reserved. 1992;326.
7. Galli A, Svegliati-Baroni G, Ceni E, et al. Oxidative stress stimulates proliferation and invasiveness of hepatic stellate cells via a MMP2-mediated mechanism. Hepatology. 2005;41(5):1074-1084. doi:10.1002/hep.20683
8. Chávez E, Castro-Sánchez L, Shibayama M, et al. Effects of acetyl salycilic acid and ibuprofen in chronic liver damage induced by CCl 4. J Appl Toxicol. 2012;32(1):51-59. doi:10.1002/jat.1638
9. Hawley SA, Fullerton MD, Ross FA, et al. The ancient drug salicylate directly activates AMP-activated protein kinase. Science (80- ). 2012;336(6083):918-922. doi:10.1126/science.1215327
10. Kim J, Yang G, Kim Y, Kim J, Ha J. AMPK activators: Mechanisms of action and physiological activities. Exp Mol Med. 2016;48(4):1-12. doi:10.1038/emm.2016.16
11. He Z, Peng Y, Duan W, et al. Aspirin regulates hepatocellular lipid metabolism by activating AMPK signaling pathway. J Toxicol Sci. 2015;40(1):127-136. doi:10.2131/jts.40.127
12. Din FVN, Valanciute A, Houde VP, et al. Aspirin inhibits mTOR signaling, activates AMP-activated protein kinase, and induces autophagy in colorectal cancer cells. Gastroenterology. 2012;142(7):1504-15.e3. doi:10.1053/j.gastro.2012.02.050
13. Thuy LTT, Hai H, Hieu VN, Dat NQ, Hoang DV, Kawada N. Antifibrotic Therapy for Liver Cirrhosis BT - The Evolving Landscape of Liver Cirrhosis Management. In: Yoshiji H, Kaji K, eds. Springer Singapore; 2019:167-189. doi:10.1007/978-981-13-7979-6_15
14. Reanmongkol W, Itharat A, Bouking P. Evaluation of the anti-inflammatory, antinociceptive and antipyretic activities of the extracts from Smilax corbularia Kunth rhizomes in mice and rats (in vivo). Songklanakarin J Sci Technol. 2007;29(SUPPL. 1):59-67.
15. Scholten D, Trebicka J, Liedtke C, Weiskirchen R. The carbon tetrachloride model in mice. Lab Anim. 2015;49:4-11. doi:10.1177/0023677215571192
16. Hau DKP, Wong RSM, Cheng GYM, et al. Novel use of silymarin as delayed therapy for acetaminophen-induced acute hepatic injury. Forsch Komplementarmed. 2010;17(4):209-213. doi:10.1159/000319317
17. Kim SH, Oh DS, Oh JY, Son TG, Yuk DY, Jung YS. Silymarin Prevents Restraint Stress-Induced Acute Liver Injury by Ameliorating Oxidative Stress and Reducing Inflammatory Response. Molecules. 2016;21(4). doi:10.3390/molecules21040443
18. Thackaberry EA, Kopytek S, Sherratt P, Trouba K, McIntyre B. Comprehensive Investigation of Hydroxypropyl Methylcellulose, Propylene Glycol, Polysorbate 80, and Hydroxypropyl-Beta-Cyclodextrin for use in General Toxicology Studies. Toxicol Sci. 2010;117(2):485-492. doi:10.1093/toxsci/kfq207
19. Gad SC, Spainhour CB, Shoemake C, et al. Tolerable Levels of Nonclinical Vehicles and Formulations Used in Studies by Multiple Routes in Multiple Species with Notes on Methods to Improve Utility. Int J Toxicol. 2016;35(2):95-178. doi:10.1177/1091581815622442
20. Sun M, Kisseleva T. Reversibility of liver fibrosis. Clin Res Hepatol Gastroenterol. 2015;39:S60-S63. doi:https://doi.org/10.1016/j.clinre.2015.06.015
21. Elsharkawy AM, Oakley F, Mann DA. The role and regulation of hepatic stellate cell apoptosis in reversal of liver fibrosis. Apoptosis. 2005;10(5):927-939. doi:10.1007/s10495-005-1055-4
22. Wang Y, Gao J, Zhang D, Zhang J, Ma J, Jiang H. New insights into the antifibrotic effects of sorafenib on hepatic stellate cells and liver fibrosis. J Hepatol. 2010;53(1):132-144. doi:10.1016/j.jhep.2010.02.027
23. Thompson AJ, Patel K. Antifibrotic therapies: Will we ever get there? Curr Gastroenterol Rep. 2010;12(1):23-29. doi:10.1007/s11894-009-0080-9
24. Sallam AM, Esmat A, Abdel-Naim AB. Cucurbitacin-B attenuates CCl 4 -induced hepatic fibrosis in mice through inhibition of STAT-3. Chem Biol Drug Des. 2018;91(4):933-941. doi:10.1111/cbdd.13160
25. Liu PP, Liu HH, Sun SH, et al. Aspirin alleviates cardiac fibrosis in mice by inhibiting autophagy. Acta Pharmacol Sin. 2017;38(4):488-497. doi:10.1038/aps.2016.143
26. Johnston DE, Kroening C. Mechanism of early carbon tetrachloride toxicity in cultured rat hepatocytes. Pharmacol Toxicol. 1998;83(6):231-239. doi:10.1111/j.1600-0773.1998.tb01475.x
27. Brattin WJ, Glende EA, Recknagel RO. Pathological mechanisms in carbon tetrachloride hepatotoxicity. J Free Radic Biol Med. 1985;1(1):27-38. doi:https://doi.org/10.1016/0748-5514(85)90026-1
28. Recknagel RO, Glende EA, Dolak JA, Waller RL. Mechanisms of carbon tetrachloride toxicity. Pharmacol Ther. 1989;43(1):139-154. doi:https://doi.org/10.1016/0163-7258(89)90050-8
29. Bahcecioglu IH, Koca SS, Poyrazoglu OK, et al. Hepatoprotective effect of infliximab, an anti-TNF-α agent, on carbon tetrachloride-induced hepatic fibrosis. Inflammation. 2008;31(4):215-221. doi:10.1007/s10753-008-9067-1
30. Yachi R, Igarashi O, Kiyose C. Protective effects of vitamin E analogs against carbon tetrachloride-induced fatty liver in rats. J Clin Biochem Nutr. 2010;47(2):148-154.
31. Subramanian V. Hepatoprotective activity of Brassica oleracea Italica against carbon tetrachloride induced in albino rats. J Pharm Res. 2011;4(4):1143.
32. KAWANO O, SAWABE T, MISAKI N, FUKAWA K. STUDIES ON COMBINATION DOSING (III) ASPIRIN AND ETHENZAMIDE. Jpn J Pharmacol. 1978;28(6):829-835. doi:10.1254/jjp.28.829
33. Carlson LM, Rasmuson A, Idborg H, et al. Low-dose aspirin delays an inflammatory tumor progression in vivo in a transgenic mouse model of neuroblastoma. Carcinogenesis. 2013;34(5):1081-1088. doi:10.1093/carcin/bgt009
34. Yoshida S, Ikenaga N, Liu SB, et al. Extrahepatic Platelet-Derived Growth Factor-β, Delivered by Platelets, Promotes Activation of Hepatic Stellate Cells and Biliary Fibrosis in Mice. Gastroenterology. 2014;147(6):1378-1392. doi:https://doi.org/10.1053/j.gastro.2014.08.038
35. Dabhi JK, Solanki JK, Mehta A. Antiatherosclerotic activity of ibuprofen, a non-selective COX inhibitor- An animal study. Indian J Exp Biol. 2008;46(6):476-481.
36. Hardie DG. AMP-activated protein kinase: A master switch in glucose and lipid metabolism. Rev Endocr Metab Disord. 2004;5(2):119-125. doi:10.1023/B:REMD.0000021433.63915.bb
37. Towler MC, Hardie DG. AMP-activated protein kinase in metabolic control and insulin signaling. Circ Res. 2007;100(3):328-341. doi:10.1161/01.RES.0000256090.42690.05
38. Jeon SM. Regulation and function of AMPK in physiology and diseases. Exp Mol Med. 2016;48(7):1-13. doi:10.1038/EMM.2016.81
39. Yang Y, Zhao Z, Liu Y, Kang X, Zhang H, Meng M. Suppression of oxidative stress and improvement of liver functions in mice by ursolic acid via LKB1-AMP-activated protein kinase signaling. J Gastroenterol Hepatol. 2015;30(3):609-618. doi:10.1111/jgh.12723
40. King JD, Lee J, Riemen CE, et al. Role of binding and nucleoside diphosphate kinase A in the regulation of the cystic fibrosis transmembrane conductance regulator by AMP-activated protein kinase. J Biol Chem. 2012;287(40):33389-33400. doi:10.1074/jbc.M112.396036
41. Hermida N, Markl A, Hamelet J, et al. HMGCoA reductase inhibition reverses myocardial fibrosis and diastolic dysfunction through AMP-activated protein kinase activation in a mouse model of metabolic syndrome. Cardiovasc Res. 2013;99(1):44-54. doi:10.1093/cvr/cvt070
42. Kim H, Moon SY, Kim JS, et al. Activation of AMP-activated protein kinase inhibits ER stress and renal fibrosis. Am J Physiol-Ren Physiol. 2015;308(3):F226-F236. doi:10.1152/ajprenal.00495.2014
43. Juban G, Saclier M, Yacoub-Youssef H, et al. AMPK Activation Regulates LTBP4-Dependent TGF-β1 Secretion by Pro-inflammatory Macrophages and Controls Fibrosis in Duchenne Muscular Dystrophy. Cell Rep. 2018;25(8):2163-2176.e6. doi:10.1016/j.celrep.2018.10.077
44. Hardie DG, Ross FA, Hawley SA. AMPK: A nutrient and energy sensor that maintains energy homeostasis. Nat Rev Mol Cell Biol. 2012;13(4):251-262. doi:10.1038/nrm3311
45. Kumar P, Smith T, Rahman K, Thorn NE, Anania FA. Adiponectin agonist ADP355 attenuates CCL4-induced liver fibrosis in mice. PLoS One. 2014;9(10). doi:10.1371/journal.pone.0110405
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Dec 16, 2023
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Jumana Fouad Ahmed Hariri , Ahmed Esmat Amer , Huda Mohammed Alkreathy. (2023). The Potential Antifibrotic Effect of AMPK Activator(s) in Experimentally-Induced Hepatic Fibrosis: An Invivo Animal Study. Journal of Population Therapeutics and Clinical Pharmacology, 30(17), 793-807. https://doi.org/10.53555/jptcp.v30i17.3738
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All articles published in JPTCP are licensed under Copyright Creative Commons Attribution-NonCommercial 4.0 International License.
How to Cite
Jumana Fouad Ahmed Hariri , Ahmed Esmat Amer , Huda Mohammed Alkreathy. (2023). The Potential Antifibrotic Effect of AMPK Activator(s) in Experimentally-Induced Hepatic Fibrosis: An Invivo Animal Study. Journal of Population Therapeutics and Clinical Pharmacology, 30(17), 793-807. https://doi.org/10.53555/jptcp.v30i17.3738