AM-1241 CB2 Receptor Agonist Attenuates Inflammation, Apoptosis and Stimulate Progenitor Cells in Bile Duct Ligated Rats

Authors

  • Hesham M. Mahmoud Cairo University Kasr Alainy, Faculty of Medicine, Pharmacology, Cairo, Egypt
  • Mona Osman Cairo University Kasr Alainy, Faculty of Medicine, Pharmacology, Cairo, Egypt
  • Osama Elshabrawy National Research Centre, Pharmacology, Cairo, Egypt
  • Heba M. I. Abdallah National Research Centre, Pharmacology, Cairo, Egypt
  • Ahmed Khairallah Pharmacology Department, National Research Centre, Dokki, Cairo 11211, Egypt

DOI:

https://doi.org/10.3889/oamjms.2019.194

Keywords:

Cannabinoid receptor 2, AM1241, Hepatic progenitor cells, IL-10, p53, Bile duct ligation, Liver fibrosis, CD34

Abstract

BACKGROUND: The cannabinoid receptor 2 (CB2) plays a pleiotropic role in the innate immunity and is considered a crucial mediator of liver disease. Cannabinoid CB2 receptor activation has been reported to attenuate liver fibrosis in CCl4 exposed mice and also plays a potential role in liver regeneration in a mouse model of I/R and protection against alcohol-induced liver injury.

AIM: In this study, we investigated the impact of CB2 receptors on the antifibrotic and regenerative process associated with cholestatic liver injury.

METHODS: Twenty-six rats had bile duct ligation co-treated with silymarin and AM1241 for 3 consecutive weeks. Serum hepatotoxicity markers were determined, and histopathological evaluation was performed.

RESULTS: Following bile duct ligation (BDL) for 3 weeks, there was increased aminotransferase levels, marked inflammatory infiltration and hepatocyte apoptosis with induced oxidative stress, as reflected by increased lipid peroxidation. Conversely, following treatment with the CB2 agonist, AM-1241, BDL rats displayed a reduction in liver injury and attenuation of fibrosis as reflected by expression of hydroxyproline and α-smooth muscle actin. AM1241 treatment also significantly attenuated lipid peroxidation end-products, p53-dependent apoptosis and also attenuated inflammatory process by stimulating IL-10 production. Moreover, AM1241 treated rats were associated with significant expression of hepatic progenitor/oval cell markers.

CONCLUSION: In conclusion, this study points out that CB2 receptors reduce liver injury and promote liver regeneration via distinct mechanisms including IL-10 dependent inhibition of inflammation, reduction of p53-reliant apoptosis and through stimulation of oval/progenitor cells. These results suggest that CB2 agonists display potent hepatoregenrative properties, in addition to their antifibrogenic effects.

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References

Caballería L, Pera G, Arteaga I, Rodríguez L, Alumà A, Morillas RM, de la Ossa N, Díaz A, Expósito C, Miranda D, Sánchez C. High prevalence of liver fibrosis among European adults with unknown liver disease: a population-based study. Clinical Gastroenterology and Hepatology. 2018; 16(7):1138-45. https://doi.org/10.1016/j.cgh.2017.12.048 PMid:29452268

Zois CD, Baltayiannis GH, Karayiannis P, Tsianos EV. Systematic review: hepatic fibrosis–regression with therapy. Alimentary pharmacology & therapeutics. 2008; 28(10):1175-87. https://doi.org/10.1111/j.1365-2036.2008.03840.x PMid:18761707

Purohit V, Rapaka R, Shurtleff D. Role of cannabinoids in the development of fatty liver (steatosis). AAPS J. 2010; 12(2):233-7. https://doi.org/10.1208/s12248-010-9178-0 PMid:20204561 PMCid:PMC2844512

Mallat A, Lotersztajn S. Cannabinoid receptors as novel therapeutic targets for the management of non-alcoholic steatohepatitis. Diabetes & metabolism. 2008; 34(6):680-4. https://doi.org/10.1016/S1262-3636(08)74604-4

Jeong WI, Osei-Hyiaman D, Park O, Liu J, Bátkai S, Mukhopadhyay P, Horiguchi N, Harvey-White J, Marsicano G, Lutz B, Gao B. Paracrine activation of hepatic CB1 receptors by stellate cell-derived endocannabinoids mediates alcoholic fatty liver. Cell metab. 2008; 7(3):227-35. https://doi.org/10.1016/j.cmet.2007.12.007 PMid:18316028

Julien B, Grenard P, Teixeira-Clerc F, Van Nhieu JT, Li L, Karsak M, Zimmer A, Mallat A, Lotersztajn S. Antifibrogenic role of the cannabinoid receptor CB2 in the liver. Gastroenterology. 2005; 128(3):742-55. https://doi.org/10.1053/j.gastro.2004.12.050 PMid:15765409

Lotersztajn S, Teixeiraâ€Clerc F, Julien B, Deveaux V, Ichigotani Y, Manin S, Tranâ€Vanâ€Nhieu J, Karsak M, Zimmer A, Mallat A. CB2 receptors as new therapeutic targets for liver diseases. British journal of pharmacology. 2008; 153(2):286-9. https://doi.org/10.1038/sj.bjp.0707511 PMid:17952109 PMCid:PMC2219531

Teixeiraâ€Clerc F, Belot MP, Manin S, Deveaux V, Cadoudal T, Chobert MN, Louvet A, Zimmer A, Tordjmann T, Mallat A, Lotersztajn S. Beneficial paracrine effects of cannabinoid receptor 2 on liver injury and regeneration. Hepatology. 2010; 52(3):1046-59. https://doi.org/10.1002/hep.23779 PMid:20597071 PMCid:PMC3246453

Bátkai S, Osei-Hyiaman D, Pan H, El-Assal O, Rajesh M, Mukhopadhyay P, Hong F, Harvey-White J, Jafri A, Hasko G, Huffman JW. Cannabinoid-2 receptor mediates protection against hepatic ischemia/reperfusion injury. The FASEB Journal. 2007; 21(8):1788-800. https://doi.org/10.1096/fj.06-7451com PMid:17327359 PMCid:PMC2228252

Rajesh M, Mukhopadhyay P, Bátkai S, Haskó G, Liaudet L, Huffman JW, Csiszar A, Ungvari Z, Mackie K, Chatterjee S, Pacher P. CB2-receptor stimulation attenuates TNF-α-induced human endothelial cell activation, transendothelial migration of monocytes, and monocyte-endothelial adhesion. American journal of physiology. Heart and circulatory physiology. 2007; 293(4):H2210-8. https://doi.org/10.1152/ajpheart.00688.2007 PMid:17660390 PMCid:PMC2229632

Mukhopadhyay P, et al. Role of superoxide, nitric oxide, and peroxynitrite in doxorubicin-induced cell death in vivo and in vitro. Am J Physiol Heart Circ Physiol. 2009. 296(5):H1466-83. https://doi.org/10.1152/ajpheart.00795.2008 PMid:19286953 PMCid:PMC2685360

Moon KH, Hood BL, Mukhopadhyay P, Rajesh M, Abdelmegeed MA, Kwon YI, Conrads TP, Veenstra TD, Song BJ, Pacher P. Oxidative inactivation of key mitochondrial proteins leads to dysfunction and injury in hepatic ischemia reperfusion. Gastroenterology. 2008; 135(4):1344-57. https://doi.org/10.1053/j.gastro.2008.06.048 PMid:18778711 PMCid:PMC2597302

Abe Y, Hines IN, Zibari G, Pavlick K, Gray L, Kitagawa Y, Grisham MB. Mouse model of liver ischemia and reperfusion injury: method for studying reactive oxygen and nitrogen metabolites in vivo. Free Radical Biology and Medicine. 2009; 46(1):1-7. https://doi.org/10.1016/j.freeradbiomed.2008.09.029 PMid:18955130 PMCid:PMC2740994

Hellerbrand C, Schattenberg JM, Peterburs P, Lechner A, Brignoli R. The potential of silymarin for the treatment of hepatic disorders. Clinical Phytoscience. 2017; 2(1):7. https://doi.org/10.1186/s40816-016-0019-2

Kilkenny C, Browne W, Cuthill IC, Emerson M, Altman DG. Animal research: reporting in vivo experiments: the ARRIVE guidelines. British journal of pharmacology. 2010; 160(7):1577-9. https://doi.org/10.1111/j.1476-5381.2010.00872.x PMid:20649561 PMCid:PMC2936830

Kountouras J, Billing BH, Scheuer PJ. Prolonged bile duct obstruction: a new experimental model for cirrhosis in the rat. British journal of experimental pathology. 1984; 65(3):305. PMid:6743531 PMCid:PMC2040968

Struck MB, Andrutis KA, Ramirez HE, Battles AH. Effect of a short-term fast on ketamine–xylazine anesthesia in rats. Journal of the American Association for Laboratory Animal Science. 2011; 50(3):344-8. PMid:21640029 PMCid:PMC3103284

Aller MA, Arias JL, Prieto I, Arias J. A suitable microsurgical method for obstructive cholestasis in the rat. Protocol Exchange. 2010. https://doi.org/10.1038/nprot.2010.56

Fahmy Ahmed A, Fouad Mahmoud M, Arafat Ouf M, El-Fathaah EA. Aminoguanidine potentiates the hepatoprotective effect of silymarin in CCL4 treated rats. Annals of hepatology. 2016; 10(2):207-15.

Barutta F, Piscitelli F, Pinach S, Bruno G, Gambino R, Rastaldi MP, Salvidio G, Di Marzo V, Perin PC, Gruden G. Protective role of cannabinoid receptor type 2 in a mouse model of diabetic nephropathy. Diabetes. 2011; 60(9):2386-96. https://doi.org/10.2337/db10-1809 PMid:21810593 PMCid:PMC3161308

Babson AL, Greeley SJ, Coleman CM, Phillips GE. Phenolphthalein monophosphate as a substrate for serum alkaline phosphatase. Clinical chemistry. 1966; 12(8):482-90. PMid:5917856

Doumas BT, Perry BW, Sasse EA, Straumfjord JV. Standardization in bilirubin assays: evaluation of selected methods and stability of bilirubin solutions. Clinical chemistry. 1973; 19(9):984-93. PMid:4744825

Reitman S, Frankel S. A colorimetric method for the determination of serum glutamic oxalacetic and glutamic pyruvic transaminases. American journal of clinical pathology. 1957; 28(1):56-63. https://doi.org/10.1093/ajcp/28.1.56 PMid:13458125

Yuksel Y, Guven M, Kaymaz B, Sehitoglu MH, Aras AB, Akman T, Tosun M, Cosar M. Effects of aloe vera on spinal cord Ischemia–Reperfusion injury of rats. Journal of Investigative Surgery. 2016; 29(6):389-98. https://doi.org/10.1080/08941939.2016.1178358 PMid:27142763

Atli O, Baysal M, Aydogan-Kilic G, Kilic V, Ucarcan S, Karaduman B, Ilgin S. Sertraline-induced reproductive toxicity in male rats: evaluation of possible underlying mechanisms. Asian journal of andrology. 2017; 19(6):672. https://doi.org/10.4103/1008-682X.192637 PMid:27976631 PMCid:PMC5676427

Li J, Yan HT, Che JX, Bai SR, Qiu QM, Ren L, Pan F, Sun XQ, Tian FZ, Li DX, Tang LJ. Effects of neurolytic celiac plexus block on liver regeneration in rats with partial hepatectomy. PloS one. 2013; 8(9):e73101. https://doi.org/10.1371/journal.pone.0073101 PMid:24039865 PMCid:PMC3764180

Lee K, Lee B, Lee MH, Kim B, Chinannai KS, Ham I, Choi HY. Effect of Ampelopsis Radix on wound healing in scalded rats. BMC complementary and alternative medicine. 2015; 15(1):213. https://doi.org/10.1186/s12906-015-0751-z PMid:26152211 PMCid:PMC4495638

Naidu S, Peterson ML, Spear BT. Alpha-fetoprotein related gene (ARG): a new member of the albumin gene family that is no longer functional in primates. Gene. 2010; 449(1-2):95-102. https://doi.org/10.1016/j.gene.2009.08.014 PMid:19733224 PMCid:PMC2799041

Omori N, Omori M, Evarts RP, Teramoto T, Miller MJ, Hoang TN, Thorgeirsson SS. Partial cloning of rat CD34 cDNA and expression during stem cellâ€dependent liver regeneration in the adult rat. Hepatology. 1997; 26(3):720-7. https://doi.org/10.1002/hep.510260325 PMid:9303503

Bancroft JD, Stevens A. Theory and Practice of Histological Techniques. Churchill Livingstone, 1996.

Coons AH, Creech HJ, Jones RN. Immunological properties of an antibody containing a fluorescent group. Proceedings of the Society for Experimental Biology and Medicine. 1941; 47(2):200-2. https://doi.org/10.3181/00379727-47-13084P

Filimonova G, Tokin II, Tokin IB, Hussar P. An assessment of morphometric analysis in liver biopsy specimens of patients with chronic hepatitis C. Papers on Anthropology. 2010; (19):69-80.

Curtis MJ, Abernethy DR. Advice on statistical analysis, and new journal guidance for experimental design and analysis. Pharmacology research & perspectives. 2015; 3(1):e00095. https://doi.org/10.1002/prp2.95 PMid:25692014 PMCid:PMC4317227

Deveaux V, Cadoudal T, Ichigotani Y, Teixeira-Clerc F, Louvet A, Manin S, Tran-Van Nhieu J, Belot MP, Zimmer A, Even P, Cani PD. Cannabinoid CB2 receptor potentiates obesity-associated inflammation, insulin resistance and hepatic steatosis. PLoS One. 2009; 4(6):e5844. https://doi.org/10.1371/journal.pone.0005844 PMid:19513120 PMCid:PMC2688760

Tarcin O, Basaranoglu M, Tahan V, Tahan G, Sücüllü I, Yilmaz N, Sood G, Snyder N, Hilman G, Celikel C, Tözün N. Time course of collagen peak in bile duct-ligated rats. BMC gastroenterology. 2011; 11(1):45. https://doi.org/10.1186/1471-230X-11-45 PMid:21527001 PMCid:PMC3117813

Copple BL, Jaeschke H, Klaassen CD. Oxidative stress and the pathogenesis of cholestasis. Semin Liver Dis. 2010; 30(2):195-204. https://doi.org/10.1055/s-0030-1253228 PMid:20422501

Gujral JS, Farhood A, Bajt ML, Jaeschke H. Neutrophils aggravate acute liver injury during obstructive cholestasis in bile duct–ligated mice. Hepatology. 2003; 38(2):355-63. https://doi.org/10.1053/jhep.2003.50341 PMid:12883479

Friedman SL. Liver fibrosis–from bench to bedside. Journal of hepatology. 2003; 38:38-53. https://doi.org/10.1016/S0168-8278(02)00429-4

Mu-oz-Luque J, Ros J, Fernández-Varo G, Tugues S, Morales-Ruiz M, Alvarez CE, Friedman SL, Arroyo V, Jiménez W. Regression of fibrosis after chronic stimulation of cannabinoid CB2 receptor in cirrhotic rats. Journal of Pharmacology and Experimental Therapeutics. 2008; 324(2):475-83. https://doi.org/10.1124/jpet.107.131896 PMid:18029545 PMCid:PMC2887659

Louvet A, Teixeiraâ€Clerc F, Chobert MN, Deveaux V, Pavoine C, Zimmer A, Pecker F, Mallat A, Lotersztajn S. Cannabinoid CB2 receptors protect against alcoholic liver disease by regulating Kupffer cell polarization in mice. Hepatology. 2011; 54(4):1217-26. https://doi.org/10.1002/hep.24524 PMid:21735467

Guillot A, Hamdaoui N, Bizy A, Zoltani K, Souktani R, Zafrani ES, Mallat A, Lotersztajn S, Lafdil F. Cannabinoid receptor 2 counteracts interleukinâ€17â€induced immune and fibrogenic responses in mouse liver. Hepatology. 2014; 59(1):296-306. https://doi.org/10.1002/hep.26598 PMid:23813495

Jackson AR, Nagarkatti P, Nagarkatti M. Anandamide attenuates Th-17 cell-mediated delayed-type hypersensitivity response by triggering IL-10 production and consequent microRNA induction. PloS one. 2014; 9(4):e93954. https://doi.org/10.1371/journal.pone.0093954 PMid:24699635 PMCid:PMC3974854

Sun YY, Li XF, Meng XM, Huang C, Zhang L, Li J. Macrophage phenotype in liver injury and repair. Scandinavian journal of immunology. 2017; 85(3):166-74. https://doi.org/10.1111/sji.12468 PMid:27491503

Naito Y, Takagi T, Higashimura Y. Heme oxygenase-1 and anti-inflammatory M2 macrophages. Archives of biochemistry and biophysics. 2014; 564:83-8. https://doi.org/10.1016/j.abb.2014.09.005 PMid:25241054

Hull TD, Agarwal A, George JF. The mononuclear phagocyte system in homeostasis and disease: a role for heme oxygenase-1. Antioxidants & redox signaling. 2014; 20(11):1770-88. https://doi.org/10.1089/ars.2013.5673 PMid:24147608 PMCid:PMC3961794

Guo B. IL-10 modulates Th17 pathogenicity during autoimmune diseases. Journal of clinical & cellular immunology. 2016; 7(2):400. https://doi.org/10.4172/2155-9899.1000400 PMid:27308096 PMCid:PMC4905582

Huber S, Gagliani N, Esplugues E, O'Connor Jr W, Huber FJ, Chaudhry A, Kamanaka M, Kobayashi Y, Booth CJ, Rudensky AY, Roncarolo MG. Th17 cells express interleukin-10 receptor and are controlled by Foxp3− and Foxp3+ regulatory CD4+ T cells in an interleukin-10-dependent manner. Immunity. 2011; 34(4):554-65. https://doi.org/10.1016/j.immuni.2011.01.020 PMid:21511184 PMCid:PMC3113617

Gu Y, Yang J, Ouyang X, Liu W, Li H, Yang J, Bromberg J, Chen SH, Mayer L, Unkeless JC, Xiong H. Interleukin 10 suppresses Th17 cytokines secreted by macrophages and T cells. European journal of immunology. 2008; 38(7):1807-13. https://doi.org/10.1002/eji.200838331 PMid:18506885 PMCid:PMC2733944

Pacher P, Hasko G. Endocannabinoids and cannabinoid receptors in ischaemia–reperfusion injury and preconditioning. British journal of pharmacology. 2008; 153(2):252-62. https://doi.org/10.1038/sj.bjp.0707582 PMid:18026124 PMCid:PMC2219536

Jaeschke H. Mechanisms of Liver Injury. II. Mechanisms of neutrophil-induced liver cell injury during hepatic ischemia-reperfusion and other acute inflammatory conditions. American Journal of Physiology-Gastrointestinal and Liver Physiology. 2006; 290(6):G1083-8. https://doi.org/10.1152/ajpgi.00568.2005 PMid:16687579

Wang Y, Mukhopadhyay P, Cao Z, Wang H, Feng D, Haskó G, Mechoulam R, Gao B, Pacher P. Cannabidiol attenuates alcohol-induced liver steatosis, metabolic dysregulation, inflammation and neutrophil-mediated injury. Scientific reports. 2017; 7(1):12064. https://doi.org/10.1038/s41598-017-10924-8 PMid:28935932 PMCid:PMC5608708

Giacoppo S, Gugliandolo A, Trubiani O, Pollastro F, Grassi G, Bramanti P, Mazzon E. Cannabinoid CB2 receptors are involved in the protection of RAW264. 7 macrophages against the oxidative stress: an in vitro study. European journal of histochemistry: EJH. 2017; 61(1):2749. https://doi.org/10.4081/ejh.2017.2749 PMid:28348416 PMCid:PMC5289301

Krstic J, Galhuber M, Schulz T, Schupp M, Prokesch A. P53 as a dichotomous regulator of liver disease: The dose makes the medicine. International journal of molecular sciences. 2018; 19(3):921. https://doi.org/10.3390/ijms19030921 PMid:29558460 PMCid:PMC5877782

Castro RE, Amaral JD, Solá S, Kren BT, Steer C, Rodrigues CM. Differential regulation of cyclin D1 and cell death by bile acids in primary rat hepatocytes. American Journal of Physiology-Gastrointestinal and Liver Physiology. 2007; 293(1):G327-34. https://doi.org/10.1152/ajpgi.00093.2007 PMid:17431217

Ferreira DM, Afonso MB, Rodrigues PM, Simão AL, Pereira DM, Borralho PM, Rodrigues CM, Castro RE. c-Jun N-terminal kinase 1/c-Jun activation of the p53/microRNA 34a/sirtuin 1 pathway contributes to apoptosis induced by deoxycholic acid in rat liver. Molecular and cellular biology. 2014; 34(6):1100-20. https://doi.org/10.1128/MCB.00420-13 PMid:24421392 PMCid:PMC3958031

Tian XF, Ji FJ, Zang HL, Cao H. Activation of the miR-34a/SIRT1/p53 signaling pathway contributes to the progress of liver fibrosis via inducing apoptosis in hepatocytes but not in HSCs. PLoS One. 2016; 11(7):e0158657. https://doi.org/10.1371/journal.pone.0158657 PMid:27387128 PMCid:PMC4936740

Eltablawy NA, Ogaly HA. Responsiveness of p53 expression and genetic mutation to CCl4-induced DNA damage in rat's liver. International Journal of Genomics and Proteomics, ISSN. 2014:0976-4887.

Guo XL, Liang B, Wang XW, Fan FG, Jin J, Lan R, Yang JH, Wang XC, Jin L, Cao Q. Glycyrrhizic acid attenuates CCl4-induced hepatocyte apoptosis in rats via a p53-mediated pathway. World Journal of Gastroenterology: WJG. 2013; 19(24):3781-91. https://doi.org/10.3748/wjg.v19.i24.3781 PMid:23840116 PMCid:PMC3699029

Cao Z, Mulvihill MM, Mukhopadhyay P, Xu H, Erdélyi K, Hao E, Holovac E, Haskó G, Cravatt BF, Nomura DK, Pacher P. Monoacylglycerol lipase controls endocannabinoid and eicosanoid signaling and hepatic injury in mice. Gastroenterology. 2013; 144(4):808-17. https://doi.org/10.1053/j.gastro.2012.12.028 PMid:23295443 PMCid:PMC3608818

Lotowska JM, Sobaniec-Lotowska ME, Lebensztejn DM, Daniluk U, Sobaniec P, Sendrowski K, Daniluk J, Reszec J, Debek W. Ultrastructural Characteristics of Rat Hepatic Oval Cells and Their Intercellular Contacts in the Model of Biliary Fibrosis: New Insights into Experimental Liver Fibrogenesis. Gastroenterology research and practice. 2017; 2017:2721547. https://doi.org/10.1155/2017/2721547 PMid:28769978 PMCid:PMC5523291

Roskams TA, Libbrecht L, Desmet VJ. Progenitor cells in diseased human liver. Semin Liver Dis. 2003; 23(4): 385-96. https://doi.org/10.1055/s-2004-815564 PMid:14722815

Lowes KN, Croager EJ, Olynyk JK, Abraham LJ, Yeoh GC. Oval cellâ€mediated liver regeneration: Role of cytokines and growth factors. Journal of gastroenterology and hepatology. 2003; 18(1):4-12. https://doi.org/10.1046/j.1440-1746.2003.02906.x PMid:12519217

Sawitza I, Kordes C, Götze S, Herebian D, Häussinger D. Bile acids induce hepatic differentiation of mesenchymal stem cells. Scientific reports. 2015; 5:13320. https://doi.org/10.1038/srep13320 PMid:26304833 PMCid:PMC4548444

Olynyk JK, Yeoh GC, Ramm GA, Clarke SL, Hall PD, Britton RS, Bacon BR, Tracy TF. Gadolinium chloride suppresses hepatic oval cell proliferation in rats with biliary obstruction. The American journal of pathology. 1998; 152(2):347-52. PMid:9466559 PMCid:PMC1857969

Palazuelos J, Aguado T, Egia A, Mechoulam R, Guzmán M, Galve-Roperh I, Palazuelos J, Aguado T, Egia A, Mechoulam R, GuzmaÌn M. Non-psychoactive CB2 cannabinoid agonists stimulate neural progenitor proliferation. The FASEB Journal. 2006; 20(13):2405-7. https://doi.org/10.1096/fj.06-6164fje PMid:17015409

Wang Y, Ma S, Wang Q, Hu W, Wang D, Li X, Su T, Qin X, Zhang X, Ma K, Chen J. Effects of cannabinoid receptor type 2 on endogenous myocardial regeneration by activating cardiac progenitor cells in mouse infarcted heart. Science China Life Sciences. 2014; 57(2):201-8. https://doi.org/10.1007/s11427-013-4604-z PMid:24430557

Published

2019-03-29

How to Cite

1.
Mahmoud HM, Osman M, Elshabrawy O, Abdallah HMI, Khairallah A. AM-1241 CB2 Receptor Agonist Attenuates Inflammation, Apoptosis and Stimulate Progenitor Cells in Bile Duct Ligated Rats. Open Access Maced J Med Sci [Internet]. 2019 Mar. 29 [cited 2024 Mar. 28];7(6):925-36. Available from: https://oamjms.eu/index.php/mjms/article/view/oamjms.2019.194

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Section

A - Basic Science

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