Effect of Effervescent Formulation of Silymarin against Experimental Hepatotoxicity in Rats: Involvement of NRF2/HO-1, PI3K/AKT and TLR4/NFκB Pathways | ||||
| Journal of Applied Veterinary Sciences | ||||
| Article 4, Volume 10, Issue 2, April 2025, Page 18-27 PDF (550.46 K) | ||||
| Document Type: Original Article | ||||
| DOI: 10.21608/javs.2025.348491.1503 | ||||
 View on SCiNiTO | ||||
| Authors | ||||
Hany G. Attia  1; Bassim M.S.A. Mohamed 2; Saeed M. Alasmari3; Sahar S. AbdelRahman4; Mohamed Aleraky5; Abdulwahab Alqahtani6; Marawan Abd Elbaset7; Hany M. Fayed 8
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| 1Department of Pharmacognosy, College of Pharmacy, Najran University, Najran 66462, Saudi Arabia | ||||
| 2Department of Pharmacology, Medical Research and Clinical Studies Institute, National Research Centre, Cairo, P.O. 12622 Bohouth St. Dokki, Egypt | ||||
| 3Department of Biology, College of Science and Arts, Najran University, Najran 1988, Saudi Arabia 4Department of Pathology, Faculty of Veterinary Medicine, Cairo University, Giza, Egypt | ||||
| 4Department of Pathology, Faculty of Veterinary Medicine, Cairo University, Giza, Egypt | ||||
| 5Department of Clinical Pathology, College of Medicine, Najran University, Najran 1988, Saudi Arabia | ||||
| 6Department of Pediatrics, College of Medicine, Najran University, Najran 1988, Saudi Arabia | ||||
| 7Pharmacology Department, National Research Center of Egypt | ||||
| 8Assistant professor of pharmacology, Medical Research and Clinical Studies Institute, National Research Centre (NRC), Dokki, Giza, Egypt | ||||
| Abstract | ||||
| Despite the exploration of pharmaceutical and natural liver-protecting drugs, the number of hepatotoxicity deaths continues to rise. Milk thistle flavonoids, silymarin, have been widely investigated and demonstrated liver disease protection. Poor solubility and absorption restrict silymarin bioavailability. Effervescent formulations may boost silymarin absorption by improving gastrointestinal solubility. Our study compared the effectiveness of silymarin effervescent formulation in protecting the liver from thioacetamide (TAA)-induced oxidative damage at both low and high doses. Study findings may have an implication on chemotherapy-induced off-target harmful oxidative insult. 24 adult male rats were separated into normal control, hepatotoxic (TAA) (100 mg/kg body weight), and TAA plus silymarin (50 and 100 mg/kg b.wt) groups. Serum liver enzyme, hepatic antioxidant, lipid peroxidation, and inflammatory indicators were measured. The modest dose's great bioavailability was shown by its potency being identical to the doubled dose. TAA caused hepatic injury, as evidenced by elevated liver enzymes (ALT and AST) and tissue levels of MDA, TLR4, TGFβ1, TNF-α, IL-6, NF-κB, and p-NFκB. TAA also decreased tissue SOD, GSH, and HO-1 levels as well as Nrf2 level and expression. Increased gene expressions of Akt, PI3K, and TLR4 were observed. Silymarin's antioxidant and anti-inflammatory actions reduced hepatotoxicity via upregulating Nrf2/HO-1 and downregulating PI3K/Akt and TLR4/NFκB pathways. This study shows that effervescent silymarin formulation is a powerful bioavailable treatment for liver oxidative toxicity in chemotherapy-related toxicities. | ||||
| Keywords | ||||
| Chemotherapy; Nrf2/ HO-1; Oxidative Damage; PI3K/Akt; Silymarin effervescent formula; Thioacetamide; TLR4/ NFκB | ||||
| References | ||||
|
ABDEL-RAHMAN, R. F., FAYED, H. M., MOHAMED, M. A., HESSIN, A. F., ASAAD, G. F., ABDELRAHMAN, S. S., SALAMA, A. A., ARBID, M. S., and OGALY, H. A., 2023. Apigenin role against thioacetamide-triggered liver fibrosis: Deciphering the PPARγ/TGF-β1/NF-κB and the HIF/FAK/AKT pathways. Journal of Herbmed Pharmacology, 12: 202-213. https://doi.org/10.34172/jhp.2023.21
ABD EL-RAHMAN, S. S. and FAYED, H. M., 2019. Targeting AngII/AT1R signaling pathway by perindopril inhibits ongoing liver fibrosis in rat. Journal of Tissue Engineering and Regenerative Medicine, 13(12): 2131-2141..https://doi.org/10.1002/term.2940
ABDELBASET, M., SAFAR, M. M., MAHMOUD, S. S., NEGM, S. A., and AGHA, A. M., 2014. Red yeast rice and coenzyme Q10 as safe alternatives to surmount atorvastatin-induced myopathy in hyperlipidemic rats. Canadian Journal of Physiology and Pharmacology, 92: 481-489. https://doi.org/10.1139/cjpp-2013-0430
AHMAD, A., MUBARAK, N. M., JANNAT, F. T., ASHFAQ, T., SANTULLI, C., RIZWAN, M., NAJDA, A., BIN-JUMAH, M., ABDEL-DAIM, M. M., HUSSAIN, S., and ALI, S., 2021. A Critical Review on the Synthesis of Natural Sodium Alginate Based Composite Materials: An Innovative Biological Polymer for Biomedical Delivery Applications. Processes, 9(1). https://doi.org/10.3390/pr9010137
AHMAD, S., KHAN, J. A., KAUSAR, T. N., MAHNASHI, M. H., ALASIRI, A., ALQAHTANI, A. A., ALQAHTANI, T. S., WALBI, I. A., ALSHEHRI, O. M., ELNOUBI, O. A., MAHMOOD, F., and SADIQ, A., 2023. Preparation, Characterization and Evaluation of Flavonolignan Silymarin Effervescent Floating Matrix Tablets for Enhanced Oral Bioavailability. Molecules, 28(6). https://doi.org/10.3390/molecules28062606
ARAUZ, J., RAMOS-TOVAR, E., and MURIEL, P., 2016. Redox state and methods to evaluate oxidative stress in liver damage: From bench to bedside. Ann Hepatol, 15(2): 160-173.
AYOUB, I. M., EL-BASET, M. A., ELGHONEMY, M. M., BASHANDY, S. A. E., IBRAHIM, F. A. A., AHMED-FARID, O. A. H., EL GENDY, A. E.-N. G., AFIFI, S. M., ESATBEYOGLU, T., FARRAG, A. R. H., FARAG, M. A., and ELSHAMY, A. I., 2022. Chemical Profile of Cyperus laevigatus and Its Protective Effects against Thioacetamide-Induced Hepatorenal Toxicity in Rats. Molecules, 27: 6470.https://doi.org/10.3390/molecules27196470
BASHANDY, S. A. E., ABDELHAMEED, M. F., AHMED-FARID, O. A. H., MORSY, F. A., IBRAHIM, F. A. A., and ELBASET, M., 2022. The Pivotal role of Cerium oxide nanoparticles in thioacetamide induced hepatorenal injury in rat. Egyptian Journal of Chemistry, 65: 267-278. https://doi.org/10.21608/ejchem.2022.115482.5242 BRUCK, R., AEED, H., AVNI, Y., SHIRIN, H., MATAS, Z., SHAHMUROV, M., AVINOACH, I., ZOZULYA, G., WEIZMAN, N., and HOCHMAN, A., 2004. Melatonin inhibits nuclear factor kappa B activation and oxidative stress and protects against thioacetamide induced liver damage in rats. J Hepatol, 40(1): 86-93. https://doi.org/10.1016/S0168-8278(03)00504-X
CENGIZ, M., OZENIRLER, S., and ELBEG, S., 2015. Role of serum toll-like receptors 2 and 4 in non-alcoholic steatohepatitis and liver fibrosis. J Gastroenterol Hepatol, 30(7): 1190-1196. https://doi.org/10.1111/jgh.12924 CHEN, I. S., CHEN, Y.C., CHOU, C.H., CHUANG, R.F., SHEEN, L.Y., and CHIU, C.-H., 2012. Hepatoprotection of silymarin against thioacetamide-induced chronic liver fibrosis. Journal of the Science of Food and Agriculture, 92(7): 1441-1447. https://doi.org/10.1002/jsfa.4723
CHEN, T. M., SUBEQ, Y. M., LEE, R. P., CHIOU, T. W., and HSU, B. G., 2008. Single dose intravenous thioacetamide administration as a model of acute liver damage in rats. Int J Exp Pathol, 89(4): 223-231. https://doi.org/10.1111/j.1365-2613.2008.00576.x CICHOZ-LACH, H., and MICHALAK, A., 2014. Oxidative stress as a crucial factor in liver diseases. World J Gastroenterol, 20(25): 8082-8091.https://doi.org/10.3748/wjg.v20.i25.8082
DELIRE, B., STARKEL, P., and LECLERCQ, I., 2015. Animal Models for Fibrotic Liver Diseases: What We Have, What We Need, and What Is under Development. J Clin Transl Hepatol, 3(1): 53-66. https://doi.org/10.14218/JCTH.2014.00035
DELMAS, D., XIAO, J., VEJUX, A., and AIRES, V., 2020. Silymarin and Cancer: A Dual Strategy in Both in Chemoprevention and Chemosensitivity. Molecules, 25(9).https://doi.org/10.3390/molecules25092009
DI COSTANZO, A., and ANGELICO, R., 2019. Formulation Strategies for Enhancing the Bioavailability of Silymarin: The State of the Art. Molecules, 24(11).https://doi.org/10.3390/molecules24112155
ELBASET, M. A., MOHAMED, B. M. S. A., GAD, S. A., AFIFI, S. M., ESATBEYOGLU, T., ABDELRAHMAN, S. S., and FAYED, H. M., 2023a. Erythropoietin mitigated thioacetamide-induced renal injury via JAK2/STAT5 and AMPK pathway. Scientific Reports, 13: 14929. https://doi.org/10.1038/s41598-023-42210-1
ELBASET, M. A., MOHAMED, B. M. S. A., MOUSTAFA, P. E., MANSOUR, D. F., AFIFI, S. M., ESATBEYOGLU, T., ABDELRAHMAN, S. S. M., and FAYED, H. M., 2023b. Erythropoietin Suppresses the Hepatic Fibrosis Caused by Thioacetamide: Role of the PI3K/Akt and TLR4 Signaling Pathways. Oxidative Medicine and Cellular Longevity, 2023: 1-14.https://doi.org/10.1155/2023/5514248
ELBASET, M. A., NASR, M., IBRAHIM, B. M. M., AHMED-FARID, O. A. H., BAKEER, R. M., HASSAN, N. S., and AHMED, R. F., 2022. Curcumin nanoemulsion counteracts hepatic and cardiac complications associated with high-fat/high-fructose diet in rats. Journal of Food Biochemistry. https://doi.org/10.1111/jfbc.14442
ELBASET, M. A., SALEM, R. S., AYMAN, F., AYMAN, N., SHABAN, N., AFIFI, S. M., ESATBEYOGLU, T., ABDELAZIZ, M., and ELALFY, Z. S., 2022. Effect of Empagliflozin on Thioacetamide-Induced Liver Injury in Rats: Role of AMPK/SIRT-1/HIF-1α Pathway in Halting Liver Fibrosis. Antioxidants, 11: 2152. https://doi.org/10.3390/antiox11112152
GILLESSEN, A., and SCHMIDT, H. H., 2020. Silymarin as Supportive Treatment in Liver Diseases: A Narrative Review. Adv Ther, 37(4): 1279-1301. https://doi.org/10.1007/s12325-020-01251-y
HAJOVSKY, H., HU, G., KOEN, Y., SARMA, D., CUI, W., MOORE, D. S., STAUDINGER, J. L., and HANZLIK, R. P., 2012. Metabolism and toxicity of thioacetamide and thioacetamide S-oxide in rat hepatocytes. Chem Res Toxicol, 25(9): 1955-1963. https://doi.org/10.1021/tx3002719
HAZEKI, K., NIGORIKAWA, K., and HAZEKI, O., 2007. Role of phosphoinositide 3-kinase in innate immunity. Biol Pharm Bull, 30(9): 1617-1623.https://doi.org/10.1248/bpb.30.1617
HUSSEIN, R. M., SAWY, D. M., KANDEIL, M. A., and FARGHALY, H. S., 2021. Chlorogenic acid, quercetin, coenzyme Q10 and silymarin modulate Keap1-Nrf2/heme oxygenase-1 signaling in thioacetamide-induced acute liver toxicity. Life Sci, 277: 119460.https://doi.org/10.1016/j.lfs.2021.119460
JIA, C., ZHANG, Z., WANG, J., and NIE, Z., 2022. Silymarin protects the rats against paraquat-induced acute kidney injury via Nrf2. Human & Experimental Toxicology, 41: 09603271221074334. https://doi.org/10.1177/09603271221074334
JIAO, F., ZHANG, Z., HU, H., ZHANG, Y., and XIONG, Y., 2022. SIRT6 Activator UBCS039 Inhibits Thioacetamide-Induced Hepatic Injury In Vitro and In Vivo. Front Pharmacol., 13: 837544. https://doi.org/10.3389/fphar.2022.837544
KIDD, L. B., SCHABBAUER, G. A., LUYENDYK, J. P., HOLSCHER, T. D., TILLEY, R. E., TENCATI, M., and MACKMAN, N., 2008. Insulin activation of the phosphatidylinositol 3-kinase/protein kinase B (Akt) pathway reduces lipopolysaccharide-induced inflammation in mice. J Pharmacol Exp Ther, 326(1): 348-353. https://doi.org/10.1124/jpet.108.138891
KIM, H. Y., KIM, J. K., CHOI, J. H., JUNG, J. Y., OH, W. Y., KIM, D. C., LEE, H. S., KIM, Y. S., KANG, S. S., LEE, S. H., and LEE, S. M., 2010. Hepatoprotective effect of pinoresinol on carbon tetrachloride-induced hepatic damage in mice. J Pharmacol Sci, 112(1): 105-112.https://doi.org/10.1254/jphs.09234FP
LAMIA, S. S., EMRAN, T., RIKTA, J. K., CHOWDHURY, N. I., SARKER, M., JAIN, P., ISLAM, T., GIAS, Z. T., SHILL, M. C., and REZA, H. M., 2021. Coenzyme Q10 and Silymarin Reduce CCl4-Induced Oxidative Stress and Liver and Kidney Injury in Ovariectomized Rats-Implications for Protective Therapy in Chronic Liver and Kidney Diseases. Pathophysiology, 28(1): 50-63. https://doi.org/10.3390/pathophysiology28010005
LAWRENCE, T. 2009. The nuclear factor NF-kappaB pathway in inflammation. Cold Spring Harb Perspect Biol, 1(6): https://doi.org/10.1101/cshperspect.a001651
MANNA, S. K., MUKHOPADHYAY, A., VAN, N. T., and AGGARWAL, B. B., 1999. Silymarin suppresses TNF-induced activation of NF-kappa B, c-Jun N-terminal kinase, and apoptosis. J Immunol, 163(12): 6800-6809. https://doi.org/10.4049/jimmunol.163.12.6800
MOHAMED, M. Z., and HAFEZ, H. M., 2019. PI3K/Akt and Nrf2/HO-1 pathways involved in the hepatoprotective effect of verapamil against thioacetamide toxicity in rats. 38(4): 381-388. https://doi.org/10.1177/0960327118817099
MOUSSA, S. A. A., IBRAHIM, F. A. A., ELBASET, M. A., AZIZ, S. W., ABDELLATIF, N. A., ATTIA, A. M., EL TOUMY, S. A., SALIB, J. Y., and BASHANDY, S. A. E., 2022. Efficacy of goldenberry extract in chelated iron overload induced by obesity: Novel safety concept for the treatment of iron overloads diseases. Journal of Applied Biology and Biotechnology, 10: 92-100. https://doi.org/10.7324/JABB.2022.100413
OGALY, H. A., ABDEL-RAHMAN, R. F., MOHAMED, M. A. E., O, A. A., KHATTAB, M. S., and ABD-ELSALAM, R. M., 2022. Thymol ameliorated neurotoxicity and cognitive deterioration in a thioacetamide-induced hepatic encephalopathy rat model; involvement of the BDNF/CREB signaling pathway. Food Funct, 13(11): 6180-6194.https://doi.org/10.1039/D1FO04292K
PALLOTTINI, V., MARTINI, C., BASSI, A. M., ROMANO, P., NANNI, G., and TRENTALANCE, A., 2006. Rat HMGCoA reductase activation in thioacetamide-induced liver injury is related to an increased reactive oxygen species content. J Hepatol, 44(2): 368-374. https://doi.org/10.1016/j.jhep.2005.06.011
RAMADAN, A., AFIFI, N., YASSIN, N. Z., ABDEL-RAHMAN, R. F., ABD EL-RAHMAN, S. S., and FAYED, H. M., 2018. Mesalazine, an osteopontin inhibitor: The potential prophylactic and remedial roles in induced liver fibrosis in rats. Chemico-Biological Interactions, 289: 109-118.https://doi.org/10.1016/j.cbi.2018.05.002
RASLAN, M., ABDEL RAHMAN, R., FAYED, H., OGALY, H., and FIKRY, R., 2021. Metabolomic Profiling of Sansevieria trifasciata hort ex. Prain Leaves and Roots by HPLC-PAD-ESI/MS and its Hepatoprotective Effect via Activation of the NRF2/ARE Signaling Pathway in an Experimentally Induced Liver Fibrosis Rat Model. Egyptian Journal of Chemistry, 64(11): 6647-6671.https://doi.org/10.21608/ejchem.2021.78970.3877
SALLER, R., MEIER, R., and BRIGNOLI, R., 2001. The use of silymarin in the treatment of liver diseases. Drugs, 61(14): 2035-2063.https://doi.org/10.2165/00003495-200161140-00003
SARMA, D., and HANZLIK, R. P., 2011. Synthesis of carbon-14, carbon-13 and deuterium labeled forms of thioacetamide and thioacetamide S-oxide. J Labelled Comp Radiopharm, 54(13): 795-798. https://doi.org/10.1002/jlcr.1933
SHIRANI, K., YOUSEFSANI, B. S., SHIRANI, M., and KARIMI, G., 2020. Protective effects of naringin against drugs and chemical toxins induced hepatotoxicity: A review. 34(8): 1734-1744. https://doi.org/10.1002/ptr.6641
TALEB, S. A. A., ISMAIL, S. A., MOHAMED, M., MOURAD, R. M., and EL-HASHEMY, H. A., 2023. Promising synthesized bis (arylmethylidene) acetone -polymeric PCL emulsified nanoparticles with enhanced antimicrobial/antioxidant efficacy: in-vitro and in-vivo evaluation. OpenNano, 11: 100139. https://doi.org/10.1016/j.onano.2023.100139
TEKSOY, O., CENGIZ, M., KOROGLU, E., SAHINTÜRK, V., INAL, B., KACAR, S., and AYHANCI, A., 2020. Hepatoprotective effect of silymarin against thioacetamide induced hepatic injury in rats. Applied Biochemistry and Biotechnology, 191:528–539.
TROUTMAN, T. D., BAZAN, J. F., and PASARE, C., 2012. Toll-like receptors, signaling adapters and regulation of the pro-inflammatory response by PI3K. Cell Cycle, 11(19): 3559-3567.https://doi.org/10.4161/cc.21572
TSAI, J. H., LIU, J. Y., WU, T. T., HO, P. C., HUANG, C. Y., SHYU, J. C., HSIEH, Y. S., TSAI, C. C., and LIU, Y. C. 2008. Effects of silymarin on the resolution of liver fibrosis induced by carbon tetrachloride in rats. Journal of Viral Hepatitis, 15(7): 508-514. https://doi.org/10.1111/j.1365-2893.2008.00971.x
VARGAS-MENDOZA, N., MADRIGAL-SANTILLÁN, E., MORALES-GONZÁLEZ, A., ESQUIVEL-SOTO, J., ESQUIVEL-CHIRINO, C., GARCÍA-LUNA, Y. G.-R. M., GAYOSSO-DE-LUCIO, J. A., and MORALES-GONZÁLEZ, J. A., 2014. Hepatoprotective effect of silymarin. World J Hepatol, 6(3): 144-149. https://doi.org/10.4254/wjh.v6.i3.144
WANG, W., GUAN, C., SUN, X., ZHAO, Z., LI, J., FU, X., QIU, Y., HUANG, M., JIN, J., and HUANG, Z., 2016. Tanshinone IIA protects against acetaminophen-induced hepatotoxicity via activating the Nrf2 pathway. Phytomedicine, 23(6): 589.https://doi.org/10.1016/j.phymed.2016.02.022
WU, J. W., LIN, L. C., and TSAI, T. H., 2009. Drug-drug interactions of silymarin on the perspective of pharmacokinetics. J Ethnopharmacol, 121(2): 185-193.https://doi.org/10.1016/j.jep.2008.10.036
XU, J., ZHANG, X., MONESTIER, M., ESMON, N. L. and ESMON, C. T., 2011. Extracellular histones are mediators of death through TLR2 and TLR4 in mouse fatal liver injury. J Immunol, 187(5): 2626-2631. https://doi.org/10.4049/jimmunol.1003930
XU, X., HU, Y., ZHAI, X., LIN, M., CHEN, Z., TIAN, X., ZHANG, F., GAO, D., MA, X., LV, L. and YAO, J., 2013. Salvianolic acid A preconditioning confers protection against concanavalin A-induced liver injury through SIRT1-mediated repression of p66shc in mice. Toxicol Appl Pharmacol, 273(1): 68-76. https://doi.org/10.1016/j.taap.2013.08.021 ZAHIN, N., ANWAR, R., TEWARI, D., KABIR, M. T., SAJID, A., MATHEW, B., UDDIN, M. S., ALEYA, L. and ABDEL-DAIM, M. M., 2020. Nanoparticles and its biomedical applications in health and diseases: special focus on drug delivery. Environ Sci Pollut Res Int, 27(16): 19151-19168. https://doi.org/10.1007/s11356-019-05211-0
ZHAI, K.-F., DUAN, H., CAO, W.-G., GAO, G.-Z., SHAN, L.-L., FANG, X.-M. and ZHAO, L., 2016. Protective effect of Rabdosia amethystoides (Benth) Hara extract on acute liver injury induced by Concanavalin A in mice through inhibition of TLR4-NF-κB signaling pathway. Journal of Pharmacological Sciences, 130(2): 94-100. https://doi.org/10.1016/j.jphs.2015.12.006 | ||||
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