Agmatine Mitigates Acetaminophen-induced Acute Liver Injury in Mice: Involvement of HMGB1/RAGE/NFκB and Nrf2/HO-1 Signaling Pathways | ||||
Journal of Applied Veterinary Sciences | ||||
Article 9, Volume 10, Issue 3, July 2025, Page 90-105 PDF (710.74 K) | ||||
Document Type: Original Article | ||||
DOI: 10.21608/javs.2025.375952.1588 | ||||
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Authors | ||||
Ahmed M. Abdelhady; Mohammed Ayman; Marwa E. Abdelmageed ![]() ![]() | ||||
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, 35516, Mansoura, Egypt | ||||
Abstract | ||||
An overdose of acetaminophen (APAP) is considered one of the primary sources of drug-induced liver injury. This study aimed to explore the mechanism of agmatine (Agma) against APAP-induced acute liver injury (ALI) in mice. Mice were allocated into six groups: normal and Agma control, APAP, N-acetyl-L-cysteine (NAC) + APAP, Agma 100 mg/kg + APAP, and Agma 200 mg/kg + APAP. After 24 h from APAP injection, tissues and serum were gathered. Compared with APAP group, Agma pretreatment ameliorated liver injury, increased hepatic reduced glutathione (GSH), decreased serum biomarkers and decreased hepatic malondialdehyde (MDA) content. Additionally, Agma administration reduced hepatic levels of high-mobility group box 1 (HMGB1), receptor for advanced glycation end products (RAGE), Toll-like receptor 4 (TLR4), nuclear factor kappa B-p 65 subunit (NFκB-p65), tumor necrosis factor-alpha (TNF-α), and interleukin-6 (IL-6). Moreover, Agma administration decreased hepatic kelch-like ECH-associated protein 1 (Keap1) and up-regulated hepatic nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) levels. Noteworthy, the Agma 200 mg/kg effect on the reduction of hepatic inflammatory and oxidative stress biomarkers was more pronounced as compared to Agma 100 mg/kg prior APAP challenge. The study demonstrated that Agma can reduce inflammation and oxidative damage induced by APAP, and the mechanism may be related to the signal transduction factors on the HMGB1/RAGE/NFκB pathway and the Nrf2/HO-1 signaling pathway. | ||||
Keywords | ||||
Acetaminophen; Agmatine; Keap1; NFκB; Nrf2 | ||||
References | ||||
ABDELAZIZ, R.R., ABDELRAHMAN, R.S., and ABDELMAGEED, M.E., 2022. SB332235, a CXCR2 antagonist, ameliorates thioacetamide-induced hepatic encephalopathy through modulation of the PI3K/AKT pathways in rats. Neurotoxicology, 92, 110-121. https://doi.org/10.1016/j.neuro.2022.08.005 ABDELRAHMAN R.S., and ABDELMAGEED, M.E., 2024. Hepatoprotective effects of the xanthine oxidase inhibitor Febuxostat against thioacetamide-induced liver injury in rats: The role of the Nrf2/ HO-1 and TLR4/ NF-κB pathways. Food Chem Toxicol, 194:115087. https://doi.org/10.1016/j.fct.2024.115087
ABDELMAGEED, M.E., NADER, M.A.,andZAGHLOUL, M.S., 2021. Targeting HMGB1/TLR4/NF-κB signaling pathway by protocatechuic acid protects against l-arginine induced acute pancreatitis and multiple organs injury in rats. European journal of pharmacology, 906, 174279. https://doi.org/10.1016/j.ejphar.2021.174279 AHMED, S.M., LUO, L., NAMANI, A., WANG, X.J.,and TANG, X., 2017. Nrf2 signaling pathway: Pivotal roles in inflammation. Biochim Biophys Acta Mol Basis Dis, 1863, 585-597. https://doi.org/10.1016/j.bbadis.2016.11.005 ANTOINE, D.J., WILLIAMS, D.P., KIPAR, A., JENKINS, R.E., REGAN, S.L., SATHISH, J.G., KITTERINGHAM, N.R., and PARK, B.K., 2009. High-mobility group box-1 protein and keratin-18, circulating serum proteins informative of acetaminophen-induced necrosis and apoptosis in vivo. Toxicol Sci, 112, 521-531. https://doi.org/10.1093/toxsci/kfp235 ANTONIADES, C.G., QUAGLIA, A., TAAMS, L.S., MITRY, R.R., HUSSAIN, M., ABELES, R., POSSAMAI, L.A., BRUCE, M., MCPHAIL, M., STARLING, C., WAGNER, B., BARNARDO, A., POMPLUN, S., AUZINGER, G., BERNAL, W., HEATON, N., VERGANI, D., THURSZ, M.R., and WENDON, J., 2012. Source and characterization of hepatic macrophages in acetaminophen-induced acute liver failure in humans. Hepatology, 56, 735-746. https://doi.org/10.1002/hep.25657 ARNDT, M.A., BATTAGLIA, V., PARISI, E., LORTIE, M.J., ISOME, M., BASKERVILLE, C., PIZZO, D.P., IENTILE, R., COLOMBATTO, S., TONINELLO, A., and SATRIANO, J., 2009. The arginine metabolite agmatine protects mitochondrial function and confers resistance to cellular apoptosis. Am J Physiol Cell Physiol, 296, C1411-1419. https://doi.org/10.1152/ajpcell.00529.2008 AZAR, Y.O., BADAWI, G.A., ZAKI, H.F., and IBRAHIM, S.M., 2022. Agmatine-mediated inhibition of NMDA receptor expression and amelioration of dyskinesia via activation of Nrf2 and suppression of HMGB1/RAGE/TLR4/MYD88/NF-κB signaling cascade in rotenone lesioned rats. Life Sci, 311, 121049. https://doi.org/10.1016/j.lfs.2022.121049 BASTA, G., NAVARRA, T., DE SIMONE, P., DEL TURCO, S., GASTALDELLI, A., and FILIPPONI, F., 2011. What is the role of the receptor for advanced glycation end products-ligand axis in liver injury? Liver Transpl, 17, 633-640. https://doi.org/10.1002/lt.22306 BERKELS, R., TAUBERT, D., GRÜNDEMANN, D., and SCHÖMIG, E., 2004. Agmatine signaling: odds and threads. Cardiovasc Drug Rev, 22, 7-16. https://doi.org/10.1111/j.1527-3466.2004.tb00128.x BRESCIANI, A., MISSINEO, A., GALLO, M., CERRETANI, M., FEZZARDI, P., TOMEI, L., CICERO, D.O., ALTAMURA, S., SANTOPRETE, A., INGENITO, R., BIANCHI, E., PACIFICI, R., DOMINGUEZ, C., MUNOZ-SANJUAN, I., HARPER, S., TOLEDO-SHERMAN, L., and PARK, L.C., 2017. Nuclear factor (erythroid-derived 2)-like 2 (NRF2) drug discovery: Biochemical toolbox to develop NRF2 activators by reversible binding of Kelch-like ECH-associated protein 1 (KEAP1). Arch Biochem Biophys, 631, 31-41. https://doi.org/10.1016/j.abb.2017.08.003 BRODSKY, M., HIRSH, S., ALBECK, M., andSREDNI, B., 2009. Resolution of inflammation-related apoptotic processes by the synthetic tellurium compound, AS101 following liver injury. J Hepatol, 51, 491-503. https://doi.org/10.1016/j.jhep.2009.04.024 CAI, X., HUA, S., DENG, J., DU, Z., ZHANG, D., LIU, Z., KHAN, N.U., ZHOU, M., andCHEN, Z., 2022. Astaxanthin Activated the Nrf2/HO-1 Pathway to Enhance Autophagy and Inhibit Ferroptosis, Ameliorating Acetaminophen-Induced Liver Injury. ACS Appl Mater Interfaces, 14, 42887-42903. https://doi.org/10.1021/acsami.2c10506 CEDERBAUM, A.I., 2006. Cytochrome P450 2E1-dependent oxidant stress and upregulation of anti-oxidant defense in liver cells. J Gastroenterol Hepatol, 21 Suppl 3, S22-25. https://doi.org/10.1111/j.1440-1746.2006.04595.x CHAI, J., LUO, L., HOU, F., FAN, X., YU, J., MA, W., TANG, W., YANG, X., ZHU, J., KANG, W., YAN, J., andLIANG, H., 2016. Agmatine Reduces Lipopolysaccharide-Mediated Oxidant Response via Activating PI3K/Akt Pathway and Up-Regulating Nrf2 and HO-1 Expression in Macrophages. PLoS One, 11, e0163634. https://doi.org/10.1371/journal.pone.0163634 CHALASANI, N.P., MADDUR, H., RUSSO, M.W., WONG, R.J., andREDDY, K.R., 2021. ACG Clinical Guideline: Diagnosis and Management of Idiosyncratic Drug-Induced Liver Injury. Am J Gastroenterol, 116, 878-898. https://doi.org/10.14309/ajg.0000000000001259 CHAN, K., HAN, X.D., andKAN, Y.W., 2001. An important function of Nrf2 in combating oxidative stress: detoxification of acetaminophen. Proc Natl Acad Sci U S A, 98, 4611-4616. https://doi.org/10.1073/pnas.081082098 CHEN, M., HUANG, W., WANG, C., NIE, H., LI, G., SUN, T., YANG, F., ZHANG, Y., SHU, K., WANG, C., andGONG, Q., 2014. High-mobility group box 1 exacerbates CCl₄-induced acute liver injury in mice. Clin Immunol, 153, 56-63. https://doi.org/10.1016/j.clim.2014.03.021 COLES, B., WILSON, I., WARDMAN, P., HINSON, J.A., NELSON, S.D., andKETTERER, B., 1988. The spontaneous and enzymatic reaction of N-acetyl-p-benzoquinonimine with glutathione: a stopped-flow kinetic study. Arch Biochem Biophys, 264, 253-260. https://doi.org/10.1016/0003-9861(88)90592-9 DAHLIN, D.C., MIWA, G.T., LU, A.Y., andNELSON, S.D., 1984. N-acetyl-p-benzoquinone imine: a cytochrome P-450-mediated oxidation product of acetaminophen. Proc Natl Acad Sci U S A, 81, 1327-1331. https://doi.org/10.1073/pnas.81.5.1327 DODSON, M., DE LA VEGA, M.R., CHOLANIANS, A.B., SCHMIDLIN, C.J., CHAPMAN, E., andZHANG, D.D., 2019. Modulating NRF2 in Disease: Timing Is Everything. Annu Rev Pharmacol Toxicol, 59, 555-575. https://doi.org/10.1146/annurev-pharmtox-010818-021856 DONG, L., ZUO, L., XIA, S., GAO, S., ZHANG, C., CHEN, J., andZHANG, J., 2009. Reduction of liver tumor necrosis factor-alpha expression by targeting delivery of antisense oligonucleotides into Kupffer cells protects rats from fulminant hepatitis. J Gene Med,11, 229-239. https://doi.org/10.1002/jgm.1293 DU, H., TONG, S., KUANG, G., GONG, X., JIANG, N., YANG, X., LIU, H., LI, N., XIE, Y., XIANG, Y., GUO, J., LI, Z., YUAN, Y., WU, S., andWAN, J., 2023. Sesamin Protects against APAP-Induced Acute Liver Injury by Inhibiting Oxidative Stress and Inflammatory Response via Deactivation of HMGB1/TLR4/NFκB Signal in Mice. J Immunol Res, 1116841. https://doi.org/10.1155/2023/1116841 DU, K., MCGILL, M.R., XIE, Y., BAJT, M.L., andJAESCHKE, H., 2015. Resveratrol prevents protein nitration and release of endonucleases from mitochondria during acetaminophen hepatotoxicity. Food Chem Toxicol, 81, 62-70. https://doi.org/10.1016/j.fct.2015.04.014 EL-AWADY, M.S.,and SUDDEK, G.M., 2014. Agmatine ameliorates atherosclerosis progression and endothelial dysfunction in high cholesterol-fed rabbits. J Pharm Pharmacol, 66, 835-843. https://doi.org/10.1111/jphp.12204 EL-KASHEF, D.H., EL-KENAWI, A.E., ABDEL RAHIM, M., SUDDEK, G.M., andSALEM, H.A., 2016. Agmatine improves renal function in gentamicin-induced nephrotoxicity in rats. Can J Physiol Pharmacol, 94, 278-286. https://doi.org/10.1139/cjpp-2015-0321 EL-SHERBEENY, N.A., NADER, M.A., ATTIA, G.M., andATEYYA, H., 2016. Agmatine protects rat liver from nicotine-induced hepatic damage via antioxidative, antiapoptotic, and antifibrotic pathways. Naunyn Schmiedebergs Arch Pharmacol, 389, 1341-1351. https://doi.org/10.1007/s00210-016-1284-9 EL GAZZAR, M. 2007. HMGB1 modulates inflammatory responses in LPS-activated macrophages. Inflamm Res, 56, 162-167. https://doi.org/10.1007/s00011-006-6112-0 ЕLMAHDY, M.K., ABDELAZIZ, R.R., ELMAHDI, H.S., andSUDDEK, G.M., 2022. Effect of Agmatine on a mouse model of allergic airway inflammation: A comparative study. Autoimmunity, 55, 608-619. https://doi.org/10.1080/08916934.2022.2093864 ELLMAN, G.L. 1959. Tissue sulfhydryl groups. Arch Biochem Biophys, 82, 70-77. https://doi.org/10.1016/0003-9861(59)90090-6 ENOMOTO, A., ITOH, K., NAGAYOSHI, E., HARUTA, J., KIMURA, T., O'CONNOR, T., HARADA, T., andYAMAMOTO, M., 2001. High sensitivity of Nrf2 knockout mice to acetaminophen hepatotoxicity associated with decreased expression of ARE-regulated drug metabolizing enzymes and antioxidant genes. Toxicol Sci, 59, 169-177. https://doi.org/10.1093/toxsci/59.1.169 FAN, X., LV, H., WANG, L., DENG, X.,and CI, X., 2018. Isoorientin Ameliorates APAP-Induced Hepatotoxicity via Activation Nrf2 Antioxidative Pathway: The Involvement of AMPK/Akt/GSK3β. Front Pharmacol, 9, 1334. https://doi.org/10.3389/fphar.2018.01334 FENG, Y., LEBLANC, M.H., and REGUNATHAN, S., 2005. Agmatine reduces extracellular glutamate during pentylenetetrazole-induced seizures in rat brain: a potential mechanism for the anticonvulsive effects. Neurosci Lett, 390, 129-133. https://doi.org/10.1016/j.neulet.2005.08.008 FISHER, E.S., andCURRY, S.C., 2019. Evaluation and treatment of acetaminophen toxicity. Adv Pharmacol, 85, 263-272. https://doi.org/10.1016/bs.apha.2018.12.004 FISHER, J.E., MCKENZIE, T.J., LILLEGARD, J.B., YU, Y., JUSKEWITCH, J.E., NEDREDAL, G.I., BRUNN, G.J., YI, E.S., MALHI, H., SMYRK, T.C., andNYBERG, S.L., 2013. Role of Kupffer cells and toll-like receptor 4 in acetaminophen-induced acute liver failure. J Surg Res, 180, 147-155. https://doi.org/10.1016/j.jss.2012.11.05 FORREST, J.A., CLEMENTS, J.A., and PRESCOTT, L.F., 1982. Clinical pharmacokinetics of paracetamol. Clin Pharmacokinet, 7, 93-107. https://doi.org/10.2165/00003088-198207020-00001 FREITAS, A.E., EGEA, J., BUENDIA, I., GÓMEZ-RANGEL, V., PARADA, E., NAVARRO, E., CASAS, A.I., WOJNICZ, A., ORTIZ, J.A., CUADRADO, A., RUIZ-NUÑO, A., RODRIGUES, A.L.S., and LOPEZ, M.G., 2016. Agmatine, by Improving Neuroplasticity Markers and Inducing Nrf2, Prevents Corticosterone-Induced Depressive-Like Behavior in Mice. Mol Neurobiol, 53, 3030-3045. https://doi.org/10.1007/s12035-015-9182-6 GIBSON-CORLEY K.N., OLIVIER A.K., andMEYERHOLZ D.K., 2013. Principles for valid histopathologic scoring in research. Vet Pathol, 50(6), 1007-15. https://doi.org/10.1177/0300985813485099 GUESDON, J.L., TERNYNCK, T., and AVRAMEAS, S., 1979. The use of avidin-biotin interaction in immunoenzymatic techniques. J Histochem Cytochem, 27, 1131-1139. https://doi.org/10.1177/27.8.90074 HAN, N., YU, L., SONG, Z., LUO, L., and WU, Y., 2015. Agmatine protects Müller cells from high-concentration glucose-induced cell damage via N-methyl-D-aspartic acid receptor inhibition. Mol Med Rep, 12, 1098-1106. https://doi.org/10.3892/mmr.2015.3540 HUANG, H., ZHANG, X., andLI, J., 2015. Protective effect of oroxylin A against lipopolysaccharide and/or D-galactosamine-induced acute liver injury in mice. J Surg Res, 195, 522-528. https://doi.org/10.1016/j.jss.2015.01.047 JAESCHKE, H., AKAKPO, J.Y., UMBAUGH, D.S., andRAMACHANDRAN, A., 2020. Novel Therapeutic Approaches Against Acetaminophen-induced Liver Injury and Acute Liver Failure. Toxicol Sci, 174, 159-167. https://doi.org/10.1093/toxsci/kfaa002 JAESCHKE, H., MCGILL, M.R., WILLIAMS, C.D.,and RAMACHANDRAN, A., 2011. Current issues with acetaminophen hepatotoxicity-a clinically relevant model to test the efficacy of natural products. Life Sci, 88, 737-745. https://doi.org/10.1016/j.lfs.2011.01.025 KASPAR, J.W., NITURE, S.K., andJAISWAL, A.K., 2009. Nrf2:INrf2 (Keap1) signaling in oxidative stress. Free Radic Biol Med, 47, 1304-1309. https://doi.org/10.1016/j.freeradbiomed.2009.07.035 KHAMBU, B., YAN, S., HUDA, N., andYIN, X.M., 2019. Role of High-Mobility Group Box-1 in Liver Pathogenesis. Int J Mol Sci, 20. https://doi.org/10.3390/ijms20215314 KHODAYAR, M.J., KALANTARI, H., KHORSANDI, L., RASHNO, M., andZEIDOONI, L., 2020. Upregulation of Nrf2-related cytoprotective genes expression by acetaminophen-induced acute hepatotoxicity in mice and the protective role of betaine. Hum Exp Toxicol, 39, 948-959. https://doi.org/10.1177/0960327120905962 KIM, J.M., LEE, J.E., CHEON, S.Y., LEE, J.H., KIM, S.Y., KAM, E.H., and KOO, B.N., 2016. The Anti-inflammatory Effects of Agmatine on Transient Focal Cerebral Ischemia in Diabetic Rats. J Neurosurg Anesthesiol, 28, 203-213. https://doi.org/10.1097/ana.0000000000000195 KIM, Y.J., KANG, K.S., CHOI, K.C., and KO, H., 2015. Cardamonin induces autophagy and an antiproliferative effect through JNK activation in human colorectal carcinoma HCT116 cells. Bioorg Med Chem Lett, 25, 2559-2564. https://doi.org/10.1016/j.bmcl.2015.04.054 LARSON, A.M., POLSON, J., FONTANA, R.J., DAVERN, T.J., LALANI, E., HYNAN, L.S., REISCH, J.S., SCHIØDT, F.V., OSTAPOWICZ, G., SHAKIL, A.O., and LEE, W.M., 2005. Acetaminophen-induced acute liver failure: results of a United States multicenter, prospective study. Hepatology, 42, 1364-1372. https://doi.org/10.1002/hep.20948 LI, L., HUANG, W., WANG, S., SUN, K., ZHANG, W., DING, Y., ZHANG, L., TUMEN, B., JI, L., and LIU, C., 2018. Astragaloside IV Attenuates Acetaminophen-Induced Liver Injuries in Mice by Activating the Nrf2 Signaling Pathway. Molecules, 23. https://doi.org/10.3390/molecules23082032 LI, X., FAN, X., ZHENG, Z.H., YANG, X., LIU, Z., GONG, J.P., and LIANG, H.P., 2013. [Protective effects of agmatine on lipopolysaccharide -induced acute hepatic injury in mice]. Zhonghua Wei Zhong Bing Ji Jiu Yi Xue, 25, 720-724, https://pubmed.ncbi.nlm.nih.gov/24620385/ LI, X., LIN, J., HUA, Y., GONG, J., DING, S., DU, Y., WANG, X., ZHENG, R., and XU, H., 2021. Agmatine Alleviates Epileptic Seizures and Hippocampal Neuronal Damage by Inhibiting Gasdermin D-Mediated Pyroptosis. Front Pharmacol 12, 627557. https://doi.org/10.3389/fphar.2021.627557 LIN, M., ZHAI, X., WANG, G., TIAN, X., GAO, D., SHI, L., WU, H., FAN, Q., PENG, J., LIU, K., and YAO, J., 2015. Salvianolic acid B protects against acetaminophen hepatotoxicity by inducing Nrf2 and phase II detoxification gene expression via activation of the PI3K and PKC signaling pathways. J Pharmacol Sci, 127, 203-210. https://doi.org/10.1016/j.jphs.2014.12.010 LIU, Z., HOU, F., JIN, H., XIAO, Y., FAN, X., YANG, X., YAN, J., and LIANG, H., 2015. Effects of agmatine on excessive inflammatory reaction and proliferation of splenic cells in mice with trauma. Zhonghua Wei Zhong Bing Ji Jiu Yi Xue, 27, 110-114. https://doi.org/10.3760/cma.j.issn.2095-4352.2015.02.007 LOTZE, M.T., and TRACEY, K.J., 2005. High-mobility group box 1 protein (HMGB1): nuclear weapon in the immune arsenal. Nat Rev Immunol, 5, 331-342. https://doi.org/10.1038/nri1594 LOVE C.J., GUBERT C., RENOIR T., and HANNAN A.J., 2022. Environmental enrichment and exercise housing protocols for mice. STARProtoc, 16;3(4):101689. https://doi.org/10.1016/j.xpro.2022.101689 MILOSEVIC, K., STEVANOVIC, I., BOZIC, I.D., MILOSEVIC, A., JANJIC, M.M., LAKETA, D., BJELOBABA, I., LAVRNJA, I., andSAVIC, D., 2022. Agmatine Mitigates Inflammation-Related Oxidative Stress in BV-2 Cells by Inducing a Pre-Adaptive Response. Int J Mol Sci, 23. https://doi.org/10.3390/ijms23073561 MOLDERINGS, G.J., andHAENISCH, B., 2012. Agmatine (decarboxylated L-arginine): physiological role and therapeutic potential. Pharmacol Ther, 133, 351-365. https://doi.org/10.1016/j.pharmthera.2011.12.005 MOSSANEN,J. C., and TACKE, F., 2015. Acetaminophen-induced acute liver injury in mice. Lab Anim, 49, 30-36. https://doi.org/10.1177/0023677215570992 MU, S.W., DANG, Y., WANG, S.S., andGU, J.J., 2018. The role of high mobility group box 1 protein in acute cerebrovascular diseases. Biomed Rep, 9, 191-197. https://doi.org/10.3892/br.2018.1127 NOH, J.R., KIM, Y.H., HWANG, J.H., CHOI, D.H., KIM, K.S., OH, W.K., andLEE, C.H., 2015. Sulforaphane protects against acetaminophen-induced hepatotoxicity. Food ChemToxicol, 80, 193-200. https://doi.org/10.1016/j.fct.2015.03.020 OHKAWA, H., OHISHI, N., andYAGI, K., 1979. Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem, 95, 351-358. https://doi.org/10.1016/0003-2697(79)90738-3 OLRY, A., MEUNIER, L., DÉLIRE, B., LARREY, D., HORSMANS, Y., and LE LOUËT, H., 2020. Drug-Induced Liver Injury and COVID-19 Infection: The Rules Remain the Same. Drug Saf, 43, 615-617. https://doi.org/10.1007/s40264-020-00954-z OWUMI, S.E., ANDRUS, J.P., HERZENBERG, L.A., andHERZENBERG, L.A., 2015. Co-administration of N-Acetylcysteine and Acetaminophen Efficiently Blocks Acetaminophen Toxicity. Drug Dev Res, 76, 251-258. https://doi.org/10.1002/ddr.21262 PARK, J.S., SVETKAUSKAITE, D., HE, Q., KIM, J.Y., STRASSHEIM, D., ISHIZAKA, A., andABRAHAM, E., 2004. Involvement of toll-like receptors 2 and 4 in cellular activation by high mobility group box 1 protein. J Biol Chem, 279, 7370-7377. https://doi.org/10.1074/jbc.M306793200 PIPER, D.R., HINZ, W.A., TALLURRI, C.K., SANGUINETTI, M.C., and TRISTANI-FIROUZI, M., 2005. Regional specificity of human ether-a'-go-go-related gene channel activation and inactivation gating. J Biol Chem, 280, 7206-7217. https://doi.org/10.1074/jbc.M411042200 QIU, W.W., andZHENG, R.Y., 2006. Neuroprotective effects of receptor imidazoline 2 and its endogenous ligand agmatine. Neurosci Bull, 22, 187-191, https://pubmed.ncbi.nlm.nih.gov/17704848/ RUBARTELLI, A., andLOTZE, M.T., 2007. Inside, outside, upside down: damage-associated molecular-pattern molecules (DAMPs) and redox. Trends Immunol, 28, 429-436. https://doi.org/10.1016/j.it.2007.08.004 SHEN, X.L., GUO, Y.N., LU, M.H., DING, K.N., LIANG, S.S., MOU, R.W., YUAN, S., HE, Y.M., andTANG, L.P., 2023. Acetaminophen-induced hepatotoxicity predominantly via inhibiting Nrf2 antioxidative pathway and activating TLR4-NF-κB-MAPK inflammatory response in mice. Ecotoxicol Environ Saf, 252, 114590. https://doi.org/10.1016/j.ecoenv.2023.114590 SILVA-ISLAS, C.A., andMALDONADO, P.D., 2018. Canonical and non-canonical mechanisms of Nrf2 activation. Pharmacol Res, 134, 92-99. https://doi.org/10.1016/j.phrs.2018.06.013 STUTCHFIELD, B.M., ANTOINE, D.J., MACKINNON, A.C., GOW, D.J., BAIN, C.C., HAWLEY, C.A., HUGHES, M.J., FRANCIS, B., WOJTACHA, D., MAN, T.Y., DEAR, J.W., DEVEY, L.R., MOWAT, A.M., POLLARD, J.W., PARK, B.K., JENKINS, S.J., SIMPSON, K.J., HUME, D.A., WIGMORE, S.J., and FORBES, S.J., 2015. CSF1 Restores Innate Immunity After Liver Injury in Mice and Serum Levels Indicate Outcomes of Patients With Acute Liver Failure. Gastroenterology, 149, 1896-1909.e1814. https://doi.org/10.1053/j.gastro.2015.08.053 TABATABAEI, M.S., and AHMED M., 2022. Enzyme-Linked Immunosorbent Assay (ELISA). Methods Mol Biol, 2508:115-134. https://doi.org/10.1007/978-1-0716-2376-3_10 TONG, Y., TANG, Z., YANG, T., YANG, Y., YANG, L., SHEN, W., andCHEN, W., 2014. Ulinastatin preconditioning attenuates inflammatory reaction of hepatic ischemia reperfusion injury in rats via high mobility group box 1(HMGB1) inhibition. Int J Med Sci, 11, 337-343. https://doi.org/10.7150/ijms.7861 UNOKI, T., AKIYAMA, M.,and KUMAGAI, Y., 2020. Nrf2 Activation and Its Coordination with the Protective Defense Systems in Response to Electrophilic Stress. Int J Mol Sci, 21. https://doi.org/10.3390/ijms21020545 VARGIU, C., CABELLA, C., BELLIARDO, S., CRAVANZOLA, C., GRILLO, M.A., andCOLOMBATTO, S., 1999. Agmatine modulates polyamine content in hepatocytes by inducing spermidine/spermine acetyltransferase. Eur J Biochem, 259, 933-938. https://doi.org/10.1046/j.1432-1327.1999.00126.x WANG, L., ZHANG, S., CHENG, H., LV, H., CHENG, G., andCI, X., 2016. Nrf2-mediated liver protection by esculentoside A against acetaminophen toxicity through the AMPK/Akt/GSK3β pathway. Free Radic Biol Med, 101, 401-412. https://doi.org/10.1016/j.freeradbiomed.2016.11.009 WU, C.T., DENG, J.S., HUANG, W.C., SHIEH, P.C., CHUNG, M.I., andHUANG, G.J., 2019. Salvianolic Acid C against Acetaminophen-Induced Acute Liver Injury by Attenuating Inflammation, Oxidative Stress, and Apoptosis through Inhibition of the Keap1/Nrf2/HO-1 Signaling. Oxid Med Cell Longev, 9056845. https://doi.org/10.1155/2019/9056845 XU, W., GAO, L., LI, T., SHAO, A., andZHANG, J., 2018. Neuroprotective Role of Agmatine in Neurological Diseases. Curr Neuropharmacol, 16, 1296-1305. https://doi.org/10.2174/1570159x15666170808120633 YANG, G., ZHANG, L., MA, L., JIANG, R., KUANG, G., LI, K., TIE, H., WANG, B., CHEN, X., XIE, T., GONG, X., and WAN, J., 2017. Glycyrrhetinic acid prevents acetaminophen-induced acute liver injury via the inhibition of CYP2E1 expression and HMGB1-TLR4 signal activation in mice. Int Immunopharmacol, 50, 186-193. https://doi.org/10.1016/j.intimp.2017.06.027 YENIÇERI M., TANOĞLU A., SALMANOĞLU M., ÇIRAK Z., CAN ŞENOYMAK M., BAŞ S., and SADE GÖKÇEN, A., 2024. Efficacy of Agmatine Treatment in Experimental Acute Pancreatitis Rat Model. Turk J Gastroenterol 35(1):27-31. https://doi.org/10.5152/tjg.2024.23017 YIN, H., CHENG, L., HOLT, M., HAIL, N., JR., MACLAREN, R.,and JU, C., 2010. Lactoferrin protects against acetaminophen-induced liver injury in mice. Hepatology, 51, 1007-1016. https://doi.org/10.1002/hep.23476 YIN, S.Q., ZHU, J.Y., LUO, L., YANG, X., LIANG, H.P., andLUO, Y., 2018. Exogenous agmatine inhibits lipopolysaccharide-induced activation and dysfunction of human umbilical vein endothelial cells. Nan Fang Yi Ke Da Xue Xue Bao, 38, 652-660. https://doi.org/10.3969/j.issn.1673-4254.2018.06.03 ZHANG, C., SHI, X., SU, Z., HU, C., MU, X., PAN, J., LI, M., TENG, F., LING, T., ZHAO, T., XU, C., JI, G., andYOU, Q., 2021. CD36 deficiency ameliorates drug-induced acute liver injury in mice. Mol Med, 27, 57. https://doi.org/10.1186/s10020-021-00325-z ZHANG, R., WANG, Q., andYANG, J., 2022. Impact of Liver Functions by Repurposed Drugs for COVID-19 Treatment. J Clin Transl Hepatol, 10, 748-756. https://doi.org/10.14218/jcth.2021.00368 ZHOU, Z., QI, J., WU, Y., LI, C., BAO, W., LIN, X.,and ZHU, A., 2023. Nuciferine Effectively Protects Mice against Acetaminophen-Induced Liver Injury. Antioxidants, (Basel) 12. https://doi.org/10.3390/antiox12040949 | ||||
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