Metadoxine inhibits the infiltration of macrophages and neutrophils into liver tissue in acute alcoholic liver injury

doi:10.5246/jcps.2022.01.005

Abstract

Abstract:

Alcohol consumption causes significant liver damage, including hepatitis, fibrosis, cirrhosis, and even primary liver carcinoma. Metadoxine (MTDX) is considered to be a beneficial treatment for alcoholic liver disease (ALD) because it accelerates the metabolism and elimination of ethanol. However, the underlying mechanism is not well understood. Here, the rat model of ALD was developed by feeding with 50% ethanol at the dose of 5 g/kg, and samples of serum and liver tissue were collected to test the levels of liver injury and inflammation and evaluate the hepatoprotective function of MTDX in alcohol-induced liver injury. Further investigation on the infiltration of immune cells was performed to understand the potential hepatoprotective mechanism of MTDX in the ALD model. The results showed that MTDX attenuated liver injury, evidenced by decreased levels of alanine transaminase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP). Meanwhile, the liver proinflammatory environment was improved after MTDX treatment, evidenced by decreased levels of TNF-α, IL-6, and NLRP3 in the liver tissue. Furthermore, inhibited infiltrations of macrophages and neutrophils were observed in MTDX-treated ALD rats compared with the untreated ALD rats. Our results indicated that MTDX played an important role in preventing the progression of ALD, and the underlying mechanisms might be related to its function of attenuating liver inflammation by inhibiting immune cell infiltration.

Key words: Metadoxine, Alcoholic liver injury, Macrophages, Neutrophils, Inflammatory

Supporting:

Wen Jiang, Yilin Wei, Qing Wen, Gexin Shi, Hengli Zhao. Metadoxine inhibits the infiltration of macrophages and neutrophils into liver tissue in acute alcoholic liver injury[J]. Journal of Chinese Pharmaceutical Sciences, 2022, 31(1): 47-54.

Figures/Tables 4

References 34

[1]	Chrystoja, B.R.; Rehm, J.; Manthey, J.; Probst, C.; Wettlaufer, A.; Shield, K.D. A systematic comparison of the global comparative risk assessments for alcohol. Addiction. 2021, 116, 2026–2038.
[2]	Haber, P.S.; Kortt, N.C. Alcohol use disorder and the gut. Addiction. 2021, 116, 658–667.
[3]	Wang, X.; He, Y.; Mackowiak, B.; Gao, B. MicroRNAs as regulators, biomarkers and therapeutic targets in liver diseases. Gut. 2021, 70, 784–795.
[4]	Stornetta, A.; Guidolin, V.; Balbo, S. Alcohol-derived acetaldehyde exposure in the oral cavity. Cancers. 2018, 10. DOI:10.3390/cancers10010020.
[5]	Dunn, W.; Shah, V.H. Pathogenesis of alcoholic liver disease. Clin. Liver Dis. 2016, 20, 445–456.
[6]	Smyth, A.; Teo, K.K.; Rangarajan, S.; O'Donnell, M.; Zhang, X.H.; Rana, P.; Leong, D.P.; Dagenais, G.; Seron, P.; Rosengren, A.; Schutte, A.E.; Lopez-Jaramillo, P.; Oguz, A.; Chifamba, J.; Diaz, R.; Lear, S.; Avezum, A.; Kumar, R.; Yusuf, S. Alcohol consumption and cardiovascular disease, cancer, injury, admission to hospital, and mortality: a prospective cohort study. Lancet. 2015, 386, 1945–1954.
[7]	Xi, B.; Veeranki, S.P.; Zhao, M.; Ma, C.W.; Yan, Y.K.; Mi, J. Relationship of alcohol consumption to all-cause, cardiovascular, and cancer-related mortality in US adults. J. Am. Coll. Cardiol. 2017, 70, 913–922.
[8]	Duddempudi, A.T. Immunology in alcoholic liver disease. Clin. Liver Dis. 2012, 16, 687–698.
[9]	Li, M.; He, Y.; Zhou, Z.; Ramirez, T.; Gao, Y.Q.; Gao, Y.H.; Ross, R.A.; Cao, H.X.; Cai, Y.; Xu, M.J.; Feng, D.C.; Zhang, P.; Liangpunsakul, S.; Gao, B. MicroRNA-223 ameliorates alcoholic liver injury by inhibiting the IL-6–p^47phox–oxidative stress pathway in neutrophils. Gut. 2017, 66, 705–715.
[10]	Acito, M.; Bartolini, D.; Ceccarini, M.R.; Russo, C.; Vannini, S.; Dominici, L.; Codini, M.; Villarini, M.; Galli, F.; Beccari, T.; Moretti, M. Imbalance in the antioxidant defence system and pro-genotoxic status induced by high glucose concentrations: In vitro testing in human liver cells. Toxicol. Vitro. 2020, 69, 105001.
[11]	Mahmoud, A.M.; Hussein, O.E.; Hozayen, W.G.; Bin-Jumah, M.; Abd El-Twab, S.M. Ferulic acid prevents oxidative stress, inflammation, and liver injury via upregulation of Nrf2/HO-1 signaling in methotrexate-induced rats. Environ. Sci. Pollut. Res. 2020, 27, 7910–7921.
[12]	Grabherr, F.; Grander, C.; Adolph, T.E.; Wieser, V.; Mayr, L.; Enrich, B.; Macheiner, S.; Sangineto, M.; Reiter, A.; Viveiros, A.; Zoller, H.; Bufler, P.; Moschen, A.R.; Dinarello, C.A.; Tilg, H. Ethanol-mediated suppression of IL-37 licenses alcoholic liver disease. Liver Int. 2018, 38, 1095–1101.
[13]	Tilg, H.; Moschen, A.R.; Szabo, G. Interleukin-1 and inflammasomes in alcoholic liver disease/acute alcoholic hepatitis and nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. Hepatology. 2016, 64, 955–965.
[14]	Mukhopadhyay, P.; Horváth, B.; Rajesh, M.; Varga, Z.V.; Gariani, K.; Ryu, D.; Cao, Z.X.; Holovac, E.; Park, O.; Zhou, Z.; Xu, M.J.; Wang, W.; Godlewski, G.; Paloczi, J.; Nemeth, B.T.; Persidsky, Y.; Liaudet, L.; Haskó, G.; Pacher, P. PARP inhibition protects against alcoholic and non-alcoholic steatohepatitis. J. Hepatol. 2017, 66, 589–600.
[15]	Zhou, Y.; Yuan, G.D.; Zhong, F.D.; He, S.Q. Roles of the complement system in alcohol-induced liver disease. Clin. Mol. Hepatol. 2020, 26, 677–685.
[16]	Zhang, M.; Zhang, Y.; Liu, L.; Prithweeraj, M.; Xu, H.; Wu, R.; Wen, X.; Niu, J. Neutrophil-to-lymphocyte ratio and albumin: new serum biomarkers to predict the prognosis of male alcoholic cirrhosis patients. Biomed. Res. Int. 2020, 2020, 7268459.
[17]	Tang, Y.M.; Banan, A.; Forsyth, C.B.; Fields, J.Z.; Lau, C.K.; Zhang, L.J.; Keshavarzian, A. Effect of alcohol on miR-212 expression in intestinal epithelial cells and its potential role in alcoholic liver disease. Alcohol. Clin. Exp. Res. 2008, 32, 355–364.
[18]	Affò, S.; Morales-Ibanez, O.; Rodrigo-Torres, D.; Altamirano, J.; Blaya, D.; Dapito, D.H.; Millán, C.; Coll, M.; Caviglia, J.M.; Arroyo, V.; Caballería, J.; Schwabe, R.F.; Ginès, P.; Bataller, R.; Sancho-Bru, P. CCL20 mediates lipopolysaccharide induced liver injury and is a potential driver of inflammation and fibrosis in alcoholic hepatitis. Gut. 2014, 63, 1782–1792.
[19]	Liang, S.; Zhong, Z.Y.; Kim, S.Y.; Uchiyama, R.; Roh, Y.S.; Matsushita, H.; Gottlieb, R.A.; Seki, E. Murine macrophage autophagy protects against alcohol-induced liver injury by degrading interferon regulatory factor 1 (IRF₁) and removing damaged mitochondria. J. Biol. Chem. 2019, 294, 12359–12369.
[20]	Zhang, L.; Pan, JC.; Ku, BS. Protective Effect of Ascorbate-Lysine on Carbon Tetrachloride and Alcohol-Induced Liver Injury in Mice. J. Chin. Pharm. Sci. 2004, 4, 288–290.
[21]	Huo, X.W.; Sun, X.K.; Cao, Z.P.; Qiao, J.Z.; Yang, S.; Meng, X.B.; Zhao, Y.Y. Optimal ratio of 18α- and 18β-glycyrrhizic acid for preventing alcoholic hepatitis in rats. Exp. Ther. Med. 2019, 18, 172–178.
[22]	Song, Z.Y.; Deaciuc, I.; Song, M.; Lee, D.Y.W.; Liu, Y.Z.; Ji, X.S.; McClain, C. Silymarin protects against acute ethanol-induced hepatotoxicity in mice. Alcohol. Clin. Exp. Res. 2006, 30, 407–413.
[23]	Addolorato, G.; Ancona, C.; Capristo, E.; Gasbarrini, G. Metadoxine in the treatment of acute and chronic alcoholism: a review. Int. J. Immunopathol. Pharmacol. 2003, 16, 207–214.
[24]	Díaz Martínez, M.C.; Díaz Martínez, A.; Villamil Salcedo, V.; Cruz Fuentes, C. Efficacy of metadoxine in the management of acute alcohol intoxication. J. Int. Med. Res. 2002, 30, 44–51.
[25]	Tijera, F.H.D.L.; Servín-Caamaño, A.I.; Cruz-Herrera, J.; Serralde-Zúñiga, A.E.; Abdo-Francis, J.M.; Gutiérrez-Reyes, G.; Pérez-Hernández, J.L. Treatment with Metadoxine and its impact on early mortality in patients with severe alcoholic hepatitis. Ann. Hepatol. 2014, 13, 343–352.
[26]	Testino, G.; Leone, S.; Fagoonee, S.; Pellicano, R. Alcoholic liver fibrosis: detection and treatment. Minerva Med. 2018, 109, 457–471.
[27]	Mazraati, P.; Minaiyan, M. Hepatoprotective effect of metadoxine on acetaminophen-induced liver toxicity in mice. Adv. Biomed. Res. 2018, 7, 67.
[28]	Gutiérrez-Ruiz, M.C.; Bucio, L.; Correa, A.; Souza, V.; Hernández, E.; Gómez-Quiroz, L.E.; Kershenobich, D. Metadoxine prevents damage produced by ethanol and acetaldehyde in hepatocyte and hepatic stellate cells in culture. Pharmacol. Res. 2001, 44, 431–436.
[29]	Wu, J.D.; Wu, D.Q.; Ma, K.L.; Wang, T.M.; Shi, G.X.; Shao, J.; Wang, C.Z.; Yan, G.M. Paeonol ameliorates murine alcohol liver disease via mycobiota-mediated Dectin-1/IL-1β signaling pathway. J. Leukoc. Biol. 2020, 108, 199–214.
[30]	Gu, G.X.; Huo, Y.F.; Xu, G.; Li, L.M.; Yu, J.; Sheng, L.X.; Yin, Z.Y. MicroRNA-204-GSDMD interaction regulates pyroptosis of fibroblast-like synoviocytes in ankylosing spondylitis. Int. Immunopharmacol. 2021, 91, 107227.
[31]	Xi, H.; Zhang, Y.; Xu, Y.; Yang, W.Y.; Jiang, X.; Sha, X.; Cheng, X.; Wang, J.; Qin, X.; Yu, J.; Ji, Y.; Yang, X.; Wang, H. Caspase-1 inflammasome activation mediates homocysteine-induced pyrop-apoptosis in endothelial cells. Circ. Res. 2016, 118, 1525–1539.
[32]	Ding, W.X.; Manley, S.; Ni, H.M. The emerging role of autophagy in alcoholic liver disease. Exp. Biol. Med. (Maywood). 2011, 236, 546–556.
[33]	Ding, W.X.; Li, M.; Chen, X.Y.; Ni, H.M.; Lin, C.W.; Gao, W.T.; Lu, B.F.; Stolz, D.B.; Clemens, D.L.; Yin, X.M. Autophagy reduces acute ethanol-induced hepatotoxicity and steatosis in mice. Gastroenterology. 2010, 139, 1740–1752.
[34]	Wang, H.F.; Huang, J.; Zhang, S.; Jia, B.; Yang, D.W. Effect and mechanisms of the metadoxin attenuates steatosis in cultured hepatic cells by inducing autophagy. Chin. J. Clin. Pharmacol. 2019, 35, 1752–1755.