Therapeutic effect of naringenin on ethanol-induced liver fibrosis in rats
DOI:
https://doi.org/10.15584/ejcem.2025.3.14Keywords:
ethanol, fibrogenic factors, histopathology, liver damage, naringeninAbstract
Introduction and aim. Liver fibrosis, a progressive disorder marked by the surplus buildup of extracellular matrix proteins, frequently results from long-term ethanol intake. Our aim of study is to investigate how naringenin’s antifibrotic properties impact ethanol induced liver fibrosis in rats.
Material and methods. Rats were divided into four groups: groups 1 and 2 received carboxymethylcellulose (CMC) containing 0.5% glucose, while groups 3 and 4 received 20% ethanol (6 g/kg of body weight) over a 60-day period. In the last 30 days, naringenin (50 mg/kg) was administered each day to groups 2 and 4.
Results. Rats treated with ethanol exhibited liver damage and fibrosis, leading to elevated serum concentrations of aspartate and alanine transaminases. Expression levels of matrix metalloproteinases (MMPs), tissue inhibitors of metalloproteinases (TIMPs), alpha-smooth muscle actin (α-SMA) and related proteins were compared with the control group.
Conclusion. Ethanol-fed rats showed an increase in serum matrix metalloproteinases, TIMPs, α-SMA, transaminases, and other proteins compared to the control group. The administration of ethanol led to liver damage and fibrosis. During the final 30 days of the trial, the inclusion of naringenin in the diets of rats notably reduced the levels of α-SMA, MMP2, MMP9, TIMP1, along with serum levels of aspartate and alanine transaminase levels and significant differences were observed compared to control group.
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References
World Health Organization. Global status report: alcohol policy. Geneva: Department of Mental Health and Substance Abuse. 2024. https://www.who.int/publications/i/item/9789240096745. Accessed April 20, 2024.
World Health Organization. Global Status Report on Alcohol and Health. 2018. https://www.who.int/publications/i/item/9789241565639. Accessed April 20, 2024.
Lucey MR, Mathurin P, Morgan TR. Alcoholic hepatitis. N Engl J Med. 2009;360: 2758-2769. doi: 10.1056/NEJM-ra0805786
Nowak AJ, Relja B. The Impact of Acute or Chronic Alcohol Intake on the NF-κB Signaling Pathway in Alcohol-Related Liver Disease. Int J Mol Sci. 2020;21:9407. doi: 10.3390/ijms21249407
Sun L, Wen S, Li Q, et al. L-theanine relieves acute alcoholic liver injury by regulating the TNF-α/NF-κB signalingpathway in C57BL/6J mice. J Funct Foods. 2021;86:104699. doi: 10.1016/j.jff.2021.104699.
Rodriguez WE, Wahlang B, Wang Y, et al. Phosphodiesterase 4 inhibition as a therapeutic target for alcoholic liver disease: from bedside to bench. Hepatology. 2019;70(6):1958-1971. doi: 10.1002/hep.30571
Friedman SL. Molecular regulation of hepatic fibrosis, an integrated cellular response to tissue injury. J Biol Chem. 2000;275:2247-2250. doi:10.1074/jbc.275.4.2247
Fallowfield JA, Iredale JP. Reversal of liver fibrosis and cirrhosis–an emerging reality. Scott Med J. 2004;49:3-6. doi: 10.1177/003693300404900102.
Weiskirchen R, Weiskirchen S, Tacke F. Recent advances in understanding liver fibrosis: bridging basic science and individualized treatment concepts. F1000Res. 2018;7:1-14. doi: 10.12688/f1000research.15238.1
McQuitty CE, Williams R, Chokshi S, Urbani L. Immunomodulatory Role of the Extracellular Matrix Within the Liver Disease Microenvironment. Front Immunol. 2020;11:574276. doi: 10.3389/fimmu.2020.574276
Lee KS, Buck M, Houglum K, Chojkier M. Activation of HSC by TGF-alpha and collagen type I is mediated by oxidative stress through c-myb expression. J Clin Invest. 1995;96:2461-2468. doi: 10.1172/JCI118117
Boyd DF, Thomas PG. Towards integrating extracellular matrix and immunological pathways. Cytokine. 2017;98: 79-86. doi: 10.1016/j.cyto.2017.03.002
Wang X, Khalil RA. Matrix Metalloproteinases, Vascular Remodeling, and Vascular Disease. Adv Pharmacol. 2018;81:241-330. doi: 10.1016/bs.apha.2017.10.003
Xu G, Bochaton-Piallat ML, Andreutti D, et al. Regulation of alpha-smooth muscle actin and CRBP-1 expression by retinoic acid and TGF-beta in cultured fibroblasts. J Cell Physiol. 2001;187(3):315-325. doi:10.1002/jcp.1111.
Gressner AM, Weiskirchen R, Breitkopf K, Dooley S. Roles of TGF-beta in hepatic fibrosis. Front Biosci. 2002;7:d793807. doi: 10.2741/741
Kim KK, Sheppard D, Chapman HA. TGF-β1 Signaling and Tissue Fibrosis. Cold Spring Harb Perspect Biol. 2018;10(4):a022293. doi: 10.1101/cshperspect.a022293
Hora S, Wuestefeld T. Liver Injury and Regeneration: Current Understanding, New Approaches, and Future Perspectives. Cells. 2023;12(17):2129. doi: 10.3390/cells12172129
Holden JM, Bhagwat SA, Patterson KY. Development of a multi-nutrient data quality evaluation system. J Food Compos Anal. 2002;15(4):339-348. doi: 10.1006/ jfca.2002.1090
Lee MH, Yoon S, Moon JO. The flavonoid naringenin inhibits dimethylnitrosamine-induced liver damage in rats. Biol Pharma Bull. 2004;27:72-76. doi: 10.1248/bpb.27.72
Rehman MU, Rahman Mir MU, Farooq A, et al. Narigenin (4,5,7-trihydroxyflavanone) suppresses the development of precancerous lesions via controlling hyperproliferation and inflammation in the colon of Wistar rats. Environ Toxicol. 2018;33(4):422-435. doi: 10.1002/tox.22661
Shilpa VS, Shams R, Dash KK, et al. Phytochemical Properties, Extraction, and Pharmacological Benefits of Naringin: A Review. Molecules. 2023;28(15):5623. doi: 10.3390/molecules28155623
Scholz E, Zitron P, Kiesecker C, et al. Orange flavonoid hesperetin modulates cardiac hERG potassium channel via binding to aminoacid F656. Nutr Metab Cardiovasc Dis. 2006;17:666-675. doi: 10.1016/j.numecd.2006.03.004
Zhao J, Chen H, Li Y. Protective effect of bicyclol on acute alcohol-induced liver injury in mice. Eur J Pharmacol. 2008;586:322–331. doi: 10.1016/j.ejphar.2008.03.061
Towbin H, Stahelin H, Gordon J. Electrophoretic transfer of proteins from polyacrylamide gel to nitrocellulose sheets: Procedure and some applications. Proc NatlAcad Sci USA. 1979;76:4350-4354. doi: 10.1073/pnas.76.9.4350.
Junqueira LC, Bignolas G, Brentani RR. Picrosirius staining plus polarization microscopy, a specific method for collagen detection in tissue sections. Histochem J. 1979;11:447-455. doi: 10.1007/BF01002709
Laronha H, Caldeira J. Structure and Function of Human Matrix Metalloproteinases. Cells. 2020;9(5):1076. doi: 10.3390/cells9051076
Chuliá-Peris L, Carreres-Rey C, Gabasa M, et al. Matrix Metalloproteinases and Their Inhibitors in Pulmonary Fibrosis: EMMPRIN/CD147 Comes into Play. Int J Mol Sci. 2022;23(13):6894. doi: 10.3390/ijms23136894
Ulrich D, Lichtenegger F, Eblenkamp M, et al. Matrix metalloproteinases, tissue inhibitors of metalloproteinases, amino terminal propeptide of procollagen type III, and hyaluronan in sera and tissue of patients with capsular contracture after augmentation with Trilucent breast implants. Plast Reconstr Surg. 2004;114:229-236. doi: 10.1097/01.PRS.0000132397.63325.0D
Nikolov A, Popovski N. Role of Gelatinases MMP-2 and MMP-9 in Healthy and Complicated Pregnancy and Their Future Potential as Preeclampsia Biomarkers. Diagnostics. 2021;11:480. doi:10.3390/diagnostics11030480
Liu H, Zang C, Fenner MH, et al. PPARgamma ligands and ATRA inhibit the invasion of human breast cancer cells in vitro. Breast Cancer Res Treat. 2003;79:63-74. doi: 10.1023/A:1022902900127
Allameh A, Niayesh-Mehr R, Aliarab A, et al. Oxidative Stress in Liver Pathophysiology and Disease. Antioxidants. 2023;12:1653. doi: 10.3390/antiox12061653
Li S, Pritchard DM, Yu LG. Regulation and Function of Matrix Metalloproteinase-13 in Cancer Progression and Metastasis. Cancers (Basel). 2022;14(13):3263. doi: 10.3390/cancers14133263
Dooley S, Delvoux B, Streckert M, et al. Transforming growth factor β signal transduction in hepatic stellate cells via Smad2/3 phosphorylation, a pathway that is abrogated during in vitro progression to myofibroblasts: TGFβ signal transduction during trans differentiation of hepatic stel-
late cells. FEBS Letters. 2001;502(1-2):4-10. doi: 10.1016/S0014-5793(01)02584-1
Lazar M, Sandulescu M, Barbu EC, et al. The Role of Cytokines and Molecular Pathways in Lung Fibrosis Following SARS-CoV-2 Infection: A Physiopathologic (Re)view. Biomedicines. 2024;12(3):639. doi: 10.3390/biomedicines12030639
Zhao F, Zhou N, Wang JL, et al. Collagen deposition in the liver is strongly and positively associated with T1rho elongation while fat deposition is associated with T1rho shortening: an experimental study of methionine and choline-deficient (MCD) diet rat model. Quant Imaging Med Surg. 2020;10(12):2307-2321. doi: 10.21037/qims-20-794
Hernández-Aquino E, Muriel P. Beneficial effects of naringenin in liver diseases: Molecular mechanisms. World J Gastroenterol. 2018;24(16):1679-1707. doi: 10.3748/wjg.v24.i16.1679
Sufleţel RT, Melincovici CS, Gheban BA, et al. Hepatic stellate cells - from past till present: morphology, human markers, human cell lines, behavior in normal and liver pathology. Rom J Morphol Embryol. 2020;61(3):615-642. doi: 10.29345/rjme.61.3.615
Chen J, Argemi J, Odena G, et al. Hepatic lipocalin 2 promotes liver fibrosis and portal hypertension. Sci Rep. 2020;10(1):15558. doi: 10.1038/s41598-020-72517-5
Lin CY, Omoscharka E, Liu Y, Cheng K. Establishment of a Rat Model of Alcoholic Liver Fibrosis with Simulated Human Drinking Patterns and Low-Dose Chemical Stimulation. Biomolecules. 2023;13(9):1293. doi:10.3390/biom13091293
Kumar S, Wang J, Rani R, Gandhi CR. Hepatic Deficiency of Augmenter of Liver Regeneration Exacerbates Alcohol-Induced Liver Injury and Promotes Fibrosis in Mice. PLoS One. 2016;11(1):e0147864. doi: 10.1371/journal.pone.0147864
Lee MH, Yoon S, Moon JO. The flavonoid naringenin inhibits dimethyl nitrosamine induced liver damage in rats. Biol Pharma Bull. 2004;27:72-76. doi: 10.1248/bpb.27.72
Yu T, Lu X, Liang Y, et al. Naringenin alleviates liver fibrosis by triggering autophagy-dependent ferroptosis in hepatic stellate cells. Heliyon. 2024;10(7). doi: 10.1016/j.heliyon.2024.e12821
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