{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T11:54:56Z","timestamp":1789473296784,"version":"build-2803163510"},"reference-count":83,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2022,5,12]],"date-time":"2022-05-12T00:00:00Z","timestamp":1652313600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Deanship of Scientific Research (DSR), King Khalid University","award":["R.G.P.1\/190\/41"],"award-info":[{"award-number":["R.G.P.1\/190\/41"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biology"],"abstract":"<jats:p>D-carvone is a natural monoterpene found in abundance in the essential oil of aromatic medicinal plants with a wide range of pharmacological values. However, the impact of D-carvone on liver fibrosis remains unclear. This study aimed to evaluate the anti-fibrotic potential of D-carvone in a rat model of liver fibrosis and to clarify the possible underlying mechanisms. Liver fibrosis was induced in rats by carbon tetrachloride, CCl4 (2.5 mL\/kg, interperitoneally every 72 h for 8 weeks). Oral treatment of rats with D-carvone (50 mg\/kg, daily) started on the 3rd week of CCl4 administration. D-carvone significantly enhanced liver functions (ALT, AST), oxidant\/antioxidant status (MDA, SOD, GSH, total antioxidant capacity; TAC), as well as histopathological changes. Moreover, D-carvone effectively attenuated the progression of liver fibrosis, evident by the decreased collagen deposition and fibrosis score by Masson trichrome staining (MT) and \u03b1-SMA protein expression. Moreover, D-carvone administration resulted in a significant downregulation of the pro-fibrogenic markers TGF-\u03b21 and SMAD3 and upregulation of MMP9. These findings reveal the anti-fibrotic effect of D-carvone and suggest regulation of the TGF-\u03b21\/SMAD3 pathway, together with the antioxidant activity as a mechanistic cassette, underlines this effect. Therefore, D-carvone could be a viable candidate for inhibiting liver fibrosis and other oxidative stress-related hepatic diseases. Clinical studies to support our hypothesis are warranted.<\/jats:p>","DOI":"10.3390\/biology11050739","type":"journal-article","created":{"date-parts":[[2022,5,12]],"date-time":"2022-05-12T21:46:53Z","timestamp":1652392013000},"page":"739","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":29,"title":["D-Carvone Attenuates CCl4-Induced Liver Fibrosis in Rats by Inhibiting Oxidative Stress and TGF-\u00df 1\/SMAD3 Signaling Pathway"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0480-5127","authenticated-orcid":false,"given":"Hanan A.","family":"Ogaly","sequence":"first","affiliation":[{"name":"Department of Chemistry, College of Science, King Khalid University, Abha 61421, Saudi Arabia"},{"name":"Department of Biochemistry, Faculty of Veterinary Medicine, Cairo University, Giza 12211, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sharah A. A.","family":"Aldulmani","sequence":"additional","affiliation":[{"name":"Department of Chemistry, College of Science, King Khalid University, Abha 61421, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fatimah A. M.","family":"Al-Zahrani","sequence":"additional","affiliation":[{"name":"Department of Chemistry, College of Science, King Khalid University, Abha 61421, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reham M.","family":"Abd-Elsalam","sequence":"additional","affiliation":[{"name":"Department of Pathology, Faculty of Veterinary Medicine, Cairo University, Giza 12211, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,5,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Poynard, T., Lebray, P., Ingiliz, P., Varaut, A., Varsat, B., Ngo, Y., Norha, P., Munteanu, M., Drane, F., and Messous, D. (2010). Prevalence of liver fibrosis and risk factors in a general population using non-invasive biomarkers (FibroTest). BMC Gastroenterol., 10.","DOI":"10.1186\/1471-230X-10-40"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/j.mam.2018.09.002","article-title":"Liver fibrosis: Pathophysiology, pathogenetic targets and clinical issues","volume":"65","author":"Parola","year":"2019","journal-title":"Mol. Aspects Med."},{"key":"ref_3","first-page":"1","article-title":"Oxidative stress and hepatic stellate cells: A paradoxical relationship","volume":"7","author":"Gandhi","year":"2012","journal-title":"Trends Cell Mol. Biol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"S51","DOI":"10.1016\/j.clinre.2015.05.005","article-title":"Liver fibrosis: Common mechanisms and antifibrotic therapies","volume":"39","author":"Schuppan","year":"2015","journal-title":"Clin. Res. Hepatol. Gastroenterol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.addr.2017.11.008","article-title":"Fibroblasts and extracellular matrix: Targeting and therapeutic tools in fibrosis and cancer","volume":"121","author":"Prakash","year":"2017","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/j.ajps.2020.06.005","article-title":"Progress in drug delivery system for fibrosis therapy","volume":"16","author":"Xing","year":"2021","journal-title":"Asian J. Pharm. Sci."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Kumar, R., Rani, R., Narang, S.K., Rai, S., and Hajam, Y.A. (2021). Hepatotoxicity: Its physiological pathways and control measures using phyto-polyphenols. Phytomedicine, Elsevier.","DOI":"10.1016\/B978-0-12-824109-7.00007-8"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"e202100960","DOI":"10.1002\/cbdv.202100960","article-title":"Phytoconstituents of Sansevieria suffruticosa NE Br. Leaves and its Hepatoprotective Effect via Activation of the NRF2\/ARE Signaling Pathway in an Experimentally Induced Liver Fibrosis Rat Model","volume":"19","author":"Fayed","year":"2022","journal-title":"Chem. Biodivers."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1016\/j.biopha.2018.12.071","article-title":"Preventive effect of D-carvone during DMBA induced mouse skin tumorigenesis by modulating xenobiotic metabolism and induction of apoptotic events","volume":"111","author":"Gopalakrishnan","year":"2019","journal-title":"Biomed. Pharmacother."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1080\/10412905.2004.9698792","article-title":"Carvone-Rich Essential Oils from Mentha longifolia (L.) Huds. ssp. schimperi Briq. and Mentha spicata L. Grown in Sudan","volume":"16","author":"Younis","year":"2004","journal-title":"J. Essent. Oil Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"113080","DOI":"10.1016\/j.phytochem.2021.113080","article-title":"Carvone and its pharmacological activities: A systematic review","volume":"196","author":"Pina","year":"2022","journal-title":"Phytochemistry"},{"key":"ref_12","first-page":"191","article-title":"Stereoselective metabolism of the monoterpene carvone by rat and human liver microsomes","volume":"52","author":"Mayer","year":"2000","journal-title":"J. Pharm. Pharmacol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"705","DOI":"10.1111\/cpr.12062","article-title":"Modulating effect of d-carvone on 1,2-dimethylhydrazine-induced pre-neoplastic lesions, oxidative stress and biotransforming enzymes, in an experimental model of rat colon carcinogenesis","volume":"46","author":"Vinothkumar","year":"2013","journal-title":"Cell Prolif."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Moro, I.J., Gondo, G.D.G.A., Pierri, E.G., Pietro, R.C.L.R., Soares, C.P., de Sousa, D.P., and Santos, A.G.d. (2017). Evaluation of antimicrobial, cytotoxic and chemopreventive activities of carvone and its derivatives. Braz. J. Pharm. Sci., 53.","DOI":"10.1590\/s2175-97902017000400076"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"e22746","DOI":"10.1002\/jbt.22746","article-title":"d-Carvone inhibits the JAK\/STAT3 signaling pathway and induced the apoptotic cell death in the human gastric cancer AGS cells","volume":"35","author":"Lv","year":"2021","journal-title":"J. Biochem. Mol. Toxicol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2241","DOI":"10.1007\/s11095-017-2230-3","article-title":"BITC and S-Carvone Restrain High-Fat Diet-Induced Obesity and Ameliorate Hepatic Steatosis and Insulin Resistance","volume":"34","author":"Alsanea","year":"2017","journal-title":"Pharm. Res."},{"key":"ref_17","first-page":"6","article-title":"Antioxidant and free radical scavenging effect of D-carvone in hypertensive rats. In vivo and in vitro study","volume":"8","author":"Rajeshwari","year":"2015","journal-title":"Int. Lett. Nat. Sci."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Asle-Rousta, M., Amini, R., and Aghazadeh, S. (2020). Carvone suppresses oxidative stress and inflammation in the liver of immobilised rats. Arch. Physiol. Biochem., 1\u20136.","DOI":"10.1080\/13813455.2020.1851726"},{"key":"ref_19","first-page":"19","article-title":"D-carvone, a monoterpene reverses alterations in heart rate, nitric oxide, aortic lipids and enzymatic antioxidant status in nitric oxide deficient hypertensive rats","volume":"5","author":"Rajeshwari","year":"2015","journal-title":"Int. Lett. Nat. Sci."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"751","DOI":"10.1021\/jf00017a008","article-title":"Effects of carvone compounds on glutathione S-transferase activity in A\/J mice","volume":"40","author":"Zheng","year":"1992","journal-title":"J. Agric. Food Chem."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"101235","DOI":"10.1016\/j.psj.2021.101235","article-title":"Protective effect of glutathione S-transferase enzyme activity against aflatoxin B1 in poultry species: Relationship between glutathione S-transferase enzyme kinetic parameters, and resistance to aflatoxin B1","volume":"100","author":"Murcia","year":"2021","journal-title":"Poult. Sci."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Galicia-Moreno, M., Lucano-Landeros, S., Monroy-Ramirez, H.C., Silva-Gomez, J., Gutierrez-Cuevas, J., Santos, A., and Armendariz-Borunda, J. (2020). Roles of Nrf2 in Liver Diseases: Molecular, Pharmacological, and Epigenetic Aspects. Antioxidants, 9.","DOI":"10.3390\/antiox9100980"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"4302","DOI":"10.1074\/jbc.M116.773085","article-title":"Transforming growth factor-\u03b2 (TGF-\u03b2) directly activates the JAK1-STAT3 axis to induce hepatic fibrosis in coordination with the SMAD pathway","volume":"292","author":"Tang","year":"2017","journal-title":"J. Biol. Chem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"110870","DOI":"10.1016\/j.biopha.2020.110870","article-title":"D-Carvone inhibit cerebral ischemia\/reperfusion induced inflammatory response TLR4\/NLRP3 signaling pathway","volume":"132","author":"Dai","year":"2020","journal-title":"Biomed. Pharmacother."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1592","DOI":"10.1016\/j.jksus.2019.12.016","article-title":"Anti-inflammatory and protective effects of D-carvone on lipopolysaccharide (LPS)-induced acute lung injury in mice","volume":"32","author":"Zhao","year":"2020","journal-title":"J. King Saud Univ."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1887","DOI":"10.1172\/JCI66028","article-title":"Evolving therapies for liver fibrosis","volume":"123","author":"Schuppan","year":"2013","journal-title":"J. Clin. Investig."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"937","DOI":"10.1016\/j.tips.2018.09.002","article-title":"Natural products as a source for antifibrosis therapy","volume":"39","author":"Chen","year":"2018","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_28","first-page":"529","article-title":"Antiresproative potency of D-carvone on ovariectomy-induced osteoporosis in rats","volume":"17","author":"Dong","year":"2021","journal-title":"Phcog. Mag."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"26520","DOI":"10.1007\/s11356-020-09036-0","article-title":"Innovative application of helium-neon laser: Enhancing the germination of Adansonia digitata and evaluating the hepatoprotective activities in mice","volume":"27","author":"Khamis","year":"2020","journal-title":"Environ. Sci. Pollut. Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1080\/713611034","article-title":"Hepatotoxicity and mechanism of action of haloalkanes: Carbon tetrachloride as a toxicological model","volume":"33","author":"Weber","year":"2003","journal-title":"Crit. Rev. Toxicol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"561","DOI":"10.2131\/jts.41.561","article-title":"Mechanisms of CCl4-induced liver fibrosis with combined transcriptomic and proteomic analysis","volume":"41","author":"Dong","year":"2016","journal-title":"J. Toxicol. Sci."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1055\/s-2008-1040483","article-title":"Carbon tetrachloride hepatotoxicity: An example of free radical-mediated injury","volume":"10","author":"Williams","year":"1990","journal-title":"Semin. Liver Dis."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"8082","DOI":"10.3748\/wjg.v20.i25.8082","article-title":"Oxidative stress as a crucial factor in liver diseases","volume":"20","author":"Michalak","year":"2014","journal-title":"World J. Gastroenterol. WJG"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Dutta, S., Chakraborty, A.K., Dey, P., Kar, P., Guha, P., Sen, S., Kumar, A., Sen, A., and Chaudhuri, T.K. (2018). Amelioration of CCl4 induced liver injury in swiss albino mice by antioxidant rich leaf extract of Croton bonplandianus Baill. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0196411"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"453","DOI":"10.4196\/kjpp.2020.24.6.453","article-title":"Anti-arthritic activity of D-carvone against complete Freund\u2019s adjuvant-induced arthritis in rats through modulation of inflammatory cytokines","volume":"24","author":"Chen","year":"2020","journal-title":"Korean J. Physiol. Pharmacol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1558","DOI":"10.1016\/j.biopha.2016.11.025","article-title":"Beneficial effect of carvone, a dietary monoterpene ameliorates hyperglycemia by regulating the key enzymes activities of carbohydrate metabolism in streptozotocin-induced diabetic rats","volume":"84","author":"Muruganathan","year":"2016","journal-title":"Biomed. Pharmacother."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"51","DOI":"10.4103\/pm.pm_508_19","article-title":"Immunomodulatory effect of d-carvone in swiss albino mice with benzo (a) pyrene-induced lung cancer","volume":"17","author":"Zhang","year":"2021","journal-title":"Pharmacogn. Mag."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1002\/ptr.6242","article-title":"Hepatoprotective activity of praecoxin A isolated from Melaleuca ericifolia against carbon tetrachloride-induced hepatotoxicity in mice. Impact on oxidative stress, inflammation, and apoptosis","volume":"33","author":"Khattab","year":"2019","journal-title":"Phyther. Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1007\/112_2018_10","article-title":"Targeting oxidative stress for the treatment of liver fibrosis","volume":"175","author":"Luangmonkong","year":"2018","journal-title":"Rev. Physiol. Biochem. Pharmacol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"144781","DOI":"10.1016\/j.scitotenv.2020.144781","article-title":"Fucoidan supplementation modulates hepato-renal oxidative stress and DNA damage induced by aflatoxin B1 intoxication in rats","volume":"768","author":"Abdeen","year":"2021","journal-title":"Sci. Total Environ."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Chang, S.N., Kim, S.H., Dey, D.K., Park, S.M., Nasif, O., Bajpai, V.K., Kang, S.C., Lee, J.T., and Park, J.G. (2021). 5-O-Demethylnobiletin Alleviates CCl4-Induced Acute Liver Injury by Equilibrating ROS-Mediated Apoptosis and Autophagy Induction. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22031083"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"4039753","DOI":"10.1155\/2018\/4039753","article-title":"Antifibrogenic influence of Mentha piperita L. essential oil against CCl4-induced liver fibrosis in rats","volume":"2018","author":"Ogaly","year":"2018","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_43","first-page":"1","article-title":"The Nrf2 Pathway in Liver Diseases","volume":"10","author":"Zhou","year":"2022","journal-title":"Front. Cell Dev. Biol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1186\/s40824-020-00192-5","article-title":"Effects of intraperitoneal injection of magnetic graphene oxide on the improvement of acute liver injury induced by CCl 4","volume":"24","author":"Foroutan","year":"2020","journal-title":"Biomater. Res."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"13518","DOI":"10.3390\/molecules200813518","article-title":"Hepatocyte growth factor mediates the antifibrogenic action of Ocimum bacilicum essential oil against CCl4-induced liver fibrosis in rats","volume":"20","author":"Ogaly","year":"2015","journal-title":"Molecules"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1615\/JEnvironPatholToxicolOncol.2020031860","article-title":"Protective Effect of D-Carvone against Dextran Sulfate Sodium Induced Ulcerative Colitis in Balb\/c Mice and LPS Induced RAW Cells via the Inhibition of COX-2 and TNF-\u03b1","volume":"39","author":"Zhu","year":"2020","journal-title":"J. Environ. Pathol. Toxicol. Oncol."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Kang, W., Choi, D., Park, S., and Park, T. (2020). Carvone Decreases Melanin Content by Inhibiting Melanoma Cell Proliferation via the Cyclic Adenosine Monophosphate (cAMP) Pathway. Molecules, 25.","DOI":"10.3390\/molecules25215191"},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Elnagdy, M., Barve, S., McClain, C., and Gobejishvili, L. (2020). cAMP Signaling in Pathobiology of Alcohol Associated Liver Disease. Biomolecules, 10.","DOI":"10.3390\/biom10101433"},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"El Awdan, S.A., Rahman, R.F.A., Ibrahim, H.M., Hegazy, R.R., el Marasy, S.A., Badawi, M., and Arbid, M.S. (2019). Regression of fibrosis by cilostazol in a rat model of thioacetamide-induced liver fibrosis: Up regulation of hepatic cAMP, and modulation of inflammatory, oxidative stress and apoptotic biomarkers. PLoS ONE, 14.","DOI":"10.1371\/journal.pone.0216301"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1136\/gut.2005.088690","article-title":"Emerging insights into transforming growth factor \u03b2 Smad signal in hepatic fibrogenesis","volume":"56","author":"Inagaki","year":"2007","journal-title":"Gut"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"867","DOI":"10.1111\/jcmm.16140","article-title":"Tgfb3 and Mmp13 regulated the initiation of liver fibrosis progression as dynamic network biomarkers","volume":"25","author":"Guo","year":"2021","journal-title":"J. Cell. Mol. Med."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1369\/0022155415627681","article-title":"TGF-\u03b2\/SMAD Pathway and Its Regulation in Hepatic Fibrosis","volume":"64","author":"Xu","year":"2016","journal-title":"J. Histochem. Cytochem. Off. J. Histochem. Soc."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"F414","DOI":"10.1152\/ajprenal.00393.2016","article-title":"Apigenin ameliorates streptozotocin-induced diabetic nephropathy in rats via MAPK-NF-\u03baB-TNF-\u03b1 and TGF-\u03b21-MAPK-fibronectin pathways","volume":"313","author":"Malik","year":"2017","journal-title":"Am. J. Physiol. Physiol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1016\/j.toxlet.2021.01.010","article-title":"Depletion of serotonin relieves concanavalin A-induced liver fibrosis in mice by inhibiting inflammation, oxidative stress, and TGF-\u03b21\/Smads signaling pathway","volume":"340","author":"Pang","year":"2021","journal-title":"Toxicol. Lett."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"4107","DOI":"10.2147\/DDDT.S186726","article-title":"Ferulic acid attenuates liver fibrosis and hepatic stellate cell activation via inhibition of TGF-\u03b2\/Smad signaling pathway","volume":"12","author":"Mu","year":"2018","journal-title":"Drug Des. Devel. Ther."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1016\/j.cbi.2018.07.008","article-title":"New insights into TGF-\u03b2\/Smad signaling in tissue fibrosis","volume":"292","author":"Hu","year":"2018","journal-title":"Chem. Biol. Interact."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1575","DOI":"10.2147\/JIR.S304180","article-title":"Inflammasome as an Effective Platform for Fibrosis Therapy","volume":"14","author":"Chen","year":"2021","journal-title":"J. Inflamm. Res."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"107511","DOI":"10.1016\/j.pharmthera.2020.107511","article-title":"Targeting the NLRP3 inflammasome to treat cardiovascular fibrosis","volume":"209","author":"Pinar","year":"2020","journal-title":"Pharmacol. Ther."},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Prestigiacomo, V., and Suter-Dick, L. (2018). Nrf2 protects stellate cells from Smad-dependent cell activation. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0201044"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"779","DOI":"10.1016\/j.biopha.2017.07.006","article-title":"Tiron ameliorates oxidative stress and inflammation in titanium dioxide nanoparticles induced nephrotoxicity of male rats","volume":"93","author":"Morgan","year":"2017","journal-title":"Biomed. Pharmacother."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1016\/j.matbio.2015.01.004","article-title":"Matrix metalloproteinases in liver injury, repair and fibrosis","volume":"44","author":"Duarte","year":"2015","journal-title":"Matrix Biol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1033","DOI":"10.7150\/ijbs.25589","article-title":"Kupffer-derived matrix metalloproteinase-9 contributes to liver fibrosis resolution","volume":"14","author":"Feng","year":"2018","journal-title":"Int. J. Biol. Sci."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1016\/j.fct.2018.07.048","article-title":"Anthocyanins isolated from blueberry ameliorates CCl(4) induced liver fibrosis by modulation of oxidative stress, inflammation and stellate cell activation in mice","volume":"120","author":"Sun","year":"2018","journal-title":"Food Chem. Toxicol. An Int. J. Publ. Br. Ind. Biol. Res. Assoc."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"783","DOI":"10.1038\/aps.2016.35","article-title":"Chinese medicine CGA formula ameliorates DMN-induced liver fibrosis in rats via inhibiting MMP2\/9, TIMP1\/2 and the TGF-\u03b2\/Smad signaling pathways","volume":"37","author":"Li","year":"2016","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1787","DOI":"10.1016\/S0002-9440(10)61125-X","article-title":"Expression of transforming growth factor-beta 1 by pancreatic stellate cells and its implications for matrix secretion and turnover in chronic pancreatitis","volume":"160","author":"Shek","year":"2002","journal-title":"Am. J. Pathol."},{"key":"ref_66","first-page":"7028314","article-title":"Therapeutic effect of Dunaliella salina microalgae on thioacetamide-(TAA-) induced hepatic liver fibrosis in rats: Role of TGF-\u03b2 and MMP9","volume":"2019","author":"Salama","year":"2019","journal-title":"Biomed Res. Int."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"112714","DOI":"10.1016\/j.jep.2020.112714","article-title":"Hepatoprotective effect of total flavonoids of Mallotus apelta (Lour.) Muell.Arg. leaf against carbon tetrachloride-induced liver fibrosis in rats via modulation of TGF-\u03b21\/Smad and NF-\u03baB signaling pathways","volume":"254","author":"Zhang","year":"2020","journal-title":"J. Ethnopharmacol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"149","DOI":"10.5114\/ceh.2021.107067","article-title":"The effect of silymarin on liver enzymes and antioxidant status in trauma patients in the intensive care unit: A randomized double blinded placebo-controlled clinical trial","volume":"7","author":"Mirzaei","year":"2021","journal-title":"Clin. Exp. Hepatol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1002\/ptr.6826","article-title":"Effect of sour tea supplementation on liver enzymes, lipid profile, blood pressure, and antioxidant status in patients with non-alcoholic fatty liver disease: A double-blind randomized controlled clinical trial","volume":"35","author":"Izadi","year":"2021","journal-title":"Phyther. Res."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"112638","DOI":"10.1016\/j.biopha.2022.112638","article-title":"Clinical use of N-acetyl cysteine during liver transplantation: Implications of oxidative stress and inflammation as therapeutic targets","volume":"147","author":"Ntamo","year":"2022","journal-title":"Biomed. Pharmacother."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1111\/liv.12975","article-title":"Natural antioxidants for non-alcoholic fatty liver disease: Molecular targets and clinical perspectives","volume":"36","author":"Salomone","year":"2016","journal-title":"Liver Int."},{"key":"ref_72","first-page":"222","article-title":"Models of hepatoprotective activity assessment","volume":"17","year":"2015","journal-title":"Med. Univ."},{"key":"ref_73","unstructured":"Bancroft, J.D., and Gamble, M. (2002). Theory and Practice of Histological Techniques, Churchill Livingstone. [5th ed.]."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"696","DOI":"10.1016\/0168-8278(95)80226-6","article-title":"Histological grading and staging of chronic hepatitis","volume":"22","author":"Ishak","year":"1995","journal-title":"J. Hepatol."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1006\/meth.2001.1262","article-title":"Analysis of relative gene expression data using real-time quantitative PCR and the 2\u2212\u0394\u0394CT method","volume":"25","author":"Livak","year":"2001","journal-title":"Methods"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"104732","DOI":"10.1016\/j.jff.2021.104732","article-title":"Gastroprotective effects and metabolomic profiling of Chasteberry fruits against indomethacin-induced gastric injury in rats","volume":"86","author":"Ogaly","year":"2021","journal-title":"J. Funct. Foods"},{"key":"ref_77","doi-asserted-by":"crossref","unstructured":"Abdel-Rahman, R.F., Fayed, H.M., Asaad, G.F., Ogaly, H.A., Hessin, A.F., Salama, A.A.A., El-Rahman, S.S.A., Arbid, M.S., and Mohamed, M.A.E. (2021). The involvement of TGF-\u03b21\/FAK\/\u03b1-SMA pathway in the antifibrotic impact of rice bran oil on thioacetamide-induced liver fibrosis in rats. PLoS ONE, 16.","DOI":"10.1371\/journal.pone.0260130"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1016\/j.jsps.2019.11.013","article-title":"Propolis ameliorates cerebral injury in focal cerebral ischemia\/reperfusion (I\/R) rat model via upregulation of TGF-\u03b21","volume":"28","author":"Alqasoumi","year":"2020","journal-title":"Saudi Pharm. J."},{"key":"ref_79","doi-asserted-by":"crossref","unstructured":"Alsharif, I.A., Fayed, H.M., Abdel-Rahman, R.F., Abd-Elsalam, R.M., and Ogaly, H.A. (2022). Miconazole Mitigates Acetic Acid-Induced Experimental Colitis in Rats: Insight into Inflammation, Oxidative Stress and Keap1\/Nrf-2 Signaling Crosstalk. Biology, 11.","DOI":"10.3390\/biology11020303"},{"key":"ref_80","doi-asserted-by":"crossref","unstructured":"Ogaly, H.A., Abdel-Rahman, R.F., Mohamed, M., Farid, O.A., Khattab, M.S., and Abd-Elsalam, R.M. (2022). Thymol Ameliorated Neurotoxicity and Cognitive Deterioration in Thioacetamide-Induced Hepatic Encephalopathy Rat Model via Enhanced BDNF\/CREB Signaling Pathway. Food Funct.","DOI":"10.1039\/D1FO04292K"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1111\/jwas.12237","article-title":"Molecular and immunohistochemical diagnosis of Photobacterium damselae subspecies piscicida during naturally occurring disease in Egypt","volume":"46","author":"Marzouk","year":"2015","journal-title":"J. World Aquac. Soc."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"53249","DOI":"10.1007\/s11356-021-14532-y","article-title":"Eruca sativa seed extract modulates oxidative stress and apoptosis and up-regulates the expression of Bcl-2 and Bax genes in acrylamide-induced testicular dysfunction in rats","volume":"28","author":"Ogaly","year":"2021","journal-title":"Environ. Sci. Pollut. Res."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"1133","DOI":"10.1007\/s00210-018-1537-x","article-title":"Neuroprotective effect of vildagliptin against cerebral ischemia in rats","volume":"391","year":"2018","journal-title":"Naunyn. Schmiedebergs. Arch. Pharmacol."}],"container-title":["Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2079-7737\/11\/5\/739\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:09:57Z","timestamp":1760137797000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2079-7737\/11\/5\/739"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,5,12]]},"references-count":83,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2022,5]]}},"alternative-id":["biology11050739"],"URL":"https:\/\/doi.org\/10.3390\/biology11050739","relation":{},"ISSN":["2079-7737"],"issn-type":[{"value":"2079-7737","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,5,12]]}}}