{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T20:20:28Z","timestamp":1791663628994,"version":"4.3.4"},"reference-count":84,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2024,8,21]],"date-time":"2024-08-21T00:00:00Z","timestamp":1724198400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Researchers Supporting Project, King Saud University, Riyadh, Saudi Arabia"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background: 5-fluorouracil (5-FU) is a widely used, highly effective chemotherapeutic agent. However, its therapeutic efficacy is often limited by associated adverse effects, with hepatotoxicity being frequently reported with 5-FU therapy. Thymol is a monoterpene found in thyme (Thymus vulgaris L., Lamiaceae) and is known for its antioxidant, anti-apoptotic, and anticancer activities. This study aimed to explore the hepatoprotective activity of thymol against 5-FU-induced liver injury. Methods: Rats received two intraperitoneal doses of 5-FU (150 mg\/kg) either alone or in combination with thymol at doses of 60 mg\/kg or 120 mg\/kg. Liver enzymes, oxidative stress, and apoptotic markers, in addition to histopathological changes, were assessed. Results: 5-FU induced marked liver injuries as evidenced by elevated liver enzymes and histopathological changes, in addition to abnormalities of oxidative and apoptotic markers. The administration of thymol ameliorated the 5-FU-induced oxidative damage through increasing hepatic antioxidants and lowering lipid peroxidation. Apoptotic response markers such as Bax, Bcl-2, Bax\/Bcl-2 ratio, and PARP were also improved. Furthermore, Western blotting analysis showed that thymol modulated the 5-FU-induced changes in the expression of Akt\/GSK-3\u03b2 and p44\/42 MAPK (ERK1\/2) signaling pathways. Conclusions: Our research is the first to shed light on thymol\u2019s potential protective effect against 5-FU- induced hepatotoxicity by inhibiting oxidative and apoptotic pathways and modulating the Akt\/ GSK-3\u03b2 as well as p44\/42 MAPK (ERK1\/2) signaling pathways.<\/jats:p>","DOI":"10.3390\/ph17081094","type":"journal-article","created":{"date-parts":[[2024,8,22]],"date-time":"2024-08-22T03:07:38Z","timestamp":1724296058000},"page":"1094","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Thymol Protects against 5-Fluorouracil-Induced Hepatotoxicity via the Regulation of the Akt\/GSK-3\u03b2 Pathway in In Vivo and In Silico Experimental Models"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6306-5616","authenticated-orcid":false,"given":"Yasmen F.","family":"Mahran","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ain Shams University, Cairo 11566, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3983-868X","authenticated-orcid":false,"given":"Amira M.","family":"Badr","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11211, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3171-771X","authenticated-orcid":false,"given":"Layla A.","family":"Al-Kharashi","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11211, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanaa N.","family":"Alajami","sequence":"additional","affiliation":[{"name":"College of Pharmacy, King Saud University, Riyadh 11211, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nouf T.","family":"Aldamry","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11211, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4285-9097","authenticated-orcid":false,"given":"Nervana Moustafa","family":"Bayoumy","sequence":"additional","affiliation":[{"name":"Department of Physiology, College of Medicine, King Saud University, Riyadh 11211, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elshaymaa I.","family":"Elmongy","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Helwan University, Ain Helwan, Cairo 11795, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0648-0979","authenticated-orcid":false,"given":"Sahar","family":"Soliman","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pharmacology, College of Osteopathic Medicine, Sam Houston State University, Conroe, TX 77304, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,8,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"332","DOI":"10.4274\/tjps.galenos.2020.95870","article-title":"Hepatoprotective Activity of Gentisic Acid on 5-Fluorouracil-Induced Hepatotoxicity in Wistar Rats","volume":"18","author":"Pujari","year":"2021","journal-title":"Turk. J. Pharm. Sci."},{"key":"ref_2","first-page":"404","article-title":"The Protective Effects of Naringin against 5-Fluorouracil-Induced Hepatotoxicity and Nephrotoxicity in Rats","volume":"21","author":"Gelen","year":"2018","journal-title":"Iran. J. Basic Med. Sci."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1569","DOI":"10.1016\/S0006-2952(97)00040-3","article-title":"An Alternative Molecular Mechanism of Action of 5-Fluorouracil, a Potent Anticancer Drug","volume":"53","author":"Ghoshal","year":"1997","journal-title":"Biochem. Pharmacol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1203","DOI":"10.1177\/0960327115626583","article-title":"Mitigation of 5-Fluorouracil\u2013Induced Liver Damage in Rats by Vitamin C via Targeting Redox\u2013Sensitive Transcription Factors","volume":"35","author":"Khan","year":"2016","journal-title":"Hum. Exp. Toxicol."},{"key":"ref_5","first-page":"530","article-title":"Taurine as a Protective Agent for 5-Fluorouracil-Induced Hepatic Damage Related to Oxidative Stress","volume":"71","author":"Fukuno","year":"2016","journal-title":"Die Pharm. Int. J. Pharm. Sci."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1111\/bcpt.13976","article-title":"Therapeutic Benefit of Melatonin in 5-Fluorouracil-Induced Renal and Hepatic Injury","volume":"134","author":"Mansoori","year":"2024","journal-title":"Basic Clin. Pharmacol. Toxicol."},{"key":"ref_7","first-page":"95","article-title":"Potential Protective Role of Cyrtopodion Scabrum in Antioxidant Parameters in Serum and Liver of Rats with 5-FU-Induced Oxidative Damage","volume":"76","author":"Diba","year":"2021","journal-title":"Arch. Razi Inst."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"40190","DOI":"10.1007\/s11356-022-18899-4","article-title":"Role of Platelet-Activating Factor and HO-1 in Mediating the Protective Effect of Rupatadine against 5-Fluorouracil-Induced Hepatotoxicity in Rats","volume":"29","author":"Khalaf","year":"2022","journal-title":"Environ. Sci. Pollut. Res."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Saleh, D.O., Mahmoud, S.S., Hassan, A., and Sanad, E.F. (2022). Doxorubicin-Induced Hepatic Toxicity in Rats: Mechanistic Protective Role of Omega-3 Fatty Acids through Nrf2\/HO-1 Activation and PI3K\/Akt\/GSK-3\u03b2 Axis Modulation. Saudi J. Biol. Sci., 29.","DOI":"10.1016\/j.sjbs.2022.103308"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Guo, C., Zheng, L., Chen, S., Liang, X., Song, X., Wang, Y., Hua, B., and Qiu, L. (2023). Thymol Ameliorates Ethanol-Induced Hepatotoxicity via Regulating Metabolism and Autophagy. Chem. Biol. Interact., 370.","DOI":"10.1016\/j.cbi.2022.110308"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Mahran, Y.F., Al-Kharashi, L.A., Atawia, R.T., Alanazi, R.T., Dhahi, A.M.B., Alsubaie, R., and Badr, A.M. (2023). Radioprotective Effects of Carvacrol and\/or Thymol against Gamma Irradiation-Induced Acute Nephropathy: In Silico and In Vivo Evidence of the Involvement of Insulin-like Growth Factor-1 (IGF-1) and Calcitonin Gene-Related Peptide. Biomedicines, 11.","DOI":"10.3390\/biomedicines11092521"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"396","DOI":"10.1080\/13813455.2018.1476979","article-title":"Effects of Thymol and Carvacrol on Sperm Quality and Oxidant\/Antioxidant Balance in Rats","volume":"125","author":"Cellat","year":"2019","journal-title":"Arch. Physiol. Biochem."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1002\/ptr.5516","article-title":"Nanotechnology in Phytotherapy: Antiinflammatory Effect of a Nanostructured Thymol Gel from Lippia Sidoides in Acute Periodontitis in Rats","volume":"30","author":"Botelho","year":"2016","journal-title":"Phytother. Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1275","DOI":"10.1007\/s10787-019-00583-8","article-title":"Thymol Reduces Acetic Acid-Induced Inflammatory Response through Inhibition of NF-kB Signaling Pathway in Rat Colon Tissue","volume":"27","author":"Chamanara","year":"2019","journal-title":"Inflammopharmacology"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Al-Khrashi, L.A., Badr, A.M., Al-Amin, M.A., and Mahran, Y.F. (2022). Thymol Ameliorates 5-Fluorouracil-Induced Intestinal Mucositis: Evidence of down-Regulatory Effect on TGF-\u03b2\/MAPK Pathways through NF-\u03baB. J. Biochem. Mol. Toxicol., 36.","DOI":"10.1002\/jbt.22932"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Badr, A.M., Alkharashi, L.A., Sherif, I.O., Alanteet, A.A., Alotaibi, H.N., and Mahran, Y.F. (2022). IL-17\/Notch1\/STAT3 Pathway Contributes to 5-Fluorouracil-Induced Intestinal Mucositis in Rats: Amelioration by Thymol Treatment. Pharmaceuticals, 15.","DOI":"10.2139\/ssrn.4137028"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Ibrahim, D., Abdelfattah-Hassan, A., Badawi, M., Ismail, T.A., Bendary, M.M., Abdelaziz, A.M., Mosbah, R.A., Mohamed, D.I., Arisha, A.H., and El-Hamid, M.I.A. (2021). Thymol Nanoemulsion Promoted Broiler Chicken\u2019s Growth, Gastrointestinal Barrier and Bacterial Community and Conferred Protection against Salmonella Typhimurium. Sci. Rep., 11.","DOI":"10.1038\/s41598-021-86990-w"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Ye, X., Ling, T., Xue, Y., Xu, C., Zhou, W., Hu, L., Chen, J., and Shi, Z. (2016). Thymol Mitigates Cadmium Stress by Regulating Glutathione Levels and Reactive Oxygen Species Homeostasis in Tobacco Seedlings. Molecules, 21.","DOI":"10.3390\/molecules21101339"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"615","DOI":"10.1021\/acs.jafc.8b05480","article-title":"Thymol Improves Barrier Function and Attenuates Inflammatory Responses in Porcine Intestinal Epithelial Cells during Lipopolysaccharide (LPS)-Induced Inflammation","volume":"67","author":"Omonijo","year":"2019","journal-title":"J. Agric. Food Chem."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Dou, X., Yan, D., Liu, S., Gao, L., and Shan, A. (2022). Thymol Alleviates LPS-Induced Liver Inflammation and Apoptosis by Inhibiting NLRP3 Inflammasome Activation and the AMPK-mTOR-Autophagy Pathway. Nutrients, 14.","DOI":"10.3390\/nu14142809"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/j.etap.2017.12.010","article-title":"Hepatoprotective Effect of Thymol against Subchronic Toxicity of Titanium Dioxide Nanoparticles: Biochemical and Histological Evidences","volume":"58","author":"Jafari","year":"2018","journal-title":"Environ. Toxicol. Pharmacol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"885","DOI":"10.1111\/j.1476-5381.2008.00085.x","article-title":"Glycogen Synthase Kinase 3: More than a Namesake","volume":"156","author":"Rayasam","year":"2009","journal-title":"Br. J. Pharmacol."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Jacobs, K.M., Bhave, S.R., Ferraro, D.J., Jaboin, J.J., Hallahan, D.E., and Thotala, D. (2012). GSK-3\u03b2: A Bifunctional Role in Cell Death Pathways. Int. J. Cell Biol., 2012.","DOI":"10.1155\/2012\/930710"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Abu-Elfotuh, K., Abdel-Sattar, S.A., Abbas, A.N., Mahran, Y.F., Alshanwani, A.R., Hamdan, A.M.E., Atwa, A.M., Reda, E., Ahmed, Y.M., and Zaghlool, S.S. (2022). The Protective Effect of Thymoquinone or\/and Thymol against Monosodium Glutamate-Induced Attention-Deficit\/Hyperactivity Disorder (ADHD)-like Behavior in Rats: Modulation of Nrf2\/HO-1, TLR4\/NF-\u03baB\/NLRP3\/Caspase-1 and Wnt\/\u03b2-Catenin Signaling Pathways in Rat Model. Biomed. Pharmacother., 155.","DOI":"10.1016\/j.biopha.2022.113799"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2227728","DOI":"10.1080\/0886022X.2023.2227728","article-title":"Protective Effect of Thymol on Glycerol-Induced Acute Kidney Injury","volume":"45","author":"Wang","year":"2023","journal-title":"Ren. Fail."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Yao, L., Swartz, P., Hamilton, P.T., and Clark, A.C. (2021). Remodeling Hydrogen Bond Interactions Results in Relaxed Specificity of Caspase-3. Biosci. Rep., 41.","DOI":"10.1042\/BSR20203495"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1002\/med.10011","article-title":"Glycogen Synthase Kinase 3 (GSK-3) Inhibitors as New Promising Drugs for Diabetes, Neurodegeneration, Cancer, and Inflammation","volume":"22","author":"Martinez","year":"2002","journal-title":"Med. Res. Rev."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1016\/j.ejphar.2008.01.019","article-title":"Olanzapine Inhibits Glycogen Synthase Kinase-3\u03b2: An Investigation by Docking Simulation and Experimental Validation","volume":"584","author":"Mohammad","year":"2008","journal-title":"Eur. J. Pharmacol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2062","DOI":"10.1021\/jm7009765","article-title":"Pharmacophore Modeling, Quantitative Structure\u2013Activity Relationship Analysis, and in Silico Screening Reveal Potent Glycogen Synthase Kinase-3\u03b2 Inhibitory Activities for Cimetidine, Hydroxychloroquine, and Gemifloxacin","volume":"51","author":"Taha","year":"2008","journal-title":"J. Med. Chem."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"755","DOI":"10.2174\/0929867043455738","article-title":"GSK-3 Inhibitors: Discoveries and Developments","volume":"11","author":"Alonso","year":"2004","journal-title":"Curr. Med. Chem."},{"key":"ref_31","unstructured":"(2023, December 06). Borek: Antioxidants and Radiation Therapy\u2014Google Scholar. Available online: https:\/\/scholar.google.com\/scholar_lookup?title=Antioxidants%20and%20radiation%20therapy&publication_year=2004&author=C.%20Borek."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1779","DOI":"10.1253\/circj.CJ-10-0632","article-title":"Cardiovascular Side-Effects of Modern Cancer Therapy","volume":"74","author":"Minami","year":"2010","journal-title":"Circ. J."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1016\/j.jobaz.2013.12.004","article-title":"Ameliorative Effect of Vitamin C against 5-Fuorouracil-Induced Hepatotoxicity in Mice: A Light and Electron Microscope Study","volume":"67","year":"2014","journal-title":"J. Basic Appl. Zool."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1007\/s13691-019-00394-2","article-title":"A Case of Severe Hepatotoxicity Induced by Cisplatin and 5-Fluorouracil","volume":"9","author":"Yaegashi","year":"2019","journal-title":"Int. Cancer Conf. J."},{"key":"ref_35","first-page":"680","article-title":"Protective Effect of Captopril against 5-Fluorouracil-Induced Hepato and Nephrotoxicity in Male Albino Rats","volume":"8","author":"Ali","year":"2012","journal-title":"J. Am. Sci."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Zeng, D., Wang, Y., Chen, Y., Li, D., Li, G., Xiao, H., Hou, J., Wang, Z., Hu, L., and Wang, L. (2021). Angelica Polysaccharide Antagonizes 5-FU-Induced Oxidative Stress Injury to Reduce Apoptosis in the Liver Through Nrf2 Pathway. Front. Oncol., 11.","DOI":"10.3389\/fonc.2021.720620"},{"key":"ref_37","first-page":"755","article-title":"Breviscapine Ameliorates CCl4-induced Liver Injury in Mice through Inhibiting Inflammatory Apoptotic Response and ROS Generation","volume":"42","author":"Liu","year":"2018","journal-title":"Int. J. Mol. Med."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/j.jnutbio.2016.09.001","article-title":"Pomegranate Protects against Arsenic-Induced P53-Dependent ROS-Mediated Inflammation and Apoptosis in Liver Cells","volume":"38","author":"Choudhury","year":"2016","journal-title":"J. Nutr. Biochem."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"856","DOI":"10.1016\/j.biopha.2018.05.154","article-title":"Immunomodulatory Effects of Thymol through Modulation of Redox Status and Trace Element Content in Experimental Model of Asthma","volume":"105","author":"Mohammadi","year":"2018","journal-title":"Biomed. Pharmacother."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"2115","DOI":"10.7314\/APJCP.2014.15.5.2115","article-title":"Preventive Effect of Hydrazinocurcumin on Carcinogenesis of Diethylnitrosamine-Induced Hepatocarcinoma in Male SD Rats","volume":"15","author":"Zhao","year":"2014","journal-title":"Asian Pac. J. Cancer Prev."},{"key":"ref_41","unstructured":"Stockham, S.L., and Scott, M.A. (2013). Fundamentals of Veterinary Clinical Pathology, John Wiley & Sons."},{"key":"ref_42","first-page":"414","article-title":"Prospective, Randomized Trial of Intravenous versus Intraperitoneal 5-Fluorouracil in Patients with Advanced Primary Colon or Rectal Cancer","volume":"98","author":"Sugarbaker","year":"1985","journal-title":"Surgery"},{"key":"ref_43","first-page":"335","article-title":"In Vitro Evaluation of Protective Effects of Ascorbic Acid and Water Extract of Spirulina Plantesis (Blue Green Algae) on 5-Fluorouracil-Induced Lipid Peroxidation","volume":"64","author":"Ray","year":"2007","journal-title":"Acta Pol. Pharm."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1016\/j.fct.2014.01.026","article-title":"Mitigation of 5-Fluorouracil Induced Renal Toxicity by Chrysin via Targeting Oxidative Stress and Apoptosis in Wistar Rats","volume":"66","author":"Rashid","year":"2014","journal-title":"Food Chem. Toxicol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"647","DOI":"10.1016\/j.tiv.2015.02.006","article-title":"In Vitro Pro-Oxidant\/Antioxidant Role of Carvacrol, Thymol and Their Mixture in the Intestinal Caco-2 Cell Line","volume":"29","author":"Puerto","year":"2015","journal-title":"Toxicol. In Vitro"},{"key":"ref_46","first-page":"501","article-title":"Clinicopathological Studies of Thymus vulgaris Extract against Cadmium Induced Hepatotoxicity in Albino Rats","volume":"8","author":"Elgaml","year":"2014","journal-title":"Glob. J. Pharmacol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"479","DOI":"10.4062\/biomolther.2022.017","article-title":"Modulation of Reactive Oxygen Species to Overcome 5-Fluorouracil Resistance","volume":"30","author":"Chun","year":"2022","journal-title":"Biomol. Ther."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1016\/0925-4439(95)00012-S","article-title":"Oxidants in Mitochondria: From Physiology to Diseases","volume":"1271","author":"Richter","year":"1995","journal-title":"Biochim. Biophys. Acta BBA Mol. Basis Dis."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"R26","DOI":"10.1152\/ajpregu.00049.2014","article-title":"Oxidative Stress and Altered Lipid Homeostasis in the Programming of Offspring Fatty Liver by Maternal Obesity","volume":"307","author":"Alfaradhi","year":"2014","journal-title":"Am. J. Physiol. Regul. Integr. Comp. Physiol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1109","DOI":"10.1016\/j.dnarep.2004.03.002","article-title":"DNA Damage Responses to Oxidative Stress","volume":"3","author":"Barzilai","year":"2004","journal-title":"DNA Repair"},{"key":"ref_51","first-page":"466","article-title":"Histopathological Effects of Cisplatin, Doxorubicin and 5-Flurouracil (5-FU) on the Liver of Male Albino Rats","volume":"5","author":"Ismail","year":"2009","journal-title":"Int. J. Biol. Sci."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1031","DOI":"10.1084\/jem.183.3.1031","article-title":"A Bcl-2 Transgene Expressed in Hepatocytes Protects Mice from Fulminant Liver Destruction but Not from Rapid Death Induced by Anti-Fas Antibody Injection","volume":"183","author":"Rodriguez","year":"1996","journal-title":"J. Exp. Med."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/j.jff.2015.01.013","article-title":"Thymol Attenuates Altered Lipid Metabolism in \u03b2-Adrenergic Agonist Induced Myocardial Infarcted Rats by Inhibiting Tachycardia, Altered Electrocardiogram, Apoptosis and Cardiac Hypertrophy","volume":"14","author":"Jagadeesh","year":"2015","journal-title":"J. Funct. Foods"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1016\/j.tem.2014.11.003","article-title":"Poly(ADP-Ribose) Polymerases as Modulators of Mitochondrial Activity","volume":"26","author":"Bai","year":"2015","journal-title":"Trends Endocrinol. Metab."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1109","DOI":"10.1016\/j.mam.2013.01.005","article-title":"PARP-1 and Gene Regulation: Progress and Puzzles","volume":"34","author":"Kraus","year":"2013","journal-title":"Mol. Asp. Med."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"589","DOI":"10.1016\/j.jhep.2016.10.023","article-title":"PARP Inhibition Protects against Alcoholic and Non-Alcoholic Steatohepatitis","volume":"66","author":"Mukhopadhyay","year":"2017","journal-title":"J. Hepatol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"588","DOI":"10.1038\/sj.cdd.4400851","article-title":"Characterization of the Necrotic Cleavage of Poly(ADP-Ribose) Polymerase (PARP-1): Implication of Lysosomal Proteases","volume":"8","author":"Gobeil","year":"2001","journal-title":"Cell Death Differ."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1217","DOI":"10.1016\/j.mam.2013.01.006","article-title":"Therapeutic Applications of PARP Inhibitors: Anticancer Therapy and Beyond","volume":"34","author":"Curtin","year":"2013","journal-title":"Mol. Asp. Med."},{"key":"ref_59","first-page":"375","article-title":"Thymol Reduces the Lipopolysaccharide-Induced Acute Kidney Inflammation by Modulating Lysosomal Stress","volume":"27","author":"Erzurumlu","year":"2023","journal-title":"J. Res. Pharm."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1925","DOI":"10.1074\/jbc.M610602200","article-title":"Ethanol-Induced Modulation of Hepatocellular Extracellular Signal-Regulated Kinase-1\/2 Activity via 4-Hydroxynonenal","volume":"282","author":"Sampey","year":"2007","journal-title":"J. Biol. Chem."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1111\/acer.12645","article-title":"Alcohol Alters the Activation of ERK1\/2, a Functional Regulator of Binge Alcohol Drinking in Adult C57BL\/6J Mice","volume":"39","author":"Agoglia","year":"2015","journal-title":"Alcohol. Clin. Exp. Res."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1326","DOI":"10.1126\/science.270.5240.1326","article-title":"Opposing Effects of ERK and JNK-P38 MAP Kinases on Apoptosis","volume":"270","author":"Xia","year":"1995","journal-title":"Science"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"20490","DOI":"10.1074\/jbc.272.33.20490","article-title":"Apoptosis Induced by Withdrawal of Trophic Factors Is Mediated by P38 Mitogen-Activated Protein Kinase","volume":"272","author":"Kummer","year":"1997","journal-title":"J. Biol. Chem."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"4281","DOI":"10.1523\/JNEUROSCI.13-10-04281.1993","article-title":"Signal Transduction Events Mediated by the BDNF Receptor Gp 145trkB in Primary Hippocampal Pyramidal Cell Culture","volume":"13","author":"Marsh","year":"1993","journal-title":"J. Neurosci."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1089\/neu.1994.11.3","article-title":"Endogenous Neuroprotection Factors and Traumatic Brain Injury: Mechanisms of Action and Implications for Therapy","volume":"11","author":"Mattson","year":"1994","journal-title":"J. Neurotrauma"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"3158","DOI":"10.1194\/jlr.M007948","article-title":"Involvement and Mechanism of DGAT2 Upregulation in the Pathogenesis of Alcoholic Fatty Liver Disease","volume":"51","author":"Wang","year":"2010","journal-title":"J. Lipid Res."},{"key":"ref_67","first-page":"2744","article-title":"Toll-like Receptor 4-Mediated Signaling Participates in Apoptosis of Hippocampal Neurons","volume":"8","author":"He","year":"2013","journal-title":"Neural Regen. Res."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"4754195","DOI":"10.1155\/2020\/4754195","article-title":"Sulforaphene Ameliorates Neuroinflammation and Hyperphosphorylated Tau Protein via Regulating the PI3K\/Akt\/GSK-3\u03b2 Pathway in Experimental Models of Alzheimer\u2019s Disease","volume":"2020","author":"Yang","year":"2020","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1038\/160297a0","article-title":"Raphanin, an Antibacterial Principle of the Radish (Raphanus sativus)","volume":"160","year":"1947","journal-title":"Nature"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"8268955","DOI":"10.1155\/2023\/8268955","article-title":"3,3\u2032-Diindolylmethane Augments 5-Fluorouracil-InducedGrowth Suppression in Gastric Cancer Cells through Suppression of the Akt\/GSK-3\u03b2 and WNT\/Beta-Catenin","volume":"2023","author":"Li","year":"2023","journal-title":"J. Oncol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1016\/j.ctrv.2003.07.007","article-title":"PI3K\/Akt Signalling Pathway and Cancer","volume":"30","author":"Casado","year":"2004","journal-title":"Cancer Treat. Rev."},{"key":"ref_72","first-page":"261","article-title":"Phospho Akt Mediates Multidrug Resistance of Gastric Cancer Cells through Regulation of P-Gp, Bcl-2 and Bax","volume":"26","author":"Han","year":"2007","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"2331","DOI":"10.1002\/cam4.1169","article-title":"CISD2 Enhances the Chemosensitivity of Gastric Cancer through the Enhancement of 5-FU-Induced Apoptosis and the Inhibition of Autophagy by AKT\/mTOR Pathway","volume":"6","author":"Sun","year":"2017","journal-title":"Cancer Med."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1016\/j.tibs.2003.12.004","article-title":"The Glamour and Gloom of Glycogen Synthase Kinase-3","volume":"29","author":"Jope","year":"2004","journal-title":"Trends Biochem. Sci."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1016\/S1471-4914(01)02266-3","article-title":"Glycogen Synthase Kinase 3: An Emerging Therapeutic Target","volume":"8","year":"2002","journal-title":"Trends Mol. Med."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"8244","DOI":"10.1074\/jbc.M109.054999","article-title":"Silencing Glycogen Synthase Kinase-3\u03b2 Inhibits Acetaminophen Hepatotoxicity and Attenuates JNK Activation and Loss of Glutamate Cysteine Ligase and Myeloid Cell Leukemia Sequence 1","volume":"285","author":"Shinohara","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"e12952","DOI":"10.1111\/nmo.12952","article-title":"May Cannabinoids Prevent the Development of Chemotherapy-Induced Diarrhea and Intestinal Mucositis? Experimental Study in the Rat","volume":"29","author":"Abalo","year":"2017","journal-title":"Neurogastroenterol. Motil."},{"key":"ref_78","doi-asserted-by":"crossref","unstructured":"Javed, H., Azimullah, S., Meeran, M.F.N., Ansari, S.A., and Ojha, S. (2019). Neuroprotective Effects of Thymol, a Dietary Monoterpene Against Dopaminergic Neurodegeneration in Rotenone-Induced Rat Model of Parkinson\u2019s Disease. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20071538"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"555855","DOI":"10.19080\/ARGH.2019.13.555855","article-title":"Implication of Sphingosine-1-P\/Sphingosine Kinase Pathway in Non-Alcoholic Fatty Liver Disease","volume":"13","author":"Badr","year":"2019","journal-title":"Adv. Res. Gastroenterol. Hepatol."},{"key":"ref_80","unstructured":"Bancroft, J., Stevens, M.A., and Bancroft, J.D. (1996). Theory and Practice of Histological Techniques, Elsevier."},{"key":"ref_81","first-page":"518","article-title":"Disulfide and Sulfhydryl Compounds in TCA Extracts of Human Blood and Plasma","volume":"70","author":"Ellman","year":"1967","journal-title":"J. Lab. Clin. Med."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1016\/0003-2697(79)90738-3","article-title":"Assay for Lipid Peroxides in Animal Tissues by Thiobarbituric Acid Reaction","volume":"95","author":"Ohkawa","year":"1979","journal-title":"Anal. Biochem."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"849","DOI":"10.1016\/S0006-291X(72)80218-3","article-title":"The Occurrence of Superoxide Anion in the Reaction of Reduced Phenazine Methosulfate and Molecular Oxygen","volume":"46","author":"Nishikimi","year":"1972","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_84","doi-asserted-by":"crossref","unstructured":"Badr, A.M., Al-Kharashi, L.A., Attia, H., Alshehri, S., Alajami, H.N., Ali, R.A., and Mahran, Y.F. (2023). TLR4\/Inflammasomes Cross-Talk and Pyroptosis Contribute to N-Acetyl Cysteine and Chlorogenic Acid Protection against Cisplatin-Induced Nephrotoxicity. Pharmaceuticals, 16.","DOI":"10.3390\/ph16030337"}],"container-title":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/17\/8\/1094\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T15:40:13Z","timestamp":1760110813000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/17\/8\/1094"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,8,21]]},"references-count":84,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2024,8]]}},"alternative-id":["ph17081094"],"URL":"https:\/\/doi.org\/10.3390\/ph17081094","relation":{},"ISSN":["1424-8247"],"issn-type":[{"value":"1424-8247","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,8,21]]}}}