{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T22:06:58Z","timestamp":1782338818188,"version":"3.54.5"},"reference-count":90,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2026,2,4]],"date-time":"2026-02-04T00:00:00Z","timestamp":1770163200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Medical University of Plovdiv","award":["NO-03\/2023"],"award-info":[{"award-number":["NO-03\/2023"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Acetaminophen (APAP) overdose can induce potentially fatal nephrotoxicity. Micromeria frivaldszkyana (M. frivaldszkyana), an endemic plant to Bulgaria, has demonstrated significant antioxidant activity. This study represents the first evaluation of the nephroprotective effects of a methanolic extract of M. frivaldszkyana in an APAP-induced rat model of kidney injury. The aim of the study was to investigate the protective potential of orally administered M. frivaldszkyana methanolic extract against APAP-induced nephrotoxicity. Male Wistar rats received a one-week treatment with saline, M. frivaldszkyana extract (250, 400, or 500 mg\/kg), rosmarinic acid (100 mg\/kg), or silymarin (125 mg\/kg). On day 7, renal injury was induced by oral administration of APAP (2000 mg\/kg). Forty-eight hours later, blood and kidney samples were collected for biochemical and histological analyses. The extract at 500 mg\/kg significantly reduced the elevated levels of serum urea (1.83 \u00b1 0.24 vs. 3.49 \u00b1 0.75, p &lt; 0.05), creatinine (59.51 \u00b1 2.30 vs. 72.27 \u00b1 3.92, p &lt; 0.05), and uric acid (477.55 \u00b1 52.48 vs. 898.33 \u00b1 65.30, p &lt; 0.001), while restoring renal glutathione (GSH) levels (4.43 \u00b1 0.19 vs. 2.64 \u00b1 0.10, p &lt; 0.001) and catalase activity (3802.78 \u00b1 142.05 vs. 2485.03 \u00b1 143.23, p &lt; 0.01), compared with APAP-treated rats. Malondialdehyde levels were significantly reduced by the extract (25.19 \u00b1 0.95 vs. 69.66 \u00b1 4.11, p &lt; 0.001), with similar effects observed across all tested doses. In conclusion, M. frivaldszkyana methanolic extract confers significant protection against APAP-induced nephrotoxicity, likely through antioxidant-mediated mechanisms, enhanced GSH restoration, and attenuation of lipid peroxidation, highlighting its potential as a nephroprotective agent.<\/jats:p>","DOI":"10.3390\/ijms27031547","type":"journal-article","created":{"date-parts":[[2026,2,4]],"date-time":"2026-02-04T17:20:14Z","timestamp":1770225614000},"page":"1547","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Nephroprotective Effect of Methanolic Extract of Micromeria frivaldszkyana (Degen) Velen Against Acetaminophen Overdose in Rats"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5167-3278","authenticated-orcid":false,"given":"Elisaveta","family":"Apostolova","sequence":"first","affiliation":[{"name":"Department of Pharmacology, Toxicology, and Pharmacotherapy, Faculty of Pharmacy, Medical University of Plovdiv, Vasil Aprilov Str. 15A, 4002 Plovdiv, Bulgaria"},{"name":"Research Institute, Medical University of Plovdiv, 4002 Plovdiv, Bulgaria"},{"name":"Center for Competence \u201cPERIMED-2\u201d, Vasil Aprilov Blvd. 15A, 4002 Plovdiv, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5578-7862","authenticated-orcid":false,"given":"Vesela","family":"Kokova","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Toxicology, and Pharmacotherapy, Faculty of Pharmacy, Medical University of Plovdiv, Vasil Aprilov Str. 15A, 4002 Plovdiv, Bulgaria"},{"name":"Research Institute, Medical University of Plovdiv, 4002 Plovdiv, Bulgaria"},{"name":"Center for Competence \u201cPERIMED-2\u201d, Vasil Aprilov Blvd. 15A, 4002 Plovdiv, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8406-1446","authenticated-orcid":false,"given":"Ivica","family":"Dimov","sequence":"additional","affiliation":[{"name":"Department of Medical Biochemistry, Faculty of Pharmacy, Medical University of Plovdiv, Vasil Aprilov Str. 15A, 4002 Plovdiv, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5489-8106","authenticated-orcid":false,"given":"Mariya","family":"Choneva","sequence":"additional","affiliation":[{"name":"Department of Medical Biochemistry, Faculty of Pharmacy, Medical University of Plovdiv, Vasil Aprilov Str. 15A, 4002 Plovdiv, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3695-5688","authenticated-orcid":false,"given":"Delyan","family":"Delev","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Clinical Pharmacology, Faculty of Medicine, Medical University of Plovdiv, Vasil Aprilov Str. 15A, 4002 Plovdiv, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2397-0988","authenticated-orcid":false,"given":"Ilia","family":"Kostadinov","sequence":"additional","affiliation":[{"name":"Research Institute, Medical University of Plovdiv, 4002 Plovdiv, Bulgaria"},{"name":"Department of Pharmacology and Clinical Pharmacology, Faculty of Medicine, Medical University of Plovdiv, Vasil Aprilov Str. 15A, 4002 Plovdiv, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ilia","family":"Bivolarski","sequence":"additional","affiliation":[{"name":"Department of General and Clinical Pathology, Faculty of Medicine, Medical University of Plovdiv, 4000 Plovdiv, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Koleva","sequence":"additional","affiliation":[{"name":"Department of General and Clinical Pathology, Faculty of Medicine, Medical University of Plovdiv, 4000 Plovdiv, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tsvetelina","family":"Mladenova","sequence":"additional","affiliation":[{"name":"Department of Botany and Biological Education, Faculty of Biology, University of Plovdiv \u201cPaisii Hilendarski\u201d, 24 Tsar Assen Str., 4000 Plovdiv, Bulgaria"},{"name":"Department of Bioorganic Chemistry, Faculty of Pharmacy, Medical University of Plovdiv, Vasil Aprilov Str. 15A, 4002 Plovdiv, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1344-624X","authenticated-orcid":false,"given":"Krasimir","family":"Todorov","sequence":"additional","affiliation":[{"name":"Department of Botany and Biological Education, Faculty of Biology, University of Plovdiv \u201cPaisii Hilendarski\u201d, 24 Tsar Assen Str., 4000 Plovdiv, Bulgaria"},{"name":"Department of Bioorganic Chemistry, Faculty of Pharmacy, Medical University of Plovdiv, Vasil Aprilov Str. 15A, 4002 Plovdiv, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2157-3858","authenticated-orcid":false,"given":"Anelia","family":"Bivolarska","sequence":"additional","affiliation":[{"name":"Department of Medical Biochemistry, Faculty of Pharmacy, Medical University of Plovdiv, Vasil Aprilov Str. 15A, 4002 Plovdiv, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Dkhil, M.A., Abdel Moneim, A.E., Hafez, T.A., Mubaraki, M.A., Mohamed, W.F., Thagfan, F.A., and Al-Quraishy, S. (2019). Myristica fragrans Kernels prevent paracetamol-induced hepatotoxicity by inducing anti-apoptotic genes and Nrf2\/HO-1 pathway. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20040993"},{"key":"ref_2","first-page":"37","article-title":"Curcumin a potential antagonist against paracetamol induced nephrotoxicity in rats","volume":"62","author":"Ibrahim","year":"2019","journal-title":"Alex. J. Vet. Sci."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Mullins, M.E. (2025). Epidemiology of acetaminophen toxicity. Acetaminophen Toxicity, Academic Press.","DOI":"10.1016\/B978-0-443-15877-3.00001-6"},{"key":"ref_4","first-page":"77","article-title":"Drug-induced liver toxicity","volume":"51","author":"Stavrakeva","year":"2024","journal-title":"Acta Med. Bulg."},{"key":"ref_5","first-page":"399","article-title":"Paracetamol overdose induces acute liver injury accompanied by oxidative stress and inflammation","volume":"66","author":"Ahmed","year":"2023","journal-title":"Egypt. J. Chem."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Apostolova, E., Stavrakeva, K., Kokova, V., Dimov, I., Choneva, M., Delev, D., Kostadinov, I., Bivolarski, I., Koleva, M., and Mladenov, R. (2025). Protective effects of methanolic extract of Micromeria frivaldszkyana (Degen) Velen against acetaminophen-induced liver toxicity in male wistar rats. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26189112"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"406","DOI":"10.1093\/toxres\/tfaa040","article-title":"Acetaminophen-induced renal toxicity: Preventive effect of silver nanoparticles","volume":"9","author":"Reshi","year":"2020","journal-title":"Toxicol. Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1016\/j.biopha.2016.11.033","article-title":"l-Methionine and silymarin: A comparison of prophylactic protective capabilities in acetaminophen-induced injuries of the liver, kidney and cerebral cortex","volume":"85","author":"Onaolapo","year":"2017","journal-title":"Biomed. Pharmacother."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"633","DOI":"10.1080\/01480545.2020.1747484","article-title":"Role of cinnamon oil against acetaminophen overdose induced neurological aberrations through brain stress and cytokine upregulation in rat brain","volume":"45","author":"Ashafaq","year":"2022","journal-title":"Drug Chem. Toxicol."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Gvozdeva, Y., and Georgieva, P. (2025). Therapeutic potential of essential oils and their bioactive compounds against colon cancer: Focus on colon-specific micro- and nanocarriers. BioChem., 5.","DOI":"10.3390\/biochem5030026"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Naguib, Y.M., Azmy, R.M., Samaka, R.M., and Salem, M.F. (2014). Pleurotus ostreatus opposes mitochondrial dysfunction and oxidative stress in acetaminophen-induced hepato-renal injury. BMC Complement. Altern. Med., 14.","DOI":"10.1186\/1472-6882-14-494"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1809","DOI":"10.1080\/13880209.2017.1331248","article-title":"Effects of rosmarinic acid on acetaminophen-induced hepatotoxicity in male Wistar rats","volume":"55","author":"Hasanein","year":"2017","journal-title":"Pharm. Biol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"8121124","DOI":"10.1155\/2022\/8121124","article-title":"Kahweol Protects against Acetaminophen-Induced Hepatotoxicity in Mice through Inhibiting Oxidative Stress, Hepatocyte Death, and Inflammation","volume":"2022","author":"Kim","year":"2022","journal-title":"Biomed. Res. Int."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1016\/j.toxlet.2011.10.023","article-title":"Hesperidin alleviates acetaminophen induced toxicity in Wistar rats by abrogation of oxidative stress, apoptosis and inflammation","volume":"208","author":"Ahmad","year":"2012","journal-title":"Toxicol. Lett."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1186\/s40816-020-0151-x","article-title":"Impact of date palm pollen (Phoenix dactylifera) treatment on paracetamol-induced hepatorenal toxicity in rats","volume":"6","author":"Abbasmanthiri","year":"2020","journal-title":"Clin. Phytosci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"589","DOI":"10.1177\/0748233713502841","article-title":"Protective effects of silymarin against acetaminophen-induced hepatotoxicity and nephrotoxicity in mice","volume":"32","author":"Bektur","year":"2016","journal-title":"Toxicol. Ind. Health"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Topal, I., \u00d6zdamar, M.Y., Catakli, T., Malkoc, \u0130., Hacimuftuoglu, A., Mamoulakis, C., Tsatsakis, A., Tsarouhas, K., Tsitsimpikou, C., and Taghizadehghalehjoughi, A. (2023). Renoprotective Effect of Taxifolin in Paracetamol-Induced Nephrotoxicity: Emerging Evidence from an Animal Model. J. Clin. Med., 12.","DOI":"10.3390\/jcm12030876"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Ivanova, S., Dzhakova, Z., Staynova, R., and Ivanov, K. (2024). Salvia verticillata (L.)\u2014Biological activity, chemical profile, and future perspectives. Pharmaceuticals, 17.","DOI":"10.3390\/ph17070859"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/j.jacme.2014.02.002","article-title":"Renoprotective effect of Tabernaemontana heyneana Wall. leaves against paracetamol-induced renotoxicity in rats and detection of polyphenols by high-performance liquid chromatography\u2013diode array detector\u2013mass spectrometry analysis","volume":"4","author":"Sathishkumar","year":"2014","journal-title":"J. Acute Med."},{"key":"ref_20","first-page":"169","article-title":"Drug-induced Nephrotoxicity and Medicinal Plants","volume":"11","author":"Rad","year":"2017","journal-title":"Iran. J. Kidney Dis."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Olukanni, A.T., Omotosho, D., Olalekan, D.T., Durugbo, E., Adewumi, A.T., Olukanni, O.D., and Mosebi, S. (2025). Hepatoprotective and Nephroprotective Effects of Leea guineensis Leaf Extract Against Paracetamol-Induced Toxicity: Combined Mouse Model-Integrated in Silico Evidence. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26136142"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Mladenova, T., Stoyanov, P., Denev, P., Dimitrova, S., Katsarova, M., Teneva, D., Todorov, K., and Bivolarska, A. (2021). Phytochemical composition, antioxidant and antimicrobial activity of the Balkan endemic Micromeria frivaldszkyana (Degen) Velen. (Lamiaceae). Plants, 10.","DOI":"10.3390\/plants10040710"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Stavrakeva, K., Metodieva, K., Benina, M., Bivolarska, A., Dimov, I., Choneva, M., Kokova, V., Alseekh, S., Ivanova, V., and Vatov, E. (2024). Metabolic composition of methanolic extract of the Balkan endemic species Micromeria frivaldszkyana (Degen) Velen and its anti-inflammatory effect on male Wistar rats. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25105396"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Apostolova, E., Stavrakeva, K., Kokova, V., Dimov, I., Choneva, M., Delev, D., Kostadinov, I., Bivolarski, I., Koleva, M., and Mladenova, T. (2025). Subchronic toxicity and effect of the methanolic extract of Micromeria frivaldszkyana (Degen) Velen on cognition in male Wistar rats. Plants, 14.","DOI":"10.3390\/plants14121837"},{"key":"ref_25","first-page":"7","article-title":"Flavonoid compounds and antioxidant activity of Bulgarian species of Micromeria","volume":"102","author":"Nikolova","year":"2017","journal-title":"Annu. L\u2019universit\u00e9 Sofia St. Kliment Ohridski Fac. Biol."},{"key":"ref_26","first-page":"949","article-title":"Linarin inhibits the acetylcholinesterase activity in-vitro and ex-vivo","volume":"14","author":"Feng","year":"2015","journal-title":"Iran. J. Pharm. Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1016\/j.biopha.2017.10.064","article-title":"Chlorogenic acid (CGA): A pharmacological review and call for further research","volume":"97","author":"Naveed","year":"2018","journal-title":"Biomed. Pharmacother."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Choi, S.S., Park, H.R., and Lee, K.A. (2021). A comparative study of rutin and rutin glycoside: Antioxidant activity, anti-inflammatory effect, effect on platelet aggregation and blood coagulation. Antioxidants, 10.","DOI":"10.3390\/antiox10111696"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"939","DOI":"10.1177\/09731296241297432","article-title":"Linarin Protects against Cisplatin-induced Nephrotoxicity via Subsiding Proinflammatory and Oxidative Stress Biomarkers in Male Wistar Rats","volume":"21","author":"Qi","year":"2024","journal-title":"Pharmacogn. Mag."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1002\/fsn3.3041","article-title":"The protective effects of rutin on the liver, kidneys, and heart by counteracting organ toxicity caused by synthetic and natural compounds","volume":"11","author":"Rahmani","year":"2022","journal-title":"Food Sci. Nutr."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"6085","DOI":"10.1080\/14786419.2022.2045603","article-title":"Apigenin and kaempferol as novel renoprotective agent against cisplatin-induced toxicity: An in vitro study","volume":"36","author":"Sharma","year":"2022","journal-title":"Nat. Prod. Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"3189","DOI":"10.1002\/ptr.6765","article-title":"Chlorogenic acid prevents vancomycin-induced nephrotoxicity without compromising vancomycin antibacterial properties","volume":"34","author":"Qu","year":"2020","journal-title":"Phytother. Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1016\/j.fct.2014.02.002","article-title":"Nephroprotective activities of rosmarinic acid against cisplatin-induced kidney injury in mice","volume":"66","year":"2014","journal-title":"Food Chem. Toxicol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"392","DOI":"10.1016\/j.tice.2011.09.001","article-title":"Effect of rosmarinic acid on inhibition of gentamicin induced nephrotoxicity in rats","volume":"43","author":"Tavafi","year":"2011","journal-title":"Tissue Cell."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Xiang, Y., Ji, M., Wu, L., Lv, L., Liang, Q., Deng, R., Deng, Z., Liu, X., Ren, L., and Feng, X. (2022). Rosmarinic acid prevents cisplatin-induced liver and kidney injury by inhibiting inflammatory responses and enhancing total antioxidant capacity, thereby activating the Nrf2 signaling pathway. Molecules, 27.","DOI":"10.3390\/molecules27227815"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Pashova, S., Karcheva-Bahchevanska, D., Ivanov, K., and Ivanova, S. (2024). Genus Stachys\u2014Phytochemistry, traditional medicinal uses, and future perspectives. Molecules, 29.","DOI":"10.3390\/molecules29225345"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"229","DOI":"10.18388\/abp.2010_2399","article-title":"Evaluation of antioxidant activity of medicinal plants containing polyphenol compounds. Comparison of two extraction systems","volume":"57","author":"Kratchanova","year":"2010","journal-title":"Acta Biochim. Pol."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Mottaghipisheh, J., Taghrir, H., Boveiri Dehsheikh, A., Zomorodian, K., Irajie, C., Mahmoodi Sourestani, M., and Iraji, A. (2021). Linarin, a glycosylated flavonoid, with potential therapeutic attributes: A comprehensive review. Pharmaceuticals, 14.","DOI":"10.3390\/ph14111104"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"3589","DOI":"10.2147\/DDDT.S433591","article-title":"Linarin protects against CCl4-induced acute liver injury via activating autophagy and inhibiting the inflammatory response: Involving the TLR4\/MAPK\/Nrf2 pathway","volume":"17","author":"Li","year":"2023","journal-title":"Drug Des. Dev. Ther."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"156440","DOI":"10.1016\/j.phymed.2025.156440","article-title":"Linarin attenuates hyperuricemic nephropathy by modulating Nrf2\/Keap1 and TLR4\/NF-\u03baB signaling pathways: Linarin attenuates hyperuricemic nephropathy","volume":"139","author":"Qian","year":"2025","journal-title":"Phytomedicine"},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Gvozdeva, Y., and Staynova, R. (2025). pH-dependent drug delivery systems for ulcerative colitis treatment. Pharmaceutics, 17.","DOI":"10.3390\/pharmaceutics17020226"},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Li, Y., Guang, C., Zhao, N., Feng, X., and Qiu, F. (2019). LC\u2013MS\/MS method for simultaneous determination of Linarin and its metabolites in rat plasma and liver tissue samples: Application to pharmacokinetic and liver tissue distribution study after oral administration of Linarin. Molecules, 24.","DOI":"10.3390\/molecules24183342"},{"key":"ref_43","first-page":"1","article-title":"Essential oils\u2014A review of the natural evolution of applications and some future perspectives","volume":"72","author":"Ivanova","year":"2025","journal-title":"Pharmacia"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1007","DOI":"10.3109\/0886022X.2016.1163998","article-title":"Ameliorative effect of naringin in acetaminophen-induced hepatic and renal toxicity in laboratory rats: Role of FXR and KIM-1","volume":"38","author":"Adil","year":"2016","journal-title":"Ren. Fail."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s44337-025-00315-8","article-title":"Advancing nephroprotective strategies: The role of naringenin in preventing gentamicin-induced nephrotoxicity","volume":"2","author":"Bwambale","year":"2025","journal-title":"Discov. Med."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1016\/j.tox.2014.07.004","article-title":"Renoprotective mechanisms of chlorogenic acid in cisplatin-induced kidney injury","volume":"324","year":"2014","journal-title":"Toxicology"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"e01545\u201318","DOI":"10.1128\/AAC.01545-18","article-title":"Rutin Attenuates Vancomycin-Induced Nephrotoxicity by Ameliorating Oxidative Stress, Apoptosis, and Inflammation in Rats","volume":"63","author":"Qu","year":"2018","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"518","DOI":"10.3109\/0886022X.2015.1006100","article-title":"Rutin attenuates gentamicin-induced renal damage by reducing oxidative stress, inflammation, apoptosis, and autophagy in rats","volume":"37","author":"Kandemir","year":"2015","journal-title":"Ren. Fail."},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Alhoshani, A.R., Hafez, M.M., Husain, S., Al-Sheikh, A.M., Alotaibi, M.R., Al Rejaie, S.S., Alshammari, M.A., Almutairi, M.M., and Al-Shabanah, O.A. (2017). Protective effect of rutin supplementation against cisplatin-induced Nephrotoxicity in rats. BMC Nephrol., 18.","DOI":"10.1186\/s12882-017-0601-y"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"65276","DOI":"10.1007\/s11356-022-20235-9","article-title":"Apigenin attenuates molecular, biochemical, and histopathological changes associated with renal impairments induced by gentamicin exposure in rats","volume":"29","author":"Hussein","year":"2022","journal-title":"Environ. Sci. Pollut. Res. Int."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"111308","DOI":"10.1016\/j.biopha.2021.111308","article-title":"Apigenin ameliorates doxorubicin-induced renal injury via inhibition of oxidative stress and inflammation","volume":"137","author":"Wu","year":"2021","journal-title":"Biomed. Pharmacother."},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Nadeem, M., Imran, M., Aslam Gondal, T., Imran, A., Shahbaz, M., Muhammad Amir, R., Wasim Sajid, M., Batool Qaisrani, T., Atif, M., and Hussain, G. (2019). Therapeutic Potential of Rosmarinic Acid: A Comprehensive Review. Appl. Sci., 9.","DOI":"10.3390\/app9153139"},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Kanner, J. (2020). Polyphenols by generating H2O2, affect cell redox signaling, Inhibit PTPs and activate Nrf2 axis for adaptation and cell surviving: In vitro, in vivo and human health. Antioxidants, 9.","DOI":"10.3390\/antiox9090797"},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"D\u2019Amico, R., Trovato Salinaro, A., Cordaro, M., Fusco, R., Impellizzeri, D., Interdonato, L., Scuto, M., Ontario, M.L., Crea, R., and Siracusa, R. (2021). Hidrox\u00ae and chronic cystitis: Biochemical evaluation of inflammation, oxidative stress, and pain. Antioxidants, 10, Erratum in Antioxidants\u00a02025, 14, 1106.","DOI":"10.3390\/antiox14091106"},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Scuto, M., Rampulla, F., Reali, G.M., Span\u00f2, S.M., Trovato Salinaro, A., and Calabrese, V. (2024). Hormetic nutrition and redox regulation in gut\u2013brain axis disorders. Antioxidants, 13.","DOI":"10.3390\/antiox13040484"},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Fusco, R., Scuto, M., Cordaro, M., D\u2019Amico, R., Gugliandolo, E., Siracusa, R., Peritore, A.F., Crupi, R., Impellizzeri, D., and Cuzzocrea, S. (2019). N-palmitoylethanolamide-oxazoline protects against middle cerebral artery occlusion injury in diabetic rats by regulating the SIRT1 pathway. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20194845"},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Wu, L., Lv, L., Xiang, Y., Yi, D., Liang, Q., Ji, M., Deng, Z., Qin, L., Ren, L., and Liang, Z. (2025). Rosmarinic Acid Protects Against Acetaminophen-Induced Hepatotoxicity by Suppressing Ferroptosis and Oxidative Stress Through Nrf2\/HO-1 Activation in Mice. Mar. Drugs, 23.","DOI":"10.3390\/md23070287"},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Wang, Q., Liu, T., Koci, M., Wang, Y., Fu, Y., Ma, M., Ma, Q., and Zhao, L. (2023). Chlorogenic Acid Alleviated AFB1-Induced Hepatotoxicity by Regulating Mitochondrial Function, Activating Nrf2\/HO-1, and Inhibiting Noncanonical NF-\u03baB Signaling Pathway. Antioxidants, 12.","DOI":"10.3390\/antiox12122027"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"4378461","DOI":"10.1155\/2016\/4378461","article-title":"Apigenin Attenuates Oxidative Injury in ARPE-19 Cells thorough Activation of Nrf2 Pathway","volume":"2016","author":"Xu","year":"2016","journal-title":"Oxidative Med. Cell. Longev."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.neuro.2024.07.010","article-title":"Rutin alleviates Pb-induced oxidative stress, inflammation and cell death via activating Nrf2\/ARE system in SH-SY5Y cells","volume":"104","author":"Li","year":"2024","journal-title":"Neurotoxicology"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1582","DOI":"10.3892\/ijmm.2017.3134","article-title":"Naringenin reduces oxidative stress and improves mitochondrial dysfunction via activation of the Nrf2\/ARE signaling pathway in neurons","volume":"40","author":"Wang","year":"2017","journal-title":"Int. J. Mol. Med."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"105341","DOI":"10.5306\/wjco.v16.i5.105341","article-title":"Natural compound rosmarinic acid displays anti-tumor activity in colorectal cancer cells by suppressing nuclear factor-kappa B signaling","volume":"16","author":"Liu","year":"2025","journal-title":"World J. Clin. Oncol."},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Chen, J., Luo, Y., Li, Y., Chen, D., Yu, B., and He, J. (2021). Chlorogenic Acid Attenuates Oxidative Stress-Induced Intestinal Epithelium Injury by Co-Regulating the PI3K\/Akt and I\u03baB\u03b1\/NF-\u03baB Signaling. Antioxidants, 10.","DOI":"10.3390\/antiox10121915"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1093\/jpp\/rgaa015","article-title":"Rutin prevents inflammation induced by lipopolysaccharide in RAW 264.7 cells via conquering the TLR4-MyD88-TRAF6-NF-\u03baB signalling pathway","volume":"73","author":"Tian","year":"2021","journal-title":"J. Pharm. Pharmacol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"100216","DOI":"10.18632\/oncotarget.22145","article-title":"Apigenin inhibits colonic inflammation and tumorigenesis by suppressing STAT3-NF-\u03baB signaling","volume":"8","author":"Ai","year":"2017","journal-title":"Oncotarget"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1017\/S0007114512005594","article-title":"Protective effect of naringenin against experimental colitis via suppression of Toll-like receptor 4\/NF-\u03baB signalling","volume":"110","author":"Dou","year":"2013","journal-title":"Br. J. Nutr."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41538-021-00084-5","article-title":"Rosmarinic acid suppresses tau phosphorylation and cognitive decline by downregulating the JNK signaling pathway","volume":"5","author":"Yamamoto","year":"2021","journal-title":"NPJ Sci. Food"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"27888","DOI":"10.1074\/jbc.M503347200","article-title":"Inhibition of activator protein-1, NF-kappaB, and MAPKs and induction of phase 2 detoxifying enzyme activity by chlorogenic acid","volume":"280","author":"Feng","year":"2005","journal-title":"J. Biol. Chem."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"2056","DOI":"10.3892\/etm.2017.4173","article-title":"Rutin attenuates isoflurane-induced neuroapoptosis via modulating JNK and p38 MAPK pathways in the hippocampi of neonatal rats","volume":"13","author":"Li","year":"2017","journal-title":"Exp. Ther. Med."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1007\/s00210-017-1454-4","article-title":"Apigenin reduces the Toll-like receptor-4-dependent activation of NF-\u03baB by suppressing the Akt, mTOR, JNK, and p38-MAPK","volume":"391","author":"Kim","year":"2018","journal-title":"Naunyn-Schmiedeberg\u2019s Arch. Pharmacol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"3049","DOI":"10.7150\/ijms.44804","article-title":"Naringenin exerts anticancer effects by inducing tumor cell death and inhibiting angiogenesis in malignant melanoma","volume":"17","author":"Choi","year":"2020","journal-title":"Int. J. Med. Sci."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"933","DOI":"10.3109\/02713683.2015.1082186","article-title":"Protective Effect of Rutin Against H2O2-Induced Oxidative Stress and Apoptosis in Human Lens Epithelial Cells","volume":"41","author":"Zhou","year":"2016","journal-title":"Curr. Eye Res."},{"key":"ref_73","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. Ren. Physiol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"796","DOI":"10.1016\/j.biopha.2017.05.112","article-title":"Naringenin protects keratinocytes from oxidative stress injury via inhibition of the NOD2-mediated NF-\u03baB pathway in pemphigus vulgaris","volume":"92","author":"Liang","year":"2017","journal-title":"Biomed. Pharmacother. Biomed. Pharmacother."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1016\/j.ejphar.2014.05.024","article-title":"Protective effect of linarin against D-galactosamine and lipopolysaccharide-induced fulminant hepatic failure","volume":"738","author":"Kim","year":"2014","journal-title":"Eur. J. Pharmacol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"e23806","DOI":"10.1002\/jbt.23806","article-title":"The inhibitory effect of chlorogenic acid on oxidative stress and apoptosis induced by PM2.5 in HaCaT keratinocytes","volume":"38","author":"Herath","year":"2024","journal-title":"J. Biochem. Mol. Toxicol."},{"key":"ref_77","first-page":"62","article-title":"Antiapoptotic and antioxidant effects of rosmarinic acid in astrocytes","volume":"60","author":"Gao","year":"2005","journal-title":"Die Pharm."},{"key":"ref_78","doi-asserted-by":"crossref","unstructured":"Scuto, M., Majz\u00fanov\u00e1, M., Torcitto, G., Antonuzzo, S., Rampulla, F., Di Fatta, E., and Trovato Salinaro, A. (2024). functional food nutrients, redox resilience signaling and neurosteroids for brain health. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms252212155"},{"key":"ref_79","doi-asserted-by":"crossref","unstructured":"Scuto, M.C., Anfuso, C.D., Lombardo, C., Di Fatta, E., Ferri, R., Musso, N., Zerbo, G., Terrana, M., Majz\u00fanov\u00e1, M., and Lupo, G. (2025). Neuronutrition and Nrf2 brain resilience signaling: Epigenomics and metabolomics for personalized medicine in nervous system disorders from bench to clinic. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26199391"},{"key":"ref_80","first-page":"615","article-title":"The ameliorative effect of the solvent extracts of Ocimum basilicum against acetaminophen-induced liver damage in albino rats","volume":"20","author":"Asala","year":"2021","journal-title":"J. Phytomedicine Ther."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1016\/j.tox.2007.10.010","article-title":"The potential protective role of alpha-lipoic acid against acetaminophen-induced hepatic and renal damage","volume":"243","author":"Mahmoud","year":"2008","journal-title":"Toxicology"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"4579149","DOI":"10.1155\/2016\/4579149","article-title":"Evaluation of hepatoprotective activity of Adansonia digitata extract on acetaminophen-induced hepatotoxicity in rats","volume":"2016","author":"Hanafy","year":"2016","journal-title":"Evid. Based Complement. Altern. Med."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"67","DOI":"10.9734\/jpri\/2020\/v32i3230935","article-title":"Hepatoprotective and reno-protective effects of artichoke leaf extract and rosemary extract against Paracetamol induced toxicity in Albino Rats","volume":"32","author":"Fadlalla","year":"2020","journal-title":"J. Pharm. Res. Int."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"112215","DOI":"10.1016\/j.biopha.2021.112215","article-title":"Epiphytic Acampe ochracea orchid relieves paracetamol-induced hepatotoxicity by inhibiting oxidative stress and upregulating antioxidant genes in in vivo and virtual screening","volume":"143","author":"Ahmed","year":"2021","journal-title":"Biomed. Pharmacother."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"260","DOI":"10.1016\/j.fct.2013.12.041","article-title":"Toxicological assessment of combined lead and cadmium: Acute and sub-chronic toxicity study in rats","volume":"65","author":"Yuan","year":"2014","journal-title":"Food Chem. Toxicol."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"2728","DOI":"10.1016\/j.fct.2008.04.035","article-title":"Safety assessment of pomegranate fruit extract: Acute and subchronic toxicity studies","volume":"46","author":"Patel","year":"2008","journal-title":"Food Chem. Toxicol."},{"key":"ref_87","first-page":"182064","article-title":"Acute and subchronic toxicity study of Euphorbia hirta L. methanol extract in rats","volume":"2013","author":"Darah","year":"2013","journal-title":"Biomed. Res. Int."},{"key":"ref_88","doi-asserted-by":"crossref","unstructured":"Ahmed, A., Al Tamimi, D., Isab, A., Alkhawajah, A., and Shawarby, M. (2012). Histological changes in kidney and liver of rats due to gold (III) compound [Au(en)Cl(2)]Cl. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0051889"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"404","DOI":"10.3897\/folmed.61.e39348","article-title":"Impact of a high-fat diet on the development of chronic inflammation in heart of Wistar rats","volume":"61","author":"Dimitrov","year":"2019","journal-title":"Folia Medica"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"5134","DOI":"10.1007\/s12011-022-03098-6","article-title":"Ginkgo biloba supplement reverses lead (II) acetate\u2013induced haematological imbalances, hepatic and renal dysfunctions in male Wistar rat","volume":"200","author":"Asiwe","year":"2022","journal-title":"Biol. Trace Elem. Res."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/3\/1547\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,4]],"date-time":"2026-02-04T17:21:55Z","timestamp":1770225715000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/3\/1547"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,4]]},"references-count":90,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2026,2]]}},"alternative-id":["ijms27031547"],"URL":"https:\/\/doi.org\/10.3390\/ijms27031547","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,2,4]]}}}