{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T12:45:57Z","timestamp":1785501957669,"version":"3.56.0"},"reference-count":85,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2025,4,29]],"date-time":"2025-04-29T00:00:00Z","timestamp":1745884800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Toxics"],"abstract":"<jats:p>Imidacloprid (IMI) is a widely used insecticide known for its high selectivity toward insects. Ellagic acid (EA) is a plant-derived polyphenolic compound recognized for its therapeutic potential and favorable safety profile in the treatment of various diseases. This study aimed to evaluate the therapeutic effects of EA, formulated as novasomes (NOV), against IMI-induced thyroid dysfunction and to investigate the underlying mechanisms. Rats were divided into four equal groups: control, EA-NOV, IMI, and IMI + EA-NOV. Thyroid function was assessed by measuring free triiodothyronine (T3), free thyroxine (T4), and thyroid-stimulating hormone (TSH) levels. Thyroid tissues were examined to evaluate histopathological alterations, as well as to assess the oxidative\/antioxidant pathway (Nrf2, SOD, TAC, MDA), inflammatory pathway (IL-1\u03b2, TNF-\u03b1, NF-\u03baB), apoptotic pathway (Bcl, BAX), and autophagy pathway (PI3K\/Akt\/mTOR, P53, Beclin-1). Exposure to IMI resulted in impaired thyroid function, the upregulated gene expression of the PI3K\/Akt\/mTOR pathway, and downregulated P53 expression. Additionally, immunohistochemical staining revealed Beclin-1-mediated autophagy, alongside increased apoptosis, oxidative stress, and elevated levels of inflammatory cytokines. Conversely, EA improved thyroid function and ameliorated histopathological alterations by enhancing autophagy-inducing pathways. Additionally, the alleviation of oxidative stress was evidenced by the increased immunohistochemical staining of Nrf2, which promoted the synthesis and activity of antioxidant enzymes and reduced apoptotic and inflammatory markers. This study proposes the use of EA as a potential protective, naturally occurring phytoceutical against IMI-induced thyroid dysfunction, primarily through the modulation of PI3K\/Akt\/mTOR-mediated autophagy.<\/jats:p>","DOI":"10.3390\/toxics13050355","type":"journal-article","created":{"date-parts":[[2025,4,29]],"date-time":"2025-04-29T07:49:36Z","timestamp":1745912976000},"page":"355","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Ellagic Acid Alleviates Imidacloprid-Induced Thyroid Dysfunction via PI3K\/Akt\/mTOR-Mediated Autophagy"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3014-9909","authenticated-orcid":false,"given":"Amina A.","family":"Farag","sequence":"first","affiliation":[{"name":"Department of Forensic Medicine and Clinical Toxicology, Faculty of Medicine, Benha University, Benha 13518, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6425-9247","authenticated-orcid":false,"given":"Mahmoud","family":"Mostafa","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics, Faculty of Pharmacy, Minia University, Minia 61519, Egypt"},{"name":"Department of Pharmaceutics, Faculty of Pharmacy, Minia National University, New Minia 61768, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6542-749X","authenticated-orcid":false,"given":"Reham M.","family":"Abdelfatah","sequence":"additional","affiliation":[{"name":"Department of Pesticides, Faculty of Agriculture, Mansoura University, Mansoura 35516, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alshimaa Ezzat","family":"ELdahshan","sequence":"additional","affiliation":[{"name":"Department of Histology, Faculty of Medicine, Benha University, Benha 13518, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samar Fawzy","family":"Gad","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Faculty of Medicine, Benha University, Benha 13518, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shimaa K.","family":"Mohamed","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, Faculty of Pharmacy, Helwan University, Cairo 11795, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mona K.","family":"Alawam","sequence":"additional","affiliation":[{"name":"Department of Physiology, Faculty of Medicine, Benha University, Benha 13518, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aya Aly","family":"Elzeer","sequence":"additional","affiliation":[{"name":"Department of Development of Animal Wealth, Faculty of Veterinary Medicine, Mansoura University, Mansoura 35516, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nesma S.","family":"Ismail","sequence":"additional","affiliation":[{"name":"Department of Forensic Medicine and Clinical Toxicology, Faculty of Medicine, Benha University, Benha 13518, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sally","family":"Elsharkawey","sequence":"additional","affiliation":[{"name":"Department of Forensic Medicine and Clinical Toxicology, Faculty of Medicine, Benha University, Benha 13518, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5838-3468","authenticated-orcid":false,"given":"Haneen A.","family":"Al-Mazroua","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7495-0592","authenticated-orcid":false,"given":"Hatun A.","family":"Alomar","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6376-9464","authenticated-orcid":false,"given":"Wedad S.","family":"Sarawi","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8267-1718","authenticated-orcid":false,"given":"Heba S.","family":"Youssef","sequence":"additional","affiliation":[{"name":"Department of Physiology, Faculty of Medicine, Benha University, Benha 13518, 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Int."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"113731","DOI":"10.1016\/j.envpol.2019.113731","article-title":"Unraveling the toxic effects of neonicotinoid insecticides on the thyroid endocrine system of lizards","volume":"258","author":"Wang","year":"2020","journal-title":"Environ. Pollut."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"131120","DOI":"10.1016\/j.chemosphere.2021.131120","article-title":"Spermiogenesis toxicity of imidacloprid in rats, possible role of CYP3A4","volume":"282","author":"Zhao","year":"2021","journal-title":"Chemosphere"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"892","DOI":"10.1016\/j.envpol.2019.05.062","article-title":"Occurrence and distribution of neonicotinoid insecticides in surface water and sediment of the Guangzhou section of the Pearl River, South China","volume":"251","author":"Yi","year":"2019","journal-title":"Environ. Pollut."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1016\/j.cotox.2019.10.003","article-title":"Mechanisms underlying disruptive effects of pesticides on the thyroid function","volume":"19","author":"Bennekou","year":"2020","journal-title":"Curr. Opin. Toxicol."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Kochman, J., Jakubczyk, K., Bargiel, P., and Janda-Milczarek, K. (2021). The Influence of Oxidative Stress on Thyroid Diseases. Antioxidants, 10.","DOI":"10.3390\/antiox10091442"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Panda, S., Kar, A., Singh, M., Singh, R.K., and Ganeshpurkar, A. (2021). Syringic acid, a novel thyroid hormone receptor-\u03b2 agonist, ameliorates propylthiouracil-induced thyroid toxicity in rats. J. Biochem. Mol. Toxicol., 35.","DOI":"10.1002\/jbt.22814"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"674","DOI":"10.1016\/j.fsi.2021.12.017","article-title":"Exposure to imidacloprid induce oxidative stress, mitochondrial dysfunction, inflammation, apoptosis and mitophagy via NF-kappaB\/JNK pathway in grass carp hepatocytes","volume":"120","author":"Miao","year":"2022","journal-title":"Fish. Shellfish. Immunol."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Qumsani, A.T. (2025). Exploring the Effects of Imidacloprid on Liver Health and the Microbiome in Rats: A Comprehensive Study. Microorganisms, 13.","DOI":"10.3390\/microorganisms13010015"},{"key":"ref_10","first-page":"2465","article-title":"miRNA-125a modulates autophagy of thyroiditis through PI3K\/Akt\/mTOR signaling pathway","volume":"17","author":"Chen","year":"2019","journal-title":"Exp. Ther. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"7223353","DOI":"10.1155\/2022\/7223353","article-title":"Protective Effect of Photobiomodulation against Hydrogen Peroxide-Induced Oxidative Damage by Promoting Autophagy through Inhibition of PI3K\/AKT\/mTOR Pathway in MC3T3-E1 Cells","volume":"2022","author":"Zuo","year":"2022","journal-title":"Oxid. Med. Cell Longev."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Liu, X., Zhou, C., Cheng, B., Xiong, Y., Zhou, Q., Wan, E., and He, Y. (2024). Genipin promotes the apoptosis and autophagy of neuroblastoma cells by suppressing the PI3K\/AKT\/mTOR pathway. Sci. Rep., 14.","DOI":"10.1038\/s41598-024-71123-w"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"59","DOI":"10.4103\/tcmj.tcmj_106_23","article-title":"Ellagic acid ameliorates renal fibrogenesis by blocking epithelial-to-mesenchymal transition","volume":"36","author":"Huang","year":"2024","journal-title":"Tzu Chi Med. J."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Mannino, F., Imbesi, C., Bitto, A., Minutoli, L., Squadrito, F., D\u2019Angelo, T., Booz, C., Pallio, G., and Irrera, N. (2023). Anti-oxidant and anti-inflammatory effects of ellagic and punicic acid in an in vitro model of cardiac fibrosis. Biomed. Pharmacother., 162.","DOI":"10.1016\/j.biopha.2023.114666"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2323","DOI":"10.1002\/bab.2288","article-title":"Ellagic acid as a potent anticancer drug: A comprehensive review on in vitro, in vivo, in silico, and drug delivery studies","volume":"69","author":"Mohammadinejad","year":"2022","journal-title":"Biotechnol. Appl. Biochem."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Ramadan, W.S., Alkarim, S., Moulay, M., Alrefeai, G., Alkudsy, F., Hakeem, K.R., and Iskander, A. (2023). Modulation of the Tumor Microenvironment by Ellagic Acid in Rat Model for Hepatocellular Carcinoma: A Potential Target against Hepatic Cancer Stem Cells. Cancers, 15.","DOI":"10.3390\/cancers15194891"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Aslan, A., Gok, O., Beyaz, S., Arslan, E., Erman, O., and A\u011fca, C.A. (2020). The preventive effect of ellagic acid on brain damage in rats via regulating of Nrf-2, NF-kB and apoptotic pathway. J. Food Biochem., 44.","DOI":"10.1111\/jfbc.13217"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.jacme.2015.02.003","article-title":"Cardioprotective effect of ellagic acid on doxorubicin induced cardiotoxicity in wistar rats","volume":"5","author":"Warpe","year":"2015","journal-title":"J. Acute Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1016\/j.toxrep.2023.04.005","article-title":"Pretreatment of ellagic acid protects ifosfamide-induced acute nephrotoxicity in rat kidneys: A mitochondrial, histopathological and oxidative stress approaches","volume":"10","author":"Shabani","year":"2023","journal-title":"Toxicol. Rep."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1016\/j.molimm.2021.08.007","article-title":"Ellagic acid protects rats from chronic renal failure via MiR-182\/FOXO3a axis","volume":"138","author":"Chen","year":"2021","journal-title":"Mol. Immunol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"706","DOI":"10.1016\/j.chemosphere.2018.12.185","article-title":"Evaluation of endocrine activities of ellagic acid and urolithins using reporter gene assays","volume":"220","author":"Dolenc","year":"2019","journal-title":"Chemosphere"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"112158","DOI":"10.1016\/j.fct.2021.112158","article-title":"Plant constituents and thyroid: A revision of the main phytochemicals that interfere with thyroid function","volume":"152","author":"Giuliani","year":"2021","journal-title":"Food Chem. Toxicol."},{"key":"ref_23","first-page":"373","article-title":"Effect of Hyperthyroidism on Lipid Metabolism and Evaluation of the Protective Role of Pomegranate Juice against the Risk of Oxidative Stress in Albino Rats","volume":"12","author":"Mahmood","year":"2022","journal-title":"Int. J. Drug Deliv. Technol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1016\/j.jff.2015.09.019","article-title":"Identifying the limits for ellagic acid bioavailability: A crossover pharmacokinetic study in healthy volunteers after consumption of pomegranate extracts","volume":"19","author":"Zafrilla","year":"2015","journal-title":"J. Funct. Foods"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Darwish, A.B., Salama, A., and Al-Samadi, I.E.I. (J. Drug Target., 2025). Formulation, optimisation, and evaluation of Lornoxicam-loaded Novasomes for targeted ulcerative colitis therapy: In vitro and in vivo investigations, J. Drug Target., accepted.","DOI":"10.1080\/1061186X.2025.2456929"},{"key":"ref_26","unstructured":"National Center for Biotechnology Information (2025, January 31). PubChem Compound Summary for CID 5281855, E.A, Available online: https:\/\/pubchem.ncbi.nlm.nih.gov\/compound\/Ellagic-Acid."},{"key":"ref_27","unstructured":"National Center for Biotechnology Information (2025, January 31). PubChem Compound Summary for CID 86287518, I.P, Available online: https:\/\/pubchem.ncbi.nlm.nih.gov\/compound\/Imidacloprid."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Daina, A., Michielin, O., and Zoete, V. (2017). SwissADME: A free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci. Rep., 7.","DOI":"10.1038\/srep42717"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"D1257","DOI":"10.1093\/nar\/gkac833","article-title":"Mattingly Comparative Toxicogenomics Database (CTD): Update 2023","volume":"51","author":"Davis","year":"2023","journal-title":"Nucleic Acids Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"W357","DOI":"10.1093\/nar\/gkz382","article-title":"SwissTargetPrediction: Updated data and new features for efficient prediction of protein targets of small molecules","volume":"47","author":"Daina","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"W26","DOI":"10.1093\/nar\/gku477","article-title":"SuperPred: Update on drug classification and target prediction","volume":"42","author":"Nickel","year":"2014","journal-title":"Nucleic Acids Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"D928","DOI":"10.1093\/nar\/gku1004","article-title":"T3DB: The toxic exposome database","volume":"43","author":"Wishart","year":"2015","journal-title":"Nucleic Acids Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1002\/cpbi.5","article-title":"The GeneCards Suite: From Gene Data Mining to Disease Genome Sequence Analyses","volume":"54","author":"Stelzer","year":"2016","journal-title":"Curr. Protoc. Bioinform."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"D1353","DOI":"10.1093\/nar\/gkac1046","article-title":"McDonagh The next-generation Open Targets Platform: Reimagined, redesigned, rebuilt","volume":"51","author":"Ochoa","year":"2023","journal-title":"Nucleic Acids Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"D523","DOI":"10.1093\/nar\/gkac1052","article-title":"UniProt: The Universal Protein Knowledgebase in 2023","volume":"51","year":"2023","journal-title":"Nucleic Acids Res."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Bardou, P., Mariette, J., Escudi\u00e9, F., Djemiel, C., and Klopp, C. (2014). jvenn: An interactive Venn diagram viewer. BMC Bioinform., 15.","DOI":"10.1186\/1471-2105-15-293"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"D638","DOI":"10.1093\/nar\/gkac1000","article-title":"The STRING database in 2023: Protein\u2013protein association networks and functional enrichment analyses for any sequenced genome of interest","volume":"51","author":"Szklarczyk","year":"2023","journal-title":"Nucleic Acids Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2498","DOI":"10.1101\/gr.1239303","article-title":"Cytoscape: A software environment for integrated models of biomolecular interaction networks","volume":"13","author":"Shannon","year":"2003","journal-title":"Genome Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"2628","DOI":"10.1093\/bioinformatics\/btz931","article-title":"ShinyGO: A graphical gene-set enrichment tool for animals and plants","volume":"36","author":"Ge","year":"2020","journal-title":"Bioinformatics"},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Abd El-Emam, M.M., Behairy, A., Mostafa, M., Khamis, T., Osman, N.M.S., Alsemeh, A.E., and Mansour, M.F. (2024). Chrysin-loaded PEGylated liposomes protect against alloxan-induced diabetic neuropathy in rats: The interplay between endoplasmic reticulum stress and autophagy. Biol. Res., 57.","DOI":"10.1186\/s40659-024-00521-1"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"119","DOI":"10.2147\/IJN.S287383","article-title":"Use of Novasomes as a Vesicular Carrier for Improving the Topical Delivery of Terconazole: In Vitro Characterization, In Vivo Assessment and Exploratory Clinical Experimentation","volume":"16","author":"Mosallam","year":"2021","journal-title":"Int. J. Nanomed."},{"key":"ref_42","first-page":"164202","article-title":"Anti-Inflammatory Effects of Ellagic Acid on Acute Lung Injury Induced by Acid in Mice","volume":"2013","author":"Teixeira","year":"2013","journal-title":"Mediat. Inflamm."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"2925","DOI":"10.1002\/ptr.7001","article-title":"Role of ellagic acid for the prevention and treatment of liver diseases","volume":"35","author":"Aishwarya","year":"2021","journal-title":"Phytother. Res."},{"key":"ref_44","unstructured":"WHO (2010). The WHO Recommended Classification of Pesticides by Hazard and Guidelines to Classification 2009. WHO."},{"key":"ref_45","first-page":"103","article-title":"Imidacloprid as reproductive toxicant and endocrine disruptor: Investigations in laboratory animals","volume":"69","year":"2018","journal-title":"Arch. Ind. Hyg. Toxicol."},{"key":"ref_46","first-page":"351","article-title":"The pesticides manual: A world compendium","volume":"14","author":"Tomlin","year":"2006","journal-title":"Br. Crop Prot. Counc."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1172\/JCI109865","article-title":"Influx of Thyroid Hormones into Rat Liver In Vivo: Differential Availability of Thyroxine and Triiodothyronine Bound by Plasma Proteins","volume":"66","author":"Pardridge","year":"1980","journal-title":"J. Clin. Investig."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1186\/1471-2105-7-85","article-title":"Statistical analysis of real-time PCR data","volume":"7","author":"Yuan","year":"2006","journal-title":"BMC Bioinform."},{"key":"ref_49","unstructured":"Suvarna, S.K., Layton, C., and Bancroft, J.D. (2019). 7\u2014Microtomy for paraffin and frozen sections. Bancroft\u2019s Theory and Practice of Histological Techniques, Elsevier. [8th ed.]."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1002\/path.1711450410","article-title":"Manual of histological techniques. J. D. Bancroft and H. C. Cook. Churchill Livingstone, Edinburgh, London, Melbourne, New York, 1984. No. of pages: Ii + 274. Price: \u00a312.50. ISBN: 0 443 02870 2","volume":"145","author":"Chaplin","year":"1985","journal-title":"J. Pathol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"644","DOI":"10.1097\/WNR.0000000000001461","article-title":"Inhibition of PI3K\/AKT\/mTOR signaling pathway promotes autophagy and relieves hyperalgesia in diabetic rats","volume":"31","author":"Liu","year":"2020","journal-title":"NeuroReport"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1016\/j.chemosphere.2014.11.061","article-title":"The neonicotinoid pesticide imidacloprid and the dithiocarbamate fungicide mancozeb disrupt the pituitary\u2013thyroid axis of a wildlife bird","volume":"122","author":"Pandey","year":"2015","journal-title":"Chemosphere"},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"El Gazzar, W.B., Bayoumi, H., Youssef, H.S., Ibrahim, T.A., Abdelfatah, R.M., Gamil, N.M., Iskandar, M.K., Abdel-Kareim, A.M., Abdelrahman, S.M., and Gebba, M.A. (2024). Role of IRE1\u03b1\/XBP1\/CHOP\/NLRP3 Signalling Pathway in Neonicotinoid Imidacloprid-Induced Pancreatic Dysfunction in Rats and Antagonism of Lycopene: In Vivo and Molecular Docking Simulation Approaches. Toxics, 12.","DOI":"10.3390\/toxics12070445"},{"key":"ref_54","first-page":"16","article-title":"Evaluation of Imidacloprid Induced Changes in Thyroid Gland and its Amelioration with Withania somnifera in Wistar Rats","volume":"19","author":"Samala","year":"2023","journal-title":"J. Vet. Sci. Biotechnol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1016\/j.toxrep.2020.12.010","article-title":"Antioxidant, anti-inflammatory and hepatoprotective activities of Terminalia bellirica and its bioactive component ellagic acid against diclofenac induced oxidative stress and hepatotoxicity","volume":"8","author":"Gupta","year":"2021","journal-title":"Toxicol. Rep."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"3878","DOI":"10.1111\/jcmm.17967","article-title":"Exploring the mechanism of ellagic acid against gastric cancer based on bioinformatics analysis and network pharmacology","volume":"27","author":"Liu","year":"2023","journal-title":"J. Cell Mol. Med."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1016\/j.chemosphere.2017.12.077","article-title":"DNA damage and oxidative stress induced by imidacloprid exposure in different tissues of the Neotropical fish Prochilodus lineatus","volume":"195","author":"Vieira","year":"2018","journal-title":"Chemosphere"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"116499","DOI":"10.1016\/j.ecoenv.2024.116499","article-title":"Melatonin counteracts polyethylene microplastics induced adreno-cortical damage in male albino rats","volume":"279","author":"Farag","year":"2024","journal-title":"Ecotoxicol. Environ. Saf."},{"key":"ref_59","first-page":"106","article-title":"Imidacloprid and\/or esfenvalerate induce apoptosis and disrupt thyroid hormones in neonatal rats","volume":"10","author":"Ibrahim","year":"2015","journal-title":"Glob. J. Biotechnol. Biochem."},{"key":"ref_60","doi-asserted-by":"crossref","unstructured":"Alfei, S., Marengo, B., and Zuccari, G. (2020). Oxidative Stress, Antioxidant Capabilities, and Bioavailability: Ellagic Acid or Urolithins?. Antioxidants, 9.","DOI":"10.3390\/antiox9080707"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"39","DOI":"10.36326\/kjvs\/2010\/v1i14231","article-title":"Effect of Ellagic Acid Extracted from Pomegranate (Punica granatum L.) on Thyroid and Parathyroid Gland of Adult Rats Exposed to Lead Acetate","volume":"1","author":"Arrak","year":"2010","journal-title":"Kufa J. Vet. Med. Sci."},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"Abd El-Emam, M.M., Mostafa, M., Farag, A.A., Youssef, H.S., El-Demerdash, A.S., Bayoumi, H., Gebba, M.A., El-Halawani, S.M., Saleh, A.M., and Badr, A.M. (2023). The Potential Effects of Quercetin-Loaded Nanoliposomes on Amoxicillin\/Clavulanate-Induced Hepatic Damage: Targeting the SIRT1\/Nrf2\/NF-\u03baB Signaling Pathway and Microbiota Modulation. Antioxidants, 12.","DOI":"10.3390\/antiox12081487"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"104397","DOI":"10.1016\/j.jff.2021.104397","article-title":"Ellagic acid protects against diabetic nephropathy in rats by regulating the transcription and activity of Nrf2","volume":"79","author":"Altamimi","year":"2021","journal-title":"J. Funct. Foods"},{"key":"ref_64","doi-asserted-by":"crossref","unstructured":"Wang, Q., Botchway, B.O.A., Zhang, Y., and Liu, X. (2022). Ellagic acid activates the Keap1-Nrf2-ARE signaling pathway in improving Parkinson\u2019s disease: A review. Biomed. Pharmacother., 156.","DOI":"10.1016\/j.biopha.2022.113848"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"9446","DOI":"10.1111\/jcmm.15616","article-title":"Ellagic acid protects dopamine neurons from rotenone-induced neurotoxicity via activation of Nrf2 signalling","volume":"24","author":"Wei","year":"2020","journal-title":"J. Cell Mol. Med."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"199","DOI":"10.3103\/S009639251804003X","article-title":"Role of Reactive Oxygen Species in Inflammation: A Minireview","volume":"73","author":"Chelombitko","year":"2018","journal-title":"Mosc. Univ. Biol. Sci. Bull."},{"key":"ref_67","doi-asserted-by":"crossref","unstructured":"Chen, P., Chen, F., and Zhou, B. (2018). Antioxidative, anti-inflammatory and anti-apoptotic effects of ellagic acid in liver and brain of rats treated by D-galactose. Sci. Rep., 8.","DOI":"10.1038\/s41598-018-19732-0"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"13513","DOI":"10.1021\/acs.jafc.8b05793","article-title":"Imidacloprid Impacts on Neurobehavioral Performance, Oxidative Stress, and Apoptotic Events in the Brain of Adolescent and Adult Rats","volume":"66","author":"Mohammed","year":"2018","journal-title":"J. Agric. Food Chem."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"3474","DOI":"10.1016\/j.sjbs.2020.09.060","article-title":"Antidiabetic effects of novel ellagic acid nanoformulation: Insulin-secreting and anti-apoptosis effects","volume":"27","author":"Harakeh","year":"2020","journal-title":"Saudi J. Biol. Sci."},{"key":"ref_70","doi-asserted-by":"crossref","unstructured":"Rostami, A., Vakili, S., Koohpeyma, F., Jahromi, B.N., Aghajari, Z.A., Mahmoudikohani, F., Saki, F., Mahmoodi, M., Jaberi, K.R., and Movahedpour, A. (2022). Ellagic acid effects on testis, sex hormones, oxidative stress, and apoptosis in the relative sterility rat model following busulfan administration. BMC Complement. Med. Ther., 22.","DOI":"10.1186\/s12906-022-03650-w"},{"key":"ref_71","doi-asserted-by":"crossref","unstructured":"Saeed, Z.M., Khattab, M.I., Khorshid, N.E., and Salem, A.E. (2022). Ellagic acid and cilostazol ameliorate amikacin-induced nephrotoxicity in rats by downregulating oxidative stress, inflammation, and apoptosis. PLoS ONE, 17.","DOI":"10.1371\/journal.pone.0271591"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"172910","DOI":"10.1016\/j.scitotenv.2024.172910","article-title":"Imidacloprid-induced lung injury in mice: Activation of the PI3K\/AKT\/NF-\u03baB signaling pathway via TLR4 receptor engagement","volume":"931","author":"Xie","year":"2024","journal-title":"Sci. Total Environ."},{"key":"ref_73","first-page":"4163","article-title":"Roles of endoplasmic reticulum stress and autophagy on H2O2-induced oxidative stress injury in HepG2 cells","volume":"18","author":"Wu","year":"2018","journal-title":"Mol. Med. Rep."},{"key":"ref_74","doi-asserted-by":"crossref","unstructured":"Karim, M.R., CFisher, R., Kapphahn, R.J., Polanco, J.R., and Ferrington, D.A. (2020). Investigating AKT activation and autophagy in immunoproteasome-deficient retinal cells. PLoS ONE, 15.","DOI":"10.1371\/journal.pone.0231212"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"658","DOI":"10.1016\/j.tem.2019.07.009","article-title":"The FoxO-Autophagy Axis in Health and Disease","volume":"30","author":"Cheng","year":"2019","journal-title":"Trends Endocrinol. Metab."},{"key":"ref_76","doi-asserted-by":"crossref","unstructured":"Deleyto-Seldas, N., and Efeyan, A. (2021). The mTOR\u2013Autophagy Axis and the Control of Metabolism. Front. Cell Dev. Biol., 9.","DOI":"10.3389\/fcell.2021.655731"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"3303","DOI":"10.7150\/jca.29738","article-title":"Ellagic acid exerts antitumor effects via the PI3K signaling pathway in endometrial cancer","volume":"10","author":"Wang","year":"2019","journal-title":"J. Cancer"},{"key":"ref_78","doi-asserted-by":"crossref","unstructured":"Yu, J., Song, S., Jiao, J., Liu, X., Zhu, H., Xiu, L., Sun, D., Li, Q., and Yue, X. (2020). ZiYinHuaTan Recipe Inhibits Cell Proliferation and Promotes Apoptosis in Gastric Cancer by Suppressing PI3K\/AKT Pathway. BioMed Res. Int., 2020.","DOI":"10.1155\/2020\/2018162"},{"key":"ref_79","doi-asserted-by":"crossref","unstructured":"Li, X., Huang, K., Liu, X., Ruan, H., Ma, L., Liang, J., Cui, Y., Wang, Y., Wu, S., and Li, H. (2021). Ellagic Acid Attenuates BLM-Induced Pulmonary Fibrosis via Inhibiting Wnt Signaling Pathway. Front. Pharmacol., 12.","DOI":"10.3389\/fphar.2021.639574"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"a026120","DOI":"10.1101\/cshperspect.a026120","article-title":"Autophagy and p53","volume":"6","author":"White","year":"2016","journal-title":"Cold Spring Harb. Perspect. Med."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"726","DOI":"10.1016\/j.bbrc.2009.03.095","article-title":"Upregulation of Beclin-1 expression and phosphorylation of Bcl-2 and p53 are involved in the JNK-mediated autophagic cell death","volume":"382","author":"Park","year":"2009","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"741","DOI":"10.1038\/nrm2239","article-title":"Self-eating and self-killing: Crosstalk between autophagy and apoptosis","volume":"8","author":"Maiuri","year":"2007","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_83","doi-asserted-by":"crossref","unstructured":"Tran, S., Fairlie, W.D., and Lee, E.F. (2021). BECLIN1: Protein Structure, Function and Regulation. Cells, 10.","DOI":"10.3390\/cells10061522"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1016\/j.fct.2016.12.008","article-title":"Molecular evidence on the protective effect of ellagic acid on phosalone-induced senescence in rat embryonic fibroblast cells","volume":"100","author":"Baeeri","year":"2017","journal-title":"Food Chem. Toxicol."},{"key":"ref_85","first-page":"311","article-title":"Ellagic acid attenuates hypoxic-ischemic brain injury by alleviating autophagy","volume":"12","author":"Cai","year":"2019","journal-title":"Chin. J. Pathophysiol."}],"container-title":["Toxics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2305-6304\/13\/5\/355\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:24:08Z","timestamp":1760030648000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2305-6304\/13\/5\/355"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,4,29]]},"references-count":85,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2025,5]]}},"alternative-id":["toxics13050355"],"URL":"https:\/\/doi.org\/10.3390\/toxics13050355","relation":{},"ISSN":["2305-6304"],"issn-type":[{"value":"2305-6304","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,4,29]]}}}