{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T05:01:11Z","timestamp":1787029271629,"version":"build-2736575974"},"reference-count":89,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2021,11,16]],"date-time":"2021-11-16T00:00:00Z","timestamp":1637020800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Numerous epidemiological findings have repeatedly established associations between Type 2 Diabetes Mellitus (T2DM) and Alzheimer\u2019s disease. Targeting different pathways in the brain with T2DM-therapy offers a novel and appealing strategy to treat diabetes-related neuronal alterations. Therefore, here we investigated the capability of a natural compound, curcumin nanoparticle (CurNP), and a biomedical metal, zinc oxide nanoparticle (ZnONP), to alleviate hippocampal modifications in T2DM-induced rats. The diabetes model was induced in male Wistar rats by feeding a high-fat diet (HFD) for eight weeks followed by intraperitoneal injection of streptozotocin (STZ). Then model groups were treated orally with curcumin, zinc sulfate, two doses of CurNP and ZnONP, as well as metformin, for six weeks. HFD\/STZ-induced rats exhibited numerous biochemical and molecular changes besides behavioral impairment. Compared with model rats, CurNP and ZnONP boosted learning and memory function, improved redox and inflammation status, lowered Bax, and upregulated Bcl2 expressions in the hippocampus. In addition, the phosphorylation level of the MAPK\/ERK pathway was downregulated significantly. The expression of amyloidogenic-related genes and amyloid-beta accumulation, along with tau hyperphosphorylation, were lessened considerably. In addition, both nanoparticles significantly improved histological lesions in the hippocampus. Based on our findings, CurNP and ZnONP appear to be potential neuroprotective agents to mitigate diabetic complications-associated hippocampal toxicity.<\/jats:p>","DOI":"10.3390\/pharmaceutics13111937","type":"journal-article","created":{"date-parts":[[2021,11,17]],"date-time":"2021-11-17T02:42:28Z","timestamp":1637116948000},"page":"1937","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":43,"title":["Protective Effect of Natural Antioxidant, Curcumin Nanoparticles, and Zinc Oxide Nanoparticles against Type 2 Diabetes-Promoted Hippocampal Neurotoxicity in Rats"],"prefix":"10.3390","volume":"13","author":[{"given":"Shaymaa","family":"Abdulmalek","sequence":"first","affiliation":[{"name":"Department of Biochemistry, Faculty of Science, Alexandria University, Alexandria 21511, Egypt"},{"name":"Center of Excellency for Preclinical Study (CE-PCS), Pharmaceutical and Fermentation Industries Development Centre, City of Scientific Research and Technological Applications (SRTA-City), New Borg El-Arab City 21934, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mayada","family":"Nasef","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Faculty of Science, Alexandria University, Alexandria 21511, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Doaa","family":"Awad","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Faculty of Science, Alexandria University, Alexandria 21511, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0876-6604","authenticated-orcid":false,"given":"Mahmoud","family":"Balbaa","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Faculty of Science, Alexandria University, Alexandria 21511, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,11,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"751","DOI":"10.1097\/00005072-199756070-00001","article-title":"Differences between the pathogenesis of senile plaques and congophilic angiopathy in Alzheimer disease","volume":"56","author":"Verbeek","year":"1997","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"e13109","DOI":"10.1111\/acel.13109","article-title":"Amyloid-beta accumulation cycle as a prevention and\/or therapy target for Alzheimer\u2019s disease","volume":"19","author":"Rao","year":"2020","journal-title":"Aging Cell"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"127","DOI":"10.3109\/01677063.2011.626471","article-title":"Targeting post-translational modifications on tau as a therapeutic strategy for Alzheimer\u2019s disease","volume":"25","author":"Marcus","year":"2011","journal-title":"J. Neurogenet."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1065","DOI":"10.1212\/01.wnl.0000310646.32212.3a","article-title":"Impaired insulin secretion increases the risk of Alzheimer disease","volume":"71","author":"Zethelius","year":"2008","journal-title":"Neurology"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1629","DOI":"10.1007\/s00125-003-1246-x","article-title":"Selective impairment of insulin signalling in the hypothalamus of obese Zucker rats","volume":"46","author":"Carvalheira","year":"2003","journal-title":"Diabetologia"},{"key":"ref_6","first-page":"1672","article-title":"Late-stage complications of diabetes and insulin resistance","volume":"2","author":"Soumya","year":"2011","journal-title":"J. Diabetes Metab."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2329","DOI":"10.1212\/WNL.0000000000001655","article-title":"Glucose indices are associated with cognitive and structural brain measures in young adults","volume":"84","author":"Weinstein","year":"2015","journal-title":"Neurology"},{"key":"ref_8","first-page":"1945","article-title":"Microglia mediates inflammation injury in mouse models of Parkinson\u2019s disease","volume":"15","author":"Lu","year":"2011","journal-title":"Zhongguo Zuzhi Gongcheng Yanjiu"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1007\/s11481-011-9340-1","article-title":"Neuroinflammation and cognitive dysfunction in chronic disease and aging","volume":"7","author":"Hein","year":"2012","journal-title":"J. Neuroimmune Pharmacol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"10","DOI":"10.5483\/BMBRep.2020.53.1.309","article-title":"Peripheral inflammatory biomarkers in Alzheimer\u2019s disease: A brief review","volume":"53","author":"Park","year":"2020","journal-title":"BMB Rep."},{"key":"ref_11","first-page":"1","article-title":"Pro-inflammatory interleukin-6 signaling links cognitive impairments and peripheral metabolic alterations in Alzheimer\u2019s disease","volume":"11","author":"Pascoal","year":"2021","journal-title":"Transl. Psychiatry"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"189","DOI":"10.2174\/157488711796575577","article-title":"Neuroinflammation and ageing: Current theories and an overview of the data","volume":"6","author":"Pizza","year":"2011","journal-title":"Rev. Recent Clin. Trials"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"679","DOI":"10.1038\/nri3495","article-title":"Mitogen-activated protein kinases in innate immunity","volume":"13","author":"Arthur","year":"2013","journal-title":"Nat. Rev. Immunol."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Albert-Gasc\u00f3, H., Ros-Bernal, F., Castillo-G\u00f3mez, E., and Olucha-Bordonau, F.E. (2020). MAP\/ERK signaling in developing cognitive and emotional function and its effect on pathological and neurodegenerative processes. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21124471"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1186\/s12974-019-1516-2","article-title":"Neuroinflammation: Friend and foe for ischemic stroke","volume":"16","author":"Jayaraj","year":"2019","journal-title":"J. Neuroinflamm."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"e11123","DOI":"10.7554\/eLife.11123","article-title":"Layer specific and general requirements for ERK\/MAPK signaling in the developing neocortex","volume":"5","author":"Xing","year":"2016","journal-title":"eLife"},{"key":"ref_17","first-page":"245","article-title":"Hippocampal injections of oligomeric amyloid \u03b2-peptide (1-42) induce selective working memory deficits and longlasting alterations of ERK signaling pathway","volume":"7","author":"Faucher","year":"2015","journal-title":"Front. Aging Neurosci."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1007\/s00125-007-0886-7","article-title":"The mechanisms of alloxan-and streptozotocin-induced diabetes","volume":"51","author":"Lenzen","year":"2008","journal-title":"Diabetologia"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"537","DOI":"10.33549\/physiolres.930111","article-title":"The mechanism of alloxan and streptozotocin action in B cells of the rat pancreas","volume":"50","author":"Szkudelski","year":"2001","journal-title":"Physiol. Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"5892","DOI":"10.1074\/jbc.M404751200","article-title":"Curcumin inhibits formation of amyloid \u03b2 oligomers and fibrils, binds plaques, and reduces amyloid in vivo","volume":"280","author":"Yang","year":"2005","journal-title":"J. Biol. Chem."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Khan, A., Jahan, S., Imtiyaz, Z., Alshahrani, S., Antar Makeen, H., Mohammed Alshehri, B., Kumar, A., Arafah, A., and Rehman, M.U. (2020). Neuroprotection: Targeting Multiple Pathways by Naturally Occurring Phytochemicals. Biomedicines, 8.","DOI":"10.3390\/biomedicines8080284"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1016\/j.phrs.2009.12.008","article-title":"Effect of curcumin on brain insulin receptors and memory functions in STZ (ICV) induced dementia model of rat","volume":"61","author":"Agrawal","year":"2010","journal-title":"Pharm. Res."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"ELBini-Dhouib, I., Doghri, R., Ellefi, A., Degrach, I., Srairi-Abid, N., and Gati, A. (2021). Curcumin Attenuated Neurotoxicity in Sporadic Animal Model of Alzheimer\u2019s Disease. Molecules, 26.","DOI":"10.3390\/molecules26103011"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Caesar, I., Jonson, M., Nilsson, K.P.R., Thor, S., and Hammarstr\u00f6m, P. (2012). Curcumin promotes A-beta fibrillation and reduces neurotoxicity in transgenic Drosophila. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0031424"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Ege, D. (2021). Action Mechanisms of Curcumin in Alzheimer\u2019s Disease and Its Brain Targeted Delivery. Materials, 14.","DOI":"10.3390\/ma14123332"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1771","DOI":"10.1002\/ijc.24967","article-title":"The dark side of curcumin Estefan\u00eda","volume":"126","author":"Salvador","year":"2010","journal-title":"Int. J. Cancer"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"4567","DOI":"10.3390\/molecules16064567","article-title":"Curcumin: An anti-inflammatory molecule from a curry spice on the path to cancer treatment","volume":"16","author":"Basnet","year":"2011","journal-title":"Molecules"},{"key":"ref_28","first-page":"1490","article-title":"Studies on solubility of curcumin","volume":"3","author":"Modasiya","year":"2012","journal-title":"Int. J. Pharm. Life Sci."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"6597","DOI":"10.1016\/j.biomaterials.2010.04.062","article-title":"The in vitro stability and in vivo pharmacokinetics of curcumin prepared as an aqueous nanoparticulate formulation","volume":"31","author":"Mohanty","year":"2010","journal-title":"Biomaterials"},{"key":"ref_30","first-page":"1825","article-title":"Zinc oxide nanoparticles: A promising nanomaterial for biomedical applications","volume":"22","author":"Mishra","year":"2017","journal-title":"Drug Discov."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"95","DOI":"10.2147\/NSA.S19419","article-title":"Titanium dioxide and zinc oxide nanoparticles in sunscreens: Focus on their safety and effectiveness","volume":"4","author":"Smijs","year":"2011","journal-title":"Nanotechnol. Sci. Appl."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1016\/j.toxrep.2017.05.006","article-title":"Neurotoxic effect of active ingredients in sunscreen products, a contemporary review","volume":"4","author":"Ruszkiewicz","year":"2017","journal-title":"Toxicol. Rep."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"5329","DOI":"10.1002\/adma.201301732","article-title":"ZnO nanoparticles applied to bioimaging and drug delivery","volume":"25","author":"Xiong","year":"2013","journal-title":"Adv. Mater."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1016\/S0021-9258(19)52451-6","article-title":"Protein measurement with the Folin phenol reagent","volume":"193","author":"Lowry","year":"1951","journal-title":"J. Biol. Chem."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"412","DOI":"10.1007\/BF00280883","article-title":"Homeostasis model assessment: Insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man","volume":"28","author":"Matthews","year":"1981","journal-title":"Diabetologia"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"326","DOI":"10.1016\/0003-9861(59)90258-9","article-title":"Lipid peroxidation in isolated mitochondria","volume":"80","author":"Tappel","year":"1959","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_37","first-page":"414","article-title":"Colorimetric determination of nitric oxide","volume":"86","author":"Montgomery","year":"1961","journal-title":"Analyst"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1159\/000136485","article-title":"Bromobenzene-induced liver necrosis. Protective role of glutathione and evidence for 3, 4-bromobenzene oxide as the hepatotoxic metabolite","volume":"11","author":"Jollow","year":"1974","journal-title":"Pharmacology"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"7130","DOI":"10.1016\/S0021-9258(19)42083-8","article-title":"Glutathione S-transferases the first enzymatic step in mercapturic acid formation","volume":"249","author":"Habig","year":"1974","journal-title":"J. Biol. Chem."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"469","DOI":"10.1111\/j.1432-1033.1974.tb03714.x","article-title":"Involvement of the superoxide anion radical in the autoxidation of pyrogallol and a convenient assay for superoxide dismutase","volume":"47","author":"Marklund","year":"1974","journal-title":"Eur. J. Biochem."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1016\/S0076-6879(84)05016-3","article-title":"Catalase in vitro","volume":"105","author":"Aebi","year":"1984","journal-title":"Methods Enzymol."},{"key":"ref_42","first-page":"158","article-title":"Studies on the quantitative and qualitative characterization of erythrocyte glutathione peroxidase","volume":"70","author":"Paglia","year":"1967","journal-title":"J. Lab. Clin. Med."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1016\/0006-2952(61)90145-9","article-title":"A new and rapid colorimetric determination of acetylcholinesterase activity","volume":"7","author":"Ellman","year":"1961","journal-title":"Biochem. Pharmacol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1006\/meth.2001.1262","article-title":"Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method","volume":"25","author":"Livak","year":"2001","journal-title":"Methods"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1016\/0003-2697(81)90281-5","article-title":"Western blotting: Electrophoretic transfer of proteins from sodium dodecyl sulfate-polyacrylamide gels to unmodified nitrocellulose and radiographic detection with antibody and radioiodinated protein A","volume":"112","author":"Burnette","year":"1981","journal-title":"Anal. Biochem."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"571721","DOI":"10.1155\/2011\/571721","article-title":"Investigation of antidiabetic, antihyperlipidemic, and in vivo antioxidant properties of Sphaeranthus indicus Linn. in type 1 diabetic rats: An identification of possible biomarkers","volume":"2011","author":"Ramachandran","year":"2011","journal-title":"Evid. Based Complement. Altern. Med."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Balbaa, M., Abdulmalek, S.A., and Khalil, S. (2017). Oxidative stress and expression of insulin signaling proteins in the brain of diabetic rats: Role of Nigella sativa oil and antidiabetic drugs. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0172429"},{"key":"ref_48","first-page":"217","article-title":"Central insulin resistance as a trigger for sporadic Alzheimer-like pathology: An experimental approach","volume":"72","author":"Hoyer","year":"2007","journal-title":"Neuropsychiatr. Disord. Integr. Approach"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1007\/s00394-011-0188-1","article-title":"New mechanisms and the anti-inflammatory role of curcumin in obesity and obesity-related metabolic diseases","volume":"50","author":"Shehzad","year":"2011","journal-title":"Eur. J. Nutr."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"834","DOI":"10.1208\/s12249-015-0405-y","article-title":"Comparative study of antidiabetic activity and oxidative stress induced by zinc oxide nanoparticles and zinc sulfate in diabetic rats","volume":"17","author":"Nazarizadeh","year":"2016","journal-title":"AAPS PharmSciTech"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"89","DOI":"10.2217\/nnm.12.205","article-title":"Zinc oxide nanoparticles show antidiabetic activity in streptozotocin-induced type 1 and 2 diabetic rats","volume":"9","author":"Umrani","year":"2014","journal-title":"Nanomedicine"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"2015","DOI":"10.3390\/ijms15022015","article-title":"Antidiabetic activity of zinc oxide and silver nanoparticles on streptozotocin-induced diabetic rats","volume":"15","author":"Alkaladi","year":"2014","journal-title":"Int. J. Mol. Sci."},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Virgen-Ortiz, A., Apolinar-Iribe, A., D\u00edaz-Reval, I., Parra-Delgado, H., Lim\u00f3n-Miranda, S., S\u00e1nchez-Pastor, E.A., Castro-S\u00e1nchez, L., Castillo, S.J., Dagnino-Acosta, A., and Bonales-Alatorre, E. (2020). Zinc Oxide Nanoparticles Induce an Adverse Effect on Blood Glucose Levels Depending on the Dose and Route of Administration in Healthy and Diabetic Rats. Nanomaterials, 10.","DOI":"10.3390\/nano10102005"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/S0074-7742(02)50072-6","article-title":"Glycation in diabetic neuropathy: Characteristics, consequences, causes, and therapeutic options","volume":"50","author":"Thornalley","year":"2002","journal-title":"Int. Rev. Neurobiol."},{"key":"ref_55","first-page":"1","article-title":"Should development of Alzheimer\u2019s disease-specific intravenous immunoglobulin be considered?","volume":"11","author":"Loeffler","year":"2014","journal-title":"J. Neuroinflamm."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"16","DOI":"10.2337\/diacare.13.1.16","article-title":"Relationship between hyperglycemia and cognitive function in older NIDDM patients","volume":"13","author":"Reaven","year":"1990","journal-title":"Diabetes Care"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1017\/S1041610202008281","article-title":"Volumetric MRI measurements can differentiate Alzheimer\u2019s disease, mild cognitive impairment, and normal aging","volume":"14","author":"Bottino","year":"2002","journal-title":"Int. Psychogeriatr."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1016\/j.neulet.2009.11.033","article-title":"Changes of some oxidative stress markers in the serum of patients with mild cognitive impairment and Alzheimer\u2019s disease","volume":"469","author":"Padurariu","year":"2010","journal-title":"Neurosci. Lett."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"2653","DOI":"10.1073\/pnas.0511154103","article-title":"Increased production of reactive oxygen species in hyperglycemic conditions requires dynamic change of mitochondrial morphology","volume":"103","author":"Yu","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"17721","DOI":"10.1074\/jbc.M800013200","article-title":"Hydrogen peroxide promotes A\u03b2 production through JNK-dependent activation of \u03b3-secretase","volume":"283","author":"Shen","year":"2008","journal-title":"J. Biol. Chem."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s13098-019-0437-7","article-title":"The effect of curcumin supplementation on anthropometric indices, insulin resistance and oxidative stress in patients with type 2 diabetes: A randomized, double-blind clinical trial","volume":"11","author":"Hodaei","year":"2019","journal-title":"Diabetol. Metab. Syndr."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"25","DOI":"10.3233\/s12349-009-0069-9","article-title":"Antioxidant effect of zinc, selenium and their combination on the liver and kidney of alloxan-induced diabetes in rats","volume":"3","author":"Ukperoro","year":"2010","journal-title":"Mediterr. J. Nutr. Metab."},{"key":"ref_63","first-page":"1","article-title":"Impact of dietary zinc oxide nanoparticles on selected serum biomarkers, lipid peroxidation and tissue gene expression of antioxidant enzymes and cytokines in Japanese quail","volume":"16","author":"Shousha","year":"2020","journal-title":"BMC Vet. Res."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"108131","DOI":"10.1016\/j.inoche.2020.108131","article-title":"Behavioral effects of zinc oxide nanoparticles on the brain of rats","volume":"119","author":"Rahdar","year":"2020","journal-title":"Inorg. Chem. Commun."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"2863","DOI":"10.1016\/j.sjbs.2020.07.009","article-title":"Neuro-biochemical changes induced by zinc oxide nanoparticles","volume":"27","author":"Dkhil","year":"2020","journal-title":"Saudi J. Biol. Sci."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"916","DOI":"10.1016\/j.freeradbiomed.2004.05.032","article-title":"Signaling pathways controlling the production of inflammatory mediators in response to crystalline silica exposure: Role of reactive oxygen\/nitrogen species","volume":"37","author":"Castranova","year":"2004","journal-title":"Free Radic. Biol. Med."},{"key":"ref_67","doi-asserted-by":"crossref","unstructured":"Boarescu, P.-M., Boarescu, I., Boc\u0219an, I.C., Gheban, D., Bulboac\u0103, A.E., Nicula, C., Pop, R.M., R\u00e2jnoveanu, R.-M., and Bolboac\u0103, S.D. (2019). Antioxidant and anti-inflammatory effects of Curcumin nanoparticles on drug-induced acute myocardial infarction in diabetic rats. Antioxidants, 8.","DOI":"10.3390\/antiox8100504"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"353","DOI":"10.4070\/kcj.2008.38.7.353","article-title":"The protective effect of curcumin on myocardial ischemia-reperfusion injury","volume":"38","author":"Kim","year":"2008","journal-title":"Korean Circ. J."},{"key":"ref_69","doi-asserted-by":"crossref","unstructured":"Gammoh, N.Z., and Rink, L. (2017). Zinc in infection and inflammation. Nutrients, 9.","DOI":"10.20944\/preprints201705.0176.v1"},{"key":"ref_70","first-page":"1","article-title":"Mitigating effect of single or combined administration of nanoparticles of zinc oxide, chromium oxide, and selenium on genotoxicity and metabolic insult in fructose\/streptozotocin diabetic rat model","volume":"28","author":"Hassan","year":"2021","journal-title":"ESPR"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1425","DOI":"10.1016\/0024-3205(81)90374-X","article-title":"A critical physiological role of zinc in the structure and function of biomembranes","volume":"28","author":"Bettger","year":"1981","journal-title":"Life Sci."},{"key":"ref_72","doi-asserted-by":"crossref","unstructured":"Attia, H., Nounou, H., and Shalaby, M. (2018). Zinc oxide nanoparticles induced oxidative DNA damage, inflammation and apoptosis in rat\u2019s brain after oral exposure. Toxics, 6.","DOI":"10.3390\/toxics6020029"},{"key":"ref_73","first-page":"136","article-title":"Effect of curcumin on expression of adiponectin in mice with insulin resistance","volume":"33","author":"Bai","year":"2013","journal-title":"J. Shanghai Jiaotong Univ. Sci."},{"key":"ref_74","doi-asserted-by":"crossref","unstructured":"Shao, W., Yu, Z., Chiang, Y., Yang, Y., Chai, T., Foltz, W., Lu, H., Fantus, I.G., and Jin, T. (2012). Curcumin prevents high fat diet induced insulin resistance and obesity via attenuating lipogenesis in liver and inflammatory pathway in adipocytes. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0028784"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"1026","DOI":"10.1046\/j.1471-4159.2003.01756.x","article-title":"Bcl-2 overexpression protects against neuron loss within the ischemic margin following experimental stroke and inhibits cytochrome c translocation and caspase-3 activity","volume":"85","author":"Zhao","year":"2008","journal-title":"J. Neurochem."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"42","DOI":"10.3109\/15376516.2012.731437","article-title":"Effects of Zn deficiency, antioxidants, and low-dose radiation on diabetic oxidative damage and cell death in the testis","volume":"23","author":"Zhao","year":"2013","journal-title":"Toxicol. Mech. Methods"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1007\/s10522-008-9195-x","article-title":"Curcumin counteracts the aluminium-induced ageing-related alterations in oxidative stress, Na+, K+ ATPase and protein kinase C in adult and old rat brain regions","volume":"10","author":"Sharma","year":"2009","journal-title":"Biogerontology"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"e7460","DOI":"10.7717\/peerj.7460","article-title":"Evaluation of the effects of the green nanoparticles zinc oxide on monosodium glutamate-induced toxicity in the brain of rats","volume":"7","author":"Hamza","year":"2019","journal-title":"PeerJ"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"a006379","DOI":"10.1101\/cshperspect.a006379","article-title":"Proteolytic degradation of amyloid \u03b2-protein","volume":"2","author":"Saido","year":"2012","journal-title":"Cold Spring Harb. Perspect. Med."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"2272","DOI":"10.1016\/j.neurobiolaging.2014.04.031","article-title":"PERK mediates eIF2\u03b1 phosphorylation responsible for BACE1 elevation, CREB dysfunction and neurodegeneration in a mouse model of Alzheimer\u2019s disease","volume":"35","author":"Devi","year":"2014","journal-title":"Neurobiol. Aging"},{"key":"ref_81","doi-asserted-by":"crossref","unstructured":"Carrasquillo, M.M., Belbin, O., Zou, F., Allen, M., Ertekin-Taner, N., Ansari, M., Wilcox, S.L., Kashino, M.R., Ma, L., and Younkin, L.H. (2010). Concordant association of insulin degrading enzyme gene (IDE) variants with IDE mRNA, A\u00df, and Alzheimer\u2019s disease. PLoS ONE, 5.","DOI":"10.1371\/journal.pone.0008764"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.bbr.2012.10.049","article-title":"Antidepressant-like effects of curcumin in WKY rat model of depression is associated with an increase in hippocampal BDNF","volume":"239","author":"Hurley","year":"2013","journal-title":"Behav. Brain Res."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"3403","DOI":"10.3892\/mmr.2016.5586","article-title":"Neuroprotective effects of caffeic acid phenethyl ester against sevoflurane-induced neuronal degeneration in the hippocampus of neonatal rats involve MAPK and PI3K\/Akt signaling pathways","volume":"14","author":"Wang","year":"2016","journal-title":"Mol. Med. Rep."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1046\/j.1471-4159.2001.00054.x","article-title":"The neuronal MAP kinase cascade: A biochemical signal integration system subserving synaptic plasticity and memory","volume":"76","author":"Sweatt","year":"2001","journal-title":"J. Neurochem."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1111\/j.1582-4934.2007.00214.x","article-title":"Tau kinases and phosphatases","volume":"12","author":"Avila","year":"2008","journal-title":"J. Cell Mol. Med."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s12906-015-0652-1","article-title":"Fructus mume alleviates chronic cerebral hypoperfusion-induced white matter and hippocampal damage via inhibition of inflammation and downregulation of TLR4 and p38 MAPK signaling","volume":"15","author":"Lee","year":"2015","journal-title":"BMC Complement. Altern. Med."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1016\/j.resp.2018.05.006","article-title":"Curcumin attenuates chronic intermittent hypoxia-induced brain injuries by inhibiting AQP4 and p38 MAPK pathway","volume":"255","author":"Wang","year":"2018","journal-title":"Respir. Physiol. Neurobiol."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"2022","DOI":"10.1016\/j.lfs.2006.06.048","article-title":"Inhibitory effect of curcumin on nitric oxide production from lipopolysaccharide-activated primary microglia","volume":"79","author":"Jung","year":"2006","journal-title":"Life Sci."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"151","DOI":"10.12688\/f1000research.2-151.v1","article-title":"A histological and functional study on hippocampal formation of normal and diabetic rats","volume":"2","author":"Amin","year":"2013","journal-title":"F1000Research"}],"container-title":["Pharmaceutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4923\/13\/11\/1937\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:30:56Z","timestamp":1760167856000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4923\/13\/11\/1937"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,11,16]]},"references-count":89,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2021,11]]}},"alternative-id":["pharmaceutics13111937"],"URL":"https:\/\/doi.org\/10.3390\/pharmaceutics13111937","relation":{},"ISSN":["1999-4923"],"issn-type":[{"value":"1999-4923","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,11,16]]}}}