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The current study examines the effect of Naringenin-loaded hybridized nanoparticles (NAR-HNPs) and NAR on depression induced by streptozotocin (STZ) in rats. NAR-HNPs formula with the highest in vitro NAR released profile, lowest polydispersity index value (0.21\u2009\u00b1\u20090.02), highest entrapment efficiency (98.7\u2009\u00b1\u20092.01%), as well as an acceptable particle size and zeta potential of 415.2\u2009\u00b1\u20099.54 nm and 52.8\u2009\u00b1\u20091.04 mV, respectively, was considered the optimum formulation. It was characterized by differential scanning calorimetry, examined using a transmission electron microscope, and a stability study was conducted at different temperatures to monitor its stability efficiency showing that NAR-HNP formulation maintains stability at 4\u00a0\u00b0C. The selected formulation was subjected to an acute toxicological test, a pharmacokinetic analysis, and a Diabetes mellitus (DM) experimental model. STZ (50 mg\/kg) given as a single i.p. rendered rats diabetic. Diabetic rat groups were allocated into 4 groups: one group received no treatment, while the remaining three received oral doses of unloaded HNPs, NAR (50 mg\/kg), NAR-HNPs (50 mg\/kg) and NAR (50 mg\/kg)\u2009+\u2009peroxisome proliferator-activated receptor-\u03b3 (PPAR<jats:italic>-<\/jats:italic>\u03b3) antagonist, GW9662 (1mg\/kg, i.p.) for three weeks. Additional four non-diabetic rat groups received: distilled water (normal), free NAR, and NAR-HNPs, respectively for three weeks. NAR and NAR-HNPs reduced immobility time in forced swimming test and serum blood glucose while increasing serum insulin level. They also reduced cortical and hippocampal 5-hydroxyindoeacetic acid, 3,4-Dihydroxy-phenylacetic acid, malondialdehyde, NLR family pyrin domain containing-3 (NLRP3) and interleukin-1beta content while raised serotonin, nor-epinephrine, dopamine and glutathione level. PPAR<jats:italic>-<\/jats:italic>\u03b3 gene expression was elevated too. So, NAR and NAR-HNPs reduced DM-induced depression by influencing brain neurotransmitters and exhibiting anti-oxidant and anti-inflammatory effects through the activation PPAR-\u03b3\/ NLRP3 pathway. NAR-HNPs showed the best pharmacokinetic and therapeutic results.<\/jats:p>","DOI":"10.1038\/s41598-024-62676-x","type":"journal-article","created":{"date-parts":[[2024,6,12]],"date-time":"2024-06-12T16:02:14Z","timestamp":1718208134000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Anti-depressant effect of Naringenin-loaded hybridized nanoparticles in diabetic rats via PPAR\u03b3\/NLRP3 pathway"],"prefix":"10.1038","volume":"14","author":[{"given":"Salma A.","family":"El-Marasy","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mona M.","family":"AbouSamra","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Passant E.","family":"Moustafa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hoda B.","family":"Mabrok","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Omar A.","family":"Ahmed-Farid","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Asmaa F.","family":"Galal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hadir","family":"Farouk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,6,12]]},"reference":[{"issue":"7","key":"62676_CR1","doi-asserted-by":"publisher","first-page":"475","DOI":"10.1007\/s12272-022-01391-5","volume":"45","author":"NF Abdelkader","year":"2022","unstructured":"Abdelkader, N. 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