Alzheimer’s disease (AD) is a progressive neurological illness characterized by memory loss and cognitive deterioration. Dapagliflozin was suggested to attenuate the memory impairment associated with AD; however, its mechanisms were not fully elucidated. This study aims to examine the possible mechanisms of the neuroprotective effects of dapagliflozin against aluminum chloride (AlCl₃)-induced AD. Rats were distributed into four groups: group 1 received saline, group 2 received AlCl₃ (70 mg/kg) daily for 9 weeks, and groups 3 and 4 were administered AlCl₃ (70 mg/kg) daily for 5 weeks. Dapagliflozin (1 mg/kg) and dapagliflozin (5 mg/kg) were then given daily with AlCl₃ for another 4 weeks. Two behavioral experiments were performed: the Morris Water Maze (MWM) and the Y-maze spontaneous alternation (Y-maze) task. Histopathological alterations in the brain, as well as changes in acetylcholinesterase (AChE) and amyloid β (Aβ) peptide activities and oxidative stress (OS) markers, were all evaluated. A western blot analysis was used for the detection of phosphorylated 5’ AMP-activated protein kinase (p-AMPK), phosphorylated mammalian target of Rapamycin (p-mTOR) and heme oxygenase-1 (HO-1). Tissue samples were collected for the isolation of glucose transporters (GLUTs) and glycolytic enzymes using PCR analysis, and brain glucose levels were also measured. The current data demonstrate that dapagliflozin represents a possible approach to combat AlCl₃-induced AD in rats through inhibiting oxidative stress, enhancing glucose metabolism and activating AMPK signaling.

Paracetamol overdose is a major cause of drug-induced acute kidney injury (AKI), driven by oxidative stress, inflammation, mitochondrial dysfunction, and tubular apoptosis. This study evaluated the nephroprotective efficacy of pH-responsive carboxymethyl cellulose-encapsulated hesperidin-stabilized selenium nanoparticles (CMC@HES-SeNPs) against paracetamol-induced AKI in rats. HES-SeNPs were synthesized using hesperidin as a reducing/stabilizing agent and further coated with CMC. The nanoparticles were characterized by DLS, zeta potential, TEM, and in vitro release kinetics at pH 7.4 and 5.5. 42 Male rats were allocated into groups of control, paracetamol (PAR), paracetamol treated with sodium selenite (PAR&Se), paracetamol treated with hesperidin (PAR&HES), paracetamol treated with hesperidin-loaded selenium nanoparticles (PAR&HES-SeNPs), and paracetamol treated with carboxy methyl cellulose-coated hesperidin-loaded selenium nanoparticles (PAR&CMC@HES-SeNPs). Paracetamol markedly impaired renal function, increasing creatinine, urea, NGAL, KIM-1, and cystatin-C, and induced oxidative/nitrosative stress, Keap-1 upregulation, Nrf2 suppression, NF-κB-mediated inflammation, cytochrome-C release, Bax/Bcl-2 imbalance, caspase-3 activation, and severe renal histopathological injury. CMC@HES-SeNPs displayed sustained, pH-enhanced hesperidin release and produced the strongest renoprotective response, restoring renal biomarkers, associated with restoration of Keap-1/Nrf2-related antioxidant markers, reduction in TNF-α, IL-6, NF-κB, and caspase-3, increased IL-10, and preservation of renal architecture. Collectively, these results indicate that CMC@HES-SeNPs represent a promising multifunctional nanoplatform for mitigating paracetamol-induced AKI in association with coordinated modulation of redox, inflammatory, and mitochondrial apoptotic markers, and highlight CMC encapsulation as a rational strategy to enhance selenium–flavonoid delivery and efficacy for future drug-induced AKI management and translation.

Cisplatin is an effective chemotherapeutic agent whose clinical use is limited by dose-dependent off-target toxicities, particularly hepatic and cardiac injury. The present study investigated the protective efficacy of rutin-mediated selenium nanoparticles (RUT-SeNPs) against cisplatin-induced hepato-cardiotoxicity in rats and compared their effects against those of free rutin and sodium selenite. RUT-SeNPs were characterized using dynamic light scattering, zeta potential analysis, transmission electron microscopy, X-ray diffraction, and UV–visible spectroscopy. Thirty-five male rats were randomly assigned to five groups: control (CON), cisplatin (CIS), CIS + Rutin, CIS + selenium, and CIS + RUT-SeNPs. Cisplatin administration caused marked hepatic and cardiac injury, as evidenced by altered liver-function indices, elevated cardiac injury biomarkers, oxidative stress, inflammatory activation, endoplasmic reticulum stress, and apoptosis. These effects were associated with increased lipid peroxidation, depletion of endogenous antioxidants, KEAP1 upregulation, Nrf2 suppression, activation of the TLR4/MAPK/NF-κB inflammatory axis, elevated TNF-α, IL-6, and COX-2 levels, and increased mRNA expression of the ER stress-related genes PERK, ATF4, ATF6, and CHOP. Cisplatin also promoted mitochondrial apoptosis, as indicated by increased Bax expression and cytochrome c release together with reduced Bcl-2 levels. Although rutin and sodium selenite partially mitigated these alterations, RUT-SeNPs produced the most pronounced protective effects by restoring redox homeostasis, suppressing inflammatory signaling, reducing the elevated expression of ER stress-related genes, and limiting mitochondrial apoptotic activation. These molecular improvements were accompanied by substantial preservation of the hepatic and cardiac histoarchitecture. Collectively, these results indicate that RUT-SeNPs may represent a promising nanoformulation for reducing cisplatin-induced hepato-cardiac toxicity through coordinated modulation of oxidative stress, inflammation, endoplasmic reticulum stress, and apoptosis.