Background/Objectives: Glyphosate-based herbicides (GBHs) are widely used agrochemicals implicated in nephrotoxicity through mechanisms involving oxidative stress, inflammation, and tissue remodeling. Natural peptides such as melittin possess potent anti-inflammatory and antioxidant properties; however, their therapeutic use is limited by instability and toxicity. Nanotechnology-based encapsulation presents a promising approach to overcoming these challenges. Objective: This study aimed to evaluate the protective effects of melittin-loaded chitosan–TPP nanoparticles (MEL-NPs) against glyphosate-induced nephrotoxicity in rats, with emphasis on oxidative, inflammatory, and apoptotic pathways. Methods: Female Wistar rats were divided into four groups: control, glyphosate (5 mg/kg/day, 25 days), glyphosate + free melittin, and glyphosate + MEL-NPs (40 µg/kg, orally, 3 times/week). Renal function biomarkers, oxidative stress parameters (MDA, GSH, SOD, CAT, NO), cytokines (TNF-α, IL-6), and serum protein/iron indices were assessed. Western blotting (Nrf2, NGAL), histopathology (H&E), and immunohistochemistry (Bax) were performed. Nanoparticles were characterized by TEM, FTIR, and UV–Vis spectroscopy. Results: Glyphosate exposure caused renal dysfunction, including elevated plasma urea and creatinine levels, and reduced creatinine clearance, indicating impaired glomerular filtration efficiency, oxidative stress (↑increased MDA, NO; ↓decreased GSH, SOD), and upregulation of pro-inflammatory cytokines. Histology revealed tubular degeneration and inflammatory infiltration, while NGAL and Bax were strongly induced. Nrf2 expression was elevated as a compensatory response. Free melittin partially ameliorated these alterations, whereas MEL-NPs provided superior protection, restoring renal function, normalizing oxidative balance, reducing NGAL and Bax expression, and preserving renal histoarchitecture. Conclusions: Melittin nanoparticles confer robust renoprotection against glyphosate-induced nephrotoxicity in rats by modulating oxidative stress, suppressing inflammation, and regulating Nrf2/Bax signaling. These findings highlight nano-melittin as a promising therapeutic platform for managing herbicide-related renal disorders.

Background: Zearalenone (ZEA) is a potent estrogenic mycotoxin that adversely affects the female reproductive system, causing hormonal imbalance, uterine enlargement, structural changes in the reproductive tract, and reduced fertility. This study evaluated the protective effects of melittin-loaded chitosan nanoparticles (MEL-NPs) against ZEA-induced ovarian toxicity in female rats. Methods: Forty-eight adult female Wistar rats (180–200 g) were divided into four groups: Control, ZEA, ZEA + MEL, and ZEA + MEL-NPs. ZEA (2.7 mg/kg b.w.) was administered orally twice weekly for two weeks. MEL and MEL-NPs (40 μg/kg b.w.) were given orally three times weekly for one month. Serum biochemical parameters were measured, and ovarian tissues were examined grossly and histopathologically. qRT-PCR was performed to assess mRNA expression of inflammatory markers (TNF-α, IL-6, IL-1β), apoptotic marker (Caspase-3), and steroidogenic enzyme (CYP19A1). Results: ZEA exposure induced significant ovarian toxicity, evidenced by increased TNF-α, IL-6, IL-1β, LH, FSH, CA-125, and Caspase-3, along with decreased progesterone, antioxidant capacity, and CYP19A1 expression. Histopathology revealed ovarian atrophy, follicular degeneration, and fibrosis. Treatment with MEL-NPs markedly reversed these alterations, normalizing cytokine and hormonal profiles, restoring CYP19A1 expression, and improving ovarian morphology. MEL-NPs demonstrated superior protective effects compared to free MEL. Conclusions: MEL-NPs effectively ameliorate ZEA-induced ovarian toxicity by restoring hormonal balance, enhancing antioxidant defense, and reducing inflammation and apoptosis. These findings suggest that MEL-NPs could be a promising therapeutic strategy for preventing mycotoxin-induced ovarian dysfunction.

Cholestatic liver diseases are characterized by disrupted bile acid homeostasis, oxidative stress, and inflammation, ultimately leading to progressive hepatic injury. Although ursodeoxycholic acid (UDCA) remains the standard pharmacological therapy, its therapeutic efficacy is limited in several cholestatic conditions. This study investigated the hepatoprotective effects of cynaroside (CYN), a naturally occurring flavonoid glycoside, against ethinylestradiol (EE)-induced cholestatic liver injury and explored its underlying molecular mechanisms. Female Wistar rats were randomly allocated into four groups (n = 7): control, EE, EE + CYN, and EE + UDCA. Liver function indices, bile acids, cholesterol, oxidative stress and inflammatory biomarkers, histopathology, immunohistochemistry, Western blotting, qRT-PCR, and molecular docking analyses were performed. EE administration induced pronounced cholestatic liver injury, as evidenced by impaired liver function, hepatic accumulation of bile acids and cholesterol, oxidative imbalance, inflammatory responses, and marked histopathological alterations. CYN significantly ameliorated these biochemical and histological abnormalities, reduced hepatic bile acid and cholesterol accumulation, restored redox homeostasis, and attenuated inflammatory responses. Mechanistically, CYN modulated the hepatic FXR/BSEP/CYP7A1/SHP regulatory network, modulated hepatic FXR and Nrf2 protein expression, suppressed NF-κB activation, and favorably regulated TNF-α, IL-1β, and BCL2 expression. Histopathological and immunohistochemical findings further confirmed substantial preservation of hepatic architecture following CYN treatment. Molecular docking revealed favorable interaction of CYN with the FXR ligand-binding domain, with a predicted binding free energy of −8.18 kcal/mol, comparable to that of UDCA (−7.95 kcal/mol). Cynaroside attenuated EE-induced cholestatic liver injury by improving bile acid homeostasis and mitigating oxidative and inflammatory responses, potentially by modulating FXR-associated signaling and its downstream regulatory network. Collectively, the results provide a rationale for continued investigation of cynaroside in the context of cholestatic liver injury.