This study investigates the antidiabetic and antioxidant potential of chitosan-encapsulated selenium nanoparticles in streptozotocin-induced diabetic model. Glibenclamide was used as a reference antidiabetic drug. Forty-eight adult male Wistar rats were used along the study and divided equally into 6 groups of (I) normal control, (II) chitosan-encapsulated selenium nanoparticles (CTS-SeNPs), (III) glibenclamide, (IV) streptozotocin (STZ), (V) STZ + CTS-SeNPs, and (VI) STZ + Glib. The animals were sacrificed on the 35th day of the experiment. Serum glucose, insulin, IGF-1, ALT, AST, CK-MB, oxidative stress, lipid profile, and inflammatory parameters were subsequently assessed. Also, the expression level of TCF7L2, CAPN10, and PPAR-γ genes were evaluated using qPCR. In addition, histopathological studies on pancreatic tissue were carried out. The results revealed that STZ induced both diabetes and oxidative stress in normal rats, manifested by the significant changes in the studied parameters and in the physical structure of pancreatic tissue. Oral administration of CTS-SeNPs or Glib results in a significant amelioration of the levels of serum fasting blood glucose, insulin, IGF-1, AST, ATL, and CK-MB as compared with STZ-induced diabetic rats. CTS-SeNPs and Glib diminished the level of lipid peroxidation, increased total antioxidant capacity level, as well as possessed strong inhibition against serum α-amylase and α-glucosidase activities. Diabetic animals received CTS-SeNPs, or Glib demonstrated a significant (p < 0.05) decrease in the expression level of TCF7L2 and CAPN10 genes with a significant increase in the expression level of PPAR-γ gene, compared to STZ group. The above findings clarify the promising antidiabetic and antioxidant effect of CTS-SeNPs, recommending its inclusion in the currently used protocols for the treatment of diabetes and in the prevention of its related complications. Graphical abstract

Fluoride and aluminum are ubiquitous toxic metals with adverse reproductive effects. The citrus flavonoid hesperidin has protective activities but poor solubility and bioavailability. Nanoparticulate delivery systems can improve flavonoid effectiveness. We conducted this study to prepare a pH-responsive chitosan-based nanogel for hesperidin delivery and evaluate its effectiveness against sodium fluoride (NaF) and aluminum chloride (AlCl₃) induced testicular toxicity in mice. The nanogel was synthesized using 2 kGy gamma irradiation, enabling a size under 200 nm and enhanced hesperidin release at pH 6 matching testicular acidity. Male mice received 200 mg/kg AlCl₃ and 10 mg/kg NaF daily for 30 days. Hesperidin nanogel at 20 mg/kg was administered orally either prophylactically (pretreatment) or after intoxication (posttreatment). The results showed that AlCl₃ + NaF induced severe oxidative stress, hormonal disturbance, apoptosis, and endoplasmic reticulum stress, evidenced by significant changes in the studied parameters and testicular histological damage. Hesperidin nanogel administration significantly inhibited oxidative stress markers, restored luteinizing hormone (LH), follicle-stimulating hormone (FSH), and testosterone levels, and alleviated tissue damage compared to the intoxicated group. It also downregulated the expression level of pro-apoptotic genes Bax, caspase-3, caspase-9, and P38MAPK, while upregulating the expression level of the anti-apoptotic BCL2 gene. Endoplasmic reticulum stress sensors PERK, ATF6, and IRE-α were also downregulated by the nanogel. The chitosan-based nanogel enhanced the delivery and efficacy of poorly bioavailable hesperidin, exhibiting remarkable protective effects against AlCl₃ and NaF reproductive toxicity. This innovative nanosystem represents a promising approach to harnessing bioactive phytochemicals with delivery challenges, enabling protective effects against chemical-induced testicular damage. Graphical Abstract

The purpose of this study was to demonstrate the neuroprotective effect of Melissa officinalis extract (MEE) against brain damage associated with hypothyroidism induced by propylthiouracil (PTU) and/or γ-radiation (IR) in rats. Hypothyroidism induction and/or exposure to IR resulted in a significant decrease in the serum levels of T3 and T4 associated with increased levels of lipid peroxidation end product, malondialdehyde (MDA), and nitrites (NO) in the brain tissue homogenate. Also, hypothyroidism and /or exposure to IR markedly enhance the endoplasmic reticulum stress by upregulating the gene expressions of the protein kinase RNA-like endoplasmic reticulum kinase (PERK), activated transcription factor 6 (ATF6), endoplasmic reticulum-associated degradation (ERAD), and CCAAT/enhancer-binding protein homologous protein (CHOP) in the brain tissue homogenate associated with a proapoptotic state which indicated by the overexpression of Bax, BCl2, and caspase-12 that culminates in brain damage. Meanwhile, the PTU and /or IR-exposed rats treated with MEE reduced oxidative stress and ERAD through ATF6. Also, the MEE treatment prevented the Bax and caspase-12 gene expression from increasing. This treatment in hypothyroid animals was associated with neuronal protection as indicated by the downregulation in the gene expressions of the microtubule-associated protein tau (MAPT) and amyloid precursor protein (APP) in the brain tissue. Furthermore, the administration of MEE ameliorates the histological structure of brain tissue. In conclusion, MEE might prevent hypothyroidism-induced brain damage associated with oxidative stress and endoplasmic reticulum stress.

The use of 5-fluorouracil (5-FU) is associated with multifaceted challenges and poor pharmacokinetics. Accordingly, our study was designed to prepare 5-FU nanogel as a new form of the colon cancer chemotherapeutic drug 5-FU using polyacrylic acid and gelatin hybrid nanogel as efficient drug carriers. Alongside the in vivo chemotherapeutic evaluation, the anti-proliferative and anti-apoptotic efficacy were carried out for 5-FU nanogel against 1,2-dimethylhydrazine (DMH, 20 mg/kg) and γ-radiation (4 Gy)-prompted colon dysplasia in rats compared to 5-FU. The morphology and size of 5-FU nanogel were characterized by transmission electron microscopy (TEM) and dynamic light scattering (DLS) in addition to cytotoxicity assay. The expression of phosphoinositide-3-kinase (PI3K)/Akt, mammalian target of rapamycin (mTOR); Toll-like receptor2 (TLR2)/nuclear factor kappa B), adenosine monophosphate (AMP)-activated protein kinase (AMPK) and its downstream autophagy-related genes in addition to apoptotic markers were measured in colon tissues. Results: 5-FU nanogel reduced the levels of the TLR2/ NF-κβ as well as the expression of PI3K/AKT/mTOR. Moreover, it promoted autophagy through the activation of the AMPK and its downstream targets which consequently augmented the intrinsic and extrinsic apoptotic pathways. Conclusion: Collectively, these data might strengthen the therapeutic potential of 5-FU nanogel which can be used as an antitumor product for colon cancer.

Background: Melissa officinalis (MO) is a well-known medicinal plant species used in the treatment of several diseases; it is widely used as a vegetable, adding flavour to dishes. This study was designed to evaluate the therapeutic effect of MO Extract against hyperthyroidism induced by Eltroxin and γ-radiation. Methods: Hyperthyroidism was induced by injecting rats with Eltroxin (100 µg/kg/ day) for 14 days and exposure to γ-radiation (IR) (5 Gy single dose). The hyperthyroid rats were orally treated with MO extract (75 mg/kg/day) at the beginning of the second week of the Eltroxin injection and continued for another week. The levels of thyroid hormones, liver enzymes and proteins besides the impaired hepatic redox status and antioxidant parameters were measured using commercial kits. The hepatic gene expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and its inhibitor Kelch-like ECH-associated protein-1(Keap-1) in addition to hepatic inflammatory mediators including tumor necrosis factor-α (TNF- α), Monocyte chemoattractant protein-1 (MCP-1) and fibrogenic markers such as transforming growth factor-beta1 (TGF-β1) were determined. Results: MO Extract reversed the effect of Eltroxin + IR on rats and attenuated the thyroid hormones. Moreover, it alleviated hyperthyroidism-induced hepatic damage by inhibiting the hepatic enzymes’ activities as well as enhancing the production of proteins concomitant with improving cellular redox homeostasis by attenuating the deranged redox balance and modulating the Nrf2/Keap-1 pathway. Additionally, MO Extract alleviated the inflammatory response by suppressing the TNF- α and MCP-1 and prevented hepatic fibrosis via Nrf2-mediated inhibition of the TGF-β1/Smad pathway. Conclusion: Accordingly, these results might strengthen the hepatoprotective effect of MO Extract in a rat model of hyperthyroidism by regulating the Nrf-2/ Keap-1 pathway.