Smart Hesperidin/Chitosan Nanogel Mitigates Apoptosis and Endoplasmic Reticulum Stress in Fluoride and Aluminum-Induced Testicular Injury

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

Protective Effects of Sophoraflavanone G by Inhibiting TNF-α-Induced MMP-9-Mediated Events in Brain Microvascular Endothelial Cells

“…However, there still exists an obstacle in clinical use due to the difficulties in flavonoid administration. Because of low bioavailability, SG needs to be formulated using some smart drug release and/or delivery technologies, like other flavonoid compounds [ 42 , 43 , 44 ]. Therefore, the optimal delivery system for SG needs to be further verified, especially in the CNS system.…”

Ameliorative Effect of Novel Nanocompound against Oxidative Stress- Induced Brain Toxicity in Mice

“…All reagents, including acrylamide (AAm), acrylic acid (AAc), and dimethyl sulfoxide (DMSO), were acquired from Sigma-Aldrich Co., Hesperidin (HSP) (95%) from Al-dawlya Co., and Chitosan (Cs) from Techno-Gen, Gisa, Egypt. Preparation of chitosan-based poly (acrylamide/acrylic acid) hesperidin (Cs/P(AAc/AAm)/HSP) Nanogel by gamma radiation, and calculation of LD50 was according to (Deiab et al, 2023). Cs/P(AAc/AAm)/HSP Nanogel was administered at a dose (20 mg/kg b.w.…”

“…/P(AAc/AAm)/HSP Nanogel Dynamic light scattering was used to validate the pH influence on the size and zeta potential of the produced Cs/p(AAc/AAm)/HSP solution, while a transmission electron microscope (TEM) was used to analyze the nanogel size and shape(Deiab et al, 2023). 3.2.…”