Diosgenin Nanoparticles Competes Plain Diosgenin on Reviving Biochemical and Histopathological Alterations in DMBA Induced Rat Mammary Carcinoma via Modulating the AhR-Nrf-2 Signaling Cascades

Abstract

Background: Diosgenin, a steroidal saponin spotted as a primary ingredient in many traditional Chinese medicines, has sparked the attention of researchers owing to its multi-targeted cytotoxicity towards a multitude of cancers. Regrettably, its true potential was bounded by its impoverished physicochemical properties. In order to fully exploit its ability, we plan to fabricate diosgenin into nanoparticle by encapsulating with biodegradable polymer chitosan. Aim: The current research intends to uncover the therapeutic potency of diosgenin encapsulated chitosan nanoparticles (DG@CS-NP) on 7,12dimethylbenz(a)anthracene (DMBA) induced rat mammary carcinoma by optimizing biochemical and histopathological modifications via attenuating Aryl hydrocarbon receptor (AhR) - nuclear factor erythroid-derived 2-related factors (Nrf-2) signaling. Methodology: Breast cancer was induced with a single dose of DMBA (25 mg/kg b.wt). Orally supplied DG 10mg/kg b.wt. and DG@CS-NP 5 mg/kg b.wt to DMBA-induced tumor-bearing rats shortly after tumor onset. After the experimental period, biochemical and histopathological studies were performed using mammary tissue sections. Furthermore, architectural immunohistochemistry was used to reveal the expression of AhR and Nrf-2 in experimental rats. Additionally, diosgenin interactions with these proteins were also evidently confirmed by molecular docking analysis. Result: We noticed that there is an elevated level of lipid peroxidative marker, phase-I detoxification enzymes, total cholesterol (TC), phospholipids (PL), triglycerides (TG), and free fatty acids (FFA) with boosted AhR expressions as well as diminished levels of enzymatic and non-enzymatic antioxidants and Phase – II detoxification enzymes with downtrodden Nrf-2 expressions in the mammary tissues of DMBA-induced rats. On the other contrary, oral dosing of DG@CS-NP 5 mg/kg b.wt, dramatically reverted them to near-normal tiers. Interestingly, molecular docking analyses also corroborate these insights by highlighting diosgenin's significant interactions with AhR and Nrf-2 targets. Conclusion: As an outcome of our observations, we conclude that nano-encapsulation of diosgenin is a potent targeted therapeutic candidate posing a massive impact on breast cancer than plain diosgenin.