Unveiling the nano-particle enabled synergistic mitigation of the Bcl2/Cyt c/CYP1A1 signaling axis as a protective therapeutic route in mitochondrial dysfunction associated diabetes

Abstract

The present study aims to assess the potential benefits of bioactive chlorophyllin (CHL) and its nano-formulation against alloxan (ALX)-induced mitochondrial dysfunction, genotoxicity, and hyperglycemia. Nano-chlorophyllin (NCHL) encapsulated in poly-lactide-co-glycolide (PLGA) was synthesized successfully and characterized by atomic force microscopy (AFM), field emission scanning electron microscopy (FESEM), and dynamic light scattering (DLS) techniques. The strong interactions between both CHL and its nano-form (NCHL) with calf thymus DNA (CT-DNA) were further investigated by circular dichroism (CD) spectroscopy, isothermal titration calorimetry (ITC) and electronic absorption studies, demonstrating protective roles of the drug against chromosomal aberrations and micronucleus formation linked to DNA damage. The findings showed that NCHL selectively activates several proteins such as Bcl2, Cyt c and CYP1A1 while modulating reactive oxygen species (ROS) levels and enhancing anti-oxidative enzyme activities, including superoxide dismutase (SOD), catalase (CAT) and lipid peroxidase (LPO). This response provides a protective effect against ALX-induced oxidative stress, mitochondrial dysfunction, and hyperglycemia. Notably, NCHL also played a significant role in modulating ATP levels and the depolarization of mitochondrial membrane potential (MMP), confirming the direct influence of CHL in mitigating ALX-induced mitochondrial dysfunction and restricting the onset of hyperglycemia. Thus, our overall findings suggest that NCHL could serve as a promising drug candidate for the therapeutic management of mitochondrial dysfunction and diabetes-related complications associated with food additive exposure.