Lipopolysaccharide-induced perturbation of redox homeostasis and organ injuries: Mitigation by cholecalciferol.

Lipopolysaccharide (LPS), a glycolipid found in the outer membrane of Gram-negative bacteria, plays a crucial role in maintaining the bacteria's structural integrity and protection. Normally, LPS does not cross the gut membrane; however, gut lesions or lipid-rich diets facilitate LPS translocation into the systemic circulation. In addition, many supplements, food products, and probiotics contain Gram-negative bacteria or LPS. LPS, at elevated levels, is causally linked to the development of multiple diseases. In humans, LPS triggers potent inflammatory and immune responses that can cause septic shock and, in severe cases, death. Cholecalciferol, or Vitamin D3 (vit-D3), is well-known for its traditional role in calcium absorption and bone metabolism. However, recent research highlights its role in modulating the innate immune system, oxidative stress, and cell proliferation. Additionally, since oxidative stress primarily triggers macromolecular damage at the DNA level, we incorporated DNA-binding studies to understand the ligand-DNA interaction behavior, providing a mechanistic basis for macromolecular protection in vivo. Our study aimed to examine the protective effects of vit-D3, against LPS-induced redox perturbation and organ injuries. Despite some findings linking LPS to hepato-renal toxicity, the potential role of vit-D3 in mitigating endotoxin-induced redox perturbation and macromolecular damage remains poorly defined. To address this gap, we employed integrated in silico, in vitro, and in vivo approaches to evaluate DNA interactions, oxidative and nitrosative stress, antioxidant defense systems, macromolecular damage, inflammatory markers, and histopathological alterations. LPS-treated groups displayed elevated serum liver and kidney markers, reactive oxygen/nitrogen species, macromolecular damage, perturbation of antioxidant machinery, and cytoarchitectural injuries in liver and kidney tissues. Notably, the combination of LPS and vit-D3 significantly ameliorated the oxidative injuries and pathological changes induced by LPS. Our findings identify vit-D3 as a previously unexplored modulator of LPS-induced different hazardous effects. Further, we may infer that vit-D3 deficient condition may be more prone to LPS-induced adverse effects. This promising discovery highlights the need for further preclinical and clinical research to validate its therapeutic potential.