Fractionated whole body γ-irradiation aggravates arthritic severity via boosting NLRP3 and RANKL expression in adjuvant-induced arthritis model: the mitigative potential of ebselen

Abstract

Rheumatoid arthritis (RA) is an autoimmune chronic inflammatory disease associated with oxidative stress that causes excruciating pain, discomfort, and joint destruction. Ebselen (EB), a synthesized versatile organo-selenium compound, protects cells from reactive oxygen species (ROS)-induced injury by mimicking glutathione peroxidase (GPx) action. This study aimed to investigate the antioxidant and anti-inflammatory effects of EB in an arthritic irradiated model. This goal was achieved by subjecting adjuvant-induced arthritis (AIA) rats to fractionated whole body γ-irradiation (2 Gy/fraction once per week for 3 consecutive weeks, for a total dose of 6 Gy) and treating them with EB (20 mg/kg/day, p.o) or methotrexate (MTX; 0.05 mg/kg; twice/week, i.p) as a reference anti-RA drug. The arthritic clinical signs, oxidative stress and antioxidant biomarkers, inflammatory response, expression of NOD-like receptor protein-3 (NLRP-3) inflammasome, receptor activator of nuclear factor κB ligand (RANKL), nuclear factor-κB (NF-κB), apoptotic indicators (caspase 1 and caspase 3), cartilage integrity marker (collagen-II), and histopathological examination of ankle joints were assessed. EB notably improved the severity of arthritic clinical signs, alleviated joint histopathological lesions, modulated oxidative stress and inflammation in serum and synovium, as well as reduced NLRP-3, RANKL, and caspase3 expression while boosting collagen-II expression in the ankle joints of arthritic and arthritic irradiated rats with comparable potency to MTX. Our findings suggest that EB, through its antioxidant and anti-inflammatory properties, has anti-arthritic and radioprotective properties in an arthritic irradiated model.

Ondansetron or beta-sitosterol antagonizes inflammatory responses in liver, kidney, lung and heart tissues of irradiated arthritic rats model

“…According to the RTqPCR results in kidney, heart, lung and liver; the IKB gene, TNF-α and 7-NACH mRNA expression varied compared to normal control group ( p < .05; Figure 4 ). In our results, the decrease in α-7nAChR in arithritic group could be associated with a reduction in IL-10 level, as Gowayed et al 72 manifested. Along with the well-established cholinergic anti-inflammatory pathway, this accelerates protein citrullination and the progression of rheumatoid arthritis.…”

Role of Mitochondria in the Chronification of Inflammation: Focus on Dysfunctional Mitophagy and Mitochondrial DNA Mutations

“…94 Persistent oxidative stress can cause damage to the biological macromolecules and tissues and impact the resolution process by perpetuating inflammation. 95 Low-grade inflammation intertwines with metabolic disequilibrium. Patients with schizophrenia have a pronounced metabolic inflammatory imbalance, as evidenced by the presence of increased pro-inflammatory activity and obesity with changes in the metabolism of carbohydrates, lipids, and their metabolites.…”