The protective role of kakkalide in sepsis-induced intestinal barrier dysfunction via inhibition of NF-κB pathway activation.

Abstract

Sepsis, a systemic inflammatory response often triggered by infection, can lead to multi-organ failure, with the intestine being one of the most vulnerable organs. The nuclear factor kappa-B (NF-κB) pathway plays a crucial role in immune responses, inflammation, and cell survival, making it central to sepsis-induced intestinal damage. Kakkalide (KA), a bioactive compound known for its anti-inflammatory, cardiovascular, neuroprotective, and anti-diabetic properties, has potential therapeutic effects. However, its impact on sepsis-induced intestinal injury remains unclear. In this study, murine sepsis models were used both in vivo and in vitro to evaluate the protective effects of KA on intestinal histopathology, apoptosis, and inflammation. Results showed that KA significantly reduced intestinal damage and apoptosis, as evidenced by hematoxylin-eosin and TUNEL staining. KA also improved intestinal barrier integrity, as indicated by reduced diamine oxidase activity, d-lactic acid content, and fluorescein isothiocyanate intensity, along with increased expression of zonula occludens-1. Furthermore, KA alleviates inflammation by reducing the levels of tumor necrosis factor-α, interleukin-1β, prostaglandin E2, inducible nitric oxide synthase, and cyclooxygenase-2. Immunofluorescence and Western blot analysis revealed that KA inhibited the sepsis-induced phosphorylation of inhibitor-kappaBα and RelA (P65) and prevented P65's translocation to the nucleus. These findings were confirmed in lipopolysaccharide-induced Caco-2 cells, suggesting that KA protected the intestinal barrier during sepsis by suppressing the NF-κB pathway.