Peptide ^Tat(48-60) YVEEL protects against necrotizing enterocolitis through inhibition of toll-like receptor 4-mediated signaling in a phosphatidylinositol 3-kinase/AKT dependent manner.

ABSTRACT: Necrotizing enterocolitis (NEC) is a catastrophic disease largely occurring in preterm infants, and toll-like receptor 4 (TLR4) has been implicated in its pathogenesis. The current therapeutic strategies for NEC are, however, far from optimal. In the present study, a whey-derived antioxidative peptide conjugated with a cell-penetrating TAT [^{Tat (48-60)} YVEEL] was prepared to endow it with enhanced cell uptake capability and bioavailability. The protective effect of ^{Tat (48-60)} YVEEL on experimental NEC was evaluated both in vitro and in vivo. Inhibition of TLR4-mediated signaling by ^{Tat (48-60)} YVEEL was assessed in FHC and IEC-6 enterocytes, neonatal rat model of NEC, and the mechanism underlying this effect was determined. ^{Tat (48-60)} YVEEL significantly inhibited TLR4-mediated expression of pro-inflammatory cytokines, p65 nuclear translocation and restored the impaired enterocyte migration in cultured enterocytes. In addition, ^{Tat (48-60)} YVEEL administration strikingly increased the survival rate, and reduced the severity of NEC in rats through inhibition of TLR4-mediated signaling. These protective effects of ^{Tat (48-60)} YVEEL occurred in a PI3K/AKT dependent manner, as administration of PI3K activator Ys49 abrogated its protective effects. Combined with liposomes, ^{Tat (48-60)} YVEEL demonstrated longer retention in the intestines that better for potential clinical applications. These data demonstrate that ^{Tat (48-60)} YVEEL protects against NEC through inhibition of TLR4-mediated signaling in a PI3K/AKT dependent manner, and offer a potential therapeutic approach to this disease.

SUBMITTER: Yan X 

PROVIDER: S-EPMC9590307 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature