N-acetyl-L-tryptophan attenuates hepatic ischemia-reperfusion injury via regulating TLR4/NLRP3 signaling pathway in rats

Abstract

The aim of this study was to investigate the changes of TLR4/NLRP3 signal during hepatic ischemia-reperfusion injury (HIRI) and to verify whether N-acetyl-L-tryptophan (L-NAT) protected hepatocytes by regulating the activation of TLR4/NLRP3 signal. We have established the rat HIRI model and H2O2-induced cell damage model to simulate ischemia-reperfusion injury and detect the corresponding indicators. Compared with the sham group, Suzuki score and the level of serum ALT increased after HIRI, accompanied by an increased expression of NLRP3, ASC, Caspase-1, IL-1β, TLR4, and NF-κB. While L-NAT pretreatment reversed the above-mentioned changes. Compared with the control group, cells in the H2O2 treated group became smaller in cell volume and round in shape with unclear boundaries. Similar to the phenotypes in vivo, H2O2 treatment also induced significant increase in expression of pyroptosis-related proteins (NLRP3, ASC, Caspase-1 and IL-1β) and inflammatory factors (TLR4 and NF-κB). While L-NAT pretreatment attenuated injuries caused by H2O2. In conclusion, the present findings demonstrate that L-NAT alleviates HIRI by regulating activation of NLRP3 inflammasome, which may be related to the TLR4/NF-κB signaling pathway.

Pyroptosis: A Newly Discovered Therapeutic Target for Ischemia-Reperfusion Injury

“…A study conducted by Li et al suggested that DHA alleviates hepatic I/R injury by activating the PI3K/Akt pathway and subsequently inhibiting the canonical pyroptotic pathway [ 104 ]. Similarly, N-acetyl-1-tryptophan can lighten hepatic I/R injury via inhibiting the TLR4/NLRP3/caspase-1 signaling pathway [ 105 ]. Moreover, hepatic I/R injury was attenuated in caspase-1/caspase-11 double-gene knockout mice, suggesting that apart from the canonical pyroptotic pathway, the non-canonical pathway of pyroptosis is also involved in liver I/R injury [ 106 ].…”

Salidroside alleviates hepatic ischemia–reperfusion injury during liver transplant in rat through regulating TLR-4/NF-κB/NLRP3 inflammatory pathway

“…As the most studied tissue-damage detector, the NLR family pyrin domain-containing 3 (NLRP3) inflammasome is composed of NLRP3, apoptosis-associated speck-like protein (ASC) and caspase-1, which is prominent in initiating and propagating the inflammatory responses 12 . Previous evidence suggests that the NF-κB signaling leads to NLRP3 activation that participates in the pathogenesis of hepatic IRI 13 . Thus, the TLR-4/NF-κB/NLRP3 inflammatory pathway might be involved in hepatic IRI.…”

Protective effect of liriodendrin against liver ischaemia/reperfusion injury in mice via modulating oxidative stress, inflammation and nuclear factor kappa B/toll-like receptor 4 pathway

“…A considerable number of experimental studies have indicated that ischemia/reperfusion-induced liver injury occurs in a biphasic manner [15]. Data obtained by several different research groups suggest that in both early and late phases of reperfusion injury, oxidative stress is one of the main pathogenic mechanisms [20,24,30,31],. SOD and GSH-Px are important antioxidants, and MDA is a product of lipid peroxidation.…”