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

Abstract

Salidroside has anti-inflammatory, antioxidant and hepatoprotective properties. However, its effect on hepatic ischemia–reperfusion injury (IRI), an unavoidable side effect associated with liver transplantation, remains undefined. Here, we aimed to determine whether salidroside alleviates hepatic IRI and elucidate its potential mechanisms. We used both in vivo and in vitro assays to assess the effect and mechanisms of salidroside on hepatic IRI. Hepatic IRI rat models were pretreated with salidroside (5, 10 or 20 mg/kg/day) for 7 days following liver transplantation while hypoxia/reoxygenation (H/R) model of RAW 264.7 macrophages were pretreated with salidroside (1, 10 or 50 μM). The effect of salidroside on hepatic IRI was assessed using hematoxylin–eosin staining, terminal deoxynucleotidyl transferase dUTP nick-end labeling staining, qRT-PCR, immunosorbent assay and western blotting. Our in vivo assays showed that salidroside significantly reduced pathological liver damage, serum aminotransferase levels and serum levels of IL-1, IL-18 and TNF-α. Besides, salidroside reduced the expression of TLR-4/NF-κB/NLRP3 inflammatory pathway associated proteins (TLR-4, MyD88, p-IKKα, p-IKKβ, p-IKK, p-IκBα, p-P65, NLRP3, ASC, Cleaved caspase-1, IL-1β, IL-18, TNF-α and IL-6) in rats after liver transplantation. On the other hand, data from the in vitro analysis demonstrated that salidroside blocks expression of TLR-4/NF-κB/NLRP3 inflammatory pathway related proteins in the RAW264.7 cells treated with H/R. The salidroside-specific anti-inflammatory effects were partially inhibited by the TLR-4 agonist lipopolysaccharide. Taken together, our study showed that salidroside inhibits hepatic IRI following liver transplantation by modulating the TLR-4/NF-κB/NLRP3 inflammatory pathway.

Functional analysis of hepatic long non‐coding ribonucleic acids during liver transplantation in humans

“…In the Biological Process ontology category of GO enrichment analysis, DEGs were mostly enriched in cellular divalent inorganic cation homeostasis, response to molecule of bacterial origin, response to lipopolysaccharide, regulation of body fluid levels, and hormone metabolic process, which is consistent with the previously known pathophysiological mechanisms of post‐transplantation HIRI 40,41 . Apart from this, KEGG enrichment analysis revealed that DEGs were mostly enriched in the PI3K‐Akt signaling pathway, focal adhesion, Hippo signaling pathway, TNFα signaling pathway, etc 42 . Some of these pathways have been recognized as canonical pathways associated with HIRI.…”

“…40,41 Apart from this, KEGG enrichment analysis revealed that DEGs were mostly enriched in the PI3K-Akt signaling pathway, focal adhesion, Hippo signaling pathway, TNFα signaling pathway, etc. 42 Some of these pathways have been recognized as canonical pathways associated with HIRI. For example, PI3K-Akt signal transduction is an important self-protective pathway in HIRI, [43][44][45][46] which enables cells to respond to various stresses, especially antiapoptotic and pro-survival responses.…”

Modafinil lightens apoptosis and inflammatory response in hepatic ischemia‐reperfusion injury through inactivation of TLR9/Myd88/p38 signaling

“…Inflammatory response has been demonstrated to contribute to the aggravation of liver damage during hepatic IRI through the release of a plethora of proinflammatory cytokines (Choi & Lim, 2023). As reported, the expressions of proinflammatory cytokines including TNF-α, IL-1β, and IL-6 are increased during the process of hepatic IRI (Liu, Zhang, et al, 2022;Ye et al, 2019) and the inactivation of proinflammatory pathways has been shown to play a critical role in the resolution of injury (Li et al, 2021;Liu, Lei, et al, 2022). It is also worth mentioning that MOD counters inflammatory response in nonalcoholic liver disease (Choi et al, 2021), IRI after testicular torsion (Yousefi-Manesh et al, 2019), as well as intestinal IRI (Kamel et al, 2020), manifested by decreased IL-1β and TNF-α levels.…”

The Interplay between Immune and Metabolic Pathways in Kidney Disease

“…Studies have shown that activation of the NLRP3 inflammasome in both donor and recipient cells can contribute to the development of acute and chronic rejection [ 182 ]. Furthermore, activation of the NLRP3 inflammasome has also been implicated in the development of ischemia–reperfusion injury, a common complication during kidney transplantation [ 183 , 184 , 185 ]. Dysregulated metabolism in immune cells has also been implicated in poor kidney transplant outcomes.…”