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

PeerJ ◽  
2021 ◽  
Vol 9 ◽  
pp. e11909
Author(s):  
Yitong Pan ◽  
Shuna Yu ◽  
Jianxin Wang ◽  
Wanzhen Li ◽  
Huiting Li ◽  
...  
Keyword(s):  
Reperfusion Injury ◽  
Signaling Pathway ◽  
Ischemia Reperfusion Injury ◽  
Cell Damage ◽  
Ischemia Reperfusion ◽  
Inflammatory Factors ◽  
Control Group ◽  
Hepatic Ischemia ◽  
Caspase 1 ◽  
Hepatic Ischemia Reperfusion

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.

scholarly journals Exosomes Mediate Hippocampal and Cortical Neuronal Injury Induced by Hepatic Ischemia-Reperfusion Injury through Activating Pyroptosis in Rats

2019 ◽  
Vol 2019 ◽  
pp. 1-17 ◽  
Author(s):  
Limei Zhang ◽  
Hanyu Liu ◽  
Lili Jia ◽  
Jingshu Lyu ◽  
Ying Sun ◽  
...  
Keyword(s):  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Neuronal Injury ◽  
Male Rats ◽  
Receptor Protein ◽  
Enzyme Linked Immunosorbent Assay ◽  
Hepatic Ischemia ◽  
Caspase 1 ◽  
Hepatic Ischemia Reperfusion

Background. The neuronal injury and cognitive dysfunction after liver transplantation have severe effects on the prognosis and life quality of patients. Accumulating evidence suggests that both exosomes and pyroptosis could participate in hepatic ischemia-reperfusion injury (HIRI) and play key roles in neuronal death. However, the link between exosomes and neuronal pyroptosis in HIRI awaits further investigation. Methods. After establishing the HIRI rat models, we primarily studied the role of pyroptosis in hippocampal and cortical neuron injury through detecting NOD-like receptor protein 3 (NLRP3), pro-caspase-1, cleaved-caspase-1, apoptosis-associated speck-like protein containing CARD (ASC), gasdermin D (GSDMD), interleukin-1beta (IL-1β), and interleukin-18 (IL-18) expressions with western blotting, immunohistochemical staining, and enzyme-linked immunosorbent assay (ELISA). Then, we intravenously injected normal male rats with exosomes isolated from the sera of HIRI-challenged rats and pretreated rats with MCC950, a specific inhibitor of NLRP3, and carried out the same assay. We also detected the levels of reactive oxygen species (ROS), superoxide dismutase (SOD), and malondialdehyde (MDA) in the hippocampal and cortical tissues. Results. The results indicated that NLRP3 inflammasome and caspase-1-dependent pyroptosis were activated in the hippocampus and cortex of HIRI rats. Furthermore, serum-derived exosomes from HIRI-challenged rats not only had the ability to cross the blood-brain barrier (BBB) but also had the similar effects on neuronal pyroptosis. Moreover, ROS and MDA productions were induced in the HIRI and exosome-challenged groups. In addition, to some degree, MCC950 could alleviate HIRI-mediated hippocampal and cortical neuronal pyroptosis. Conclusion. This study experimentally demonstrated that circulating exosomes play a critical role in HIRI-mediated hippocampal and cortical injury through regulating neuronal pyroptosis.

scholarly journals Protective Effects of Human Liver Stem Cell-Derived Extracellular Vesicles in a Mouse Model of Hepatic Ischemia-Reperfusion Injury

2020 ◽  
Author(s):  
Alberto Calleri ◽  
Dorotea Roggio ◽  
Victor Navarro-Tableros ◽  
Nicola De Stefano ◽  
Chiara Pasquino ◽  
...  
Keyword(s):  
Stem Cell ◽  
Reperfusion Injury ◽  
Extracellular Vesicles ◽  
Human Liver ◽  
Imaging System ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Control Group ◽  
Hepatic Ischemia ◽  
Hepatic Ischemia Reperfusion

AbstractHepatic ischemia-reperfusion injury (IRI) is observed in liver transplantation and hepato-biliary surgery and is associated with an inflammatory response. Human liver stem cell-derived extracellular vesicles (HLSC-EV) have been demonstrated to reduce liver damage in different experimental settings by accelerating regeneration and by modulating inflammation. The aim of the present study was to investigate whether HLSC-EV may protect liver from IRI in a mouse experimental model. Segmental IRI was obtained by selective clamping of intrahepatic pedicles for 90 min followed by 6 h of reperfusion. HLSC-EV were administered intravenously at the end of the ischemic period and histopathological and biochemical alterations were evaluated in comparison with controls injected with vehicle alone. Intra liver localization of labeled HLSC-EV was assessed by in in vivo Imaging System (IVIS) and the internalization into hepatocytes was confirmed by fluorescence analyses. As compared to the control group, administration of 3 × 109 particles (EV1 group) significantly reduced alanine aminotransferase (ALT) and lactate dehydrogenase (LDH) release, necrosis extension and cytokines expression (TNF-α, CCL-2 and CXCL-10). However, the administration of an increased dose of HLSC-EV (7.5 × 109 particles, EV2 group) showed no significant improvement in respect to controls at enzyme and histology levels, despite a significantly lower cytokine expression. In conclusion, this study demonstrated that 3 × 109 HLSC-EV were able to modulate hepatic IRI by preserving tissue integrity and by reducing transaminases release and inflammatory cytokines expression. By contrast, a higher dose was ineffective suggesting a restricted window of biological activity.

Electroacupuncture stimulation at Yanglingquan acupoint ameliorates hepatic ischemia-reperfusion injury by down-regulating ET-1 to inhibit TAK1-JNK/p38 pathway

2021 ◽  
Author(s):  
Lai Wei ◽  
Yinyin Su ◽  
Siyou Tan ◽  
Yi Zou ◽  
Yixun Tang ◽  
...  
Keyword(s):  
Reperfusion Injury ◽  
Signaling Pathway ◽  
Caspase 3 ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Expression Patterns ◽  
Hepatic Ischemia ◽  
Tnf Α ◽  
Hepatic Ischemia Reperfusion ◽  
Liver Tissues

The current study set out to investigate the molecular mechanism of electroacupuncture (EA) stimulation at Yanglingquan acupoint (GB34) in hepatic ischemia-reperfusion injury (HIRI) in rats via regulation of the endothelin-1 (ET-1) mediated transforming growth factor-β-activated kinase-1 (TAK1)-c-Jun NH2-terminal kinase (JNK)/p38 signaling pathway. First, EA stimulation was applied to the constructed rat model of HIRI at GB34. Subsequently, the activities of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) and myeloperoxidase (MPO) in liver tissues were measured. Apoptotic changes in liver tissues in rats with HIRI were observed using TUNEL staining. Western blot assay was employed to determine the expression patterns of Bcl-2, Bax, c-caspase-3 and the activation of TAK1-JNK/p38 signaling pathway, and immunohistochemistry was conducted to determine the protein expression patterns of c-caspase-3 and ET-1. In addition, ELISA was performed to determine the levels of tumor necrosis factor-α (TNF-α), interleukin (IL)-1β and IL-6 in serum. The results demonstrated a significant decline in the activities of AST and ALT and hepatocyte apoptosis in rats with HIRI following EA stimulation. Meanwhile, EA stimulation brought about decreases in the expression levels of Bcl-2, Bax and c-caspase-3, MPO activity, TNF-α, IL-1β and IL-6 in serum, and diminished those of ET-1 in liver tissues, in addition to inhibiting the TAK1-JNK/p38 signaling pathway. Over-expression of ET-1 could counter the inhibitory effects of EA stimulation of HIRI in rats. Together, our findings indicate that EA stimulation at GB34 down-regulates the expression of ET-1, which inhibits the TAK1-JNK/p38 signaling pathway, consequently alleviating HIRI in rats.

Effect of Edaravone on MicroRNA Expression in Exosomes after Hepatic Ischemia-reperfusion Injury

2021 ◽  
Vol 14 ◽  
Author(s):  
Yanxia Fei ◽  
Jiali Shao ◽  
Ge Huang ◽  
Lijuan Wang ◽  
Shuangfa Zou ◽  
...  
Keyword(s):  
Protective Effect ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Quantitative Polymerase Chain Reaction ◽  
Inflammatory Factors ◽  
Enzyme Linked Immunosorbent Assay ◽  
Hepatic Ischemia ◽  
Second Generation Sequencing ◽  
Hepatic Ischemia Reperfusion

Background and Objective: Hepatic ischemia-reperfusion injury (HIRI) results in serious complications after liver resection and transplantation. Edaravone (ED) has a protective effect on IRI. This study was designed to evaluate whether ED could protect the liver of rats from HIRI injury and explored its exosomal miRNA-related mechanism. Methods: The sham group, hepatic ischemia/reperfusion (IR group), and hepatic ischemia/reperfusion + edaravone (ED group) models were established. We determined the protective effect of ED by measuring alanine aminotransferase (ALT), aspartate aminotransferase (AST), malondialdehyde (MDA), superoxide dismutase (SOD); enzyme-linked immunosorbent assay for tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β); hematoxylin-eosin staining and immunohistochemistry for histopathological changes. Exosomal miRNAs were subjected to second-generation sequencing to identify their differential expression. The results were analyzed using bioinformatics methods and validated using real-time quantitative polymerase chain reaction (RT-qPCR). Results: HIRI rats showed higher levels of ALT, AST, oxidative stress, and inflammatory markers; ED attenuated these effects. The sequencing results showed 6 upregulated and 13 downregulated miRNAs in the IR vs. sham groups, 10 upregulated and 10 downregulated miRNAs in the ED vs. IR groups. PC-3p-190-42101 was screened as an overlapping differentially expressed miRNA, and RT-qPCR validation showed that its expression in HIRI rats was significantly decreased; ED prevented this downregulation. Moreover, the expression of PC-3P-190-42101 was significantly correlated with the level of inflammatory factors. Conclusion: These findings indicate that ED can regulate the level of inflammatory factors by affecting the expression of miRNA PC-3p-190-42101 in plasma exosomes to protect the liver from IRI.

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