scholarly journals Global proteome profiling of human livers upon ischemia/reperfusion treatment

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Haijian Cai ◽  
Shunli Qi ◽  
Qi Yan ◽  
Jun Ling ◽  
Jian Du ◽  
...  
Keyword(s):  
Proteomic Analysis ◽  
Metabolic Pathways ◽  
Inflammatory Responses ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Research Direction ◽  
Bioinformatic Analysis ◽  
Pringle Maneuver ◽  
Hepatic Ischemia ◽  
Hepatic Ischemia Reperfusion

AbstractHepatic ischemia/reperfusion (I/R) injury represents a major risk factor for liver transplantation and is related to graft dysfunction and acute/chronic rejection. However, a significant part of these processes remain poorly characterized. To reveal differences in the proteome during liver I/R injury, we collected human liver biopsy samples during hepatectomy before and after the Pringle maneuver and conducted a TMT-based proteomic analysis through quantitative high-throughput mass spectrometry. We used a fold-change threshold of 1.3 and a t-test p-value < 0.05 as the criteria to identify 5,257 total quantifiable proteins. The levels of 142 proteins were increased, while the levels of 103 proteins were decreased in response to hepatic I/R treatment. Bioinformatic analysis further revealed that these differentially expressed proteins are mainly involved in multiple biological functions and enzyme-regulated metabolic pathways. Most proteins whose expression was changed are related to the defense, immune and inflammatory responses as well as lipid and steroid metabolic processes. Based on this finding, we developed a panel for targeted proteomic analysis and used the parallel reaction monitoring (PRM) method, qPCR and western blotting experiments to validate alterations in the expression of some of the identified proteins. The upregulated proteins were found to be involved in immunity and inflammatory responses, and downregulated proteins were enriched in metabolic pathways. This study therefore may provide a research direction for the design of new therapeutic strategies for hepatic ischemia/reperfusion injury.

scholarly journals Danger-Associated Molecular Patterns (DAMPs): Molecular Triggers for Sterile Inflammation in the Liver

2018 ◽  
Vol 19 (10) ◽  
pp. 3104 ◽  
Author(s):  
Sabine Mihm
Keyword(s):  
Inflammatory Responses ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Sterile Inflammation ◽  
Type I Interferons ◽  
Neutrophil Granulocytes ◽  
Type I ◽  
Hepatic Ischemia ◽  
Hepatic Ischemia Reperfusion ◽  
Molecular Patterns

Inflammatory liver diseases in the absence of pathogens such as intoxication by xenobiotics, cholestatic liver injury, hepatic ischemia-reperfusion injury (I/R), non-alcoholic steatohepatitis (NASH), or alcoholic liver disease (ALD) remain threatening conditions demanding specific therapeutic options. Caused by various different noxae, all these conditions have been recognized to be triggered by danger- or death-associated molecular patterns (DAMPs), discompartmentalized self-structures released by dying cells. These endogenous, ectopic molecules comprise proteins, nucleic acids, adenosine triphosphate (ATP), or mitochondrial compounds, among others. This review resumes the respective modes of their release—passively by necrotic hepatocytes or actively by viable or apoptotic parenchymal cells—and their particular roles in sterile liver pathology. It addresses their sensors and the initial inflammatory responses they provoke. It further addresses a resulting second wave of parenchymal death that might be of different mode, boosting the release of additional, second-line DAMPs. Thus, triggering a more complex and pronounced response. Initial and secondary inflammatory responses comprise the activation of Kupffer cells (KCs), the attraction and activation of monocytes and neutrophil granulocytes, and the induction of type I interferons (IFNs) and their effectors. A thorough understanding of pathophysiology is a prerequisite for identifying rational therapeutic targets.

scholarly journals Differential Effects of Three Techniques for Hepatic Vascular Exclusion during Resection for Liver Cirrhosis on Hepatic Ischemia-Reperfusion Injury in Rats

2018 ◽  
Vol 2018 ◽  
pp. 1-10 ◽  
Author(s):  
Changjun Jia ◽  
Chaoliu Dai ◽  
Hailiang Wang ◽  
Yi Wan ◽  
Yunyu Qiao ◽  
...  
Keyword(s):  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Vascular Occlusion ◽  
Pringle Maneuver ◽  
Hepatic Ischemia ◽  
Necrosis Factor Alpha ◽  
Differential Effects ◽  
Vascular Exclusion ◽  
Hepatic Ischemia Reperfusion ◽  
Underlying Mechanisms

Background/Aims. Hepatic ischemia-reperfusion (I/R) injury is a serious concern during hepatic vascular occlusion. The objectives of this study were to assess effects of three techniques for hepatic vascular occlusion on I/R injury and to explore the underlying mechanisms. Methods. Liver cirrhotic rats had undertaken Pringle maneuver (PR), hemihepatic vascular occlusion (HH), or hepatic blood inflow occlusion without hemihepatic artery control (WH). Levels of tumor necrosis factor alpha (TNF-α), nuclear factor kappa B (NF-κB), toll-like receptor 4 (TLR4), TIR-domain-containing adapter-inducing interferon-β (TRIF), and hemeoxygenase 1 (HMOX1) were assayed. Results. The histopathologic analysis displayed that liver harm was more prominent in the PR group, but similar in the HH and WH groups. The HH and WH groups responded to hepatic I/R inflammation similarly but better than the PR group. Mechanical studies suggested that TNF-α/NF-κB signaling and TLR4/TRIF transduction pathways were associated with the differential effects. In addition, the HH and WH groups had significantly higher levels of hepatic HMOX1 (P<0.05) than the PR group. Conclusions. HH and WH confer better preservation of liver function and protection than the Pringle maneuver in combating I/R injury. Upregulation of HMOX1 may lead to better protection and clinical outcomes after liver resection.

scholarly journals MicroRNA-141-3p Attenuates Oxidative Stress-induced Hepatic Ischemia Reperfusion Injury via Keap1/Nrf2 Pathway

2021 ◽  
Author(s):  
Tingting Li ◽  
Qingsong Chen ◽  
Jiangwen Dai ◽  
Zuotian Huang ◽  
Yunhai Luo ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Liver Transplantation ◽  
Reperfusion Injury ◽  
Inflammatory Responses ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Hepatic Ischemia ◽  
Hepatic Ischemia Reperfusion

Abstract Hepatic ischemia reperfusion injury (IRI) is a major factor affecting the prognosis of liver transplantation through a series of severe cell death and inflammatory responses. MicroRNA-141-3p (miR-141-3p) has been reported to be associated with hepatic steatosis and other liver diseases. However, the potential role of miR-141-3p in hepatic IRI is currently unknown. In the present study, we found that miR-141-3p levels were negatively correlated with alanine aminotransferase (ALT)/aspartate aminotransferase (AST) in liver transplantation patients. The results demonstrated that miR-141-3p was decreased in mouse liver tissue after hepatic IRI in mice and in hepatocytes after hypoxia/reoxygenation (H/R). Overexpression of miR-141-3p directly decreased Kelch-like ECH-associated protein 1 (Keap1) levels and attenuated cell apoptosis in vivo and in vitro, while inhibition of miR-141-3p facilitated apoptosis. Further experiments revealed that overexpression of miR-141-3p also attenuated oxidative stress-induced damage in hepatocytes under H/R conditions. Taken together, our results indicate that miR-141-3p plays a major role in hepatic IRI through the Keap1 signaling pathway, and the present study suggests that miR-141-3p might have a protective effect on hepatic IRI to some extent.

scholarly journals Circular RNA Microarray Analyses in Hepatic Ischemia-Reperfusion Injury With Ischemic Preconditioning Prevention

2021 ◽  
Vol 8 ◽  
Author(s):  
Xinyao Tian ◽  
Yan Hu ◽  
Yuanxing Liu ◽  
Zhe Yang ◽  
Haiyang Xie ◽  
...  
Keyword(s):  
Reperfusion Injury ◽  
Ischemic Preconditioning ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Bioinformatic Analysis ◽  
Circular Rna ◽  
Vital Role ◽  
Protective Mechanisms ◽  
Hepatic Ischemia ◽  
Hepatic Ischemia Reperfusion

Ischemic preconditioning (IPC) represents an effective intervention to relieve hepatic ischemia-reperfusion injury (IRI). Systematic detection of circRNA expression revealing the protection effect of IPC still remains to be elucidated. Here, we applied a microarray to detect circRNA and mRNA expression in ischemic liver with and without IPC (n = 3 in each group). Compared with the sham group, there were 39 circRNAs and 432 mRNAs increased and 38 circRNAs and 254 mRNAs decreased (fold change ≥1.5, P &lt; 0.05) in the group of hepatic IRI. As the result of IPC intervention, 43 circRNAs and 64 mRNAs were increased, and 7 circRNAs and 31 mRNAs were decreased in the IPC group when compared with IRI. We then identified circRNA_017753 as the most possible target that may closely relate to IPC protective signaling and predicted Jade1 as the target related to circRNA_017753. Three possible circRNA–miRNA–mRNA axes were constructed that may play a vital role in protective mechanisms in IPC. The study for the first time systematically detects the dysregulated circRNAs and mRNAs in response to hepatic IRI and IPC intervention. Our profile and bioinformatic analysis provide numerous novel clues to understanding the pathophysiologic mechanism of IPC protection against hepatic IRI.

scholarly journals YAP-Dependent Induction of CD47-Enriched Extracellular Vesicles Inhibits Dendritic Cell Activation and Ameliorates Hepatic Ischemia-Reperfusion Injury

2021 ◽  
Vol 2021 ◽  
pp. 1-15
Author(s):  
Zenan Yuan ◽  
Linsen Ye ◽  
Xiao Feng ◽  
Tian Zhou ◽  
Yi Zhou ◽  
...  
Keyword(s):  
Reperfusion Injury ◽  
Cell Activation ◽  
Inflammatory Responses ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Dependent Manner ◽  
Dendritic Cell Activation ◽  
Iri Model ◽  
Hepatic Ischemia ◽  
Hepatic Ischemia Reperfusion

Hepatic ischemia-reperfusion injury (IRI) is the most common cause of liver damage leading to surgical failures in hepatectomy and liver transplantation. Extensive inflammatory reactions and oxidative responses are reported to be the major processes exacerbating IRI. The involvement of Yes-associated protein (YAP) in either process has been suggested, but the role and mechanism of YAP in IRI remain unclear. In this study, we constructed hepatocyte-specific YAP knockout (YAP-HKO) mice and induced a hepatic IRI model. Surprisingly, the amount of serum EVs decreased in YAP-HKO compared to WT mice during hepatic IRI. Then, we found that the activation of YAP increased EV secretion through F-actin by increasing membrane formation, while inhibiting the fusion of multivesicular body (MVB) and lysosomes in hepatocytes. Further, to explore the essential elements of YAP-induced EVs, we applied mass spectrometry and noticed CD47 was among the top targets highly expressed on hepatocyte-derived EVs. Thus, we enriched CD47+ EVs by microbeads and applied the isolated CD47+ EVs on IRI mice. We found ameliorated IRI symptoms after CD47+ EV treatment in these mice, and CD47+ EVs bound to CD172α on the surface of dendritic cells (DCs), which inhibited DC activation and the cascade of inflammatory responses. Our data showed that CD47-enriched EVs were released in a YAP-dependent manner by hepatocytes, which could inhibit DC activation and contribute to the amelioration of hepatic IRI. CD47+ EVs could be a potential strategy for treating hepatic IRI.

scholarly journals MD-2 is required for disulfide HMGB1–dependent TLR4 signaling

2015 ◽  
Vol 212 (1) ◽  
pp. 5-14 ◽  
Author(s):  
Huan Yang ◽  
Haichao Wang ◽  
Zhongliang Ju ◽  
Ahmed A. Ragab ◽  
Peter Lundbäck ◽  
...  
Keyword(s):  
Inflammatory Responses ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Chemical Toxicity ◽  
Hepatic Ischemia ◽  
Chemokine Production ◽  
Tlr4 Signaling ◽  
Hepatic Ischemia Reperfusion ◽  
Molecular Patterns ◽  
Myeloid Differentiation Factor

Innate immune receptors for pathogen- and damage-associated molecular patterns (PAMPs and DAMPs) orchestrate inflammatory responses to infection and injury. Secreted by activated immune cells or passively released by damaged cells, HMGB1 is subjected to redox modification that distinctly influences its extracellular functions. Previously, it was unknown how the TLR4 signalosome distinguished between HMGB1 isoforms. Here we demonstrate that the extracellular TLR4 adaptor, myeloid differentiation factor 2 (MD-2), binds specifically to the cytokine-inducing disulfide isoform of HMGB1, to the exclusion of other isoforms. Using MD-2–deficient mice, as well as MD-2 silencing in macrophages, we show a requirement for HMGB1-dependent TLR4 signaling. By screening HMGB1 peptide libraries, we identified a tetramer (FSSE, designated P5779) as a specific MD-2 antagonist preventing MD-2–HMGB1 interaction and TLR4 signaling. P5779 does not interfere with lipopolysaccharide-induced cytokine/chemokine production, thus preserving PAMP-mediated TLR4–MD-2 responses. Furthermore, P5779 can protect mice against hepatic ischemia/reperfusion injury, chemical toxicity, and sepsis. These findings reveal a novel mechanism by which innate systems selectively recognize specific HMGB1 isoforms. The results may direct toward strategies aimed at attenuating DAMP-mediated inflammation while preserving antimicrobial immune responsiveness.

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