A comprehensive analysis of m6A/m7G/m5C/m1A-related gene expression and immune infiltration in liver ischemia-reperfusion injury by integrating bioinformatics and machine learning algorithms.

BACKGROUND: Liver ischemia-reperfusion injury (LIRI) is closely associated with immune infiltration, which commonly occurs after liver surgery, especially liver transplantation. Therefore, it is crucial to identify the genes responsible for LIRI and develop effective therapeutic strategies that target immune response. Methylation modifications in mRNA play various crucial roles in different diseases. This study aimed to identify potential methylation-related markers in patients with LIRI and evaluate the corresponding immune infiltration. METHODS: Two Gene Expression Omnibus datasets containing human liver transplantation data (GSE12720 and GSE151648) were downloaded for integrated analysis. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses were conducted to investigate the functional enrichment of differentially expressed genes (DEGs). Differentially expressed methylation-related genes (DEMRGs) were identified by overlapping DEG sets and 65 genes related to N6-methyladenosine (m6A), 7-methylguanine (m7G), 5-methylcytosine (m5C), and N1-methyladenosine (m1A). To evaluate the relationship between DEMRGs, a protein-protein interaction (PPI) network was utilized. The core DEMRGs were screened using three machine learning algorithms: least absolute shrinkage and selection operator, random forest, and support vector machine-recursive feature elimination. After verifying the diagnostic efficacy using the receiver operating characteristic curve, we validated the expression of the core DEMRGs in clinical samples and performed relative cell biology experiments. Additionally, the immune status of LIRI was comprehensively assessed using the single sample gene set enrichment analysis algorithm. The upstream microRNA and transcription factors of the core DEMRGs were also predicted. RESULTS: In total, 2165 upregulated and 3191 downregulated DEGs were identified, mainly enriched in LIRI-related pathways. The intersection of DEGs and methylation-related genes yielded 28 DEMRGs, showing high interaction in the PPI network. Additionally, the core DEMRGs YTHDC1, METTL3, WTAP, and NUDT3 demonstrated satisfactory diagnostic efficacy and significant differential expression and corresponding function based on cell biology experiments. Furthermore, immune infiltration analyses indicated that several immune cells correlated with all core DEMRGs in the LIRI process to varying extents. CONCLUSIONS: We identified core DEMRGs (YTHDC1, METTL3, WTAP, and NUDT3) associated with immune infiltration in LIRI through bioinformatics and validated them experimentally. This study may provide potential methylation-related gene targets for LIRI immunotherapy.

Nepetoidin B Alleviates Liver Ischemia/Reperfusion Injury via Regulating MKP5 and JNK/P38 Pathway.

Background: Nepetoidin B (NB) has been reported to possess anti-inflammatory, antibacterial, and antioxidant properties. However, its effects on liver ischemia/reperfusion (I/R) injury remain unclear. Methods: In this study, a mouse liver I/R injury model and a mouse AML12 cell hypoxia reoxygenation (H/R) injury model were used to investigate the potential role of NB. Serum transaminase levels, liver necrotic area, cell viability, oxidative stress, inflammatory response, and apoptosis were evaluated to assess the effects of NB on liver I/R and cell H/R injury. Quantitative polymerase chain reaction (qPCR) and Western blotting were used to measure mRNA and protein expression levels, respectively. Molecular docking was used to predict the binding capacity of NB and mitogen-activated protein kinase phosphatase 5 (MKP5). Results: The results showed that NB significantly reduced serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, liver necrosis, oxidative stress, reactive oxygen species (ROS) content, inflammatory cytokine content and expression, inflammatory cell infiltration, and apoptosis after liver I/R and AML12 cells H/R injury. Additionally, NB inhibited the JUN protein amino-terminal kinase (JNK)/P38 pathway. Molecular docking results showed good binding between NB and MKP5 proteins, and Western blotting results showed that NB increased the protein expression of MKP5. MKP5 knockout (KO) significantly diminished the protective effects of NB against liver injury and its inhibitory effects on the JNK/P38 pathway. Conclusion: NB exerts hepatoprotective effects against liver I/R injury by regulating the MKP5-mediated P38/JNK signaling pathway.

Oridonin attenuates liver ischemia-reperfusion injury by suppressing PKM2/NLRP3-mediated macrophage pyroptosis.

BACKGROUND: The NOD-like receptor protein 3 (NLRP3) mediated pyroptosis of macrophages is closely associated with liver ischemia reperfusion injury (IRI). As a covalent inhibitor of NLRP3, Oridonin (Ori), has strong anti-inflammasome effect, but its effect and mechanisms for liver IRI are still unknown. METHODS: Mice and liver macrophages were treated with Ori, respectively. Co-IP and LC-MS/MS analysis of the interaction between PKM2 and NLRP3 in macrophages. Liver damage was detected using H&E staining. Pyroptosis was detected by WB, TEM, and ELISA. RESULTS: Ori ameliorated liver macrophage pyroptosis and liver IRI. Mechanistically, Ori inhibited the interaction between pyruvate kinase M2 isoform (PKM2) and NLRP3 in hypoxia/reoxygenation（H/R）-induced macrophages, while the inhibition of PKM2/NLRP3 reduced liver macrophage pyroptosis and liver IRI. CONCLUSION: Ori exerted protective effects on liver IRI via suppressing PKM2/NLRP3-mediated liver macrophage pyroptosis, which might become a potential therapeutic target in the clinic.

Novel anti-inflammatory peptide alleviates liver ischemia-reperfusion injury.

Ischemia-reperfusion injury (IRI) remains inevitable in liver surgeries, macrophages play a critical role in the development of IRI, but little is known about the macrophages regulate pathogenesis of IRI. Based on target-guided screening, we identified a small 3 kDa peptide (SjDX5-271) from various schistosome egg-derived peptides that induced M2 macrophage polarization. SjDX5-271 treatment protected the mice against liver IRI through promoting M2 macrophage polarization, the protective effect was abrogated when the macrophages were depleted. Transcriptomic sequencing showed that the TLR signaling pathway was significantly inhibited in macrophages derived from the SjDX5-271 treatment group. We further identified that SjDX5-271 promotes M2 macrophage polarization by inhibiting the TLR4/MyD88/NF-κB signaling pathway and further alleviates hepatic inflammation in liver IRI. Collectively, SjDX5-271 exhibits promising therapeutic effects in IRI and represents a novel therapeutic approach for IRI, even in immune-related diseases. This study revealed the development of a new biologic from the parasite and enhanced our understanding of host-parasite interplay, providing a blueprint for future therapies for immune-related diseases.

Remimazolam relieved the injury of hypoxia/reperfusion treated human embryo liver cell line through the targeting METTL3 mediated m6A modification of P53.

Background: This study was performed to explore the role of Re in liver IRI progression. Hypoxia and reperfusion (H/R) treated human embryo liver cell line (L-02) was used to establish a liver IRI model. Materials and methods: Cell behaviors were detected using CCK-8, flow cytometry and TUNEL staining assays. The m6A content was detected using m6A dot blot assay. RT-qPCR and western blot assays were used to assessed the relative mRNA and protein levels. MeRIP assay was conducted to determine the m6A levels of P53. The relationship between METTL3 and P53 was demonstrated using RIP and dual-luciferase reporter assays. Results: The results showed that Re treatment significantly decreased the cell apoptosis and promoted the cell viability in the H/R treated L-02 cells. Besides, H/R treatment increased the METTL3 and m6A levels in the L-02 cells, and Re treatment decreased them. Additionally, METTL3 overexpression reversed the role of Re in the H/R treated L-02 cells. Mechanistically, METTL3 overexpression enhanced the m6A levels and mRNA stability and expressions of P53. The combination of METTL3 and P53 was further confirmed. Conclusion: In conclusion, this study demonstrated that Re treatment relieved the H/R induced injury in the L-02 cells through decreasing the METTL3 levels. METTL3 enhanced the mRNA stability and expressions of P53 through m6A modification. Re-METTL3-P53 axis might a new direction for the treatment of liver IRI in the future.

Proanthocyanidin Alleviates Liver Ischemia/Reperfusion Injury by Suppressing Autophagy and Apoptosis via the PPARα/PGC1α Signaling Pathway.

Background and Aims: Hepatic ischemia-reperfusion injury (IRI) is a common pathophysiological phenomenon in clinical practice, which usually occurs in liver transplantation, liver resection, severe trauma, and hemorrhagic shock. Proanthocyanidin (PC), exerted from various plants with antioxidant, antitumor, and antiaging activity, were administrated in our study to investigate the underlying mechanism of its protective function on IRI. Methods: Two doses of PC (50 mg/kg, 100 mg/kg) were given to BALB/c mice by intragastric administration for 7 days before partial (70%) warm IR surgery. Serum and liver tissues were collected 2, 8, and 24 h after reperfusion for relevant experiments. Results: The results of transaminase and hematoxylin and eosin staining indicated that PC pretreatment significantly alleviated IRI in mice. Serum total superoxide dismutase increased and malondialdehyde decreased in PC pretreatment groups. Enzyme-linked immunosorbent assays, western blotting, quantitative real-time polymerase chain reaction, and immunohistochemistry showed that inflammation, apoptosis, and autophagy in PC preprocessing groups were significantly inhibited and were dose-dependent. The protein, mRNA expression, and immunohistochemical staining results of peroxisome proliferator-activated receptor alpha (PPARα) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) in the PC pretreatment groups were significantly upregulated compared with the IR group in a dose-dependent manner. Conclusions: PC pretreatment suppressed inflammation, apoptosis, and autophagy via the PPAR-α signaling pathway to protect against IRI of the liver in mice.

TRIM37 exacerbates hepatic ischemia/reperfusion injury by facilitating IKKγ translocation.

BACKGROUND: Hepatic ischemia/reperfusion (I/R) injury is one of the major pathological processes associated with various liver surgeries. However, there is still a lack of strategies to protect against hepatic I/R injury because of the unknown underlying mechanism. The present study aimed to identify a potential strategy and provide a fundamental experimental basis for treating hepatic I/R injury. METHOD: A classic 70% ischemia/reperfusion injury was established. Immunoprecipitation was used to identify direct interactions between proteins. The expression of proteins from different subcellular localizations was detected by Western blotting. Cell translocation was directly observed by immunofluorescence. HE, TUNEL and ELISA were performed for function tests. RESULT: We report that tripartite motif containing 37 (TRIM37) aggravates hepatic I/R injury through the reinforcement of IKK-induced inflammation following dual patterns. Mechanistically, TRIM37 directly interacts with tumor necrosis factor receptor-associated factor 6 (TRAF6), inducing K63 ubiquitination and eventually leading to the phosphorylation of IKKß. TRIM37 enhances the translocation of IKKγ, a regulatory subunit of the IKK complex, from the nucleus to the cytoplasm, thereby stabilizing the cytoplasmic IKK complex and prolonging the duration of inflammation. Inhibition of IKK rescued the function of TRIM37 in vivo and in vitro. CONCLUSION: Collectively, the present study discloses some potential function of TRIM37 in hepatic I/R injury. Targeting TRIM37 might be potential for treatment against hepatic I/R injury.Targeting TRIM37 might be a potential treatment strategy against hepatic I/R injury.

Blackberry-Loaded AgNPs Attenuate Hepatic Ischemia/Reperfusion Injury via PI3K/Akt/mTOR Pathway.

Liver ischemia-reperfusion injury (IRI) is a pathophysiological insult that often occurs during liver surgery. Blackberry leaves are known for their anti-inflammatory and antioxidant activities. AIMS: To achieve site-specific delivery of blackberry leaves extract (BBE) loaded AgNPs to the hepatocyte in IRI and to verify possible molecular mechanisms. METHODS: IRI was induced in male Wister rats. Liver injury, hepatic histology, oxidative stress markers, hepatic expression of apoptosis-related proteins were evaluated. Non-targeted metabolomics for chemical characterization of blackberry leaves extract was performed. KEY FINDINGS: Pre-treatment with BBE protected against the deterioration caused by I/R, depicted by a significant improvement of liver functions and structure, as well as reduction of oxidative stress with a concomitant increase in antioxidants. Additionally, BBE promoted phosphorylation of antiapoptotic proteins; PI3K, Akt and mTOR, while apoptotic proteins; Bax, Casp-9 and cleaved Casp-3 expressions were decreased. LC-HRMS-based metabolomics identified a range of metabolites, mainly flavonoids and anthocyanins. Upon comprehensive virtual screening and molecular dynamics simulation, the major annotated anthocyanins, cyanidin and pelargonidin glucosides, were suggested to act as PLA2 inhibitors. SIGNIFICANCE: BBE can ameliorate hepatic IRI augmented by BBE-AgNPs nano-formulation via suppressing, oxidative stress and apoptosis as well as stimulation of PI3K/Akt/mTOR signaling pathway.

Gut Microbiota-Derived Glutamine Attenuates Liver Ischemia/Reperfusion Injury via Macrophage Metabolic Reprogramming.

BACKGROUND & AIMS: Many studies have revealed crucial roles of the gut microbiota and its metabolites in liver disease progression. However, the mechanism underlying their effects on liver ischemia/reperfusion (I/R) injury remain largely unknown. Here, we investigate the function of gut microbiota and its metabolites in liver I/R injury. METHODS: C57BL/6 mice was pretreated with an antibiotic cocktail. Then, we used multi-omics detection methods including 16s rRNA sequencing, ultra-performance liquid chromatography coupled to tandem mass spectrometry (UPLC-MS/MS) to explore the changes of gut microbiota and metabolites in both feces and portal blood to reveal the mechanism of their protective effect in liver I/R injury. RESULTS: We found that antibiotic pretreatment (ABX) could significantly reduce the severity of I/R-induced hepatic injury, and this effect could be transferred to germ-free mice by fecal microbiota transplantation (FMT), suggesting a protective role of the gut microbiota depletion. During I/R, the rates of serum α-ketoglutarate (αKG) production and glutamate reduction, downstream products of gut microbiota-derived glutamine, were more significant in the ABX mice. Then, we showed that αKG could promote alternative (M2) macrophage activation through oxidative phosphorylation, and oligomycin A could inhibit M2 macrophage polarization and reversed this protective effect. CONCLUSIONS: These findings show that the gut microbiota and its metabolites play critical roles in hepatic I/R injury by modulating macrophage metabolic reprogramming. Potential therapies that target macrophage metabolism, including antibiotic therapies and novel immunometabolism modulators, can be exploited for the treatment of liver I/R injury.

CD4+ T Cell NRF2 Signaling Improves Liver Transplantation Outcomes by Modulating T Cell Activation and Differentiation.

Aims: Innate and adaptive immune responses regulate hepatic ischemia-reperfusion injury (IRI) in orthotopic liver transplantation (OLT). While the mechanism of how nuclear factor erythroid 2-related factor 2 (NRF2) plays a role in liver IRI has been studied, the contribution of T cell-specific NRF2 in OLT remains unknown. In the current translational study, we investigated whether and how CD4+ T cell-specific NRF2 signaling affects liver transplant outcomes in mice and humans. Results: In the experimental arm, cold-stored (4°C/18 h) wild-type (WT) mouse livers transplanted to NRF2-deficient (NRF2-knockout [NRF2-KO]) recipients experienced greater hepatocellular damage than those in Nrf2-proficient (WT) counterparts, evidenced by Suzuki's histological scores, frequency of TdT-mediated dUTP nick end labeling (TUNEL)+ cells, and elevated serum aspartate aminotransferase/alanine aminotransferase (AST/ALT) levels. In vitro studies showed that NRF2 signaling suppressed CD4+ T cell differentiation to a proinflammatory phenotype (Th1, Th17) while promoting the regulatory (Foxp3+) T cell lineage. Furthermore, OLT injury deteriorated in immune-compromised RAG2-KO test recipients repopulated with CD4+ T cells from NRF2-KO compared with WT donor mice. In the clinical arm of 45 human liver transplant patients, the perioperative increase of NRF2 expression in donor livers negatively regulated innate and adaptive immune activation, resulting in reduced hepatocellular injury in NRF2-proficient OLT. Innovation and Conclusion: CD4+ T cell population expressing NRF2 attenuated ischemia and reperfusion (IR)-triggered hepatocellular damage in a clinically relevant mouse model of extended donor liver cold storage, followed by OLT, whereas the perioperative increase of NRF2 expression reduced hepatic injury in human liver transplant recipients. Thus, CD4+ T cell NRF2 may be a novel cytoprotective sentinel against IR stress in OLT recipients. Antioxid. Redox Signal. 38, 670-683.

Neutrophil extracellular traps regulating tumorimmunity in hepatocellular carcinoma.

As a component of the innate immune system, there is emerging evidence to suggest that neutrophils may play a critical role in the initiation and progression of hepatocellular carcinoma (HCC). Neutrophil extracellular traps (NETs) are web-like chromatin structures that protrude from the membranes during neutrophil activation. Recent research has shown that NETs, which are at the forefront of the renewed interest in neutrophil studies, are increasingly intertwined with HCC. By exploring the mechanisms of NETs in HCC, we aim to improve our understanding of the role of NETs and gain deeper insights into neutrophil biology. Therefore, this article provides a summary of key findings and discusses the emerging field of NETs in HCC.

FOXO1 Alleviates Liver Ischemia-reperfusion Injury by Regulating the Th17/Treg Ratio through the AKT/Stat3/FOXO1 Pathway.

Background and Aims: Hepatic ischemic reperfusion injury (IRI) occurring during surgery seriously affects patient prognosis. The specific mechanism of IRI has not been fully elucidated. The study aim was to explore the changes of inflammatory environment, and the relationship of the Th17/Treg cell ratio and FOXO1 expression in hepatic IRI. Methods: Liver samples at different ischemic times were collected from patients and mice. The expression of inflammatory markers and FOXO1 in the liver was detected by western blotting and qPCR. Phenotypic changes of liver lymphocytes were analyzed by flow cytometry. The AKT/Stat3/FOXO1 pathway was verified by targeting AKT with GSK2141795. The role of FOXO1 in liver inflammation and changes in lymphocyte phenotype was confirmed by upregulating FOXO1 with resveratrol. Results: Prolonged ischemic time aggravates liver injury in both humans and mouse models of hepatic IRI. IR-stress caused Th17/Treg imbalance and FOXO1 down-regulation by activating the AKT/Stat3/FOXO1 signaling pathway. Upregulation of FOXO1 reversed the Th17/Treg cytokine imbalance and altered the inflammation environment in the liver. Conclusions: Liver IRI induced Th17/Treg imbalance. Upregulation of FOXO1 reversed the imbalance and alleviated liver inflammation.

Isolongifolene alleviates liver ischemia/reperfusion injury by regulating AMPK-PGC1α signaling pathway-mediated inflammation, apoptosis, and oxidative stress.

Isolongifolene (ISO) has antioxidant, anti-inflammatory, anticancer, and neuroprotective effects; however, it is unclear whether ISO has a protective effects against liver ischemia/reperfusion (I/R) injury. In this study, a mouse liver I/R injury model and a mouse AML12 cell Hypoxia reoxygenation (H/R) model were established after pretreatment with different concentrations of ISO. Serum transaminase levels, necrotic liver area, cell viability, inflammation response, oxidative stress, and apoptosis were used to evaluate the effect of ISO on liver I/R or cell H/R injury. Western blotting was used to detect Bax, Bcl-2, C-Caspase3, AMPK, P-AMPK, and PGC1α protein expression levels. The AMPK inhibitor, compound C, was used to inhibit the AMPK expression. The results showed that ISO reduced serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, liver necrosis, inflammatory factors IL-1ß, IL-6, MCP-1, and TNF-α expression, MPO+ inflammatory cell infiltration, MDA content, TUNEL-positive cell number, cell apoptosis rate, and the expression of pro-apoptotic proteins Bax and C-Caspase3, while increasing cell viability, SOD and GSH activity, and the expression of anti-apoptotic protein Bcl-2. Moreover, Western blotting results showed that ISO could increase the protein expression of P-AMPK and PGC1α. Following the addition of compound C, the protective effect of ISO was significantly weakened. Therefore, our results suggest that ISO alleviates liver I/R injury by regulating AMPK-PGC1α signaling pathway-mediated anti-inflammatory, and antioxidant and anti-apoptotic effects.

Integrative analyses of genes related to liver ischemia reperfusion injury.

BACKGROUND: Liver ischemia reperfusion injury (LIRI) is not only a common injury during liver transplantation and major hepatic surgery, but also one of the primary factors that affect the outcome of postoperative diseases. However, there are still no reliable ways to tackle the problem. Our study aimed to find some characteristic genes associated with immune infiltration that affect LIRI, which can provide some insights for future research in the future. Therefore, it is essential for the treatment of LIRI, the elucidation of the mechanisms of LIRI, and exploring the potential biomarkers. Efficient microarray and bioinformatics analyses can promote the understanding of the molecular mechanisms of disease occurrence and development. METHOD: Data from GSE151648 were downloaded from GEO data sets, and we performed a comprehensive analysis of the differential expression, biological functions and interactions of LIRI-associated genes. Then we performed Gene ontology (GO) analysis and Kyotoencydlopedia of genes and genomes (KEGG) enrichment analysis of DEGs. At last, we performed a protein-protein interaction network to screen out hub genes. RESULTS: A total of 161 differentially expressed genes (DEGs) were identified. GO analysis results revealed that the changes in the modules were mostly enriched in the neutrophil degranulation, neutrophil activation involved in immune response, and neutrophil mediated immunity. KEGG enrichment analysis of DEGs demonstrated that LIRI mainly involved the cytokine-cytokine receptor interaction. Our data indicated that macrophages and neutrophils are closely related to LIRI. 9 hub genes were screened out in the protein-protein interaction network. CONCLUSIONS: In summary, our data indicated that neutrophil degranulation, neutrophil activation involved in immune response, neutrophil mediated immunity and cytokine-cytokine receptor interaction may play a key role in LIRI, HRH1, LRP2, P2RY6, PKD1L1, SLC8A3 and TNFRSF8, which were identified as potential biomarkers in the occurrence and development of LIRI. However, further studies are needed to validate these findings and explore the molecular mechanism of these biomarkers in LIRI.

Prussian Blue Scavenger Ameliorates Hepatic Ischemia-Reperfusion Injury by Inhibiting Inflammation and Reducing Oxidative Stress.

Oxidative stress and excessive inflammatory responses are the two critical mechanisms of hepatic ischemia-reperfusion injury (HIRI) encountered in many clinical settings, including following hepatectomy and liver transplantation. Effective anti-inflammatory and anti-oxidative pharmacological interventions are urgently needed to counter HIRI. The present study showed that a biocompatible Prussian blue (PB) scavenger with reactive oxygen species (ROS) scavenging and anti-inflammatory properties might be used a promising treatment for HIRI. Following intravenous administration, PB scavenger was mainly distributed in the liver, where it showed excellent ability to alleviate apoptosis, tissue injury and organ dysfunction after HIRI. PB scavenger was found to protect liver tissue by scavenging ROS, reducing neutrophil infiltration and promoting macrophage M2 polarization. In addition, PB scavenger significantly reduced oxidative stress in primary hepatocytes, restoring cell viability under oxidative stress condition. PB scavenger effectively reduced lipopolysaccharide-stimulated inflammation in RAW 264.7 cells. These findings indicate that PB scavenger may be a potential therapeutic agent for the treatment of HIRI, providing an alternative treatment for ROS-associated and inflammatory liver diseases.

Propionic Acid, Induced in Gut by an Inulin Diet, Suppresses Inflammation and Ameliorates Liver Ischemia and Reperfusion Injury in Mice.

Liver ischemia and reperfusion injury (IRI) is one of the obstacles in liver surgery such as liver resection and transplantation. In this study, we investigated the preventive effect on mouse liver IRI by feeding mice with inulin, which is a heterogeneous blend of indigestible fructose polymer. Mice were fed either a control ordinary diet (CD) or an inulin diet (ID) containing 5% inulin in the CD, for 14 days before the ischemia and reperfusion (IR) maneuver. IR induced-liver damages were significantly ameliorated in the ID group, compared with those in the CD group. Feeding mice with an ID, but not a CD, elevated levels of Bacteroidetes among gut microbiota, and especially increased Bacteroides acidifaciens in mouse feces, which resulted in significant elevation of short-chain fatty acids (SCFAs) in the portal vein of mice. Among SCFAs, propionic acid (PA) was most significantly increased. The microbial gene functions related to PA biosynthesis were much higher in the fecal microbiome of the ID group compared to the CD. However, the action of PA on liver IRI has not been yet clarified. Direct intraperitoneal administration of PA alone prior to the ischemia strongly suppressed liver cell damages as well as inflammatory responses caused by liver IR. Furthermore, PA suppressed the secretion of inflammatory cytokines from peritoneal macrophages stimulated in vitro through TLR-4 with high-mobility group box 1 protein (HMGB-1), known to be released from apoptotic liver cells during the IR insult. The present study shows that PA may play a key role in the inulin-induced amelioration of mouse liver IRI.

Role of the PI3K/Akt signaling pathway in liver ischemia reperfusion injury: a narrative review.

OBJECTIVE: To explore the role of phosphatidylinositol-3-kinase/protein kinase B and alpha serine/threonine protein kinase PI3K/PKB (also known as PI3K/Akt) signaling pathway in liver ischemia reperfusion injury. BACKGROUND: The PI3K/Akt signaling pathway is one of the major signal transduction pathways that regulates numerous cellular activities in vivo. The main functions of this pathway include induction of stem cell differentiation and metastasis, promotion of cell proliferation, inhibition of apoptosis, and regulation of tissue inflammation, tumor growth, and invasion. Liver ischemia reperfusion injury is an inevitable clinical problem that can occur during liver transplantation, liver resection, and various circulatory shock events, and it is one of the primary reasons for postoperative liver dysfunction, and poor disease outcome and patient prognosis. In recent years, it has been found that PI3K/Akt signaling pathway is closely related to liver ischemia reperfusion injury. METHODS: In this review, a large number of relevant literatures were collected to explain the biological basis of PI3K/Akt signaling pathway and its role in liver ischemia reperfusion injury. The review was based on a PubMed search using the terms "liver ischemia reperfusion injury", "PI3K/Akt signaling pathway", and "PI3K/Akt signaling pathway AND liver ischemia reperfusion injury", so as to understand the complex interaction between them. CONCLUSIONS: Activated PI3K/Akt signaling pathway can exert anti-inflammatory, antioxidant stress, anti-apoptosis and autophagy regulation effects through downstream related targeted pathways and proteins, thus alleviating liver ischemia-reperfusion injury. Therefore, the regulation of PI3K/Akt signaling pathway is expected to become an effective targeted pathway for clinical prevention and alleviation of liver ischemia reperfusion injury.

The role and function of CD4+ T cells in hepatic ischemia-reperfusion injury.

INTRODUCTION: Hepatic ischemia-reperfusion injury (IRI) is a severe complication frequently encountered in liver surgery, seriously affecting the therapeutic effects, tissue function. Various immune cells are involved in hepatic IRI, including macrophages, NKT cells, DCs, CD4 + T cells, and CD8 + T cells, among which CD4 + T cells play a critical role in this process. This article aims to summarize the functions and changes in various CD4 + T cell type counts and related cytokine levels in hepatic IRI and to review the possible mechanisms of mutual conversion between T cell types. AREAS COVERED: We have covered the functions and changes that occur in Th1, Th17, and Treg cells in liver IRI, as well as the pathways and factors associated with them. We also discuss the prospects of clinical application and future directions for therapeutic advances. EXPERT OPINION: This section explores the current clinical trials involving CD4 + T cells, especially Tregs, explains the limitations of their application, and summarizes the future development trends of cell engineering and their combination with the CAT technology. We also provide new ideas and therapeutic targets for alleviating liver IRI or other liver inflammatory diseases.

Aging deteriorated liver Ischemia and reperfusion injury by suppressing Tribble's proteins 1 mediated macrophage polarization.

Aggravated liver injury has been reported in aged ischemia/reperfusion-stressed livers; however, the mechanism of aged macrophage inflammatory regulation is not well understood. Here, we found that the adaptor protein TRIB1 plays a critical role in the differentiation of macrophages and the inflammatory response in the liver after ischemia/reperfusion injury. In the present study, we determined that aging promoted macrophage-mediated liver injury and that inflammation was mainly responsible for lower M2 polarization in liver transplantation-exposed humans post I/R. Young and aged mice were subjected to hepatic I/R modeling and showed that aging aggravated liver injury and suppressed macrophage TRIB1 protein expression and anti-inflammatory function in I/R-stressed livers. Restoration of TRIB1 is mediated by lentiviral infection-induced macrophage anti-inflammatory M2 polarization and alleviated hepatic I/R injury. Moreover, TRIB1 overexpression in macrophages facilitates M2 polarization and anti-inflammation by activating MEK1-ERK1/2 signaling under IL-4 stimulation. Taken together, our results demonstrated that aging promoted hepatic I/R injury by suppressing TRIB1-mediated MEK1-induced macrophage M2 polarization and anti-inflammatory function.

Long non-coding RNA MALAT1 aggravated liver ischemia-reperfusion injury via targeting miR-150-5p/AZIN1.

Long non-coding RNA (lncRNA) metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) plays a crucial role in the process of renal ischemia-reperfusion (IR) injury and myocardial IR injury. However, its mechanism in liver IR injury is not clear. IR and hypoxia/reoxygenation (H/R) model were built on C57BL/6 mice. Blood samples were obtained from the inferior vena cava of the model mice. MALAT1 expression was detected in IR model and H/R model. Supported by experimental results, the impacts of MALAT1 on viability, apoptosis, and inflammation of H/R model cells were detected. The correlation between MALAT1 and downstream genes was analyzed by mechanism assays. MALAT1 was detected to be upregulated in IR model and H/R model. MALAT1 knockdown had inhibitory effects on apoptosis and inflammatory reaction while promoting liver cell viability in H/R condition. Meanwhile, MALAT1 targeted miR-150-5p to regulate antizyme inhibitor 1 (AZIN1) in liver cells. Finally, MALAT1 regulated viability, apoptosis, and inflammatory reaction of liver cells by targeting miR-150-5p and AZIN1. To conclude, MALAT1 targeted miR-150-5p/AZIN1 to accelerate liver IR injury, suggesting that MALAT1 might be a novel target for liver IR injury.