Liver Ischemia-reperfusion Injury Research Articles

Ischemia-reperfusion Injury in Allogeneic Liver Transplantation: A Role of CD4 T Cells in Early Allograft Injury.

A major discrepancy between clinical and most experimental settings of liver ischemia-reperfusion injury (IRI) is the allogenicity. In the current study, we first established a murine model of allogeneic orthotopic liver transplantation with extended cold ischemia time (18 h). Roles of CD4 T cells in the pathogenesis of IRI in liver allografts were determined using a depleting anti-CD4 antibody. The clinical relevance of CD4 as a marker of liver IRI was analyzed retrospectively in 55 liver transplant patients. CD4 depletion in both donors and recipients resulted in the most effective protection of liver allografts from IRI, as measured by serum transaminase levels and liver histology. CD4 depletion inhibited IR-induced intragraft neutrophil/macrophage infiltration and proinflammatory gene expressions. Quantitative reverse-transcriptase polymerase chain reaction analysis of human liver biopsies (2 h postreperfusion) revealed that posttransplant, rather than pretransplant, CD4 transcript levels correlated positively with proinflammatory gene expression profile. When we divided patients into subgroups according to intragraft CD4 levels, the high CD4 cohort developed a more severe hepatocellular damage than that with low CD4 levels. CD4 T cells play a key pathogenic role in IRI of allogeneic liver transplants, and intragraft CD4 levels in the early postreperfusion phase may serve as a potential biomarker and therapeutic target to ameliorate liver IRI and improve orthotopic liver transplantation outcomes.

Effect of Sunitinib on Liver Oxidative and Proinflammatory Damage Induced by Ischemia-Reperfusion in Rats

Ischemia-reperfusion (IR) injury is defined as a complex pathologic process that begins with the oxygen deprivation of tissue, continues with the production of reactive oxygen radicals (ROS), and expands with an inflammatory response. This study investigates the protective effects of sunitinib, an anticancer drug with demonstrated antioxidant and anti-inflammatory activity, against liver IR damage. Our study aims to investigate the biochemical and histopathologic effects of sunitinib on IR-induced liver damage in rats. Albino Wistar male rats were divided into 3 groups: liver IR control (IR), 25 mg/kg sunitinib+liver IR (S+IR), and sham operation (SHAM). In the liver tissue of the IR group, oxidant and proinflammatory cytokine levels such as malondialdehyde, nuclear factor κ B, tumor necrosis factor-α, and interleukin-1β increased compared with the SHAM and S+IR groups. In addition, antioxidant levels such as total glutathione, glutathione reductase, and glutathione peroxidase were found to be significantly lower in the IR group than in the SHAM and S+IR groups. Although severe histopathologic damage was observed in the IR group, it was evaluated as mild in the S+IR group. The results obtained suggest that sunitinib may be helpful in the treatment of liver IR injury.

T-Cell Immunoglobulin and Mucin Domain-Containing Protein-4 Is Critical for Kupffer Cell Homeostatic Function in the Activation and Resolution of Liver Ischemia Reperfusion Injury.

Liver ischemia reperfusion injury (IRI) remains an unresolved clinical problem. This study dissected roles of liver-resident macrophage Kupffer cells (KCs), with a functional focus on efferocytosis receptor T-cell immunoglobulin and mucin domain-containing protein-4 (TIM-4), in both the activation and resolution of IRI in a murine liver partial warm ischemia model. Fluorescence-activated cell sorting results showed that TIM-4 was expressed exclusively by KCs, but not infiltrating macrophages (iMФs), in IR livers. Anti-TIM-4 antibody depleted TIM-4+ macrophages in vivo, resulting in either alleviation or deterioration of liver IRI, which was determined by the repopulation kinetics of the KC niche with CD11b+ macrophages. To determine the KC-specific function of TIM-4, we reconstituted clodronate-liposome-treated mice with exogenous wild-type or TIM-4-deficient KCs at either 0hour or 24hours postreperfusion. TIM-4 deficiency in KCs resulted in not only increases in the severity of liver IRI (at 6hours postreperfusion), but also impairment of the inflammation resolution (at 7days postreperfusion). In vitro analysis revealed that TIM-4 promoted KC efferocytosis to regulate their Toll-like receptor response by up-regulating IL-10 and down-regulating TNF-α productions. TIM-4 is critical for KC homeostatic function in both the activation and resolution of liver IRI by efferocytosis.

Rat Model Investigation on the Role of Biomarkers in Hepatic Ischemia-Reperfusion Injury.

Liver function is affected by ischemiareperfusion. Ischemia-reperfusion injury to the liver often follows hepatobiliary surgery. Here, we investigated biomarkers of liver ischemia-reperfusion injury using an animal model. For this study, 24 male Sprague Dawley rats (146-188 g) were divided into 4 groups: group A was the control group, group B was the partial hepatic ischemia-reperfusion group, group C was the total hepatic ischemia-reperfusion group, and group D was the intermittent total hepatic ischemiareperfusion group. Laboratory liver function levels were measured before ischemia, after ischemia, and after reperfusion. We used liver and renal biopsies for histopathological examination at the end of the study. After clamping and reperfusion, alanine aminotransferase and cystatin C levels in groups B, C, and D were significantly higher than levels in group A. In group B, after clamping, neutrophil gelatinaseassociated lipocalin levels were higher than in groups A and D, with significantly higher level than in group D after reperfusion. Neutrophil gelatinase-associated lipocalin levels decreased significantly in groups B, C, and D after reperfusion. There was significantly greater hepatic damage in groups B, C, and D compared with group A but no significant differences in renal injury scores among the groups. There was a significant positive correlation between hepatic damage and renal injury. With regard to histopathological examination versus laboratory results, a statistically significant positive correlation was shown between grade of hepatic damage and serum alanine aminotransferase and cystatin C levels. Similarly, there was a positive correlation between renal damage score and alanine aminotransferase level. In our animal model, alanine amino - transferase and cystatin C levels tended to increase with ischemia-reperfusion injury levels but neutrophil gelatinase-associated lipocalin decreased during reperfusion. In liver ischemia, we suggest that neutrophil gelatinase-associated lipocalin may be an important biomarker for distinguishing the reperfusion phase.

Dual Versus Single Oxygenated Hypothermic Machine Perfusion of Porcine Livers: Impact on Hepatobiliary and Endothelial Cell Injury.

Hypothermic oxygenated machine perfusion (HOPE) reduces ischemia-reperfusion injury of donor livers and is increasingly used in clinical transplantation. However, it remains unclear whether perfusion via the portal vein alone (HOPE) or via both the portal vein and hepatic artery (dual HOPE or DHOPE) is superior. Twelve porcine livers donated after circulatory death were randomized for 2 h of HOPE (n = 6) or DHOPE (n = 6), followed by 4 h of warm reperfusion with whole blood, to mimic transplantation. Hepatobiliary and endothelial cell function and injury markers were determined in perfusate and bile samples. Biopsies of bile ducts, hepatic arteries, and liver parenchyma were collected to assess histological damage and the expression of endothelial protective genes (KLF-2, eNOS, ET-1, CD31, VWF, VEGF-A). There were no differences in hepatobiliary function and injury after warm reperfusion between the groups, apart from a 2-fold lower concentration of alanine aminotransferase in the perfusate (P = 0.045) and a lower peak lactate dehydrogenase in bile (P = 0.04) of livers preserved by DHOPE. Endothelial cell function and injury, as assessed by perfusate nitric oxide and von Willebrand factor antigen levels, as well as endothelial protective gene expressions, were similar between the groups. The hepatic arteries of both groups showed no microscopic evidence of injury. This study did not reveal major differences in hepatobiliary or endothelial function and injury after preservation by single or dual HOPE of porcine livers donated after circulatory death.

Protective effect of ischemic postconditioning on ischemia reperfusion injury in steatotic rat livers.

BackgroundHepatic steatosis creates a significant risk of liver resection and transplantation and is extremely susceptible to ischemia/reperfusion (I/R) injury. Ischemic postconditioning (IPostC) has been shown to attenuate I/R injury in normal livers; however, its role in steatotic livers remains unknown. The current study sought to explore whether IPostC could attenuate normothermic I/R injury in rats with steatotic livers and to investigate potential protective measures.MethodsHepatic steatosis was triggered in Wistar rats fed high-fat diets. The role of IPostC was detected in normal and steatotic livers with 30 min of ischemia and 6 h of reperfusion. Blood and liver tissues were collected to assess hepatocyte damage, lipid peroxidation, inflammatory factors, neutrophil accumulation, and adenosine triphosphate (ATP) content.ResultsCompared to normal livers, steatotic livers were more susceptible to I/R damage, as evidenced by incremental concentrations of liver enzymes in the blood and more severe pathological changes in the liver. Hepatic I/R injury was significantly reduced by IPostC in both normal and steatotic livers. We further found that endogenous protective measures moderated lipid peroxidation, inflammatory cytokine expression and neutrophil accumulation, and reduced follow-up hepatic injury. The ATP content of steatotic livers was also significantly lower than that of Normal livers before and after I/R injury. IPostC greatly preserved the ATP content of normal and steatotic livers with I/R injury.ConclusionsIPostC appears to provide important protection against hepatic I/R injury in normal and steatotic livers under normothermic conditions. These data have important clinical implications for liver surgery and transplantation.

New Insights in Mechanisms and Therapeutics for Short- and Long-Term Impacts of Hepatic Ischemia Reperfusion Injury Post Liver Transplantation.

Liver transplantation has been identified as the most effective treatment for patients with end-stage liver diseases. However, hepatic ischemia reperfusion injury (IRI) is associated with poor graft function and poses a risk of adverse clinical outcomes post transplantation. Cell death, including apoptosis, necrosis, ferroptosis and pyroptosis, is induced during the acute phase of liver IRI. The release of danger-associated molecular patterns (DAPMs) and mitochondrial dysfunction resulting from the disturbance of metabolic homeostasis initiates graft inflammation. The inflammation in the short term exacerbates hepatic damage, leading to graft dysfunction and a higher incidence of acute rejection. The subsequent changes in the graft immune environment due to hepatic IRI may result in chronic rejection, cancer recurrence and fibrogenesis in the long term. In this review, we mainly focus on new mechanisms of inflammation initiated by immune activation related to metabolic alteration in the short term during liver IRI. The latest mechanisms of cancer recurrence and fibrogenesis due to the long-term impact of inflammation in hepatic IRI is also discussed. Furthermore, the development of therapeutic strategies, including ischemia preconditioning, pharmacological inhibitors and machine perfusion, for both attenuating acute inflammatory injury and preventing late-phase disease recurrence, will be summarized in the context of clinical, translational and basic research.

The protective effect of isoflurane pretreatment on liver IRI by suppressing noncanonical pyroptosis of liver macrophages

BackgroundLiver ischaemia–reperfusion injury (IRI) is a major complication in the perioperative period and often leads to liver failure and even systemic inflammation. Sufficient evidence has demonstrated that isoflurane has anti-inflammatory effects. We aimed to determine whether isoflurane pretreatment protects against liver IRI and to investigate the mechanisms involved in this protection. MethodsMale C57BL/6 mice were pretreated with or without isoflurane and subjected to 90 min of 70% liver ischaemia, followed by reperfusion for 6 h. Liver tissues and serum were analysed to assess liver IRI. To probe the mechanisms, liver macrophages isolated from C57BL/6 mice were pretreated with or without emulsified isoflurane for 30 min before incubation with 1 µg/ml lipopolysaccharide (LPS) for 24 h. Inflammatory cytokine production, intracellular Ca2+ levels, caspase-11 expression, NF-κB transcription, and NLRP3 inflammasome activation were assessed by ELISA, an intracellular Ca2+ concentration assay, immunohistochemistry, or Western blotting. ResultsIsoflurane preconditioning significantly relieved liver IRI in mice and LPS-induced inflammation in liver macrophages. Additionally, isoflurane pretreatment inhibited caspase-11 expression and noncanonical pyroptosis-related production of cytokines (IL-1β and IL-18). Interestingly, isoflurane preconditioning reduced intracellular Ca2+ levels, NF-κB translocation, and NLRP3 inflammasome activation in LPS-induced macrophages. Our results indicated that isoflurane preconditioning ameliorated liver IRI by suppressing noncanonical pyroptosis in liver macrophages. These findings suggest that isoflurane could be a pharmacological agent for liver IRI prevention and thus deserves more attention and further investigation.

Rosuvastatin alleviated the liver ischemia reperfusion injury by activating the expression of peroxisome proliferator-activated receptor gamma (PPARγ).

Liver ischemia and reperfusion could cause serious damage to liver tissues. Abnormal liver function could induce serious damage and threaten human health. Evidence emerged to suggest that rosuvastatin could relieve cerebral ischemia-reperfusion injury and alleviate the disease related to vessels by activating the expression of PPARγ. However, whether rosuvastatin could relieve the liver ischemia reperfusion injury by enhancing the expression of PPARγ is unclear. For the strictness of experimental findings, we established both the rat models and the cell model of liver ischemia reperfusion injury by respectively treating rats and cells with rosuvastatin. PPARγ inhibitor was also used for the stimulation of these cells and rats. Reactive oxygen species (ROS) levels, apoptosis and related protein levels were determined with ROS staining, ROS staining and western blotting for the detection of injury induced by oxygen-glucose deprivation and re-oxygenation (OGD/R). Pretreatment of rosuvastatin promoted the expression of PPARγ in liver tissues and MIHA cells. It also inhibited the ischemia reperfusion and OGD/R induced production of ROS while promoted the release of SOD in liver tissues and MIHA cells. Furthermore, rosuvastatin also alleviated the ischemia reperfusion -induced apoptosis of liver tissues and OGD/R-induced MIHA cells apoptosis. However, application of PPARγ inhibitor abolished the restorative effects of rosuvastatin on the apoptosis and oxidative stress on liver tissues and MIHA cells. Rosuvastatin prevented the liver ischemia reperfusion injury of rats by activating PPARγ.

FBXW5 aggravates hepatic ischemia/reperfusion injury via promoting phosphorylation of ASK1 in a TRAF6-dependent manner

Liver ischemia/reperfusion injury (IRI) is an inevitable pathological process exacerbating the occurrence of rejection in liver transplantation. At present, there is still a lack of sufficient cognition for the mechanism as well as effective clinical strategies. F-box/WD repeat-containing protein 5 (FBXW5), a key modulator of stress signalling, was recently reported to participate in hepatic immunity. However, the role of FBXW5 in liver IRI is still unclear. In the present study, we found expression of FBXW5 was increased in liver IRI both in vivo and in vitro. Inhibition of FBXW5 significantly alleviated both mitogen-activated protein kinase (MAPK) and inhibitor of nuclear factor kappa-B kinase (IKK) pathways, thus resulting in cytokine release, hepatic pathological injury and apoptosis. Over-expression of FBXW5 achieved an opposite effect. Investigations on the mechanism showed that FBXW5 intensified hepatic inflammation by promoting phosphorylation of ASK1, while blockade of TRAF6 could abolish this process. Moreover, reinforce of mTOR amplified the anti-inflammatory efficacy derived from inhibition of FBXW5, indicating the function of FBXW5/ASK1/TRAF6 axis in hepatic IRI might be relatively independent of mTOR-guided M2 polarization of Kupffer cell. Taken together, FBXW5 could be a key accelerator in liver IRI by enhancing activation of ASK1 in a TRAF6-dependent manner. The joint intervention towards both FBXW5 and mTOR might be a promising strategy to protect liver from IRI.

The Effects of Esmolol on Erythrocyte Deformability in Rat Liver Ischemia-Reperfusion Injury

The Effects of Esmolol on Erythrocyte Deformability in Rat Liver Ischemia-Reperfusion Injury

Dendritic Cell-Mediated Regulation of Liver Ischemia-Reperfusion Injury and Liver Transplant Rejection.

Liver allograft recipients are more likely to develop transplantation tolerance than those that receive other types of organ graft. Experimental studies suggest that immune cells and other non-parenchymal cells in the unique liver microenvironment play critical roles in promoting liver tolerogenicity. Of these, liver interstitial dendritic cells (DCs) are heterogeneous, innate immune cells that appear to play pivotal roles in the instigation, integration and regulation of inflammatory responses after liver transplantation. Interstitial liver DCs (recruited in situ or derived from circulating precursors) have been implicated in regulation of both ischemia/reperfusion injury (IRI) and anti-donor immunity. Thus, livers transplanted from mice constitutively lacking DCs into syngeneic, wild-type recipients, display increased tissue injury, indicating a protective role of liver-resident donor DCs against transplant IRI. Also, donor DC depletion before transplant prevents mouse spontaneous liver allograft tolerance across major histocompatibility complex (MHC) barriers. On the other hand, mouse liver graft-infiltrating host DCs that acquire donor MHC antigen via “cross-dressing”, regulate anti-donor T cell reactivity in association with exhaustion of graft-infiltrating T cells and promote allograft tolerance. In an early phase clinical trial, infusion of donor-derived regulatory DCs (DCreg) before living donor liver transplantation can induce alterations in host T cell populations that may be conducive to attenuation of anti-donor immune reactivity. We discuss the role of DCs in regulation of warm and liver transplant IRI and the induction of liver allograft tolerance. We also address design of cell therapies using DCreg to reduce the immunosuppressive drug burden and promote clinical liver allograft tolerance.

CD47-Mediated Hedgehog/SMO/GLI1 Signaling Promotes Mesenchymal Stem Cell Immunomodulation in Mouse Liver Inflammation.

The cluster ofdifferentiation 47 (CD47)-signal regulatory protein alpha (SIRPα) signaling pathway plays important roles in immune homeostasis and tissue inflammatory response. Activation of the Hedgehog/smoothened (SMO)/GLI family zinc finger 1 (Gli1) pathway regulates cell growth, differentiation, and immune function. However, it remains unknown whether and how the CD47-SIRPα interaction may regulate Hedgehog/SMO/Gli1 signaling in mesenchymal stem cell (MSC)-mediated immune regulation during sterile inflammatory liver injury. In a mouse model of ischemia/reperfusion (IR)-induced sterile inflammatory liver injury, we found that adoptive transfer of MSCs increased CD47 expression and ameliorated liver IR injury. However, deletion of CD47 in MSCs exacerbated IR-induced liver damage, with increased serum ALT levels, macrophage/neutrophil infiltration, and pro-inflammatory mediators. MSC treatment augmented SIRPα, Hedgehog/SMO/Gli1, and Notch1 intracellular domain (NICD), whereas CD47-deficient MSC treatment reduced these gene expressions in IR-stressed livers. Moreover, disruption of myeloid SMO or Notch1 increased IR-triggered liver inflammation with diminished Gli1 and NICD, but enhanced NIMA related kinase 7 (NEK7) and NLR family pyrin domain containing 3 (NLRP3) activation in MSC-transferred mice. Using a MSC/macrophage co-culture system, we found that MSC CD47 and macrophage SIRPα expression were increased after LPS stimulation. The CD47-SIRPα interaction increased macrophage Gli1 and NICD nuclear translocation, whereby NICD interacted with Gli1 and regulated its target gene Dvl2 (dishevelled segment polarity protein 2), which in turn inhibited NEK7/NLRP3 activity. The CD47-SIRPα signaling activates the Hedgehog/SMO/Gli1 pathway, which controls NEK7/NLRP3 activity through a direct interaction between Gli1 and NICD. NICD is a coactivator of Gli1, and the target gene Dvl2 regulated by the NICD-Gli1 complex is crucial for the modulation of NLRP3-driven inflammatory response in MSC-mediated immune regulation. Our findings provide potential therapeutic targets in MSC-mediated immunotherapy of sterile inflammatory liver injury.

Cellular communication network factor 1 (CCN1) knockdown exerts a protective effect for hepatic ischemia/reperfusion injury by deactivating the MEK/ERK pathway

ObjectiveHepatic ischemia/reperfusion injury (IRI) is an unsettled and intractable conundrum in clinical treatment after liver transplantation and resection. Cellular communication network factor 1 (CCN1) is upregulated in liver IRI and may play a key role in this process. The objective of this study is to investigate the regulatory mechanism of CCN1 in liver IRI, which may provide new insight into liver IRI clinical treatment. MethodsThe hepatic ischemia/reperfusion model was established in male C57BL/6 mice by occlusion of vessels in the liver followed by reperfusion. The mice were transfected with two small interfering RNAs (siRNAs) against CCN1 for CCN1 knockdown. The hypoxia/reoxygenation (HR) model was established in vitro using mouse hepatic cells followed by transfection with a siRNA and treatment with an ERK activator TPA to confirm the effects of CCN1 on the MEK/ERK pathway in liver IRI. ResultsIn hepatic IRI, CCN1 was upregulated and its knockdown reduced alanine aminotransferase and aspartate transaminase levels, myeloperoxidase activity, and the levels of IL-6 and TNF-α. CCN1 downregulation alleviated inflammatory cell infiltration and apoptosis in the liver. The expressions of cleaved caspase-9, cleaved caspase-3, Bax, and CHOP were decreased with an increased Bcl-2 level after CCN1 knockdown. The phosphorylation and activation of proteins in ER stress and MEK/ERK pathway were inhibited by CCN1 knockdown. In vitro, the levels of proinflammatory cytokines, apoptosis-inducing proteins, and proteins in ER stress and MEK/ERK pathway, which were decreased by CCN1 knockdown in HR, were restored by TPA, confirming that the activation of ERK aggravated cell apoptosis after reoxygenation. ConclusionOverall, CCN1 knockdown may suppress the inflammation, apoptosis during hepatic IRI by reducing the MEK/ERK pathway activation, which may be a breakthrough point in clinical alleviation of hepatic IRI caused by liver transplantation and resection.

Augmenter of liver regeneration ameliorates ischemia-reperfusion injury in steatotic liver via inhibition of the TLR4/NF-κB pathway.

Hepatocytes from donors with preexisting hepatic steatosis exhibited increased sensitivity to ischemia-reperfusion injury (IRI) during liver transplantation. Augmenter of liver regeneration (ALR) protected the liver against IRI, but the mechanism was not clarified. Therefore, the hypothesis that ALR attenuated IRI in steatotic liver by inhibition of inflammation and downregulation of the Toll-like receptor 4 (TLR4)/nuclear factor-κB (NF-κB) pathway was examined. C57BL/6 mice were subjected to a methionine-choline-deficient (MCD) diet to induce liver steatosis. Mice were transfected with ALR-containing adenovirus 3 days prior to partial warm hepatic IRI. After 30 min of ischemia and 6 h of reperfusion injury, liver function, hepatic injury, the inflammatory response and TLR4/NF-κB signaling pathway activation were assessed. ALR maintained liver function and alleviated hepatic injury as indicated by the decreased levels of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST), preserved hepatic structure and reduced apoptosis. ALR also reduced the IRI-induced inflammatory response by suppressing Kupffer cell activation, inhibiting neutrophil chemotaxis and reducing inflammatory cytokine production. Further investigation using reverse transcription-quantitative PCR, western blotting and immunohistochemistry revealed that ALR reduced TLR4/NF-κB signaling pathway activation, which led to a decreased synthesis of inflammatory cytokines. ALR functioned as a regulator of the IRI-induced inflammatory response by suppressing the TLR4/NF-κB pathway, which supports the use of ALR in therapeutic applications for fatty liver transplantation.

Histidine-Rich Glycoprotein Alleviates Liver Ischemia/Reperfusion Injury in Mice With Nonalcoholic Steatohepatitis.

Hepatic ischemia/reperfusion injury (IRI) is a major complication of liver surgery and transplantation, especially in patients with nonalcoholic steatohepatitis (NASH). The mechanism of NASH susceptibility to IRI has not been fully clarified. We investigated the role of liver-produced histidine-rich glycoprotein (HRG) in NASH IRI. A NASH mouse model was established using C57BL/6J mice fed a methionine-choline-deficient diet (MCDD) for 6weeks. The MCDD and standard diet groups were exposed to 60minutes of partial hepatic ischemia/reperfusion (I/R). We further evaluated the impact of HRG in this context using HRG knockdown (KD) mice. IRI increased HRG expression in the standard diet group, but not in the MCDD group after I/R. HRG expression was inversely correlated with neutrophil infiltration and the formation of neutrophil extracellular traps (NETs). HRG KD mice showed severe liver injury with neutrophil infiltration and the formation of NETs. Pretreatment with supplementary HRG protected against I/R with the inhibition of neutrophil infiltration and the formation of NETs. In vitro, hepatocytes showed that the expression of HRG was upregulated under hypoxia/reoxygenation conditions, but not in response to oleic acid-treated hepatocytes. The decrease in HRG expression in fatty hepatocytes was accompanied by decreased farnesoid X receptor and hypoxia inducible factor 2 alpha subunit expression. HRG is a hepatoprotective factor during hepatic IRI because it decreases neutrophil infiltration and the formation of NETs. The decrease in HRG is a cause of susceptibility to IRI in steatotic livers. Therefore, HRG is a new therapeutic target for minimizing liver damage in patients with NASH.

A meta-analysis and systematic review of propofol on liver ischemia-reperfusion injury protection during hepatocellular carcinoma anesthesia surgery.

At present, liver cancer deaths of China account for about half of the global liver cancer deaths. The most common physiological change in anesthesia surgery for liver cancer is liver ischemia-reperfusion injury (LIRI). The Chinese and English medical databases were searched using a combination of the following search terms: "propofol", "liver cancer", "anesthesia surgery", and "ischemia reperfusion injury" in Chinese or English language, respectively. The articles taking patients received propofol intravenous anesthesia surgery for LIRI in the experimental group and patients received intravenous anesthesia with non-propofol drugs for LIRI in the control group were searched. Rev Man 5.3 software was used for meta-analysis. A total of 18 articles were included, and most were considered to have low-risk bias (that is, medium- and high-quality publications). The meta-analysis results indicated that the superoxide dismutase (SOD) levels from the blockage of the hepatic hilum (B-HH) to the 15-minute opening of the hepatic hilum (O-HH) showed a mean deviation (MD) of -0.33 nU/mL and 95% confidential interval (CI) of -1.81 to 1.15 nmol/L (P<0.05). The levels of malondialdehyde (MDA) from B-HH to O-HH showed a MD of 1.80 nmol/L and 95% CI of 1.53 to 2.07 nmol/l (P<0.05). The MD of alanine transaminase (ALT) levels from B-HH to O-HH was 8.24 IU/L with 95% CI 6.43 to 10.06 IU/L (P<0.05). The MD of aspartate transaminase (AST) levels from B-HH to O-HH was -11.73 IU/L with 95% CI -14.04 to -9.43 IU/L (P<0.05). The RevMan5.3 software was used to draw the funnel chart for each indicator from B-HH to OHH. The results revealed that the circles in some articles were concentrated on the midline and were basically symmetrical with the midline, indicating that the research accuracy was high and there was no bias in publication. This meta-analysis confirmed that propofol exerted a protective effect on LIRI during anesthesia surgery with hepatic hilar blockade.

Protective effect of Coriandrum sativum extract against inflammation and apoptosis in liver ischaemia/reperfusion injury.

The aim of this study was to investigate the anti-inflammatory and antioxidant effects of Coriandrum sativum extract on liver ischaemia reperfusion injury at light microscopic and biochemical levels. Sham, ischaemia/reperfusion injury (IRI), IRI + Coriandrum sativum extract and only Coriandrum sativum extract groups were formed. Sixty minutes of ischaemia and 60 minutes of reperfusion were performed. In the treatment group, 300 mg/kg/day Coriandrum sativum was given by gavage. Hepatic tissues were fixed in 4% paraformaldehyde. Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP) enzymes were measured. Nuclear factor-kappa beta (NF-κB), tumour necrosis factor-alpha (TNF-α) and caspase-3 immunohistochemistry staining was performed. Microscopic scoring was performed in terms of sinusoidal congestion, vacuolisation, and necrosis. Sinusoidal enlargement and diffuse congestion, Kupffer cell increase, neutrophil increase in necrotic areas, vacuolisation in hepatocytes, and bile duct proliferation in the portal triad were observed in ischaemia/reperfusion hepatic tissue. Very rare, necrotic areas were observed in the Coriandrum sativum treatment group, while congestion and vacuolisation and bile duct proliferation were decreased compared to the ischaemic group. The AST and ALT levels were increased in the IRI and IRI + Coriandrum sativum groups. When compared to the IRI group, the AST and ALT levels of the Coriandrum sativum were considerably decreased. The IRI and IRI + Coriandrum sativum groups had statistically significant differences in ALP compared to that of the Coriandrum sativum and Sham groups. There was no significant difference between the ALP levels of the IRI and IRI + Coriandrum sativum groups TNF-α, NF-κB and caspase-3 immune positive stained hepatocytes were numerous and widely observed in the injury group. There were positive TNF-α immunohistochemical staining Kupffer cells in the IRI group. In the group treated with Coriandrum sativum, Kupffer cells were not stained, while TNF-α, NF κB and caspase-3 expressing hepatocytes were found to be decreased compared to the IRI group. When the expression values of the TNF-α, NF-κB and caspase-3 groups were evaluated statistically, it was seen that there was a significant decrease in the group treated with Coriandrum sativum. It was found that Coriandrum sativum extract decreased proinflammatory cytokine TNF-α and apoptotic cell death and liver enzymes in liver ischaemia/reperfusion injury.

Direct, remote and combined ischemic conditioning in liver surgery.

Liver ischemia-reperfusion injury is a major cause of postoperative liver dysfunction, morbidity and mortality following liver resection and transplantation. Ischemic conditioning has been shown to ameliorate ischemia-reperfusion injury in small animal models. It can be applied directly or remotely when cycles of ischemia and reperfusion are applied to a distant site or organ. Considering timing of the procedure, different protocols are available. Ischemic preconditioning refers to that performed before the duration of ischemia of the target organ. Ischemic perconditioning is performed over the duration of ischemia of the target organ. Ischemic postconditioning applies brief episodes of ischemia at the onset of reperfusion following a prolonged ischemia. Animal studies pointed towards suppressing cytokine release, enhancing the production of hepatoprotective adenosine and reducing liver apoptotic response as the potential mechanisms responsible for the protective effect of direct tissue conditioning. Interactions between neural, humoral and systemic pathways all lead to the protective effect of remote ischemic preconditioning. Despite promising animal studies, none of the aforementioned protocols proved to be clinically effective in liver surgery with the exception of morbidity reduction in cirrhotic patients undergoing liver resection. Further human clinical trials with application of novel conditioning protocols and combination of methods are warranted before implementation of ischemic conditioning in day-to-day clinical practice.

Nanozyme Impregnated Mesenchymal Stem Cells for Hepatic Ischemia-Reperfusion Injury Alleviation.

Mesenchymal stem cell (MSC) based therapy holds great potential for treating numerous diseases owing to their capability to heal injured tissue/organs through paracrine factors secretion and immunomodulation. Despite the high hopes, the low viability of transplanted cells in the injured tissues due to the elevated oxidative stress levels remains the largest obstacle in MSC-based cell therapy. To achieve desired therapeutic efficiency, the survival of the transplanted MSCs in the high oxidative stress environment needs to be ensured. Herein, we proposed the use of a ROS-scavenging nanozyme to protect transplanted MSCs from oxidative stress-mediated apoptosis and thereby improve the therapeutic effect. Prussian blue (PB) nanoparticles as a biocompatible ROS-scavenging nanozyme were incorporated into the MSCs without affecting the stemness and differentiation potential of MSCs. The nanozyme impregnation significantly improved the survival of MSCs in a high oxidative stress condition as well as augmented their paracrine effect and anti-inflammatory properties, resulting in a profound therapeutic effect in vivo in the liver ischemia-reperfusion (I/R) injury animal model. Our results indicated that the nanozyme incorporation into MSCs is a simple but efficient way to improve the therapeutic potential of MSC-based cell therapy.