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Liver transplantation is an effective treatment for the end-stage liver disease. However, hepatic ischemia-reperfusion injury (HIRI) will inevitably occur during liver transplantation, which might lead to early graft dysfunction or aggravate rejection. The underlying protective mechanism remains to be further elucidated. Programmed cell death is an important mechanism of HIRI, and multiple novel types of programmed cell death participate in the pathological process of HIRI. In-depth study of programmed cell death is expected to further improve the therapeutic effect of liver transplantation. In this article, research progresses on apoptosis, autophagy and autophagy-dependent cell death, ferroptosis, necroptosis, pyroptosis, pathanatos and other common programmed cell death patterns in HIRI were reviewed, aiming to provide reference for enhancing the success rate of liver transplantation and improving clinical prognosis of the recipients.
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Hepatic ischemia/reperfusion injury (HIRI) is a serious complication that occurs following shock and/or liver surgery. Gut microbiota and their metabolites are key upstream modulators of development of liver injury. Herein, we investigated the potential contribution of gut microbes to HIRI. Ischemia/reperfusion surgery was performed to establish a murine model of HIRI. 16S rRNA gene sequencing and metabolomics were used for microbial analysis. Transcriptomics and proteomics analysis were employed to study the host cell responses. Our results establish HIRI was significantly increased when surgery occurred in the evening (ZT12, 20:00) when compared with the morning (ZT0, 08:00); however, antibiotic pretreatment reduced this diurnal variation. The abundance of a microbial metabolite 3,4-dihydroxyphenylpropionic acid was significantly higher in ZT0 when compared with ZT12 in the gut and this compound significantly protected mice against HIRI. Furthermore, 3,4-dihydroxyphenylpropionic acid suppressed the macrophage pro-inflammatory response in vivo and in vitro. This metabolite inhibits histone deacetylase activity by reducing its phosphorylation. Histone deacetylase inhibition suppressed macrophage pro-inflammatory activation and diminished the diurnal variation of HIRI. Our findings revealed a novel protective microbial metabolite against HIRI in mice. The potential underlying mechanism was at least in part, via 3,4-dihydroxyphenylpropionic acid-dependent immune regulation and histone deacetylase (HDAC) inhibition in macrophages.
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Hepatic ischemia-reperfusion injury(HIRI) is a kind of liver injury caused by reperfusion after ischemic injury, which is clinically manifested by a series of deterioration phenomena such as liver function impairment, jaundice and even multi-organ failure after restoration of blood supply to the liver. HIRI seriously affects the patient's regression and prognosis. The essence of HIRI is a sterile inflammatory response. High mobility histone 1 (HMGB1) is an important intermediate mediator of HIRI and is a multiple cell type effector involved in HIRI. The receptor for glycosylated end products(RAGE) signaling axis of HMGB1 plays a key role in HIRI, but its mechanism is unclear. In this paper, the recent studies related to the pro-inflammatory mechanism of HMGB1-RAGE signaling axis in HIRI were summarized, and the relationship between HMGB1-RAGE signaling pathway and HIRI was discussed. The research progress of preventing and treating HIRI with surgical operation, ischemic preconditioning, drug and gene therapy using HMGB1-RAGE signaling axis as the target was reviewed.
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Hepatic ischemia/reperfusion injury (HIRI) occurs in liver surgical interventions or systemic hemorrhagic shock, especially in liver transplantation, which can lead to serious postoperative complications and strongly threats the utilization of marginal donor livers and the prognosis of recipients. Here, how to effectively intervene HIRI has always been the important topic in liver surgery. The pathogenesis of HIRI has been gradually elucidated, but no effective prevention and treatment measures have been performed to reduce the injury in clinic. Peptides are small molecules without a quaternary protein structure, which can effectively regulate physiological processes such as stress and metabolism in the body, and participate in the occurrence and development of diseases. Recently, with the successful application of insulin and other peptides in the bedside, the effect of bioactive peptides on HIRI has been attracting wide attention, numbers of studies have confirmed that bioactive peptides have great potential for liver protection during HIRI. This article reviews the roles of bioactive peptides in HIRI and provides new sight and reference to protect liver from HIRI.
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This study investigates the protective role of IMM-H004, a novel coumarin derivative, on hepatic ischemia-reperfusion injury (HIRI) in mice. All animal experiments in this paper have been approved by the Ethics Committee of Institute of Materia Medica, Chinese Academy of Medical Sciences. The experimental animals were divided into three groups, including sham group, model group, and IMM-H004 treatment group. Serum biochemical indicators were detected and H&E staining was used to assess liver damage. Real-time quantitative PCR (qPCR) was performed to analysis the mRNA content of inflammatory factors. Immunohistochemistry and immunofluorescence were used to observe neutrophil infiltration. Western blot was used to examine the protein levels of NOD-like receptor protein 3 (NLRP3), apoptosis-associated speck-like protein (ASC), cysteinyl aspartate specific proteinase-1 (caspase-1), and interleukin-1β (IL-1β). The results showed that IMM-H004 could significantly reduce the serum levels of alanine transaminase (ALT), aspartate transaminase (AST), lactate dehydrogenase (LDH). H&E results showed IMM-H004 could alleviate liver damage caused by HIRI. The mRNA expression of tumor necrosis factor-α (TNF-α), IL-1β, and interleukin-6 (IL-6) were decreased by IMM-H004 administration. Meanwhile, IMM-H004 could markedly inhibit neutrophil infiltration. Furthermore, IMM-H004 could significantly down-regulate the protein expression of NLRP3, ASC, caspase-1, and IL-1β, inhibiting the activation of NLRP3 inflammasome pathway. Our results confirmed that IMM-H004 could protect mice from HIRI and provide a theoretical foundation for IMM-H004 application for treating HIRI.
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OBJECTIVE@#To investigate the protective effect of serine hydroxymethyl transferase 2 (SHMT2) against hepatic ischemia-reperfusion injury in mice.@*METHODS@#Sixty C57BL/6 mice were divided equally into sham-operated group, saline adeno-associated virus group (AVV-GFP), and adeno-associated virus silencing group (AAV-SHMT2). The adeno-associated virus and normal saline were injected into the tail vein of the mice 2 weeks before establishment of a 70% ischemia-reperfusion model in the liver. qPCR, Western blotting, immunofluorescence and immunohistochemistry were used to detect the changes of AST/ALT concentration, SHMT2, JNK, NF-κB, caspase-3 and downstream inflammatory factors in the mice, and HE staining was used to observe the pathological damage of the liver tissue in each group; the cell apoptosis in the liver was detected using TUNEL assay.@*RESULTS@#The expression of SHMT2 increased with time after hepatic ischemia-reperfusion and reached the highest level at 24 h (the relative expression was 1.5, < 0.05). At 24 h after hepatic ischemia-reperfusion, the levels of AST/ALT in AAV-SHMT2 group (588/416 U/L) were significantly higher than those in the control group (416/345 U/L) and the empty vector group (387/321 U/L) ( < 0.05). Compared with those in the control group and the empty vector group, the level of SHMT2 was significantly decreased in AAV-SHMT2 group (with a relative expression of 0.24, < 0.05), the levels of p-JNK and p-p65 were significantly increased (relative expression of 0.80 and 0.97, respectively, < 0.05), and the levels TNF-α and IL-1β were consistently elevated (relative expression levels of 1.6 and 1.2, respectively, < 0.05). No significant differences were found in these parameters between the empty vector group and the control group (>0.05).@*CONCLUSIONS@#SHMT2 may alleviate liver cell apoptosis in mice with hepatic ischemia-reperfusion injury by inhibiting the activation of JNK pathway and excessive activation of NF-κB pathway to reduce hepatic damage.
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Animals , Mice , Apoptosis , Liver , Methyltransferases , Mice, Inbred C57BL , NF-kappa B , Reperfusion Injury , SerineABSTRACT
OBJECTIVE@#To study the protective effect of isoflurane preconditioning on hepatic ischemia-reperfusion (I/R) injury mediated by the noncanonical pyroptosis pathway.@*METHODS@#Thirty C57BL/6 mice were randomly divided into sham-operated group, isoflurane group and I/R group, and in the latter two groups, hepatic I/R injury was induced by clamping the portal vein for 30 min. In isoflurane group, the mice were pretreated with 1.4% isoflurane 30 min before the surgery. The protective effect of isoflurane preconditioning against hepatic I/R injury was evaluated by assessing the pathological score of HE staining of the liver tissue and serum ALT and AST levels. Serum IL-1β and IL-18 levels and the protein expression of GSDMS were detected by ELISA and Western blotting to evaluate the inhibitory effect of isoflurane preconditioning on pyroptosis. Western blotting and immunofluroescence were used to detect the protein expression of caspase-11 in the liver tissues to evaluate the inhibitory effect of isoflurane preconditioning on noncanonical pyroptosis pathway.@*RESULTS@#The Suzuki's score of the liver tissue was significantly higher in I/R group than in the sham group ( < 0.05), while the score in the isoflurane group was significantly lower than that in the I/R group ( < 0.05). Serum ALT and AST levels significantly increased in the sham group ( < 0.05), and were significantly lower in isoflurane group than in I/R group ( < 0.05). The serum levels of IL-1β and IL-18 were significantly higher in I/R group than in sham group ( < 0.05), and were significantly lower in isoflurane group than in I/R group ( < 0.05). The expression of GSDMD in the I/R group was significantly higher than that in sham group, and was significantly lower in isoflurane group than in I/R group ( < 0.05). The hepatic expression of caspase-11 was significantly higher in I/R group than in sham group ( < 0.05), and was significantly lower in isoflurane group than in I/R group ( < 0.05).@*CONCLUSIONS@#Isoflurane preconditioning has protective effect against hepatic I/R injury, which is related to the inhibition of the noncanonical pyroptosis pathway.
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Animals , Mice , Caspases, Initiator , Ischemic Preconditioning , Isoflurane , Liver , Mice, Inbred C57BL , Pyroptosis , Reperfusion InjuryABSTRACT
OBJECTIVE: To explore the protective effect of electroacupuncture (EA) on hepatic ischemia-reperfusion injury (HIRI) and the expression of high mobility group protein 1 (HMGB1) in liver tissues in rats. METHODS: A total of 40 male SD rats were randomly divided into 4 groups, namely sham control, HIRI model, "Ganshu"(BL18) -"Yanglingquan"(GB34) and non-acupoint group, with 10 rats in each group. The HIRI model was induced by blocking the arteries, veins and bile ducts supplying the middle and left lobes of the liver for 1 h, and reperfusion for 4 h to induce an area of about 70% HIRI. EA was applied to bila-teral BL18 and GB34, or non-acupoints about 6-8 mm to the bilateral BL18 for 30 min before modeling. Serum alanine transaminase (ALT) and aspartate aminotransferase (AST) levels were measured by using an automatic biochemical analyzer. Serum tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and HMGB1 levels were assayed by ELISA. Hematoxylin - eosin (H.E.) staining was used to observe histopathological changes of the liver tissue by using tissue injury scaling (0-3 scores). The expression of HMGB1 protein in liver tissues was detected by immunohistochemical staining, Western blot and PCR, separately. RESULTS: Following modeling and compared with the sham group, the levels of serum ALT, AST, TNF-α, IL-6, and HMGB1 contents, the number of HMGB1 immunoreaction (IR)-positive cells, and HMGB1 protein and mRNA were significantly increased (P＜0.01). After the treatment, the contents of serum ALT, AST, TNF-α, IL-6, and HMGB1, liver HMGB1 IR-positive cells, protein and mRNA were considerably down-regulated in the BL18-GB34 group (P0.05) in contrast to the model group. H.E. stain showed a higher liver injury score in the model group than in the sham group (P<0.01), and a lower liver injury score in the BL18-GB34 group (not the non-acupoint group) relevant to the model group (P<0.05). CONCLUSION: EA of BL18 and GB34 points has a protective effect on ischemic liver injury in rats with HIRI, which may be associated with its functions in inhibiting the migration and release of HMGB1 from the nucleus to the cytoplasm and in down-regulating the expression of inflammatory factors.
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OBJECTIVES@#To investigate the role of transient receptor potential cation channel subfamily M member 2 (TRPM2) in hepatic ischemia-reperfusion injury of mouse (HIRI) and the possible mechanisms.@*METHODS@#Sixty adult male C57BL/6 mice were randomly divided into 4 groups: a sham group (S group), a HIRI model group (M group), a TRPM2 adenovirus interference vector group (T group), and a TRPM2 adenovirus control vector group (C group) (=15 in each group). The liver tissues of mice before perfusion were obtained. The efficiency of adenovirus infection was detected by fluorescence microscopy, and the silencing efficiency of adenovirus against TRPM2 was detected by real-time PCR.The abdominal aorta blood and liver tissues were collected from mice at 2, 4 and 8 h after reperfusion. The activities of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in serum of mice were detected. Hepatic pathological changes were examined by hematoxylin-eosin (HE) staining. The protein expression of TRPM2 and Rac family small GTPase 1 (RAC1) in liver tissues was detected by Western blotting. Changes of malondialdehyde (MDA), superoxide dismutase (SOD) and myeloperoxidase (MPO) activities in liver tissues were detected by enzyme-linked immunosorbent assay.@*RESULTS@#A strong signal of green fluorescence was observed in the liver tissues of mice in the T and C groups compared to the S or M group. Compared with the S, M or C group, the expression of TRPM2 mRNA in liver tissue in the T group was significantly down-regulated (all <0.05). The morphology of hepatocytes was normal in the S group under light microscope.Hepatic sinus dilatation, congestion, hepatocyte degeneration, central necrosis of lobule, and massive inflammatory granulocyte infiltration were observed in the M and C group, respectively. The degree of hepatocyte damage in the T group was significantly reduced compared with that in the M and C group, respectively. Compared with the S group, the serum ALT and AST activities in the M, T and C groups were significantly increased at 2, 4 and 8 h after reperfusion (all <0.05). Compared with the M or C group, the serum ALT and AST activities in the T group were significantly lower in serum of mice at 2, 4, and 8 h after reperfusion (all <0.05). Compared with the M or C group, the serum SOD activity in the T group was significantly increased at 2, 4, and 8 h after reperfusion (all <0.05), while the serum MDA and MPO activities were significantly decreased (all <0.05). The protein expression of TRPM2 and RAC1 in liver tissues in the T group were significantly lower than those in the M and C groups at 2, 4 and 8 h after reperfusion (all <0.05).@*CONCLUSIONS@#Pretreatment with TRPM2 adenovirus interference vector can effectively silence TRPM2 gene expression in liver tissues of mice and attenuate HIRI, which may be related to inhibiting oxidative stress and reducing the expression of RAC1 protein.
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Animals , Male , Mice , Alanine Transaminase , Aspartate Aminotransferases , Liver , Mice, Inbred C57BL , Neuropeptides , Rats, Sprague-Dawley , Reperfusion Injury , TRPM Cation Channels , Genetics , Transient Receptor Potential Channels , rac1 GTP-Binding ProteinABSTRACT
Objective To investigate the effect and related mechanism of microRNA (miR)-494 on the hepatic ischemia-reperfusion injury (HIRI). Methods Twenty-four male SD rats were randomly divided into four groups (n=6 in each group). In the sham operation group, abdominal surgery without hepatic ischemia-reperfusion was performed. In the HIRI group, partial liver ischemia was performed for 60 min, followed by 6 h perfusion. In the HIRI+agomir-miR-494 group, intraperitoneal injection of agomir-miR-494 (20 μL) was daily given within preoperative 7 d. In HIRI+agomir-NC group, an equivalent quantity of agomir-NC was daily injected intraperitoneally within preoperative 7 d. The expression level of miR-494 messenger RNA(mRNA) in the liver tissues in each group was detected by reverse transcription polymerase chain reaction (RT-PCR). The expression levels of liver injury and oxidative stress related indexes were measured by relevant kits. The histopathological changes of the liver in each group were observed. The quantity of apoptotic cells and cytoplasmic histone-related DNA fragments in the liver tissues of rats was detected by relevant kits. The expression levels of the proteins related to the phosphatidylinositol-3-kinase(PI3K)/protein kinase(AKT) signaling pathway were measured by Western blot. Results The expression level of miR-494 mRNA in the rat liver tissues in the HIRI+agomir-miR-494 group was significantly higher than that in the HIRI+agomir-NC group (P < 0.01). The levels of the serum liver injury and oxidative stress related indexes in the HIRI+agomir-miR-494 group were significantly lower than those in the HIRI+agomir-NC group (all P < 0.01). Compared with those in the HIRI+agomir-NC group, the quantity of cellular necrosis was significantly reduced, the cell integrity was considerably increased and the quantity of TUNELpositive cells was evidently decreased in the HIRI+agomir-miR-494 group (all P < 0.05). The expression levels of poly ADP-ribose polymerase(PARP), cysteinyl aspartate specific proteinase-3(Caspase-3) and Bax in the HIRI+agomirmiR-494 group were significantly lower than those in the HIRI+agomir-NC group (all P < 0.05). The quantity of DNA fragments in the HIRI+agomir-miR-494 group was significantly less than that in the HIRI+agomir-NC group (P < 0.01). The expression levels of p-AKT, p-mammalian target of rapamycin(mTOR) and p-p70S6K in the HIRI+agomir-miR-494 group were significantly higher than those in the HIRI+agomir-NC group (all P < 0.05). Conclusions miR-494 can alleviate the severity of HIRI in rats by activating the PI3K/AKT signaling pathway.
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AIM:To investigate the effect of trans-activator of transcription-Rab guanine nucleotide exchange factor 1 (Tat-RabGEF1) fusion protein by intravenous injection on hepatic ischemia/reperfusion (IR) -induced lung injury, and its underlying mechanism.METHODS:Adult male C57BL/6 rats (n=24) were randomized into 3 groups with 8 rats each:sham group, IR group, and Tat-RabGEF1 group.IR was induced by occlusion of the vessels in the hepatic pedicle for 90 min followed by 4 h of reperfusion.The Tat-RabGEF1 protein was intravenously administered right after reperfusion through the caudal vein.The levels of tumor necrosis factor-α (TNF-α) , interleukin-6 (IL-6) and interleukin-1β (IL-1β) in bronchoalveolar lavage fluid (BALF) were assessed by ELISA.The lung histopathological injury score and lung wet/dry weight ratio were evaluated, and the levels ofβ-hexosaminidase A (β-Hex A) and myeloperoxidase (MPO) in the lung tissues were also measured.The expression of tryptase in the lung was determined by Western blot.RESULTS:The pathological changes after ischemia for 90 min followed by reperfusion for 4 h were significant, along with increased lung wet/dry weight ratio and lung injury score.Intravenous injection of Tat-RabGEF1 protein effectively alleviated the lung pathological injury (P<0.05).Compared with IR group, lower levels of TNF-α, IL-6 and IL-1βin BALF, and lower expression ofβ-Hex A, MPO and tryptase in the lung tissues in Tat-RabGEF1 group were observed (P<0.05).CONCLUSION:Intravenous injection of Tat-RabGEF1 protein attenuates the lung injury after IR, and its mechanism may be related with inhibition of mast cell activation, reduced releases ofβ-Hex A and tryptase, and decreased levels of TNF-α, IL-6, IL-1βand MPO.
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Toll-like receptor 4 (TLR4) is a member of the toll-like receptor family and belongs to the family of pattern recognition receptors. The role of TLR4 signaling pathway in liver ischemia-reperfusion injury has been widely studied in recent years, and its control methods in inflammatory response is becoming the most important research hotspot. In this paper, the research progress of the molecules and their regulatory mechanisms involved with TLR4 signaling pathway in liver ischemia-reperfusion injury is reviewed, which act as a new foundation of clinical research to study the pathogenic mechanisms and treatment plan.
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The occurrence and development of hepatic ischemia-reperfusion injury (HIR) has important clinical significance,while interleukin-6 (IL-6) is closely related to HIR and it plays an important role in the signaling pathway between downstream signal transducer and activator of transcription 3 (STAT3).IL-6 has been considered to be a typical proinflammatory cytokine.Activation of the gpl30 homodimer by IL-6 leads to the initiation of Janus kinase (JAK)-STAT path-way that is often constitutively switched on in inflammatory diseases.However,a plethora of studies in the last decade showed that only signaling via the soluble IL-6R (trans-signaling) accounts for the deleterious effects of IL-6,whereas the signaling via the membrane-bound receptor (classic signaling) is essential for the regenerative and anti-inflammatory effects of IL-6.In this paper,the latest progresses in the research field of the IL-6/STAT3 signaling pathway in HIR is discussed.
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Objective To observe the effect of pre-intervention with electroacupuncture on oxidative stress (OS) and inflammatory reaction after hepatectomy under portal occlusion.Method Thirty patients going to receive hepatectomy under Pringle's portal occlusion were randomized into an electroacupuncture group and a sham electroacupuncture group, 15 cases each. Three days prior to the surgery, the patients started to receive corresponding acupuncture or sham electroacupuncture treatment by selecting bilateral Riyue (GB24), Qichong (ST30) and Yanglingquan (GB34), once a day. The anesthesia method was general (inhalational and intravenous) anesthesia. Central venous blood was drawn before the surgery, and respectively 6 h, 24 h, 48 h and 72 h after the surgery to examine the OS-relatedparameters, superoxide dismutase (SOD) and malondialdehyde (MDA), as well as the inflammatory mediators, including tumor necrosis factor-α(TNF-α), interleukin (IL)-1, IL-6, and IL-10.Result Compared to the sham electroacupuncture group, the SOD activity significantly increased (241±11.4 U/mL,180±12.6 U/mL,P0.05).Conclusion Pre-intervention with electroacupuncture can up-regulate the activity of SOD and down-regulate the level of MDA in patients after hepatic portal occlusion, and thus partially reduce OS, but it doesn't shownoticeable effecton inflammatory response.
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Objective To identify the role of autopahgy in the protective mechanism of heme oxygenase 1(HO-1) against hepatic ischemia/reperfusion (I/R) injury.Methods Forty healthy male Sprague-Dawley (SD) rats were randomly (random number table) divided into five groups (n =8 in each group),namely sham group,model group,cobalt protoporphyrin (CoPP) group,zinc protoporphyrin (ZnPP) group and 6-amino-3-methylpurine (3-MA) group.Partial hepatic I/R model was established by clamping the pedicles of left and median lobes for 1 hour and reopening for 6 hours in rats,and the rats in sham group were only received celiotomp without hepatic I/R.In the CoPP group,CoPP (a HO-1 inducer,5 mg/kg) was administered i.p 24 hours before I/R.In the ZnPP or 3-MA group,besides pretreatment with CoPP,the rats were given ZnPP (a HO-1 inhibitor,25 mg/kg) or 3-MA (an autophagy inhibitor,30 mg/kg) i.p 1 hour before I/R.Serum alanine aminotransferase (ALT) was determined with automatic biochemistry analyzer.The hepatic pathological scores (PS) were determined under light microscope using hematoxylin-eosin (HE) staining.The hepatocyte apoptosis index (AI) was assessed with terminal dexynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining.Autophagosomes in liver tissue were counted under electron microscope.The mRNA expressions of HO-1,caspase-3,Beclin-1 and Atg-5 in the liver were determined by reverse transcription-polymerase chain reaction (RT-PCR).The HO-1 activity was also measured by the generation of bilirubin with the method of double-wave spectrophotometry.Results Compared with the sham group,the level of serum ALT significantly increased in the I/R group (U/L:560.3±73.6 vs.49.1 ± 13.8,P ＜ 0.01),HE staining showed a severe hepatic injury (PS:12.0±2.0 vs.1.3±0.9,P ＜ 0.01),TUNEL staining showed a higher hepatocytes apoptosis and the expression of caspase-3 significantly increased [AI:(19.38±3.07)％ vs.(3.25±1.28)％,caspase-3 mRNA (2-△△CT):4.62±0.40 vs.1.05±0.15,both P ＜ 0.01].However,there was no significant difference in the expression of HO-1 and the genes associated with autophagy between the two groups.In the CoPP group,the hepatic injury was blunted compared with that in the I/R group [ALT (U/L):223.3 ± 34.4 vs.560.3 ± 73.6,PS:5.6 ± 2.3 vs.12.0 ± 2.0,AI:(11.38± 2.39)％ vs.(19.38 ± 3.07)％,caspase-3mRNA (2-△△CT):2.42±0.33 vs.4.62±0.40,all P ＜ 0.01].HO-1 was induced in the CoPP group and autophagy was also increased significantly after I/R when compared with those in the I/R group [HO-1 mRNA (2-△△CT):3.01 ±0.71vs.1.14 ± 0.20,HO-1 activity (pmol ·mg-1 · h-1):259 ± 37 vs.113 ± 26,the number of autophagosomes:8.75 ± 0.87 vs.1.25±0.71,Beclin-1 mRNA (2-△△CT):2.85±0.28 vs.1.15±0.11,Atg-5 mRNA (2-△△CT):2.44±0.25 vs.1.14±0.12,all P ＜ 0.01].In the ZnPP group,the activity of HO-1 was much lower than that in the CoPP group,and as a result autophagy was decreased and liver injury was increased.In the 3-MA group,although there was no difference in the activity of HO-1 compared with that in the CoPP group,autophagy was inhibited,and the protective effect of CoPP was eliminated.Conclusion HO-1 could regulate the level of autophagy during liver I/R,and in turn autophagy might mediate the protective effects of HO-1 against liver I/R injury.
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ABSTRACT:Objective To investigate the effect and mechanism of anthocyanin on hepatic ischemia reperfusion injury in rats .Methods Totally 30 SD rats were randomly divided into sham group ,model group and anthocyanin group (n=10 in each) .Hepatic ischemia was constructed in model group and anthocyanin group by ligating left middle lobe of liver vascular branches for 90 min . Anthocyanin was administered at 90 min before ischemia by intraperitoneal injection at the concentration of 100 mg/kg for rats in anthocyanin group .Rats in model group and sham group were injected with the same dosage of normal saline at the same time .Serum and liver tissues were collected at 4 h after reperfusion by putting the rats to death .The expressions of ALT ,AST ,IL‐6 ,IL‐1βand TNF‐αin the serum were examined by ELISA .The pathological changes of liver tissue were evaluated by HE .The mRNA levels of IL‐6 ,IL‐1βand TNF‐αwere measured by RT‐PCR .The content of MDA was examined by TBA . The activities of CAT ,GPx and SOD were evaluated by xanthine oxidase method and the expression of p‐JAK2 ,p‐STAT3 ,JAK2 ,STAT3 and P53 were measured by Western blot .Results Compared with those in the sham group ,the activities of ALT and AST ,the expressions of p‐JAK2 ,p‐STAT3 ,P53 ,IL‐6 ,IL‐1β,TNF‐α and the content of MDA as well as the pathological changes of the liver in model group were significantly increased . However ,the activities of CAT ,GPx and SOD in model group were decreased and the expressions of JAK2 and STAT3 between the two groups did not differ .Compared with those in model group ,the activities of ALT and AST ,the expressions of p‐JAK2 ,p‐STAT3 ,P53 ,IL‐6 ,IL‐1β,TNF‐α,the content of MDA and the pathological changes of the liver in anthocyanin group were significantly decreased . But the activities of CAT , GPx and SOD in anthocyanin group were increased and the expressions of JAK 2 and STAT3 between the two groups did not differ , either .Conclusion Anthocyanin pretreatment can significantly decrease hepatic ischemia/reperfusion injury by suppressing oxidative stress and inflammation ,and the mechanism may be associated with reducing JAK2/STAT3/P53 signaling activation .
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Objective To investigate the protective effects of Codonopsis lanceolata saponin (CLS) on hepatic ischemia-reperfusion injury (HIRI) and its mechanism in rats.Methods The rats were divided randomly into 3 groups:sham-operated (SO) group, HIRI group and CLS group.HIRI model was made by Pringle method.CLS group was pretreated with CLS (200 mg · kg-1 · d-1) by intragastric administration for 7 days before operation, while SO group and HIRI group were given with distilled water 10 ml · kg-1 · d-1 for 7 days.ALT, AST, SOD, MDA in serum, and SOD and MDA in hepatic tissue were detected by colorimetric method.IL-18 in serum and hepatic tissue was detected by ELISA.Results The levels of serum ALT, AST, MDA, IL-18, TNF-α and tissue MDA, IL-18 in HIRI group were significantly higher than those in SO group and CLS group (all P ＜ 0.05), respectively.The serum and hepatic tissue SOD activity in HIRI group was significantly lower than that in SO group and CLS group (all P ＜ 0.05).Histological observation revealed that the obvious cell necrotic foci with a large number of inflammatory cells infiltration in the HIRI group, while the lesion was obviously alleviated in CLS group.Conclusions Codonopsis lanceolata saponin preconditioning alleviates hepatic ischemia/reperfusion injury.The mechanism may be correlated with inhibiting inflammatory factors and enhancing anti-oxidation.
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Objective To explore the effect of moderate hypothermia (MH) in liver ischemiareperfusion (IR) injury.Methods Male BALB/c mice (8 weeks old,n =15) were randomly divided into three groups:IR group:five mice subjected to 70％ hepatic IR (hepatic vascular triad above the bifurcation occlusion for 35 min before 24 h reperfusion) in normal temperature condition (37 ±0.5 ℃);MH + IR group:five mice were treated with MH (32 ±0.5 ℃) for 2 h before 70％ hepatic IR was performed;sham group:the other five mice were subjected to laparotomy and liver manipulations without vascular occlusion.AST and ALT in plasma were detected in all mice,and the morphological changes,cell apoptosis and the cold-inducible RNA-binding protein (CIRP) expression after MH in liver tissues were detected.Results Compared with IR group,the ALT and AST levels in MH + IR group were significantly decreased.In IR group,the liver morphology deteriorated with more severe hydropic degeneration and more cell apoptosis.In MH + IR group,the expression of CIRP began to increase after MH preconditioning.Conclusion MH preconditioning could protect against the liver ischemia-reperfusion injury.
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OBJECTIVE: To analyze recent studies on the role of the endocannabinoid system in liver disease and related mechanism. METHODS: Reading domestic and international documents in recent years, we concluded a comprehensive integrated about them. RESULTS: This paper reviews the important role of the endocannabinoid in the development of liver disease, which focuses on the prevention and protection of the endocannabinoid on viral hepatitis, alcoholic fatty liver disease, non-alcoholic fatty liver disease, cholestatic liver disease and liver ischemia-reperfusion injury and the development of hepatic fibrosis and hepatic encephalopathy. CONCLUSION: Endocannabinoid system plays an important role in the treatment of liver disease. But for its complex mechanism of action, we need further research.
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Objective To explore the effect of Radix Isatidis( indigowoad root,RI) polysaccharide on NO and ET-1 in orthopotic liver autotransplantation of rats.Methods The rats used in the experiment were randomly divided into three groups:normal control group (NC), autotransplantation group (AT) and RI polysaccharide group (RIPS).At 1, 6, 12 and 24 hours after autotransplantation, the content of NO,ET-1, alanine aminotransferase ( ALT), and aspartate amin-otransferase ( AST) in serum was assayed.Morphological observation of hepatic tissues was also performed.Results The serum level of ET-1 in RIPS group was significantly lower than that of AT group (P<0.05), and NO content in serum of RIPS group was increased significantly compared with AT group ( P<0.05) at 1, 6, 12 and 24 hours after autotransplanta-tion.The serum level of ALT and AST in RIPS group was lower than that of AT group (P<0.05) at each measurement point.The morphology of hepatocytes changed abnormally under light microscopy.The blood stasis and swelling of hepatic tissues, denaturalization and necrosis of hepatocytes in RIPS group were milder than that in AT group.Conclusion RIPS has a protective effect on hepatic ischemia reperfusion injury after orthotopic liver autotransplantation, which may be related to increased NO levels and lower levels of ET-1.