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Abstract The incidence of non-alcoholic fatty liver (NAFLD) remains high, and many NAFLD patients suffer from severe ischemia-reperfusion injury (IRI). Currently, no practical approach can be used to treat IRI. Puerarin plays a vital role in treating multiple diseases, such as NAFLD, stroke, diabetes, and high blood pressure. However, its role in the IRI of the fatty liver is still unclear. We aimed to explore whether puerarin could protect the fatty liver from IRI. C57BL/6J mice were fed with a high‐fat diet (HFD) followed by ischemia reperfusion injury. We showed that hepatic IRI was more severe in the fatty liver compared with the normal liver, and puerarin could significantly protect the fatty liver against IRI and alleviate oxidative stress. The PI3K-AKT signaling pathway was activated during IRI, while liver steatosis decreased the level of activation. Puerarin significantly protected the fatty liver from IRI by reactivating the PI3K-AKT signaling pathway. However, LY294002, a PI3K-AKT inhibitor, attenuated the protective effect of puerarin. In conclusion, puerarin could significantly protect the fatty liver against IRI by activating the PI3K-AKT signaling pathway.
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ObjectiveTo investigate the mechanism of modified Shenhong Tongluo prescription on cell apoptosis in rats with myocardial ischemia-reperfusion injury （MIRI）. MethodSixty Sprague-Dawley （SD） rats were randomly divided into a blank group， a model group， low-， medium-， and high-dose groups of modified Shenhong Tongluo prescription， and a simvastatin group. Except for the blank group， a rat model of MIRI was prepared by ligating the left anterior descending coronary artery. Starting from the first day after successful modeling， the blank group （1.0 mL·kg-1 physiological saline）， model group （1.0 mL·kg-1 physiological saline）， low-， medium-， and high-dose groups of modified Shenhong Tongluo prescription （1.031， 2.063， and 4.126 g·kg-1 Shenhong Tongluo prescriptiona standard concentrate）， and simvastatin group （0.71 mg·kg-1 simvastatin） were orally administered once daily for 2 weeks. Hematoxylin-eosin （HE） staining was used to observe the pathological changes of cardiomyocytes. Enzyme-linked immunosorbent assay （ELISA） was used to detect the levels of serum creatine kinase isoenzyme （CK-MB）， interleukin-6 （IL-6）， and tumor necrosis factor-α （TNF-α）. TdT-mediated dUTP nick-end labeling（TUNEL） staining was used to detect the apoptosis rate of rat cardiomyocytes. Western blot was used to detect the expression levels of apoptosis-related proteins B-cell lymphoma-2 （Bcl-2）， Bcl-2-associated X protein （Bax）， and caspase-3. ResultCompared with the blank group， in the model group， HE staining showed disturbed arrangement of cardiomyocytes， incomplete fibers， focal necrosis of cardiomyocytes， and inflammatory cell infiltration； serum CK-MB， IL-6， and TNF-α levels were significantly increased （P<0.05）； apoptosis rate of cardiomyocytes was significantly increased （P<0.01）， with significantly increased expression levels of Bax and Caspase-3 proteins， and significantly decreased Bcl-2 expression （P<0.05）. Compared with the model group， the low-， medium-， and high-dose groups of modified Shenhong Tongluo prescription significantly reduced CK-MB， IL-6， and TNF-α levels （P<0.05）， significantly downregulated cardiomyocyte apoptosis rate （P<0.05）， significantly decreased Bax and Caspase-3 proteins， and significantly increased Bcl-2 expression levels （P<0.01）. In the modified Shenhong Tongluo prescription groups， the expression levels of Bax and Caspase-3 proteins significantly decreased with increasing dosage， while the expression level of Bcl-2 significantly increased with increasing dosage of modified Shenhong Tongluo prescription （P<0.05）. ConclusionShenhong Tongluo prescription can alleviate myocardial tissue pathological damage and reduce myocardial cell apoptosis， possibly by inhibiting Caspase-3 and Bax expression and promoting Bcl-2 expression.
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Liver transplantation is the optimal treatment for end-stage liver disease and hepatocellular carcinoma, which can significantly improve clinical prognosis and quality of life of patients. However, multiple challenges, such as rejection, immune tolerance, shortage of donor liver, preservation of donor liver, ischemia-reperfusion injury and postoperative complications, <i>etc.</i>, limit the efficacy of liver transplantation in clinical practice. Research teams in China have made significant contributions to the basic research related to liver transplantation by making continuous efforts and combining the development of emerging technologies, interdisciplinary integration and other emerging fields. In this article, the frontier progress in the basic research of liver transplantation in 2023 was reviewed, highlighting the progress made by Chinese research teams in the basic research of liver transplantation, aiming to provide reference for promoting the integration of Chinese characteristics into the research of liver transplantation, accelerate the integration of Chinese liver transplantation research with international community, and promote further advancement of liver transplantation in China.
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As a mature organ transplantation, liver transplantation has become the optimal treatment for end-stage liver disease, which can improve the quality of life of recipients. However, liver transplantation still faces multiple challenges, such as rejection, infection, biliary complications, delayed graft function, ischemia-reperfusion injury, recurrence of hepatocellular carcinoma after liver transplantation, kidney-related diseases after transplantation, and donor shortage, <i>etc.</i>, which remain to be improved and urgently resolved. With persistent attempts and experience accumulated by Chinese experts and scholars, these problems related to liver transplantation have been gradually resolved year by year. In 2023, liver transplantation teams in China have achieved a series of significant progresses in the field of clinical research. In this article, clinical frontiers and novel technological progresses in the field of liver transplantation in 2023 were reviewed, and the achievements of clinical liver transplantation in China in 2023 were summarized, aiming to provide novel ideas for promoting further development of liver transplantation in China.
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Kidney transplantation has achieved significant success in treating end-stage renal disease. Nevertheless, it still faces a series of complex and significant challenges after surgery, such as infection, rejection, ischemia-reperfusion injury and chronic renal allograft dysfunction, <i>etc.</i> With the development of science and technology, including biomaterials, gene sequencing and other emerging technologies, Chinese researchers have launched a series of remarkable research in the field of kidney transplantation, aiming to solve these thorny issues. In 2023, relevant research of kidney transplantation in China not only focused on resolving the above challenges, but also highlighting on expanding novel technologies and concepts to build a brighter future of kidney transplantation. In this article, academic achievements of Chinese research teams in the field of kidney transplantation in 2023 were systematically reviewed, covering the frontiers of basic and clinical research and the application of emerging technologies, aiming to provide novel ideas and strategies for major clinical problems in the field of kidney transplantation from the local perspective and accelerate the advancement of kidney transplantation in China to a higher peak.
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<b>Objective</b> To evaluate the effect of glycogen synthase kinase 3β (GSK3β) on hypoxia/reoxygenation (H/R)-induced injury of senescent renal tubular epithelial cell (RTEC) in aged mice and its regulatory mechanism. <b>Methods</b> RTEC were divided into the Young group (young RTEC with normal growth), Old group (aged RTEC induced by Etoposide), Old+Ad-shNC+H/R group [aged RTEC induced by Etoposide and then transfected with adenovirus negative control (Ad-shNC) for H/R treatment], and Old+Ad-shGSK3β+H/R group (aged RTEC induced by Etoposide and then transfected with short-hairpin RNA-expressing adenovirus with targeted silencing GSK3β for H/R treatment), respectively. Apoptosis level and mitochondrial reactive oxygen species level were detected by flow cytometry. Calcium ion level was determined by immunofluorescence staining. The expression and phosphorylation levels of GSK3β, mitochondria-associated endoplasmic reticulum membrane (MAM)-related proteins of inositol 1,4,5-trisphosphate receptor1 (ITPR1), voltage dependent anion-selective channel 1(VDAC1) and glucose-regulated protein 75 (GRP75) were detected by Western blot. The interaction between GSK3β and MAM-related proteins was analyzed by immunoprecipitation. <b>Results</b> Compared with the Young group, the apoptosis, mitochondrial reactive oxygen species and mitochondrial calcium ion levels were higher in the Old group. Compared with the Old group, the apoptosis, mitochondrial reactive oxygen species and mitochondrial calcium ion levels were higher in the Old+Ad-shNC+H/R group. Compared with the Old+Ad-shNC+H/R group, the apoptosis, mitochondrial reactive oxygen species and mitochondrial calcium ion levels were lower in the Old+Ad-shGSK3β+H/R group, and the differences were statistically significant (all <i>P</i><0.05). Compared with the Young group, the expression levels of ITPR1, GRP75 and GSK3β proteins were up-regulated, the phosphorylation levels of ITPR1 and GRP75 were increased, whereas the total protein and phosphorylation levels of VDAC1 were decreased in the Old group. Compared with the Old group, the expression level of GSK3β protein was unchanged, the total protein and phosphorylation levels of ITPR1 and GRP75 were increased, the expression level of total VDAC1 protein remained unchanged and the phosphorylation level was increased in the Old+Ad-shNC+H/R group. Compared with the Old+Ad-shNC+H/R group, the expression level of GSK3β protein was decreased, the expression levels of total ITPR1, GRP75 and VDAC1 proteins were unchanged, whereas the phosphorylation levels were decreased in the Old+Ad-shGSK3β+H/R group. Immunoprecipitation showed that GSK3β could interact with ITPR1, GRP75 and VDAC1 proteins. <b>Conclusions</b> The expression level of GSK3β is up-regulated in senescent RTEC. Down-regulating GSK3β expression may reduce the phosphorylation level of ITPR1-GRP75-VDAC1 complex, constrain the overload of mitochondrial calcium ion, protect mitochondrial function and mitigate cell damage during reperfusion.
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Objective:To explore the role and mechanism of neurotrophin-3(NT-3)in promoting neurological func-tion recovery after cerebral ischemia-reperfusion injury in rats.Methods:Twenty-four SD rats were randomly divided into sham operation group(Sham),middle cerebral artery occlusion/reperfusion(MCAO/R)group,and MCAO/R+NT-3 group.The neurological function scores of rats in each group were evaluated using the modified Garcia score.Western Blot was used to detect the expression of NT-3 and LC3B in brain tissues of rats.Culture dishes with the same density of neurons were randomly divided into normal group(Normal),oxygen-glucose deprivation(OGD)group,OGD+NT-3 group,OGD+NT-3+PF-06273340(TrkC inhibitor)group,OGD+NT-3+ZSTK474(PI3K inhibitor)group,and OGD+NT-3+CCT128930(AKT inhibitor)group.Western Blot was used to detect the expression of TrkC,the phosphorylation of PI3K/AKT,and LC3B in neurons.The morphological changes of neurons and the phenomenon of neuronal autophagy were observed using autophagy-specific fluorescent staining.Results:The animal experiment found that the expression of NT-3 increased in the brain tissue with ischemia-reperfusion injury(P＜0.05),and after the treatment with exogenous NT-3,the modified Garcia score increased(P＜0.05),and the level of autophagy weakened(P＜0.05).The cell experiment found that NT-3 can inhibit neuronal autophagy under ischemic hypoxia and maintain the neuronal morphology to the maximum extent.After using PF-06273340,the expression of p-PI3K and p-AKT de-creased(P＜0.05).After using ZSTK474 and CCT128930,the autophagy-inhibiting effect of NT-3 weakened(P＜0.05).Conclusion:NT-3 inhibits autophagy via the PI3K/AKT signaling pathway to maintain neuronal survival,thereby promoting the recovery of neurological function after cerebral ischemia-reperfusion injury in rats.
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Myocardial ischemia-reperfusion injury （MIRI） is a serious complication of revascularization in patients with myocardial infarction. The nuclear factor erythroid 2-related factor 2 （Nrf2）/heme oxygenase-1 （HO-1） signaling pathway plays an important role in the pathological process of MIRI. Currently，research has found that traditional Chinese medicine has a good effect on myocardial injury caused by ischemia-reperfusion. Based on the Nrf2/HO-1 signaling pathway，this article summarizes the action mechanism of traditional Chinese medicine formulas and monomers in intervening with MIRI. It is found that traditional Chinese medicine formulas （Yixin formula，Wenyang tongmai formula，Dingxin formula Ⅰ），monomers such as terpenoids （ginkgolides， astragaloside Ⅳ，ginsenosides），phenols （brazilin，hematoxylin A，resveratrol） and quinones （aloe，emodin） can alleviate MIRI by activating the Nrf2/HO-1 signaling pathway，inhibiting oxidative stress and inflammatory reactions，etc.
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Ischemia-reperfusion injury (IRI) is an extremely complicated pathophysiological process, which may occur during the process of myocardial infarction, stroke, organ transplantation and temporary interruption of blood flow during surgery, etc. As key molecules of immune system, macrophages play a vital role in the pathogenesis of IRI. M1 macrophages are pro-inflammatory cells and participate in the elimination of pathogens. M2 macrophages exert anti-inflammatory effect and participate in tissue repair and remodeling and extracellular matrix remodeling. The balance between macrophage phenotypes is of significance for the outcome and treatment of IRI. This article reviewed the role of macrophages in IRI, including the balance between M1/M2 macrophage phenotype, the mechanism of infiltration and recruitment into different ischemic tissues. In addition, the potential therapeutic strategies of targeting macrophages during IRI were also discussed, aiming to provide reference for alleviating IRI and promoting tissue repair.
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Objective To investigate the role and mechanism of spliced X-box binding protein 1 (XBP1s) in the senescence of primary renal tubular epithelial cells induced by hypoxia/reoxygenation (H/R). Methods Primary renal tubular epithelial cells were divided into the normal control group (NC group), H/R group, empty adenovirus negative control group (Ad-shNC group), targeted silencing XBP1s adenovirus group (Ad-shXBP1s group), empty adenovirus+H/R treatment group (Ad-shNC+H/R group) and targeted silencing XBP1s adenovirus+H/R treatment group (Ad-shXBP1s +H/R group), respectively. The expression levels of XBP1s in the NC, H/R, Ad-shNC and Ad-shXBP1s groups were measured. The number of cells stained with β-galactosidase, the expression levels of cell aging markers including p53, p21 and γH2AX, and the levels of reactive oxygen species (ROS), malondialdehyde (MDA) and superoxide dismutase (SOD) were determined in the Ad-shNC, Ad-shNC+H/R and Ad-shXBP1s+H/R groups. Chromatin immunoprecipitation was employed to verify Sirtuin 3 (Sirt3) of XBP1s transcription regulation, and the expression levels of Sirt3 and downstream SOD2 after down-regulation of XBP1s were detected. Mitochondrial reactive oxygen species (mtROS) were detected by flow cytometry. Results Compared with the NC group, the expression level of XBP1s was up-regulated in the H/R group. Compared with the Ad-shNC group, the expression level of XBP1s was down-regulated in the Ad-shXBP1s group (both P<0.001). Compared with the Ad-shNC group, the number of cells stained with β-galactosidase was increased, the expression levels of p53, p21 and γH2AX were up-regulated, the levels of ROS, MDA and mtROS were increased, the SOD activity was decreased, the expression level of Sirt3 was down-regulated, and the ratio of Ac-SOD2/SOD2 was increased in the Ad-shNC+H/R group. Compared with the Ad-shNC+H/R group, the number of cells stained with β-galactosidase was decreased, the expression levels of p53, p21 and γH2AX were down-regulated, the levels of ROS, MDA and mtROS were decreased, the SOD activity was increased, the expression level of Sirt3 was up-regulated and the ratio of Ac-SOD2/SOD2 was decreased in the Ad-shXBP1s+H/R group (all P<0.05). Conclusions Down-regulation of XBP1s may ameliorate the senescence of primary renal tubular epithelial cells induced by H/R, which probably plays a role through the Sirt3/SOD2/mtROS signaling pathway.
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Objective To analyze the core genes of lung ischemia-reperfusion injury and construct a competitive endogenous RNA (ceRNA) network. Methods Original data of GSE145989 were downloaded from the Gene Expression Omnibus (GEO) database as the training set, and the GSE172222 and GSE9634 datasets were used as the validation sets, and the differentially-expressed genes (DEG) were identified. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were performed. Protein-protein interaction (PPI) network was constructed, and the core genes were screened, and the diagnostic values of these core genes and the immune infiltration levels of immune cells were evaluated. The ceRNA network was constructed and validated. The targeted drugs based on ceRNA network were assessed. Results A total of 179 DEG were identified, including 61 down-regulated and 118 up-regulated genes. GO analysis showed that DEGs were associated with multiple biological processes, such as cell migration, differentiation and regulation, etc. They were correlated with cell components, such as vesicle membrane, serosa and membrane raft, etc. They were also associated with multiple molecular functions, such as chemokine receptor, G protein-coupled receptor, immune receptor activity and antigen binding, etc. KEGG pathway enrichment analysis revealed that DEG were involved in tumor necrosis factor (TNF), Wnt, interleukin (IL)-17 and nuclear factor (NF)-κB signaling pathways, etc. PPI network suggested that CD8A, IL2RG, STAT1, CD3G and SYK were the core genes of lung ischemia-reperfusion injury. The ceRNA network prompted that miR-146a-3p, miR-28-5p and miR-593-3p were related to the expression level of CD3G. The miR-149-3p, miR-342-5p, miR-873-5p and miR-491-5p were correlated with the expression level of IL-2RG. The miR-194-3p, miR-512-3p, miR-377-3p and miR-590-3p were associated with the expression level of SYK. The miR-590-3p and miR-875-3p were related to the expression level of CD8A. The miR-143-5p, miR-1231, miR-590-3p and miR-875-3p were associated with the expression level of STAT1. There were 13 targeted drugs for CD3G, 4 targeted drugs for IL-2RG, 28 targeted drugs for SYK and 3 targeted drugs for lncRNA MUC2. No targeted drugs were identified for CD8A, STAT1 and other ceRNA network genes. Conclusions CD8A, IL2RG, STAT1, CD3G and SYK are the core genes of lung ischemia-reperfusion injury. The research and analysis of these core genes probably contribute to the diagnosis of lung ischemia-reperfusion injury and providing novel research ideas and therapeutic targets.
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Organ preservation fluid could mitigate cold ischemia injury and maintain normal function of the grafts. At present, how to reduce a series of injury caused by cold ischemia of donor liver and improve the preservation quality of grafts are the hot and challenging spots in this field. Currently, preservation fluid in clinical practice has not achieved ideal preservation effect, especially for the protection of marginal donor organs. In the context of severe donor shortage, the key solution is still to explore the optimal preservation protocol for donor liver to prevent grafts from cold ischemia injury. In this article, the mechanism of donor liver injury during cold ischemia, the classification and evolution of donor liver preservation fluid were summarized, the development direction and challenges of donor liver preservation fluid were discussed, aiming to provide novel ideas and references for the research and development of donor liver preservation fluid.
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@#BACKGROUND: Resuscitative endovascular balloon occlusion of the aorta (REBOA) can temporarily control traumatic bleeding. However, its prolonged use potentially leads to ischemia-reperfusion injury (IRI). Partial REBOA (pREBOA) can alleviate ischemic burden; however, its security and effectiveness prior to operative hemorrhage control remains unknown. Hence, we aimed to estimate the efficacy of pREBOA in a swine model of liver injury using an experimental sliding-chamber ballistic gun. METHODS: Twenty Landrace pigs were randomized into control (no aortic occlusion) (n=5), intervention with complete REBOA (cREBOA) (n=5), continuous pREBOA (C-pREBOA) (n=5), and sequential pREBOA (S-pREBOA) (n=5) groups. In the cREBOA and C-pREBOA groups, the balloon was inflated for 60 min. The hemodynamic and laboratory values were compared at various observation time points. Tissue samples immediately after animal euthanasia from the myocardium, liver, kidneys, and duodenum were collected for histological assessment using hematoxylin and eosin staining. RESULTS: Compared with the control group, the survival rate of the REBOA groups was prominently improved (all P<0.05). The total volume of blood loss was markedly lower in the cREBOA group (493.14±127.31 mL) compared with other groups (P<0.01). The pH was significantly lower at 180 min in the cREBOA and S-pREBOA groups (P<0.05). At 120 min, the S-pREBOA group showed higher alanine aminotransferase (P<0.05) but lower blood urea nitrogen compared with the cREBOA group (P<0.05). CONCLUSION: In this trauma model with liver injury, a 60-minute pREBOA resulted in improved survival rate and was effective in maintaining reliable aortic pressure, despite persistent hemorrhage. Extended tolerance time for aortic occlusion in Zone I for non-compressible torso hemorrhage was feasible with both continuous partial and sequential partial measures, and the significant improvement in the severity of acidosis and distal organ injury was observed in the sequential pREBOA.
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Objective To study the effect and mechanism of Anchusa italica Retz on cerebral ischemia-reperfusion inju-ry in rats based on the target network of active compounds in Anchusa italica Retz.Methods The rat model of cerebral ische-mia-reperfusion injury was established by the thread occlusion method.After performing ischemia for 1.5 h and then reperfusion for 24 h,the neurological function of rats was scored and the volume of cerebral infarction was measured by the 2,3,5-triphenyltet-razolium chloride staining method.The molecular network analysis technique of network pharmacology,protein-protein interaction network,gene ontology(GO)enrichment analysis,KEGG signal pathway analysis,and molecular docking was used to study the mechanism of Anchusa italica Retz in the treatment of cerebral ischemia-reperfusion injury.Results The administration of An-chusa italica Retz could significantly improve the neurobehavioral dysfunction caused by cerebral ischemia-reperfusion injury and reduce the pathological injury of brain tissue.Anchusa italica Retz could regulate inflammation,apoptosis,protein phosphorylation,and other biological processes through 143 ischemic stroke-related targets,and interfere with the TNF signal pathway,VEGF signal pathway,HIF-1 signal pathway,and other pathways.Conclusion Network pharmacology and experimental verification had shown that Anchusa italica Retz could effectively reduce brain injury and protect neurological function through multi-target,multi-mechanism,and holistic treatment of cerebral ischemia-reperfusion injury.
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Currently,revascularization is an effective rescue strategy for patients with acute myocardial infarc-tion.However,myocardial ischemia/reperfusion(I/R)injury induced by revascularization has become a significant risk factor affecting the long-term prognosis of patients with ischemic cardiomyopathy after revascularization,without precise treatment.Extracellular vehicles derived from mesenchymal stem cells are characterized by easy access,editability,and easy absorption of cells,and their application in treating myocardial I/R injury is considered valuable to study.This review focuses on the advances in research on mesenchymal stem cell-derived extracellular vehicles and their function of regulating myocardial I/R injury after natural drug intervention,hopefully offering ideas for the research of prevention and treatment of myocardial I/R injury.
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AIM:Using bioinformatics analysis methods to identify the hub genes involved in myocardial isch-emia-reperfusion injury(MIRI).METHODS:Firstly,the rat MIRI related dataset GSE122020,E-MEXP-2098,and E-GEOD-4105 were downloaded from the database.Secondly,differentially expressed genes(DEGs)were screened from each dataset using the linear models for microarray data(limma)package,and robust DEGs were filtered using the robust rank aggregation(RRA)method.In addition,the surrogate variable analysis(SVA)package was used to merge all datas-ets into one,and merged DEGs were screened using the limma package.The common DEGs were obtained by taking the intersection of the two channels of DEGs.Next,the protein-protein interaction(PPI)network of common DEGs was con-structed,and the hub genes were identified using the density-maximizing neighborhood component(DMNC)algorithm.The receiver operating characteristic curve(ROC)was plotted to evaluate the diagnostic performance of the hub gene.Then,the mRNA and protein expression levels of hub genes were detected in the rat MIRI model,and the literature re-view analysis was carried out on the involvement of hub genes in MIRI.Finally,the gene set enrichment analysis(GSEA)was performed on hub gene to further reveal the possible mechanism in mediating MIRI.RESULTS:A total of 143 robust DEGs and 48 merged DEGs were identified.After taking the intersection of the two,48 common DEGs were obtained.In the PPI network of common DEGs,5 hub genes were screened out,namely MYC proto-oncogene bHLH transcription fac-tor(MYC),prostaglandin-endoperoxide synthase 2(PTGS2),heme oxygenase 1(HMOX1),caspase-3(CASP3),and plasminogen activator urokinase receptor(PLAUR).The ROC results showed that the area under the curve values for all hub genes were greater than 0.8.MYC,PTGS2,CASP3,and PLAUR showed high mRNA and protein expression in rat MIRI,while there was no difference in mRNA and protein expression for HMOX1.The literature review revealed that among the 5 hub genes,only PLAUR has not been reported to be involved in MIRI.The GSEA results for PLAUR indicat-ed that its functional enrichment mainly focused on pathways such as NOD-like receptor signaling pathway,P53 signaling pathway,Toll-like receptor signaling pathway,apoptosis,and fatty acid metabolism.CONCLUSION:MYC,PTGS2,CASP3,HMOX1,and PLAUR are involved in the pathological process of MIRI.PLAUR is a potential hub gene that can mediate MIRI by regulating pathways such as NOD like receptor signaling,P53 signaling,Toll like receptor signaling,cell apoptosis,and fatty acid metabolism.The results can provide reference for further investigation into the molecular mechanisms and therapeutic targets of MIRI.
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Objective:To correlate neutrophil/lymphocyte ratio (NLR) with cardiac function in patients with acute myocardial infarction (ACI) after percutaneous coronary intervention (PCI) and investigate its clinical value in predicting major adverse cardiovascular events (MACEs) in patients.Methods:A total of 120 patients with AMI who underwent PCI at Wenzhou Hospital of Integrated Traditional Chinese and Western Medicine from March 2020 to February 2023 were included in this prospective study. The difference in NLR measured 1 day after PCI relative to that measured at 5 days after surgery (?NLR) was correlated with cardiac function ultrasound indicators measured at 3 months after surgery, myocardial injury, and inflammatory biochemical indicators at 1 day after surgery. The MACEs occurring within 3 months after surgery were recorded. The value of ΔNLR recorded during the early stage after PCI for predicting MACEs in patients with AMI was evaluated.Results:At 3 months after surgery, 13 out of 120 patients with AMI (10.83%) had MACEs. The ?NLR in patients with AMI who had MACEs was (3.55 ± 0.47), which was significantly higher than (2.06 ± 0.34) in patients with AMI who had no MACEs ( t = 17.25, P < 0.001). An optimal critical value of ?NLR for predicting MACEs after PCI in patients with AMI was 2.75, with an area under the receiver operating characteristic curve of 0.972, a sensitivity of 90.70%, and a specificity of 91.10%. Conclusion:Increased NLR during the early stage after PCI in patients with AMI is closely related to decreased cardiac function, and worsened myocardial injury and inflammatory reactions. Changes in NLR after PCI in patients with AMI have a highly valuable value for predicting MACEs in these patients.
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Objective:To investigate the role of HMGB1-TLR4-NF-κB signaling pathway in cerebral ischemia-reperfusion in-jury and the effect of adenosine preconditioning on the signaling pathway.Methods:Total 80 adult male Sprague-Dawley rats weighing 220～270 g were selected from the Animal Center of Xinxiang Medical University.The rats were randomly divided into F group(sham operation group),I/R group(ischemia reperfusion group)and AP group(adenosine preconditioning group).The MCAO model of rats was established by wire embolization.Quantitative analysis of neural function in successfully modeled rats using animal behavior scor-ing method,the morphological changes of brain cells were observed by HE staining,TTC staining was used to observe cerebral infarc-tion and cerebral infarction volume was calculated;Immunohistochemical staining was used to detect HMGB1,TLR4 and NF-κB pro-tein expression levels in brain tissues of each group.The data were statistically analyzed by one-way ANOVA in SPSS26.0 software.Results:After ischemia reperfusion,the neurological function of I/R group and AP group showed different degrees of impairment,and the neurological function scores of the two groups were significantly higher than that of F group,the difference was statistically signifi-cant(P<0.05),and the neurological function of the AP group was significantly less than that of I/R group,the difference was also sta-tistically significant(P<0.05).TTC staining showed that AP group,I/R group rat cerebral infarction volume was significantly more than F group[(93.670±4.509)mm3,(123.670±7.234)mm3 vs(0.000±0.000)mm3],and AP group rats infarction volume was signifi-cantly reduced than that in I/R group,the difference had statistical significance(P<0.05).Immunohistochemistry showed that HMGB1,TLR4,NF-κB protein in F group with a small amount of expressions in rats,while significantly expressed in AP group and I/R group relatively,and the AP group of each subgroup rat HMGB1,TLR4,NF-κB protein expressions significantly lower than the amount of I/R group,the difference had statistical significance(P<0.05).Conclusion:Adenosine preconditioning can reduce the expressions of HMGB1,TLR4 and NF-κB protein,and then protect the rats with cerebral ischemia-reperfusion injury.
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Objective To explore the effect of lidocaine(LID)on ischemia-reperfusion injury in orthotopic liver transplantation(OLT)rats and to analyze its mechanism of action.Methods Sixty rats were randomly divided into Verteporfin group,high-dose LID(High LID),medium-dose LID(Medium LID),low-dose LID(Low LID),Model and Control groups,on average.The rest of the rats except the control rats were used to establish OLT models.Observe the pathological changes in liver tissue were with hematoxylin-eosin staining.Serum aspartate transaminase(AST),total bilirubin(TBIL),lactate dehydrogenase(LDH)activities and alanine transaminase(ALT)were detected.Measure liver tissue levels of proinflammatory factors tumor necrosis factor-α(TNF-α),interleukin(IL)-6,IL-1β,and IL-10 with enzyme-linked immunosorbent assays.Reactive oxygen species(ROS)was detected by a fluorescence probe.Malondialdehyde(MDA)was detected by the thiobarbituric acid colorimetric method.Superoxide dismutase(SOD)was detected by nitrogen blue tetrazole colorimetry.Glutathione peroxidase(GSH-Px)was detected by a spectrophotometry method.Apoptosis of liver histiocytes was detected by in situ end labeling.Detect the expression of mammalian STE20 like protein kinase(MST1),phosphorylation(p)-MST1,large tumor suppressor factor 1(LATS1),p-LATS1,Yes associated protein(YAP),p-YAP,and apoptosis-related proteins B-cell lymphoma 2(Bcl-2)and Bcl-2 related X protein(Bax)with Western blot.Results Compared with the Control group,liver tissue in Model group rats showed injury,liver cell necrosis,and a large degree of inflammatory cell infiltration.Moreover,the cell apoptosis rate;serum AST,ALT,TBIL,and LDH activities;and liver tissue levels of TNF-α,IL-6,IL-1β,MDA,ROS,and Bax were significantly increased.Furthermore,liver tissue levels of IL-10,SOD,GSH-Px,Bcl-2,p-MST1/MST1,p-LATS1/LATS1,and p-YAP/YAP proteins were significantly reduced(P＜0.05).Compared with the Model group,liver tissue injury was reduced in Low LID,Medium LID,and High LID groups.The cell apoptosis rate;serum AST,ALT,TBIL,and LDH activities;and liver tissue levels of TNF-α,IL-6,1L-1β,MDA,ROS,and Bax were significantly reduced.Moreover,liver tissue levels of IL-10,SOD,GSH-Px,Bcl-2,p-MST1/MST1,p-LATS1/LATS1,and p-YAP/YAP proteins were significantly increased(P＜0.05).Hippo-YAP signaling pathway inhibitor verteporfin reversed the improving effect of LID on ischemia-reperfusion injury in OLT rats(P＜0.05).Conclusions LID may activate the Hippo-YAP pathway,which reduces the inflammatory response,oxidative stress,and liver cell apoptosis,and improves liver ischemia-reperfusion injury in OLT rats.
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Objective To identify and validate co-expressed genes associated with myocardial ischemia/reperfusion injury(MI/RI)and necrotic apoptosis by bioinformatics analysis.Methods Gene expression profile data for MI/RI were obtained by GSE67308 and GSE19875 datasets from the Gene Expression Omnibus(GEO)database.Differential expression analysis was conducted on the GSE67308 dataset to identify differentially expressed genes(DEGs),followed by gene set enrichment analysis and biological pathway analysis.More-over,immune cell infiltration analysis was performed on the GSE67308 dataset.Necrotic apoptosis-related genes were retrieved from the Molecular Signatures Database and the Kyoto Encyclopedia of Genes and Genomes(KEGG).A protein-protein interaction(PPI)network was constructed by overlapping DEGs with these necrotic apoptosis-related genes to identify key genes.Furthermore,the expression pat-terns of these key genes across various cardiac cell types were analyzed using a single-cell sequencing analysis platform,and validation of key gene expression was performed using the GSE19875 dataset.Results A total of 1054 DEGs were identified,comprising 363 upregu-lated and 691 downregulated genes.Gene enrichment analysis revealed that DEGs were primarily associated with processes related to apoptosis,immune responses,and intracellular signaling regulation.Moreover,biological pathway analysis demonstrated that DEGs were predominantly involved in the regulation of signaling pathways such as tumor necrosis factor(TNF)and NF-κB.Immune infiltration anal-ysis indicated a high degree of immune infiltration,particularly with natural killer cells and monocytes,in MI/RI myocardial tissue.PPI network analysis identified Il1b,TNF,Birc3,and Ripk1as crucial genes in the context of necrotic apoptosis.Single-cell sequencing anal-ysis showed the elevated expression of key genes within white blood cells.In comparison to the control group,the MI/RI model group in the GSE19875 dataset exhibited significantly increased expression of Il1b,TNF,Birc3,and Ripk1(P<0.01).Conclusion MI/RI is strongly correlated with the TNF signaling pathway and the NF-κB signaling pathway,both of which play pivotal roles in regulating necrotic apop-tosis.Il1b,TNF,Birc3,and Ripk1emerge as key genes that concurrently regulate both MI/RI and necrotic apoptosis.It is plausible that IL-1b,TNF,Birc3,and Ripk1 may serve as critical regulatory factors in the context of necrotic apoptosis during MI/RI.