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Resumen El tratamiento del infarto agudo de miocardio con elevación del segmento ST tiene barreras dependiendo de la región geográfica. La angioplastia coronaria primaria es el tratamiento de elección, siempre y cuando sea realizada dentro de tiempo y por operadores experimentados. Sin embargo, cuando no está disponible, la administración de fibrinólisis y el envío para angioplastia de rescate, en caso de reperfusión negativa, es la mejor estrategia. De la misma manera, la angioplastia coronaria, como parte de una estrategia farmacoinvasiva, es la mejor alternativa cuando hay reperfusión positiva. El desarrollo de redes de tratamiento del infarto aumenta el número de pacientes reperfundidos dentro de los tiempos recomendados y mejora los desenlaces. En América Latina, los programas nacionales para el tratamiento del infarto deben centrarse en mejorar los resultados y el éxito a largo plazo depende de trabajar hacia objetivos definidos y obtener métricas de rendimiento, por lo tanto, estos deben desarrollar métricas para cuantificar su desempeño. El siguiente documento discute todas estas alternativas y sugiere oportunidades de mejora.
Abstract The treatment of ST-segment elevation myocardial infarction has barriers depending on the geographic region. Primary coronary angioplasty is the treatment of choice, if it is performed on time and by experienced operators. However, when it is not available, the administration of fibrinolysis and referral for rescue angioplasty, in case of negative reperfusion, is the best strategy. In the same way, coronary angioplasty, as part of a pharmacoinvasive strategy, is the best alternative when there is positive reperfusion. The development of infarct treatment networks increases the number of patients reperfused within the recommended times and improves outcomes. In Latin America, national myocardial infarction treatment programs should focus on improving outcomes, and long-term success depends on working toward defined goals and enhancing functionality, therefore programs should develop capacity to measure their performance. The following document discusses all of these alternatives and suggests opportunities for improvement.
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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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Objective Cardio-cerebral infarction(CCI)is a severe clinical syndrome in which acute myocardial infarction(AMI)and acute ischemic stroke(AIS)occurs simultaneously(synchronous CCI,SCCI)or successively(metachronous CCI,MCCI).The study aims to explore its clinical profile,management and outcomes.Methods This is a single-center retrospective study of inpatients with CCI who presented to Xuanwu hospital from January 2014 to December 2021.The study collected and analyzed demographic informa-tion,clinical profile,management and outcomes(all-cause death,MACE events,mRS scores,bleeding events).Results Totally 137 patients with CCI were enrolled in the study,including 28 SCCI and 109 MCCI.Hypertension,smoking and diabetes were prominent risk factors for CCI.The heart function decreased significantly,including 42.9％suffered Killip Ⅲ-Ⅳ and 40.0％suffered decreased left ventricular ejection fraction.Large artery atherosclerosis was the most predominant etiology of AIS.The average NIHSS score was 11.24± 10.50.The rate of emergency reperfusion therapy was low(29.2％).Compared to the group that did not received emergence reperfusion therapy,the patients received emergency reperfusion therapy had a lower in-hospital mortality(P=0.042).All-cause mortality oc-curred in up to 27.0％,including 11.7％cardiovascular death.Heart failure(43.8％)was the most frequent MACE events.34.3％pa-tients had good neurological function(mRS 0-2)at discharge.27 patients(19.7％)experiencing major bleeding events,including 19 patients(13.9％)had the hemorrhagic transformation of AIS.Conclusion The CCI therapy still faces challenges,such as low reperfu-sion rate,differentiated antithrombotic options,and poor clinical prognosis.Large clinical research is need for promote the optimization of CCI treatment.
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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:To investigate the effect of conditioned medium from hypoxia/reoxygenation(H/R)-treated rat cardiac fibroblasts(CFs)on gap junction between cardiomyocytes and determine whether its mechanism is related to matrix metalloproteinase 2(MMP2)activity.METHODS:(1)H9c2 cells were randomly divided into five groups:con-trol group,normal group,ARP-100 group,H/R group,and H/R+ARP-100 group.Scrape loading/dye transfer assay was used to assess the gap junction function.Western blot was used to detect the expression and phosphorylation levels of Cx43.Gelatin zymography assay was performed to measure MMP2 activity.(2)SD rats were randomly divided into control group,ARP-100 group,ischemia-reperfusion(I/R)group,and I/R+ARP-100 group,with 8 rats in each group.Micro-electrode array technology was used to record the type and duration of arrhythmia.Immunohistochemistry experiment was performed to assess expression levels and distribution of Cx43 in myocardial tissues.RESULTS:Compared with the con-trol group,the H/R group showed decreased protein expression of Cx43(P＜0.01),narrowed distance of lucifer yellow dif-fusion(P＜0.01),and increased MMP2 activity(P＜0.01).ARP-100 attenuated H/R-induced gap junction dysfunction(P＜0.05).The arrhythmia score was also reduced after perfusion with ARP-100(P＜0.01).CONCLUSION:H/R-treated rat CFs can inhibit gap junction between cardiomyocytes,and its mechanism may involve increased MMP2 activity.
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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 effect of exercise preconditioning on angiogenesis in ischemic brain tissue in rats with cerebral ischemia-reperfusion injury in the view of VEGF/VEGFR2/dock6 signaling pathway. Method:SD male rats were divided into sham group,model group and exercise preconditioning group by ran-dom number table method,with 18 rats in each group.The sham operation group and the model group were not given any treatment,while the exercise preconditioning group was given adaptive running training for 3 days at a speed of 10 m/min,once a day for 20 minutes each time.After the adaptive training,the exercise preconditioning group was given formal running training for 3 weeks,continuous training for 6 days a week,rest for 1 day,electric treadmill slope of 0°,speed of 15m/min,30min/d.Model group and exercise precondi-tioning group were modified to prepare the middle cerebal artery occlusion(MACO)models by Koizumi thread method,while sham operation group only given skin cutting without thread insertion.Zea longa score and modi-fied neurological severity score(mNSS)were used to score neurological deficit in rats,the relative infarct size of the brain was detected by TTC staining,the morphological changes of the ischemic cerebral cortex was ob-served by HE staining,the expression of CD31 in ischemic cerebral cortex was detected by immunohistochemis-try and the expressions of VEGFA,VEGFR2,Dock6 in ischemic cerebral cortex were detected by western blot. Result:①Zea-Longa scoring:after awaking from anesthetizati,compared with the sham group,the Zea-Longa scores of the other two groups were increased(P＜0.01),and there was no statistical significance in the Zea-Lon-ga scores between the two groups.At 72 hours after reperfusion,compared with the sham group,the Zea-Longa score of the rats in the model group was significantly increased(P＜0.01);compared with the model group,the Zea-Longa score of the rats in the exercise preconditioning group was significantly decreased(P＜0.05).②mNSS scoring:At 72 hours after reperfusion,compared with the sham group,the mNSS score of the rats in the mod-el group was significantly increased(P＜0.01);compared with the model group,the mNSS score of the rats in the exercise preconditioning group was significantly decreased(P＜0.05).③TTC staining:Compared with the sham group,the cerebral infarction volume in the model group was increased(P＜0.01),and compared with the mod-el group,the cerebral infarction volume in the exercise preconditioning group was decreased(P＜0.05).④ HE staining:Compared with the sham group,the model group rats appeared significant pathological changes in the cerebral cortex on the ischemic side.Compared with the model group,the pathological changes of the cerebral cortex on the ischemic side of the rats in the exercise preconditioning group were alleviated.⑤ Immunohisto-chemistry of CD31:Compared with the sham group,the expression of CD31 in the ischemic cerebral cortex of the model group was significantly increased(P＜0.05).The expression of CD31 in the ischemic cerebral cortex of the exercise preconditioning group was further increased(P＜0.05).⑥Western blot of VEGF,VEGFR2 and Dock6:Compared with the sham group,the expressions of VEGF(P＜0.05),VEGFR2(P＜0.05)and Dock6(P＜0.01)in the ischemic cerebral cortex of the model group were significantly increased;compared with the model group,the expressions of VEGF(P＜0.05),VEGFR2(P＜0.05)and Dock6(P＜0.01)in the ischemic cerebral cor-tex of the exercise preconditioning group were further increased. Conclusion:Exercise preconditioning can effectively promote angiogenesis after cerebral ischemia and reduce cerebral ischemia-reperfusion injury,which may be related to the activation of VEGF/VEGFR2/Dock6 signaling pathway.
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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 investigate the mechanism of icariin regulating the NLRP3 inflammasome in the treatment of cerebral ischemia-reperfusion injury in rats.Methods A rat model of focal cerebral ischemia-reperfusion was induced using the thread embolism method.At 24 hours post-operation,the rats were randomly allocated into a sham operation group,model group,butylphthalide group(70 mg/kg),ICA-low dose(20 mg/kg),ICA-middle dose(40 mg/kg),and ICA-high dose(80 mg/kg)groups.The corresponding drugs were administered by gavage at 10 mL/kg once a day for 13 consecutive days.One hour after the last administration,neurological function was scored.The cerebral cortex was observed by hematoxylin-eosin(HE)staining.Expression of interleukin(IL)-1β and IL-18 in the cerebral cortex was determined by immunohistochemistry.Expression of NLRP3,ASC,and Caspase-1 in the cerebral cortex was determined by Western Blot.Results In contrast to the sham operation group,there was a notable increase in neural function scores within the model group.The ischemic area around the visible cerebral cortex showed neuron necrosis at various level or glial cell proliferation,and the number of intact neurons was significantly reduced.IL-1β and IL-18 positive cells were significantly increased.Expression of NLRP3,ASC,and Caspase-1 was significantly increased(P＜0.01,P＜0.05).After treatment with icariin,the neural function score was decreased significantly.The degree of neuronal necrosis in the peri-ischemic area was significantly reduced,and the number of intact neurons was significantly increased.IL-1 β and IL-18-positive cells were decreased significantly.Expressions of NLRP3,ASC,and Caspase-1 were significantly decreased(P＜0.01,P＜0.05).Conclusions Treatment of cerebral ischemia-reperfusion injury by icariin may be related to regulation of the NLRP3 inflammasome.
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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.
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Acute myocardial infarction(AMI)is a common cardiovascular emergency in clinic.Early reperfusion is a typical and effective method for the treatment of AMI.However,the recovery of blood supply after reperfusion therapy will accelerate the damage of ischemic myocardium and cause myocardial ischemia-reperfusion injury(MI/RI).In recent years,studies have found that TCM has the unique advantages of multi-component,multi-channel and multi-target in the intervention of MI/RI.Janus tyrosine kinase/signal transducer and activator of transcription(JAK/STAT)signaling pathway is closely related to MI/RI,which can reduce MI/RI process by regulating inflammation,oxidative stress,cell proliferation,differentiation and apoptosis.This article reviewed the mechanism of JAK/STAT signaling pathway in MI/RI and the research of TCM targeting this pathway,in order to provide references for the prevention and treatment of MI/RI and further drug development.
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Objective:To investigate the myocardial protective effect of extracorporeal cardiac shock wave therapy (CSWT) combined with sulfur hexafluoride microbubble post-conditioning on myocardial ischemia-reperfusion injury (MI/RI) in rats, and to provide theoretical support for clinical treatment of MI/RI.Methods:A total of 32 male SD rats were randomly divided into 4 groups: sham operation group (Sham group), MI/RI group (IR group), CSWT group (IR+ SW group), and CSWT combined with sulfur hexafluoride microbubble treatment group (IR+ SW+ MB group), with 8 rats in each group. Therapeutic intervention was performed in IR+ SW group and IR+ SW+ MB group on the 1st, 3rd and 5th day after modeling. The left ventricular end-diastolic diameter (LVEDD), left ventricular end-systolic diameter (LVESD), left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS) of the rats were measured by echocardiography before and after treatment. On the 7th day, myocardial fibrosis was assessed by Masson staining, and cardiomyocyte apoptosis was observed by TUNEL staining. The myocardial apoptotic proteins Bcl-2, BAX, Cleaved-Caspase-3 and Cleaved-Caspase-9 in the infarct boundary area were detected by Western blot. The differences of the above indexes among different groups were compared.Results:①There was no significant change in heart rhythm and heart rate among the groups before and after treatment, and there was no significant difference in heart rate ( P>0.05). ②The echocardiographic results after treatment showed that, compared with IR group, LVEDD and LVESD in IR+ SW group and IR+ SW+ MB group decreased in turn, while LVEF and LVFS increased in turn with significant differences between each two groups (all P<0.05). ③Compared with IR group, the degrees of myocardial fibrosis and apoptosis in IR+ SW group and IR+ SW+ MB group were alleviated in turn, and the relief in IR+ SW+ MB group was the most obvious. Quantitative analysis showed that compared with IR group, the proportions of cardiomyocyte apoptosis in IR+ SW group and IR+ SW+ MB group decreased in turn, and there were significant differences between each two groups (all P<0.05). ④The results of Western blot detection showed that compared with IR group, the levels of Bcl-2 in IR+ SW group and IR+ SW+ MB group increased in turn, while the levels of BAX and the activation level of Caspase-3 and Caspase-9 protein decreased in turn. These differences were all statistically significant between each two groups (all P<0.05) except for the activation level of Caspase-3 protein between IR+ SW group and IR+ SW+ MB group ( P>0.05). Conclusions:CSWT combined with sulfur hexafluoride microbubble therapy can improve left ventricular remodeling and left ventricular systolic function by inhibiting cardiomyocyte apoptosis.
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Objective To observe the effect of coronary reperfusion therapy on the differential ex-pression of plasma exosomal miRNAs in patients with acute myocardial infarction(AMI).Meth-ods Three elderly male AMI patients undergoing coronary reperfusion therapy in our hospital from October to November 2022 were recruited in this study.The venous blood samples were col-lected at admission and 2 and 24 h after recanalization.MiRNA-sequencing was used to screen the differentially expressed miRNAs which were commonly expressed in the plasma exosomes of the 3 patients.Bioinformatics analysis was performed on the target genes,and then the differentially expressed miR-499a-5p was verified by qPCR.Results Compared with the plasma exosomal miRNAs at admission,there were 418 up-regulated and 406 down-regulated miRNAs at 2 h after operation,and 320 up-regulated and 225 down-regulated miRNAs at 24 h after operation(P＜0.05);Compared with the miRNAs at 2 h after operation,there were 344 up-regulated and 350 down-regulated ones at 24 h after operation(P＜0.05).Kyoto Encyclopedia of Genes and Ge-nomes enrichment analysis showed that the differentially expressed miRNAs were enriched in phosphatidylinositol-3-kinase-protein kinase B,hypoxia-inducible factor 1,and vascular smooth muscle contraction pathways.Gene Ontology analysis indicated that the molecular functions of dif-ferentially expressed miRNA target genes were mainly enriched in protein binding and DNA bind-ing;cellular components were mainly enriched in cell membrane and cytoplasm;and biological processes were mainly enriched in signaling and transcription of DNA templates.The miR-499a-5p level was significantly lower at 2 h postoperatively than at admission[(0.577±0.020)vs(1.000± 0.023),P＜0.05],and at 24 h postoperatively than at 2 h postoperatively[(0.068±0.006)vs(0.577±0.020),P＜0.05].Conclusion Plasma exosomal miRNAs can be used as a biomarker for early diagnosis of elderly AMI patients and for predicting the efficacy of reperfusion therapy.
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Objective To investigate the effect of electroacupuncture preconditioning on microglia polarization in rats after cerebral ischemia reperfusion(IR)injury and explore the role of tyrosine kinase 2(J AK2)/signal transducer and activator of transcription 3(STAT3)pathway in the process.Methods Forty-five clean-grade healthy male Sprague-Dawley rats were randomly and equally divided into sham operation group,IR group and electroacupuncture preconditioning group.Rat model of IR injury was induced with thread occlusion of the internal carotid artery.Before modeling,electroacupuncture preconditioning was applied to Baihui acupoint for 5 consec-utive days in the preconditioning group,and exposure of the cervical blood vessels were inflicted in the sham-operation group.At 24 h after reperfusion,the severity of neurological deficit was observed by modified neurological deficit score(mNSS),and the cerebral infarct volume was observed by TTC staining.Western blotting was used to detect the protein levels of classical acti-vated type(M1)marker inducible nitric oxide synthase(iNOS),alternative activated type(M2)marker arginase 1(Arg-1),JAK2 and p-JAK2,and STAT3 and p-STAT3,and q-PCR was applied to detect the mRNA expression of iNOS and Arg-1.The expression of TNF-α and IL-10 was measured by ELISA.Results Compared with the sham operation group,the mNSS,infarct vol-ume,protein levels of p-JAK2/JAK2,p-STAT3/STAT3,protein and mRNA levels of iNOS and Arg-1,and expression of TNF-α and IL-10 were significantly increased in the IR and electroacu-puncture preconditioning groups(P＜0.01).The preconditioning group had obviously lower mNSS,smaller infarct volume,decreased protein levels of p-JAK2/JAK2,p-STAT3/STAT3,re-duced protein and mRNA levels of iNOS,and declined TNF-α expression,but elevated expression of Arg-1 at protein(2.0±0.2 vs 1.5±0.1)and mRNA(4.2±0.8 vs 3.1±0.3)levels and increased IL-10 expression(49.1±7.1 pg/mg vs 27.9±5.9 pg/mg)when compared with the IR group(P＜0.01).Conclusion Electroacupuncture preconditioning can promote the polarization of microglia to M2 and inhibit the polarization of microglia to M1 after cerebral IR injury,which may be relat-ed to the inhibition of JAK2/STAT3 pathway.
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Objective To investigate the action mechanism of long non-coding RNA(lncRNA)-N1LR on blood-brain barrier(BBB)after cerebral ischemia-reperfusion(I/R)injury.Methods Primary rat brain microvascular endothelial cells(BMECs)were cultured and treated with OGD/R to simulate cerebral I/R injury.The experiment was divided into normal control group,ln-cRNA-N1LR OGD group,overexpression group(lncRNA-N1LR overexpression after OGD treat-ment)and silence group(lncRNA-N1LR silence after OGD treatment).The mRNA levels of ln-cRNA-N1LR,claudin-5 and occludin in each group were detected by RT-qPCR.The BBB permea-bility was detected by FITC-dextran infiltration assay.The expression of claudin-5 and occludin were detected by Western blotting.Results The mRNA levels of lncRNA-N1LR,occludin and claudin-5 were significantly decreased(0.31±0.01 vs 1.00±0.10,0.42±0.03 vs 1.01±0.13,0.38±0.03 vs 1.00±0.15,P＜0.05),and the BBB permeability was significantly increased(58.79± 3.04 vs 8.87±0.63,P＜0.05)in the OGD group than the control group.The lncRNA-N1LR over-expression group increased the mRNA expression of lncRNA-N1LR,occludin and claudin-5(0.67±0.07 vs 0.31±0.01,0.92±0.02 vs 0.42±0.03,0.70±0.08 vs 0.38±0.03,P＜0.05),and decreased the BBB permeability(41.57±2.43 vs 58.79±3.04,P＜0.05)than the OGD group.lncRNA-N1LR silence resulted in lower mRNA levels of lncRNA-N1LR,occludin and claudin-5(0.21±0.02 vs 0.31±0.01,0.31±0.03 vs 0.42±0.03,0.22±0.02 vs 0.38±0.03,P＜0.05),and enhanced BBB permeability(72.34±1.43 vs 58.79±3.04,P＜0.05)when compared with the OGD group.Conclusion Up-regulation of lncRNA-N1LR may play a neuroprotective role by reducing BBB permeability.
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Objective:To evaluate the role of O-sialoglycoprotein endopeptidase (OSGEP) in hepatic ischemia-reperfusion injury (HIRI) and the relationship with oxidative stress in mice.Methods:Experiment Ⅰ Twenty-four SPF healthy male C57BL/6 mice, 12 wild-type and 12 OSGEP knockdown, aged 6-8 weeks, weighing 18-22 g, were divided into 4 groups ( n=6 each) by the random number table method: wild-type shamoperation group (Sham group), wild-type HIRI group (HIRI group), OSGEP knockdown+ sham operation group (Sham+ KD group) and OSGEP knockdown+ HIRI group (HIRI+ KD group). Ischemia-reperfusion model was prepared by blocking the hepatic artery and portal vein for 60 min followed by reperfusion in anesthetized animals, the blood vessels were only exposed without occlusion in Sham group and Sham+ KD group, and the blood vessels were clamped for 60 min followed by reperfusion in HIRI group and HIRI+ KD group. The mice were sacrificed after 6-h reperfusion to extract liver tissue samples for microscopic examination of histopathological changes (with an optical microscope after HE staining) which were evaluated using Suzuki score and for determination of the serum concentrations of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), level of reactive oxygen species (ROS) (using the DCFH-DA fluorescent probe method), contents of malondialdehyde (MDA) and glutathione(GSH) in liver tissues (using a colorimetric method) and expression of OSGEP (using Western blot). Experiment Ⅱ The well-growing AML12 cells were divided into 4 groups ( n=30 each) using a random number table method: control group (C group), oxygen-glucose deprivation/restoration (OGD/R) group, OGD/R+ OSGEP knockdown group (OGD/R+ KD group), and OGD/R+ OSGEP knockdown negative control group (OGD/R+ NC group). Group C was cultured under normal conditions. Group OGD/R was subjected to O 2-glucose deprivation for 6 h followed by restoration of O 2-glucose supply for 24 h in OGD/R group. In OGD/R+ KD group, stable transfection of AML12 cells with OSGEP knockdown was performed prior to the experiment, and the other procedures were the same as those previously described. The cell survival rate was measured by the CCK-8 assay, the release of lactate dehydrogenase (LDH) was measured, the DCFH-DA method was used to detect the levels of ROS, and the contents of MDA and GSH were determined using a colorimetric method. Results:Experiment Ⅰ Compared with Sham group, the expression of OSGEP was significantly down-regulated, the serum concentrations of AST and ALT, Suzuki score, levels of ROS and content of MDA were increased, and the GSH content was decreased in HIRI group ( P<0.05), and no significant change was found in each parameter in Sham+ KD group ( P>0.05). Compared with HIRI group, the serum concentrations of AST and ALT, Suzuki score, levels of ROS and content of MDA were significantly increased, and the GSH content was decreased in HIRI+ KD group ( P<0.05). Experiment Ⅱ Compared with group C, the expression of OSGEP was significantly down-regulated, the cell survival rate and GSH content were decreased, and the release of LDH, levels of ROS and content of MDA were increased in group OGD/R ( P<0.05). Compared with OGD/R group, the cell survival rate and GSH content were significantly decreased, and the release of LDH, levels of ROS and content of MDA were increased in OGD/R+ KD group ( P<0.05), and no significant change was found in each parameter in OGD/R+ NC group ( P>0.05). Conclusions:OSGEP plays an endogenous protective role in HIRI by inhibiting oxidative stress in mice.
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Objective:To evaluate the role of nuclear factor E2-related factor 2 (Nrf2)/heme oxidase-1 (HO-1) in reduction of renal ischemia-reperfusion (I/R) injury by the human umbilical cord mesenchymal stem cells (hucMSCs)-derived exosomes (hucMSCs-exo) in mice.Methods:The hucMSCs were cultured, and exosomes were extracted and identified by transmission electron microscopy, nanoparticle tracking analysis and Western blot. Thirty-six male SPF-grade C57BL/6 mice, weighing 20-25 g, were used. Thirty mice were selected and divided into 5 groups ( n=6 each) by a random number table method: sham operation group (Sham group), sham operation + Nrf2 inhibitor ML385 group (Sham + ML385 group), renal I/R group (I/R group), renal I/R + exosome group (I/R+ EXO group), and renal I/R + exosome + Nrf2 inhibitor ML385 group (I/R+ EXO+ ML385 group). A model of renal I/R injury was prepared by clamping the bilateral renal pedicles for 45 min followed by perfusion in anesthetized animals. ML385 30 mg/kg was intraperitoneally injected at 45 min before preparing the model in Sham+ ML385 group and I/R+ EXO+ ML385 group, and hucMSCs-exo 100 μg was injected via the tail vein at 15 min before reperfusion in I/R+ EXO group and I/R+ EXO+ ML385 group. Serum blood urea nitrogen (BUN) and creatinine (Cr) concentrations were detected at 24 h of reperfusion. The renal tissues were obtained for examination of the pathological changes and for determination of contents of interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α) and malondialdehyde (MDA), superoxide dismutase (SOD) activity and reactive oxygen species (ROS) levels and expression of Nrf2 and HO-1 protein and mRNA (by Western blot and quantitative real-time polymerase chain reaction). The left 6 mice were allocated to sham operation group (Sham-IM group, n=3) and renal I/R group (I/R-IM group, n=3) by a random number table method for VISQUE in living imaging observation. Results:The exosomes showed a typical cup-shaped morphology with a transmission electron microscope, the nanoparticles tracked and analyzed the average diameter of the exosome, with an average diameter of 96.7 nm, and the positive expression of surface markers CD9, CD63 and TSG101 was detected using Western blot. The renal fluorescence intensity value was significantly increased in I/R-IM group as compared with Sham-IM group ( P<0.05). Compared with Sham group, the serum BUN and Cr concentrations were significantly increased, the contents of IL-6, TNF-α and MDA and ROS levels were increased, the activity of SOD was decreased, the expression of Nrf2 and HO-1 protein and mRNA was down-regulated ( P<0.05), and the pathological changes of renal tissues were aggravated in I/R group, and no significant change was found in serum BUN and Cr concentrations in Sham+ ML385 group ( P>0.05). Compared with I/R group, the serum BUN and Cr concentrations were significantly decreased, the contents of IL-6, TNF-α and MDA and ROS levels were decreased, the activity of SOD was increased, the expression of Nrf2 and HO-1 protein and mRNA was up-regulated ( P<0.05), and the pathological changes of renal tissues were significantly attenuated in I/R+ EXO group. Compared with I/R+ EXO group, the serum BUN and Cr concentrations were significantly increased, the contents of IL-6, TNF-α and MDA and ROS levels were increased, the activity of SOD was decreased, the expression of Nrf2 and HO-1 protein and mRNA was down-regulated ( P<0.05), and the pathological changes of renal tissues were aggravated in I/R+ EXO+ ML385 group. Conclusions:The mechanism by which hucMSCs-exo reduces renal I/R injury may be related to activation of the Nrf2/HO-1 signaling pathway in mice.