Objective MicroRNA-1(miR-1)aggravates myocardial ischemia–reperfusion(I/R)injury,whereas insulin-like growth factor-1(IGF-1)maintains cardiomyocyte homeostasis.In this study,the aim is to investigate whether miR-1 ca...Objective MicroRNA-1(miR-1)aggravates myocardial ischemia–reperfusion(I/R)injury,whereas insulin-like growth factor-1(IGF-1)maintains cardiomyocyte homeostasis.In this study,the aim is to investigate whether miR-1 can exacerbate I/R injury through the regulation of IGF-1.Methods The infarct area,lactate dehydrogenase,miR-1 level,and apoptosis level were examined in the Langendorff isolated rat I/R model.The hypoxia–reoxygenation model of rat cardiacmyocytes and H9c2 cells were developed to determine the levels of miR-1,IGF-1 mRNA,and IGF-1 protein.Furthermore,the dual-luciferase assay was used to verify the relationship between miR-1 and IGF-1.Results Overexpression of miR-1 increased the level of apoptosis and decreased the IGF-1 expression.However,inhibition of miR-1 expression decreased the level of apoptosis,alleviated the degree of injury,and increased the IGF-1 expression.Overexpression of IGF-1 also reduced the degree of cellular damage and level of apoptosis caused by the overexpression of miR-1.When IGF-1 was knocked down,myocardial cells displayed more severe damage and a higher apoptosis level,even with decreased levels of miR-1.Conclusion miR-1 promotes apoptosis and aggravates I/R injury by downregulating IGF-1.展开更多
Several studies have shown that activation of unfolded protein response and endoplasmic reticulum(ER)stress plays a crucial role in severe cerebral ischemia/reperfusion injury.Autophagy occurs within hours after cereb...Several studies have shown that activation of unfolded protein response and endoplasmic reticulum(ER)stress plays a crucial role in severe cerebral ischemia/reperfusion injury.Autophagy occurs within hours after cerebral ischemia,but the relationship between ER stress and autophagy remains unclear.In this study,we established experimental models using oxygen-glucose deprivation/reoxygenation in PC12 cells and primary neurons to simulate cerebral ischemia/reperfusion injury.We found that prolongation of oxygen-glucose deprivation activated the ER stress pathway protein kinase-like endoplasmic reticulum kinase(PERK)/eukaryotic translation initiation factor 2 subunit alpha(e IF2α)-activating transcription factor 4(ATF4)-C/EBP homologous protein(CHOP),increased neuronal apoptosis,and induced autophagy.Furthermore,inhibition of ER stress using inhibitors or by si RNA knockdown of the PERK gene significantly attenuated excessive autophagy and neuronal apoptosis,indicating an interaction between autophagy and ER stress and suggesting PERK as an essential target for regulating autophagy.Blocking autophagy with chloroquine exacerbated ER stress-induced apoptosis,indicating that normal levels of autophagy play a protective role in neuronal injury following cerebral ischemia/reperfusion injury.Findings from this study indicate that cerebral ischemia/reperfusion injury can trigger neuronal ER stress and promote autophagy,and suggest that PERK is a possible target for inhibiting excessive autophagy in cerebral ischemia/reperfusion injury.展开更多
Reperfusion following cerebral ischemia causes both structural and functional damage to brain tissue and could aggravate a patient's condition;this phenomenon is known as cerebral ischemia-reperfusion injury.Curre...Reperfusion following cerebral ischemia causes both structural and functional damage to brain tissue and could aggravate a patient's condition;this phenomenon is known as cerebral ischemia-reperfusion injury.Current studies have elucidated the neuroprotective role of the sirtuin protein family(Sirtuins)in modulating cerebral ischemia-reperfusion injury.However,the potential of utilizing it as a novel intervention target to influence the prognosis of cerebral ischemia-reperfusion injury requires additional exploration.In this review,the origin and research progress of Sirtuins are summarized,suggesting the involvement of Sirtuins in diverse mechanisms that affect cerebral ischemia-reperfusion injury,including inflammation,oxidative stress,blood-brain barrier damage,apoptosis,pyroptosis,and autophagy.The therapeutic avenues related to Sirtuins that may improve the prognosis of cerebral ischemia-reperfusion injury were also investigated by modulating Sirtuins expression and affecting representative pathways,such as nuclear factor-kappa B signaling,oxidative stress mediated by adenosine monophosphate-activated protein kinase,and the forkhead box O.This review also summarizes the potential of endogenous substances,such as RNA and hormones,drugs,dietary supplements,and emerging therapies that regulate Sirtuins expression.This review also reveals that regulating Sirtuins mitigates cerebral ischemia-reperfusion injury when combined with other risk factors.While Sirtuins show promise as a potential target for the treatment of cerebral ischemiareperfusion injury,most recent studies are based on rodent models with circadian rhythms that are distinct from those of humans,potentially influencing the efficacy of Sirtuinstargeting drug therapies.Overall,this review provides new insights into the role of Sirtuins in the pathology and treatment of cerebral ischemia-reperfusion injury.展开更多
Cerebral ischemia/reperfusion(I/R)injury is an important pathophysiological condition of ischemic stroke that involves a variety of physiological and pathological cell death pathways,including autophagy,apoptosis,necr...Cerebral ischemia/reperfusion(I/R)injury is an important pathophysiological condition of ischemic stroke that involves a variety of physiological and pathological cell death pathways,including autophagy,apoptosis,necroptosis,and phagoptosis,among which autophagy is the most studied.We have reviewed studies published in the past 5 years regarding the association between autophagy and cerebral I/R injury.To the best of our knowledge,this is the first review article summarizing potential candidates targeting autophagic pathways in the treatment of I/R injury post ischemic stroke.The findings of this review may help to better understand the pathogenesis and mechanisms of I/R events and bridge the gap between basic and translational research that may lead to the development of novel therapeutic approaches for I/R injury.展开更多
Ischemia–reperfusion injury is a common pathophysiological mechanism in retinal degeneration.PANoptosis is a newly defined integral form of regulated cell death that combines the key features of pyroptosis,apoptosis,...Ischemia–reperfusion injury is a common pathophysiological mechanism in retinal degeneration.PANoptosis is a newly defined integral form of regulated cell death that combines the key features of pyroptosis,apoptosis,and necroptosis.Oligomerization of mitochondrial voltage-dependent anion channel 1 is an important pathological event in regulating cell death in retinal ischemia–reperfusion injury.However,its role in PANoptosis remains largely unknown.In this study,we demonstrated that voltage-dependent anion channel 1 oligomerization-mediated mitochondrial dysfunction was associated with PANoptosis in retinal ischemia–reperfusion injury.Inhibition of voltage-dependent anion channel 1 oligomerization suppressed mitochondrial dysfunction and PANoptosis in retinal cells subjected to ischemia–reperfusion injury.Mechanistically,mitochondria-derived reactive oxygen species played a central role in the voltagedependent anion channel 1-mediated regulation of PANoptosis by promoting PANoptosome assembly.Moreover,inhibiting voltage-dependent anion channel 1 oligomerization protected against PANoptosis in the retinas of rats subjected to ischemia–reperfusion injury.Overall,our findings reveal the critical role of voltage-dependent anion channel 1 oligomerization in regulating PANoptosis in retinal ischemia–reperfusion injury,highlighting voltage-dependent anion channel 1 as a promising therapeutic target.展开更多
Vascular endothelial growth factor and its mimic peptide KLTWQELYQLKYKGI(QK)are widely used as the most potent angiogenic factors for the treatment of multiple ischemic diseases.However,conventional topical drug deliv...Vascular endothelial growth factor and its mimic peptide KLTWQELYQLKYKGI(QK)are widely used as the most potent angiogenic factors for the treatment of multiple ischemic diseases.However,conventional topical drug delivery often results in a burst release of the drug,leading to transient retention(inefficacy)and undesirable diffusion(toxicity)in vivo.Therefore,a drug delivery system that responds to changes in the microenvironment of tissue regeneration and controls vascular endothelial growth factor release is crucial to improve the treatment of ischemic stroke.Matrix metalloproteinase-2(MMP-2)is gradually upregulated after cerebral ischemia.Herein,vascular endothelial growth factor mimic peptide QK was self-assembled with MMP-2-cleaved peptide PLGLAG(TIMP)and customizable peptide amphiphilic(PA)molecules to construct nanofiber hydrogel PA-TIMP-QK.PA-TIMP-QK was found to control the delivery of QK by MMP-2 upregulation after cerebral ischemia/reperfusion and had a similar biological activity with vascular endothelial growth factor in vitro.The results indicated that PA-TIMP-QK promoted neuronal survival,restored local blood circulation,reduced blood-brain barrier permeability,and restored motor function.These findings suggest that the self-assembling nanofiber hydrogel PA-TIMP-QK may provide an intelligent drug delivery system that responds to the microenvironment and promotes regeneration and repair after cerebral ischemia/reperfusion injury.展开更多
Nitric oxide(NO)is a gaseous molecule produced by 3 different NO synthase(NOS)isoforms:Neural/brain NOS(nNOS/bNOS,type 1),endothelial NOS(eNOS,type 3)and inducible NOS(type 2).Type 1 and 3 NOS are constitutively expre...Nitric oxide(NO)is a gaseous molecule produced by 3 different NO synthase(NOS)isoforms:Neural/brain NOS(nNOS/bNOS,type 1),endothelial NOS(eNOS,type 3)and inducible NOS(type 2).Type 1 and 3 NOS are constitutively expressed.NO can serve different purposes:As a vasoactive molecule,as a neurotransmitter or as an immunomodulator.It plays a key role in cerebral ischemia/reperfusion injury(CIRI).Hypoxic episodes simulate the production of oxygen free radicals,leading to mitochondrial and phospholipid damage.Upon reperfusion,increased levels of oxygen trigger oxide synthases;whose products are associated with neuronal damage by promoting lipid peroxidation,nitrosylation and excitotoxicity.Molecular pathways in CIRI can be altered by NOS.Neuroprotective effects are observed with eNOS activity.While nNOS interplay is prone to endothelial inflammation,oxidative stress and apoptosis.Therefore,nNOS appears to be detrimental.The interaction between NO and other free radicals develops peroxynitrite;which is a cytotoxic agent.It plays a main role in the likelihood of hemorrhagic events by tissue plasminogen activator(t-PA).Peroxynitrite scavengers are currently being studied as potential targets to prevent hemorrhagic transformation in CIRI.展开更多
BACKGROUND Myocardial ischemia/reperfusion(I/R)injury,which is associated with high morbidity and mortality,is a main cause of unexpected myocardial injury after acute myocardial infarction.However,the underlying mech...BACKGROUND Myocardial ischemia/reperfusion(I/R)injury,which is associated with high morbidity and mortality,is a main cause of unexpected myocardial injury after acute myocardial infarction.However,the underlying mechanism remains unclear.Circular RNAs(circRNAs),which are formed from protein-coding genes,can sequester microRNAs or proteins,modulate transcription and interfere with splicing.Authoritative studies suggest that circRNAs may play an important role in myocardial I/R injury.AIM To explore the role and mechanism of circRNAs in myocardial I/R injury.METHODS We constructed a myocardial I/R injury model using ligation of the left anterior descending coronary artery,and evaluated the success of the validated model using triphenyltetrazolium chloride and hematoxylin-eosin staining.Then,left ventricular samples from different groups were selected for mRNA-sequence,and differential gene screening was performed on the obtained results.The differentially obtained mRNAs were divided into up-regulated and down-regulated according to their expression levels,and Gene Ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)functional enrichment analysis were performed,respectively.Then,the obtained circRNA and microRNA(miRNA)were paired for analysis,and the binding sites of miRNA and mRNA were virtual screened.Finally,the obtained circRNA,miRNA and mRNA were constructed by ceRNA mutual most useful network.RESULTS We used an RNA sequencing array to investigate the expression signatures of circRNAs in myocardial I/R injury using three samples from the I/R group and three samples from the sham group.A total of 142 upregulated and 121 downregulated circRNAs were found to be differentially expressed(fold change≥2,P<0.05).GO and KEGG functional analyses of these circRNAs were performed.GO analysis revealed that these circRNAs were involved mainly in cellular and intracellular processes.KEGG analysis demonstrated that 6 of the top 20 pathways were correlated with cell apoptosis.Furthermore,a circRNA-miRNA coexpression network and ceRNA network based on these genes were constructed,revealing that mmu-circ-0001452,mmu-circ-0001637,and mmu-circ-0000870 might be key regulators of myocardial I/R injury.CONCLUSION This research provides new insights into the mechanism of myocardial I/R,which mmu-circ-0001452,mmu-circ-0001637,and mmu-circ-0000870 are expected to be new therapeutic targets for myocardial I/R injury.展开更多
Background:Astrocyte endfeet(AEF)serves as a key element of the blood-brain barrier and is important for the survival and maintenance of neuronal function.However,the immunohistochemical and ultrastructural changes of...Background:Astrocyte endfeet(AEF)serves as a key element of the blood-brain barrier and is important for the survival and maintenance of neuronal function.However,the immunohistochemical and ultrastructural changes of AEF in the CA1 and CA3 areas of the hippocampus over time following cerebral ischemia-reperfusion(IR)injury have not been well elucidated.Objectives:We investigated chronological changes in AEF in the gerbil hippocampal CA1 area from 3 h to 10 days following transient forebrain ischemia(TFI),and examined their association with neuronal death and tissue repair following IR injury.Changes in the CA3 area were also examined at 10 days post-TFI for comparative purposes.Methods:Neuronal death was confirmed using histochemistry,immunohistochemistry,and histofluorescence.Changes in AEF were examined by double immunofluorescence with glial fibrillary acidic protein(GFAP)and glucose transporter 1(GLUT1),and by transmission electron microscopy(TEM)for ultrastructural changes.Results:Significant TFI-induced neuronal death occurred in the CA1 area on day 5 following IR injury and persisted until 10 days after TFI,while no neuronal death(or loss)was found in the CA3 area after TFI.Looking at TFI-induced changes in AEF,at 3 and 6 h after TFI,GFAP-immunoreactive(+)AEF in the CA1 area appeared swollen and harbored enlarged,dark mitochondria,and the swelling was reduced by 1-day post-TFI.On 2 and 5 days following TFI,GFAP+AEF were markedly enlarged and fragmented,containing shrunken mitochondria,vacuolations,and sparse organelles.Ten days post-TFI,the ends of GFAP+astrocytic processes extended to microvessels,appeared edematous,and were filled with cellular debris.In the CA3 area,AEF was slightly dilated at 10 days after TFI.These findings indicate that damage to or disruption of AEF in the CA1 area occurs in the early phase after 5-min TFI but is rarely observed in the CA3 area.Conclusion:Taken together,damage to or disruption of AEF following ischemic insults may be strongly linked to neuronal death/loss.展开更多
Objectives:Skeletal muscle ischemia/reperfusion injury(IRI)occurs as a result of a marked reduction in arterial perfusion to a limb and can lead to tissue death and threaten limb viability.This work assessed the effec...Objectives:Skeletal muscle ischemia/reperfusion injury(IRI)occurs as a result of a marked reduction in arterial perfusion to a limb and can lead to tissue death and threaten limb viability.This work assessed the effects of 20-hydroxyecdysone(20E)on hindlimb skeletal tissue following tourniquet-induced ischemia/reperfusion injury.Methods:Animals were divided into 4 groups—control group(Control),Control+20E(C+20E),mice with IRI(IRI),and mice with IRI+20E(IRI+20E).IRI was modeled by applying a tourniquet to the hind limb for 2 h with reperfusion for 1 h.5 mg/kg of 20E was administered intraperitoneally for 14 days.Afterward,the physical activity of mice,the histological structure of the quadriceps femoris,the expression of genes encoding proteins induced by hypoxia and involved in tissue adaptation to ischemia,and the functional parameters of skeletal muscle mitochondria were assessed.Results:It was shown that IRI of the limbs leads to functional disorders,depression of muscle function,accumulation of malondialdehyde(MDA)in mitochondria,and a decrease in their Ca2+buffering capacity,as well as an increase in the expression of HIF-1α,VGEF-A,PGC1αand PDGF-BB genes associated with adaptation to ischemia.20E reduced the intensity of degenerative processes in skeletal muscles,which was expressed in a decrease in the number of centrally nucleated fibers.Analysis of gene expression levels indicated a high degree of adaptation of animals to IRI.20E reduced the level of MDA in mitochondria,but did not affect the rate of respiration and calcium retention capacity of organelles both in normal conditions and during IRI.Conclusion:20E partially alleviates the skeletal muscle damage caused by IRI and can be used as part of combination therapy.展开更多
OBJECTIVE:To evaluate the effect of Yiqi Liangxue Shengji prescription(益气凉血生肌方,YQLXSJ)on cardiac function and outcomes in acute myocardial infarction(AMI)patients with myocardial ischemiareperfusion injury(MIRI...OBJECTIVE:To evaluate the effect of Yiqi Liangxue Shengji prescription(益气凉血生肌方,YQLXSJ)on cardiac function and outcomes in acute myocardial infarction(AMI)patients with myocardial ischemiareperfusion injury(MIRI)and to determine its clinical efficacy.METHODS:This prospective,randomized,double-blind,placebo-controlled trial enrolled hospitalized patients with AMI who underwent percutaneous coronary intervention and experienced MIRI either intraoperatively or postoperatively.Participants were randomly allocated to the treatment group,which received YQLXSJ,or the control group,which received a placebo,concurrent with standard Western Medicine therapy.The intervention period lasted 8 weeks.The primary outcome measure was left ventricular ejection fraction(LVEF),determined by echocardiography.Secondary outcomes included Nterminal pro brain natriuretic peptide(NT-pro BNP)and cardiac troponin I(cTnI)levels,left ventricular internal diameter,major adverse cardiovascular events(MACE),angina pectoris scores,and Chinese medicine evidence scores.RESULTS:Following 8 weeks of intervention,the treatment group demonstrated a significant increase in LVEF and a marked reduction in NT-pro BNP when compared to the control group.There was also a significant decrease in peak cTnI levels,Chinese medicine evidence scores,and angina pectoris scores.The control group's left ventricular end-systolic diameter(LVESD)significantly increased compared to baseline after 8 weeks(P<0.05),whereas the treatment group's LVESD showed no significant change from baseline(P>0.05).Although the treatment group showed a downward trend in MACE incidence compared to the control group,this difference was not statistically significant(P>0.05).CONCLUSIONS:This study demonstrated that the addition of YQLXSJ to standard therapy can improve cardiac function and alleviate clinical symptoms in AMI patients with MIRI,and also showed a potential to mitigate the incidence of MACE.Furthermore,YQLXSJ displayed a favorable safety profile in clinical application.展开更多
Increasing evidence of the significant clinical value of protection against ischemia/reperfusion injury has contributed to the realization of the independent importance of this approach in improving prognosis and redu...Increasing evidence of the significant clinical value of protection against ischemia/reperfusion injury has contributed to the realization of the independent importance of this approach in improving prognosis and reducing cardiovascular mortality.Extracellular vesicles(EVs)derived by adipose mesenchymal stem cells may mediate the paracrine effects of stem cells and provide regenerative and anti-inflammatory properties,which are enhanced byγ-aminobutyric acid.The protective effects on cardiac myocytes may result from the EV embarked by miR-21-5p,which is a target for thioredoxin-interacting protein,regulating the formation of thioredoxin-interacting protein-thioredoxin complexes and subsequently enhancing the antioxidant activity of thioredoxin.It has been found thatγ-aminobutyric acid governs myocardial bioenergetics through suppressing inflammation and supporting mitochondrial structure.Finally,stem cell-based cell-free therapy based on adipose-derived stem cell EVs is considered a promising approach to individualized management of ischemia-induced cardiomyopathy.展开更多
Ferroptosis is a novel form of non-apoptotic cell death that has been widely studied in recent years and is involved in a variety of pathophysiological processes.The core treatment goal of ischemic stroke is to restor...Ferroptosis is a novel form of non-apoptotic cell death that has been widely studied in recent years and is involved in a variety of pathophysiological processes.The core treatment goal of ischemic stroke is to restore blood flow as early as possible,while the pathological mechanism of reperfusion injury after restoring blood flow is complex,involving oxidative stress,calcium overload,and inflammatory response.In recent years,more and more studies have found that ferroptosis mediation is involved in the occurrence and development of cerebral ischemia-reperfusion injury.This paper elaborates on the concept,mechanisms,and regulation of ferroptosis,detailing its role in cerebral ischemia-reperfusion injury and potential inhibition strategies.The aim is to deepen the understanding of ferroptosis in this pathological process and provide insights for possible targeted therapies.展开更多
Hepatic ischemia/reperfusion injury(IRI)remains a critical complication contributing to graft dysfunction following liver surgery.As part of an ongoing search for hepatoprotective natural products,five previously unre...Hepatic ischemia/reperfusion injury(IRI)remains a critical complication contributing to graft dysfunction following liver surgery.As part of an ongoing search for hepatoprotective natural products,five previously unreported homoadamantane-type polycyclic polyprenylated acylphloroglucinols(PPAPs),named hyperhomanoons A-E(1-5),and one known analog,hypersampsone O(6),were isolated from Hypericum patulum.Among these,compound 6 demonstrated potent protective effects against CoCl_(2)-induced hypoxic injury in hepatocytes.Furthermore,in a murine model of hepatic IRI induced by vascular occlusion,pretreatment with 6 markedly alleviated liver damage and reduced hepatocyte apoptosis.This study is the first to identify PPAPs as promising scaffolds for the development of therapeutic agents targeting hepatic IRI,underscoring their potential as lead compounds in drug discovery efforts for ischemic liver diseases.展开更多
Introduction: Renal ischemia-reperfusion (IR) is responsible for injuries such as destruction or dysfunction of tubular epithelial cells with inflammatory reaction and oxidative stress. Several therapeutic methods hav...Introduction: Renal ischemia-reperfusion (IR) is responsible for injuries such as destruction or dysfunction of tubular epithelial cells with inflammatory reaction and oxidative stress. Several therapeutic methods have been tested to alleviate ischemia-perfusion injury, ranging from using anti-inflammatory drugs, antioxidants, and plants from traditional pharmacopeia to administering RNA interference. However, there is currently no effective therapeutic option available for the treatment of renal IR injury, other than supportive therapies such as renal replacement therapy or hydration. Objective: This present study aimed to evaluate the effect of Guiera senegalensis on renal ischemia reperfusion, a recognized plant for its antioxidant and anti-inflammatory properties. Materials and Methods: Twenty-four (24) adult male Wistar rats were divided into four following groups: SLAM (subjected to a median laparotomy with simulated ischemia);GUIERRA (animals that received 250 mg/kg of guierra senegalensis orally, once a day, for 5 days, with simulated renal ischemia);IR (animals that underwent laparotomy followed by clamping of bilateral renal pedicles for 45 min and followed by reperfusion);GUIERRA + IR (animals given GUIERRA at the dosage of 250 mg/kg per day, for 5 days and then subjected to renal ischemia-reperfusion). Data analysis was performed by ANOVA, and a significance level of p Results: Compared with the I/R group, rats in the GUIERRA + IR group showed reduced histopathological damage scores (p Conclusion: The results of this preliminary work suggest that Guiera senegalensis decreases the degree of tissue damage in renal ischemia-reperfusion cases. This plant seems to be a promising therapeutic;further studies could help to precise the targets of its compounds on ischemia-reperfusion pathways.展开更多
Objective Atrial natriuretic peptide(ANP)and Zn^(2+)have been shown to confer cardioprotection against ischemia/reperfu-sion(I/R)injury.Zn^(2+)alleviates myocardial hypertrophy and pulmonary hypertension by regulating...Objective Atrial natriuretic peptide(ANP)and Zn^(2+)have been shown to confer cardioprotection against ischemia/reperfu-sion(I/R)injury.Zn^(2+)alleviates myocardial hypertrophy and pulmonary hypertension by regulating ANP expression,but its precise role in ANP-mediated cardioprotection remains unclear.This study aimed to investigate whether ANP protects the heart during reperfusion by modulating Zn^(2+)levels and to explore the underlying mechanisms involved.Methods In this study,we utilized an isolated reperfused heart model in rats,as well as wild-type(WT)and ANP knockout(ANP^(-/-))mouse models,for in vivo I/R experiments.For clinical investigations,plasma samples were collected from 216 patients with ischemia-related diseases.Evans blue and TTC staining,radioimmunoassay,ICP-OES,echocardiography,Hydro-Cy3-mediated ROS detection,and Western blotting were employed to evaluate the effect of ANP on Zn^(2+)homeostasis.Results Plasma ANP levels were significantly elevated in patients with ST-elevation myocardial infarction(STEMI),non-ST-elevation myocardial infarction(NSTEMI),and heart failure(HF).ANP secretion increased during reperfusion,rather than infarction,both ex vivo and in vivo,promoting Zn^(2+)accumulation in reperfused tissue.ANP and Zn^(2+)protected mito-chondria and reduced infarct size;these effects were reversed by the Zn^(2+)chelator TPEN.In WT and ANP^(-/-)mice,EF%and FS%decreased after reperfusion,with ANP^(-/-)mice exhibiting significantly worse cardiac function.ANP pretreatment alone improved cardiac function,but combined pretreatment with ANP and TPEN decreased EF%and FS%while increas-ing LVID.Reperfusion increased ROS levels in both WT and ANP^(-/-)hearts,which were reduced by ANP pretreatment.I/R injury elevated Zn^(2+)transporter 8(ZnT8)expression,an effect that was counteracted by ANP,although this effect was reversed by TPEN.Hypoxia-inducible factor 1-alpha(HIF-1α)expression was elevated in I/R rats and ANP^(-/-)mice,and it was inhibited by both Zn^(2+)and ANP pretreatment.However,the HIF-1αinhibitor 2-Me did not reverse the effect of ANP on ZnT8 expression.Additionally,ANP increased PI3K expression in both WT and ANP^(-/-)I/R mice,but this effect was blocked by the PI3K inhibitor LY294002.Conclusions ANP modulates Zn^(2+)homeostasis during reperfusion injury by downregulating ZnT8 through the PI3K signal-ling pathway,thereby reducing myocardial I/R injury.展开更多
OBJECTIVE:To observe the effects of electroacupuncture at Neiguan(PC6)at different time points on reperfusion arrhythmia(RA)after myocardial ischemia and reperfusion in rats,and to investigate the correlation of this ...OBJECTIVE:To observe the effects of electroacupuncture at Neiguan(PC6)at different time points on reperfusion arrhythmia(RA)after myocardial ischemia and reperfusion in rats,and to investigate the correlation of this protective effect with nerve growth factor(NGF),tyrosine kinase A(Trk A),tyrosine hydroxylase(TH),and norepinephrine(NE).METHODS:A total of 72 Sprague-Dawley male rats were randomly divided into six groups(n=12 rats/group):normal group(Norm),sham operation group(Sham),ischemia reperfusion group(I/R),pre-ischemic electroacupuncture group(EAI),pre-reperfusion electroacupuncture group(EAII),post-reperfusion electroacupuncture group(EAIII).The myocardial ischemia-reperfusion injury(MIRI)model was induced by occlusion of left anterior descending coronary artery for 20 min followed by reperfusion for 40 min in rats.With no intervention in the Norm group and only threading without ligation in the Sham group.Electroacupuncture pretreatment at 20 min/d for 7 d before ligation in the EAⅠgroup,20 min of electroacupuncture before reperfusion in the EAII group and 20 min of electroacupuncture after reperfusion in the EAIII group.The electrocardiogram(ECG)of each group was recorded throughout the whole process,and the success of the MIRI model was determined based on the changs of J-point and T-wave in the ECG.The arrhythmia score was used to record premature ventricular contractions,ventricular tachycardia and ventricular fibrillation during the reperfusion period to assess the reperfusion induced arrhythmias.The expression levels of NGF,Trk A,TH protein were measured by Western blot.Moreover,the expression levels of plasma and myocardial NE levels were detected by enzyme linked immunosorbent assay.RESULTS:The differences between Norm group and Sham group were not statistically significant in all indexes.Arrhythmia score,myocardial NGF,Trk A,TH,and NE expression were significantly higher in the I/R group compared with the Sham group.Arrhythmia score,myocardial NGF,Trk A,TH,and NE expression were significantly lower in each EA group compared with the I/R group.CONCLUSION:Electroacupuncture at Neiguan(PC6)at different time points can reduce the incidence and severity of reperfusion arrhythmias in rats.This protective effect is related to electroacupuncture regulating NGF,Trk A,TH,NE expression and reducing sympathetic hyperactivation.展开更多
β-Sitosterol is a type of phytosterol that occurs naturally in plants.Previous studies have shown that it has anti-oxidant,anti-hyperlipidemic,anti-inflammatory,immunomodulatory,and anti-tumor effects,but it is unkno...β-Sitosterol is a type of phytosterol that occurs naturally in plants.Previous studies have shown that it has anti-oxidant,anti-hyperlipidemic,anti-inflammatory,immunomodulatory,and anti-tumor effects,but it is unknown whetherβ-sitosterol treatment reduces the effects of ischemic stroke.Here we found that,in a mouse model of ischemic stroke induced by middle cerebral artery occlusion,β-sitosterol reduced the volume of cerebral infarction and brain edema,reduced neuronal apoptosis in brain tissue,and alleviated neurological dysfunction;moreover,β-sitosterol increased the activity of oxygen-and glucose-deprived cerebral cortex neurons and reduced apoptosis.Further investigation showed that the neuroprotective effects ofβ-sitosterol may be related to inhibition of endoplasmic reticulum stress caused by intracellular cholesterol accumulation after ischemic stroke.In addition,β-sitosterol showed high affinity for NPC1L1,a key transporter of cholesterol,and antagonized its activity.In conclusion,β-sitosterol may help treat ischemic stroke by inhibiting neuronal intracellular cholesterol overload/endoplasmic reticulum stress/apoptosis signaling pathways.展开更多
Studies have shown that C1q/tumor necrosis factor-related protein-6 (CTRP6) can alleviate renal ischemia/reperfusion injury in mice. However, its role in the brain remains poorly understood. To investigate the role of...Studies have shown that C1q/tumor necrosis factor-related protein-6 (CTRP6) can alleviate renal ischemia/reperfusion injury in mice. However, its role in the brain remains poorly understood. To investigate the role of CTRP6 in cerebral ischemia/reperfusion injury associated with diabetes mellitus, a diabetes mellitus mouse model of cerebral ischemia/reperfusion injury was established by occlusion of the middle cerebral artery. To overexpress CTRP6 in the brain, an adeno-associated virus carrying CTRP6 was injected into the lateral ventricle. The result was that oxygen injury and inflammation in brain tissue were clearly attenuated, and the number of neurons was greatly reduced. In vitro experiments showed that CTRP6 knockout exacerbated oxidative damage, inflammatory reaction, and apoptosis in cerebral cortical neurons in high glucose hypoxia-simulated diabetic cerebral ischemia/reperfusion injury. CTRP6 overexpression enhanced the sirtuin-1 signaling pathway in diabetic brains after ischemia/reperfusion injury. To investigate the mechanism underlying these effects, we examined mice with depletion of brain tissue-specific sirtuin-1. CTRP6-like protection was achieved by activating the sirtuin-1 signaling pathway. Taken together, these results indicate that CTRP6 likely attenuates cerebral ischemia/reperfusion injury through activation of the sirtuin-1 signaling pathway.展开更多
Calcium influx into neurons triggers neuronal death during cerebral ischemia/reperfusion injury.Various calcium channels are involved in cerebral ischemia/reperfusion injury.Cav3.2 channel is a main subtype of T-type ...Calcium influx into neurons triggers neuronal death during cerebral ischemia/reperfusion injury.Various calcium channels are involved in cerebral ischemia/reperfusion injury.Cav3.2 channel is a main subtype of T-type calcium channels.T-type calcium channel blockers,such as pimozide and mibefradil,have been shown to prevent cerebral ischemia/reperfusion injury-induced brain injury.However,the role of Cav3.2 channels in cerebral ischemia/reperfusion injury remains unclear.Here,in vitro and in vivo models of cerebral ischemia/reperfusion injury were established using middle cerebral artery occlusion in mice and high glucose hypoxia/reoxygenation exposure in primary hippocampal neurons.The results showed that Cav3.2 expression was significantly upregulated in injured hippocampal tissue and primary hippocampal neurons.We further established a Cav3.2 gene-knockout mouse model of cerebral ischemia/reperfusion injury.Cav3.2 knockout markedly reduced infarct volume and brain water content,and alleviated neurological dysfunction after cerebral ischemia/reperfusion injury.Additionally,Cav3.2 knockout attenuated cerebral ischemia/reperfusion injury-induced oxidative stress,inflammatory response,and neuronal apoptosis.In the hippocampus of Cav3.2-knockout mice,calcineurin overexpression offset the beneficial effect of Cav3.2 knockout after cerebral ischemia/reperfusion injury.These findings suggest that the neuroprotective function of Cav3.2 knockout is mediated by calcineurin/nuclear factor of activated T cells 3 signaling.Findings from this study suggest that Cav3.2 could be a promising target for treatment of cerebral ischemia/reperfusion injury.展开更多
基金supported by the National Natural Science Foundation of China(81473453,81673800)the Projects of International Science and Technology Cooperation in Henan(182102410084).
文摘Objective MicroRNA-1(miR-1)aggravates myocardial ischemia–reperfusion(I/R)injury,whereas insulin-like growth factor-1(IGF-1)maintains cardiomyocyte homeostasis.In this study,the aim is to investigate whether miR-1 can exacerbate I/R injury through the regulation of IGF-1.Methods The infarct area,lactate dehydrogenase,miR-1 level,and apoptosis level were examined in the Langendorff isolated rat I/R model.The hypoxia–reoxygenation model of rat cardiacmyocytes and H9c2 cells were developed to determine the levels of miR-1,IGF-1 mRNA,and IGF-1 protein.Furthermore,the dual-luciferase assay was used to verify the relationship between miR-1 and IGF-1.Results Overexpression of miR-1 increased the level of apoptosis and decreased the IGF-1 expression.However,inhibition of miR-1 expression decreased the level of apoptosis,alleviated the degree of injury,and increased the IGF-1 expression.Overexpression of IGF-1 also reduced the degree of cellular damage and level of apoptosis caused by the overexpression of miR-1.When IGF-1 was knocked down,myocardial cells displayed more severe damage and a higher apoptosis level,even with decreased levels of miR-1.Conclusion miR-1 promotes apoptosis and aggravates I/R injury by downregulating IGF-1.
基金supported by the National Natural Science Foundation of China,Nos.82260245(to YX),81660207(to YX),81960253(to YL),82160268(to YL),U1812403(to ZG)Science and Technology Projects of Guizhou Province,Nos.[2019]1440(to YX),[2020]1Z067(to WH)+1 种基金Cultivation Foundation of Guizhou Medical University,No.[20NSP069](to YX)Excellent Young Talents Plan of Guizhou Medical University,No.(2022)101(to WH)。
文摘Several studies have shown that activation of unfolded protein response and endoplasmic reticulum(ER)stress plays a crucial role in severe cerebral ischemia/reperfusion injury.Autophagy occurs within hours after cerebral ischemia,but the relationship between ER stress and autophagy remains unclear.In this study,we established experimental models using oxygen-glucose deprivation/reoxygenation in PC12 cells and primary neurons to simulate cerebral ischemia/reperfusion injury.We found that prolongation of oxygen-glucose deprivation activated the ER stress pathway protein kinase-like endoplasmic reticulum kinase(PERK)/eukaryotic translation initiation factor 2 subunit alpha(e IF2α)-activating transcription factor 4(ATF4)-C/EBP homologous protein(CHOP),increased neuronal apoptosis,and induced autophagy.Furthermore,inhibition of ER stress using inhibitors or by si RNA knockdown of the PERK gene significantly attenuated excessive autophagy and neuronal apoptosis,indicating an interaction between autophagy and ER stress and suggesting PERK as an essential target for regulating autophagy.Blocking autophagy with chloroquine exacerbated ER stress-induced apoptosis,indicating that normal levels of autophagy play a protective role in neuronal injury following cerebral ischemia/reperfusion injury.Findings from this study indicate that cerebral ischemia/reperfusion injury can trigger neuronal ER stress and promote autophagy,and suggest that PERK is a possible target for inhibiting excessive autophagy in cerebral ischemia/reperfusion injury.
文摘Reperfusion following cerebral ischemia causes both structural and functional damage to brain tissue and could aggravate a patient's condition;this phenomenon is known as cerebral ischemia-reperfusion injury.Current studies have elucidated the neuroprotective role of the sirtuin protein family(Sirtuins)in modulating cerebral ischemia-reperfusion injury.However,the potential of utilizing it as a novel intervention target to influence the prognosis of cerebral ischemia-reperfusion injury requires additional exploration.In this review,the origin and research progress of Sirtuins are summarized,suggesting the involvement of Sirtuins in diverse mechanisms that affect cerebral ischemia-reperfusion injury,including inflammation,oxidative stress,blood-brain barrier damage,apoptosis,pyroptosis,and autophagy.The therapeutic avenues related to Sirtuins that may improve the prognosis of cerebral ischemia-reperfusion injury were also investigated by modulating Sirtuins expression and affecting representative pathways,such as nuclear factor-kappa B signaling,oxidative stress mediated by adenosine monophosphate-activated protein kinase,and the forkhead box O.This review also summarizes the potential of endogenous substances,such as RNA and hormones,drugs,dietary supplements,and emerging therapies that regulate Sirtuins expression.This review also reveals that regulating Sirtuins mitigates cerebral ischemia-reperfusion injury when combined with other risk factors.While Sirtuins show promise as a potential target for the treatment of cerebral ischemiareperfusion injury,most recent studies are based on rodent models with circadian rhythms that are distinct from those of humans,potentially influencing the efficacy of Sirtuinstargeting drug therapies.Overall,this review provides new insights into the role of Sirtuins in the pathology and treatment of cerebral ischemia-reperfusion injury.
基金Shanghai Rehabilitation Medical Association,Grant/Award Number:2023JGKT24China Rehabilitation Medical Association,Grant/Award Number:KFKT-2023Shanghai“14th Five-Year Plan”Traditional Chinese Medicine Specialty and Traditional Chinese Medicine Emergency Capacity Improvement Project,Grant/Award Number:ZYTSZK2-7。
文摘Cerebral ischemia/reperfusion(I/R)injury is an important pathophysiological condition of ischemic stroke that involves a variety of physiological and pathological cell death pathways,including autophagy,apoptosis,necroptosis,and phagoptosis,among which autophagy is the most studied.We have reviewed studies published in the past 5 years regarding the association between autophagy and cerebral I/R injury.To the best of our knowledge,this is the first review article summarizing potential candidates targeting autophagic pathways in the treatment of I/R injury post ischemic stroke.The findings of this review may help to better understand the pathogenesis and mechanisms of I/R events and bridge the gap between basic and translational research that may lead to the development of novel therapeutic approaches for I/R injury.
基金supported by the National Natural Science Foundation of China,Nos.82172196(to KX),82372507(to KX)the Natural Science Foundation of Hunan Province,China,No.2023JJ40804(to QZ)the Key Laboratory of Emergency and Trauma(Hainan Medical University)of the Ministry of Education,China,No.KLET-202210(to QZ)。
文摘Ischemia–reperfusion injury is a common pathophysiological mechanism in retinal degeneration.PANoptosis is a newly defined integral form of regulated cell death that combines the key features of pyroptosis,apoptosis,and necroptosis.Oligomerization of mitochondrial voltage-dependent anion channel 1 is an important pathological event in regulating cell death in retinal ischemia–reperfusion injury.However,its role in PANoptosis remains largely unknown.In this study,we demonstrated that voltage-dependent anion channel 1 oligomerization-mediated mitochondrial dysfunction was associated with PANoptosis in retinal ischemia–reperfusion injury.Inhibition of voltage-dependent anion channel 1 oligomerization suppressed mitochondrial dysfunction and PANoptosis in retinal cells subjected to ischemia–reperfusion injury.Mechanistically,mitochondria-derived reactive oxygen species played a central role in the voltagedependent anion channel 1-mediated regulation of PANoptosis by promoting PANoptosome assembly.Moreover,inhibiting voltage-dependent anion channel 1 oligomerization protected against PANoptosis in the retinas of rats subjected to ischemia–reperfusion injury.Overall,our findings reveal the critical role of voltage-dependent anion channel 1 oligomerization in regulating PANoptosis in retinal ischemia–reperfusion injury,highlighting voltage-dependent anion channel 1 as a promising therapeutic target.
基金supported by the Natural Science Foundation of Shandong Province,No.ZR2023MC168the National Natural Science Foundation of China,No.31670989the Key R&D Program of Shandong Province,No.2019GSF107037(all to CS).
文摘Vascular endothelial growth factor and its mimic peptide KLTWQELYQLKYKGI(QK)are widely used as the most potent angiogenic factors for the treatment of multiple ischemic diseases.However,conventional topical drug delivery often results in a burst release of the drug,leading to transient retention(inefficacy)and undesirable diffusion(toxicity)in vivo.Therefore,a drug delivery system that responds to changes in the microenvironment of tissue regeneration and controls vascular endothelial growth factor release is crucial to improve the treatment of ischemic stroke.Matrix metalloproteinase-2(MMP-2)is gradually upregulated after cerebral ischemia.Herein,vascular endothelial growth factor mimic peptide QK was self-assembled with MMP-2-cleaved peptide PLGLAG(TIMP)and customizable peptide amphiphilic(PA)molecules to construct nanofiber hydrogel PA-TIMP-QK.PA-TIMP-QK was found to control the delivery of QK by MMP-2 upregulation after cerebral ischemia/reperfusion and had a similar biological activity with vascular endothelial growth factor in vitro.The results indicated that PA-TIMP-QK promoted neuronal survival,restored local blood circulation,reduced blood-brain barrier permeability,and restored motor function.These findings suggest that the self-assembling nanofiber hydrogel PA-TIMP-QK may provide an intelligent drug delivery system that responds to the microenvironment and promotes regeneration and repair after cerebral ischemia/reperfusion injury.
文摘Nitric oxide(NO)is a gaseous molecule produced by 3 different NO synthase(NOS)isoforms:Neural/brain NOS(nNOS/bNOS,type 1),endothelial NOS(eNOS,type 3)and inducible NOS(type 2).Type 1 and 3 NOS are constitutively expressed.NO can serve different purposes:As a vasoactive molecule,as a neurotransmitter or as an immunomodulator.It plays a key role in cerebral ischemia/reperfusion injury(CIRI).Hypoxic episodes simulate the production of oxygen free radicals,leading to mitochondrial and phospholipid damage.Upon reperfusion,increased levels of oxygen trigger oxide synthases;whose products are associated with neuronal damage by promoting lipid peroxidation,nitrosylation and excitotoxicity.Molecular pathways in CIRI can be altered by NOS.Neuroprotective effects are observed with eNOS activity.While nNOS interplay is prone to endothelial inflammation,oxidative stress and apoptosis.Therefore,nNOS appears to be detrimental.The interaction between NO and other free radicals develops peroxynitrite;which is a cytotoxic agent.It plays a main role in the likelihood of hemorrhagic events by tissue plasminogen activator(t-PA).Peroxynitrite scavengers are currently being studied as potential targets to prevent hemorrhagic transformation in CIRI.
基金Supported by Zhejiang Provincial Natural Science Foundation of China,No.LQ23H020004The Medical and Health Research Project of Zhejiang province,No.2024KY983Basic Medical Health Technology Project of Wenzhou Science and Technology Bureau,No.Y20210818 and No.Y20210140.
文摘BACKGROUND Myocardial ischemia/reperfusion(I/R)injury,which is associated with high morbidity and mortality,is a main cause of unexpected myocardial injury after acute myocardial infarction.However,the underlying mechanism remains unclear.Circular RNAs(circRNAs),which are formed from protein-coding genes,can sequester microRNAs or proteins,modulate transcription and interfere with splicing.Authoritative studies suggest that circRNAs may play an important role in myocardial I/R injury.AIM To explore the role and mechanism of circRNAs in myocardial I/R injury.METHODS We constructed a myocardial I/R injury model using ligation of the left anterior descending coronary artery,and evaluated the success of the validated model using triphenyltetrazolium chloride and hematoxylin-eosin staining.Then,left ventricular samples from different groups were selected for mRNA-sequence,and differential gene screening was performed on the obtained results.The differentially obtained mRNAs were divided into up-regulated and down-regulated according to their expression levels,and Gene Ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)functional enrichment analysis were performed,respectively.Then,the obtained circRNA and microRNA(miRNA)were paired for analysis,and the binding sites of miRNA and mRNA were virtual screened.Finally,the obtained circRNA,miRNA and mRNA were constructed by ceRNA mutual most useful network.RESULTS We used an RNA sequencing array to investigate the expression signatures of circRNAs in myocardial I/R injury using three samples from the I/R group and three samples from the sham group.A total of 142 upregulated and 121 downregulated circRNAs were found to be differentially expressed(fold change≥2,P<0.05).GO and KEGG functional analyses of these circRNAs were performed.GO analysis revealed that these circRNAs were involved mainly in cellular and intracellular processes.KEGG analysis demonstrated that 6 of the top 20 pathways were correlated with cell apoptosis.Furthermore,a circRNA-miRNA coexpression network and ceRNA network based on these genes were constructed,revealing that mmu-circ-0001452,mmu-circ-0001637,and mmu-circ-0000870 might be key regulators of myocardial I/R injury.CONCLUSION This research provides new insights into the mechanism of myocardial I/R,which mmu-circ-0001452,mmu-circ-0001637,and mmu-circ-0000870 are expected to be new therapeutic targets for myocardial I/R injury.
基金supported by 2024 Research Grant from Kangwon National University(M.C.S)and the Basic Science Research Program through the National Research Foundation of Korea(NRF)funded by the Ministry of Education(NRF-2021R1A2C1094224)(J.H.A).
文摘Background:Astrocyte endfeet(AEF)serves as a key element of the blood-brain barrier and is important for the survival and maintenance of neuronal function.However,the immunohistochemical and ultrastructural changes of AEF in the CA1 and CA3 areas of the hippocampus over time following cerebral ischemia-reperfusion(IR)injury have not been well elucidated.Objectives:We investigated chronological changes in AEF in the gerbil hippocampal CA1 area from 3 h to 10 days following transient forebrain ischemia(TFI),and examined their association with neuronal death and tissue repair following IR injury.Changes in the CA3 area were also examined at 10 days post-TFI for comparative purposes.Methods:Neuronal death was confirmed using histochemistry,immunohistochemistry,and histofluorescence.Changes in AEF were examined by double immunofluorescence with glial fibrillary acidic protein(GFAP)and glucose transporter 1(GLUT1),and by transmission electron microscopy(TEM)for ultrastructural changes.Results:Significant TFI-induced neuronal death occurred in the CA1 area on day 5 following IR injury and persisted until 10 days after TFI,while no neuronal death(or loss)was found in the CA3 area after TFI.Looking at TFI-induced changes in AEF,at 3 and 6 h after TFI,GFAP-immunoreactive(+)AEF in the CA1 area appeared swollen and harbored enlarged,dark mitochondria,and the swelling was reduced by 1-day post-TFI.On 2 and 5 days following TFI,GFAP+AEF were markedly enlarged and fragmented,containing shrunken mitochondria,vacuolations,and sparse organelles.Ten days post-TFI,the ends of GFAP+astrocytic processes extended to microvessels,appeared edematous,and were filled with cellular debris.In the CA3 area,AEF was slightly dilated at 10 days after TFI.These findings indicate that damage to or disruption of AEF in the CA1 area occurs in the early phase after 5-min TFI but is rarely observed in the CA3 area.Conclusion:Taken together,damage to or disruption of AEF following ischemic insults may be strongly linked to neuronal death/loss.
基金supported by a grant from the Russian Science Foundation(23-75-01061)。
文摘Objectives:Skeletal muscle ischemia/reperfusion injury(IRI)occurs as a result of a marked reduction in arterial perfusion to a limb and can lead to tissue death and threaten limb viability.This work assessed the effects of 20-hydroxyecdysone(20E)on hindlimb skeletal tissue following tourniquet-induced ischemia/reperfusion injury.Methods:Animals were divided into 4 groups—control group(Control),Control+20E(C+20E),mice with IRI(IRI),and mice with IRI+20E(IRI+20E).IRI was modeled by applying a tourniquet to the hind limb for 2 h with reperfusion for 1 h.5 mg/kg of 20E was administered intraperitoneally for 14 days.Afterward,the physical activity of mice,the histological structure of the quadriceps femoris,the expression of genes encoding proteins induced by hypoxia and involved in tissue adaptation to ischemia,and the functional parameters of skeletal muscle mitochondria were assessed.Results:It was shown that IRI of the limbs leads to functional disorders,depression of muscle function,accumulation of malondialdehyde(MDA)in mitochondria,and a decrease in their Ca2+buffering capacity,as well as an increase in the expression of HIF-1α,VGEF-A,PGC1αand PDGF-BB genes associated with adaptation to ischemia.20E reduced the intensity of degenerative processes in skeletal muscles,which was expressed in a decrease in the number of centrally nucleated fibers.Analysis of gene expression levels indicated a high degree of adaptation of animals to IRI.20E reduced the level of MDA in mitochondria,but did not affect the rate of respiration and calcium retention capacity of organelles both in normal conditions and during IRI.Conclusion:20E partially alleviates the skeletal muscle damage caused by IRI and can be used as part of combination therapy.
基金Supported by the Capital’s Funds for Health Improvement and Research:Clinical Study on Yiqi Liangxue Shengji Prescription for Improving Cardiac Function after Myocardial Ischemia Reperfusion Injury in Patients with Acute Myocardial Infarction(CFH 2020-4-4204)Beijing University of Traditional Chinese Medicine Qihuang Yingcai·Excellent Young Science and Technology Talent Cultivation Program(K2023A03)Beijing University of Traditional Chinese Medicine Dongfang Hospital High-level Capacity Building Project"Zhuoyuan"Project National Talent Precision Cultivation Program(DFRCZY-2024GJRC012)。
文摘OBJECTIVE:To evaluate the effect of Yiqi Liangxue Shengji prescription(益气凉血生肌方,YQLXSJ)on cardiac function and outcomes in acute myocardial infarction(AMI)patients with myocardial ischemiareperfusion injury(MIRI)and to determine its clinical efficacy.METHODS:This prospective,randomized,double-blind,placebo-controlled trial enrolled hospitalized patients with AMI who underwent percutaneous coronary intervention and experienced MIRI either intraoperatively or postoperatively.Participants were randomly allocated to the treatment group,which received YQLXSJ,or the control group,which received a placebo,concurrent with standard Western Medicine therapy.The intervention period lasted 8 weeks.The primary outcome measure was left ventricular ejection fraction(LVEF),determined by echocardiography.Secondary outcomes included Nterminal pro brain natriuretic peptide(NT-pro BNP)and cardiac troponin I(cTnI)levels,left ventricular internal diameter,major adverse cardiovascular events(MACE),angina pectoris scores,and Chinese medicine evidence scores.RESULTS:Following 8 weeks of intervention,the treatment group demonstrated a significant increase in LVEF and a marked reduction in NT-pro BNP when compared to the control group.There was also a significant decrease in peak cTnI levels,Chinese medicine evidence scores,and angina pectoris scores.The control group's left ventricular end-systolic diameter(LVESD)significantly increased compared to baseline after 8 weeks(P<0.05),whereas the treatment group's LVESD showed no significant change from baseline(P>0.05).Although the treatment group showed a downward trend in MACE incidence compared to the control group,this difference was not statistically significant(P>0.05).CONCLUSIONS:This study demonstrated that the addition of YQLXSJ to standard therapy can improve cardiac function and alleviate clinical symptoms in AMI patients with MIRI,and also showed a potential to mitigate the incidence of MACE.Furthermore,YQLXSJ displayed a favorable safety profile in clinical application.
文摘Increasing evidence of the significant clinical value of protection against ischemia/reperfusion injury has contributed to the realization of the independent importance of this approach in improving prognosis and reducing cardiovascular mortality.Extracellular vesicles(EVs)derived by adipose mesenchymal stem cells may mediate the paracrine effects of stem cells and provide regenerative and anti-inflammatory properties,which are enhanced byγ-aminobutyric acid.The protective effects on cardiac myocytes may result from the EV embarked by miR-21-5p,which is a target for thioredoxin-interacting protein,regulating the formation of thioredoxin-interacting protein-thioredoxin complexes and subsequently enhancing the antioxidant activity of thioredoxin.It has been found thatγ-aminobutyric acid governs myocardial bioenergetics through suppressing inflammation and supporting mitochondrial structure.Finally,stem cell-based cell-free therapy based on adipose-derived stem cell EVs is considered a promising approach to individualized management of ischemia-induced cardiomyopathy.
基金Natural Science Basic Research Program of Shaanxi Province(Project No.:2021JM-554)。
文摘Ferroptosis is a novel form of non-apoptotic cell death that has been widely studied in recent years and is involved in a variety of pathophysiological processes.The core treatment goal of ischemic stroke is to restore blood flow as early as possible,while the pathological mechanism of reperfusion injury after restoring blood flow is complex,involving oxidative stress,calcium overload,and inflammatory response.In recent years,more and more studies have found that ferroptosis mediation is involved in the occurrence and development of cerebral ischemia-reperfusion injury.This paper elaborates on the concept,mechanisms,and regulation of ferroptosis,detailing its role in cerebral ischemia-reperfusion injury and potential inhibition strategies.The aim is to deepen the understanding of ferroptosis in this pathological process and provide insights for possible targeted therapies.
基金supported by the National Natural Science Foundation for Distinguished Young Scholars(No.81725021)the National Natural Science Foundation of China(Nos.82003633 and 82173705)。
文摘Hepatic ischemia/reperfusion injury(IRI)remains a critical complication contributing to graft dysfunction following liver surgery.As part of an ongoing search for hepatoprotective natural products,five previously unreported homoadamantane-type polycyclic polyprenylated acylphloroglucinols(PPAPs),named hyperhomanoons A-E(1-5),and one known analog,hypersampsone O(6),were isolated from Hypericum patulum.Among these,compound 6 demonstrated potent protective effects against CoCl_(2)-induced hypoxic injury in hepatocytes.Furthermore,in a murine model of hepatic IRI induced by vascular occlusion,pretreatment with 6 markedly alleviated liver damage and reduced hepatocyte apoptosis.This study is the first to identify PPAPs as promising scaffolds for the development of therapeutic agents targeting hepatic IRI,underscoring their potential as lead compounds in drug discovery efforts for ischemic liver diseases.
文摘Introduction: Renal ischemia-reperfusion (IR) is responsible for injuries such as destruction or dysfunction of tubular epithelial cells with inflammatory reaction and oxidative stress. Several therapeutic methods have been tested to alleviate ischemia-perfusion injury, ranging from using anti-inflammatory drugs, antioxidants, and plants from traditional pharmacopeia to administering RNA interference. However, there is currently no effective therapeutic option available for the treatment of renal IR injury, other than supportive therapies such as renal replacement therapy or hydration. Objective: This present study aimed to evaluate the effect of Guiera senegalensis on renal ischemia reperfusion, a recognized plant for its antioxidant and anti-inflammatory properties. Materials and Methods: Twenty-four (24) adult male Wistar rats were divided into four following groups: SLAM (subjected to a median laparotomy with simulated ischemia);GUIERRA (animals that received 250 mg/kg of guierra senegalensis orally, once a day, for 5 days, with simulated renal ischemia);IR (animals that underwent laparotomy followed by clamping of bilateral renal pedicles for 45 min and followed by reperfusion);GUIERRA + IR (animals given GUIERRA at the dosage of 250 mg/kg per day, for 5 days and then subjected to renal ischemia-reperfusion). Data analysis was performed by ANOVA, and a significance level of p Results: Compared with the I/R group, rats in the GUIERRA + IR group showed reduced histopathological damage scores (p Conclusion: The results of this preliminary work suggest that Guiera senegalensis decreases the degree of tissue damage in renal ischemia-reperfusion cases. This plant seems to be a promising therapeutic;further studies could help to precise the targets of its compounds on ischemia-reperfusion pathways.
基金supported by the National Natural Science Foundation of China(NSFC)(No.82360065 and No.81760047).
文摘Objective Atrial natriuretic peptide(ANP)and Zn^(2+)have been shown to confer cardioprotection against ischemia/reperfu-sion(I/R)injury.Zn^(2+)alleviates myocardial hypertrophy and pulmonary hypertension by regulating ANP expression,but its precise role in ANP-mediated cardioprotection remains unclear.This study aimed to investigate whether ANP protects the heart during reperfusion by modulating Zn^(2+)levels and to explore the underlying mechanisms involved.Methods In this study,we utilized an isolated reperfused heart model in rats,as well as wild-type(WT)and ANP knockout(ANP^(-/-))mouse models,for in vivo I/R experiments.For clinical investigations,plasma samples were collected from 216 patients with ischemia-related diseases.Evans blue and TTC staining,radioimmunoassay,ICP-OES,echocardiography,Hydro-Cy3-mediated ROS detection,and Western blotting were employed to evaluate the effect of ANP on Zn^(2+)homeostasis.Results Plasma ANP levels were significantly elevated in patients with ST-elevation myocardial infarction(STEMI),non-ST-elevation myocardial infarction(NSTEMI),and heart failure(HF).ANP secretion increased during reperfusion,rather than infarction,both ex vivo and in vivo,promoting Zn^(2+)accumulation in reperfused tissue.ANP and Zn^(2+)protected mito-chondria and reduced infarct size;these effects were reversed by the Zn^(2+)chelator TPEN.In WT and ANP^(-/-)mice,EF%and FS%decreased after reperfusion,with ANP^(-/-)mice exhibiting significantly worse cardiac function.ANP pretreatment alone improved cardiac function,but combined pretreatment with ANP and TPEN decreased EF%and FS%while increas-ing LVID.Reperfusion increased ROS levels in both WT and ANP^(-/-)hearts,which were reduced by ANP pretreatment.I/R injury elevated Zn^(2+)transporter 8(ZnT8)expression,an effect that was counteracted by ANP,although this effect was reversed by TPEN.Hypoxia-inducible factor 1-alpha(HIF-1α)expression was elevated in I/R rats and ANP^(-/-)mice,and it was inhibited by both Zn^(2+)and ANP pretreatment.However,the HIF-1αinhibitor 2-Me did not reverse the effect of ANP on ZnT8 expression.Additionally,ANP increased PI3K expression in both WT and ANP^(-/-)I/R mice,but this effect was blocked by the PI3K inhibitor LY294002.Conclusions ANP modulates Zn^(2+)homeostasis during reperfusion injury by downregulating ZnT8 through the PI3K signal-ling pathway,thereby reducing myocardial I/R injury.
基金Transversal Project:Scenario-based Application of Wearable Devices for the Treatment of Cardiac Arrhythmias with Superficial Stimulation at the Neiguan(PC6)Point Research(BUCM-2022-JS-FW-003)。
文摘OBJECTIVE:To observe the effects of electroacupuncture at Neiguan(PC6)at different time points on reperfusion arrhythmia(RA)after myocardial ischemia and reperfusion in rats,and to investigate the correlation of this protective effect with nerve growth factor(NGF),tyrosine kinase A(Trk A),tyrosine hydroxylase(TH),and norepinephrine(NE).METHODS:A total of 72 Sprague-Dawley male rats were randomly divided into six groups(n=12 rats/group):normal group(Norm),sham operation group(Sham),ischemia reperfusion group(I/R),pre-ischemic electroacupuncture group(EAI),pre-reperfusion electroacupuncture group(EAII),post-reperfusion electroacupuncture group(EAIII).The myocardial ischemia-reperfusion injury(MIRI)model was induced by occlusion of left anterior descending coronary artery for 20 min followed by reperfusion for 40 min in rats.With no intervention in the Norm group and only threading without ligation in the Sham group.Electroacupuncture pretreatment at 20 min/d for 7 d before ligation in the EAⅠgroup,20 min of electroacupuncture before reperfusion in the EAII group and 20 min of electroacupuncture after reperfusion in the EAIII group.The electrocardiogram(ECG)of each group was recorded throughout the whole process,and the success of the MIRI model was determined based on the changs of J-point and T-wave in the ECG.The arrhythmia score was used to record premature ventricular contractions,ventricular tachycardia and ventricular fibrillation during the reperfusion period to assess the reperfusion induced arrhythmias.The expression levels of NGF,Trk A,TH protein were measured by Western blot.Moreover,the expression levels of plasma and myocardial NE levels were detected by enzyme linked immunosorbent assay.RESULTS:The differences between Norm group and Sham group were not statistically significant in all indexes.Arrhythmia score,myocardial NGF,Trk A,TH,and NE expression were significantly higher in the I/R group compared with the Sham group.Arrhythmia score,myocardial NGF,Trk A,TH,and NE expression were significantly lower in each EA group compared with the I/R group.CONCLUSION:Electroacupuncture at Neiguan(PC6)at different time points can reduce the incidence and severity of reperfusion arrhythmias in rats.This protective effect is related to electroacupuncture regulating NGF,Trk A,TH,NE expression and reducing sympathetic hyperactivation.
基金supported by the National Natural Science Foundation of China,Nos.82104158(to XT),31800887(to LY),31972902(to LY),82001422(to YL)China Postdoctoral Science Foundation,No.2020M683750(to LY)partially by Young Talent Fund of University Association for Science and Technology in Shaanxi Province of China,No.20200307(to LY).
文摘β-Sitosterol is a type of phytosterol that occurs naturally in plants.Previous studies have shown that it has anti-oxidant,anti-hyperlipidemic,anti-inflammatory,immunomodulatory,and anti-tumor effects,but it is unknown whetherβ-sitosterol treatment reduces the effects of ischemic stroke.Here we found that,in a mouse model of ischemic stroke induced by middle cerebral artery occlusion,β-sitosterol reduced the volume of cerebral infarction and brain edema,reduced neuronal apoptosis in brain tissue,and alleviated neurological dysfunction;moreover,β-sitosterol increased the activity of oxygen-and glucose-deprived cerebral cortex neurons and reduced apoptosis.Further investigation showed that the neuroprotective effects ofβ-sitosterol may be related to inhibition of endoplasmic reticulum stress caused by intracellular cholesterol accumulation after ischemic stroke.In addition,β-sitosterol showed high affinity for NPC1L1,a key transporter of cholesterol,and antagonized its activity.In conclusion,β-sitosterol may help treat ischemic stroke by inhibiting neuronal intracellular cholesterol overload/endoplasmic reticulum stress/apoptosis signaling pathways.
基金supported by the National Natural Science Foundation of China,Nos.82102295(to WG),82071339(to LG),82001119(to JH),and 81901994(to BZ).
文摘Studies have shown that C1q/tumor necrosis factor-related protein-6 (CTRP6) can alleviate renal ischemia/reperfusion injury in mice. However, its role in the brain remains poorly understood. To investigate the role of CTRP6 in cerebral ischemia/reperfusion injury associated with diabetes mellitus, a diabetes mellitus mouse model of cerebral ischemia/reperfusion injury was established by occlusion of the middle cerebral artery. To overexpress CTRP6 in the brain, an adeno-associated virus carrying CTRP6 was injected into the lateral ventricle. The result was that oxygen injury and inflammation in brain tissue were clearly attenuated, and the number of neurons was greatly reduced. In vitro experiments showed that CTRP6 knockout exacerbated oxidative damage, inflammatory reaction, and apoptosis in cerebral cortical neurons in high glucose hypoxia-simulated diabetic cerebral ischemia/reperfusion injury. CTRP6 overexpression enhanced the sirtuin-1 signaling pathway in diabetic brains after ischemia/reperfusion injury. To investigate the mechanism underlying these effects, we examined mice with depletion of brain tissue-specific sirtuin-1. CTRP6-like protection was achieved by activating the sirtuin-1 signaling pathway. Taken together, these results indicate that CTRP6 likely attenuates cerebral ischemia/reperfusion injury through activation of the sirtuin-1 signaling pathway.
基金supported by the Natural Science Foundation of Anhui Province of China,No.2208085Y32Scientific Research Plan Project of Anhui Province of China,No.2022AH020076the Chen Xiao-Ping Foundation for the Development of Science and Technology of Hubei Province,No.CXPJJH12000005-07-115(all to CT).
文摘Calcium influx into neurons triggers neuronal death during cerebral ischemia/reperfusion injury.Various calcium channels are involved in cerebral ischemia/reperfusion injury.Cav3.2 channel is a main subtype of T-type calcium channels.T-type calcium channel blockers,such as pimozide and mibefradil,have been shown to prevent cerebral ischemia/reperfusion injury-induced brain injury.However,the role of Cav3.2 channels in cerebral ischemia/reperfusion injury remains unclear.Here,in vitro and in vivo models of cerebral ischemia/reperfusion injury were established using middle cerebral artery occlusion in mice and high glucose hypoxia/reoxygenation exposure in primary hippocampal neurons.The results showed that Cav3.2 expression was significantly upregulated in injured hippocampal tissue and primary hippocampal neurons.We further established a Cav3.2 gene-knockout mouse model of cerebral ischemia/reperfusion injury.Cav3.2 knockout markedly reduced infarct volume and brain water content,and alleviated neurological dysfunction after cerebral ischemia/reperfusion injury.Additionally,Cav3.2 knockout attenuated cerebral ischemia/reperfusion injury-induced oxidative stress,inflammatory response,and neuronal apoptosis.In the hippocampus of Cav3.2-knockout mice,calcineurin overexpression offset the beneficial effect of Cav3.2 knockout after cerebral ischemia/reperfusion injury.These findings suggest that the neuroprotective function of Cav3.2 knockout is mediated by calcineurin/nuclear factor of activated T cells 3 signaling.Findings from this study suggest that Cav3.2 could be a promising target for treatment of cerebral ischemia/reperfusion injury.
