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
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
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
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
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
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
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
Objective:To evaluate the cardioprotective effects of sinomenine using the ischemia/reperfusion(I/R)rat model.Methods:Wistar rats were randomly divided into 6 groups:group Ⅰ with reperfusion,group Ⅱ perfused with si...Objective:To evaluate the cardioprotective effects of sinomenine using the ischemia/reperfusion(I/R)rat model.Methods:Wistar rats were randomly divided into 6 groups:group Ⅰ with reperfusion,group Ⅱ perfused with sinomenine,group Ⅲ perfused with 5-hydroxydecanoate(5-HD),group Ⅳ perfused with 5-HD+sinomenine,group Ⅴ perfused with L-nitro arginine methyl ester(L-NAME),group Ⅵ perfused with L-NAME+sinomenine.Myocardial ischemia was induced by interrupting the aortic blood supply for 30 min,followed by reperfusion(55 min).Cardiac,hepatic,antioxidant,and inflammatory parameters were assessed.Additionally,endothelin,tissue factor,platelet-activating factor,plasminogen activator inhibitor,plasma fibrinogen,and thromboxane B2 were also analyzed.Results:Administration of 5-HD or L-NAME,used as the selective antagonist of mitoKATP and NO system,respectively,resulted in significantly increased levels of premature ventricular complexes,lactate dehydrogenase,ventricular fibrillation,ventricular tachycardia,and arrhythmia intensity(P<0.05).In contrast,sinomenine significantly reduced the level of troponin Ⅰ,lactate dehydrogenase,creatine kinase,and creatine kinase MB compared to the 5-HD group and the L-NAME group(P<0.05).Additionally,sinomenine significantly reduced malondialdehyde level and enhanced the levels of superoxide dismutase,glutathione peroxidase,catalase,and glutathione/glutathione disulfide ratio(P<0.05).It also significantly suppressed the levels of endothelin-1,platelet-activating factor,tissue factor,plasminogen activator inhibitor 1,thromboxane B2,and plasma fibrinogen(P<0.05).Conclusions:These results suggest that sinomenine exhibits significant cardioprotection effects against I/R-induced cardiac injury in rats.展开更多
Ligustrazine （2,3,5,6-tetramethylpyrazine） is a major active ingredient of the Szechwan lovage rhizome and is extensively used in treatment of ischemic cerebrovascular disease. The mecha- nism of action of ligustraz...Ligustrazine （2,3,5,6-tetramethylpyrazine） is a major active ingredient of the Szechwan lovage rhizome and is extensively used in treatment of ischemic cerebrovascular disease. The mecha- nism of action of ligustrazine use against ischemic cerebrovascular diseases remains unclear at present. This study summarizes its protective effect, the optimum time window of administra- tion, and the most effective mode of administration for clinical treatment of cerebral ischemia/ reperfusion injury. We examine the effects of ligustrazine on suppressing excitatory amino acid release, promoting migration, differentiation and proliferation of endogenous neural stem cells. We also looked at its effects on angiogenesis and how it inhibits thrombosis, the inflammatory response, and apoptosis after cerebral ischemia. We consider that ligustrazine gives noticeable protection from cerebral ischemia/reperfusion injury. The time window of ligustrazine admin- istration is limited. The protective effect and time window of a series of derivative monomers of ligustrazine such as 2-[（1,1-dimethylethyl）oxidoimino]methyl]-3,5,6-trimethylpyrazine, CXC137 and CXC 195 after cerebral ischemia were better than ligustrazine.展开更多
Signal transducer and activator of transcription（STAT）is a unique protein family that binds to DNA,coupled with tyrosine phosphorylation signaling pathways,acting as a transcriptional regulator to mediate a variety ...Signal transducer and activator of transcription（STAT）is a unique protein family that binds to DNA,coupled with tyrosine phosphorylation signaling pathways,acting as a transcriptional regulator to mediate a variety of biological effects.Cerebral ischemia and reperfusion can activate STATs signaling pathway,but no studies have confirmed whether STAT activation can be verified by diffusion-weighted magnetic resonance imaging（DWI）in rats after cerebral ischemia/reperfusion.Here,we established a rat model of focal cerebral ischemia injury using the modified Longa method.DWI revealed hyperintensity in parts of the left hemisphere before reperfusion and a low apparent diffusion coefficient.STAT3 protein expression showed no significant change after reperfusion,but phosphorylated STAT3 expression began to increase after 30 minutes of reperfusion and peaked at 24 hours.Pearson correlation analysis showed that STAT3 activation was correlated positively with the relative apparent diffusion coefficient and negatively with the DWI abnormal signal area.These results indicate that DWI is a reliable representation of the infarct area and reflects STAT phosphorylation in rat brain following focal cerebral ischemia/reperfusion.展开更多
Aim Salvia miltiorrhiza Bunge （SM） and lignum dalbergiae odoriferae （DO） are both traditional Chi- nese medicine that have cardioprotective effects. Here, we further examined the combined effects of SM and DO on r...Aim Salvia miltiorrhiza Bunge （SM） and lignum dalbergiae odoriferae （DO） are both traditional Chi- nese medicine that have cardioprotective effects. Here, we further examined the combined effects of SM and DO on rat myocardial ischemia/reperfusion injury. The possible mechanism of SM and DO also were elucidated. Methods DO was divided into aqueous extract of lignum dalbergiae odoriferae （DOW） and lignum dalbergiae odoriferae oil （DOO）. Sprague-Dawley rats were randomized to seven groups： sham group, model group, treatment groups inclu- ding SM （10 g · kg^-1）, DOW （5 g · kg^-1）, DOO （0.5 ml · kg^-1）, SM ＋ DOW （10 g · kg^-1 ＋ 5 g · kg^-1）, SM ＋ DOO （ 10 g · kg^-1 ＋ 0. 5 ml · kg^-1）. Rats were pretreated with homologous drug for 7 days and then subjec- ted to 30 rain of ischemia followed by 180 rain of reperfusion. Electrocardiogram （ECG） and heart rate were moni- tored and recorded continuously. At the end of reperfusion, blood samples were collected to determine the serum levels of creatine kinase-MB （CK-MB） and lactate dehydrogenase （LDH）. Hearts were harvested to assess heart- body rate, infarct size and histopathological changes as well. Maximum and minimum effective points were deter- mined by measuring indicators associate with myocardial injury at different time-points of reperfusion （Smin, 15min, 30min, 45rain, 60min, 120min, 180min）. The potential therapeutic mechanism of SM and SM ＋ DOO were carried out by detecting superoxide dismutase （SOD）, malondialdehyde （MDA）, tumor necrosis factor-alpha （TNF-alpha） and interleukin 6 （IL-6）. Results The results showed SM and DO can ameliorate cardiac function respectively, and this cardioprotective effect was further strengthened by their combinations. Among all the combi- nations, SM ＋ DOO showed predominant potential to improve ECG and heart rate, reduce heart-body rate （28.5% ＋ 1.4% , P 〈 0.01 vs model） and myocardial infarct size （ 20.96% ＋ 1.61% , P 〈 0.01 vs model, P 〈 0.05 vs SM） , attenuate histopathological damage, decrease the levels of CK-MB and LDH （P 〈 0.01 vs model, P 〈 0.05 vs SM）. The maximum effective points of SM and SM ＋ DOO were 15min and 30rain respectively, and the minimum effective points of them were 180rain. In reducing serum level of MDA, TNF-alpha, IL-6 and increasing SOD activ- ity, SM ＋ DOO was similar to SM. Conclusion The results of this study indicated that SM ＋ DOO have combined effects that are highly effective than single pretreatment against myocardial ischemie reperfusion injury in rats. The possible mechanism of SM and DO were likely through its anti-oxidant and anti-inflammatory properties, and thus may be an effective and promising medicine for both prophylaxis and treatment of ischemic heart disease.展开更多
The aim of this study was to explore the neuroprotective effect and mechanism of XingNaoJing injections(XNJ) on cerebral ischemia injury and blood-brain barrier(BBB) disruption. Middle cerebral artery occlusion(MCAO) ...The aim of this study was to explore the neuroprotective effect and mechanism of XingNaoJing injections(XNJ) on cerebral ischemia injury and blood-brain barrier(BBB) disruption. Middle cerebral artery occlusion(MCAO) method was applicated to establish the model of cerebral ischemia/reperfusion(I/R) injury in rats. BBB permeability after I/R injury was assessed with the leaking amount of Evans Blue and the expression of occludin and ZO-1. The expression of NOD-like receptor family, pyrin domain containing(NLRP3) was checked to explore the inhibition of inflammation by XNJ. The results showed that XNJ could significantly increase the survival percent, decrease the infarct area and ameliorate neurological deficits and brain damage after I/R injury. Leaking amount of Evans Blue was reduced by XNJ, and the expression of tight junction protein, occludin and ZO-1 was also up-regulated by XNJ, which showed a role of protection on BBB disruption. The expression of NLRP3 was inhibited after exposure of XNJ, which was associated with inhibition of the inflammatory response. In summary, XNJ could suppress NLRP3 inflammasomes and improve BBB disruption and brain damage in rats after cerebral I/R injury, which provided a beneficial insight to further explore XNJ.展开更多
AIM:To examine whether heme oxygenase (HO)-1 overexpression would exert direct or indirect effects on Kupffer cells activation, which lead to aggravation of reperfusion injury.METHODS: Donors were pretreated with coba...AIM:To examine whether heme oxygenase (HO)-1 overexpression would exert direct or indirect effects on Kupffer cells activation, which lead to aggravation of reperfusion injury.METHODS: Donors were pretreated with cobalt protoporphyrin (CoPP) or zinc protoporphyrin (ZnPP), HO-1 inducer and antagonist, respectively. Livers were stored at 4℃ for 24 h before transplantation. Kupffer cells were isolated and cultured for 6 h after liver reperfusion.RESULTS: Postoperatively, serum transaminases were significantly lower and associated with less liver injury when donors were pretreated with CoPP, as compared with the ZnPP group. Production of the cytokines tumor necrosis factor-α and interleukin-6 generated by Kupffer cells decreased in the CoPP group. The CD14 expression levels (RT-PCR/Western blots) of Kupffer cells from CoPP-pretreated liver grafts reduced.CONCLUSION: The study suggests that the potential utility of HO-1 overexpression in preventing ischemia/reperfusion injury results from inhibition of Kupffer cells activation.展开更多
Electroacupuncture is known as an effective adjuvant therapy in ischemic cerebrovascular disease. However, its underlying mechanisms remain unclear. Studies suggest that autophagy, which is essential for cell survival...Electroacupuncture is known as an effective adjuvant therapy in ischemic cerebrovascular disease. However, its underlying mechanisms remain unclear. Studies suggest that autophagy, which is essential for cell survival and cell death, is involved in cerebral ischemia reperfusion injury and might be modulate by electroacupuncture therapy in key ways. This paper aims to provide novel insights into a therapeutic target of electroacupuncture against cerebral ischemia/reperfusion injury from the perspective of autophagy. Here we review recent studies on electroacupuncture regulation of autophagy-related markers such as UNC-51-like kinase-1 complex, Beclin1, microtubule-associated protein-1 light chain 3, p62, and autophagosomes for treating cerebral ischemia/reperfusion injury. The results of these studies show that electroacupuncture may affect the initiation of autophagy, vesicle nucleation, expansion and maturation of autophagosomes, as well as fusion and degradation of autophagolysosomes. Moreover, studies indicate that electroacupuncture probably modulates autophagy by activating the mammalian target of the rapamycin signaling pathway.This review thus indicates that autophagy is a therapeutic target of electroacupuncture treatment against ischemic cerebrovascular diseases.展开更多
Ischemia/reperfusion (I/R) injury of the gut is a significant problem in a variety of clinical settings and is associated with a high morbidity and mortality. Although the mechanisms involved in the pathogenesis of gu...Ischemia/reperfusion (I/R) injury of the gut is a significant problem in a variety of clinical settings and is associated with a high morbidity and mortality. Although the mechanisms involved in the pathogenesis of gut I/R injury have not been fully elucidated, it is generally believed that oxidative stress with subsequent inflammatory injury plays an important role. Heme oxygenase (HO) is the rate-limiting enzyme in the catabolism of heme, followed by production of CO, biliverdin, and free iron. The HO system is believed to confer cytoprotection by inhibiting inflammation, oxidation, and apoptosis, and maintaining microcirculation. HO-1, an inducible form of HO, serves a vital metabolic function as the rate-limiting step in the heme degradation pathway, and affords protection in models of intestinal I/R injury. HO-1 system is an important player in intestinal I/R injury condition, and may offer new targets for the management of this condition.展开更多
Objective: Skin damage induced by ischemia/reperfusion (I/R) is a multifactorial process that often occurs in plastic surgery. The mechanisms of I/R injury include hypoxia, inflammation, and oxidative damage. Hydrogen...Objective: Skin damage induced by ischemia/reperfusion (I/R) is a multifactorial process that often occurs in plastic surgery. The mechanisms of I/R injury include hypoxia, inflammation, and oxidative damage. Hydrogen gas has been reported to alleviate cerebral I/R injury by acting as a free radical scavenger. Here, we assessed the protective effect of hydrogen-rich saline (HRS) on skin flap I/R injury. Methods: Abdominal skin flaps of rats were elevated and ischemia was induced for 3 h; subsequently, HRS or physiological saline was administered intraperitoneally 10 min before reperfusion. On postoperative Day 5, flap survival, blood perfusion, the accumulation of reactive oxygen species (ROS), and levels of cytokines were evaluated. Histological examinations were performed to assess inflammatory cell infiltration. Results: Skin flap survival and blood flow perfusion were improved by HRS relative to the controls. The production of malondialdehyde (MDA), an indicator of lipid peroxidation, was markedly reduced. A multiplex cytokine assay revealed that HRS reduced the elevation in the levels of inflammatory cytokines, chemokines and growth factors, with the exception of RANTES (regulated on activation, normal T-cell expressed and secreted) growth factor. HRS treatment also reduced inflammatory cell infiltration induced by I/R injury. Conclusions: Our findings suggest that HRS mitigates I/R injury by decreasing inflammation and, therefore, has the potential for application as a therapy for improving skin flap survival.展开更多
BACKGROUND: Hepatic ischemia/reperfusion injury may induce intestinal microflora imbalance. Salvia miltiorrhiza is effective in promoting blood circulation and counteracting peroxidation in tissues. The aim of the pre...BACKGROUND: Hepatic ischemia/reperfusion injury may induce intestinal microflora imbalance. Salvia miltiorrhiza is effective in promoting blood circulation and counteracting peroxidation in tissues. The aim of the present study was to determine the effects of Salvia miltiorrhiza on intestinal mi- croflora, endotoxemia, and bacterial translocation in rats with hepatic I/R injury. METHODS: Sprague-Dawley rats in specific pathogen free grade were divided into 3 groups: group I(n =6) for sham operation: groups ( n = 7) for liver ische- mia for 20 minutes and reperfusion for 22 hours. Group was also pretreated with 4 ml/day of Salvia miltiorrhiza solu- tion (250 mg/kg) by daily gavage for 7 days. The levels of serum alanine aminotransferase (ALT), aspartate amino- transferase (AST), malondialdehyde ( MDA) and supero- xide dismutase ( SOD ) in liver tissues, serum endotoxin, intestinal bacterial counts, intestinal mucosal histology and bacterial translocation were studied. RESULTS: The levels of ALT, AST, plasma endotoxin and MDA in liver tissues were decreased more markedly in group (57.57 ± 18.08 U/L, 147.57 ±40.84 U/L, 0.42 ± 0.144 EU/ml and 0. 52 ±0.19 nmol/mg-prot respectively) in group 295.9±216.92 U/L, 0.80± 0.262 EU/ml and 0.72±0.12 nmol/mg-prot; P <0.05-0.01 respectively). Liver SOD activity was increased more sig- nificantly in group (318.47±64.62 U/mg-prot) than in group U/mg-prot, P<0.05). The counts of Bifidobacteria and Bacteroides increased more significantly in group than in group but were similar to those in group I. Bacterial translocation to the kidney in group was 50% (5/10), whereas no bacterial translocation to the kidney occurred in the other two groups (P <0. 01). Ileal mucosal structure was markedly ameliorated in group as compared with group CONCLUSIONS: Salviae miltiorrhiza could partially restore intestinal microflora balance, improve intestinal mucosal integrity, and reduce bacterial translocation and plasma en- dotoxin in rats with hepatic ischemia/reperfusion injury.展开更多
BACKGROUND: Toll-like receptor 4 (TLR4) is involved in innate immunity by recognizing endotoxin resulting in a burst of inflammatory cascade. We investigated the relation between activation of TLR4 and liver injury in...BACKGROUND: Toll-like receptor 4 (TLR4) is involved in innate immunity by recognizing endotoxin resulting in a burst of inflammatory cascade. We investigated the relation between activation of TLR4 and liver injury in partial hepa- tic ischemia/reperfusion (I/R) injury in mice. METHODS: TLR4-deficient mice ( C3H/Hej) and wild type mice (WT, C3H/Heouj) were used in the model of I/R injury. Partial hepatic ischemia was produced by oc- clusion of inflow to the median and left lobes for 45 mi- nutes. Blood was drawn at 1 and 3 hours after reperfusion. The blood was analyzed for aspartate aminotransferase (AST) and tumor necrosis factor alpha (TNF-α). TNF-α mRNA expression and myeloperoxidase (MPO) level in the ischemic lobes were examined by northern blot and myeloperoxidase assay respectively. RESULTS: AST levels were significantly decreased in TLR4- deficient mice compared with WT mice at both time points (WT: 1215.5 ±174. 03, 2958. 17 ± 186. 81 IU/L at 1 and 3 hours respectively vs TLR4def: 661.83±106.09, 1145.17± 132.43 IU/L at 1 and 3 hours, mean ± SD, 6 mice/group, (=-6.65 and -5.57, P <0.001). Consistent with the role of TNF-α in hepatic I/R, serum TNF-α was decreased in TLR4 deficient mice at 3 hours after reperfusion compared with WT (152.39±43.3 vs 249.12 ± 51.89, n=6, t=-3.13, P<0.05). MPO level in the ischemic lobes in TLR4 defi- cient mice at 3 hours after reperfusion was significantly low- er than that in WT mice (0.059±0.004 vs 0.173±0.025, n=6, F=33.49, P<0.001). This difference appears to be mediated at the gene level since TLR4 deficient mice had decreased TNF-α mRNA expression at 1 hour after reperfu- sion compared with WT mice (80.3±28.8 vs 189.4±24.6, t=-3.25, P<0.05). CONCLUSIONS: Compared with WT mice, TLR4-defi- cient mice appear to have a mild I/R injury. Regulation of TNF-a at mRNA level seems to have a critical effect. These suggest TLR4 be involved in the mechanism of he-patic I/R injury in mice.展开更多
Objective:To investigate the protective effect of different cyclosporin A(CsA)doses on myocardial ischemia/reperfusion injury in rat models.Methods:A rat model of myocardial ischemia/reperfusion injury was established...Objective:To investigate the protective effect of different cyclosporin A(CsA)doses on myocardial ischemia/reperfusion injury in rat models.Methods:A rat model of myocardial ischemia/reperfusion injury was established in vivo and the rats were randomly divided into four groups:placebo(PBS;T1),low-dose(CsA dose:1.0 mg/kg:T2),medium-dose(CsA dose:2.5 mg/kg:T3),and high-dose(CsA dose:5.0 mg/kg;T4)groups.Heart function indexes were monitored at different time points,the extent of myocardial infarction was assessed by Evans Blue-TTC staining,and creatine kinase MB mass and cardiac troponin 1 values were measured by biochemical assays.Results:Compared with the T1 and T2 groups,both the creatine kinase MB mass and cardiac troponin 1 were significantly lower in the T3 and T4 groups(P<0.05).The mean arterial pressure(MAP)and left ventricular systolic pressure(LVSP)decreased sequentially in each group,with the extending reperfusion time.Significant decreases in LVSP and MAP were observed in the T3 and T4 groups as compared to the T1 and T2 group(P<0.05)and the T2 group showed a significantly lower LVSP and MAP decline than the T1 group(P<0.05).Compared with the Tl group,the rats from the T2.T3,and T4 groups suffered from a significantly lower extent of myocardial infarction(P<0.05).Also,the a animals in the T3 and T4 groups had a significantly smaller extent of myocardial infarction than those in the T2 group(P<0.05).Conclusions:Various CsA doses exert different degrees of protection against ischemia/reperfusion injury,and this protective effect peaks at approximately 2.5 mg/kg in rat models.展开更多
Selective brain hypothermia is considered an effective treatment for neuronal injury after stroke,and avoids the complications of general hypothermia.However,the mechanisms by which selective brain hypothermia affects...Selective brain hypothermia is considered an effective treatment for neuronal injury after stroke,and avoids the complications of general hypothermia.However,the mechanisms by which selective brain hypothermia affects mitochondrial fission remain unknown.In this study,we investigated the effect of selective brain hypothermia on the expression of fission 1 (Fis1) protein,a key factor in the mitochondrial fission system,during focal cerebral ischemia/reperfusion injury.Sprague-Dawley rats were divided into four groups.In the sham group,the carotid arteries were exposed only.In the other three groups,middle cerebral artery occlusion was performed using the intraluminal filament technique.After 2 hours of occlusion,the filament was slowly removed to allow blood reperfusion in the ischemia/reperfusion group.Saline,at 4℃ and 37℃,were perfused through the carotid artery in the hypothermia and normothermia groups,respectively,followed by restoration of blood flow.Neurological function was assessed with the Zea Longa 5-point scoring method.Cerebral infarct volume was assessed by 2,3,5-triphenyltetrazolium chloride staining,and apoptosis was assessed by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling staining.Fis1 and cytosolic cytochrome c levels were assessed by western blot assay.Fis1 mRNA expression was assessed by quantitative reverse transcription-polymerase chain reaction.Mitochondrial ultrastructure was evaluated by transmission electron microscopy.Compared with the sham group,apoptosis,Fis1 protein and mRNA expression and cytosolic cytochrome c levels in the cortical ischemic penumbra and cerebral infarct volume were increased after reperfusion in the other three groups.These changes caused by cerebral ischemia/reperfusion were inhibited in the hypothermia group compared with the normothermia group.These findings show that selective brain hypothermia inhibits Fis1 expression and reduces apoptosis,thereby ameliorating focal cerebral ischemia/reperfusion injury in rats.Experiments were authorized by the Ethics Committee of Qingdao Municipal Hospital of China (approval No.2019008).展开更多
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 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.
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 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 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Objective:To evaluate the cardioprotective effects of sinomenine using the ischemia/reperfusion(I/R)rat model.Methods:Wistar rats were randomly divided into 6 groups:group Ⅰ with reperfusion,group Ⅱ perfused with sinomenine,group Ⅲ perfused with 5-hydroxydecanoate(5-HD),group Ⅳ perfused with 5-HD+sinomenine,group Ⅴ perfused with L-nitro arginine methyl ester(L-NAME),group Ⅵ perfused with L-NAME+sinomenine.Myocardial ischemia was induced by interrupting the aortic blood supply for 30 min,followed by reperfusion(55 min).Cardiac,hepatic,antioxidant,and inflammatory parameters were assessed.Additionally,endothelin,tissue factor,platelet-activating factor,plasminogen activator inhibitor,plasma fibrinogen,and thromboxane B2 were also analyzed.Results:Administration of 5-HD or L-NAME,used as the selective antagonist of mitoKATP and NO system,respectively,resulted in significantly increased levels of premature ventricular complexes,lactate dehydrogenase,ventricular fibrillation,ventricular tachycardia,and arrhythmia intensity(P<0.05).In contrast,sinomenine significantly reduced the level of troponin Ⅰ,lactate dehydrogenase,creatine kinase,and creatine kinase MB compared to the 5-HD group and the L-NAME group(P<0.05).Additionally,sinomenine significantly reduced malondialdehyde level and enhanced the levels of superoxide dismutase,glutathione peroxidase,catalase,and glutathione/glutathione disulfide ratio(P<0.05).It also significantly suppressed the levels of endothelin-1,platelet-activating factor,tissue factor,plasminogen activator inhibitor 1,thromboxane B2,and plasma fibrinogen(P<0.05).Conclusions:These results suggest that sinomenine exhibits significant cardioprotection effects against I/R-induced cardiac injury in rats.
基金supported by a grant from the Health and Family Planning Commission of Heilongjiang Province Research Project in China,No.2014-195the Education Department Science and Technology Foundation of Heilongjiang Province in China,No.12531741the Natural Science Foundation of Heilongjiang Province of China,No.H2015083
文摘Ligustrazine （2,3,5,6-tetramethylpyrazine） is a major active ingredient of the Szechwan lovage rhizome and is extensively used in treatment of ischemic cerebrovascular disease. The mecha- nism of action of ligustrazine use against ischemic cerebrovascular diseases remains unclear at present. This study summarizes its protective effect, the optimum time window of administra- tion, and the most effective mode of administration for clinical treatment of cerebral ischemia/ reperfusion injury. We examine the effects of ligustrazine on suppressing excitatory amino acid release, promoting migration, differentiation and proliferation of endogenous neural stem cells. We also looked at its effects on angiogenesis and how it inhibits thrombosis, the inflammatory response, and apoptosis after cerebral ischemia. We consider that ligustrazine gives noticeable protection from cerebral ischemia/reperfusion injury. The time window of ligustrazine admin- istration is limited. The protective effect and time window of a series of derivative monomers of ligustrazine such as 2-[（1,1-dimethylethyl）oxidoimino]methyl]-3,5,6-trimethylpyrazine, CXC137 and CXC 195 after cerebral ischemia were better than ligustrazine.
文摘Signal transducer and activator of transcription（STAT）is a unique protein family that binds to DNA,coupled with tyrosine phosphorylation signaling pathways,acting as a transcriptional regulator to mediate a variety of biological effects.Cerebral ischemia and reperfusion can activate STATs signaling pathway,but no studies have confirmed whether STAT activation can be verified by diffusion-weighted magnetic resonance imaging（DWI）in rats after cerebral ischemia/reperfusion.Here,we established a rat model of focal cerebral ischemia injury using the modified Longa method.DWI revealed hyperintensity in parts of the left hemisphere before reperfusion and a low apparent diffusion coefficient.STAT3 protein expression showed no significant change after reperfusion,but phosphorylated STAT3 expression began to increase after 30 minutes of reperfusion and peaked at 24 hours.Pearson correlation analysis showed that STAT3 activation was correlated positively with the relative apparent diffusion coefficient and negatively with the DWI abnormal signal area.These results indicate that DWI is a reliable representation of the infarct area and reflects STAT phosphorylation in rat brain following focal cerebral ischemia/reperfusion.
文摘Aim Salvia miltiorrhiza Bunge （SM） and lignum dalbergiae odoriferae （DO） are both traditional Chi- nese medicine that have cardioprotective effects. Here, we further examined the combined effects of SM and DO on rat myocardial ischemia/reperfusion injury. The possible mechanism of SM and DO also were elucidated. Methods DO was divided into aqueous extract of lignum dalbergiae odoriferae （DOW） and lignum dalbergiae odoriferae oil （DOO）. Sprague-Dawley rats were randomized to seven groups： sham group, model group, treatment groups inclu- ding SM （10 g · kg^-1）, DOW （5 g · kg^-1）, DOO （0.5 ml · kg^-1）, SM ＋ DOW （10 g · kg^-1 ＋ 5 g · kg^-1）, SM ＋ DOO （ 10 g · kg^-1 ＋ 0. 5 ml · kg^-1）. Rats were pretreated with homologous drug for 7 days and then subjec- ted to 30 rain of ischemia followed by 180 rain of reperfusion. Electrocardiogram （ECG） and heart rate were moni- tored and recorded continuously. At the end of reperfusion, blood samples were collected to determine the serum levels of creatine kinase-MB （CK-MB） and lactate dehydrogenase （LDH）. Hearts were harvested to assess heart- body rate, infarct size and histopathological changes as well. Maximum and minimum effective points were deter- mined by measuring indicators associate with myocardial injury at different time-points of reperfusion （Smin, 15min, 30min, 45rain, 60min, 120min, 180min）. The potential therapeutic mechanism of SM and SM ＋ DOO were carried out by detecting superoxide dismutase （SOD）, malondialdehyde （MDA）, tumor necrosis factor-alpha （TNF-alpha） and interleukin 6 （IL-6）. Results The results showed SM and DO can ameliorate cardiac function respectively, and this cardioprotective effect was further strengthened by their combinations. Among all the combi- nations, SM ＋ DOO showed predominant potential to improve ECG and heart rate, reduce heart-body rate （28.5% ＋ 1.4% , P 〈 0.01 vs model） and myocardial infarct size （ 20.96% ＋ 1.61% , P 〈 0.01 vs model, P 〈 0.05 vs SM） , attenuate histopathological damage, decrease the levels of CK-MB and LDH （P 〈 0.01 vs model, P 〈 0.05 vs SM）. The maximum effective points of SM and SM ＋ DOO were 15min and 30rain respectively, and the minimum effective points of them were 180rain. In reducing serum level of MDA, TNF-alpha, IL-6 and increasing SOD activ- ity, SM ＋ DOO was similar to SM. Conclusion The results of this study indicated that SM ＋ DOO have combined effects that are highly effective than single pretreatment against myocardial ischemie reperfusion injury in rats. The possible mechanism of SM and DO were likely through its anti-oxidant and anti-inflammatory properties, and thus may be an effective and promising medicine for both prophylaxis and treatment of ischemic heart disease.
基金surported by the National Natural Science Foundation of China(No.81803608)the Administration of Traditional Chinese Medicine of Jilin Province,China(No.2019133)
文摘The aim of this study was to explore the neuroprotective effect and mechanism of XingNaoJing injections(XNJ) on cerebral ischemia injury and blood-brain barrier(BBB) disruption. Middle cerebral artery occlusion(MCAO) method was applicated to establish the model of cerebral ischemia/reperfusion(I/R) injury in rats. BBB permeability after I/R injury was assessed with the leaking amount of Evans Blue and the expression of occludin and ZO-1. The expression of NOD-like receptor family, pyrin domain containing(NLRP3) was checked to explore the inhibition of inflammation by XNJ. The results showed that XNJ could significantly increase the survival percent, decrease the infarct area and ameliorate neurological deficits and brain damage after I/R injury. Leaking amount of Evans Blue was reduced by XNJ, and the expression of tight junction protein, occludin and ZO-1 was also up-regulated by XNJ, which showed a role of protection on BBB disruption. The expression of NLRP3 was inhibited after exposure of XNJ, which was associated with inhibition of the inflammatory response. In summary, XNJ could suppress NLRP3 inflammasomes and improve BBB disruption and brain damage in rats after cerebral I/R injury, which provided a beneficial insight to further explore XNJ.
基金Supported by The Natural Science Foundation of Yunnan Province,China, No.2007C137Mthe Joint Funds of Natural Science Foundation of Yunnan Province,China,No.2007C0009R
文摘AIM:To examine whether heme oxygenase (HO)-1 overexpression would exert direct or indirect effects on Kupffer cells activation, which lead to aggravation of reperfusion injury.METHODS: Donors were pretreated with cobalt protoporphyrin (CoPP) or zinc protoporphyrin (ZnPP), HO-1 inducer and antagonist, respectively. Livers were stored at 4℃ for 24 h before transplantation. Kupffer cells were isolated and cultured for 6 h after liver reperfusion.RESULTS: Postoperatively, serum transaminases were significantly lower and associated with less liver injury when donors were pretreated with CoPP, as compared with the ZnPP group. Production of the cytokines tumor necrosis factor-α and interleukin-6 generated by Kupffer cells decreased in the CoPP group. The CD14 expression levels (RT-PCR/Western blots) of Kupffer cells from CoPP-pretreated liver grafts reduced.CONCLUSION: The study suggests that the potential utility of HO-1 overexpression in preventing ischemia/reperfusion injury results from inhibition of Kupffer cells activation.
文摘Electroacupuncture is known as an effective adjuvant therapy in ischemic cerebrovascular disease. However, its underlying mechanisms remain unclear. Studies suggest that autophagy, which is essential for cell survival and cell death, is involved in cerebral ischemia reperfusion injury and might be modulate by electroacupuncture therapy in key ways. This paper aims to provide novel insights into a therapeutic target of electroacupuncture against cerebral ischemia/reperfusion injury from the perspective of autophagy. Here we review recent studies on electroacupuncture regulation of autophagy-related markers such as UNC-51-like kinase-1 complex, Beclin1, microtubule-associated protein-1 light chain 3, p62, and autophagosomes for treating cerebral ischemia/reperfusion injury. The results of these studies show that electroacupuncture may affect the initiation of autophagy, vesicle nucleation, expansion and maturation of autophagosomes, as well as fusion and degradation of autophagolysosomes. Moreover, studies indicate that electroacupuncture probably modulates autophagy by activating the mammalian target of the rapamycin signaling pathway.This review thus indicates that autophagy is a therapeutic target of electroacupuncture treatment against ischemic cerebrovascular diseases.
基金Supported by Natural Science Foundation of Ningbo City, No.2012A610194National Natural Science Foundation of China,No. 81071697Natural Science Foundation of Guangdong Province, No. S2011040003694
文摘Ischemia/reperfusion (I/R) injury of the gut is a significant problem in a variety of clinical settings and is associated with a high morbidity and mortality. Although the mechanisms involved in the pathogenesis of gut I/R injury have not been fully elucidated, it is generally believed that oxidative stress with subsequent inflammatory injury plays an important role. Heme oxygenase (HO) is the rate-limiting enzyme in the catabolism of heme, followed by production of CO, biliverdin, and free iron. The HO system is believed to confer cytoprotection by inhibiting inflammation, oxidation, and apoptosis, and maintaining microcirculation. HO-1, an inducible form of HO, serves a vital metabolic function as the rate-limiting step in the heme degradation pathway, and affords protection in models of intestinal I/R injury. HO-1 system is an important player in intestinal I/R injury condition, and may offer new targets for the management of this condition.
基金Project (No. 7132169) supported by the Beijing Natural Science Foundation, China
文摘Objective: Skin damage induced by ischemia/reperfusion (I/R) is a multifactorial process that often occurs in plastic surgery. The mechanisms of I/R injury include hypoxia, inflammation, and oxidative damage. Hydrogen gas has been reported to alleviate cerebral I/R injury by acting as a free radical scavenger. Here, we assessed the protective effect of hydrogen-rich saline (HRS) on skin flap I/R injury. Methods: Abdominal skin flaps of rats were elevated and ischemia was induced for 3 h; subsequently, HRS or physiological saline was administered intraperitoneally 10 min before reperfusion. On postoperative Day 5, flap survival, blood perfusion, the accumulation of reactive oxygen species (ROS), and levels of cytokines were evaluated. Histological examinations were performed to assess inflammatory cell infiltration. Results: Skin flap survival and blood flow perfusion were improved by HRS relative to the controls. The production of malondialdehyde (MDA), an indicator of lipid peroxidation, was markedly reduced. A multiplex cytokine assay revealed that HRS reduced the elevation in the levels of inflammatory cytokines, chemokines and growth factors, with the exception of RANTES (regulated on activation, normal T-cell expressed and secreted) growth factor. HRS treatment also reduced inflammatory cell infiltration induced by I/R injury. Conclusions: Our findings suggest that HRS mitigates I/R injury by decreasing inflammation and, therefore, has the potential for application as a therapy for improving skin flap survival.
基金This study was supported by grants from the NationalBasic Research Program (973) of China ( No. 2003CB515506),Postdoctoral Fund of China (20040350233), and Research Grantawarded by the First Affiliated Hospital, Zhejiang UniversitySchool of Medicine, Hangzhou, China.
文摘BACKGROUND: Hepatic ischemia/reperfusion injury may induce intestinal microflora imbalance. Salvia miltiorrhiza is effective in promoting blood circulation and counteracting peroxidation in tissues. The aim of the present study was to determine the effects of Salvia miltiorrhiza on intestinal mi- croflora, endotoxemia, and bacterial translocation in rats with hepatic I/R injury. METHODS: Sprague-Dawley rats in specific pathogen free grade were divided into 3 groups: group I(n =6) for sham operation: groups ( n = 7) for liver ische- mia for 20 minutes and reperfusion for 22 hours. Group was also pretreated with 4 ml/day of Salvia miltiorrhiza solu- tion (250 mg/kg) by daily gavage for 7 days. The levels of serum alanine aminotransferase (ALT), aspartate amino- transferase (AST), malondialdehyde ( MDA) and supero- xide dismutase ( SOD ) in liver tissues, serum endotoxin, intestinal bacterial counts, intestinal mucosal histology and bacterial translocation were studied. RESULTS: The levels of ALT, AST, plasma endotoxin and MDA in liver tissues were decreased more markedly in group (57.57 ± 18.08 U/L, 147.57 ±40.84 U/L, 0.42 ± 0.144 EU/ml and 0. 52 ±0.19 nmol/mg-prot respectively) in group 295.9±216.92 U/L, 0.80± 0.262 EU/ml and 0.72±0.12 nmol/mg-prot; P <0.05-0.01 respectively). Liver SOD activity was increased more sig- nificantly in group (318.47±64.62 U/mg-prot) than in group U/mg-prot, P<0.05). The counts of Bifidobacteria and Bacteroides increased more significantly in group than in group but were similar to those in group I. Bacterial translocation to the kidney in group was 50% (5/10), whereas no bacterial translocation to the kidney occurred in the other two groups (P <0. 01). Ileal mucosal structure was markedly ameliorated in group as compared with group CONCLUSIONS: Salviae miltiorrhiza could partially restore intestinal microflora balance, improve intestinal mucosal integrity, and reduce bacterial translocation and plasma en- dotoxin in rats with hepatic ischemia/reperfusion injury.
文摘BACKGROUND: Toll-like receptor 4 (TLR4) is involved in innate immunity by recognizing endotoxin resulting in a burst of inflammatory cascade. We investigated the relation between activation of TLR4 and liver injury in partial hepa- tic ischemia/reperfusion (I/R) injury in mice. METHODS: TLR4-deficient mice ( C3H/Hej) and wild type mice (WT, C3H/Heouj) were used in the model of I/R injury. Partial hepatic ischemia was produced by oc- clusion of inflow to the median and left lobes for 45 mi- nutes. Blood was drawn at 1 and 3 hours after reperfusion. The blood was analyzed for aspartate aminotransferase (AST) and tumor necrosis factor alpha (TNF-α). TNF-α mRNA expression and myeloperoxidase (MPO) level in the ischemic lobes were examined by northern blot and myeloperoxidase assay respectively. RESULTS: AST levels were significantly decreased in TLR4- deficient mice compared with WT mice at both time points (WT: 1215.5 ±174. 03, 2958. 17 ± 186. 81 IU/L at 1 and 3 hours respectively vs TLR4def: 661.83±106.09, 1145.17± 132.43 IU/L at 1 and 3 hours, mean ± SD, 6 mice/group, (=-6.65 and -5.57, P <0.001). Consistent with the role of TNF-α in hepatic I/R, serum TNF-α was decreased in TLR4 deficient mice at 3 hours after reperfusion compared with WT (152.39±43.3 vs 249.12 ± 51.89, n=6, t=-3.13, P<0.05). MPO level in the ischemic lobes in TLR4 defi- cient mice at 3 hours after reperfusion was significantly low- er than that in WT mice (0.059±0.004 vs 0.173±0.025, n=6, F=33.49, P<0.001). This difference appears to be mediated at the gene level since TLR4 deficient mice had decreased TNF-α mRNA expression at 1 hour after reperfu- sion compared with WT mice (80.3±28.8 vs 189.4±24.6, t=-3.25, P<0.05). CONCLUSIONS: Compared with WT mice, TLR4-defi- cient mice appear to have a mild I/R injury. Regulation of TNF-a at mRNA level seems to have a critical effect. These suggest TLR4 be involved in the mechanism of he-patic I/R injury in mice.
基金financially supported by Key Science and Technology Project of Haikou City,with grant number 2011-0142
文摘Objective:To investigate the protective effect of different cyclosporin A(CsA)doses on myocardial ischemia/reperfusion injury in rat models.Methods:A rat model of myocardial ischemia/reperfusion injury was established in vivo and the rats were randomly divided into four groups:placebo(PBS;T1),low-dose(CsA dose:1.0 mg/kg:T2),medium-dose(CsA dose:2.5 mg/kg:T3),and high-dose(CsA dose:5.0 mg/kg;T4)groups.Heart function indexes were monitored at different time points,the extent of myocardial infarction was assessed by Evans Blue-TTC staining,and creatine kinase MB mass and cardiac troponin 1 values were measured by biochemical assays.Results:Compared with the T1 and T2 groups,both the creatine kinase MB mass and cardiac troponin 1 were significantly lower in the T3 and T4 groups(P<0.05).The mean arterial pressure(MAP)and left ventricular systolic pressure(LVSP)decreased sequentially in each group,with the extending reperfusion time.Significant decreases in LVSP and MAP were observed in the T3 and T4 groups as compared to the T1 and T2 group(P<0.05)and the T2 group showed a significantly lower LVSP and MAP decline than the T1 group(P<0.05).Compared with the Tl group,the rats from the T2.T3,and T4 groups suffered from a significantly lower extent of myocardial infarction(P<0.05).Also,the a animals in the T3 and T4 groups had a significantly smaller extent of myocardial infarction than those in the T2 group(P<0.05).Conclusions:Various CsA doses exert different degrees of protection against ischemia/reperfusion injury,and this protective effect peaks at approximately 2.5 mg/kg in rat models.
基金supported by the Natural Science Foundation of Shandong Province of China,No.ZR2015HM023(to MSW)the Science and Technology Plan Project of Qingdao City of China,No.19-6-1-50-nsh(to MSW)
文摘Selective brain hypothermia is considered an effective treatment for neuronal injury after stroke,and avoids the complications of general hypothermia.However,the mechanisms by which selective brain hypothermia affects mitochondrial fission remain unknown.In this study,we investigated the effect of selective brain hypothermia on the expression of fission 1 (Fis1) protein,a key factor in the mitochondrial fission system,during focal cerebral ischemia/reperfusion injury.Sprague-Dawley rats were divided into four groups.In the sham group,the carotid arteries were exposed only.In the other three groups,middle cerebral artery occlusion was performed using the intraluminal filament technique.After 2 hours of occlusion,the filament was slowly removed to allow blood reperfusion in the ischemia/reperfusion group.Saline,at 4℃ and 37℃,were perfused through the carotid artery in the hypothermia and normothermia groups,respectively,followed by restoration of blood flow.Neurological function was assessed with the Zea Longa 5-point scoring method.Cerebral infarct volume was assessed by 2,3,5-triphenyltetrazolium chloride staining,and apoptosis was assessed by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling staining.Fis1 and cytosolic cytochrome c levels were assessed by western blot assay.Fis1 mRNA expression was assessed by quantitative reverse transcription-polymerase chain reaction.Mitochondrial ultrastructure was evaluated by transmission electron microscopy.Compared with the sham group,apoptosis,Fis1 protein and mRNA expression and cytosolic cytochrome c levels in the cortical ischemic penumbra and cerebral infarct volume were increased after reperfusion in the other three groups.These changes caused by cerebral ischemia/reperfusion were inhibited in the hypothermia group compared with the normothermia group.These findings show that selective brain hypothermia inhibits Fis1 expression and reduces apoptosis,thereby ameliorating focal cerebral ischemia/reperfusion injury in rats.Experiments were authorized by the Ethics Committee of Qingdao Municipal Hospital of China (approval No.2019008).
