Cerebral ischemia is a major health risk that requires preventive approaches in addition to drug therapy.Physical exercise enhances neurogenesis and synaptogenesis,and has been widely used for functional rehabilitatio...Cerebral ischemia is a major health risk that requires preventive approaches in addition to drug therapy.Physical exercise enhances neurogenesis and synaptogenesis,and has been widely used for functional rehabilitation after stroke.In this study,we determined whether exercise training before disease onset can alleviate the severity of cerebral ischemia.We also examined the role of exercise-induced circulating factors in these effects.Adult mice were subjected to 14 days of treadmill exercise training before surgery for middle cerebral artery occlusion.We found that this exercise pre-conditioning strategy effectively attenuated brain infarct area,inhibited gliogenesis,protected synaptic proteins,and improved novel object and spatial memory function.Further analysis showed that circulating adiponectin plays a critical role in these preventive effects of exercise.Agonist activation of adiponectin receptors by Adipo Ron mimicked the effects of exercise,while inhibiting receptor activation abolished the exercise effects.In summary,our results suggest a crucial role of circulating adiponectin in the effects of exercise pre-conditioning in protecting against cerebral ischemia and supporting the health benefits of exercise.展开更多
Brain injuries like ischemic stroke induce endogenous stem cell production. Although the precise traits of stem cells in pathological brains remain unclear, we previously demonstrated that injury/ischemia-induced stem...Brain injuries like ischemic stroke induce endogenous stem cell production. Although the precise traits of stem cells in pathological brains remain unclear, we previously demonstrated that injury/ischemia-induced stem cells(iSCs)are present in the post-stroke mouse(Nakagomi et al.,2009)and human brains(Beppu et al.,2019).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
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 Acute mesenteric ischemia is a life-threatening disease.Intrasplenic gas is an extremely rare finding in such cases.CASE SUMMARY We report a case of a 79-year-old woman with a history of end-stage renal dis...BACKGROUND Acute mesenteric ischemia is a life-threatening disease.Intrasplenic gas is an extremely rare finding in such cases.CASE SUMMARY We report a case of a 79-year-old woman with a history of end-stage renal disease on hemodialysis for approximately 20 years,type 2 diabetes mellitus,and atrial fibrillation who presented with two days of epigastric pain.A computed tomography scan of the abdomen revealed intraperitoneal free air and significant intrasplenic gas.Laparoscopy revealed diffuse intestinal gangrene,and acute superior mesenteric ischemia was diagnosed.The patient died within 24 hours owing to profound shock.CONCLUSION Intrasplenic gas is an extremely rare finding on computed tomography imaging in cases of acute mesenteric ischemia.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
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
The macrophage-mediated inflammatory response is crucial for the recovery of skeletal muscle following ischemia.Therefore,macrophage-based therapeutic targets need to be explored for ischemic disease.In the current st...The macrophage-mediated inflammatory response is crucial for the recovery of skeletal muscle following ischemia.Therefore,macrophage-based therapeutic targets need to be explored for ischemic disease.In the current study,we found that the mRNA levels of scavenger receptor A1(Sr-a1)were elevated in patients with critical limb ischemia,based on an analysis of the Gene Expression Omnibus data.We then investigated the role and underlying mechanisms of macrophage SR-A1 in a mouse hindlimb ischemia(HLI)model.Compared with the Sr-a1^(fl/fl)mice,the Lyz^(Cre+)/Sr-a1^(flox/flox)(Sr-a1~(ΔMΦ))mice showed significantly reduced laser Doppler blood flow in the ischemic limb on day seven after HLI.Consistently,histological analysis revealed that the ischemic limb of the Sr-a1~(ΔMΦ)mice exhibited more severe and prolonged necrotic morphology,inflammation,fibrosis,decreased vessel density,and delayed regeneration than that of the control Sr-a1~(fl/fl)mice.Furthermore,restoring wild-type myeloid cells to the Sr-a1 knockout mice effectively improved the Doppler perfusion in the ischemic limb and mitigated skeletal muscle damage seven days after HLI.Consistent with these in vivo findings,co-cultivating macrophages with the mouse myoblast cell line C2C12 revealed that the Sr-a1^(-/-)bone marrow macrophages significantly inhibited myoblast differentiation in vitro.Mechanistically,SR-A1 enhanced the skeletal muscle regeneration in response to HLI by inhibiting oncostatin M production via suppression of the NF-κB signaling activation.These findings indicate that SR-A1 may be a promising candidate protein to improve tissue repair and regeneration in peripheral ischemic arterial disease.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
Background:The study aimed to investigate the protective effect and mechanism of total flavonoids of Scutellaria baicalensis(TFSB)on acute myocardial ischemia(AMI)rats by using functional metabonomics.Methods:Rats wer...Background:The study aimed to investigate the protective effect and mechanism of total flavonoids of Scutellaria baicalensis(TFSB)on acute myocardial ischemia(AMI)rats by using functional metabonomics.Methods:Rats were divided into the Control,Model,AMI positive control(Propranolol hydrochloride,30 mg/kg),low dose TFSB(50 mg/kg),and high dose TFSB(100 mg/kg)groups.Rats received the corresponding treatment by intragastric administration once daily for 10 consecutive days.Electrocardiogram,myocardial enzyme,triphenyltetrazolium chloride staining,hematoxylin-eosin,and enzyme-linked immunosorbent assay were performed to evaluate the protective effect of TFSB on AMI rats.Then,the UHPLC-Q-Orbitrap MS method based on serum metabolomics was utilised to search for metabolic biomarkers and metabolic pathways.Subsequently,Western blot and RT-PCR techniques were employed to identify the respective genes and proteins.Results:Pharmacodynamics revealed that TFSB could ameliorate AMI in rats.The results of the metabolomics analysis indicated that the alterations in metabolic profile observed in rats with AMI were partially improved by treatment with TFSB.Moreover,the mRNA expression levels of 5-lipoxygenase(5-LOX)and 15-lipoxygenase(15-LOX)and the protein expression levels of 5-LOX,15-LOX,interleukin-1β(IL-1β),and NF-κB p65 were reduced following treatment with TFSB.Conclusion:The potential treatment of TFSB in AMI may be ascribed to its ability to regulate arachidonic acid metabolism.展开更多
Hepatic ischemia–reperfusion injury(HIRI)is an important cause of liver injury following liver transplantation and major resections,and neutrophils are the key effector cells in HIRI.Double-negative T regulatory cell...Hepatic ischemia–reperfusion injury(HIRI)is an important cause of liver injury following liver transplantation and major resections,and neutrophils are the key effector cells in HIRI.Double-negative T regulatory cells(DNT)are increasingly recognized as having critical regulatory functions in the immune system.Whether DNT expresses distinct immunoregulatory mechanisms to modulate neutrophils,as in HIRI,remains largely unknown.In this study,we found that murine and human DNT highly expressed CD39that protected DNT from extracellular ATP-induced apoptosis and generated adenosine in tandem with CD73,to induce high levels of neutrophil apoptosis.Furthermore,extracellular adenosine enhanced DNT survival and suppressive function by upregulating survivin and NKG2D expression via the A2AR/pAKT/FOXO1 signaling pathway.Adoptive transfer of DNT ameliorated HIRI in mice through the inhibition of neutrophils in a CD39-dependent manner.Lastly,the adoptive transfer of A2ar^(-/-)DNT validated the importance of adenosine/A2AR signaling,in promoting DNT survival and immunomodulatory function to protect against HIRI in vivo.In conclusion,purinergic signaling is crucial for DNT homeostasis in HIRI.Augmentation of CD39 or activation of A2AR signaling in DNT may provide novel therapeutic strategies to target innate immune disorders.展开更多
With the wide application of thrombolytic drugs and the advancement of endovascular therapeutic techniques, the recanalization treatment of acute artery occlusion in ischemic stroke (IS) has made a leap forward, but i...With the wide application of thrombolytic drugs and the advancement of endovascular therapeutic techniques, the recanalization treatment of acute artery occlusion in ischemic stroke (IS) has made a leap forward, but ischemic brain tissues still face ischemia-reperfusion injury after recanalization. Nowadays, effective neurological protective agents still cannot completely resist the multiple damages of ischemia-reperfusion injury. As an iron-dependent mode of programmed cell death, ferroptosis occupies an important position in ischemia-reperfusion injury. Selenium plays a unique protective role in ischemia-reperfusion injury as an active site element in the center of glutathione peroxidase. Therefore, the study mainly aims to review the protective role of selenium in IS and the related mechanisms, as well as the effect of selenium on the risk factors of IS.展开更多
Coronary artery anomaly is known as one of the causes of angina pectoris and sudden death and is an important clinical entity that cannot be overlooked.The incidence of coronary artery anomalies is as low as 1%-2%of t...Coronary artery anomaly is known as one of the causes of angina pectoris and sudden death and is an important clinical entity that cannot be overlooked.The incidence of coronary artery anomalies is as low as 1%-2%of the general population,even when the various types are combined.Coronary anomalies are practically challenging when the left and right coronary ostium are not found around their normal positions during coronary angiography with a catheter.If there is atherosclerotic stenosis of the coronary artery with an anomaly and percutaneous coronary intervention(PCI)is required,the suitability of the guiding catheter at the entrance and the adequate back up force of the guiding catheter are issues.The level of PCI risk itself should also be considered on a caseby-case basis.In this case,emission computed tomography in the R-1 subtype single coronary artery proved that ischemia occurred in an area where the coronary artery was not visible to the naked eye.Meticulous follow-up would be crucial,because sudden death may occur in single coronary arteries.To prevent atherosclerosis with full efforts is also important,as the authors indicated admirably.展开更多
The standard approach to organ preservation in liver transplantation is by static cold storage and the time between the cross-clamping of a graft in a donor and its reperfusion in the recipient is defined as cold isch...The standard approach to organ preservation in liver transplantation is by static cold storage and the time between the cross-clamping of a graft in a donor and its reperfusion in the recipient is defined as cold ischemia time(CIT).This simple definition reveals a multifactorial time frame that depends on donor hepatectomy time,transit time,and recipient surgery time,and is one of the most important donor-related risk factors which may influence the graft and recipient’s survival.Recently,the growing demand for the use of marginal liver grafts has prompted scientific exploration to analyze ischemia time factors and develop different organ preservation strategies.This review details the CIT definition and analyzes its different factors.It also explores the most recent strategies developed to implement each timestamp of CIT and to protect the graft from ischemic injury.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
Background:The Mongolian gerbil is an excellent laboratory animal for preparing the cerebral ischemia model due to its inherent deficiency in the circle of Willis.However,the low incidence and unpredictability of symp...Background:The Mongolian gerbil is an excellent laboratory animal for preparing the cerebral ischemia model due to its inherent deficiency in the circle of Willis.However,the low incidence and unpredictability of symptoms are caused by numerous complex variant types of the circle.Additionally,the lack of an evaluation system for the cer-ebral ischemia/reperfusion(I/R)model of gerbils has shackled the application of this model.Methods:We created a symptom-oriented principle and detailed neurobehavioral scoring criteria.At different time points of reperfusion,we analyzed the alteration in locomotion by rotarod test and grip force score,infarct volume by triphenyltetrazo-lium chloride(TTC)staining,neuron loss using Nissl staining,and histological charac-teristics using hematoxylin-eosin(H&E)straining.Results:With a successful model rate of 56%,32 of the 57 gerbils operated by our method harbored typical features of cerebral I/R injury,and the mortality rate in the male gerbils was significantly higher than that in the female gerbils.The suc-cessfully prepared I/R gerbils demonstrated a significant reduction in motility and grip strength at 1 day after reperfusion;formed obvious infarction;exhibited typi-cal pathological features,such as tissue edema,neuronal atrophy and death,and vacuolated structures;and were partially recovered with the extension of reperfu-sion time.Conclusion:This study developed a new method for the unilateral common carotid artery ligation I/R model of gerbil and established a standardized evaluation system for this model,which could provide a new cerebral I/R model of gerbils with more practical applications.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
Elevated intraocular pressure(IOP)is one of the causes of retinal ischemia/reperfusion injury,which results in NRP3 inflammasome activation and leads to visual damage.Homerla is repo rted to play a protective role in ...Elevated intraocular pressure(IOP)is one of the causes of retinal ischemia/reperfusion injury,which results in NRP3 inflammasome activation and leads to visual damage.Homerla is repo rted to play a protective role in neuroinflammation in the cerebrum.However,the effects of Homerla on NLRP3inflammasomes in retinal ischemia/reperfusion injury caused by elevated IOP remain unknown.In our study,animal models we re constructed using C57BL/6J and Homer1^(flox/-)/Homerla^(+/-)/Nestin-Cre^(+/-)mice with elevated IOP-induced retinal ischemia/repe rfusion injury.For in vitro expe riments,the oxygen-glucose deprivation/repe rfusion injury model was constructed with M uller cells.We found that Homerla ove rexpression amelio rated the decreases in retinal thickness and Muller cell viability after ischemia/reperfusion injury.Furthermore,Homerla knockdown promoted NF-κB P65^(Ser536)activation via caspase-8,NF-κB P65 nuclear translocation,NLRP3 inflammasome formation,and the production and processing of interleukin-1βand inte rleukin-18.The opposite results we re observed with Homerla ove rexpression.Finally,the combined administration of Homerla protein and JSH-23 significantly inhibited the reduction in retinal thickness in Homer1^(flox/-)Homer1a^(+/-)/Nestin-Cre^(+/-)mice and apoptosis in M uller cells after ischemia/reperfusion injury.Taken together,these studies demonstrate that Homer1a exerts protective effects on retinal tissue and M uller cells via the caspase-8/NF-KB P65/NLRP3 pathway after I/R injury.展开更多
Objective Formononetin(FOR),a traditional Chinese medicine,has been widely used for nerve protection and nerve function rehabilitation after cerebral stroke.However,the role of FOR in autophagic lysosome function in c...Objective Formononetin(FOR),a traditional Chinese medicine,has been widely used for nerve protection and nerve function rehabilitation after cerebral stroke.However,the role of FOR in autophagic lysosome function in cerebral ischemiareperfusion damage has not been investigated.This study aimed to explore whether the therapeutic benefits of FOR were influenced by the regulation of autophagy flux.Methods Male Sprague-Dawley rats were separated into sham,model,and MCAO+FOR(30 mg/kg)groups after undergoing middle cerebral artery occlusion(MCAO)and ischemia-reperfusion(I/R).Then,the brain tissues in the ischemic penumbra were obtained to detect the proteins in autophagic/lysosomal pathway with antibodies of Beclin-1,LC3,SQSTM1/P62,Ubiquitin,LAMP-2,Cathepsin B(CTSB)and Cathepsin D(CTSD)by Western blot and immunofluorescence,respectively.Meanwhile,the therapeutic effectiveness was evaluated by measuring infarct volume,neurological impairments,and neuronal necrosis.Results The findings of this study demonstrate that FOR treatment exhibits a dual effect by enhancing the autophagic activities of Beclin-1 and LC3 in neurons,while simultaneously improving the autophagic clearance function,as evidenced by reinforced lysosomal activities of LAMP-2,CTSB,and CTSD,as well as reduced autophagic accumulation of Ubiquitin and P62 in the MCAO+FOR group compared to the MCAO group.Additionally,7 d of FOR treatment dramatically reduced neurological deficits,infarct volume,and neuronal death caused by cerebral ischemia.Conclusion These findings suggest that the neuroprotective mechanism of FOR therapy in accelerating recovery from ischemic stroke may involve the increase of autophagy flux in the penumbra.展开更多
基金supported by STI2030-Major Projects,No.2022ZD0207600(to LZ)the National Natural Science Foundation of China,Nos.32070955(to LZ),U22A20301(to KFS)+3 种基金the Natural Science Foundation of Guangdong Province,No.2021A1515012197(to HO)Guangzhou Core Medical Disciplines Project,No.2021-2023(to HO)Key Research and Development Plan of Ningxia Hui Automomous Region,No.2022BEG01004(to KFS)Science and Technology Program of Guangzhou,China,No.202007030012(to KFS and LZ)。
文摘Cerebral ischemia is a major health risk that requires preventive approaches in addition to drug therapy.Physical exercise enhances neurogenesis and synaptogenesis,and has been widely used for functional rehabilitation after stroke.In this study,we determined whether exercise training before disease onset can alleviate the severity of cerebral ischemia.We also examined the role of exercise-induced circulating factors in these effects.Adult mice were subjected to 14 days of treadmill exercise training before surgery for middle cerebral artery occlusion.We found that this exercise pre-conditioning strategy effectively attenuated brain infarct area,inhibited gliogenesis,protected synaptic proteins,and improved novel object and spatial memory function.Further analysis showed that circulating adiponectin plays a critical role in these preventive effects of exercise.Agonist activation of adiponectin receptors by Adipo Ron mimicked the effects of exercise,while inhibiting receptor activation abolished the exercise effects.In summary,our results suggest a crucial role of circulating adiponectin in the effects of exercise pre-conditioning in protecting against cerebral ischemia and supporting the health benefits of exercise.
基金partially supported by the Japan Society for the Promotion of Science (JSPS) KAKENHI (15K0672318K07380)the Japan Agency for Medical Research and Development (AMED) (21nk0101538h0002) (to TN)。
文摘Brain injuries like ischemic stroke induce endogenous stem cell production. Although the precise traits of stem cells in pathological brains remain unclear, we previously demonstrated that injury/ischemia-induced stem cells(iSCs)are present in the post-stroke mouse(Nakagomi et al.,2009)and human brains(Beppu et al.,2019).
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.
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BACKGROUND Acute mesenteric ischemia is a life-threatening disease.Intrasplenic gas is an extremely rare finding in such cases.CASE SUMMARY We report a case of a 79-year-old woman with a history of end-stage renal disease on hemodialysis for approximately 20 years,type 2 diabetes mellitus,and atrial fibrillation who presented with two days of epigastric pain.A computed tomography scan of the abdomen revealed intraperitoneal free air and significant intrasplenic gas.Laparoscopy revealed diffuse intestinal gangrene,and acute superior mesenteric ischemia was diagnosed.The patient died within 24 hours owing to profound shock.CONCLUSION Intrasplenic gas is an extremely rare finding on computed tomography imaging in cases of acute mesenteric ischemia.
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.
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(Grant Nos.82030012,81670263,82170444,82270476,82270361,and 82100433)the Natural Science Foundation of the Jiangsu Higher Education Institutions of China(Grant No.24KJA310003)。
文摘The macrophage-mediated inflammatory response is crucial for the recovery of skeletal muscle following ischemia.Therefore,macrophage-based therapeutic targets need to be explored for ischemic disease.In the current study,we found that the mRNA levels of scavenger receptor A1(Sr-a1)were elevated in patients with critical limb ischemia,based on an analysis of the Gene Expression Omnibus data.We then investigated the role and underlying mechanisms of macrophage SR-A1 in a mouse hindlimb ischemia(HLI)model.Compared with the Sr-a1^(fl/fl)mice,the Lyz^(Cre+)/Sr-a1^(flox/flox)(Sr-a1~(ΔMΦ))mice showed significantly reduced laser Doppler blood flow in the ischemic limb on day seven after HLI.Consistently,histological analysis revealed that the ischemic limb of the Sr-a1~(ΔMΦ)mice exhibited more severe and prolonged necrotic morphology,inflammation,fibrosis,decreased vessel density,and delayed regeneration than that of the control Sr-a1~(fl/fl)mice.Furthermore,restoring wild-type myeloid cells to the Sr-a1 knockout mice effectively improved the Doppler perfusion in the ischemic limb and mitigated skeletal muscle damage seven days after HLI.Consistent with these in vivo findings,co-cultivating macrophages with the mouse myoblast cell line C2C12 revealed that the Sr-a1^(-/-)bone marrow macrophages significantly inhibited myoblast differentiation in vitro.Mechanistically,SR-A1 enhanced the skeletal muscle regeneration in response to HLI by inhibiting oncostatin M production via suppression of the NF-κB signaling activation.These findings indicate that SR-A1 may be a promising candidate protein to improve tissue repair and regeneration in peripheral ischemic arterial disease.
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sponsored by Shandong Provincial Key Research and Development Program(Major Technological Innovation Project)([2021]CXGC010508)Guizhou Province Youth Science and Technology Talent Plan(YQK[2023]038)+1 种基金Science and Technology Department of Zunyi City of Guizhou province of China([2020]7)Key project at central government level:the ability establishment of sustainable use for valuable Chinese medicine resources(2060302).
文摘Background:The study aimed to investigate the protective effect and mechanism of total flavonoids of Scutellaria baicalensis(TFSB)on acute myocardial ischemia(AMI)rats by using functional metabonomics.Methods:Rats were divided into the Control,Model,AMI positive control(Propranolol hydrochloride,30 mg/kg),low dose TFSB(50 mg/kg),and high dose TFSB(100 mg/kg)groups.Rats received the corresponding treatment by intragastric administration once daily for 10 consecutive days.Electrocardiogram,myocardial enzyme,triphenyltetrazolium chloride staining,hematoxylin-eosin,and enzyme-linked immunosorbent assay were performed to evaluate the protective effect of TFSB on AMI rats.Then,the UHPLC-Q-Orbitrap MS method based on serum metabolomics was utilised to search for metabolic biomarkers and metabolic pathways.Subsequently,Western blot and RT-PCR techniques were employed to identify the respective genes and proteins.Results:Pharmacodynamics revealed that TFSB could ameliorate AMI in rats.The results of the metabolomics analysis indicated that the alterations in metabolic profile observed in rats with AMI were partially improved by treatment with TFSB.Moreover,the mRNA expression levels of 5-lipoxygenase(5-LOX)and 15-lipoxygenase(15-LOX)and the protein expression levels of 5-LOX,15-LOX,interleukin-1β(IL-1β),and NF-κB p65 were reduced following treatment with TFSB.Conclusion:The potential treatment of TFSB in AMI may be ascribed to its ability to regulate arachidonic acid metabolism.
基金supported by the grants from the National Natural Science Foundation of China(81970503,82100670,82202021and 82270606)Chinese Institutes for Medical Research+7 种基金Beijing(CX24PY16)R&D Program of Beijing Municipal Education Commission(KZ202210025036)Beijing Municipal Administration of Hospitals’Ascent Plan(DFL20220103)Beijing Nova Program(Z211100002121036)Youth Beijing Scholar(035)and the Reform and Development Program of Beijing Institute of Respiratory Medicine(Ggyfz202403)Generation of reagents and mutant mice are also supported by the National Institutes of Health(R01 DK108894R21 CA164970 and R21 CA221702)Department of Defense Award W81XWH-16-0464。
文摘Hepatic ischemia–reperfusion injury(HIRI)is an important cause of liver injury following liver transplantation and major resections,and neutrophils are the key effector cells in HIRI.Double-negative T regulatory cells(DNT)are increasingly recognized as having critical regulatory functions in the immune system.Whether DNT expresses distinct immunoregulatory mechanisms to modulate neutrophils,as in HIRI,remains largely unknown.In this study,we found that murine and human DNT highly expressed CD39that protected DNT from extracellular ATP-induced apoptosis and generated adenosine in tandem with CD73,to induce high levels of neutrophil apoptosis.Furthermore,extracellular adenosine enhanced DNT survival and suppressive function by upregulating survivin and NKG2D expression via the A2AR/pAKT/FOXO1 signaling pathway.Adoptive transfer of DNT ameliorated HIRI in mice through the inhibition of neutrophils in a CD39-dependent manner.Lastly,the adoptive transfer of A2ar^(-/-)DNT validated the importance of adenosine/A2AR signaling,in promoting DNT survival and immunomodulatory function to protect against HIRI in vivo.In conclusion,purinergic signaling is crucial for DNT homeostasis in HIRI.Augmentation of CD39 or activation of A2AR signaling in DNT may provide novel therapeutic strategies to target innate immune disorders.
文摘With the wide application of thrombolytic drugs and the advancement of endovascular therapeutic techniques, the recanalization treatment of acute artery occlusion in ischemic stroke (IS) has made a leap forward, but ischemic brain tissues still face ischemia-reperfusion injury after recanalization. Nowadays, effective neurological protective agents still cannot completely resist the multiple damages of ischemia-reperfusion injury. As an iron-dependent mode of programmed cell death, ferroptosis occupies an important position in ischemia-reperfusion injury. Selenium plays a unique protective role in ischemia-reperfusion injury as an active site element in the center of glutathione peroxidase. Therefore, the study mainly aims to review the protective role of selenium in IS and the related mechanisms, as well as the effect of selenium on the risk factors of IS.
文摘Coronary artery anomaly is known as one of the causes of angina pectoris and sudden death and is an important clinical entity that cannot be overlooked.The incidence of coronary artery anomalies is as low as 1%-2%of the general population,even when the various types are combined.Coronary anomalies are practically challenging when the left and right coronary ostium are not found around their normal positions during coronary angiography with a catheter.If there is atherosclerotic stenosis of the coronary artery with an anomaly and percutaneous coronary intervention(PCI)is required,the suitability of the guiding catheter at the entrance and the adequate back up force of the guiding catheter are issues.The level of PCI risk itself should also be considered on a caseby-case basis.In this case,emission computed tomography in the R-1 subtype single coronary artery proved that ischemia occurred in an area where the coronary artery was not visible to the naked eye.Meticulous follow-up would be crucial,because sudden death may occur in single coronary arteries.To prevent atherosclerosis with full efforts is also important,as the authors indicated admirably.
文摘The standard approach to organ preservation in liver transplantation is by static cold storage and the time between the cross-clamping of a graft in a donor and its reperfusion in the recipient is defined as cold ischemia time(CIT).This simple definition reveals a multifactorial time frame that depends on donor hepatectomy time,transit time,and recipient surgery time,and is one of the most important donor-related risk factors which may influence the graft and recipient’s survival.Recently,the growing demand for the use of marginal liver grafts has prompted scientific exploration to analyze ischemia time factors and develop different organ preservation strategies.This review details the CIT definition and analyzes its different factors.It also explores the most recent strategies developed to implement each timestamp of CIT and to protect the graft from ischemic injury.
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National Key Research and Development Program of China,Grant/Award Number:2021YFF0702402National Natural Science Foundation of China,Grant/Award Number:32070531。
文摘Background:The Mongolian gerbil is an excellent laboratory animal for preparing the cerebral ischemia model due to its inherent deficiency in the circle of Willis.However,the low incidence and unpredictability of symptoms are caused by numerous complex variant types of the circle.Additionally,the lack of an evaluation system for the cer-ebral ischemia/reperfusion(I/R)model of gerbils has shackled the application of this model.Methods:We created a symptom-oriented principle and detailed neurobehavioral scoring criteria.At different time points of reperfusion,we analyzed the alteration in locomotion by rotarod test and grip force score,infarct volume by triphenyltetrazo-lium chloride(TTC)staining,neuron loss using Nissl staining,and histological charac-teristics using hematoxylin-eosin(H&E)straining.Results:With a successful model rate of 56%,32 of the 57 gerbils operated by our method harbored typical features of cerebral I/R injury,and the mortality rate in the male gerbils was significantly higher than that in the female gerbils.The suc-cessfully prepared I/R gerbils demonstrated a significant reduction in motility and grip strength at 1 day after reperfusion;formed obvious infarction;exhibited typi-cal pathological features,such as tissue edema,neuronal atrophy and death,and vacuolated structures;and were partially recovered with the extension of reperfu-sion time.Conclusion:This study developed a new method for the unilateral common carotid artery ligation I/R model of gerbil and established a standardized evaluation system for this model,which could provide a new cerebral I/R model of gerbils with more practical applications.
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.
基金supported by the Youth Development Project of Air Force Military Medical University,No.21 QNPY072Key Project of Shaanxi Provincial Natural Science Basic Research Program,No.2023-JC-ZD-48(both to FF)。
文摘Elevated intraocular pressure(IOP)is one of the causes of retinal ischemia/reperfusion injury,which results in NRP3 inflammasome activation and leads to visual damage.Homerla is repo rted to play a protective role in neuroinflammation in the cerebrum.However,the effects of Homerla on NLRP3inflammasomes in retinal ischemia/reperfusion injury caused by elevated IOP remain unknown.In our study,animal models we re constructed using C57BL/6J and Homer1^(flox/-)/Homerla^(+/-)/Nestin-Cre^(+/-)mice with elevated IOP-induced retinal ischemia/repe rfusion injury.For in vitro expe riments,the oxygen-glucose deprivation/repe rfusion injury model was constructed with M uller cells.We found that Homerla ove rexpression amelio rated the decreases in retinal thickness and Muller cell viability after ischemia/reperfusion injury.Furthermore,Homerla knockdown promoted NF-κB P65^(Ser536)activation via caspase-8,NF-κB P65 nuclear translocation,NLRP3 inflammasome formation,and the production and processing of interleukin-1βand inte rleukin-18.The opposite results we re observed with Homerla ove rexpression.Finally,the combined administration of Homerla protein and JSH-23 significantly inhibited the reduction in retinal thickness in Homer1^(flox/-)Homer1a^(+/-)/Nestin-Cre^(+/-)mice and apoptosis in M uller cells after ischemia/reperfusion injury.Taken together,these studies demonstrate that Homer1a exerts protective effects on retinal tissue and M uller cells via the caspase-8/NF-KB P65/NLRP3 pathway after I/R injury.
文摘Objective Formononetin(FOR),a traditional Chinese medicine,has been widely used for nerve protection and nerve function rehabilitation after cerebral stroke.However,the role of FOR in autophagic lysosome function in cerebral ischemiareperfusion damage has not been investigated.This study aimed to explore whether the therapeutic benefits of FOR were influenced by the regulation of autophagy flux.Methods Male Sprague-Dawley rats were separated into sham,model,and MCAO+FOR(30 mg/kg)groups after undergoing middle cerebral artery occlusion(MCAO)and ischemia-reperfusion(I/R).Then,the brain tissues in the ischemic penumbra were obtained to detect the proteins in autophagic/lysosomal pathway with antibodies of Beclin-1,LC3,SQSTM1/P62,Ubiquitin,LAMP-2,Cathepsin B(CTSB)and Cathepsin D(CTSD)by Western blot and immunofluorescence,respectively.Meanwhile,the therapeutic effectiveness was evaluated by measuring infarct volume,neurological impairments,and neuronal necrosis.Results The findings of this study demonstrate that FOR treatment exhibits a dual effect by enhancing the autophagic activities of Beclin-1 and LC3 in neurons,while simultaneously improving the autophagic clearance function,as evidenced by reinforced lysosomal activities of LAMP-2,CTSB,and CTSD,as well as reduced autophagic accumulation of Ubiquitin and P62 in the MCAO+FOR group compared to the MCAO group.Additionally,7 d of FOR treatment dramatically reduced neurological deficits,infarct volume,and neuronal death caused by cerebral ischemia.Conclusion These findings suggest that the neuroprotective mechanism of FOR therapy in accelerating recovery from ischemic stroke may involve the increase of autophagy flux in the penumbra.
