Ischemia–reperfusion injury is a common pathophysiological mechanism in retinal degeneration.PANoptosis is a newly defined integral form of regulated cell death that combines the key features of pyroptosis,apoptosis,...Ischemia–reperfusion injury is a common pathophysiological mechanism in retinal degeneration.PANoptosis is a newly defined integral form of regulated cell death that combines the key features of pyroptosis,apoptosis,and necroptosis.Oligomerization of mitochondrial voltage-dependent anion channel 1 is an important pathological event in regulating cell death in retinal ischemia–reperfusion injury.However,its role in PANoptosis remains largely unknown.In this study,we demonstrated that voltage-dependent anion channel 1 oligomerization-mediated mitochondrial dysfunction was associated with PANoptosis in retinal ischemia–reperfusion injury.Inhibition of voltage-dependent anion channel 1 oligomerization suppressed mitochondrial dysfunction and PANoptosis in retinal cells subjected to ischemia–reperfusion injury.Mechanistically,mitochondria-derived reactive oxygen species played a central role in the voltagedependent anion channel 1-mediated regulation of PANoptosis by promoting PANoptosome assembly.Moreover,inhibiting voltage-dependent anion channel 1 oligomerization protected against PANoptosis in the retinas of rats subjected to ischemia–reperfusion injury.Overall,our findings reveal the critical role of voltage-dependent anion channel 1 oligomerization in regulating PANoptosis in retinal ischemia–reperfusion injury,highlighting voltage-dependent anion channel 1 as a promising therapeutic target.展开更多
Ischemic stroke(IS)presents a major threat to human life and health due to its high disability and mortality rates.3-n-Butylphthalide(NBP),derived from celery seeds of the Apiaceae family native to the Mediterranean r...Ischemic stroke(IS)presents a major threat to human life and health due to its high disability and mortality rates.3-n-Butylphthalide(NBP),derived from celery seeds of the Apiaceae family native to the Mediterranean region,was first introduced in China for acute IS treatment in 2004.NBP demonstrates multiple therapeutic actions,including reconstruction of microcirculation in the cerebral ischemia area,inhibition of platelet aggregation,reduction of cerebral infarction volume,maintenance of blood-brain barrier(BBB)integrity,and enhancement of cerebral blood perfusion.However,its overall efficacy remains moderate,limited by poor water solubility and low bioavailability,which constrains its clinical application.To address these limitations,researchers have actively pursued the development of NBP derivatives and analogs,achieving notable progress.These efforts,including substituent introduction,ring opening derivatization,esterification,and atom substitution,have generated diverse NBP derivatives.Several of these derivatives have advanced to clinical studies.Specifically,potassium 2-(1-hydroxypentyl)-benzoate(PHPB),brozopentyl sodium(BZP),and XY-03-EA(ZONK1103)have reached phase II clinical trials,while(S)-2-(1-acetoxypentyl)benzoic acid L-arginine salt(AAPB)has received clinical trial approval for 2024.This review examines the structural modification and optimization of NBP over the past two decades from a medicinal chemistry perspective,aiming to facilitate the development of superior derivatives and advance cerebral ischemia treatment.展开更多
Background:American ginseng has been used in the food processing and pharmaceutical industry as a medicinal plant with both nutritional value and economic benefit.Panax quinquefolius saponins(PQS),the main active comp...Background:American ginseng has been used in the food processing and pharmaceutical industry as a medicinal plant with both nutritional value and economic benefit.Panax quinquefolius saponins(PQS),the main active component,have significant antioxidant,neuroprotective,and cardioprotective effects.Clinically,myocardial ischemia(MI)and depression often interact,which has increasing morbidity and mortality rates.However,the mechanism of PQS on MI with depression remains unclear.Methods:The study employed both in vivo and in vitro experiments.Depression-like behaviour changes and cardiac function were observed in mice with MI and depression induced by a high-fat diet(HFD)and intraperitoneal injection of isoproterenol(ISO)plus chronic unpredictable mild stress(CUMS).Both ISO-exposed H9c2 cells and corticosterone(CORT)-induced HT22 cells were selected for in vitro experiments.Biochemical indices and PI3K/Akt/eNOS pathway-related proteins were measured through enzyme-linked immunosorbent assay(ELISA)and Western blotting.Results:PQS significantly improved depression-like behaviour and heart damage in mice and substantially increased H9c2 and HT22 cell activities in vitro.Western blotting analysis showed that PQS could dramatically reverse the changes in the PI3K/AKT/eNOS signalling pathway both in vivo and in vitro.In addition,applying the PI3K inhibitor LY294002 weakened the neuroprotective and cardioprotective effects of PQS.Conclusion:PQS can effectively improve MI with depression,probably through activating PI3K/Akt/eNOS pathway.展开更多
Objective:Leucine-rich alpha-2 glycoprotein 1(Lrg1)could regulate diverse cells in cerebral ischemiareperfusion.Our study seeks to uncover Lrg1’s impact on endothelial cell heterogeneity via differentiation pathways ...Objective:Leucine-rich alpha-2 glycoprotein 1(Lrg1)could regulate diverse cells in cerebral ischemiareperfusion.Our study seeks to uncover Lrg1’s impact on endothelial cell heterogeneity via differentiation pathways and transcription factors.Method:The CSOmap model measured cell-to-brain-center distances using single-cell RNA sequencing(scRNA-seq)data in middle cerebral artery occlusion reperfusion(MCAO/R).Monocle2 mapped endothelial differentiation paths.Gene set enrichment analysis(GSEA)analyzed endothelial subcluster variations.Database searches revealed a zinc finger MIZ-type containing 1 protein-frizzled 3(Zmiz1-Fzd3)promoter interaction.Endothelial cells were transfected with a Fzd3 promoter-luciferase plasmid.Polymerase chain reaction(PCR)and western blotting assessed MCAO/R or Zmiz1 overexpression effects on Fzd3-related mRNA and proteins.A retroviral vector carrying Zmiz1 was injected into the brains of mice to study its effect on Fzd3.Result:Lrg1−/−mice exhibited elevated cell adhesion proteins and decreased microvascular leakage after MCAO/R.CSOmap showed widened astrocyte spacing in thesemice.RSS revealed Zmiz1 overexpression inMCAO/R+Lrg1−/−mice.MCAO/R and pcDNA3-Zmiz1 transfection both enhanced luciferase activity with Fzd3,indicating Zmiz1 binding to Fzd3.Retroviral Zmiz1 injection or knockdown disrupted ischemic brain tight junctions,highlighting Zmiz1’s key role in blood-brain barrier protection,likely through Fzd3 pathway modulation.Conclusion:The findings indicate Lrg1 knockout induces endothelial differentiation by activating Zmiz1,which is crucial for maintaining blood-brain barrier function,possibly via modulating the Fzd3 pathway.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
BACKGROUND Chronic mesenteric ischemia(CMI)is a rare but serious cause of postprandial abdominal pain and weight loss,often diagnosed late.CASE SUMMARY We report two cases with prolonged history of vague abdominal pai...BACKGROUND Chronic mesenteric ischemia(CMI)is a rare but serious cause of postprandial abdominal pain and weight loss,often diagnosed late.CASE SUMMARY We report two cases with prolonged history of vague abdominal pain,early satiety,and significant weight loss.Extensive workups for functional and structural gastrointestinal disorders were unrevealing.The diagnosis was ultimately prompted by gastroenterologist re-review of prior computed tomography abdomen studies—performed earlier during the investigation but not specifically targeting the mesenteric vasculature.On close inspection,both scans revealed extensive vascular calcifications involving the superior mesenteric and celiac arteries,which had not been mentioned in the original radiology reports.Subsequent dedicated vascular imaging confirmed significant mesenteric artery stenosis.Both patients underwent successful endovascular intervention with complete resolution of symptoms.CONCLUSION These cases highlight the importance of clinician-led image review and maintaining a high index of suspicion for CMI in elderly patients with unexplained gastrointestinal symptoms presenting to the gastroenterology department.展开更多
BACKGROUND Peripheral endovascular intervention(PEVI)is performed using radiation.Radiation has deleterious health consequences for patients and operators.AIM To investigate the gender radiation disparities and proced...BACKGROUND Peripheral endovascular intervention(PEVI)is performed using radiation.Radiation has deleterious health consequences for patients and operators.AIM To investigate the gender radiation disparities and procedural outcomes in PEVI.METHODS A prospective observational study was performed in 186 consecutive patients(65±12 years)at an academic medical center from January 2019 to April 2020(mean follow-up of 3.9±3.6 months)comparing the gender radiation disparity and outcomes of PEVI(n=147 underwent intervention,79.0%).Groups were divided into women(n=99,53.2%)and men(n=87,48.4%).Primary endpoints included air kerma,dose area product(DAP),fluoroscopy time,and contrast use.Secondary endpoints included all-cause mortality,acute myocardial infarction,acute kidney injury,stroke,repeat revascularization,major adverse limb event,and the composite of complications.RESULTS Men showed increased DAP compared with women(15221.2±25858.5µGy×m^(2) vs 9251.7±9555.3µGy×m^(2),P=0.047),but no significant difference in air kerma or any other primary endpoints.In the secondary endpoints,no significant diffe-rence was found between gender.CONCLUSION Men had increased DAP indicating more radiation absorption in the exposed area.Gender outcomes showed no difference in complications.Thus,PEVI can be safely performed in men or women.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
Nitric oxide(NO)is a gaseous molecule produced by 3 different NO synthase(NOS)isoforms:Neural/brain NOS(nNOS/bNOS,type 1),endothelial NOS(eNOS,type 3)and inducible NOS(type 2).Type 1 and 3 NOS are constitutively expre...Nitric oxide(NO)is a gaseous molecule produced by 3 different NO synthase(NOS)isoforms:Neural/brain NOS(nNOS/bNOS,type 1),endothelial NOS(eNOS,type 3)and inducible NOS(type 2).Type 1 and 3 NOS are constitutively expressed.NO can serve different purposes:As a vasoactive molecule,as a neurotransmitter or as an immunomodulator.It plays a key role in cerebral ischemia/reperfusion injury(CIRI).Hypoxic episodes simulate the production of oxygen free radicals,leading to mitochondrial and phospholipid damage.Upon reperfusion,increased levels of oxygen trigger oxide synthases;whose products are associated with neuronal damage by promoting lipid peroxidation,nitrosylation and excitotoxicity.Molecular pathways in CIRI can be altered by NOS.Neuroprotective effects are observed with eNOS activity.While nNOS interplay is prone to endothelial inflammation,oxidative stress and apoptosis.Therefore,nNOS appears to be detrimental.The interaction between NO and other free radicals develops peroxynitrite;which is a cytotoxic agent.It plays a main role in the likelihood of hemorrhagic events by tissue plasminogen activator(t-PA).Peroxynitrite scavengers are currently being studied as potential targets to prevent hemorrhagic transformation in CIRI.展开更多
Background: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
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
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
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
Objective:Acute kidney injury(AKI)is a clinical syndrome characterized by sudden deterioration of renal function,with ischemia reperfusion injury(IRI)being the most common cause.Long noncoding RNA(lncRNA)regulate cell...Objective:Acute kidney injury(AKI)is a clinical syndrome characterized by sudden deterioration of renal function,with ischemia reperfusion injury(IRI)being the most common cause.Long noncoding RNA(lncRNA)regulate cell fate through interactions with microRNA(miRNA)and messenger RNAs(mRNA),but the mechanisms and regulatory networks underlying lncRNA AK154753(AK154753)in IRI-induced AKI remain unclear.This study aims to investigate the role of AK154753 in acute renal IRI and to elucidate the molecular mechanism of the AK154753 via miR-345-3p/Bcl-2 homologous antagonist/killer(Bak)and miR-708-5p/Bcl-2 interacting mediator of cell death(Bim)axis.Methods:A bilateral renal artery ischemia model was established in mice(30 minutes ischemia followed by 24 hours and 48 hours reperfusion).Kidney tissues were analyzed using microarray-based transcriptomic sequencing to identify differentially expressed lncRNAs,miRNAs,and mRNAs.RNA levels of AK154753,miR-345-3p,miR-708-5p,Bak,and Bim were validated using real-time reverse transcription PCR(real-time RTPCR).Oxygen and glucose deprivation/reperfusion(OGD/R)models were constructed in mouse proximal renal tubular epithelial BUMPT cells to simulate in vitro IRI conditions.Adeno-associated virus(AAV)-mediated shRNA was used to silence AK154753 in vivo.Apoptosis was assessed using TUNEL staining and flow cytometry.Protein levels of Bak,Bim,and cleaved-caspase-3 were measured using Western blotting.Fluorescence in situ hybridization(FISH)was used to determine intracellular localization of AK154753.Binding relationships between AK154753 and miR-345-3p/Bak and miR-708-5p/Bim were verified using dual-luciferase reporter assays.MiRNA mimics and inhibitors were used to evaluate regulatory-network integrity.Results:IRI significantly elevated serum blood urea nitrogen(BUN)and serum creatinine(Scr),accompanied by tubular-structure damage and increased cell apoptosis(all P<0.05).Transcriptome profiling and real-time RT-PCR validation demonstrated that lncRNA AK154753,along with the pro-apoptotic proteins Bak and Bim,was significantly upregulated after IRI,whereas miR-345-3p and miR-708-5p were markedly downregulated(P<0.01).In vitro,OGD/R treatment significantly induced AK154753 expression in renal tubular epithelial cells and suppressed the expression of miR-345-3p and miR-708-5p,while markedly increasing the protein levels of Bak,Bim,and cleaved-caspase 3,resulting in a significant increase in apoptosis(all P<0.01).Silencing AK154753 significantly attenuated OGD/R-induced apoptosis,reduced the expression of Bak,Bim,and cleaved caspase 3,and decreased cell apoptosis(all P<0.01),while significantly upregulating miR-345-3p and miR-708-5p expression(P<0.01).In vivo,adeno-associated virus(AAV)-mediated knockdown of AK154753 significantly improved renal function in IRI mice,alleviated tubular injury,and suppressed renal tissue apoptosis,as evidenced by reduced BUN and Scr levels,improved histopathological injury scores,and decreased expression of Bak,Bim,and cleaved caspase-3(all P<0.01),accompanied by significant upregulation of miR-345-3p and miR-708-5p(all P<0.01).Luciferase reporter assays further confirmed that miR-345-3p directly binds to the 3'-untranslated region(3'-UTR)of AK154753 and Bak,whereas miR-708-5p directly binds to the 3'-UTRs of AK154753 and Bim.Inhibition of miR-345-3p or miR-708-5p abolished the anti-apoptotic effects induced by AK154753 silencing and restored Bak and Bim expression levels(all P<0.01).Conclusion:AK154753 is upregulated in acute renal IRI and promotes apoptosis by suppressing miR-345-3p and miR-708-5p,thereby upregulating Bak and Bim,and participates in the initiation and progression of acute renal IRI.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
Descriptive signs in radiology can aid in easier pattern recognition and quicker diagnosis.In spinal cord ischemia,paired anterior-horn T2-hyperintensities have traditionally been known as the“owl’s eyes”or“snake ...Descriptive signs in radiology can aid in easier pattern recognition and quicker diagnosis.In spinal cord ischemia,paired anterior-horn T2-hyperintensities have traditionally been known as the“owl’s eyes”or“snake eyes”sign.We discuss how these signs,while visually apt,convey no pathophysiologic context and propose renaming this finding the“snake bite sign”.The image still evokes two punctate marks,yet the metaphor extends to a snake bite(two fang-like dots)rather than two bright foci(eyes)staring back at the viewer.Moreover,besides the sign metaphorically resembling a traumatic puncture of the two fangs,on the occasion of a venomous snake bite occurring elsewhere,additional neurological consequences may occur,paralleling the neurological deficits seen in anterior spinal artery infarction and several mimicking myelopathies,thus further high-lighting the analogy.Such clinically driven terminology may facilitate teaching,enable diagnostic recall,and improve interdisciplinary communication.展开更多
Objective:To explore the potential mechanisms of a baicalin-geniposide combination against cerebral ischemia using a network pharmacology strategy.Method:We used network pharmacology integrating drug-target-disease in...Objective:To explore the potential mechanisms of a baicalin-geniposide combination against cerebral ischemia using a network pharmacology strategy.Method:We used network pharmacology integrating drug-target-disease interactions to identify key pathways which were validated in a rat middle cerebral artery occlusion model treated with baicalin(55 mg/kg),geniposide(5 mg/kg),or their 11:1 combination.Therapeutic efficacy and mechanistic insights were evaluated using triphenyltetrazolium chloride staining,Evans blue assay,enzyme-linked immunosorbent assay,and Western blot.Results:The results revealed that the nuclear factor-kappa B(NF-κB)signaling pathway is inhibited in combination treatment of cerebral ischemia.Ten targets were identified as key nodes in the protein-protein interaction network:interleukin 6(IL-6),interleukin-1β,interleukin 18,C-C motif ligand 2,C-C motif ligand 4,interleukin 10,interferon-γ-inducible protein 10,C-C motif ligand 3,tumor necrosis factor-α(TNF-α),interleukin-1α.The baicalin-geniposide combination significantly reduced infarct volume,improved neurological deficits,and alleviated brain edema/blood-brain barrier leakage compared with monotherapy.Additionally,it significantly inhibited toll-like receptor 4(TLR4)/NF-κB signaling and downregulated pro-inflammatory cytokines TNF-αand IL-6 levels.Conclusion:The baicalin-geniposide combination alleviated cerebral ischemia-reperfusion injury by synergistically suppressing the TLR4/NF-κB pathway and its downstream inflammatory factors.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
基金supported by the National Natural Science Foundation of China,Nos.82172196(to KX),82372507(to KX)the Natural Science Foundation of Hunan Province,China,No.2023JJ40804(to QZ)the Key Laboratory of Emergency and Trauma(Hainan Medical University)of the Ministry of Education,China,No.KLET-202210(to QZ)。
文摘Ischemia–reperfusion injury is a common pathophysiological mechanism in retinal degeneration.PANoptosis is a newly defined integral form of regulated cell death that combines the key features of pyroptosis,apoptosis,and necroptosis.Oligomerization of mitochondrial voltage-dependent anion channel 1 is an important pathological event in regulating cell death in retinal ischemia–reperfusion injury.However,its role in PANoptosis remains largely unknown.In this study,we demonstrated that voltage-dependent anion channel 1 oligomerization-mediated mitochondrial dysfunction was associated with PANoptosis in retinal ischemia–reperfusion injury.Inhibition of voltage-dependent anion channel 1 oligomerization suppressed mitochondrial dysfunction and PANoptosis in retinal cells subjected to ischemia–reperfusion injury.Mechanistically,mitochondria-derived reactive oxygen species played a central role in the voltagedependent anion channel 1-mediated regulation of PANoptosis by promoting PANoptosome assembly.Moreover,inhibiting voltage-dependent anion channel 1 oligomerization protected against PANoptosis in the retinas of rats subjected to ischemia–reperfusion injury.Overall,our findings reveal the critical role of voltage-dependent anion channel 1 oligomerization in regulating PANoptosis in retinal ischemia–reperfusion injury,highlighting voltage-dependent anion channel 1 as a promising therapeutic target.
基金supported by the National Natural Science Foundation of China(Nos.21977058 and 82473840)the Key R&D Program of Jiangsu Province(No.BE2021677)+2 种基金China Postdoctoral Science Foundation(No.2018T110533)the Key Natural Science Foundation of Jiangsu Higher Education Institutions(No.20KJA350002)Jiangsu Province Innovation Project of Postgraduate Training(No.KYCX22_3380).
文摘Ischemic stroke(IS)presents a major threat to human life and health due to its high disability and mortality rates.3-n-Butylphthalide(NBP),derived from celery seeds of the Apiaceae family native to the Mediterranean region,was first introduced in China for acute IS treatment in 2004.NBP demonstrates multiple therapeutic actions,including reconstruction of microcirculation in the cerebral ischemia area,inhibition of platelet aggregation,reduction of cerebral infarction volume,maintenance of blood-brain barrier(BBB)integrity,and enhancement of cerebral blood perfusion.However,its overall efficacy remains moderate,limited by poor water solubility and low bioavailability,which constrains its clinical application.To address these limitations,researchers have actively pursued the development of NBP derivatives and analogs,achieving notable progress.These efforts,including substituent introduction,ring opening derivatization,esterification,and atom substitution,have generated diverse NBP derivatives.Several of these derivatives have advanced to clinical studies.Specifically,potassium 2-(1-hydroxypentyl)-benzoate(PHPB),brozopentyl sodium(BZP),and XY-03-EA(ZONK1103)have reached phase II clinical trials,while(S)-2-(1-acetoxypentyl)benzoic acid L-arginine salt(AAPB)has received clinical trial approval for 2024.This review examines the structural modification and optimization of NBP over the past two decades from a medicinal chemistry perspective,aiming to facilitate the development of superior derivatives and advance cerebral ischemia treatment.
基金supported by the study on the material basis and mechanism of action of American ginseng in the treatment of myocardial ischaemia comorbid depression(2024JH2/102500059).
文摘Background:American ginseng has been used in the food processing and pharmaceutical industry as a medicinal plant with both nutritional value and economic benefit.Panax quinquefolius saponins(PQS),the main active component,have significant antioxidant,neuroprotective,and cardioprotective effects.Clinically,myocardial ischemia(MI)and depression often interact,which has increasing morbidity and mortality rates.However,the mechanism of PQS on MI with depression remains unclear.Methods:The study employed both in vivo and in vitro experiments.Depression-like behaviour changes and cardiac function were observed in mice with MI and depression induced by a high-fat diet(HFD)and intraperitoneal injection of isoproterenol(ISO)plus chronic unpredictable mild stress(CUMS).Both ISO-exposed H9c2 cells and corticosterone(CORT)-induced HT22 cells were selected for in vitro experiments.Biochemical indices and PI3K/Akt/eNOS pathway-related proteins were measured through enzyme-linked immunosorbent assay(ELISA)and Western blotting.Results:PQS significantly improved depression-like behaviour and heart damage in mice and substantially increased H9c2 and HT22 cell activities in vitro.Western blotting analysis showed that PQS could dramatically reverse the changes in the PI3K/AKT/eNOS signalling pathway both in vivo and in vitro.In addition,applying the PI3K inhibitor LY294002 weakened the neuroprotective and cardioprotective effects of PQS.Conclusion:PQS can effectively improve MI with depression,probably through activating PI3K/Akt/eNOS pathway.
基金supported by the Foundation Project:National Natural Science.Foundation of China(Nos.:82460249,82100417,81760094)The Foundation of Jiangxi Provincial Department of Science and Technology Outstanding Youth Fund Project(20212BAB206022,20242BAB23080).
文摘Objective:Leucine-rich alpha-2 glycoprotein 1(Lrg1)could regulate diverse cells in cerebral ischemiareperfusion.Our study seeks to uncover Lrg1’s impact on endothelial cell heterogeneity via differentiation pathways and transcription factors.Method:The CSOmap model measured cell-to-brain-center distances using single-cell RNA sequencing(scRNA-seq)data in middle cerebral artery occlusion reperfusion(MCAO/R).Monocle2 mapped endothelial differentiation paths.Gene set enrichment analysis(GSEA)analyzed endothelial subcluster variations.Database searches revealed a zinc finger MIZ-type containing 1 protein-frizzled 3(Zmiz1-Fzd3)promoter interaction.Endothelial cells were transfected with a Fzd3 promoter-luciferase plasmid.Polymerase chain reaction(PCR)and western blotting assessed MCAO/R or Zmiz1 overexpression effects on Fzd3-related mRNA and proteins.A retroviral vector carrying Zmiz1 was injected into the brains of mice to study its effect on Fzd3.Result:Lrg1−/−mice exhibited elevated cell adhesion proteins and decreased microvascular leakage after MCAO/R.CSOmap showed widened astrocyte spacing in thesemice.RSS revealed Zmiz1 overexpression inMCAO/R+Lrg1−/−mice.MCAO/R and pcDNA3-Zmiz1 transfection both enhanced luciferase activity with Fzd3,indicating Zmiz1 binding to Fzd3.Retroviral Zmiz1 injection or knockdown disrupted ischemic brain tight junctions,highlighting Zmiz1’s key role in blood-brain barrier protection,likely through Fzd3 pathway modulation.Conclusion:The findings indicate Lrg1 knockout induces endothelial differentiation by activating Zmiz1,which is crucial for maintaining blood-brain barrier function,possibly via modulating the Fzd3 pathway.
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.
文摘BACKGROUND Chronic mesenteric ischemia(CMI)is a rare but serious cause of postprandial abdominal pain and weight loss,often diagnosed late.CASE SUMMARY We report two cases with prolonged history of vague abdominal pain,early satiety,and significant weight loss.Extensive workups for functional and structural gastrointestinal disorders were unrevealing.The diagnosis was ultimately prompted by gastroenterologist re-review of prior computed tomography abdomen studies—performed earlier during the investigation but not specifically targeting the mesenteric vasculature.On close inspection,both scans revealed extensive vascular calcifications involving the superior mesenteric and celiac arteries,which had not been mentioned in the original radiology reports.Subsequent dedicated vascular imaging confirmed significant mesenteric artery stenosis.Both patients underwent successful endovascular intervention with complete resolution of symptoms.CONCLUSION These cases highlight the importance of clinician-led image review and maintaining a high index of suspicion for CMI in elderly patients with unexplained gastrointestinal symptoms presenting to the gastroenterology department.
文摘BACKGROUND Peripheral endovascular intervention(PEVI)is performed using radiation.Radiation has deleterious health consequences for patients and operators.AIM To investigate the gender radiation disparities and procedural outcomes in PEVI.METHODS A prospective observational study was performed in 186 consecutive patients(65±12 years)at an academic medical center from January 2019 to April 2020(mean follow-up of 3.9±3.6 months)comparing the gender radiation disparity and outcomes of PEVI(n=147 underwent intervention,79.0%).Groups were divided into women(n=99,53.2%)and men(n=87,48.4%).Primary endpoints included air kerma,dose area product(DAP),fluoroscopy time,and contrast use.Secondary endpoints included all-cause mortality,acute myocardial infarction,acute kidney injury,stroke,repeat revascularization,major adverse limb event,and the composite of complications.RESULTS Men showed increased DAP compared with women(15221.2±25858.5µGy×m^(2) vs 9251.7±9555.3µGy×m^(2),P=0.047),but no significant difference in air kerma or any other primary endpoints.In the secondary endpoints,no significant diffe-rence was found between gender.CONCLUSION Men had increased DAP indicating more radiation absorption in the exposed area.Gender outcomes showed no difference in complications.Thus,PEVI can be safely performed in men or women.
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 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 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.
基金supported by the National Natural Science Foundation of China(81770692)。
文摘Objective:Acute kidney injury(AKI)is a clinical syndrome characterized by sudden deterioration of renal function,with ischemia reperfusion injury(IRI)being the most common cause.Long noncoding RNA(lncRNA)regulate cell fate through interactions with microRNA(miRNA)and messenger RNAs(mRNA),but the mechanisms and regulatory networks underlying lncRNA AK154753(AK154753)in IRI-induced AKI remain unclear.This study aims to investigate the role of AK154753 in acute renal IRI and to elucidate the molecular mechanism of the AK154753 via miR-345-3p/Bcl-2 homologous antagonist/killer(Bak)and miR-708-5p/Bcl-2 interacting mediator of cell death(Bim)axis.Methods:A bilateral renal artery ischemia model was established in mice(30 minutes ischemia followed by 24 hours and 48 hours reperfusion).Kidney tissues were analyzed using microarray-based transcriptomic sequencing to identify differentially expressed lncRNAs,miRNAs,and mRNAs.RNA levels of AK154753,miR-345-3p,miR-708-5p,Bak,and Bim were validated using real-time reverse transcription PCR(real-time RTPCR).Oxygen and glucose deprivation/reperfusion(OGD/R)models were constructed in mouse proximal renal tubular epithelial BUMPT cells to simulate in vitro IRI conditions.Adeno-associated virus(AAV)-mediated shRNA was used to silence AK154753 in vivo.Apoptosis was assessed using TUNEL staining and flow cytometry.Protein levels of Bak,Bim,and cleaved-caspase-3 were measured using Western blotting.Fluorescence in situ hybridization(FISH)was used to determine intracellular localization of AK154753.Binding relationships between AK154753 and miR-345-3p/Bak and miR-708-5p/Bim were verified using dual-luciferase reporter assays.MiRNA mimics and inhibitors were used to evaluate regulatory-network integrity.Results:IRI significantly elevated serum blood urea nitrogen(BUN)and serum creatinine(Scr),accompanied by tubular-structure damage and increased cell apoptosis(all P<0.05).Transcriptome profiling and real-time RT-PCR validation demonstrated that lncRNA AK154753,along with the pro-apoptotic proteins Bak and Bim,was significantly upregulated after IRI,whereas miR-345-3p and miR-708-5p were markedly downregulated(P<0.01).In vitro,OGD/R treatment significantly induced AK154753 expression in renal tubular epithelial cells and suppressed the expression of miR-345-3p and miR-708-5p,while markedly increasing the protein levels of Bak,Bim,and cleaved-caspase 3,resulting in a significant increase in apoptosis(all P<0.01).Silencing AK154753 significantly attenuated OGD/R-induced apoptosis,reduced the expression of Bak,Bim,and cleaved caspase 3,and decreased cell apoptosis(all P<0.01),while significantly upregulating miR-345-3p and miR-708-5p expression(P<0.01).In vivo,adeno-associated virus(AAV)-mediated knockdown of AK154753 significantly improved renal function in IRI mice,alleviated tubular injury,and suppressed renal tissue apoptosis,as evidenced by reduced BUN and Scr levels,improved histopathological injury scores,and decreased expression of Bak,Bim,and cleaved caspase-3(all P<0.01),accompanied by significant upregulation of miR-345-3p and miR-708-5p(all P<0.01).Luciferase reporter assays further confirmed that miR-345-3p directly binds to the 3'-untranslated region(3'-UTR)of AK154753 and Bak,whereas miR-708-5p directly binds to the 3'-UTRs of AK154753 and Bim.Inhibition of miR-345-3p or miR-708-5p abolished the anti-apoptotic effects induced by AK154753 silencing and restored Bak and Bim expression levels(all P<0.01).Conclusion:AK154753 is upregulated in acute renal IRI and promotes apoptosis by suppressing miR-345-3p and miR-708-5p,thereby upregulating Bak and Bim,and participates in the initiation and progression of acute renal IRI.
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.
文摘Descriptive signs in radiology can aid in easier pattern recognition and quicker diagnosis.In spinal cord ischemia,paired anterior-horn T2-hyperintensities have traditionally been known as the“owl’s eyes”or“snake eyes”sign.We discuss how these signs,while visually apt,convey no pathophysiologic context and propose renaming this finding the“snake bite sign”.The image still evokes two punctate marks,yet the metaphor extends to a snake bite(two fang-like dots)rather than two bright foci(eyes)staring back at the viewer.Moreover,besides the sign metaphorically resembling a traumatic puncture of the two fangs,on the occasion of a venomous snake bite occurring elsewhere,additional neurological consequences may occur,paralleling the neurological deficits seen in anterior spinal artery infarction and several mimicking myelopathies,thus further high-lighting the analogy.Such clinically driven terminology may facilitate teaching,enable diagnostic recall,and improve interdisciplinary communication.
基金supported by grants from the National Natural Science Foundation of China(U21A20400,81973789,82004327).
文摘Objective:To explore the potential mechanisms of a baicalin-geniposide combination against cerebral ischemia using a network pharmacology strategy.Method:We used network pharmacology integrating drug-target-disease interactions to identify key pathways which were validated in a rat middle cerebral artery occlusion model treated with baicalin(55 mg/kg),geniposide(5 mg/kg),or their 11:1 combination.Therapeutic efficacy and mechanistic insights were evaluated using triphenyltetrazolium chloride staining,Evans blue assay,enzyme-linked immunosorbent assay,and Western blot.Results:The results revealed that the nuclear factor-kappa B(NF-κB)signaling pathway is inhibited in combination treatment of cerebral ischemia.Ten targets were identified as key nodes in the protein-protein interaction network:interleukin 6(IL-6),interleukin-1β,interleukin 18,C-C motif ligand 2,C-C motif ligand 4,interleukin 10,interferon-γ-inducible protein 10,C-C motif ligand 3,tumor necrosis factor-α(TNF-α),interleukin-1α.The baicalin-geniposide combination significantly reduced infarct volume,improved neurological deficits,and alleviated brain edema/blood-brain barrier leakage compared with monotherapy.Additionally,it significantly inhibited toll-like receptor 4(TLR4)/NF-κB signaling and downregulated pro-inflammatory cytokines TNF-αand IL-6 levels.Conclusion:The baicalin-geniposide combination alleviated cerebral ischemia-reperfusion injury by synergistically suppressing the TLR4/NF-κB pathway and its downstream inflammatory factors.
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.
