Neuronal cell death is a common outcome of multiple pathophysiological processes and a key factor in neurological dysfunction after subarachnoid hemorrhage.Neuronal ferroptosis in particular plays an important role in...Neuronal cell death is a common outcome of multiple pathophysiological processes and a key factor in neurological dysfunction after subarachnoid hemorrhage.Neuronal ferroptosis in particular plays an important role in early brain injury.Bromodomain-containing protein 4,a member of the bromo and extraterminal domain family of proteins,participated in multiple cell death pathways,but the mechanisms by which it regulates ferroptosis remain unclear.The primary aim of this study was to investigate how bromodomain-containing protein 4 affects neuronal ferroptosis following subarachnoid hemorrhage in vivo and in vitro.Our findings revealed that endogenous bromodomain-containing protein 4 co-localized with neurons,and its expression was decreased 48 hours after subarachnoid hemorrhage of the cerebral cortex in vivo.In addition,ferroptosis-related pathways were activated in vivo and in vitro after subarachnoid hemorrhage.Targeted inhibition of bromodomain-containing protein 4 in neurons increased lipid peroxidation and intracellular ferrous iron accumulation via ferritinophagy and ultimately led to neuronal ferroptosis.Using cleavage under targets and tagmentation analysis,we found that bromodomain-containing protein 4 enrichment in the Raf-1 promoter region decreased following oxyhemoglobin stimulation in vitro.Furthermore,treating bromodomain-containing protein 4-knockdown HT-22 cell lines with GW5074,a Raf-1 inhibitor,exacerbated neuronal ferroptosis by suppressing the Raf-1/ERK1/2 signaling pathway.Moreover,targeted inhibition of neuronal bromodomain-containing protein 4 exacerbated early and long-term neurological function deficits after subarachnoid hemorrhage.Our findings suggest that bromodomain-containing protein 4 may have neuroprotective effects after subarachnoid hemorrhage,and that inhibiting ferroptosis could help treat subarachnoid hemorrhage.展开更多
Intracerebral hemorrhage is the most dangerous subtype of stroke,characterized by high mortality and morbidity rates,and frequently leads to significant secondary white matter injury.In recent decades,studies have rev...Intracerebral hemorrhage is the most dangerous subtype of stroke,characterized by high mortality and morbidity rates,and frequently leads to significant secondary white matter injury.In recent decades,studies have revealed that gut microbiota can communicate bidirectionally with the brain through the gut microbiota–brain axis.This axis indicates that gut microbiota is closely related to the development and prognosis of intracerebral hemorrhage and its associated secondary white matter injury.The NACHT,LRR,and pyrin domain-containing protein 3(NLRP3)inflammasome plays a crucial role in this context.This review summarizes the dysbiosis of gut microbiota following intracerebral hemorrhage and explores the mechanisms by which this imbalance may promote the activation of the NLRP3 inflammasome.These mechanisms include metabolic pathways(involving short-chain fatty acids,lipopolysaccharides,lactic acid,bile acids,trimethylamine-N-oxide,and tryptophan),neural pathways(such as the vagus nerve and sympathetic nerve),and immune pathways(involving microglia and T cells).We then discuss the relationship between the activated NLRP3 inflammasome and secondary white matter injury after intracerebral hemorrhage.The activation of the NLRP3 inflammasome can exacerbate secondary white matter injury by disrupting the blood–brain barrier,inducing neuroinflammation,and interfering with nerve regeneration.Finally,we outline potential treatment strategies for intracerebral hemorrhage and its secondary white matter injury.Our review highlights the critical role of the gut microbiota–brain axis and the NLRP3 inflammasome in white matter injury following intracerebral hemorrhage,paving the way for exploring potential therapeutic approaches.展开更多
This study investigated the neuroprotective effects of lactate in subarachnoid hemorrhage,a severe cerebrovascular disease that is commonly caused by arterial aneurysm rupture and has limited early treatment options.L...This study investigated the neuroprotective effects of lactate in subarachnoid hemorrhage,a severe cerebrovascular disease that is commonly caused by arterial aneurysm rupture and has limited early treatment options.Lactate,a metabolic byproduct,has been shown to have neuroprotective properties,including enhancing cerebral microcirculation and reducing intracranial pressure in acute brain injury patients.However,the protective mechanisms of lactate in subarachnoid hemorrhage remain unknown.In this study,we showed that lactate alleviates early brain damage in subarachnoid hemorrhage by promoting neuronal lipid synthesis and the formation of lipid droplets in astrocytes.In vivo experiments using a subarachnoid hemorrhage mouse model showed that lactate treatment significantly improved neurological scores,reduced brain inflammation,and promoted lipid droplet formation in astrocytes within 24 hours.Lactate treatment increased free fatty acids levels in the brain.The results suggest that astrocytes absorbed these free fatty acids and converted them into lipid droplets,thus reducing cellular lipotoxicity.Moreover,lactate enhanced the antiapoptotic capacity of astrocytes by upregulating the expression of PLIN5,a protein crucial for lipid droplet formation.The inhibition of lipid synthesis or lipid droplet formation counteracted the neuroprotective effects of lactate,indicating that lactate’s protective role is closely linked to lipid metabolism and lipid droplet formation.In vitro experiments on HT22 neuronal cells exposed to hemin-an agent used to simulate subarachnoid hemorrhage injury-demonstrated that lactate mitigated cellular damage by reducing lipid peroxidation and preserving mitochondrial membrane potential.Lactate treatment in HT22 cells and astrocytes also showed that inhibition of lipid synthesis or lipid droplet formation reversed its protective effects,further emphasizing the importance of lipid metabolism in the neuroprotective action of lactate.This study provides insights into the neuroprotective mechanisms of lactate in subarachnoid hemorrhage.It indicates that lactate plays a role in promoting lipid synthesis in neurons and enhancing lipid droplet formation in astrocytes,thus mitigating brain damage and improving cell survival.These findings suggest that lactate,through its regulation of lipid metabolism,could be a potential therapeutic agent for subarachnoid hemorrhage.展开更多
Ferroptosis plays a key role in nerve injury in intracerebral hemorrhage and is associated with the upregulation of murine double minute 2.Investigating the mechanism underlying murine double minute 2-related ferropto...Ferroptosis plays a key role in nerve injury in intracerebral hemorrhage and is associated with the upregulation of murine double minute 2.Investigating the mechanism underlying murine double minute 2-related ferroptosis could help identify new therapies for intracerebral hemorrhage.An in vitro intracerebral hemorrhage model was established by treating BV2 microglial cells with oxygen-glucose deprivation combined with hemin.The role of murine double minute 2 in regulating ferroptosis was investigated via transduction with RNA interference and lentivirus overexpression.Furthermore,intracerebral hemorrhage mouse models were constructed with and without an murine double minute 2 inhibitor(brigimadlin),and behavioral assays were performed to assess the learning ability and cognitive function.Murine double minute 2 dysregulation was associated with oxygen-glucose deprivation combined with hemin-induced BV2 microglial cell ferroptosis and M1/M2 polarization.The results suggested that murine double minute 2 induced glutathione peroxidase 4 ubiquitination and degradation to regulate ferroptosis and inflammatory responses in BV2 microglial cells.Mechanistically,Wilms tumor 1-associated protein induced murine double minute 2 N6-methyladenosine(m6A)modification and regulated ferroptosis and inflammatory responses.In vivo analysis showed that brigimadlin improved neurological deficits and spatial memory in mice with intracerebral hemorrhage.In summary,the results indicate that Wilms tumor 1-associated protein regulates murine double minute 2 m6A modification,and murine double minute 2 induces glutathione peroxidase 4 ubiquitination and degradation.This regulation promotes ferroptosis and inflammatory responses in oxygen-glucose deprivation combined with hemin-induced BV2 microglial cells,suggesting that the murine double minute 2-glutathione peroxidase 4-ferroptosis regulatory axis exerts neurotoxic effects.These findings identify glutathione peroxidase 4 as a potential gene therapy target for intracerebral hemorrhage-related brain injury.展开更多
Subarachnoid hemorrhage is a subtype of stroke that causes severe neurological damage and is associated with poor long-term prognosis.Cognitive impairment is a major manifestation of long-term neurological dysfunction...Subarachnoid hemorrhage is a subtype of stroke that causes severe neurological damage and is associated with poor long-term prognosis.Cognitive impairment is a major manifestation of long-term neurological dysfunction in patients with subarachnoid hemorrhage.However,there is notable absence of biological markers to predict long-term prognosis in this patient population.Given the aging-like neurocognitive phenomena associated with subarachnoid hemorrhage,this study postulates that telomere length,a recognized biomarker for aging,could be used as a prognostic indicator for subarachnoid hemorrhage.A left internal carotid artery intravascular puncture mouse model was used to simulate subarachnoid hemorrhage.Comprehensive neurological test scores were obtained through neurobehavioral assessments conducted at one-month intervals.Concurrently,the relative telomere length was analyzed by quantitative polymerase chain reaction,which was performed using DNA extracted from ear notch and brain tissue after each assessment.Furthermore,proteomic analysis was employed to investigate differential protein expression in hippocampal tissue.Subarachnoid hemorrhage mice exhibited persistent neurocognitive impairment over a prolonged period of time.There was a significant positive correlation between telomere length and neurological test scores,confirming the usefulness of telomere length as a prognostic indicator in subarachnoid hemorrhage.Hippocampal tissue from subarachnoid hemorrhage mice showed reduced expression of acetyl-coenzyme A synthetase-2 and abnormalities in the expression of proteins related to ribosomes,energy metabolism,and cellular signal transduction.This study confirmed telomere shortening in the brain and metabolic disturbances in the hippocampi of subarachnoid hemorrhage mice.Thus,telomere length is a predictive marker for long-term impairment of cognitive function in mice following experimental subarachnoid hemorrhage.展开更多
Objective:To explore the impact of systematic stepwise rehabilitation nursing intervention on the prognosis and disease uncertainty of patients with hypertensive intracerebral hemorrhage,and to provide feasible strate...Objective:To explore the impact of systematic stepwise rehabilitation nursing intervention on the prognosis and disease uncertainty of patients with hypertensive intracerebral hemorrhage,and to provide feasible strategies for clinical nursing.Methods:Eighty patients with hypertensive intracerebral hemorrhage admitted to our hospital from January 2023 to June 2025 were selected and randomly divided into an observation group(n=40,receiving systematic stepwise rehabilitation nursing)and a control group(n=40,receiving conventional nursing).The intervention effects were analyzed by comparing changes in the National Institutes of Health Stroke Scale(NIHSS)scores for neurological recovery,Short Form 36 Health Survey(SF-36)scores for quality of life,Exercise of Self-Care Agency Scale(ESCA)scores for self-management ability,compliance,and the Mishel Uncertainty in Illness Scale(MUIS)scores between the two groups.Results:All scores in the observation group were significantly better than those in the control group after the intervention(p<0.05).Specifically,the NIHSS scores decreased more significantly,the total SF-36 scores increased,the ESCA scores increased significantly,while the MUIS scores decreased significantly,and compliance improved markedly,indicating a reduction in disease uncertainty among patients.Conclusion:Systematic stepwise rehabilitation nursing intervention can significantly improve neurological recovery,quality of life,self-management ability,and compliance in patients with hypertensive intracerebral hemorrhage,while effectively reducing disease uncertainty.It is worthy of clinical promotion and application.展开更多
Germinal matrix hemorrhage in preterm neonates often leads to white matter injury,contributing to long-term neurodevelopmental impairments.As resident brain immune cells,microglia play a complex role in injury respons...Germinal matrix hemorrhage in preterm neonates often leads to white matter injury,contributing to long-term neurodevelopmental impairments.As resident brain immune cells,microglia play a complex role in injury response,including inflammation and repair.Although colony-stimulating factor 1 receptor inhibitors such as PLX5622 enable the selective depletion of microglia,their therapeutic potential in neonatal germinal matrix hemorrhage remains underexplored.Here,we used a collagenase-induced germinal matrix hemorrhage model in postnatal day 5 mice,and intraperitoneally administered PLX562272 hours post-germinal matrix hemorrhage to achieve targeted,temporary microglial depletion during the peak injury response.We then assessed the effects of this delayed intervention on oligodendrocyte lineage cell maturation,white matter integrity,and neurobehavioral outcomes.Additionally,RNA sequencing data from a germinal matrix hemorrhage rat model were analyzed using weighted gene co-expression network analysis to identify the critical phases for interventions.RNA sequencing data revealed a critical period in which key synaptic functions declined while immune responses intensified post-germinal matrix hemorrhage,thus pinpointing the critical response phases for potential interventions.Delayed PLX5622 treatment effectively depleted activated microglia,protecting against white matter injury and enhancing oligodendrocyte lineage cell maturation and myelination in subcortical white matter regions.Moreover,magnetic resonance imaging analysis revealed reduced brain lesion volumes in treated mice.Behaviorally,PLX5622-treated mice exhibited significant improvements in motor coordination and reduced hyperactivity compared with vehicle-treated germinal matrix hemorrhage model mice.These findings suggest that,when timed to avoid interference with initial oligodendrocyte lineage cell proliferation,targeted microglial depletion with PLX5622 significantly mitigates white matter damage and improves neurobehavioral outcomes in neonatal germinal matrix hemorrhage.The present study highlights the therapeutic potential of selectively modulating microglial reactivity to support neurodevelopment in preterm infants with brain injury.展开更多
AIM:To compare spontaneous brain regional activities between diabetic vitreous hemorrhage patients(DVHs)and healthy controls(HCs).METHODS:Thirty-two DVHs and 32 HCs were enrolled in this study.Baseline demographic and...AIM:To compare spontaneous brain regional activities between diabetic vitreous hemorrhage patients(DVHs)and healthy controls(HCs).METHODS:Thirty-two DVHs and 32 HCs were enrolled in this study.Baseline demographic and vision data were compared between groups using an independent sample t-test.Resting-state functional magnetic resonance imaging(rs-fMRI)was used in all participants.fMRI data was obtained and analyzed using MRIcro and SPM8 software.Fractional amplitude of low-frequency fluctuation(fALFF)technology was used to measure regional spontaneous brain activity,and sensitivity was tested using receiver operating characteristic curves(ROCs).The fALFF values were analyzed using REST software and two-sample t-tests were used to compare values between groups.Hospital anxiety and depression scale(HADS)score was assessed in DVHs and Pearson’s correlation was used to test relationships between mean fALFF value and both HADS score and duration of DVH.RESULTS:Except for the best-corrected visual acuity(BCVA)in both eyes,which showed a statistically significant difference(P<0.05),there were no statistically significant differences in the other indicators(P>0.05)between the HCs and DVHs group.Compared with controls,fALFF value was higher in DVH in cerebellum posterior lobe(CPL)and lower in right anterior cingulate cortex(ACC)and right medial orbitofrontal cortex(OFC).In DVH patients,mean fALFF value of CPL was positively correlated with HADS score and duration of diabetes.However,no such correlation was found,for right ACC or right medial OFC.DVH may lead to abnormal activities in certain brain regions related to visual control and mood.CONCLUSION:Visual impairment caused by DVH may lead to adjustment in regional visual brain activities and may be related to depression or reward system processing in some brain regions.展开更多
Recombinant tissue plasminogen activator is commonly used for hematoma evacuation in minimally invasive surgery following intracerebral hemorrhage.However,during minimally invasive surgery,recombinant tissue plasminog...Recombinant tissue plasminogen activator is commonly used for hematoma evacuation in minimally invasive surgery following intracerebral hemorrhage.However,during minimally invasive surgery,recombinant tissue plasminogen activator may come into contact with brain tissue.Therefore,a thorough assessment of its safety is required.In this study,we established a mouse model of intracerebral hemorrhage induced by type VII collagenase.We observed that the administration of recombinant tissue plasminogen activator without hematoma aspiration significantly improved the neurological function of mice with intracerebral hemorrhage,reduced pathological damage,and lowered the levels of apoptosis and autophagy in the tissue surrounding the hematoma.In an in vitro model of intracerebral hemorrhage using primary cortical neurons induced by hemin,the administration of recombinant tissue plasminogen activator suppressed neuronal apoptosis,autophagy,and endoplasmic reticulum stress.Transcriptome sequencing analysis revealed that recombinant tissue plasminogen activator upregulated the phosphoinositide 3-kinase/RAC-alpha serine/threonine-protein kinase/mammalian target of rapamycin pathway in neurons.Moreover,the phosphoinositide 3-kinase inhibitor LY294002 abrogated the neuroprotective effects of recombinant tissue plasminogen activator in inhibiting excessive apoptosis,autophagy,and endoplasmic reticulum stress.Furthermore,to specify the domain of recombinant tissue plasminogen activator responsible for its neuroprotective effects,various inhibitors were used to target distinct domains.It has been revealed that the epidermal growth factor receptor inhibitor AG-1478 reversed the effect of recombinant tissue plasminogen activator on the phosphoinositide 3-kinase/RAC-alpha serine/threonineprotein kinase/mammalian target of rapamycin pathway.These findings suggest that recombinant tissue plasminogen activator exerts a direct neuroprotective effect on neurons following intracerebral hemorrhage,possibly through activation of the phosphoinositide 3-kinase/RAC-alpha serine/threonine-protein kinase/mammalian target of rapamycin pathway.展开更多
Phosphodiesterase 4 is a key enzyme involved in the regulation of cell signal transduction,but its role in subarachnoid hemorrhage remains unclear.Neuronal pyroptosis has been reported to be involved in early brain in...Phosphodiesterase 4 is a key enzyme involved in the regulation of cell signal transduction,but its role in subarachnoid hemorrhage remains unclear.Neuronal pyroptosis has been reported to be involved in early brain injury after subarachnoid hemorrhage.This study aimed to investigate whether phosphodiesterase 4 contributes to early brain injury after subarachnoid hemorrhage by mediating neuronal pyroptosis and its related mechanisms.Endovascular perforation of male C57BL/6J mice was performed to model subarachnoid hemorrhage in vivo,and oxyhemoglobin was added to the culture medium of primary neurons to model subarachnoid hemorrhage in vitro.A phosphodiesterase 4-specific inhibitor,etazolate,was intraperitoneally injected 30 minutes after subarachnoid hemorrhage induction.Small interfering RNA(siRNA)was administered intracerebroventricularly 72 hours before subarachnoid hemorrhage to achieve genetic knockdown of phosphodiesterase 4.To investigate the mechanism,a nucleotide-binding oligomerization domain-like receptor pyrin domain containing 3(NLRP3)-specific agonist,nigericin,was intracerebroventricularly injected 60 minutes before subarachnoid hemorrhage.Neuronal phosphodiesterase 4 expression increased after subarachnoid hemorrhage and reached the highest point at 24 hours.Etazolate treatment reduced neurological deficits and brain edema in mice,alleviated neuronal pyroptosis and inflammatory response,and improved neuronal injury.Treatment with phosphodiesterase 4 siRNA had the same neuroprotective effects as etazolate.Mechanistically,phosphodiesterase 4 triggered the nuclear factor kappa-B pathway,and simultaneously caused lysosomal and mitochondrial dysfunction after subarachnoid hemorrhage,which promoted NLRP3 inflammasome activation and induced neuronal pyroptosis.Blocking of phosphodiesterase 4 inhibited the nuclear factor kappa-B pathway,and improved lysosome and mitochondrial function.Activation of NLRP3 reversed the neuroprotective effects of etazolate without affecting phosphodiesterase 4 expression.Together,the results indicate that phosphodiesterase 4 regulates NLRP3-mediated neuronal pyroptosis in early brain injury after subarachnoid hemorrhage.Phosphodiesterase 4 may be a potential therapeutic molecular target for subarachnoid hemorrhage.展开更多
The prognosis for patients who experience intracerebral hemorrhage is poor because of a lack of effective treatments.Tumor necrosis factor-α-stimulated gene 6(TSG6)is a secreted glycoprotein that exerts anti-inflamma...The prognosis for patients who experience intracerebral hemorrhage is poor because of a lack of effective treatments.Tumor necrosis factor-α-stimulated gene 6(TSG6)is a secreted glycoprotein that exerts anti-inflammatory effects in various inflammatory diseases.We previously showed that adipose-derived stem cells can inhibit inflammation by upregulating TSG6 secretion in an in vitro model of intracerebral hemorrhage.However,the direct effects of TSG6 on hematoma clearance in vivo remain largely unknown.The aim of this study was to determine how TSG6 affects hematoma absorption in mice subjected to intracerebral hemorrhage and to explore the potential underlying mechanisms.We first analyzed the gene profiles of patients with intracerebral hemorrhage from the GEO database and examined changes in TSG6 expression in the brain tissues of mice subjected to intracerebral hemorrhage.We found that TSG6 expression exhibited a transient increase following intracerebral hemorrhage,and that there was a negative correlation between the initial hematoma volume and TSG6 levels.Immunofluorescence analysis showed that TSG6 was primarily expressed in microglia and macrophages.Furthermore,we found that TSG6 promoted functional recovery in mice subjected to intracerebral hemorrhage by accelerating hematoma clearance,reducing the number of apoptotic cells and degenerated neurons,increasing the proportion of phagocytic microglia/macrophages,and decreasing iron deposition.Western blotting and immunofluorescence analysis indicated that TSG6 promoted M2 polarization of microglia/macrophages.In vitro phagocytosis experiments confirmed that TSG6 enhanced the ability of microglia to phagocytize red blood cells.Finally,we identified the signal transducer and activator of transcription 6/growth arrest-specific protein 6 signaling pathway as playing a critical role in TSG6-mediated hematoma absorption.In summary,our results demonstrate an essential role for TSG6 in promoting hematoma absorption in a mouse model of intracerebral hemorrhage.These findings suggest that TSG6 accelerates hematoma clearance and improves neurological function by promoting microglia/macrophage polarization to the M2 phenotype,activating the STAT6/GAS6 signaling pathway,and increasing phagocytic receptor expression on the surface of phagocytes,thereby enhancing their ability to phagocytize red blood cells.展开更多
Subarachnoid hemorrhage(SAH) is a devastating condition that affects a total of 8 million people worldwide each year(Lauzier and Athiraman, 2024). Etiologies of SAH can be traumatic or nontraumatic, with the majority ...Subarachnoid hemorrhage(SAH) is a devastating condition that affects a total of 8 million people worldwide each year(Lauzier and Athiraman, 2024). Etiologies of SAH can be traumatic or nontraumatic, with the majority of non-traumatic SAH occurring due to intracranial aneurysm rupture(Rutledge et al., 2014).展开更多
In this article,we comment on the paper by Kakinuma et al published recently.We focus specifically on the diagnosis of uterine pseudoaneurysm,but we also review other uterine vascular anomalies that may be the cause o...In this article,we comment on the paper by Kakinuma et al published recently.We focus specifically on the diagnosis of uterine pseudoaneurysm,but we also review other uterine vascular anomalies that may be the cause of life-threating hemorrhage and the different causes of uterine pseudoaneurysms.Uterine artery pseudoaneurysm is a complication of both surgical gynecological and nontraumatic procedures.Massive hemorrhage is the consequence of the rupture of the pseudoaneurysm.Uterine artery pseudoaneurysm can develop after obstetric or gynecological procedures,being the most frequent after cesarean or vaginal deliveries,curettage and even during pregnancy.However,there are several cases described unrelated to pregnancy,such as after conization,hysteroscopic surgery or laparoscopic myomectomy.Hemorrhage is the clinical manifestation and it can be life-threatening so suspicion of this vascular lesion is essential for early diagnosis and treatment.However,there are other uterine vascular anomalies that may be the cause of severe hemorrhage,which must be taken into account in the differential diagnosis.Computed tomography angiography and embolization is supposed to be the first therapeutic option in most of them.展开更多
Background:Hemorrhagic expansion into the fourth ventricle is an independent risk factor for poor outcomes in intraventricular hemorrhage(IVH)patients.However,to date,available animal models of IVH are limited to mode...Background:Hemorrhagic expansion into the fourth ventricle is an independent risk factor for poor outcomes in intraventricular hemorrhage(IVH)patients.However,to date,available animal models of IVH are limited to models of supratentorial ventricular hemorrhage,and there are no specific models of fourth ventricle hemorrhage.This limitation hinders comprehensive basic research and the understanding of the pathophysiological changes that occur following fourth ventricle hemorrhage.Therefore,the development of an animal model of fourth ventricle hemorrhage is highly important.Methods:In this study,a novel rat model of fourth ventricle hemorrhage was established via autologous blood injection through the foramen of Magendie.Anesthetized rats were positioned in a stereotaxic apparatus with their heads tilted downward at an angle of approximately 20°relative to the vertical axis.A needle was inserted through the foramen,and autologous blood obtained from the rat's heart was injected into the fourth ventricle via a microinfusion pump.Systematic evaluations of the model were conducted using small-animal magnetic resonance imaging,histopathological analysis,and neurological function assessment.Results:The rats developed stable and reproducible fourth ventricle hematomas and ventricular dilation.They also exhibited acute-phase hydrocephalus and pathological features of perilesional brain tissue injury,with observed neurological deficits comparable to patients with fourth ventricle hemorrhage.Conclusion:This model successfully recapitulates the clinicopathological and pathophysiological characteristics of patients with fourth ventricle hemorrhage and can be utilized for further investigation into the pathophysiological mechanisms underlying posthemorrhagic hydrocephalus and perilesional brainstem tissue injury.展开更多
Dear Editor,We present the reported case of repetitive bilateral suprachoroidal expulsive hemorrhage(SEH)after anti-glaucoma surgeries.SEH is a rare but potentially devastating complication of intraocular surgery.Long...Dear Editor,We present the reported case of repetitive bilateral suprachoroidal expulsive hemorrhage(SEH)after anti-glaucoma surgeries.SEH is a rare but potentially devastating complication of intraocular surgery.Long-term ocular hypertension,high myopia,older age,arterial sclerosis,and aphakia have been reported as preoperative risk factors for developing SEH^([1]).The prognosis for the visual acuity is poor without proper management.A suggested time for surgical drainage is said to be 10-14d when the hemorrhagic clot begins to liquefy^([2]).展开更多
Spinal subarachnoid hemorrhage(SSAH)is a relatively uncommon but significant cause of acute and progressive neurological impairment.It represents less than 1.5%of all instances of bleeding within the subarachnoid spac...Spinal subarachnoid hemorrhage(SSAH)is a relatively uncommon but significant cause of acute and progressive neurological impairment.It represents less than 1.5%of all instances of bleeding within the subarachnoid space.[1]The early stages of SSAH often present atypical clinical symptoms,making diagnosis challenging and potentially leading to treatment delays,which further result in irreversible neurological damage.Lower back pain is a common complaint in the emergency department(ED).[2]Common causes include overuse resulting in back strain.展开更多
Objective:To preliminarily construct and apply a longitudinal trajectory model for the prognosis of intracerebral hemorrhage(ICH)based on blood urea nitrogen(BUN)characteristics.Methods:Clinical data from 320 ICH pati...Objective:To preliminarily construct and apply a longitudinal trajectory model for the prognosis of intracerebral hemorrhage(ICH)based on blood urea nitrogen(BUN)characteristics.Methods:Clinical data from 320 ICH patients admitted to our hospital between 2020 and 2024 were collected,including demographic information,National Institutes of Health Stroke Scale(NIHSS)scores at admission,dynamic changes in BUN levels during treatment,and 30-day survival outcomes.A latent class growth model(LCGM)was first used for preliminary modeling,followed by a latent growth mixture modeling(GMM)approach to determine the final model.Three classes of BUN trajectories for ICH prognosis were identified,and latent classes were established.GMM modeling was then performed on these latent classes,considering linear,quadratic,and cubic polynomial forms;six GMM models were constructed and individuals were assigned to latent trajectory groups for validation.Results:LCGM analysis ultimately identified three dynamic BUN trajectory groups:Sustained low-level group(76 cases,23.8%):BUN remained stable between 3.1-9.0 mmol/L,with the highest 30-day survival rate(98.7%).Fluctuating-declining group(222 cases,69.4%):BUN initially increased and then slowly decreased(peak at day 3:15.2 mmol/L),with a 30-day mortality of 8.1%(18/222),higher than the sustained low-level group.Sustained high-level group(22 cases,6.9%):BUN mean>9.0 mmol/L,with a 30-day mortality of 41.7%(P=0.000).GMM model fitting showed that the cubic polynomial GMM model was optimal(AIC=6754.474,BIC=6852.450,Entropy=0.905).Incorporating gender,age,and BMI as covariates revealed significant effects for gender(Estimate=0.045,-0.011,P=0.000,0.000).The AUC for predicting 30-day mortality was 0.88(sensitivity 82.8%,specificity 77.9%),which increased to 0.89 when combined with admission NIHSS scores.Conclusion:The LCGM+GMM model based on dynamic BUN trajectories effectively distinguishes prognostic subgroups in ICH patients.Patients with persistently elevated or fluctuating-rising BUN levels have a significantly higher mortality risk compared to those with sustained low levels.This model provides a new quantitative tool for early identification of high-risk patients and poor prognoses.展开更多
Cholesterol is an important component of plasma membranes and participates in many basic life functions,such as the maintenance of cell membrane stability,the synthesis of steroid hormones,and myelination.Cholesterol ...Cholesterol is an important component of plasma membranes and participates in many basic life functions,such as the maintenance of cell membrane stability,the synthesis of steroid hormones,and myelination.Cholesterol plays a key role in the establishment and maintenance of the central nervous system.The brain contains 20%of the whole body’s cholesterol,80%of which is located within myelin.A huge number of processes(e.g.,the sterol regulatory element-binding protein pathway and liver X receptor pathway)participate in the regulation of cholesterol metabolism in the brain via mechanisms that include cholesterol biosynthesis,intracellular transport,and efflux.Certain brain injuries or diseases involving crosstalk among the processes above can affect normal cholesterol metabolism to induce detrimental consequences.Therefore,we hypothesized that cholesterol-related molecules and pathways can serve as therapeutic targets for central nervous system diseases.Intracerebral hemorrhage is the most severe hemorrhagic stroke subtype,with high mortality and morbidity.Historical cholesterol levels are associated with the risk of intracerebral hemorrhage.Moreover,secondary pathological changes after intracerebral hemorrhage are associated with cholesterol metabolism dysregulation,such as neuroinflammation,demyelination,and multiple types of programmed cell death.Intracellular cholesterol accumulation in the brain has been found after intracerebral hemorrhage.In this paper,we review normal cholesterol metabolism in the central nervous system,the mechanisms known to participate in the disturbance of cholesterol metabolism after intracerebral hemorrhage,and the links between cholesterol metabolism and cell death.We also review several possible and constructive therapeutic targets identified based on cholesterol metabolism to provide cholesterol-based perspectives and a reference for those interested in the treatment of intracerebral hemorrhage.展开更多
Subarachnoid hemorrhage leads to a series of pathological changes,including vascular spasm,cellular apoptosis,blood–brain barrier damage,cerebral edema,and white matter injury.Microglia,which are the key immune cells...Subarachnoid hemorrhage leads to a series of pathological changes,including vascular spasm,cellular apoptosis,blood–brain barrier damage,cerebral edema,and white matter injury.Microglia,which are the key immune cells in the central nervous system,maintain homeostasis in the neural environment,support neurons,mediate apoptosis,participate in immune regulation,and have neuroprotective effects.Increasing evidence has shown that microglia play a pivotal role in the pathogenesis of subarachnoid hemorrhage and affect the process of injury and the prognosis of subarachnoid hemorrhage.Moreover,microglia play certain neuroprotective roles in the recovery phase of subarachnoid hemorrhage.Several approaches aimed at modulating microglia function are believed to attenuate subarachnoid hemorrhage injury.This provides new targets and ideas for the treatment of subarachnoid hemorrhage.However,an in-depth and comprehensive summary of the role of microglia after subarachnoid hemorrhage is still lacking.This review describes the activation of microglia after subarachnoid hemorrhage and their roles in the pathological processes of vasospasm,neuroinflammation,neuronal apoptosis,blood–brain barrier disruption,cerebral edema,and cerebral white matter lesions.It also discusses the neuroprotective roles of microglia during recovery from subarachnoid hemorrhage and therapeutic advances aimed at modulating microglial function after subarachnoid hemorrhage.Currently,microglia in subarachnoid hemorrhage are targeted with TLR inhibitors,nuclear factor-κB and STAT3 pathway inhibitors,glycine/tyrosine kinases,NLRP3 signaling pathway inhibitors,Gasdermin D inhibitors,vincristine receptorαreceptor agonists,ferroptosis inhibitors,genetic modification techniques,stem cell therapies,and traditional Chinese medicine.However,most of these are still being evaluated at the laboratory stage.More clinical studies and data on subarachnoid hemorrhage are required to improve the treatment of subarachnoid hemorrhage.展开更多
Cerebral edema caused by blood-brain barrier injury after intracerebral hemorrhage is an important factor leading to poor prognosis.Human-induced pluripotent stem cell-derived neural stem cell exosomes(hiPSC-NSC-Exos)...Cerebral edema caused by blood-brain barrier injury after intracerebral hemorrhage is an important factor leading to poor prognosis.Human-induced pluripotent stem cell-derived neural stem cell exosomes(hiPSC-NSC-Exos)have shown potential for brain injury repair in central nervous system diseases.In this study,we explored the impact of hiPSC-NSC-Exos on blood-brain barrier preservation and the underlying mechanism.Our results indicated that intranasal delivery of hiPSC-NSC-Exos mitigated neurological deficits,enhanced blood-brain barrier integrity,and reduced leukocyte infiltration in a mouse model of intracerebral hemorrhage.Additionally,hiPSC-NSC-Exos decreased immune cell infiltration,activated astrocytes,and decreased the secretion of inflammatory cytokines like monocyte chemoattractant protein-1,macrophage inflammatory protein-1α,and tumor necrosis factor-αpost-intracerebral hemorrhage,thereby improving the inflammatory microenvironment.RNA sequencing indicated that hiPSC-NSC-Exo activated the PI3K/AKT signaling pathway in astrocytes and decreased monocyte chemoattractant protein-1 secretion,thereby improving blood-brain barrier integrity.Treatment with the PI3K/AKT inhibitor LY294002 or the monocyte chemoattractant protein-1 neutralizing agent C1142 abolished these effects.In summary,our findings suggest that hiPSC-NSC-Exos maintains blood-brain barrier integrity,in part by downregulating monocyte chemoattractant protein-1 secretion through activation of the PI3K/AKT signaling pathway in astrocytes.展开更多
基金supported by the National Natural Science Foundation of China,Nos.82371310(to YJ),82271306(to JP)the Sichuan Science and Technology Support Program,Nos.2023YFH0069(to JP),2023NSFSC0028(to YJ),2023NSFSC1559(to YJ),2022YFS0615(to JP),2022NSFSC1421(to JP)+1 种基金Scientific Research Project of Sichuan Provincial Health Commission,No.23LCYJ040(to YJ)Youth Foundation of Southwestern Medical University and Southwest Medical University Project,Nos.2020ZRQNA038(to JP),2021ZKZD013(to JP),2021LZXNYD-P01(to YJ),2023QN014(to JP).
文摘Neuronal cell death is a common outcome of multiple pathophysiological processes and a key factor in neurological dysfunction after subarachnoid hemorrhage.Neuronal ferroptosis in particular plays an important role in early brain injury.Bromodomain-containing protein 4,a member of the bromo and extraterminal domain family of proteins,participated in multiple cell death pathways,but the mechanisms by which it regulates ferroptosis remain unclear.The primary aim of this study was to investigate how bromodomain-containing protein 4 affects neuronal ferroptosis following subarachnoid hemorrhage in vivo and in vitro.Our findings revealed that endogenous bromodomain-containing protein 4 co-localized with neurons,and its expression was decreased 48 hours after subarachnoid hemorrhage of the cerebral cortex in vivo.In addition,ferroptosis-related pathways were activated in vivo and in vitro after subarachnoid hemorrhage.Targeted inhibition of bromodomain-containing protein 4 in neurons increased lipid peroxidation and intracellular ferrous iron accumulation via ferritinophagy and ultimately led to neuronal ferroptosis.Using cleavage under targets and tagmentation analysis,we found that bromodomain-containing protein 4 enrichment in the Raf-1 promoter region decreased following oxyhemoglobin stimulation in vitro.Furthermore,treating bromodomain-containing protein 4-knockdown HT-22 cell lines with GW5074,a Raf-1 inhibitor,exacerbated neuronal ferroptosis by suppressing the Raf-1/ERK1/2 signaling pathway.Moreover,targeted inhibition of neuronal bromodomain-containing protein 4 exacerbated early and long-term neurological function deficits after subarachnoid hemorrhage.Our findings suggest that bromodomain-containing protein 4 may have neuroprotective effects after subarachnoid hemorrhage,and that inhibiting ferroptosis could help treat subarachnoid hemorrhage.
基金supported by the Guangdong Basic and Applied Basic Research Foundation,No.2023A1515030045(to HS)Presidential Foundation of Zhujiang Hospital of Southern Medical University,No.yzjj2022ms4(to HS)。
文摘Intracerebral hemorrhage is the most dangerous subtype of stroke,characterized by high mortality and morbidity rates,and frequently leads to significant secondary white matter injury.In recent decades,studies have revealed that gut microbiota can communicate bidirectionally with the brain through the gut microbiota–brain axis.This axis indicates that gut microbiota is closely related to the development and prognosis of intracerebral hemorrhage and its associated secondary white matter injury.The NACHT,LRR,and pyrin domain-containing protein 3(NLRP3)inflammasome plays a crucial role in this context.This review summarizes the dysbiosis of gut microbiota following intracerebral hemorrhage and explores the mechanisms by which this imbalance may promote the activation of the NLRP3 inflammasome.These mechanisms include metabolic pathways(involving short-chain fatty acids,lipopolysaccharides,lactic acid,bile acids,trimethylamine-N-oxide,and tryptophan),neural pathways(such as the vagus nerve and sympathetic nerve),and immune pathways(involving microglia and T cells).We then discuss the relationship between the activated NLRP3 inflammasome and secondary white matter injury after intracerebral hemorrhage.The activation of the NLRP3 inflammasome can exacerbate secondary white matter injury by disrupting the blood–brain barrier,inducing neuroinflammation,and interfering with nerve regeneration.Finally,we outline potential treatment strategies for intracerebral hemorrhage and its secondary white matter injury.Our review highlights the critical role of the gut microbiota–brain axis and the NLRP3 inflammasome in white matter injury following intracerebral hemorrhage,paving the way for exploring potential therapeutic approaches.
基金National Nature Science Foundation of China,No.81870944(to FL).
文摘This study investigated the neuroprotective effects of lactate in subarachnoid hemorrhage,a severe cerebrovascular disease that is commonly caused by arterial aneurysm rupture and has limited early treatment options.Lactate,a metabolic byproduct,has been shown to have neuroprotective properties,including enhancing cerebral microcirculation and reducing intracranial pressure in acute brain injury patients.However,the protective mechanisms of lactate in subarachnoid hemorrhage remain unknown.In this study,we showed that lactate alleviates early brain damage in subarachnoid hemorrhage by promoting neuronal lipid synthesis and the formation of lipid droplets in astrocytes.In vivo experiments using a subarachnoid hemorrhage mouse model showed that lactate treatment significantly improved neurological scores,reduced brain inflammation,and promoted lipid droplet formation in astrocytes within 24 hours.Lactate treatment increased free fatty acids levels in the brain.The results suggest that astrocytes absorbed these free fatty acids and converted them into lipid droplets,thus reducing cellular lipotoxicity.Moreover,lactate enhanced the antiapoptotic capacity of astrocytes by upregulating the expression of PLIN5,a protein crucial for lipid droplet formation.The inhibition of lipid synthesis or lipid droplet formation counteracted the neuroprotective effects of lactate,indicating that lactate’s protective role is closely linked to lipid metabolism and lipid droplet formation.In vitro experiments on HT22 neuronal cells exposed to hemin-an agent used to simulate subarachnoid hemorrhage injury-demonstrated that lactate mitigated cellular damage by reducing lipid peroxidation and preserving mitochondrial membrane potential.Lactate treatment in HT22 cells and astrocytes also showed that inhibition of lipid synthesis or lipid droplet formation reversed its protective effects,further emphasizing the importance of lipid metabolism in the neuroprotective action of lactate.This study provides insights into the neuroprotective mechanisms of lactate in subarachnoid hemorrhage.It indicates that lactate plays a role in promoting lipid synthesis in neurons and enhancing lipid droplet formation in astrocytes,thus mitigating brain damage and improving cell survival.These findings suggest that lactate,through its regulation of lipid metabolism,could be a potential therapeutic agent for subarachnoid hemorrhage.
基金the National Natural Science Foundation of China,Nos.82311530117(to RJ),82260260(to FC).
文摘Ferroptosis plays a key role in nerve injury in intracerebral hemorrhage and is associated with the upregulation of murine double minute 2.Investigating the mechanism underlying murine double minute 2-related ferroptosis could help identify new therapies for intracerebral hemorrhage.An in vitro intracerebral hemorrhage model was established by treating BV2 microglial cells with oxygen-glucose deprivation combined with hemin.The role of murine double minute 2 in regulating ferroptosis was investigated via transduction with RNA interference and lentivirus overexpression.Furthermore,intracerebral hemorrhage mouse models were constructed with and without an murine double minute 2 inhibitor(brigimadlin),and behavioral assays were performed to assess the learning ability and cognitive function.Murine double minute 2 dysregulation was associated with oxygen-glucose deprivation combined with hemin-induced BV2 microglial cell ferroptosis and M1/M2 polarization.The results suggested that murine double minute 2 induced glutathione peroxidase 4 ubiquitination and degradation to regulate ferroptosis and inflammatory responses in BV2 microglial cells.Mechanistically,Wilms tumor 1-associated protein induced murine double minute 2 N6-methyladenosine(m6A)modification and regulated ferroptosis and inflammatory responses.In vivo analysis showed that brigimadlin improved neurological deficits and spatial memory in mice with intracerebral hemorrhage.In summary,the results indicate that Wilms tumor 1-associated protein regulates murine double minute 2 m6A modification,and murine double minute 2 induces glutathione peroxidase 4 ubiquitination and degradation.This regulation promotes ferroptosis and inflammatory responses in oxygen-glucose deprivation combined with hemin-induced BV2 microglial cells,suggesting that the murine double minute 2-glutathione peroxidase 4-ferroptosis regulatory axis exerts neurotoxic effects.These findings identify glutathione peroxidase 4 as a potential gene therapy target for intracerebral hemorrhage-related brain injury.
基金National Natural Science Foundation of China,No.81901336(to JM).
文摘Subarachnoid hemorrhage is a subtype of stroke that causes severe neurological damage and is associated with poor long-term prognosis.Cognitive impairment is a major manifestation of long-term neurological dysfunction in patients with subarachnoid hemorrhage.However,there is notable absence of biological markers to predict long-term prognosis in this patient population.Given the aging-like neurocognitive phenomena associated with subarachnoid hemorrhage,this study postulates that telomere length,a recognized biomarker for aging,could be used as a prognostic indicator for subarachnoid hemorrhage.A left internal carotid artery intravascular puncture mouse model was used to simulate subarachnoid hemorrhage.Comprehensive neurological test scores were obtained through neurobehavioral assessments conducted at one-month intervals.Concurrently,the relative telomere length was analyzed by quantitative polymerase chain reaction,which was performed using DNA extracted from ear notch and brain tissue after each assessment.Furthermore,proteomic analysis was employed to investigate differential protein expression in hippocampal tissue.Subarachnoid hemorrhage mice exhibited persistent neurocognitive impairment over a prolonged period of time.There was a significant positive correlation between telomere length and neurological test scores,confirming the usefulness of telomere length as a prognostic indicator in subarachnoid hemorrhage.Hippocampal tissue from subarachnoid hemorrhage mice showed reduced expression of acetyl-coenzyme A synthetase-2 and abnormalities in the expression of proteins related to ribosomes,energy metabolism,and cellular signal transduction.This study confirmed telomere shortening in the brain and metabolic disturbances in the hippocampi of subarachnoid hemorrhage mice.Thus,telomere length is a predictive marker for long-term impairment of cognitive function in mice following experimental subarachnoid hemorrhage.
文摘Objective:To explore the impact of systematic stepwise rehabilitation nursing intervention on the prognosis and disease uncertainty of patients with hypertensive intracerebral hemorrhage,and to provide feasible strategies for clinical nursing.Methods:Eighty patients with hypertensive intracerebral hemorrhage admitted to our hospital from January 2023 to June 2025 were selected and randomly divided into an observation group(n=40,receiving systematic stepwise rehabilitation nursing)and a control group(n=40,receiving conventional nursing).The intervention effects were analyzed by comparing changes in the National Institutes of Health Stroke Scale(NIHSS)scores for neurological recovery,Short Form 36 Health Survey(SF-36)scores for quality of life,Exercise of Self-Care Agency Scale(ESCA)scores for self-management ability,compliance,and the Mishel Uncertainty in Illness Scale(MUIS)scores between the two groups.Results:All scores in the observation group were significantly better than those in the control group after the intervention(p<0.05).Specifically,the NIHSS scores decreased more significantly,the total SF-36 scores increased,the ESCA scores increased significantly,while the MUIS scores decreased significantly,and compliance improved markedly,indicating a reduction in disease uncertainty among patients.Conclusion:Systematic stepwise rehabilitation nursing intervention can significantly improve neurological recovery,quality of life,self-management ability,and compliance in patients with hypertensive intracerebral hemorrhage,while effectively reducing disease uncertainty.It is worthy of clinical promotion and application.
基金supported by the National Key Research and Development Program of China,No.2022YFC2704801(to CZhu)the National Natural Science Foundation of China,Nos.U21A20347(to CZhu),82203969(to YX),82371472(to XZ)+3 种基金Health Commission of Henan Province,Nos.SBGJ202303039(to XZ),SBGJ202301009(to CZhu),YQRC2024018(to XZ),YQRC2024019(to YX)Henan Science and Technology Department,Nos.242102311054(to XZ),241111521300(to CZhu),GZS2023003(to XW)Swedish Research Council,Nos.2022-01019(to CZhu),2021-01950(to XW)Swedish Governmental Grants to Scientists Working in Healthcare,Nos.ALFGBG-1005209(to CZhu),ALFBG-1005257(to XW),ALFGBG-965197(to CZhu).
文摘Germinal matrix hemorrhage in preterm neonates often leads to white matter injury,contributing to long-term neurodevelopmental impairments.As resident brain immune cells,microglia play a complex role in injury response,including inflammation and repair.Although colony-stimulating factor 1 receptor inhibitors such as PLX5622 enable the selective depletion of microglia,their therapeutic potential in neonatal germinal matrix hemorrhage remains underexplored.Here,we used a collagenase-induced germinal matrix hemorrhage model in postnatal day 5 mice,and intraperitoneally administered PLX562272 hours post-germinal matrix hemorrhage to achieve targeted,temporary microglial depletion during the peak injury response.We then assessed the effects of this delayed intervention on oligodendrocyte lineage cell maturation,white matter integrity,and neurobehavioral outcomes.Additionally,RNA sequencing data from a germinal matrix hemorrhage rat model were analyzed using weighted gene co-expression network analysis to identify the critical phases for interventions.RNA sequencing data revealed a critical period in which key synaptic functions declined while immune responses intensified post-germinal matrix hemorrhage,thus pinpointing the critical response phases for potential interventions.Delayed PLX5622 treatment effectively depleted activated microglia,protecting against white matter injury and enhancing oligodendrocyte lineage cell maturation and myelination in subcortical white matter regions.Moreover,magnetic resonance imaging analysis revealed reduced brain lesion volumes in treated mice.Behaviorally,PLX5622-treated mice exhibited significant improvements in motor coordination and reduced hyperactivity compared with vehicle-treated germinal matrix hemorrhage model mice.These findings suggest that,when timed to avoid interference with initial oligodendrocyte lineage cell proliferation,targeted microglial depletion with PLX5622 significantly mitigates white matter damage and improves neurobehavioral outcomes in neonatal germinal matrix hemorrhage.The present study highlights the therapeutic potential of selectively modulating microglial reactivity to support neurodevelopment in preterm infants with brain injury.
基金Supported by National Natural Science Foundation of China(No.82160195,No.82460203)Zhejiang Traditional Chinese Medicine Science and Technology Plan Project(No.2025ZR172).
文摘AIM:To compare spontaneous brain regional activities between diabetic vitreous hemorrhage patients(DVHs)and healthy controls(HCs).METHODS:Thirty-two DVHs and 32 HCs were enrolled in this study.Baseline demographic and vision data were compared between groups using an independent sample t-test.Resting-state functional magnetic resonance imaging(rs-fMRI)was used in all participants.fMRI data was obtained and analyzed using MRIcro and SPM8 software.Fractional amplitude of low-frequency fluctuation(fALFF)technology was used to measure regional spontaneous brain activity,and sensitivity was tested using receiver operating characteristic curves(ROCs).The fALFF values were analyzed using REST software and two-sample t-tests were used to compare values between groups.Hospital anxiety and depression scale(HADS)score was assessed in DVHs and Pearson’s correlation was used to test relationships between mean fALFF value and both HADS score and duration of DVH.RESULTS:Except for the best-corrected visual acuity(BCVA)in both eyes,which showed a statistically significant difference(P<0.05),there were no statistically significant differences in the other indicators(P>0.05)between the HCs and DVHs group.Compared with controls,fALFF value was higher in DVH in cerebellum posterior lobe(CPL)and lower in right anterior cingulate cortex(ACC)and right medial orbitofrontal cortex(OFC).In DVH patients,mean fALFF value of CPL was positively correlated with HADS score and duration of diabetes.However,no such correlation was found,for right ACC or right medial OFC.DVH may lead to abnormal activities in certain brain regions related to visual control and mood.CONCLUSION:Visual impairment caused by DVH may lead to adjustment in regional visual brain activities and may be related to depression or reward system processing in some brain regions.
基金supported by the National Natural Science Foundation of China,Nos.92148206,82071330(both to ZT)a grant from the Major Program of Hubei Province,No.2023BAA005(to ZT)+1 种基金a grant from the Key Research and Discovery Program of Hubei Province,No.2021BCA109(to ZT)the Research Foundation of Tongji Hospital,No.2022B37(to PZ)。
文摘Recombinant tissue plasminogen activator is commonly used for hematoma evacuation in minimally invasive surgery following intracerebral hemorrhage.However,during minimally invasive surgery,recombinant tissue plasminogen activator may come into contact with brain tissue.Therefore,a thorough assessment of its safety is required.In this study,we established a mouse model of intracerebral hemorrhage induced by type VII collagenase.We observed that the administration of recombinant tissue plasminogen activator without hematoma aspiration significantly improved the neurological function of mice with intracerebral hemorrhage,reduced pathological damage,and lowered the levels of apoptosis and autophagy in the tissue surrounding the hematoma.In an in vitro model of intracerebral hemorrhage using primary cortical neurons induced by hemin,the administration of recombinant tissue plasminogen activator suppressed neuronal apoptosis,autophagy,and endoplasmic reticulum stress.Transcriptome sequencing analysis revealed that recombinant tissue plasminogen activator upregulated the phosphoinositide 3-kinase/RAC-alpha serine/threonine-protein kinase/mammalian target of rapamycin pathway in neurons.Moreover,the phosphoinositide 3-kinase inhibitor LY294002 abrogated the neuroprotective effects of recombinant tissue plasminogen activator in inhibiting excessive apoptosis,autophagy,and endoplasmic reticulum stress.Furthermore,to specify the domain of recombinant tissue plasminogen activator responsible for its neuroprotective effects,various inhibitors were used to target distinct domains.It has been revealed that the epidermal growth factor receptor inhibitor AG-1478 reversed the effect of recombinant tissue plasminogen activator on the phosphoinositide 3-kinase/RAC-alpha serine/threonineprotein kinase/mammalian target of rapamycin pathway.These findings suggest that recombinant tissue plasminogen activator exerts a direct neuroprotective effect on neurons following intracerebral hemorrhage,possibly through activation of the phosphoinositide 3-kinase/RAC-alpha serine/threonine-protein kinase/mammalian target of rapamycin pathway.
基金supported by the National Natural Science Foundation of China,No.81870927(to ZH)the Natural Science Foundation Project ofChongqing Science and Technology Commission,No.CSTB2023NSCQ-MSX0112(to ZH).
文摘Phosphodiesterase 4 is a key enzyme involved in the regulation of cell signal transduction,but its role in subarachnoid hemorrhage remains unclear.Neuronal pyroptosis has been reported to be involved in early brain injury after subarachnoid hemorrhage.This study aimed to investigate whether phosphodiesterase 4 contributes to early brain injury after subarachnoid hemorrhage by mediating neuronal pyroptosis and its related mechanisms.Endovascular perforation of male C57BL/6J mice was performed to model subarachnoid hemorrhage in vivo,and oxyhemoglobin was added to the culture medium of primary neurons to model subarachnoid hemorrhage in vitro.A phosphodiesterase 4-specific inhibitor,etazolate,was intraperitoneally injected 30 minutes after subarachnoid hemorrhage induction.Small interfering RNA(siRNA)was administered intracerebroventricularly 72 hours before subarachnoid hemorrhage to achieve genetic knockdown of phosphodiesterase 4.To investigate the mechanism,a nucleotide-binding oligomerization domain-like receptor pyrin domain containing 3(NLRP3)-specific agonist,nigericin,was intracerebroventricularly injected 60 minutes before subarachnoid hemorrhage.Neuronal phosphodiesterase 4 expression increased after subarachnoid hemorrhage and reached the highest point at 24 hours.Etazolate treatment reduced neurological deficits and brain edema in mice,alleviated neuronal pyroptosis and inflammatory response,and improved neuronal injury.Treatment with phosphodiesterase 4 siRNA had the same neuroprotective effects as etazolate.Mechanistically,phosphodiesterase 4 triggered the nuclear factor kappa-B pathway,and simultaneously caused lysosomal and mitochondrial dysfunction after subarachnoid hemorrhage,which promoted NLRP3 inflammasome activation and induced neuronal pyroptosis.Blocking of phosphodiesterase 4 inhibited the nuclear factor kappa-B pathway,and improved lysosome and mitochondrial function.Activation of NLRP3 reversed the neuroprotective effects of etazolate without affecting phosphodiesterase 4 expression.Together,the results indicate that phosphodiesterase 4 regulates NLRP3-mediated neuronal pyroptosis in early brain injury after subarachnoid hemorrhage.Phosphodiesterase 4 may be a potential therapeutic molecular target for subarachnoid hemorrhage.
基金supported by the National Natural Science Foundation of China,Nos.92148206,82071330(both to ZT),82201474(to GL)a grant from Tongji Hospital,No.2022ZHFY01(to ZT).
文摘The prognosis for patients who experience intracerebral hemorrhage is poor because of a lack of effective treatments.Tumor necrosis factor-α-stimulated gene 6(TSG6)is a secreted glycoprotein that exerts anti-inflammatory effects in various inflammatory diseases.We previously showed that adipose-derived stem cells can inhibit inflammation by upregulating TSG6 secretion in an in vitro model of intracerebral hemorrhage.However,the direct effects of TSG6 on hematoma clearance in vivo remain largely unknown.The aim of this study was to determine how TSG6 affects hematoma absorption in mice subjected to intracerebral hemorrhage and to explore the potential underlying mechanisms.We first analyzed the gene profiles of patients with intracerebral hemorrhage from the GEO database and examined changes in TSG6 expression in the brain tissues of mice subjected to intracerebral hemorrhage.We found that TSG6 expression exhibited a transient increase following intracerebral hemorrhage,and that there was a negative correlation between the initial hematoma volume and TSG6 levels.Immunofluorescence analysis showed that TSG6 was primarily expressed in microglia and macrophages.Furthermore,we found that TSG6 promoted functional recovery in mice subjected to intracerebral hemorrhage by accelerating hematoma clearance,reducing the number of apoptotic cells and degenerated neurons,increasing the proportion of phagocytic microglia/macrophages,and decreasing iron deposition.Western blotting and immunofluorescence analysis indicated that TSG6 promoted M2 polarization of microglia/macrophages.In vitro phagocytosis experiments confirmed that TSG6 enhanced the ability of microglia to phagocytize red blood cells.Finally,we identified the signal transducer and activator of transcription 6/growth arrest-specific protein 6 signaling pathway as playing a critical role in TSG6-mediated hematoma absorption.In summary,our results demonstrate an essential role for TSG6 in promoting hematoma absorption in a mouse model of intracerebral hemorrhage.These findings suggest that TSG6 accelerates hematoma clearance and improves neurological function by promoting microglia/macrophage polarization to the M2 phenotype,activating the STAT6/GAS6 signaling pathway,and increasing phagocytic receptor expression on the surface of phagocytes,thereby enhancing their ability to phagocytize red blood cells.
文摘Subarachnoid hemorrhage(SAH) is a devastating condition that affects a total of 8 million people worldwide each year(Lauzier and Athiraman, 2024). Etiologies of SAH can be traumatic or nontraumatic, with the majority of non-traumatic SAH occurring due to intracranial aneurysm rupture(Rutledge et al., 2014).
文摘In this article,we comment on the paper by Kakinuma et al published recently.We focus specifically on the diagnosis of uterine pseudoaneurysm,but we also review other uterine vascular anomalies that may be the cause of life-threating hemorrhage and the different causes of uterine pseudoaneurysms.Uterine artery pseudoaneurysm is a complication of both surgical gynecological and nontraumatic procedures.Massive hemorrhage is the consequence of the rupture of the pseudoaneurysm.Uterine artery pseudoaneurysm can develop after obstetric or gynecological procedures,being the most frequent after cesarean or vaginal deliveries,curettage and even during pregnancy.However,there are several cases described unrelated to pregnancy,such as after conization,hysteroscopic surgery or laparoscopic myomectomy.Hemorrhage is the clinical manifestation and it can be life-threatening so suspicion of this vascular lesion is essential for early diagnosis and treatment.However,there are other uterine vascular anomalies that may be the cause of severe hemorrhage,which must be taken into account in the differential diagnosis.Computed tomography angiography and embolization is supposed to be the first therapeutic option in most of them.
基金Natural Science Foundation of Hubei Province,Grant/Award Number:2024AFB877the Chongqing Medical Scientific Research Project(Joint Project of Chongqing Health Commission and Science&Technology Bureau),Grant/Award Number:2023GGXM003+3 种基金Chongqing Municipal Health Commission,Grant/Award Number:YXGD202451Organization Department of Chongqing Municipal Party Committee,Grant/Award Number:cstc2024ycjh-bgzxm0103National Natural Science Foundation of China,Grant/Award Number:82371361Jingmen Science and Technology Bureau,Grant/Award Number:2024ZDYF012。
文摘Background:Hemorrhagic expansion into the fourth ventricle is an independent risk factor for poor outcomes in intraventricular hemorrhage(IVH)patients.However,to date,available animal models of IVH are limited to models of supratentorial ventricular hemorrhage,and there are no specific models of fourth ventricle hemorrhage.This limitation hinders comprehensive basic research and the understanding of the pathophysiological changes that occur following fourth ventricle hemorrhage.Therefore,the development of an animal model of fourth ventricle hemorrhage is highly important.Methods:In this study,a novel rat model of fourth ventricle hemorrhage was established via autologous blood injection through the foramen of Magendie.Anesthetized rats were positioned in a stereotaxic apparatus with their heads tilted downward at an angle of approximately 20°relative to the vertical axis.A needle was inserted through the foramen,and autologous blood obtained from the rat's heart was injected into the fourth ventricle via a microinfusion pump.Systematic evaluations of the model were conducted using small-animal magnetic resonance imaging,histopathological analysis,and neurological function assessment.Results:The rats developed stable and reproducible fourth ventricle hematomas and ventricular dilation.They also exhibited acute-phase hydrocephalus and pathological features of perilesional brain tissue injury,with observed neurological deficits comparable to patients with fourth ventricle hemorrhage.Conclusion:This model successfully recapitulates the clinicopathological and pathophysiological characteristics of patients with fourth ventricle hemorrhage and can be utilized for further investigation into the pathophysiological mechanisms underlying posthemorrhagic hydrocephalus and perilesional brainstem tissue injury.
基金Supported by National Natural Science Foundation of China(No.82171087No.82201228)+1 种基金Natural Science Foundation of Hunan Province(No.2024JJ6570)the Scientific Research Launch Project for new employees of the Second Xiangya Hospital of Central South University.
文摘Dear Editor,We present the reported case of repetitive bilateral suprachoroidal expulsive hemorrhage(SEH)after anti-glaucoma surgeries.SEH is a rare but potentially devastating complication of intraocular surgery.Long-term ocular hypertension,high myopia,older age,arterial sclerosis,and aphakia have been reported as preoperative risk factors for developing SEH^([1]).The prognosis for the visual acuity is poor without proper management.A suggested time for surgical drainage is said to be 10-14d when the hemorrhagic clot begins to liquefy^([2]).
基金National Natural Science Foundation of China(82472218)National Key Clinical Specialist Construction Project(Z155080000004)+4 种基金National Key Research and Development Program of China(2024YFC3044400)Noncommunicable Chronic Diseases-National Science and Technology Major Project(2023ZD0506502)the Science and Technology of Shanghai Committee(23Y31900100)Shen Kang Hospital Development Center Project for Technical Standardization Management and Promotion(SHDC22023239)Key Supporting Discipline of Shanghai Healthcare System(2023ZDFC0102).
文摘Spinal subarachnoid hemorrhage(SSAH)is a relatively uncommon but significant cause of acute and progressive neurological impairment.It represents less than 1.5%of all instances of bleeding within the subarachnoid space.[1]The early stages of SSAH often present atypical clinical symptoms,making diagnosis challenging and potentially leading to treatment delays,which further result in irreversible neurological damage.Lower back pain is a common complaint in the emergency department(ED).[2]Common causes include overuse resulting in back strain.
文摘Objective:To preliminarily construct and apply a longitudinal trajectory model for the prognosis of intracerebral hemorrhage(ICH)based on blood urea nitrogen(BUN)characteristics.Methods:Clinical data from 320 ICH patients admitted to our hospital between 2020 and 2024 were collected,including demographic information,National Institutes of Health Stroke Scale(NIHSS)scores at admission,dynamic changes in BUN levels during treatment,and 30-day survival outcomes.A latent class growth model(LCGM)was first used for preliminary modeling,followed by a latent growth mixture modeling(GMM)approach to determine the final model.Three classes of BUN trajectories for ICH prognosis were identified,and latent classes were established.GMM modeling was then performed on these latent classes,considering linear,quadratic,and cubic polynomial forms;six GMM models were constructed and individuals were assigned to latent trajectory groups for validation.Results:LCGM analysis ultimately identified three dynamic BUN trajectory groups:Sustained low-level group(76 cases,23.8%):BUN remained stable between 3.1-9.0 mmol/L,with the highest 30-day survival rate(98.7%).Fluctuating-declining group(222 cases,69.4%):BUN initially increased and then slowly decreased(peak at day 3:15.2 mmol/L),with a 30-day mortality of 8.1%(18/222),higher than the sustained low-level group.Sustained high-level group(22 cases,6.9%):BUN mean>9.0 mmol/L,with a 30-day mortality of 41.7%(P=0.000).GMM model fitting showed that the cubic polynomial GMM model was optimal(AIC=6754.474,BIC=6852.450,Entropy=0.905).Incorporating gender,age,and BMI as covariates revealed significant effects for gender(Estimate=0.045,-0.011,P=0.000,0.000).The AUC for predicting 30-day mortality was 0.88(sensitivity 82.8%,specificity 77.9%),which increased to 0.89 when combined with admission NIHSS scores.Conclusion:The LCGM+GMM model based on dynamic BUN trajectories effectively distinguishes prognostic subgroups in ICH patients.Patients with persistently elevated or fluctuating-rising BUN levels have a significantly higher mortality risk compared to those with sustained low levels.This model provides a new quantitative tool for early identification of high-risk patients and poor prognoses.
基金supported by the National Natural Science Foundation of China,No.82072110Suzhou Municipal Science and Technology Bureau,No.SKJY2021046+1 种基金Shanghai Key Lab of Forensic Medicine&Key Lab of Forensic Science,Ministry of Justice,China(Academy of Forensic Science),No.KF202201a Project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions(PAPD)(all to TW).
文摘Cholesterol is an important component of plasma membranes and participates in many basic life functions,such as the maintenance of cell membrane stability,the synthesis of steroid hormones,and myelination.Cholesterol plays a key role in the establishment and maintenance of the central nervous system.The brain contains 20%of the whole body’s cholesterol,80%of which is located within myelin.A huge number of processes(e.g.,the sterol regulatory element-binding protein pathway and liver X receptor pathway)participate in the regulation of cholesterol metabolism in the brain via mechanisms that include cholesterol biosynthesis,intracellular transport,and efflux.Certain brain injuries or diseases involving crosstalk among the processes above can affect normal cholesterol metabolism to induce detrimental consequences.Therefore,we hypothesized that cholesterol-related molecules and pathways can serve as therapeutic targets for central nervous system diseases.Intracerebral hemorrhage is the most severe hemorrhagic stroke subtype,with high mortality and morbidity.Historical cholesterol levels are associated with the risk of intracerebral hemorrhage.Moreover,secondary pathological changes after intracerebral hemorrhage are associated with cholesterol metabolism dysregulation,such as neuroinflammation,demyelination,and multiple types of programmed cell death.Intracellular cholesterol accumulation in the brain has been found after intracerebral hemorrhage.In this paper,we review normal cholesterol metabolism in the central nervous system,the mechanisms known to participate in the disturbance of cholesterol metabolism after intracerebral hemorrhage,and the links between cholesterol metabolism and cell death.We also review several possible and constructive therapeutic targets identified based on cholesterol metabolism to provide cholesterol-based perspectives and a reference for those interested in the treatment of intracerebral hemorrhage.
基金supported by the Natural Science Foundation of Shandong Province,No.ZR2022MH124the Youth Science Foundation of Shandong First Medical University,No.202201–105(both to YX)。
文摘Subarachnoid hemorrhage leads to a series of pathological changes,including vascular spasm,cellular apoptosis,blood–brain barrier damage,cerebral edema,and white matter injury.Microglia,which are the key immune cells in the central nervous system,maintain homeostasis in the neural environment,support neurons,mediate apoptosis,participate in immune regulation,and have neuroprotective effects.Increasing evidence has shown that microglia play a pivotal role in the pathogenesis of subarachnoid hemorrhage and affect the process of injury and the prognosis of subarachnoid hemorrhage.Moreover,microglia play certain neuroprotective roles in the recovery phase of subarachnoid hemorrhage.Several approaches aimed at modulating microglia function are believed to attenuate subarachnoid hemorrhage injury.This provides new targets and ideas for the treatment of subarachnoid hemorrhage.However,an in-depth and comprehensive summary of the role of microglia after subarachnoid hemorrhage is still lacking.This review describes the activation of microglia after subarachnoid hemorrhage and their roles in the pathological processes of vasospasm,neuroinflammation,neuronal apoptosis,blood–brain barrier disruption,cerebral edema,and cerebral white matter lesions.It also discusses the neuroprotective roles of microglia during recovery from subarachnoid hemorrhage and therapeutic advances aimed at modulating microglial function after subarachnoid hemorrhage.Currently,microglia in subarachnoid hemorrhage are targeted with TLR inhibitors,nuclear factor-κB and STAT3 pathway inhibitors,glycine/tyrosine kinases,NLRP3 signaling pathway inhibitors,Gasdermin D inhibitors,vincristine receptorαreceptor agonists,ferroptosis inhibitors,genetic modification techniques,stem cell therapies,and traditional Chinese medicine.However,most of these are still being evaluated at the laboratory stage.More clinical studies and data on subarachnoid hemorrhage are required to improve the treatment of subarachnoid hemorrhage.
基金supported by the National Natural Science Foundation of China,No.8227050826(to PL)Tianjin Science and Technology Bureau Foundation,No.20201194(to PL)Tianjin Graduate Research and Innovation Project,No.2022BKY174(to CW).
文摘Cerebral edema caused by blood-brain barrier injury after intracerebral hemorrhage is an important factor leading to poor prognosis.Human-induced pluripotent stem cell-derived neural stem cell exosomes(hiPSC-NSC-Exos)have shown potential for brain injury repair in central nervous system diseases.In this study,we explored the impact of hiPSC-NSC-Exos on blood-brain barrier preservation and the underlying mechanism.Our results indicated that intranasal delivery of hiPSC-NSC-Exos mitigated neurological deficits,enhanced blood-brain barrier integrity,and reduced leukocyte infiltration in a mouse model of intracerebral hemorrhage.Additionally,hiPSC-NSC-Exos decreased immune cell infiltration,activated astrocytes,and decreased the secretion of inflammatory cytokines like monocyte chemoattractant protein-1,macrophage inflammatory protein-1α,and tumor necrosis factor-αpost-intracerebral hemorrhage,thereby improving the inflammatory microenvironment.RNA sequencing indicated that hiPSC-NSC-Exo activated the PI3K/AKT signaling pathway in astrocytes and decreased monocyte chemoattractant protein-1 secretion,thereby improving blood-brain barrier integrity.Treatment with the PI3K/AKT inhibitor LY294002 or the monocyte chemoattractant protein-1 neutralizing agent C1142 abolished these effects.In summary,our findings suggest that hiPSC-NSC-Exos maintains blood-brain barrier integrity,in part by downregulating monocyte chemoattractant protein-1 secretion through activation of the PI3K/AKT signaling pathway in astrocytes.
