RESUMO
Cerebral aneurysm (CA) represents a significant clinical challenge, characterized by pathological dilation of cerebral arteries. Recent evidence underscores the crucial involvement of immune cells in CA pathogenesis. This study aims to explore the complex interplay between immune cells and CA formation. We analyzed single-cell RNA sequencing data from the GSE193533 dataset, focusing on unruptured CA and their controls. Comprehensive cell-type identification and pseudo-time trajectory analyses were conducted to delineate the dynamic shifts in immune cell populations. Additionally, a two-sample Mendelian randomization (MR) approach was employed to investigate the causal influence of various immunophenotypes on CA susceptibility and the reciprocal effect of CA formation on immune phenotypes. Single-cell transcriptomic analysis revealed a progressive loss of vascular smooth muscle cells (VSMCs) and an increase in monocytes/macrophages (Mo/MΦ) and other immune cells, signifying a shift from a structural to an inflammatory milieu in CA evolution. MR analysis identified some vital immunophenotypes, such as CD64 on CD14+ CD16+ monocytes (OR: 1.236, 95% CI: 1.064-1.435, Pâ =â 0.006), as potential risk factors for CA development, while others, like CD28- CD8br %CD8br (OR: 0.883, 95% CI: 0.789-0.988, Pâ =â 0.030), appeared protective. Reverse MR analysis demonstrated that CA formation could modulate specific immunophenotypic expressions, highlighting a complex bidirectional interaction between CA pathology and immune response. This study underscores the pivotal role of immune cells in this process through the integration of single-cell transcriptomics with MR analysis, offering a comprehensive perspective on CA pathogenesis, and potentially guiding future therapeutic strategies targeting specific immune pathways.
Assuntos
Aneurisma Intracraniano , Análise da Randomização Mendeliana , Monócitos , Análise de Célula Única , Transcriptoma , Aneurisma Intracraniano/genética , Aneurisma Intracraniano/imunologia , Humanos , Análise de Célula Única/métodos , Transcriptoma/imunologia , Monócitos/imunologia , Macrófagos/imunologia , Perfilação da Expressão Gênica , Músculo Liso Vascular/imunologia , ImunofenotipagemRESUMO
Subdural hematoma (SDH) drains into the extracranial lymphatic system through the meningeal lymphatic vessels (mLVs) but the formation of SDH impairs mLVs. Because vitamin D (Vit D) can protect the endothelial cells, we hypothesized that Vit D may enhance the SDH clearance. SDH was induced in Sprague-Dawley rats and treated with Vit D or vehicle. Hematoma volume in each group was measured by H&E staining and hemoglobin quantification. Evans blue (EB) quantification and red blood cells injection were used to evaluated the drainage of mLVs. Western blot analysis and immunofluorescence were conducted to assess the expression of lymphatic protein markers. We also examined the inflammatory factors levels in subdural space by ELISA. Vit D treatment significantly reduced SDH volume and improved the drainage of SDH to cervical lymph nodes. The structure of mLVs in SDH rats were protected by Vit D, and the expressions of LYVE1, PROX1, FOXC2, and VE-cadherin were increased after Vit D treatment. The TNF-α, IL-6, and IL-8 levels were reduced in Vit D group. In vitro, Vit D also increased the VE-cadherin expression levels under inflammation. Vit D protects the structure of mLVs and enhances the absorption of SDH, partly by the anti-inflammatory effect of Vit D.
RESUMO
PURPOSE: To develop and validate a prediction model based on imaging data for the prognosis of mild chronic subdural hematoma undergoing atorvastatin treatment. METHODS: We developed the prediction model utilizing data from patients diagnosed with CSDH between February 2019 and November 2021. Demographic characteristics, medical history, and hematoma characteristics in non-contrast computed tomography (NCCT) were extracted upon admission to the hospital. To reduce data dimensionality, a backward stepwise regression model was implemented to build a prognostic prediction model. We calculated the area under the receiver operating characteristic curve (AUC) of the prognostic prediction model by a tenfold cross-validation procedure. RESULTS: Maximum thickness, volume, mean density, morphology, and kurtosis of the hematoma were identified as the most significant predictors of good hematoma dissolution in mild CSDH patients undergoing atorvastatin treatment. The prediction model exhibited good discrimination, with an area under the curve (AUC) of 0.82 (95% confidence interval [CI], 0.74-0.90) and good calibration (p = 0.613). The validation analysis showed the AUC of the final prognostic prediction model is 0.80 (95% CI 0.71-0.86) and it has good prediction performance. CONCLUSION: The imaging data-based prediction model has demonstrated great prediction accuracy for good hematoma dissolution in mild CSDH patients undergoing atorvastatin treatment. The study results emphasize the importance of imaging data evaluation in the management of CSDH patients.
Assuntos
Atorvastatina , Hematoma Subdural Crônico , Tomografia Computadorizada por Raios X , Humanos , Atorvastatina/uso terapêutico , Feminino , Hematoma Subdural Crônico/diagnóstico por imagem , Hematoma Subdural Crônico/tratamento farmacológico , Masculino , Tomografia Computadorizada por Raios X/métodos , Idoso , Prognóstico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Pessoa de Meia-Idade , Estudos Retrospectivos , Idoso de 80 Anos ou mais , Valor Preditivo dos TestesRESUMO
BACKGROUND: The Cisternostomy is a novel surgical concept in the treatment of Traumatic Brain Injury (TBI), which can effectively drain the bloody cerebrospinal fluid from the skull base cistern, reduce the intracranial pressure, and improve the return of bone flap, but its preventive role in post-traumatic hydrocephalus (PTH) is unknow. The purpose of this paper is to investigate whether Cisternostomy prevents the occurrence of PTH in patients with moderate and severe TBI. METHODS: A retrospective analysis of clinical data of 86 patients with moderate and severe TBI from May 2019 to October 2021 was carried out in the Brain Trauma Center of Tianjin Huanhu Hospital. Univariate analysis was performed to examine the gender, age, preoperative Glasgow Coma Scale (GCS) score, preoperative Rotterdam CT score, decompressive craniectomy rate, intracranial infection rate, the incidence of subdural fluid, and incidence of hydrocephalus in patients between the Cisternostomy group and the non-Cisternostomy surgery group. we also analyzed the clinical outcome indicators like GCS at discharge,6 month GOS-E and GOS-E ≥ 5 in two groups.Additionaly, the preoperative GCS score, decompressive craniectomy rate, age, and gender of patients with PTH and non hydrocephalus were compared. Further multifactorial logistic binary regression was performed to explore the risk factors for PTH. Finally, we conducted ROC curve analysis on the statistically significant results from the univariate regression analysis to predict the ability of each risk factor to cause PTH. RESULTS: The Cisternostomy group had a lower bone flap removal rate(48.39% and 72.73%, p = 0.024)., higer GCS at discharge(11.13 ± 2.42 and 8.93 ± 3.31,p = 0.000) and better 6 month GOS-E(4.55 ± 1.26 and 3.95 ± 1.18, p = 0.029)than the non-Cisternostomy group However, there was no statistical difference in the incidence of hydrocephalus between the two groups (25.81% and 30.91%, p = 0.617). Moreover, between the hydrocephalus group and no hydrocephalus group,there were no significant differences in the incidence of gender, age, intracranial infection, and subdural fluid. While there were statistical differences in peroperative GCS score, Rotterdam CT score, decompressive craniectomy rate, intracranial infection rate, and the incidence of subdural fluid in the two groups, there was no statistical difference in the percentage of cerebral cisterns open drainage between the hydrocephalus group and no hydrocephalus group (32.00% and 37.70%, p = 0.617). Multifactorial logistic binary regression analysis results revealed that the independent risk factors for PTH were intracranial infection (OR = 18.460, 95% CI: 1.864-182.847 p = 0.013) and subdural effusion (OR = 10.557, 95% CI: 2.425-35.275 p = 0.001). Further, The ROC curve analysis showed that peroperative GCS score, Rotterdam CT score and subdural effusion had good ACU(0.785,0.730,and 0.749), with high sensitivity and specificity to predict the occurrence of PTH. CONCLUSIONS: Cisternostomy may decrease morbidities associated with removal of the bone flap and improve the clinical outcome, despite it cannot reduce the disability rate in TBI patients.Intracranial infection and subdural fluid were found to be the independent risk factors for PTH in patients with TBI,and the peroperative GCS score, Rotterdam CT score and subdural effusion had higher sensitivity and specificity to predict the occurrence of PTH. And more importantly, no correlation was observed between open drainage of the cerebral cisterns and the occurrence of PTH, indicating that Cisternostomy may not be beneficial in preventing the occurrence of PTH in patients with moderate and severe TBI.
Assuntos
Lesões Encefálicas Traumáticas , Hidrocefalia , Humanos , Masculino , Feminino , Lesões Encefálicas Traumáticas/cirurgia , Lesões Encefálicas Traumáticas/complicações , Pessoa de Meia-Idade , Adulto , Hidrocefalia/cirurgia , Hidrocefalia/etiologia , Hidrocefalia/prevenção & controle , Estudos Retrospectivos , Craniectomia Descompressiva/métodos , Idoso , Complicações Pós-Operatórias/prevenção & controle , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/epidemiologia , Adulto Jovem , Escala de Coma de GlasgowRESUMO
Electrical stimulation of the right median nerve can aid coma arousal after traumatic brain injury (TBI). This study aimed to confirm the efficacy further and explore possible mechanisms of right median nerve electrical stimulation (RMNS). Five comatose patients after severe TBI from May to September 2020 in the Tianjin Medical University General Hospital received RMNS for 2 weeks besides standard management. After the 2-week treatment, the mean Glasgow Coma Scale (GCS) and neurophysiological examination were used. We then investigated the alterations in microRNA (miRNA) expression in cerebrospinal fluid (CSF) by high-throughput whole transcriptome sequencing, analyzed the data by Gene Ontology (GO) and pathway analysis, and constructed the miRNA-target gene network. Patient awareness and brain function showed a more rapid increase after treatment. We also found 38 differently expressed miRNAs, 34 of which were upregulated and 4 downregulated. GO analysis showed a relation of these differentially expressed miRNAs with neuronal growth, repair, and neural signal transmission. The most highly correlated pathways were primarily associated with the tumor necrosis factor (TNF) signaling pathway and dopaminergic synapse. The application of RMNS effectively promoted early awakening in comatose patients with severe TBI. Moreover, differentially expressed miRNAs might reduce neuronal apoptosis and increase dopamine levels by regulating target gene expression, thus participating in the specific biological process after arousal therapy. Our study provided novel targets for further research on the molecular mechanisms of RMNS arousal treatment and a new way to treat neurotraumatic diseases.
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Lesões Encefálicas Traumáticas , MicroRNAs , Lesões Encefálicas Traumáticas/complicações , Lesões Encefálicas Traumáticas/genética , Lesões Encefálicas Traumáticas/metabolismo , Coma/etiologia , Coma/terapia , Escala de Coma de Glasgow , Humanos , Nervo MedianoRESUMO
BACKGROUND: To examine the association between low-density lipoprotein cholesterol (LDL-C) concentrations and the risk of a large hematoma volume after intracerebral hemorrhage (ICH). METHODS: Patients from the Kailuan study (Tangshan, China) who were hospitalized with ICH during 2006 and 2020 were included in this study. The concentration of lipid concentrations, hematoma volume and other clinical characteristics were retrospectively collected and analyzed. Hematoma volumes were measured on the first available brain scan using the ABC/2 method. LDL-C concentrations were obtained from the last physical examination before the occurrence of ICH. LDL-C concentration was categorized into four groups in accordance with the quartiles. Logistic regression was used to assess the association between LDL-C concentrations and the risk of a large hematoma volume of ≥30 ml. A generalized linear regression model was used to analyze the dose-response relationship between LDL-C concentration and hematoma volume. RESULTS: A total of 836 patients with ICH were evaluated. In the Multivariate logistic regression, compared to the second quartile of LDL_C, the first quartile of LDL_C had a significantly higher risk of a large hematoma volume (OR 2.49 [95% CI 1.54-4.01]), and the higher quartile of LDL_C is not associated with higher odds of large hematoma volume. In the generalized linear regression model, the adjusted ß for the association between LDL-C concentration and hematoma volume was 9.46 (95% confidence interval 2.87-16.04), whereas higher LDL-C concentration was not associated with a large hematoma volume. CONCLUSIONS: This study confirmed that low LDL-C concentrations prior to ICH are associated with a higher risk of a large hematoma volume.
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Hemorragia Cerebral , Hematoma , Humanos , LDL-Colesterol , Estudos Retrospectivos , Hemorragia Cerebral/epidemiologia , Hemorragia Cerebral/complicações , Hematoma/etiologia , Hematoma/complicações , NeuroimagemRESUMO
BACKGROUND: Chronic subdural hematoma (CSDH) is a common neurosurgical disease with an increasing incidence. The absorption route of CSDH is not clear. Whether inflammatory factors enter the peripheral blood and cause systemic reactions is unknown. METHODS: We screened 105 CSDH patients and 105 control individuals. Their clinical characteristics and blood routine results were collected and compared. The blood routine changes of CSDH patients before and after treatment were compared. Age-stratified analysis was performed due to age may affect the inflammatory markers. RESULTS: The white blood cell count, absolute neutrophil count, neutrophil percentage, neutrophil-lymphocyte count ratio (NLR), and platelet to lymphocyte count ratio (PLR) of CSDH patients before treatment were within the normal range, while were significantly higher than the control individuals (p < 0.001). The absolute lymphocyte count and lymphocyte percentage of control individuals were higher than those of patients (p < 0.001). The inflammatory cells in patients of different age groups were similar. After the patient was cured, the white blood cell count, the absolute value and percentage of neutrophils decreased (p < 0.05), while the number of monocytes increased. CONCLUSIONS: CSDH caused slight systemic inflammatory responses in the peripheral blood, implying that there is a non-hematologic route for the absorption of hematoma.
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Hematoma Subdural Crônico , Hematoma Subdural Crônico/epidemiologia , Hematoma Subdural Crônico/etiologia , Hematoma Subdural Crônico/cirurgia , Humanos , Contagem de Leucócitos , Contagem de Linfócitos , Linfócitos , Neutrófilos , Estudos RetrospectivosRESUMO
Myelination of axons in the central nervous system (CNS) is a concerted effort between many cell types, resulting in significant cross-talk and communication among cells. Adhesion G protein-coupled receptor ADGRG1 (GPR56) is expressed in all major glial cells and regulates a wide variety of physiological processes by mediating cell-cell and cell-matrix communications. Previous literature has demonstrated the requirement of ADGRG1 in oligodendrocyte precursor cells (OPCs) during developmental myelination. However, it is unknown if ADGRG1 is responsible for myelin formation in a cell-type-specific manner. To that end, here we profiled myelin status in response to deletion of Adgrg1 specifically in OPCs, microglia, astrocytes, and neurons. Interestingly, we find that knocking out Adgrg1 in OPCs significantly decreases OPC proliferation and reduced number of myelinated axons. However, deleting Adgrg1 in microglia, astrocytes, and neurons does not impact developmental myelination. These data support an autonomous functional role for Adgrg1 in OPCs related to myelination.
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Sistema Nervoso Central , Animais , Camundongos , Camundongos Knockout , Bainha de Mielina , Oligodendroglia , Receptores Acoplados a Proteínas G/genéticaRESUMO
BACKGROUND: We have recently showed that atorvastatin (ATO) combined with low dose of dexamethasone (DEX) was more efficacious in treating patients with chronic subdural haematoma (CSDH) than ATO monotherapy. This study was designed to investigate the underlying mechanisms of the improved efficacy of this combined therapy. METHODS: Mass spectrometry was performed to quantitatively detect drugs in haematoma fluids and serum samples from CSDH patients and also in cultured macrophages after treatment with either ATO alone or in combination with DEX. The differentiation and apoptosis of macrophages were evaluated using flow cytometry. The expression of cytokines, chemokines and angiogenesis-related proteins was evaluated using proteome profile arrays, immunoblots and ELISA, respectively. RESULTS: ATO was detected in haematoma fluids and serum samples, whose levels were increased significantly in samples collected from patients treated with both ATO and DEX. ATO was also increased in cultured macrophages treated with ATO and DEX. The numbers of M1-polarized macrophages were higher than the M2 phenotype in the haematoma fluids of patients. Cultured macrophages treated with ATO and DEX had reduced numbers of M1-polarized macrophages, increased numbers of M2-polarized macrophages as compared to monotherapies, and decreased rate of apoptosis induced by high-dose DEX. DEX enhanced the anti-inflammatory and anti-angiogenic activity of ATO by suppressing VEGFA and other inflammatory angiogenic factors. Consistent with the finding, patients responded well to the drug treatments had lower serum levels of VEGFA. CONCLUSIONS: We have shown for the first time that ATO given orally was detected in CSDH haematoma fluids. DEX enhances the anti-inflammatory and anti-angiogenic effects of ATO, primarily by increasing the presence of ATO in haematoma and macrophages and by regulating the functions of macrophages.
Assuntos
Dexametasona , Macrófagos , Atorvastatina/farmacologia , Atorvastatina/uso terapêutico , Dexametasona/farmacologia , Dexametasona/uso terapêutico , Glucocorticoides/farmacologia , Humanos , Inflamação/metabolismo , Macrófagos/metabolismoRESUMO
Repetitive mild traumatic brain injury (rmTBI) is considered to be an important risk factor for long-term neurodegenerative disorders such as Alzheimer's disease, which is characterized by ß-amyloid abnormalities and impaired cognitive function. Microglial exosomes have been reported to be involved in the transportation, distribution, and clearance of ß-amyloid in Alzheimer's disease. However, their impacts on the development of neurodegeneration after rmTBI are not yet known. The role of miRNAs in microglial exosomes on regulating post-traumatic neurodegeneration was investigated in the present study. We demonstrated that miR-124-3p level in microglial exosomes from injured brain was significantly altered in the acute, sub-acute, and chronic phases after rmTBI. In in vitro experiments, microglial exosomes with upregulated miR-124-3p (EXO-124) alleviated neurodegeneration in repetitive scratch-injured neurons. The effects were exerted by miR-124-3p targeting Rela, an inhibitory transcription factor of ApoE that promotes the ß-amyloid proteolytic breakdown, thereby inhibiting ß-amyloid abnormalities. In mice with rmTBI, the intravenously injected microglial exosomes were taken up by neurons in injured brain. Besides, miR-124-3p in the exosomes was transferred into hippocampal neurons and alleviated neurodegeneration by targeting the Rela/ApoE signaling pathway. Consequently, EXO-124 treatments improved the cognitive outcome after rmTBI, suggesting a promising therapeutic strategy for future clinical translation.
Assuntos
Concussão Encefálica/etiologia , Concussão Encefálica/metabolismo , Cognição , Exossomos/metabolismo , MicroRNAs/genética , Microglia/metabolismo , Doenças Neurodegenerativas/etiologia , Animais , Apolipoproteínas E/metabolismo , Concussão Encefálica/patologia , Concussão Encefálica/reabilitação , Biologia Computacional/métodos , Modelos Animais de Doenças , Perfilação da Expressão Gênica , Masculino , Camundongos , Modelos Biológicos , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/patologia , Doenças Neurodegenerativas/reabilitação , Neurônios/metabolismo , Interferência de RNA , Índice de Gravidade de Doença , Transdução de Sinais , Fator de Transcrição RelA/metabolismoRESUMO
Hemangioblastoma (HB) is an abnormal intracranial buildup of blood vessels that exhibit a great potential for hemorrhage. Surgical options are limited, and few medications are available for treatment. We show here by immunohistochemical analysis that HB lesions display highly increased levels of VEGF expression and macrophage/microglia infiltration compared with those in normal brain tissues. In the meantime, TNF superfamily 15 (TNFSF15) (also known as vascular endothelial growth inhibitor), an antiangiogenic cytokine, is highly expressed in normal brain blood vessels but diminished in HB lesions. We set up a brain hemangioma model by using mouse bEnd.3 cells of a T antigen-transformed endothelial cell line that produce a large amount of VEGF. When implanted in mouse brains, these cells form lesions that closely resemble the pathologic characteristics of HB. Retroviral infection of bEnd.3 cells with TNFSF15 leads to inhibition of VEGF production and retardation of hemangioma formation. Similar results are obtained when wild-type bEnd.3 cells are implanted in the brains of transgenic mice overexpressing TNFSF15. Additionally, TNFSF15 treatment results in enhanced pericyte coverage of the blood vessels in the lesions together with reduced inflammatory cell infiltration and decreased hemorrhage. These findings indicate that the ability of TNFSF15 to counterbalance the abnormally highly angiogenic and inflammatory potential of the microenvironment of HB is of therapeutic value for the treatment of this disease.-Yang, G.-L., Han, Z., Xiong, J., Wang, S., Wei, H., Qin, T.-T., Xiao, H., Liu, Y., Xu, L.-X., Qi, J.-W., Zhang, Z.-S., Jiang, R., Zhang, J., Li, L.-Y. Inhibition of intracranial hemangioma growth and hemorrhage by TNFSF15.
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Terapia Baseada em Transplante de Células e Tecidos , Modelos Animais de Doenças , Células Endoteliais/transplante , Hemangioma/prevenção & controle , Hemorragias Intracranianas/prevenção & controle , Membro 15 da Superfamília de Ligantes de Fatores de Necrose Tumoral/genética , Animais , Apoptose , Proliferação de Células , Células Endoteliais/citologia , Hemangioma/metabolismo , Hemangioma/patologia , Humanos , Hemorragias Intracranianas/metabolismo , Hemorragias Intracranianas/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Prognóstico , Células Tumorais Cultivadas , Microambiente Tumoral , Membro 15 da Superfamília de Ligantes de Fatores de Necrose Tumoral/administração & dosagemRESUMO
This study was designed to investigate the effect of low-temperature laminar flow ward (LTLFW) on the Acinetobacter baumannii pneumonia (MDR-ABP) in neurosurgical intensive care unit (NICU) patients. We evaluated whether patients in a LTLFW had significantly improved clinical outcomes as compared to those in nonconstant-temperature NICU (room temperature). The association of temperature with the prevalence of ABP and A. baumannii isolates (ABI) found in NICU patients was specifically investigated. In vitro microbiological experiments were conducted to measure the proliferation, antibiotic sensitivity, and genomic profiles of A. baumannii (AB) that grew in variable temperatures. MDR-ABP patients in LTLFW had significantly improved outcomes than those in the room temperature NICU. In addition, the numbers of ABI were positively associated with mean ambient outdoor temperatures (P = 0.002), with the incidence of ABP and average numbers of ABI among NICU patients being substantially lower in the winter as compared to other seasons. However, there were no significant seasonal variations in the other strains of the top five bacteria. Consistent with these clinical observations, AB growing at 20°C and 25°C had significantly reduced viability and antibiotic resistance compared to those growing at 35°C. The expression of genes related to AB survival ability, drug resistance, and virulence also differed between AB growing at 20°C and those at 35°C. LTLFW is effective in promoting the recovery of MDR-ABP patients because low temperatures reduced the density and virulence of AB and enhanced the efficacy of antibiotics, likely at the genetic level.
Assuntos
Infecções por Acinetobacter/tratamento farmacológico , Antibacterianos/uso terapêutico , Temperatura Baixa , Farmacorresistência Bacteriana Múltipla , Ambiente Controlado , Pneumonia Bacteriana/tratamento farmacológico , Infecções por Acinetobacter/microbiologia , Acinetobacter baumannii/efeitos dos fármacos , Acinetobacter baumannii/genética , Idoso , Feminino , Humanos , Unidades de Terapia Intensiva , Masculino , Testes de Sensibilidade Microbiana , Viabilidade Microbiana , Pessoa de Meia-Idade , Quartos de Pacientes , Estudos Retrospectivos , Resultado do Tratamento , Virulência/efeitos dos fármacosRESUMO
BACKGROUND Endothelial injury is the early pathological change of cerebral aneurysm (CA) formation. In addition to its lipid-lowering activity, atorvastatin (ATR) also reportedly promotes vascular repair via mobilizing endothelial progenitor cells (EPC). Here, we investigated the influence of ATR on vascular worsening after CA induction in rats. MATERIAL AND METHODS Adult male Sprague-Dawley rats were randomly assigned to 3 groups: a control (CTR) group, a CA group, and a CA+ATR treatment group. Circulating EPC level and hematological and lipid profiles were measured 3 months after CA induction. Verhoeff-Van Gieson staining and transmission electron microscopy were performed to assess pathological changes in the artery wall. RT-PCR was also performed to evaluate the expression of inflammation-related genes in the aneurysmal wall. RESULTS ATR significantly restored the impaired level of circulating EPC without changing hematological and lipid profiles 3 months after CA induction. ATR markedly inhibited endothelial injury, media thinning, and CA enlargement, accompanied by reduced vascular inflammation. CONCLUSIONS Our preliminary results demonstrate that the mobilization of EPC and improvement of endothelial function by ATR contribute to the prevention of cerebral aneurysm. Further studies are warranted to investigate the detailed mechanism.
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Atorvastatina/metabolismo , Aneurisma Intracraniano/patologia , Animais , Atorvastatina/farmacologia , Movimento Celular , Modelos Animais de Doenças , Células Progenitoras Endoteliais/efeitos dos fármacos , Células Progenitoras Endoteliais/patologia , Mobilização de Células-Tronco Hematopoéticas/métodos , Aneurisma Intracraniano/tratamento farmacológico , Aneurisma Intracraniano/prevenção & controle , Masculino , Substâncias Protetoras/metabolismo , Ratos , Ratos Sprague-DawleyRESUMO
The nucleotide-binding oligomerization domain (NOD)-like receptor family pyrin domain containing 3 (NLRP3) inflammasome-mediated inflammatory response has emerged as a prominent contributor to the pathophysiological processes of traumatic brain injury (TBI). Recently, a potent, selective, small-molecule NLRP3 inflammasome inhibitor, MCC950, was described. Here, we investigated the effect of MCC950 on inflammatory brain injury and long-term neurological outcomes in a mouse model of TBI. Male C57/BL6 mice were subjected to TBI using the controlled cortical impact injury (CCI) system. Western blotting, flow cytometry, and immunofluorescence assays were utilized to analyze post-traumatic NLRP3 inflammasome expression and determine its cellular source. We found that NLRP3 inflammasome expression was significantly increased in the peri-contusional cortex and that microglia were the primary source of this expression. The effects of MCC950 on mice with TBI were then determined using post-assessments including analyses of neurological deficits, brain water content, traumatic lesion volume, neuroinflammation, blood-brain barrier (BBB) integrity, and cell death. MCC950 treatment resulted in a better neurological outcome after TBI by alleviating brain edema, reducing lesion volume, and improving long-term motor and cognitive functions. The therapeutic window for MCC950 against TBI was as long as 6â¯h. Furthermore, the neuroprotective effect of MCC950 was associated with reduced microglial activation, leukocyte recruitment, and pro-inflammatory cytokine production. In addition, MCC950 preserved BBB integrity, alleviated TBI-induced loss of tight junction proteins, and attenuated cell death. Notably, the efficacy of MCC950 was abolished in microglia-depleted mice. These results indicate that microglia-derived NLRP3 inflammasome may be primarily involved in the inflammatory response to TBI, and specific NLRP3 inflammasome inhibition using MCC950 may be a promising therapeutic approach for patients with TBI.
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Lesões Encefálicas Traumáticas/tratamento farmacológico , Lesões Encefálicas Traumáticas/metabolismo , Compostos Heterocíclicos de 4 ou mais Anéis/uso terapêutico , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Sulfonas/uso terapêutico , Animais , Modelos Animais de Doenças , Furanos , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Indenos , Inflamassomos/antagonistas & inibidores , Inflamassomos/biossíntese , Inflamassomos/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Distribuição Aleatória , Sulfonamidas , Sulfonas/farmacologia , Fatores de Tempo , Resultado do TratamentoRESUMO
Vascular hyperpermeability is critical in ischemic diseases, including stroke and myocardial infarction, as well as in inflammation and cancer. It is well known that the VEGF-VEGFR2 signaling pathways are pivotal in promoting vascular permeability; however, counterbalancing mechanisms that restrict vascular permeability to maintain the integrity of blood vessels are not yet fully understood. We report that TNF superfamily member 15 (TNFSF15), a cytokine largely produced by vascular endothelial cells and a specific inhibitor of the proliferation of these same cells, can inhibit VEGF-induced vascular permeability in vitro and in vivo, and that death receptor 3 (DR3), a cell surface receptor of TNFSF15, mediates TNFSF15-induced dephosphorylation of VEGFR2. Src homology region 2 domain-containing phosphatase-1 (SHP-1) becomes associated with DR3 upon TNFSF15 interaction with the latter. In addition, a protein complex consisting of VEGFR2, DR3, and SHP-1 is formed in response to the effects of TNFSF15 and VEGF on endothelial cells. It is plausible that this protein complex provides a structural basis for the molecular mechanism in which TNFSF15 induces the inhibition of VEGF-stimulated vascular hyperpermeability.-Yang, G.-L., Zhao, Z., Qin, T.-T., Wang, D., Chen, L., Xiang, R., Xi, Z., Jiang, R., Zhang, Z.-S., Zhang, J., Li. L.-Y. TNFSF15 inhibits VEGF-stimulated vascular hyperpermeability by inducing VEGFR2 dephosphorylation.
Assuntos
Células Endoteliais/metabolismo , Membro 15 da Superfamília de Ligantes de Fatores de Necrose Tumoral/farmacologia , Fator A de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Humanos , Permeabilidade , Fosforilação , Membro 15 da Superfamília de Ligantes de Fatores de Necrose Tumoral/metabolismo , Fator de Necrose Tumoral alfaRESUMO
BACKGROUND AND PURPOSE: Although stroke in the young and middle aged accounts for 31% of all strokes in China, the disease burden is unknown. We aimed to determine the secular trends in stroke incidence and the transition of subtypes in rural China over a 24-year period. METHODS: In 1992, 14 920 residents were recruited to participate in the Tianjin Brain Study. Stroke events and all deaths were registered annually. We assessed the trends in incidence of first-ever stroke, including intracerebral hemorrhage and ischemic stroke, among adults aged 35 to 64 years during 1992 to 1999, 2000 to 2007, and 2008 to 2015. The annual proportion of change in stroke incidence was evaluated from 1992 to 2015. RESULTS: The age-standardized incidence of first-ever stroke per 100 000 person-years increased significantly, from 122 in 1992 to 1999, to 215.8 in 2000 to 2007, to 471.8 in 2008 to 2015. The incidence of first-ever stroke increased annually by 11.9% overall (12.4% in men, 9.0% in women, 8.7% for intracerebral hemorrhage, and 10.7% for ischemic stroke; P<0.001). The greatest increases were observed in adults aged 55 to 64 years, with an annual increase of 11.6% for ischemic stroke (10.8% in men and 6.9% in women). However, the proportion of intracerebral hemorrhage has not changed over the past 24 years. CONCLUSIONS: In contrast with that in developed countries, the burden of stroke in China originates primarily from young and middle-aged adults. Thus, control of risk factors in this population is required to reduce the future burden of stroke in China.
Assuntos
Efeitos Psicossociais da Doença , Pobreza/economia , Pobreza/tendências , População Rural/tendências , Acidente Vascular Cerebral/economia , Acidente Vascular Cerebral/epidemiologia , Adulto , China/epidemiologia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Neuroinflammation is an important secondary injury mechanism that has dual beneficial and detrimental roles in the pathophysiology of traumatic brain injury (TBI). Compelling data indicate that statins, a group of lipid-lowering drugs, also have extensive immunomodulatory and anti-inflammatory properties. Among statins, atorvastatin has been demonstrated as a neuroprotective agent in experimental TBI; however, there is a lack of evidence regarding its effects on neuroinflammation during the acute phase of TBI. The current study aimed to evaluate the effects of atorvastatin therapy on modulating the immune reaction, and to explore the possible involvement of peripheral leukocyte invasion and microglia/macrophage polarization in the acute period post-TBI. METHODS: C57BL/6 mice were subjected to TBI using a controlled cortical impact (CCI) device. Either atorvastatin or vehicle saline was administered orally starting 1 h post-TBI for three consecutive days. Short-term neurological deficits were evaluated using the modified neurological severity score (mNSS) and Rota-rod. Brain-invading leukocyte subpopulations were analyzed by flow cytometry and immunohistochemistry. Pro- and anti-inflammatory cytokines and chemokines were examined using enzyme-linked immunosorbent assay (ELISA). Markers of classically activated (M1) and alternatively activated (M2) microglia/macrophages were then determined by quantitative real-time PCR (qRT-PCR) and flow cytometry. Neuronal apoptosis was identified by double staining of terminal deoxynucleotidyl transferase-dUTP nick end labeling (TUNEL) staining and immunofluorescence labeling for neuronal nuclei (NeuN). RESULTS: Acute treatment with atorvastatin at doses of 1 mg/kg/day significantly reduced neuronal apoptosis and improved behavioral deficits. Invasions of T cells, neutrophils and natural killer (NK) cells were attenuated profoundly after atorvastatin therapy, as was the production of pro-inflammatory cytokines (IFN-γ and IL-6) and chemokines (RANTES and IP-10). Notably, atorvastatin treatment significantly increased the proportion of regulatory T cells (Tregs) in both the peripheral spleen and brain, and at the same time, increased their main effector cytokines IL-10 and TGF-ß1. We also found that atorvastatin significantly attenuated total microglia/macrophage activation but augmented the M2/M1 ratio by both inhibiting M1 polarization and enhancing M2 polarization. CONCLUSIONS: Our data demonstrated that acute atorvastatin administration could modulate post-TBI neuroinflammation effectively, via a mechanism that involves altering peripheral leukocyte invasion and the alternative polarization of microglia/macrophages.
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Anti-Inflamatórios/uso terapêutico , Atorvastatina/uso terapêutico , Lesões Encefálicas Traumáticas/tratamento farmacológico , Modelos Animais de Doenças , Fatores Imunológicos/uso terapêutico , Mediadores da Inflamação/antagonistas & inibidores , Animais , Lesões Encefálicas Traumáticas/metabolismo , Lesões Encefálicas Traumáticas/patologia , Mediadores da Inflamação/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BLRESUMO
Aneurysmal subarachnoid hemorrhage still has a high mortality and morbidity despite notable advances in surgical approaches to cerebral aneurysm (CA). We examined the role of aspirin in vascular inflammation and degeneration. CA was induced in male Sprague-Dawley rats by ligating left common carotid artery and bilateral posterior renal arteries with or without aspirin treatment. The right anterior cerebral artery/olfactory artery (ACA/OA) bifurcations were stripped and assessed morphologically after Verhoeff's Van Gieson staining. Blood sample was obtained to examine circulating CD34(+) CD133(+) endothelial progenitor cells (EPCs), platelet aggregation and platelet counts. Macrophages infiltration in aneurysmal wall was evaluated by immunohistochemistry. Expression of matrix metalloproteinase-2 and 9 (MMP-2 and 9), nuclear factor kappa B (NF-κB), macrophage chemoattractant protein-1 (MCP-1) and vascular cell adhesion molecule-1 (VCAM-1) was examined by RT-PCR. 2 months after CA induction, surgically treated rats manifested aneurysmal degeneration in ACA/OA bifurcations. Aspirin-treated rats exhibited a significant decrease in degradation of internal elastic lamina (IEL), medial layer thinning, CA size and macrophages infiltration with reduced expression of MMP-2 and 9 compared with rats in the CA group. RT-PCR demonstrated that the upregulation of NF-κB, MCP-1 and VCAM-1 after CA induction was reversed by aspirin treatment. Aspirin treatment following CA induction increased circulating EPCs to near control levels and reduced platelet aggregation without changing platelet counts. The evidence suggested that aspirin significantly reduced degeneration of aneurysm walls by inhibiting macrophages-mediated chronic inflammation and mobilizing EPCs.
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Aspirina/farmacologia , Aneurisma Intracraniano/patologia , Inibidores da Agregação Plaquetária/farmacologia , Túnica Íntima/efeitos dos fármacos , Animais , Masculino , Ratos , Ratos Sprague-Dawley , Túnica Íntima/patologiaRESUMO
Decompressive craniectomy (DC) is widely used to treat acute subdural haematoma and hemispheric swelling following traumatic brain injury (TBI). The therapeutic effect of DC on severe TBI treatment is still controversial. The aim of our study was to evaluate effectiveness of DC treatment and seek some prognostic predictors. According to the therapy method, we divided the patients into 2 groups: DC group and standard care group. Between 2010 and 2014, a total number of 223 severe TBI patients, containing 112 patients undergoing DC and 111 patients undergoing standard care, were enrolled into the study according to Glasgow Coma Scale (GCS). The long-term prognosis was evaluated by Extended Glasgow Outcome Scale 12 months after discharging from hospital. We used univariate analysis and receiver operating characteristic curves to explore prognostic predictors. The results showed that patients in the DC group had a lower mortality, but there was no statistical significance in long-term prognosis between these 2 groups. It seemed that admission GCS, platelet, neutrophile granulocyte, total protein, and albumin were associated with long-term prognosis in DC group and reactivity of pupils in standard care group. Simultaneously, using the multivariable logistic regression model, we confirmed that admission GCS and albumin were independent prognostic predictors for patients undergoing DC, and reactivity of pupils for those undergoing standard care. Our data suggested that DC was an effective therapy for severe TBI patients in reducing mortality, but it failed to improve long-term prognosis. Through our study, we could comprehend the characteristics of the 2 treatments and provide more scientific individuation therapy for severe TBI patients.
Assuntos
Lesões Encefálicas/cirurgia , Craniectomia Descompressiva/métodos , Adolescente , Adulto , Proteínas Sanguíneas/análise , Hemorragia Encefálica Traumática/cirurgia , Craniectomia Descompressiva/estatística & dados numéricos , Feminino , Seguimentos , Previsões , Escala de Coma de Glasgow , Escala de Resultado de Glasgow , Humanos , Contagem de Leucócitos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Neutrófilos/patologia , Alta do Paciente , Contagem de Plaquetas , Prognóstico , Reflexo Pupilar/fisiologia , Estudos Retrospectivos , Albumina Sérica/análise , Adulto JovemRESUMO
OBJECTIVE: To evaluate the association between serum levels of angiopoietins (Ang) during an early period (within 72 h) and clinical outcomes after aneurysmal subarachnoid haemorrhage (aSAH). METHODS: This prospective study was conducted at Department of Neurosurgery, Tianjin Medical University General Hospital. Blood samples from 37 aSAH patients were collected at 8 h (or < 8 h), 24 h, 72 h after an onset of SAH. The serum levels of Ang-1, Ang-2 and Tie-2 were measured by enzyme-linked immunosorbent assay (ELISA). They were followed up for 3 months by Glasgow outcome score extended (GOSE). Those with GOSE > 5 were counted as a good outcome while those with GOSE ≤ 5 had a poor outcome. RESULTS: A total of 37 patients with aSAH and 39 healthy controls (HC) were enrolled. The aSAH patients showed a significant rise of Ang-1 within 8 h as compared with HC. The outcomes were good (n = 15) and poor (n = 22). Serum Ang-1 at 8 h (or < 8 h), 24 h and 72 h in good outcomers showed significantly higher than that in poor outcomers [(52 ± 24) vs (37 ± 17) mg/L, (62 ± 26) vs (45 ± 17) mg/L, (107 ± 27) vs (72 ± 18) mg/L]. The serum level of Ang-1 at 8 h and 24 h was one of independent risk factors for aSAH patients by multiariable Logistic regression analysis [adjected OR (95% CI) 1.095 (1.015-1.181) and 1.109 (1.016-1.211)] (P < 0.05). High serum level of Ang-1 during an early period (within 72 h) was associated with good outcomers (r = 0.627, P < 0.001). CONCLUSION: The serum levels of angiopoietins are significantly altered in aSAH patients, especially higher in good outcomers. And abnormal levels of angiopoietins may affect early brain injury (EBI) after SAH, structural integrity and recovery of blood-brain barrier (BBB) and long-term outcomes in aSAH patients.