RESUMEN
Cerebral microbleeds are strongly linked to cognitive dysfunction in the elderly. Iron accumulation plays an important role in the pathogenesis of intracranial hemorrhage. Deferoxamine (DFX), a metal chelator, removes iron overload and protects against brain damage in intracranial hemorrhage. In this study, the protective effects of DFX against microhemorrhage were examined in mice. C57BL6 and Thy-1 green fluorescent protein transgenic mice were subjected to perforating artery microhemorrhages on the right posterior parietal cortex using two-photon laser irradiation. DFX (100 mg/kg) was administered 6 h after microhemorrhage induction, followed by every 12 h for three consecutive days. The water maze task was conducted 7 days after induction of microhemorrhages, followed by measurement of blood-brain barrier permeability, iron deposition, microglial activation, and dendritic damage. Laser-induced multiple microbleeds in the right parietal cortex clearly led to spatial memory disruption, iron deposits, microglial activation, and dendritic damage, which were significantly attenuated by DFX, supporting the targeting of iron overload as a therapeutic option and the significant potential of DFX in microhemorrhage treatment. Irons accumulation after intracranial hemorrhage induced a serious secondary damage to the brain. We proposed that irons accumulation after parietal microhemorrhages impaired spatial cognition. After parietal multiple microhemorrhages, increased irons and ferritin contents induced blood-brain barrier disruption, microglial activation, and further induced dendrites loss, eventually impaired the water maze, deferoxamine treatment protected from these damages.
Asunto(s)
Barrera Hematoencefálica/efectos de los fármacos , Hemorragia Cerebral/tratamiento farmacológico , Deferoxamina/farmacología , Dendritas/efectos de los fármacos , Memoria Espacial/efectos de los fármacos , Animales , Barrera Hematoencefálica/metabolismo , Hemorragia Cerebral/patología , Dendritas/metabolismo , Modelos Animales de Enfermedad , Hierro/metabolismo , Sobrecarga de Hierro , Masculino , Ratones Endogámicos C57BL , Ratones Transgénicos , Sideróforos/farmacologíaRESUMEN
We have previously demonstrated that dl-3n-butylphthalide (NBP) has a potential angiogenic activity. In this study, we investigated the angiogenic effect of NBP and the molecular mechanisms underlying NBP-mediated angiogenesis. Zebrafish embryos and human umbilical vein endothelial cells were treated with various doses of NBP and several signaling pathway inhibitors. NBP induced ectopic subintestinal vessel production in zebrafish embryos and induced invasion, migration, and endothelial cell tube formation of human umbilical vein endothelial cells in a dose-dependent manner. These NBP-induced angiogenic effects were partially suppressed by SU5402, a fibroblast growth factor receptor 1 inhibitor; U0126, an extracellular signal-regulated kinase 1/2 (ERK1/2) inhibitor; LY294002, a phosphatidylinositol 3-kinase inhibitor; 1L6-hydroxymethyl-chiro-inositol-2-(R)-2-O-methyl-3-O-octadecyl-sn-glycerocarbonate, an Akt inhibitor; cavtratin, an endothelial nitric oxide synthase (eNOS) inhibitor and completely inhibited by a combination of U0126 and LY294002. NBP enhanced phosphorylation of ERK1/2 and fibroblast growth factor receptor 2 expression, which were inhibited by U0126. NBP increased the phosphorylation of Akt and eNOS at serine 1177, which was blocked by LY294002. NBP-stimulated nitric oxide production, which was reduced by LY294002. Our data demonstrated that (1) NBP promoted angiogenesis and (2) the angiogenic effects of NBP were mediated by the ERK1/2 and phosphatidylinositol 3-kinase/Akt-eNOS signaling pathways. Our findings suggest that NBP could be a novel agent for therapeutic angiogenesis in ischemic diseases.
Asunto(s)
Benzofuranos/farmacología , Neovascularización Fisiológica/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Transducción de Señal/efectos de los fármacos , Animales , Benzofuranos/administración & dosificación , Relación Dosis-Respuesta a Droga , Células Endoteliales de la Vena Umbilical Humana , Humanos , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Fármacos Neuroprotectores/administración & dosificación , Óxido Nítrico Sintasa de Tipo III/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Fosforilación , Proteínas Proto-Oncogénicas c-akt/metabolismo , Pez Cebra/embriologíaRESUMEN
Cyclotripeptide X-13 is a core of novel marine compound xyloallenoide A isolated from mangrove fungus Xylaria sp. (no. 2508). We found that X-13 dose-dependently induced angiogenesis in zebrafish embryos and in human endothelial cells, which was accompanied by increased phosphorylation of eNOS and Akt and NO release. Inhibition of PI3K/Akt/eNOS by LY294002 or L-NAME suppressed X-13-induced angiogenesis. The present work demonstrates that X-13 promotes angiogenesis via PI3K/Akt/eNOS pathways.
Asunto(s)
Inductores de la Angiogénesis/farmacología , Organismos Acuáticos/química , Neovascularización Fisiológica/efectos de los fármacos , Óxido Nítrico Sintasa de Tipo III/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal/efectos de los fármacos , Inductores de la Angiogénesis/síntesis química , Inductores de la Angiogénesis/química , Inductores de la Angiogénesis/aislamiento & purificación , Animales , Productos Biológicos/síntesis química , Productos Biológicos/química , Productos Biológicos/aislamiento & purificación , Productos Biológicos/farmacología , Línea Celular , Cromonas/farmacología , Células Endoteliales/efectos de los fármacos , Células Endoteliales/metabolismo , Hongos/química , Células Endoteliales de la Vena Umbilical Humana , Humanos , Morfolinas/farmacología , NG-Nitroarginina Metil Éster/farmacología , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa de Tipo III/antagonistas & inhibidores , Inhibidores de las Quinasa Fosfoinosítidos-3 , Fosforilación/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Pez Cebra/metabolismoRESUMEN
1. Whether damage to the blood-brain barrier (BBB) occurs in remote areas after a focal cortical lesion remains unknown. The present study investigated tight junction-related proteins and tight junction microstructure in the ipsilateral thalamus during the acute stage after middle cerebral artery occlusion (MCAO) and cortical aspiration lesion (CAL) in rats. 2. Thirty-six hypertensive and normotensive rats were subjected to MCAO or CAL; another 18 rats in each group were submitted to sham operation. Zonula Occluden (ZO)-1, occludin and albumin were detected by western blotting 12 and 24 h after surgery. Tight junction microstructure was evaluated using electron microscopy, whereas albumin location in the ipsilateral thalamus was determined using double immunostaining for albumin and occludin or albumin and neuronal nuclei (NeuN) 24 h after surgery. 3. Twenty-four hours after MCAO or CAL, occludin expression was reduced to 78.4% and 81.3%, respectively, compared with control. A reduction in ZO-1 expression in the ipsilateral thalamus (to 79%) was seen only after CAL (P < 0.05). Membrane contact at the tight junction was discontinuous in the ipsilateral thalamus in both MCAO and CAL rats. Albumin levels were 23.2% and 82.5% higher in the ipsilateral thalamus after MCAO and CAL, respectively (P < 0.05). The percentage of the albumin-positive area that coincided with the occludin-positive area in the MCAO and CAL groups was 76.8% and 64.6%, respectively, indicating that albumin was mainly localized around the microvessels. 4. The results of the present study suggest that tight junction integrity decreases during the acute stage in the ipsilateral thalamus after MCAO and CAL in rats.
Asunto(s)
Barrera Hematoencefálica/fisiopatología , Corteza Cerebral/fisiopatología , Infarto Cerebral/fisiopatología , Infarto de la Arteria Cerebral Media/fisiopatología , Tálamo/fisiopatología , Uniones Estrechas/patología , Albúminas/metabolismo , Animales , Barrera Hematoencefálica/metabolismo , Corteza Cerebral/metabolismo , Infarto Cerebral/metabolismo , Hipertensión/metabolismo , Hipertensión/fisiopatología , Infarto de la Arteria Cerebral Media/metabolismo , Masculino , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Microvasos/metabolismo , Microvasos/fisiopatología , Ocludina , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , Ratas , Ratas Sprague-Dawley , Tálamo/metabolismo , Uniones Estrechas/metabolismo , Uniones Estrechas/ultraestructura , Proteína de la Zonula Occludens-1RESUMEN
In China, stroke is a major cause of mortality, and long-term physical and cognitive impairment. To meet this challenge, the Ministry of Health China Stroke Prevention Project Committee (CSPPC) was established in April 2011. This committee actively promotes stroke prevention and control in China. With government financial support of 838.4 million CNY, 8.352 million people from 536 screening points in 31 provinces have received stroke screening and follow-up over the last seven years (2012-2018). In 2016, the CSPPC issued a plan to establish stroke centers. To shorten the pre-hospital period, the CSPPC established a stroke center network, stroke map, and stroke "Green Channel" to create three 1-h gold rescue circles, abbreviated as "1-1-1" (onset to call time <1 h; pre-hospital transfer time < 1 h, and door-to-needle time < 1 h). From 2017 to 2018, the median door-to-needle time dropped by 4.0% (95% confidence interval (CI), 1.4-9.4) from 50 min to 48 min, and the median onset-to-needle time dropped by 2.8% (95% CI, 0.4-5.2) from 180 min to 175 min. As of 31 December 2018, the CSPPC has established 380 stroke centers in mainland China. From 1 November 2018, the CSPPC has monitored the quality of stroke care in stroke center hospitals through the China Stroke Data Center Data Reporting Platform. The CSPPC Stroke program has led to a significant improvement in stroke care. This program needs to be further promoted nationwide.
Asunto(s)
Accidente Cerebrovascular , China/epidemiología , Hospitales , Humanos , Accidente Cerebrovascular/epidemiología , Accidente Cerebrovascular/prevención & control , Terapia Trombolítica , Tiempo de TratamientoRESUMEN
Inflammation is a key component of Alzheimer's disease (AD), and we have examined the effect of two polymorphisms (-174G/C and -572C/G) in the promoter of the inflammatory cytokine interleukin-6 (IL-6) gene on risk of AD in 318 AD patients. Significant differences in genotype and allele frequencies of -572C/G IL-6 promoter polymorphism were observed between AD patients and controls. The GG genotype was associated with a decreased risk of developing AD (OR 0.423, 95% CI 0.200-0.894). Similarly, logistic regression analysis revealed that G allele was a protective factor for AD (OR 0.732, 95% CI 0.567-0.945). For -174G/C variability, no C variability was found in all the subjects. The frequency of the IL-6 -174G/C promoter polymorphism is very low or no variability in Henan Han population. The -572C/G polymorphism of IL-6 gene promoter region is associated with AD, and G allele is an independent protective factor for AD.
Asunto(s)
Enfermedad de Alzheimer/genética , Interleucina-6/genética , Polimorfismo Genético , Regiones Promotoras Genéticas , Anciano de 80 o más Años , Pueblo Asiatico/genética , China , Femenino , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Modelos Logísticos , Masculino , Oportunidad Relativa , Análisis de Secuencia de ADNRESUMEN
OBJECTIVE: To investigate the damage within the ventroposterior nucleus (VPN) of the thalamus after focal cortical infarction and its mechanism, and explore the effect of ebselen on the oxidative damage after cerebral cortex infarction in hypertensive rats. METHODS: Middle cerebral artery occlusion (MCAO) was induced in stroke-prone renovascular hypertensive rats (RHRSP), and the rats were divided into four groups by table of random number: sham operation group, model group, vehicle group and ebselen group, each group consisted of 8 rats. In animals subjected to sham surgery the middle cerebral artery was exposed only. Ebselen (5 ml/kg) or vehicle (a mixed solvent consisting of 0.5% carboxymethyl cellulose and 0.02% Tween 20, 5 ml/kg) was given by gastric gavage starting 24 hours after cerebral cortical infarction. Two weeks after the MCAO, the rats were sacrificed, and VPN from each group was sectioned and stained with hematoxylin-eosin (HE), and apurinic/apyrimidinic endonuclease (APE) and Escherichia coli MutY DNA glycosylase (MYH) were determined by immunohistochemistry. RESULTS: HE staining showed that ebselen ameliorated the VPN damage induced by ischemia. Immunohistochemical imaging analysis revealed a distinct nuclear staining of APE and nuclear and cytoplasm distribution of MYH in the entire region of the VPN. Compared with sham operation group, the number of APE and MYH positive cells decreased in model group and vehicle group (APE: 57.0±14.7, 49.4±12.5 vs. 101.0±13.6, MYH: 15.0±4.7, 10.4±2.5 vs. 56.0±13.2, all P<0.05). Compared with model group and vehicle group, the number of APE and MYH positive cells increased significantly in ebselen group (APE: 72.2±7.6 vs. 57.0±14.7, 49.4±12.5, MYH: 32.2±7.6 vs. 15.0±4.7, 10.4±2.5, all P<0.05); the difference of the number of APE and MYH positive cells between model group and vehicle group showed no statistical significance. CONCLUSION: After 2 weeks of MCAO, there is a marked decrease of APE and MYH in VPN; ebselen can obviously increase the level of APE and MYH, and ebselen may protect the VPN of the thalamus from damage after focal cortical infarction in rats.
Asunto(s)
Corteza Cerebral/metabolismo , Infarto Cerebral/metabolismo , Enzimas Reparadoras del ADN/metabolismo , Infarto de la Arteria Cerebral Media/metabolismo , Infarto de la Arteria Cerebral Media/patología , Tálamo/metabolismo , Animales , Corteza Cerebral/patología , Infarto Cerebral/patología , Hipertensión , Masculino , Ratas , Ratas Sprague-DawleyRESUMEN
BACKGROUND: Cerebral microbleeds (CMBs) were found in patients with and without hypertension. We aimed to investigate different distribution patterns of CMBs in patients with and without hypertension. METHODS: We examined acute ischemic stroke patients using a standardized MRI protocol that included T(1), T(2) and gradient-echo T(2)*. Clinical and imaging characteristics were collected from all patients. RESULTS: Among 998 patients, CMBs were detected in 273 patients (27.3%). Of these, 62 did not have hypertension (22.7%). The incidence of CMBs among patients without hypertension (62/335, 18.5%) was lower than among those with hypertension (211/663, 31.8%; p < 0.01). The location of CMBs in patients without hypertension was limited to the cortical-subcortical (CSC) region in 40.3% (25/62) compared to 20.4% of those with hypertension (43/211; p = 0.01). No significant difference was found between CMB locations within the intra-CSC region in both groups. The severity of white matter changes and systolic blood pressure on admission were found to be independent predictors for CMBs in patients without hypertension. CONCLUSIONS: CMBs in patients with and without hypertension have different distribution patterns and may have a different pathogenesis. Blood pressure controlling is important in both groups because systolic blood pressure is an independent predictor of CMBs in patients without hypertension.
Asunto(s)
Corteza Cerebral/fisiopatología , Hemorragia Cerebral/complicaciones , Hemorragia Cerebral/fisiopatología , Infarto Cerebral/complicaciones , Infarto Cerebral/fisiopatología , Hipertensión/complicaciones , Hipertensión/fisiopatología , Anciano , Mapeo Encefálico , Corteza Cerebral/irrigación sanguínea , Corteza Cerebral/patología , Hemorragia Cerebral/patología , Infarto Cerebral/patología , Circulación Cerebrovascular , Femenino , Humanos , Interpretación de Imagen Asistida por Computador , Imagen por Resonancia Magnética , Masculino , Microcirculación , Selección de Paciente , Análisis de RegresiónRESUMEN
RNA methylation is emerging as an important regulator of gene expression. Dysregulation of methyltransferase that is essential for RNA modification contributes to the development and progression of human cancers. Here we show that methyltransferase-like 1 (METTL1) is upregulated in hepatocellular carcinoma (HCC) and exhibits oncogenic activities via PTEN/AKT signaling pathway. High expression of METTL1 is correlated with larger tumor size, higher serum AFP level, tumor vascular invasion, and poor prognosis in two independent cohorts containing 892 patients with HCC. Multivariate analyses suggest METTL1 as an independent factor for unfavorable overall survival. In vitro studies demonstrate that METTL1 overexpression promotes cell proliferation and migration, whereas its knockdown results in opposite phenotypes. Gene set enrichment analysis (GSEA) indicates PTEN pathway is activated in patients with low METTL1 expression. Ectopic expression of PTEN or inhibition of AKT activity significantly attenuates the METTL1-mediated malignant phenotypes. In clinical samples, METTL1 expression is reversely associated with PTEN expression. Combination of low METTL1 expression and high PTEN expression is significantly correlated with overall survival, more so than either METTL1 or PTEN expression alone. Collectively, our data suggest that METTL1 serves as a promising prognostic biomarker and that targeting METTL1/PTEN axis may provide therapeutic potential in HCC intervention. KEY MESSAGES: METTL1 is upregulated in HCC and correlated with poor outcomes. METTL1 promotes cell proliferation and migration in HCC. METTL1 exerts oncogenic activities via suppression of PTEN signaling.
Asunto(s)
Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Metiltransferasas/metabolismo , Fosfohidrolasa PTEN/metabolismo , Movimiento Celular/genética , Movimiento Celular/fisiología , Proliferación Celular/genética , Proliferación Celular/fisiología , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Inmunohistoquímica , Metiltransferasas/genética , Fosfohidrolasa PTEN/genética , Pronóstico , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal , Análisis de Matrices TisularesRESUMEN
Malignant peripheral nerve sheath tumors (MPNSTs) are unusual and aggressive malignant soft-tissue tumors that comprise 5-10% of all soft-tissue sarcomas. Approximately 50% of MPNST cases are associated with neurofibromatosis type-1 (NF-1). As a rare MPNST subset, the epithelioid variant of MPNST (eMPNST) is histologically characterized by the predominant presence of epithelioid tumor cells, and accounts for <5% of all MPNSTs. In addition, eMPNST is rarely associated with NF-1 when compared with conventional MPNST. Although extensive clinicopathological studies have been conducted on eMPNST, clinicians face difficulty when attempting to make an accurate diagnosis. Subsequently, the biological consequences, including recurrence, metastasis and mortality rate in patients with eMPNST remain unclear. The current study presents the case of a 71-year-old woman with eMPNST and a family history of NF-1 in whom tumors had recurred twice on the lower back. A literature search for eMPNSTs was conducted by browsing PubMed and MEDLINE for English-language articles, as well as references from review articles, and revealed 129 published cases. Only 5 cases of eMPNST were associated with NF-1. The studies were retrospectively reviewed and the clinicopathological data of the patients, including tumor site, treatment, follow-up, prognosis, and immunohistochemical positivity were collected.
RESUMEN
Polycomb chromobox (CBX) proteins are involved in gene silencing to function as oncogenes or tumor suppressors through the polycomb repressive complex (PRC1). CBX4 has been implicated in the progression of human cancers, but its role and clinical significance in breast cancer remain unclear. Here, we show that CBX4 is up-regulated in breast cancer and exerts oncogenic activities via miR-137-mediated activation of Notch1 signaling pathway. CBX4 expression was increased in breast cancer, compared with the nontumorous tissues. High CBX4 expression was closely correlated with tumor metastasis, advanced clinical stage and poor overall survival in a cohort of 179 patients with breast cancer. In vitro studies demonstrated that CBX4 overexpression enhanced, whereas CBX4 knockdown inhibited cell growth and migration. Mechanistically, in a PRC1-dependent manner, CBX4 inhibited the promoter activity of miR-137 and suppressed its expression. miR-137 decreased the expression of Notch1, Jag1 and Hey2 via targeting their 3'-UTRs. The suppression of Notch1 by siRNA or overexpression of miR-137 markedly attenuated CBX4-promoted phenotypes. Collectively, these findings indicate that CBX4 promotes breast cancer via miR-137-mediated Notch1 signaling. Our data, therefore, suggest that CBX4 serve as a prognostic biomarker and that targeting CBX4/miR-137 axis may provide therapeutic potent in the treatment of breast cancer.
Asunto(s)
Neoplasias de la Mama/metabolismo , Mama/metabolismo , Regulación Neoplásica de la Expresión Génica , Ligasas/metabolismo , MicroARNs/antagonistas & inhibidores , Proteínas del Grupo Polycomb/metabolismo , Receptor Notch1/agonistas , Transducción de Señal , Animales , Mama/enzimología , Mama/patología , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/patología , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Estudios de Cohortes , Femenino , Humanos , Ligasas/antagonistas & inhibidores , Ligasas/genética , Metástasis Linfática , Masculino , Ratones Endogámicos BALB C , MicroARNs/metabolismo , Clasificación del Tumor , Proteínas de Neoplasias/agonistas , Proteínas de Neoplasias/antagonistas & inhibidores , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Estadificación de Neoplasias , Trasplante de Neoplasias , Proteínas del Grupo Polycomb/antagonistas & inhibidores , Proteínas del Grupo Polycomb/genética , Interferencia de ARN , ARN Neoplásico/antagonistas & inhibidores , ARN Neoplásico/metabolismo , Receptor Notch1/antagonistas & inhibidores , Receptor Notch1/genética , Receptor Notch1/metabolismo , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo , Análisis de Supervivencia , Carga TumoralRESUMEN
The purpose of the study is to establish a model of cold-induced stroke in hypertensive rats, and to study the preventive effect of dl-3n-butylphthalide ( NBP ) on stroke. Stroke-prone renovascular hypertension(RHRSP) was created in Sprague-Dawley rats. The animals were assigned randomly to NBP, aspirin treated and vehicle control group, with administration of the medications for 7 days, and then subjected to cold treatment in an environmentally controlled chamber for 3 days to induce the occurrence of stroke. The incidence of stroke, the volume of the brain lesion, patency of the microvessels by FITC-dextran perfusion and the number of microvessels by immunohisochemical detection of vwF were investigated. Cold induced different types of stroke in RHRSP. The incidence of ischemic stroke and the volume of the infarct were decreased, and the perfused microvessels were increased with NBP pretreatment. Our data suggest that NBP prevents cold-induced ischemic stroke via improvement of cerebral microvessels.
Asunto(s)
Benzofuranos/uso terapéutico , Arterias Cerebrales/efectos de los fármacos , Hipertensión Renal/complicaciones , Microcirculación/efectos de los fármacos , Accidente Cerebrovascular/prevención & control , Animales , Aspirina/uso terapéutico , Benzofuranos/química , Encéfalo/irrigación sanguínea , Encéfalo/patología , Encéfalo/fisiopatología , Isquemia Encefálica/tratamiento farmacológico , Isquemia Encefálica/fisiopatología , Isquemia Encefálica/prevención & control , Arterias Cerebrales/patología , Arterias Cerebrales/fisiopatología , Circulación Cerebrovascular/efectos de los fármacos , Circulación Cerebrovascular/fisiología , Frío/efectos adversos , Dextranos , Modelos Animales de Enfermedad , Fluoresceína-5-Isotiocianato/análogos & derivados , Hipertensión Renal/fisiopatología , Masculino , Microcirculación/patología , Microcirculación/fisiopatología , Estructura Molecular , Fármacos Neuroprotectores/química , Fármacos Neuroprotectores/uso terapéutico , Ratas , Ratas Sprague-Dawley , Accidente Cerebrovascular/fisiopatología , Resultado del TratamientoRESUMEN
Age is characterized by chronic inflammation, leading to synaptic dysfunction and dementia because the clearance of protein waste is reduced. The clearance of proteins depends partly on the permeation of the blood-brain barrier (BBB) or on the exchange of water and soluble contents between the cerebrospinal fluid (CSF) and the interstitial fluid (ISF). A wealth of evidence indicates that physical exercise improves memory and cognition in neurodegenerative diseases during aging, such as Alzheimer's disease (AD), but the influence of physical training on glymphatic clearance, BBB permeability and neuroinflammation remains unclear. In this study, glymphatic clearance and BBB permeability were evaluated in aged mice using in vivo two-photon imaging. The mice performed voluntary wheel running exercise and their water-maze cognition was assessed; the expression of the astrocytic water channel aquaporin 4 (AQP4), astrocyte and microglial activation, and the accumulation of amyloid beta (Aß) were evaluated with immunofluorescence or an enzyme-linked immunosorbent assay (ELISA); synaptic function was investigated with Thy1-green fluorescent protein (GFP) transgenic mice and immunofluorescent staining. Voluntary wheel running significantly improved water-maze cognition in the aged mice, accelerated the efficiency of glymphatic clearance, but which did not affect BBB permeability. The numbers of activated astrocytes and microglia decreased, AQP4 expression increased, and the distribution of astrocytic AQP4 was rearranged. Aß accumulation decreased, whereas dendrites, dendritic spines and postsynaptic density protein (PSD95) increased. Our study suggests that voluntary wheel running accelerated glymphatic clearance but not BBB permeation, improved astrocytic AQP4 expression and polarization, attenuated the accumulation of amyloid plaques and neuroinflammation, and ultimately protected mice against synaptic dysfunction and a decline in spatial cognition. These data suggest possible mechanisms for exercise-induced neuroprotection in the aging brain.
RESUMEN
BACKGROUND: There are no reports on exnografting cultured human fetal neocortical cells in this infracted cavities of adult rat brains. This study was undertaken to observe whether cultured human cortical neurons and astrocytes can survive and grow in the infarcted cavities of adult rat brains and whether they interconnect with host brains. METHODS: The right middle cerebral artery was ligated distal to the striatal branches in 16 adult stroke-prone renovascular hypertensive rats. One week later, cultured cells from human embryonic cerebral cortexes were stereotaxically transferred to the infarcted cavity of 11 rats. The other 5 rats receiving sham transplants served as controls. For immunosuppression, all transplanted rats received intraperitoneal injection of cyclosporine A daily starting on the day of grafting. Immunohistochemistry for glial fibrillary acidic protein (GFAP), synaptophysin, neurofilament, and microtubule associated protein-2 (MAP-2) was performed on brain sections perfused in situ 8 weeks after transplantation. RESULTS: Grafts in the infarcted cavities of 6 of 10 surviving rats consisted of bands of neurons with an immature appearance, bundles of fibers, and GFAP-immunopositive astrocytes, which were unevenly distributed. The grafts were rich in synaptophysin, neurofilament, and MAP2-positive neurons with long processes. The graft/host border was diffuse with dendrites apparently bridging over to the host brain, into which neurofilament immunopositive fibers protruded. CONCLUSION: Cultured human fetal brain cells can survive and grow in the infarcted cavities of immunodepressed rats and integrate with the host brain.
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Astrocitos/trasplante , Encéfalo/patología , Infarto Cerebral/terapia , Trasplante de Tejido Fetal , Neocórtex/citología , Neuronas/trasplante , Animales , Proliferación Celular , Supervivencia Celular , Células Cultivadas , Infarto Cerebral/metabolismo , Infarto Cerebral/patología , Proteína Ácida Fibrilar de la Glía/análisis , Humanos , Proteínas Asociadas a Microtúbulos/análisis , Ratas , Sinaptofisina/análisisRESUMEN
OBJECTIVE: To explore the effects of intraventricular injection of EphB2-Fc on activation of inherent neural stem cells after cerebral cortex infarction. METHODS: Stroke-prone renovascular hypertension model was established in 96 SD rats by two-kidney, two-clip method. Middle cerebral artery occlusion (MCAO) model was established in 72 of these 96 stroke-prone renovascular hypertensive rats and the other 24 rats were used as sham operation group. Then the 72 rats were randomly divided into 3 equal groups: cerebral infarction group without any treatment after the MCAO, MCAO + EphB2-Fc group undergoing stereotaxical infusion of EphB2-Fc at the dose of 20 microl x 200 microg/ml into the lateral ventricle 4 days after the distal ligation of right middle cerebral artery, and MCAO + IgG-Fc group undergoing stereotaxical infusion of IgG-Fc at the dose of 20 microl x 200 microg/ml into the lateral ventricle 4 days after the distal ligation of right middle cerebral artery. By the ends of the first and fourth weeks after the MCAO procedure 12 rats from each group were killed and their brains were taken out to undergo in situ hybridization, immunohistochemistry and Western blotting analysis in order to determine the expression of EphB2 protein and mRNA, nestin and polysialic acid-neural cell adhesion molecule (PSA-NCAM). RESULTS: One week after the distal ligation of right middle cerebral artery, the EphB2 protein and mRNA expression levels in the ipsilateral cortex and subventricular zone (SVZ) of the cerebral infraction group were both lower than those of the sham operation group (P < 0.05), such levels of the MCAO + EphB2-Fc group were higher than those of the MCAO + IgG-Fc group (both P < 0.05), but there was no significant difference between the cerebral infraction group and IgG-Fc group (both P > 0.05), and there were no differences in such levels between the cerebral infarction group and MCAO + IgG-Fc group (both P > 0.05); the nestin and PSA-NCAM expression levels in the ipsilateral SVZ of the cerebral infraction group were both higher than those of the sham operation group (both P < 0.05), such levels of the MCAO + EphB2-Fc group were both higher than those of the MCAO + IgG-Fc group (both P < 0.05), and migration of PSA-NCAM positive cells to corpus callosum could be seen. Four weeks after, there were no significant differences in the expression levels of EphB2 protein and mRNA among different groups (all P > 0.05), the nestin and PSA-NCAM expression levels in the ipsilateral SVZ decreased in all groups, there were no significant differences in the expression of nestin among all groups, but the PSA-NCAM expression in the ipsilateral SVZ of the cerebral infraction group was still higher than that of the sham operation group. CONCLUSION: Disruption of EphB2 signal promotes the proliferation and migration of endogenous neural stem cells in the SVZ after cerebral cortex infarction.
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Infarto Cerebral , Hipertensión , Infarto de la Arteria Cerebral Media , Células-Madre Neurales/citología , Receptor EphB2/farmacología , Animales , Corteza Cerebral/citología , Corteza Cerebral/fisiopatología , Proteínas del Tejido Nervioso/farmacología , Ratas , Ratas Sprague-DawleyRESUMEN
AIMS: Cerebrovascular white matter lesion (WML) is a major subtype of cerebral small vessel disease. Clinical drugs are not available for WML. We investigated whether peroxisome proliferator-activated receptor-γ agonist pioglitazone, with properties of vascular protection and antiinflammation, exerts beneficial effect in hypertensive WML rats. METHODS: Stroke-prone renovascular hypertensive rats (RHRSP) were treated with pioglitazone for 12 weeks. Morris water maze experiment was conducted to assess cognition. WML was observed by Luxol fast blue staining. Smooth muscle actin-alpha, collagen I, collagen IV, glial fibrillary acidic protein, and ionized calcium-binding adaptor molecule-1 were evaluated by immunohistochemistry. Interleukin-1 beta (IL-1ß) and tumor necrosis factor alpha (TNF-α) in brain and soluble intercellular adhesion molecule-1 (sICAM-1) in serum were detected. RESULTS: Pioglitazone significantly attenuated WML in corpus callosum, caudate putamen, external capsule, and internal capsule. Cognitive impairment in RHRSP was ameliorated by pioglitazone. Pioglitazone attenuated arteriolar remodeling and reduced sICAM-1 level in serum. Pioglitazone decreased the proliferation of microglia and astrocyte and lowered the expression of proinflammatory cytokines IL-1ß and TNF-α in the white matter. CONCLUSIONS: Long-term treatment of pioglitazone has beneficial effect on hypertension-induced WML and cognition decline, which may partly through its effect on attenuation of arteriolar remodeling, endothelial activation, and brain inflammation.
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Encéfalo/efectos de los fármacos , Trastornos del Conocimiento/tratamiento farmacológico , Fármacos Neuroprotectores/farmacología , Nootrópicos/farmacología , Tiazolidinedionas/farmacología , Sustancia Blanca/efectos de los fármacos , Animales , Presión Sanguínea/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/patología , Trastornos del Conocimiento/metabolismo , Trastornos del Conocimiento/patología , Modelos Animales de Enfermedad , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Aprendizaje por Laberinto/fisiología , Neuroinmunomodulación/efectos de los fármacos , Neuroinmunomodulación/fisiología , PPAR gamma/agonistas , PPAR gamma/metabolismo , Pioglitazona , Distribución Aleatoria , Ratas Sprague-Dawley , Sustancia Blanca/metabolismo , Sustancia Blanca/patologíaRESUMEN
BACKGROUND: The objective of this study was to examine the clinical, pathological and genetic features of a family suffering from hereditary endotheliopathy with retinopathy and encephalopathy. METHODS: The index case was male, and his symptoms were detected at 18 years of age. The clinical manifestation included recurrent headache, fever, consciousness disturbances and haemiplegia. Bilateral cerebral hemispheric lesions were detected via MRI as low signals on T1 and high signals on T2 and FLAIR, with moderate enhancement. Video EEG revealed an increase in the slow wave frequency. An EMG displayed neurogenic atrophy. Similar clinical and imaging characteristics were detected in his mother and his uncle. Pathological examinations of the brain, muscle and sural nerve were performed on the index case. Sequence analysis of the TREX1 gene was performed on the index case, his sister and his father. RESULTS: A brain biopsy revealed spongiform alterations as well as inflammatory cell infiltration in a few small vessels. Neurogenic muscular atrophy was detected based on a biopsy of the muscle. Demyelination was detected based on a biopsy of the sural nerve. Electron microscopic examination of the sural nerve revealed thickening and delamination of the basement membrane. No reported TREX1 gene mutation was detected for any of the patients. CONCLUSION: Hereditary endotheliopathy presented with peripheral nerve involvement. Multi-laminar thickening of the basement membrane of the capillaries also appeared in the extracerebral tissue. The involvement of a novel gene should be further examined.
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Encefalopatías/patología , Endotelio Vascular/patología , Nervios Periféricos/patología , Enfermedades de la Retina/patología , Enfermedades Vasculares/patología , Encéfalo/patología , Encefalopatías/genética , Humanos , Masculino , Linaje , Enfermedades de la Retina/genética , Enfermedades Vasculares/genética , Adulto JovenRESUMEN
OBJECTIVE: To explore the changes of mitogen activated protein kinase (MAPK) cascade pathway and anti-stress response of hepatocytes after liver transplantation. METHODS: Ten normal liver specimens and 18 punctured donor liver specimens were divided into 3 groups: A (control:10), B (no rejection:10) and C (acute rejection:8). MAPK, Ras, Jun and heat shock protein 70 (HSP70) were tested immunohistochemically while Ras and HSP70 were tested by in situ hybridization. All sections were subjected to image analysis. RESULTS: Protein expressions of MAPK, Ras and Jun were increased by an ascending order of groups A, B and C. The protein expression of HSP70 was the highest in group B but lower in group C. Expressions of Ras and HSP70 mRNA were consistent with those of protein. CONCLUSIONS: The changes of the MAPK cascade pathway and anti-stress response of hepatocytes after liver transplantation are one of regulation mechanisms for protecting the hepatocytes from damage after liver transplantation. This mechanism is active to support individual survival
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Rechazo de Injerto/fisiopatología , Trasplante de Hígado , Sistema de Señalización de MAP Quinasas/fisiología , Estrés Fisiológico/fisiopatología , Expresión Génica , Proteínas HSP70 de Choque Térmico/genética , Proteínas HSP70 de Choque Térmico/metabolismo , Humanos , Inmunohistoquímica , Proteínas Proto-Oncogénicas c-jun/metabolismo , Proteínas ras/genética , Proteínas ras/metabolismoRESUMEN
OBJECTIVE: Endothelial regeneration is an essential process for the prevention of excessive neointimal formation following endothelial denudation. Beclin 1, a mammalian autophagy gene, is a link between autophagy and apoptosis. We hypothesized that the interference of Beclin 1 can influence re-endothelialization and ultimately affect neointimal formation by regulating autophagy and apoptosis. METHODS: A rat carotid injury model of endothelial denudation was used, and small interfering RNA of Beclin 1 was perivascularly administered. Neointima was evaluated by morphological analysis. von Willebrand factor, Beclin 1, LC3, autophagic substrate p62 and caspase-3 levels were detected by immunofluorescence or Western blotting. Terminal deoxynucleotidyl transferase-mediated digoxigenin-dUTP-biotin nick-end labeling assay was performed to evaluate apoptosis. RESULTS: Carotid injury induced an upregulation of Beclin 1 protein which was down regulated by more than 50% with small RNA interference. Beclin 1 knockdown significantly retarded re-endothelialization 7 days after injury and subsequently augmented neointima by more than 2 folds at 14 and 21 days. Autophagy and apoptosis were detected to reveal the regulatory effect of Beclin 1. The injury-activated autophagy, shown by the increased levels of punctate LC3 and LC3II as well as decreased p62 expression, was significantly inhibited by Beclin 1 knockdown. Meanwhile, the apoptotic endothelial cell number was increased and caspase-3 was up-regulated, though the expression of truncated BID was not significantly influenced. CONCLUSION: Beclin 1 knockdown exacerbated neointimal formation after rat carotid injury, associated with retarded re-endothelialization due to enhanced apoptosis, while simultaneously prohibiting autophagic activation. The data suggested an essential role of Beclin 1 as a regulator between autophagy and apoptosis in the setting of neointimal formation.
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Proteínas Reguladoras de la Apoptosis/metabolismo , Autofagia , Traumatismos de las Arterias Carótidas/patología , Regulación de la Expresión Génica , Neointima , Animales , Apoptosis , Proteínas Reguladoras de la Apoptosis/genética , Beclina-1 , Caspasa 3/metabolismo , Endotelio Vascular/patología , Proteínas de Choque Térmico/metabolismo , Masculino , Proteínas Asociadas a Microtúbulos/metabolismo , ARN Interferente Pequeño/metabolismo , Ratas , Ratas Sprague-Dawley , Proteína Sequestosoma-1 , Factor de von Willebrand/metabolismoRESUMEN
Focal cerebral infarction causes secondary damage in the ipsilateral ventroposterior thalamic nucleus (VPN). Chondroitin sulfate proteoglycans (CSPGs) are a family of putative inhibitory components, and its degradation by chondroitinase ABC (ChABC) promotes post-injury neurogenesis. This study investigated the role of ChABC in the primary and secondary injury post stroke in hypertension. Renovascular hypertensive Sprague-Dawley rats underwent middle cerebral artery occlusion (MCAO), and were subjected to continuous intra-infarct infusion of ChABC (0.12 U/d for 7 days) 24 h later. Neurological function was evaluated by a modified neurologic severity score. Neurons were counted in the peri-infarct region and the ipsilateral VPN 8 and 14 days after MCAO by Nissl staining and NeuN labeling. The expressions of CSPGs, growth-associated protein-43 (GAP-43) and synaptophysin (SYN) were detected with immunofluorescence or Western blotting. The intra-infarct infusion of ChABC, by degrading accumulated CSPGs, rescued neuronal loss and increased the levels of GAP-43 and SYN in both the ipsilateral cortex and VPN, indicating enhancd neuron survival as well as augmented axonal growth and synaptic plasticity, eventually improving overall neurological function. The study demonstrated that intra-infarct ChABC infusion could salvage the brain from both primary and secondary injury by the intervention on the neuroinhibitory environment post focal cerebral infarction.