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1.
Theranostics ; 11(16): 7879-7895, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34335970

RESUMO

Rationale: Previous studies have shown that human embryonic stem cell-derived cardiomyocytes improved myocardial recovery when administered to infarcted pig and non-human primate hearts. However, the engraftment of intramyocardially delivered cells is poor and the effectiveness of clinically relevant doses of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) in large animal models of myocardial injury remains unknown. Here, we determined whether thymosin ß4 (Tb4) could improve the engraftment and reparative potency of transplanted hiPSC-CMs in a porcine model of myocardial infarction (MI). Methods: Tb4 was delivered from injected gelatin microspheres, which extended the duration of Tb4 administration for up to two weeks in vitro. After MI induction, pigs were randomly distributed into 4 treatment groups: the MI Group was injected with basal medium; the Tb4 Group received gelatin microspheres carrying Tb4; the CM Group was treated with 1.2 × 108 hiPSC-CMs; and the Tb4+CM Group received both the Tb4 microspheres and hiPSC-CMs. Myocardial recovery was assessed by cardiac magnetic resonance imaging (MRI), arrhythmogenesis was monitored with implanted loop recorders, and tumorigenesis was evaluated via whole-body MRI. Results: In vitro, 600 ng/mL of Tb4 protected cultured hiPSC-CMs from hypoxic damage by upregulating AKT activity and BcL-XL and promoted hiPSC-CM and hiPSC-EC proliferation. In infarcted pig hearts, hiPSC-CM transplantation alone had a minimal effect on myocardial recovery, but co-treatment with Tb4 significantly enhanced hiPSC-CM engraftment, induced vasculogenesis and the proliferation of cardiomyocytes and endothelial cells, improved left ventricular systolic function, and reduced infarct size. hiPSC-CM implantation did not increase incidence of ventricular arrhythmia and did not induce tumorigenesis in the immunosuppressed pigs. Conclusions: Co-treatment with Tb4-microspheres and hiPSC-CMs was safe and enhanced the reparative potency of hiPSC-CMs for myocardial repair in a large-animal model of MI.


Assuntos
Infarto do Miocárdio/terapia , Miócitos Cardíacos/metabolismo , Timosina/farmacologia , Animais , Diferenciação Celular , Proliferação de Células , Células Cultivadas , China , Modelos Animais de Doenças , Células Endoteliais/patologia , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Infarto do Miocárdio/metabolismo , Miocárdio/patologia , Regeneração , Transplante de Células-Tronco/métodos , Suínos , Timosina/metabolismo , Timosina/fisiologia
2.
Oecologia ; 196(1): 27-35, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33825007

RESUMO

Identifying intrinsic and extrinsic sources of variation in life history traits among populations has been well-studied at the post-embryonic stage but rarely at the embryonic stage. To reveal these sources of variation in the developmental success of embryos, we measured the physical characteristics of nest environments and conducted reciprocal egg-swap experiments in two populations of the toad-headed agamid lizard (Phrynocephalus przewalskii), isolated from each other by a mountain range. We determined the effects of population origin and nest environment on embryonic and offspring traits related to developmental success, including incubation period, hatching success, and offspring growth and survival. Females from the northern population constructed deeper nests that were colder and wetter than those from the southern population. Northern embryos had higher hatching success than the southern embryos when incubated at the northern nest environment, but not when they were incubated at the southern nest environment. The southern hatchlings grew faster than the northern hatchlings when incubated at the southern nest environment, but not after incubation at the northern nest environment. These phenomena likely reflect local adaptation of embryonic development to their nest environments among populations in lizards. In addition, the southern hatchlings had higher survivorship than the northern hatchlings regardless of nest environment, suggesting the southern population has evolved a superior phenotype at the hatchling stage to maximize its fitness.


Assuntos
Lagartos , Adaptação Fisiológica , Animais , Desenvolvimento Embrionário , Feminino , Fenótipo , Temperatura
3.
Mol Med Rep ; 22(6): 4725-4733, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33174002

RESUMO

Spinal cord injury (SCI) is a devastating disorder that often results in temporary and/or permanent functional impairment below the injured level. To date, few satisfactory therapeutic strategies are available to treat SCI. Hence, exploring novel strategies for SCI is an essential public health concern. Cell transplantation therapy, which is associated with neuroprotection, immunomodulation, axon regeneration, neuronal relay formation and myelin regeneration, provides a promising therapeutic strategy for SCI. The neuronal stem cell (NSC) preconditioning method is an emerging approach, which facilitates NSC survival and neuronal differentiation after implantation. The aim of the present study was to develop a feasible candidate for cell­based therapy following SCI in rats and to investigate the role of high mobility group box­1 (HMGB1) in NSC activation. The results of the present study showed that transplantation of NSCs, preconditioned with 1 ng/ml HMGB1, facilitated functional improvement of injured spinal cords, as indicated by Basso, Beattie and Bresnahan mean scores, mechanical hypersensitivity and cold stimulation. Meanwhile, the histological examination of hematoxylin and eosin staining indicated that engraftment of HMGB1­preconditioned NSCs resulted in decreased atrophy of the injured spinal cord. Meanwhile, the transplantation of HMGB1­preconditioned NSCs resulted in an increased number of functional Nissl bodies in neurons, as detected by Nissl staining, and an increase in the number of ßIII­tubulin+ cells in the epicenter of injured spinal cords in rats with SCI. In addition, the results also demonstrated that 1 ng/ml HMGB1 promoted the differentiation of NSCs into neurons, and that the ERK signaling pathway played an important role in this process. In conclusion, the present data indicated that the preconditioning strategy with 1 ng/ml HMGB1 may present a feasible candidate for cell­based therapy following SCI in rats, which may enlarge the scope of HMGB1 in NSC activation.


Assuntos
Células-Tronco Neurais/metabolismo , Traumatismos da Medula Espinal/terapia , Transplante de Células-Tronco/métodos , Animais , Axônios/metabolismo , Diferenciação Celular/fisiologia , Sobrevivência Celular/fisiologia , Proteínas HMGB/metabolismo , Proteína HMGB1/metabolismo , Proteína HMGB1/uso terapêutico , Masculino , Atividade Motora/fisiologia , Regeneração Nervosa/fisiologia , Neurônios/metabolismo , Ratos , Ratos Sprague-Dawley , Recuperação de Função Fisiológica/fisiologia , Medula Espinal/metabolismo
4.
Huan Jing Ke Xue ; 41(11): 5027-5036, 2020 Nov 08.
Artigo em Chinês | MEDLINE | ID: mdl-33124246

RESUMO

In this study, the relative molecular weight distribution and fluorescent characteristics of the organic matter in sediments during the thermal stratification of a drinking water reservoir were studied. The nitrogen removal, growth performance, and carbon removal ability of an aerobic denitrifier were investigated when the organic matter in sediments was used as a carbon source. The results found that:① during the stratification period in the drinking water reservoir, the organic matter in sediments has a larger proportion of relative molecular mass>100×103. It can be observed that compared with the relative molecular weight distribution in different months, the percentage of macromolecular organic matter in sediments is the lowest in July (44.62%), showing a characteristic of smaller relative molecular weight; ② the organic matter in sediments of the drinking water reservoir was composed of terrestrial humic-like substance component C1 (250 nm, 425 nm), tryptophan and amino acid-like substances component C2 (230 nm/280 nm, 322 nm), and traditional microbial humic-like substances component C3 (250 nm, 340 nm). Component C2 accounted for a higher percentage, and the organic matter in July showed a higher total fluorescence intensity; ③ during the aerobic denitrification process, organic matter in May displayed better characteristics as an electron donor, while organic matter in July exhibited excellent performance as an energy substance and better denitrification characteristics of the strain WGX-9; ④ the aerobic denitrification performance of the strain WGX-9 can be significantly promoted when the organic matter in sediments is a carbon source, compared with natural organic matter, algae organic matter, and actual water of the drinking water reservoir. This study clarifies the characteristics of the organic matter in sediments during the thermal stratification period of the drinking water reservoir and its effect on an aerobic denitrifier. This will provide a scientific basis for the research of nitrogen pollution control in micro-polluted water sources.


Assuntos
Carbono , Nitrogênio
5.
Arch Oral Biol ; 118: 104875, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32795622

RESUMO

OBJECTIVE: The objective of the present study was to evaluate the accuracy of the Demirjian, Willems, and Nolla methods for dental age estimation on a sample of the northern Chinese population. DESIGN: The study consisted of 2000 panoramic radiographs (1000 boys and 1000 girls) with an age range between 5 and 14 years. The mean error and absolute mean error were calculated according to each method, and the accuracy was statistically analysed. RESULTS: The three methods used for Chinese subjects overestimated the dental age by 1.16, 0.50, and 0.07 years. The absolute mean error was largest in most age groups for the Demirjian method, which was considered inaccurate in age estimation for teenagers, and it was more than 1.00 years for only several age groups for the Willems method and only girls aged 14 years for the Nolla method. The mean error and absolute mean error were lowest for the Nolla method and highest for the Demirjian method. CONCLUSIONS: Although the Demirjian method is frequently used in Chinese subjects for legal and medical purposes, the Willems and Nolla methods were more reliable than the Demirjian method. Among the three methods, the accuracy in the northern Chinese subjects was highest for the Nolla method. Therefore, it is recommended to evaluate the accuracy of different methods before assessing the age in specific populations.


Assuntos
Determinação da Idade pelos Dentes/métodos , Adolescente , Grupo com Ancestrais do Continente Asiático , Criança , Pré-Escolar , China , Feminino , Humanos , Masculino , Radiografia Panorâmica
6.
Huan Jing Ke Xue ; 41(5): 2166-2176, 2020 May 08.
Artigo em Chinês | MEDLINE | ID: mdl-32608834

RESUMO

To explore the effect mechanism of the artificial mixing process on the temporal and spatial succession of algae community structure in a water body, this study used water-lifting aerators to induce in-situ artificial mixing of the water body of Jinpen Reservoir, and in-situ spot physical-chemical parameters and algae of the water body of the reservoir were observed during an artificial mixing process. A total of 51 species of 28 genera of 6 families of algae were identified in the water body of the Jinpen Reservoir. The artificial mixing effect of the water-lifting aerators significantly inhibited the growth of algae in the water, and had a significant impact on the community structure. Before activation of the water-lifting aerators, algae were mainly distributed in the surface water body, and Chlorella vulgaris was the dominant species. With the operation of the water-lifting aerators, the algal density of surface water body decreased significantly, and the vertical distribution of the algae density in the water body tended to be uniform. The dominant species tended to succeed in Cyclotella sp. This study used the method of redundancy analysis, combined with critical depth theory and the characteristics of algae growth, to analyze the relationship between the spatial-temporal succession of algae community structure and the changes in the main physical-chemical parameters in Jinpen Reservoir during the artificial process. The analysis results showed that the artificial mixing of the water-lifting aerators mainly affects the temporal and spatial succession of the algae community structure by rapidly destroying the thermal stratification stability of the water body and significantly increasing the water mixing depth.


Assuntos
Chlorella vulgaris , Diatomáceas , Água , Qualidade da Água
7.
Huan Jing Ke Xue ; 41(5): 2188-2197, 2020 May 08.
Artigo em Chinês | MEDLINE | ID: mdl-32608836

RESUMO

Aerobic anoxygenic photosynthesis bacteria (AAPB) play a significant role in the material circulation of the hydrosphere, with diverse community structure and unique metabolic functions. To investigate the spatial and temporal succession characteristics of AAPB abundance and community structure in Jinpen Reservoir, a quantitative real-time polymerase chain reaction and Illumina MiSeq high-throughput sequencing technique targeting the pufM gene were applied. Furthermore, redundancy analysis was used to determine the influence of environmental factors on their community structure. The results showed that the AAPB abundance ranged from (6.70±0.43)×103 to (2.69±0.15)×104 copies·mL-1, with the maximum value appearing in October, and decreased with an increase in water depth. Samples were mainly classified into 19 genera (except for the unclassified genus); the most abundant AAPB genera were Bradyrhizobium sp. and Methylobacterium sp., which were affiliated to the α-Proteobacteria, and the proportion of the Bradyrhizobium sp. was highest in November, accounting for more than 60% (except 10 m). Furthermore, Rubrivivax sp., belonging to ß-Proteobacteria, was found to have a low proportion. There was a strong interaction relationship between AAPB genera. For example, Rhodobacter sp. was positively correlated with Rhodovulum sp., while Hydrogenophaga sp. was negatively correlated with Bradyrhizobium sp.. The community structure composition and distribution of AAPB were significantly different, mainly affected by temperature (T), total nitrogen (TN), NO3--N, and light intensity and comprehensively regulated by environmental factors. For instance, T, TN, and total phosphorus had a significant impact on the AAPB community structure of water samples at 0, 5, and 15 m in October, whereas light intensity, pH, DO, and chlorophyll-a were major structuring factors in the AAPB assemblages of water samples at 5 m in December. The results have guiding significance for parsing the spatial and temporal variability of AAPB abundance and diversity in stratified reservoirs, and simultaneously provide a theoretical basis for exploring the driving factors of AAPB population structure.

8.
Huan Jing Ke Xue ; 41(7): 3231-3239, 2020 Jul 08.
Artigo em Chinês | MEDLINE | ID: mdl-32608896

RESUMO

In response to the annual hypolimnetic anoxia in stratified reservoirs, water-lifting aerators (WLAs) were used in Jinpen Reservoir to supplement the dissolved oxygen in the bottom water and suppress the release of reduced pollutants from sediment. However, due to the influence of geomorphic characteristics at the bottom of the reservoir, there were some differences in the efficiency of artificial mixing and aeration. After the deactivation of WLAs, the dissolved oxygen in the bottom water of some deeper areas was rapidly depleted, resulting in the re-release of pollutants. To explore the release mechanisms and diffusion intensity of iron and manganese during this period, the representative samples in the main reservoir area were collected to measure the distribution of dissolved iron and manganese in the pore water and overlying water and calculate the diffusive flux of dissolved iron and manganese across the sediment-water interface. The results showed that the bottom water of the lower terrain rapidly entered the anaerobic condition after the system was deactivated, resulting in the release of a large amount of dissolved manganese into the overlying water, the maximum concentration of which was 0.42 mg·L-1. However, the bottom water of the higher terrain briefly entered a state of hypoxia, after which the dissolved oxygen concentration increased rapidly, so the dissolved manganese concentration increased moderately to 0.17 mg·L-1. The distribution of iron and manganese in the pore-water-overlying water showed that the dissolved manganese was released more easily into the overlying water than the iron under anaerobic conditions and constant accumulation in the upper sediments and overlying water. However, the release of dissolved iron was not only suppressed by dissolved oxygen but also by other oxidants such as manganese oxide. The diffusion flux of dissolved manganese declined after the system was deactivated. A mass balance calculation demonstrated that the accumulation of dissolved manganese in the anaerobic layer was not only related to the diffusion flux but also to the sedimentation flux and the thickness of the anaerobic layer. Therefore, the biogeochemical cycle of iron and manganese in the anaerobic layer requires further study.

9.
Chem Biodivers ; 16(11): e1900357, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31573145

RESUMO

The ginger extract obtained with supercritical CO2 fluid was purified by molecular distillation (MD), and the chemical compositions, antioxidant and cytotoxic activities of ginger extract and its distillates were investigated. Analysis revealed that the ginger extract was rich in terpene hydrocarbons, along with oxygenated terpenes and other non-volatile compounds. The MD distillates were prepared in a series of stages and the active compounds like terpenes and gingerols could be separated by MD. The major compounds of the distillates purified by MD at 40 °C, 80 Pa and 60 °C, 80 Pa were terpene hydrocarbons. Additional distillates obtained by MD at 80 °C, 80 Pa and 100 °C, 60 Pa were predominated by terpene hydrocarbons and oxygenated terpenes. Until the operating conditions of MD reached 150 °C and 2 Pa, some non-volatile compounds were concentrated in the final distillate. Moreover, antioxidant activities and the cytotoxic effects on three human cancer cells in final MD distillate were superior to other extracts, and this phenomenon could be mainly supported by the phenols. The MD could be used to prepare ginger distillates with better antioxidant and cytotoxic activities.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Antioxidantes/farmacologia , Compostos de Bifenilo/antagonistas & inibidores , Dióxido de Carbono/química , Gengibre/química , Picratos/antagonistas & inibidores , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Antioxidantes/química , Antioxidantes/isolamento & purificação , Proliferação de Células/efeitos dos fármacos , Destilação , Ensaios de Seleção de Medicamentos Antitumorais , Cromatografia Gasosa-Espectrometria de Massas , Humanos , Extratos Vegetais/isolamento & purificação , Células Tumorais Cultivadas
10.
Circulation ; 138(24): 2798-2808, 2018 12 11.
Artigo em Inglês | MEDLINE | ID: mdl-30030417

RESUMO

BACKGROUND: The adult mammalian heart has limited ability to repair itself after injury. Zebrafish, newts, and neonatal mice can regenerate cardiac tissue, largely by cardiac myocyte (CM) proliferation. It is unknown whether hearts of young large mammals can regenerate. METHODS: We examined the regenerative capacity of the pig heart in neonatal animals (ages 2, 3, or 14 days postnatal) after myocardial infarction or sham procedure. Myocardial scar and left ventricular function were determined by cardiac magnetic resonance imaging and echocardiography. Bromodeoxyuridine pulse-chase labeling, histology, immunohistochemistry, and Western blotting were performed to study cell proliferation, sarcomere dynamics, and cytokinesis and to quantify myocardial fibrosis. RNA-sequencing was also performed. RESULTS: After myocardial infarction, there was early and sustained recovery of cardiac function and wall thickness in the absence of fibrosis in 2-day-old pigs. In contrast, older animals developed full-thickness myocardial scarring, thinned walls, and did not recover function. Genome-wide analyses of the infarct zone revealed a strong transcriptional signature of fibrosis in 14-day-old animals that was absent in 2-day-old pigs, which instead had enrichment for cytokinesis genes. In regenerating hearts of the younger animals, up to 10% of CMs in the border zone of the myocardial infarction showed evidence of DNA replication that was associated with markers of myocyte division and sarcomere disassembly. CONCLUSIONS: Hearts of large mammals have regenerative capacity, likely driven by cardiac myocyte division, but this potential is lost immediately after birth.


Assuntos
Coração/fisiologia , Infarto do Miocárdio/patologia , Animais , Animais Recém-Nascidos , Citocinese/genética , Ecocardiografia , Fibrose , Imagem Cinética por Ressonância Magnética , Infarto do Miocárdio/diagnóstico por imagem , Miocárdio/patologia , Miócitos Cardíacos/fisiologia , Regeneração , Suínos , Troponina I/análise , Função Ventricular Esquerda
11.
PLoS One ; 8(7): e68796, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23861942

RESUMO

It is well-established that hyperthermia increases neuronal death and worsens stroke outcome. However, little is known about the mechanisms of how hyperthermia is involved in this neuronal death process. In the present study, we examined how temperature increase exacerbates neuronal death using a model of chemical ischemia. Chemical ischemia was induced by treating SH-SY5Y neuroblastoma cells with sodium azide and deoxyglucose. Temperature increase was treated by placing the cells at 37°C (control) and 41°C (experimental). Cell survival was determined by trypan blue assay and ATP levels were measured with ATP assay kits. Protein expression was detected by western blot. Treatment with sodium azide resulted in cell death in a dose-responsive manner. Increased temperature worsened the ATP depletion and cell volume shrinkage. Temperature increase also enhanced ER stress as demonstrated by the elevated level of phospho-eIF2α and C/EBP homologous protein (CHOP). Inhibition of CHOP expression significantly decreased sodium azide-induced neuronal death. In addition, the increased temperature intensified the activation of caspase-3, an apoptotic effector protease, and inhibition of capspase-3 significantly reduced cell death. These findings support that temperature increase worsened the neuronal death by depleting intracellular ATP, inducing ER stress response and activating apoptotic signal transduction.


Assuntos
Apoptose/efeitos dos fármacos , Isquemia/induzido quimicamente , Isquemia/patologia , Temperatura , Trifosfato de Adenosina/metabolismo , Caspase 3/metabolismo , Inibidores de Caspase/farmacologia , Linhagem Celular Tumoral , Desoxiglucose/toxicidade , Retículo Endoplasmático/metabolismo , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Ativação Enzimática/efeitos dos fármacos , Espaço Extracelular/metabolismo , Humanos , Espaço Intracelular/metabolismo , Isquemia/enzimologia , Transdução de Sinais , Azida Sódica/toxicidade
12.
Int J Hyperthermia ; 28(1): 24-32, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22235782

RESUMO

PURPOSE: Basal lamina is a major part of the microvascular wall and plays a critical role in the integrity of microvasculature. The aim of this study is to determine whether hyperthermia worsens the destruction of microvascular integrity in the ischaemic injured brain. MATERIALS AND METHODS: Focal cerebral ischaemia was induced by embolising a pre-formed clot into the middle cerebral artery (MCA). Rats received either normothermic or hyperthermic treatment. Neurological score and infarct size were evaluated at 24 h after the MCA occlusion. Microvascular collagen type IV and laminin were measured with fluorescence microscopy. The activities of matrix metalloproteinases (MMP-2 and MMP-9) and plasminogen activators (tPA and uPA) were determined by zymography. RESULTS: Treatment with hyperthermia significantly increased infarct volume (p<0.01), cortex swelling (p<0.01), striatum swelling (p<0.05) and neurologic score (p<0.01) at 24 h after the MCA occlusion. Compared to the normothermic groups, hyperthermia significantly worsened the losses of microvascular basal lamina structure proteins, collagen type IV and laminin, at 6 h (p<0.001) and 24 h (p<0.01) after MCA occlusion. Hyperthermia increased the MMP-9 activity at 6 and 24 h after MCA occlusion compared with normothermia (p<0.05), whereas increased the MMP-2 activity at 6 h only (p<0.05). Hyperthermia also elevated uPA activity significantly at 6 and 24 h after MCA occlusion compared to normothermia (p<0.05). CONCLUSIONS: These results demonstrate that hyperthermia exacerbates the destruction of microvascular integrity possibly by increasing the activities of MMP-2, MMP-9 and uPA in the ischaemic cerebral tissues.


Assuntos
Membrana Basal/irrigação sanguínea , Infarto Encefálico/patologia , Isquemia Encefálica/patologia , Hipertermia Induzida/efeitos adversos , Microvasos/patologia , Animais , Membrana Basal/patologia , Comportamento Animal , Infarto Encefálico/fisiopatologia , Isquemia Encefálica/fisiopatologia , Córtex Cerebral/irrigação sanguínea , Córtex Cerebral/patologia , Colágeno Tipo IV/metabolismo , Corpo Estriado/irrigação sanguínea , Corpo Estriado/patologia , Modelos Animais de Doenças , Laminina/metabolismo , Masculino , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Ativadores de Plasminogênio/metabolismo , Ratos , Ratos Sprague-Dawley
13.
J Neurosci Methods ; 187(1): 8-12, 2010 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-20005255

RESUMO

Cerebrospinal fluid (CSF) is in direct contact with the extracellular space in the central nervous system (CNS), and biological changes in the brain can be reflected in CSF. In the present article, a procedure for collection of CSF in rats is described. The technique quickly and reliably yields large quantities of CSF (50-150 microl) in rats. More importantly, blood contamination of the CSF is avoided. Furthermore, detections of ATP and interleukin (IL)-1 beta in the CSF have been carried out. ATP concentration in the CSF samples was between 8.3 and 15.8 nM, with an average of 10.5+/-0.83 nM (mean+/-SEM). The concentrations of IL-1beta were below the detection limit in the CSF in the laminectomy control rats, but it increased to 0.26+/-0.07 ng/ml at 1h after spinal cord injury. This technique offers an alternative method to surgical cannulation for the collection of CSF in rats.


Assuntos
Líquido Cefalorraquidiano , Cisterna Magna , Manejo de Espécimes/métodos , Trifosfato de Adenosina/líquido cefalorraquidiano , Animais , Sangue , Tronco Encefálico/patologia , Líquido Cefalorraquidiano/química , Ensaio de Imunoadsorção Enzimática , Interleucina-1beta/líquido cefalorraquidiano , Laminectomia , Masculino , Testes Neuropsicológicos , Ratos , Ratos Sprague-Dawley , Traumatismos da Medula Espinal/líquido cefalorraquidiano , Fatores de Tempo
14.
J Neuroimaging ; 20(3): 272-6, 2010 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-19888934

RESUMO

Reperfusion with intravenous tissue plasminogen activator (tPA) has been the goal of therapy for acute ischemic stroke; however, tPA is contraindicated in many patients, has low recanalization rates in major occlusions, and carries a substantial risk of symptomatic intracerebral hemorrhage. In the present study, we hypothesized that partial intra-aortic occlusion of the abdominal aorta would increase salvage of ischemic penumbra and reduce infarct volume after focal embolic stroke in rats. We examined the effects of aortic occlusion on infarct volume, expression and activation of matrix metalloprotease-9, and hemorrhagic transformation with or without treatment with tPA. We then examined the effects of aortic occlusion on perfusion deficits following embolic occlusion. Results showed that partial aortic occlusion significantly reduces brain infarction volume with or without treatment with tPA after focal ischemia, but does not increase risk for hemorrhagic transformation or matrix metalloprotease-9 expression and activation. Partial intra-aortic occlusion also reduces perfusion deficits after focal cerebral ischemia as compared to control. The present study shows that partial intra-aortic occlusion significantly decreases infarction volume and perfusion deficits following ischemic injury in an embolic model of cerebral ischemia. Moreover, combination treatment with tPA and partial intra-aortic occlusion further reduces infarction volume without any increase in hemorrhagic transformation.


Assuntos
Aorta , Oclusão com Balão , Isquemia Encefálica/patologia , Isquemia Encefálica/terapia , Encéfalo/patologia , Análise de Variância , Animais , Encéfalo/metabolismo , Isquemia Encefálica/metabolismo , Masculino , Metaloproteinase 9 da Matriz/metabolismo , Ratos , Ratos Sprague-Dawley
15.
J Cereb Blood Flow Metab ; 29(10): 1683-94, 2009 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-19553906

RESUMO

In this study, we examined whether rosiglitazone, a peroxisome proliferator-activated receptor gamma (PPARgamma) agonist, is neuroprotective in focal ischemic brain injury, and whether rosiglitazone can enhance the protective action of tissue plasminogen activator (tPA), an agent used clinically for thrombolytic therapy. Rats were subjected to ischemic brain injury by embolizing preformed clots into the middle cerebral artery (MCA). Treatment with rosiglitazone reduced infarction and improved functional recovery; it also enhanced the neuroprotective action of tPA and lengthened the time window for initiating tPA treatment. Occlusion of MCA resulted in a loss of collagen type IV, a major structural protein of the microvascular basal lamina, and tPA treatment worsened this loss. Rosiglitazone treatment prevented the reduction of collagen type IV in the ischemic injured brain by inhibiting the activation of matrix metallopeptidase-9 (MMP-9). In addition, rosiglitazone treatment reduced inflammatory reactions in the ischemic injured brain. Rosiglitazone either alone or in combination with tPA is an effective agent in the reduction of ischemic brain injury. The reduction of microvascular damage and inflammation contributes to the beneficial actions of rosiglitazone.


Assuntos
Isquemia Encefálica/tratamento farmacológico , Tiazolidinedionas/farmacologia , Ativador de Plasminogênio Tecidual/farmacologia , Animais , Colágeno Tipo IV/efeitos dos fármacos , Modelos Animais de Doenças , Quimioterapia Combinada , Embolia/complicações , Hipoglicemiantes , Metaloproteinase 9 da Matriz/efeitos dos fármacos , Artéria Cerebral Média , Fármacos Neuroprotetores , PPAR gama/antagonistas & inibidores , Ratos , Rosiglitazona , Tiazolidinedionas/administração & dosagem , Ativador de Plasminogênio Tecidual/administração & dosagem , Resultado do Tratamento
16.
J Neurosurg ; 109(3): 522-9, 2008 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-18759586

RESUMO

OBJECT: Statins have been used for induction of ischemic tolerance after cerebral ischemia. The authors have previously shown that simvastatin is protective after ischemic cerebral injury in normothermic conditions. In this study they further examined whether treatment with simvastatin can reduce ischemic brain injury in a hyperthermic condition. METHODS: Focal ischemic brain injury was induced by embolizing a preformed clot into the middle cerebral artery in rats. The authors initially examined whether treatment with simvastatin could reduce ischemic brain injury without or with hyperthermia. The infarct volume, edema, and neurological deficits were examined. They then studied whether simvastatin could reduce the perfusion deficits, damage to the blood-brain barrier (BBB), and degeneration of neurons in the ischemic injured brain. RESULTS: Simvastatin significantly reduced the infarct volume in both normothermic and hyperthermic conditions, compared with appropriate controls. Concomitantly, this treatment also significantly reduced neurological deficits and brain edema. Administration of simvastatin significantly decreased perfusion deficits, BBB permeability, and degenerated neurons. CONCLUSIONS: These studies suggest that simvastatin is an effective agent for ischemic brain injury not only in normothermic but also in hyperthermic conditions, which may be through the decrease of BBB permeability, degenerated neurons, and perfusion deficits.


Assuntos
Isquemia Encefálica/prevenção & controle , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Hipertermia Induzida , Sinvastatina/administração & dosagem , Animais , Edema Encefálico/patologia , Edema Encefálico/fisiopatologia , Edema Encefálico/prevenção & controle , Isquemia Encefálica/patologia , Isquemia Encefálica/fisiopatologia , Circulação Cerebrovascular , Terapia Combinada , Modelos Animais de Doenças , Masculino , Ratos , Ratos Sprague-Dawley
17.
Exp Neurol ; 213(1): 171-5, 2008 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-18598697

RESUMO

Melagatran is a potent direct thrombin inhibitor and it is an effective agent in the prevention of stroke in patients with atrial fibrillation (AF); however, there are no data about its actions in the treatment of acute ischemic stroke. In the present study, we evaluated the neuroprotective actions of melagatran using an embolic model of stroke in rats. We first examined protective effects at increasing doses of melagatran. Then, we examined the effects of melagatran administered at different time points following middle cerebral artery (MCA) occlusion. We also evaluated the effects of combination therapy with melagatran and tissue plasminogen activator (tPA) in this model. Finally, we examined if melagatran can improve compromised microcirculation in the ischemic injured brain. The medication alone or in combination with tPA was well tolerated. Melagatran reduced ischemic brain injury in a dose-response manner, and also in a time dependent manner. Combination treatment of melagatran and tPA was superior to either treatment alone. There was no significant increase in symptomatic or asymptomatic hemorrhages in the treated animals. Melagatran treatment also reduced perfusion deficits in the ischemic injured brain. The present study is the first report on the usefulness of melagatran in embolic ischemic stroke. Our research shows that melagatran is an effective agent in the treatment of ischemic brain injury. The protective effects of this medication are likely due to its actions in enhancing thrombus dissolution and preventing formation of microthrombosis in the ischemic injured brain. Finally, the combination with melagatran and tPA appears safe and superior to each treatment offered alone.


Assuntos
Azetidinas/farmacologia , Benzilaminas/farmacologia , Isquemia Encefálica/tratamento farmacológico , Fibrinolíticos/farmacologia , Embolia Intracraniana/tratamento farmacológico , Terapia Trombolítica/métodos , Animais , Anticoagulantes/farmacologia , Anticoagulantes/uso terapêutico , Azetidinas/uso terapêutico , Benzilaminas/uso terapêutico , Isquemia Encefálica/metabolismo , Isquemia Encefálica/fisiopatologia , Artérias Cerebrais/efeitos dos fármacos , Artérias Cerebrais/fisiopatologia , Circulação Cerebrovascular/efeitos dos fármacos , Circulação Cerebrovascular/fisiologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Quimioterapia Combinada , Fibrinolíticos/uso terapêutico , Embolia Intracraniana/metabolismo , Embolia Intracraniana/fisiopatologia , Masculino , Microcirculação/efeitos dos fármacos , Microcirculação/fisiopatologia , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Ratos , Ratos Wistar , Ativador de Plasminogênio Tecidual/farmacologia , Ativador de Plasminogênio Tecidual/uso terapêutico , Resultado do Tratamento
18.
Prog Neurobiol ; 83(3): 140-8, 2007 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-17868971

RESUMO

Cerebral vascular system can be divided into two categories: the macrovessels and microvessels. The microvessels consist of arterioles, capillaries and venules. There are three basic components in the microvasculature: endothelial cells, basal lamina and end-feet of astrocytes. The basal lamina is situated between the endothelial cells and the end-feet of astrocytes, and connects these two layers together. Damage to the basal lamina causes the dismantlement of microvascular wall structures, which in turn results in increase of microvascular permeability, hemorrhagic transformation, brain edema and compromise of the microcirculation. The present article reviews microvascular changes during ischemic brain injury, with emphasis on basal lamina damage.


Assuntos
Membrana Basal/fisiopatologia , Isquemia Encefálica/patologia , Artérias Cerebrais/fisiopatologia , Microcirculação/fisiopatologia , Animais , Barreira Hematoencefálica/fisiopatologia , Isquemia Encefálica/fisiopatologia , Permeabilidade Capilar/fisiologia , Humanos
19.
Exp Neurol ; 205(2): 563-8, 2007 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-17466978

RESUMO

Antithrombotic therapy has been shown to be effective in preventing secondary strokes. Inhibition of platelet function may reduce formation of thrombi thereby reducing the incidence of stroke. However, stronger inhibition of platelets is correlated with increased risk of bleeding events. The purpose of this study was to test the protective effects of combination therapy with dipyridamole and acetylsalicylic acid (ASA) in comparison to ASA alone, and whether such combination treatment may produce any added benefits when tissue plasminogen activator (tPA) treatment is also used. The study was divided into three parts. In part A, effect of antiplatelets on infarct volume was assessed. In part B, perfusion deficits were measured. In part C, efficacy of antiplatelet therapy in combination with tPA was assessed. In part A, dipyridamole and aspirin treatment significantly reduced infarct volume (P<0.05). In part B, treatment with dipyridamole significantly reduced the perfusion deficits as compared to control (P<0.05). In part C, dipyridamole plus tPA or dipyridamole and aspirin plus tPA significantly decreased infarct volume as compared to tPA alone (P<0.05). The present study suggests that there is significant protection with dipyridamole as both infarct volume and perfusion deficits are significantly reduced. Dipyridamole with tPA also significantly reduced infarct volume as compared to tPA alone. Our data suggests that higher doses of antithrombotic therapy with dipyridamole offer best neuroprotection.


Assuntos
Aspirina/uso terapêutico , Dipiridamol/uso terapêutico , Embolia Intracraniana/complicações , Embolia Intracraniana/tratamento farmacológico , Inibidores da Agregação Plaquetária/uso terapêutico , Acidente Vascular Cerebral/tratamento farmacológico , Acidente Vascular Cerebral/etiologia , Ativador de Plasminogênio Tecidual/uso terapêutico , Animais , Aspirina/sangue , Encéfalo/patologia , Infarto Cerebral/patologia , Circulação Cerebrovascular/efeitos dos fármacos , Circulação Cerebrovascular/fisiologia , Dipiridamol/sangue , Quimioterapia Combinada , Masculino , Inibidores da Agregação Plaquetária/sangue , Ratos , Ratos Sprague-Dawley , Ativador de Plasminogênio Tecidual/sangue
20.
Atherosclerosis ; 192(1): 92-9, 2007 May.
Artigo em Inglês | MEDLINE | ID: mdl-16884727

RESUMO

OBJECTIVE: Endothelial progenitor cells (EPCs) are implicated as an important marker of endothelial function and cardiovascular risk. In the present study, we examined whether high-density lipoprotein (HDL) cholesterol plays a role in the peripheral EPC levels and its underlying mechanisms in the HDL cholesterol-induced elevation of EPCs. METHODS: For the clinical study, vascular risk factors and blood markers were measured and EPC colony forming units were counted after 7 days of culture. For the in vitro study, after 7 days of culture, EPCs were incubated in the presence or absence of HDL for 24h followed by measurements of eNOS and pro-MMP-9 expression and caspase-3 activity. RESULTS: EPC colony levels significantly correlated with HDL levels (P=0.017). HDL treatment significantly increased eNOS protein expression in EPCs (P<0.001) while it significantly decreased pro-MMP-9 levels at the concentration of 50 microg/mL (P=0.002). Homocysteine treatment significantly increased caspase-3 activity whereas HDL significantly decreased it as compared to the homocysteine-only treated group. INTERPRETATION: The data demonstrate that EPC colony levels are significantly lower in individuals with low HDL and that HDL increases eNOS and decreases pro-MMP-9 in EPCs. HDL also prevents EPC apoptosis through inhibition of caspase-3 activity suggesting a possible mechanism for its positive effects on circulating EPC numbers.


Assuntos
Apoptose/fisiologia , Caspase 3/metabolismo , HDL-Colesterol/fisiologia , Óxido Nítrico Sintase Tipo III/metabolismo , Serina Endopeptidases/metabolismo , Células-Tronco/metabolismo , Idoso , Técnicas de Cultura de Células , HDL-Colesterol/sangue , Células Endoteliais/citologia , Células Endoteliais/enzimologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
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