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1.
Cell Mol Life Sci ; 76(16): 3117-3140, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31165904

RESUMO

Stroke is a leading cause of death and disability worldwide. However, after years of in-depth research, the pathophysiology of stroke is still not fully understood. Increasing evidence shows that matrix metalloproteinases (MMPs) and "a disintegrin and metalloproteinase" (ADAMs) participate in the neuro-inflammatory cascade that is triggered during stroke but also in recovery phases of the disease. This review covers the involvement of these proteins in brain injury following cerebral ischemia which has been widely studied in recent years, with efforts to modulate this group of proteins in neuroprotective therapies, together with their implication in neurorepair mechanisms. Moreover, the review also discusses the role of these proteins in specific forms of neurovascular disease, such as small vessel diseases and intracerebral hemorrhage. Finally, the potential use of MMPs and ADAMs as guiding biomarkers of brain injury and repair for decision-making in cases of stroke is also discussed.


Assuntos
Proteínas ADAM/metabolismo , Metaloproteinases da Matriz/metabolismo , Acidente Vascular Cerebral/patologia , Biomarcadores/sangue , Barreira Hematoencefálica/metabolismo , Doenças de Pequenos Vasos Cerebrais/metabolismo , Doenças de Pequenos Vasos Cerebrais/patologia , Humanos , Hemorragias Intracranianas/metabolismo , Hemorragias Intracranianas/patologia , Acidente Vascular Cerebral/metabolismo
2.
Nanomedicine ; 20: 101986, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31059794

RESUMO

The potential biomedical applications of the MNPs nanohybrids coated with m-carboranylphosphinate (1-MNPs) as a theranostic biomaterial for cancer therapy were tested. The cellular uptake and toxicity profile of 1-MNPs from culture media by human brain endothelial cells (hCMEC/D3) and glioblastoma multiform A172 cell line were demonstrated. Prior to testing 1-MNPs' in vitro toxicity, studies of colloidal stability of the 1-MNPs' suspension in different culture media and temperatures were carried out. TEM images and chemical titration confirmed that 1-MNPs penetrate into cells. Additionally, to explore 1-MNPs' potential use in Boron Neutron Capture Therapy (BNCT) for treating cancer locally, the presence of the m-carboranyl coordinated with the MNPs core after uptake was proven by XPS and EELS. Importantly, thermal neutrons irradiation in BNCT reduced by 2.5 the number of cultured glioblastoma cells after 1-MNP treatment, and the systemic administration of 1-MNPs in mice was well tolerated with no major signs of toxicity.

3.
Artigo em Inglês | MEDLINE | ID: mdl-30133323

RESUMO

Stroke is one of the leading causes of death and disability worldwide. Tremendous improvements have been achieved in the acute care of stroke patients with the implementation of stroke units, thrombolytic drugs and endovascular trombectomies. However, stroke survivors with neurological deficits require long periods of neurorehabilitation, which is the only approved therapy for post- stroke recovery. With this scenario more treatments are urgently needed, and only the understanding of the mechanisms of brain recovery might contribute to identify new therapeutic agents. Fortunately brain injury after stroke is counteracted by the birth and migration of several populations of progenitor cells towards the injured areas, where angiogenesis and vascular remodeling play a key role providing trophic support and guidance during neurorepair. Endothelial Progenitor cells (EPC) constitute a pool of circulating bone-marrow derived cells that mobilize after an ischemic injury with the potential to incorporate into the damaged endothelium, to form new vessels or to secrete trophic factors stimulating vessel remodeling. The circulating levels of EPC are altered after stroke and several subpopulations have proved to boost brain neurorepair in pre-clinical models of cerebral ischemia. The goal of this review is to discuss the current state of the neuroreparative actions of EPC focusing on their paracrine signaling mechanisms thorough their secretome and released extracellular vesicles (EVs).

4.
Front Neurol ; 9: 508, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30008694

RESUMO

Background: Rehabilitation therapy is the only available treatment for stroke survivors presenting neurological deficits; however, the underlying molecules and mechanisms associated with functional/motor improvement during rehabilitation are poorly understood. Objective: Our aim is to study the modulation of angiogenin and endothelial progenitor cells (EPCs) as repair-associated factors in a cohort of stroke patients and mouse models of rehabilitation after cerebral ischemia. Methods: The clinical study included 18 ischemic strokes admitted to an intensive rehabilitation therapy (IRT) unit, 18 non-ischemic controls and brain samples from three deceased patients. Angiogenin and EPCs were measured in blood obtained before and up to 6 months after IRT together with an extensive evaluation of the motor/functional status. In parallel, C57BL/6 mice underwent middle cerebral artery occlusion, and the pasta matrix reaching-task or treadmill exercises were used as rehabilitation models. Angiogenin RNA expression was measured after 2 or 12 days of treatment together with cell counts from EPCs cultures. Results: Brain angiogenin was identified in both human and mouse tissue, whereas serum levels increased after 1 month of IRT in association with motor/functional improvement. EPC populations were increased after stroke and remained elevated during follow-up after IRT. The mouse model of rehabilitation by the task-specific pasta matrix exercise increased the number of EPCs at 2 days and increased angiogenin expression after 12 days of rehabilitation. Conclusions: Angiogenin and EPCs are modulated by rehabilitation after cerebral ischemia, suggesting that both angiogenin and EPCs could serve as biomarkers of improvement during rehabilitation or future therapeutic targets.

5.
Sci Rep ; 8(1): 7899, 2018 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-29784938

RESUMO

The limited accessibility to the brain has turned the cerebrospinal fluid (CSF) into a valuable source that may contribute to the complete understanding of the stroke pathophysiology. Here we have described the CSF proteome in the hyper-acute phase of cerebral ischemia by performing an aptamer-based proteomic assay (SOMAscan) in CSF samples collected before and 30 min after male Wistar rats had undergone a 90 min Middle Cerebral Artery Occlusion (MCAO) or sham-surgery. Proteomic results indicated that cerebral ischemia acutely increased the CSF levels of 716 proteins, mostly overrepresented in leukocyte chemotaxis and neuronal death processes. Seven promising candidates were further evaluated in rat plasma and brain (CKB, CaMK2A, CaMK2B, CaMK2D, PDXP, AREG, CMPK). The 3 CaMK2 family-members and CMPK early decreased in the infarcted brain area and, together with AREG, co-localized with neurons. Conversely, CKB levels remained consistent after the insult and specifically matched with astrocytes. Further exploration of these candidates in human plasma revealed the potential of CKB and CMPK to diagnose stroke, while CaMK2B and CMPK resulted feasible biomarkers of functional stroke outcome. Our findings provided insights into the CSF proteome following cerebral ischemia and identified new outstanding proteins that might be further considered as potential biomarkers of stroke.

6.
Stem Cells ; 36(9): 1404-1410, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29781122

RESUMO

Endothelial progenitor cells (EPCs) have been pursued as a potential cellular therapy for stroke and central nervous system injury. However, their underlying mechanisms remain to be fully defined. Recent experimental studies suggest that mitochondria may be released and transferred between cells. In this proof-of-concept study, we asked whether beneficial effects of EPCs may partly involve a mitochondrial phenomenon as well. First, EPC-derived conditioned medium was collected and divided into supernatant and particle fractions after centrifugation. Electron microscopy, Western blots, and flow cytometry showed that EPCs were able to release mitochondria. ATP and oxygen consumption assays suggested that these extracellular mitochondria may still be functionally viable. Confocal microscopy confirmed that EPC-derived extracellular mitochondria can be incorporated into normal brain endothelial cells. Adding EPC particles to brain endothelial cells promoted angiogenesis and decreased the permeability of brain endothelial cells. Next, we asked whether EPC-derived mitochondria may be protective. As expected, oxygen-glucose deprivation (OGD) increased brain endothelial permeability. Adding EPC-derived mitochondria particles to the damaged brain endothelium increased levels of mitochondrial protein TOM40, mitochondrial DNA copy number, and intracellular ATP. Along with these indirect markers of mitochondrial transfer, endothelial tightness was also restored after OGD. Taken together, these findings suggest that EPCs may support brain endothelial energetics, barrier integrity, and angiogenic function partly through extracellular mitochondrial transfer. Stem Cells 2018;36:1404-1410.

7.
Stroke ; 49(4): 1003-1010, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29511131

RESUMO

BACKGROUND AND PURPOSE: Endothelial progenitor cells (EPCs) have been extensively investigated as a therapeutic approach for repairing the vascular system in cerebrovascular diseases. Beyond vascular regeneration per se, EPCs may also release factors that affect the entire neurovascular unit. Here, we aim to study the effects of the EPC secretome on oligovascular remodeling in a mouse model of white matter injury after prolonged cerebral hypoperfusion. METHODS: The secretome of mouse EPCs was analyzed with a proteome array. In vitro, the effects of the EPC secretome and its factor angiogenin were assessed on primary oligodendrocyte precursor cells and mature human cerebral microvascular endothelial cells (hCMED/D3). In vivo, mice were subjected to permanent bilateral common carotid artery stenosis, then treated with EPC secretome at 24 hours and at 1 week, and cognitive outcome was evaluated with the Y maze test together with oligodendrocyte precursor cell proliferation/differentiation and vascular density in white matter at 4 weeks. RESULTS: Multiple growth factors, cytokines, and proteases were identified in the EPC secretome, including angiogenin. In vitro, the EPC secretome significantly enhanced endothelial and oligodendrocyte precursor cell proliferation and potentiated oligodendrocyte precursor cell maturation. Angiogenin was proved to be a key factor since pharmacological blockade of angiogenin signaling negated the positive effects of the EPC secretome. In vivo, treatment with the EPC secretome increased vascular density, myelin, and mature oligodendrocytes in white matter and rescued cognitive function in the mouse hypoperfusion model. CONCLUSIONS: Factors secreted by EPCs may ameliorate white matter damage in the brain by boosting oligovascular remodeling.

8.
Inorg Chem ; 57(1): 462-470, 2018 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-29257676

RESUMO

All-inorganic-made nanohybrid icosahedral boron cluster magnetic nanoparticles have been prepared. These magnetic nanoparticles (MNPs) consist of a magnetic core and an inorganic carboranylphosphinate shell. The phosphinate is directly bonded to the iron atoms of the surface in a bidentated coordination mode. The nanoparticles have been characterized by TEM, X-ray powder diffraction, infrared spectroscopy, energy dispersive X-ray analysis, high resolution X-ray photoelectron spectroscopy, magnetometry measurements, and redox titration, among other techniques. These studies have led to a composition (1-OPH(O)-1,7-closo-C2B10H11)8(2Fe3O4·Fe2O3)13 that implies a surface coverage of 61.3 ± 7.4% by the ligand. When these MNPs go through sterilization in one autoclave, the magnetic hysteresis studies suggest minimal change before and after sterilization; this could erroneously indicate that there have not been any changes in the MNP composition. However, the Fe2+ titration demonstrates that after sterilization only 1/7 of the Fe is Fe2+, leading to a core formula of Fe3O4·2Fe2O3 with a concomitant loss of ligand to a final ratio of 1:70 (carborane: Fe), and a final coverage by the ligand of 11.2 ± 1.4%. These studies bring relevant information on the behavior of the widely used MNPs and clearly show how the sterilization process needed for biological tests may alter the composition of the core and the loading of a peripheral ligand. In the particular case reported here, the liberated ligand has not been oxidized nor altered through the sterilization process.


Assuntos
Boro/química , Nanopartículas de Magnetita/química , Coloides/síntese química , Coloides/química , Hidrodinâmica , Estrutura Molecular , Tamanho da Partícula , Propriedades de Superfície
9.
J Cereb Blood Flow Metab ; 37(11): 3488-3517, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28797196

RESUMO

Most in vivo models of ischaemic stroke target the middle cerebral artery and a spectrum of stroke severities, from mild to substantial, can be achieved. This review describes opportunities to improve the in vivo modelling of ischaemic stroke and animal welfare. It provides a number of recommendations to minimise the level of severity in the most common rodent models of middle cerebral artery occlusion, while sustaining or improving the scientific outcomes. The recommendations cover basic requirements pre-surgery, selecting the most appropriate anaesthetic and analgesic regimen, as well as intraoperative and post-operative care. The aim is to provide support for researchers and animal care staff to refine their procedures and practices, and implement small incremental changes to improve the welfare of the animals used and to answer the scientific question under investigation. All recommendations are recapitulated in a summary poster (see supplementary information).


Assuntos
Bem-Estar do Animal/normas , Isquemia Encefálica/patologia , Acidente Vascular Cerebral/patologia , Animais , Modelos Animais de Doenças , Guias como Assunto , Humanos , Infarto da Artéria Cerebral Média/patologia
12.
Cardiovasc Res ; 113(10): 1219-1229, 2017 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-28379489

RESUMO

Aims: Early reperfusion with tissue-type plasminogen activator (tPA) is an effective therapeutic strategy to treat acute ischemic stroke, but only 1/3 of tPA-treated patients recover and are free from disability. tPA has also shown neurotoxicity in experimental models of cerebral ischemia. Considering that MMP-10 improves stroke injury, we have examined the therapeutic and protective effect of MMP10 and tPA/MMP10 as clot-dissolving and neuroprotective agent in an experimental model of ischemic stroke and studied in vitro the molecular pathways involved in MMP10-mediated effects. Methods and results: Cerebral ischemia was induced by the local injection of thrombin into the middle cerebral artery followed by reperfusion with MMP10 (6.5 µg/kg) and tPA (10 mg/kg) alone or in combination with MMP10. Cell cultures were also performed to determine the effect of MMP10 and tPA/MMP10 on brain endothelial cells and neurons. tPA/MMP10 significantly reduced the infarct size in the ischemic stroke model compared with tPA alone (P < 0.05). In vitro, MMP10 reduced the tPA-promoted endothelial ionic permeability, preserved the expression of claudin-5 and decreased ERK1/2 activation. Moreover, combination of tPA/MMP10 prevented tPA-mediated neuronal excitotoxicity and calcium influx. These effects were reversed by blocking MMP10 activity with a monoclonal antibody. Conclusion: These results show that MMP10, either alone or in combination with tPA, might represent a new strategy for thrombolysis in ischemic stroke, providing higher protection against cerebrovascular damage.


Assuntos
Encéfalo/efeitos dos fármacos , Fibrinolíticos/administração & dosagem , Infarto da Artéria Cerebral Média/prevenção & controle , Metaloproteinase 10 da Matriz/administração & dosagem , Fármacos Neuroprotetores/administração & dosagem , Terapia Trombolítica/métodos , Ativador de Plasminogênio Tecidual/administração & dosagem , Animais , Comportamento Animal/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Encéfalo/fisiopatologia , Sinalização do Cálcio/efeitos dos fármacos , Permeabilidade Capilar/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Claudina-5/metabolismo , Modelos Animais de Doenças , Quimioterapia Combinada , Impedância Elétrica , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Fibrinolíticos/toxicidade , Humanos , Infarto da Artéria Cerebral Média/metabolismo , Infarto da Artéria Cerebral Média/patologia , Infarto da Artéria Cerebral Média/fisiopatologia , Masculino , Camundongos Endogâmicos C57BL , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Atividade Motora/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Terapia Trombolítica/efeitos adversos , Fatores de Tempo , Ativador de Plasminogênio Tecidual/toxicidade
13.
J Proteomics ; 152: 243-253, 2017 01 30.
Artigo em Inglês | MEDLINE | ID: mdl-27888142

RESUMO

The identification of proteins involved in brain ischemia might allow the discovery of putative biomarkers or therapeutic targets for ischemic stroke. Our aim is to study the distribution of proteins within mouse brain after an ischemic insult using MALDI imaging-mass-spectrometry and to identify relevant proteins involved in brain damage. We occluded the middle cerebral artery of C57BL/6J mice. Brain slices were analyzed by MALDI-TOF and infarct (IC) and contralateral (CL) regions were compared using ClinProTools. The ion distribution maps of relevant m/z values were obtained by FlexImagin3.0. Protein identification was conducted through a bottom-up approach consisting on complementary sample fractionation methods. Some identifications were confirmed by immunohistochemistry and western blot. We identified 102 m/z values with different abundances between IC and CL (p<0.05), from which 21 m/z peaks were selected as more relevant. Thirteen of them were found increased in the infarct region and 4 m/z values showed AUC>90% between IC and CL. Identification analyses confirmed altered expressions of ATP5i, COX6C and UMP-CMP kinase in IC compared to CL. BIOLOGICAL SIGNIFICANCE: Using MALDI-IMS we identified for the first time new proteins that might be involved in brain ischemia representing potential diagnostic biomarkers or target molecules for neurological recovery.


Assuntos
Isquemia Encefálica/diagnóstico por imagem , Diagnóstico por Imagem/métodos , Proteínas/análise , Proteômica/métodos , Animais , Biomarcadores/análise , Química Encefálica , Isquemia Encefálica/metabolismo , Perfilação da Expressão Gênica , Camundongos , Proteínas/metabolismo , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz/métodos , Acidente Vascular Cerebral/diagnóstico por imagem
14.
Nat Med ; 22(11): 1303-1313, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27775704

RESUMO

Triple-negative breast cancers (TNBCs) have poor prognosis and lack targeted therapies. Here we identified increased copy number and expression of the PIM1 proto-oncogene in genomic data sets of patients with TNBC. TNBC cells, but not nonmalignant mammary epithelial cells, were dependent on PIM1 for proliferation and protection from apoptosis. PIM1 knockdown reduced expression of the anti-apoptotic factor BCL2, and dynamic BH3 profiling of apoptotic priming revealed that PIM1 prevents mitochondrial-mediated apoptosis in TNBC cell lines. In TNBC tumors and their cellular models, PIM1 expression was associated with several transcriptional signatures involving the transcription factor MYC, and PIM1 depletion in TNBC cell lines decreased, in a MYC-dependent manner, cell population growth and expression of the MYC target gene MCL1. Treatment with the pan-PIM kinase inhibitor AZD1208 impaired the growth of both cell line and patient-derived xenografts and sensitized them to standard-of-care chemotherapy. This work identifies PIM1 as a malignant-cell-selective target in TNBC and the potential use of PIM1 inhibitors for sensitizing TNBC to chemotherapy-induced apoptotic cell death.


Assuntos
Apoptose/genética , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica , Proteínas Proto-Oncogênicas c-pim-1/genética , Neoplasias de Mama Triplo Negativas/genética , Animais , Apoptose/efeitos dos fármacos , Compostos de Bifenilo/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Variações do Número de Cópias de DNA , Feminino , Técnicas de Silenciamento de Genes , Humanos , Camundongos , Mitocôndrias/metabolismo , Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , Transplante de Neoplasias , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteínas Proto-Oncogênicas c-myc/metabolismo , Proteínas Proto-Oncogênicas c-pim-1/antagonistas & inibidores , Reação em Cadeia da Polimerase em Tempo Real , Tiazolidinas/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
15.
Curr Biol ; 26(19): 2635-2641, 2016 10 10.
Artigo em Inglês | MEDLINE | ID: mdl-27618263

RESUMO

In addition to its role in membrane abscission during cytokinesis, viral budding, endosomal sorting, and plasma membrane repair [1], the endosomal sorting complex required for transport-III (ESCRT-III) machinery has recently been shown to seal holes in the reforming nuclear envelope (NE) during mitotic exit [2, 3]. ESCRT-III also acts during interphase to repair the NE upon migration-induced rupture [4, 5], highlighting its key role as an orchestrator of membrane integrity at this organelle. While NE localization of ESCRT-III is dependent upon the ESCRT-III component CHMP7 [3], it is unclear how this complex is able to engage nuclear membranes. Here we show that the N terminus of CHMP7 acts as a novel membrane-binding module. This membrane-binding ability allows CHMP7 to bind to the ER, an organelle continuous with the NE, and it provides a platform to direct NE recruitment of ESCRT-III during mitotic exit. CHMP7's N terminus comprises tandem Winged-Helix domains [6], and, by using homology modeling and structure-function analysis, we identify point mutations that disrupt membrane binding and prevent both ER localization of CHMP7 and its subsequent enrichment at the reforming NE. These mutations also prevent assembly of downstream ESCRT-III components at the reforming NE and proper establishment of post-mitotic nucleo-cytoplasmic compartmentalization. These data identify a novel membrane-binding activity within an ESCRT-III subunit that is essential for post-mitotic nuclear regeneration.


Assuntos
Complexos Endossomais de Distribuição Requeridos para Transporte/metabolismo , Membrana Nuclear/metabolismo , Sequência de Aminoácidos , Animais , Células COS , Divisão Celular , Linhagem Celular Tumoral , Cercopithecus aethiops , Complexos Endossomais de Distribuição Requeridos para Transporte/química , Complexos Endossomais de Distribuição Requeridos para Transporte/genética , Células HeLa , Humanos , Alinhamento de Sequência
16.
Int J Nanomedicine ; 11: 3035-48, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27418824

RESUMO

BACKGROUND AND AIMS: Although the beneficial effects of statins on stroke have been widely demonstrated both in experimental studies and in clinical trials, the aim of this study is to prepare and characterize a new liposomal delivery system that encapsulates simvastatin to improve its delivery into the brain. MATERIALS AND METHODS: In order to select the optimal liposome lipid composition with the highest capacity to reach the brain, male Wistar rats were submitted to sham or transitory middle cerebral arterial occlusion (MCAOt) surgery and treated (intravenous [IV]) with fluorescent-labeled liposomes with different net surface charges. Ninety minutes after the administration of liposomes, the brain, blood, liver, lungs, spleen, and kidneys were evaluated ex vivo using the Xenogen IVIS(®) Spectrum imaging system to detect the load of fluorescent liposomes. In a second substudy, simvastatin was assessed upon reaching the brain, comparing free and encapsulated simvastatin (IV) administration. For this purpose, simvastatin levels in brain homogenates from sham or MCAOt rats at 2 hours or 4 hours after receiving the treatment were detected through ultra-high-protein liquid chromatography. RESULTS: Whereas positively charged liposomes were not detected in brain or plasma 90 minutes after their administration, neutral and negatively charged liposomes were able to reach the brain and accumulate specifically in the infarcted area. Moreover, neutral liposomes exhibited higher bioavailability in plasma 4 hours after being administered. The detection of simvastatin by ultra-high-protein liquid chromatography confirmed its ability to cross the blood-brain barrier, when administered either as a free drug or encapsulated into liposomes. CONCLUSION: This study confirms that liposome charge is critical to promote its accumulation in the brain infarct after MCAOt. Furthermore, simvastatin can be delivered after being encapsulated. Thus, simvastatin encapsulation might be a promising strategy to ensure that the drug reaches the brain, while increasing its bioavailability and reducing possible side effects.


Assuntos
Sistemas de Liberação de Medicamentos/métodos , Lipossomos/administração & dosagem , Sinvastatina/administração & dosagem , Acidente Vascular Cerebral/tratamento farmacológico , Animais , Disponibilidade Biológica , Barreira Hematoencefálica/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Isquemia Encefálica/tratamento farmacológico , Infarto da Artéria Cerebral Média , Rim/efeitos dos fármacos , Lipossomos/química , Lipossomos/metabolismo , Fígado/efeitos dos fármacos , Pulmão/efeitos dos fármacos , Masculino , Ratos Wistar , Sinvastatina/química , Sinvastatina/farmacocinética , Sinvastatina/farmacologia , Baço/efeitos dos fármacos , Distribuição Tecidual
17.
Arch Phys Med Rehabil ; 97(11): 1832-1840, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27373742

RESUMO

OBJECTIVE: To study plasma levels of matrix metalloproteinases (MMPs) as potential markers of recovery during intensive rehabilitation therapy (IRT) after stroke. DESIGN: Prospective and descriptive 3-month follow-up study. SETTING: Rehabilitation unit and research center. PARTICIPANTS: Patients with first-ever ischemic stroke (n=15) enrolled to IRT (≥3h/d and 5d/wk) and healthy volunteers (n=15) (N=30). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: The primary outcome was to measure plasma MMP3, MMP12, and MMP13 levels and evaluate potential associations with motor/functional scales using a battery of tests (National Institutes of Health Stroke Scale, modified Rankin scale, Barthel Index, Fugl-Meyer Assessment, Functional Ambulation Categories, Medical Research Council scale, Chedoke Arm and Hand Activity Inventory, and the 10-m walk test) before IRT and at 1- and 3-month follow-ups. The secondary outcome was to evaluate the use of these MMPs as biomarkers as predictors of patient's outcome. RESULTS: MMP levels remained stable during the study period and were similar to those in the healthy volunteer group. However, baseline MMP12 and MMP13 levels were strongly associated with stroke severity and were found to be elevated in those patients with the poorest outcomes. Interestingly, plasma MMP3 was independent of baseline stroke characteristics but was found to be increased in patients with better motor/functional recovery and in patients with larger improvements during rehabilitation. CONCLUSIONS: MMPs might act as biologic markers of recovery during rehabilitation therapy related to their roles in both injury and tissue remodeling. Future confirmatory investigations in multicenter studies are warranted by our data.


Assuntos
Metaloproteinases da Matriz/metabolismo , Reabilitação do Acidente Vascular Cerebral/métodos , Acidente Vascular Cerebral/fisiopatologia , Idoso , Biomarcadores , Feminino , Humanos , Masculino , Metaloproteinase 12 da Matriz/metabolismo , Metaloproteinase 13 da Matriz/metabolismo , Metaloproteinase 3 da Matriz/metabolismo , Metaloproteinases da Matriz/sangue , Pessoa de Meia-Idade , Modalidades de Fisioterapia , Estudos Prospectivos , Recuperação de Função Fisiológica , Fatores de Risco , Índice de Gravidade de Doença
18.
Neurobiol Dis ; 91: 236-46, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27001146

RESUMO

New neuroreparative and neuroprotective therapies are being sought to treat stroke patients. One approach is the remodeling of extracellular matrix, which participates in both brain injury and neurovascular repair when matrix metalloproteinases (MMPs) are thought to be key players. Our aim was to investigate the role of MMP-13 (collagenase-3) in the acute (24h and 3days) and delayed (2weeks) phases of stroke. Permanent and transient cerebral ischemia models involving the cortex were induced in MMP-13 knock-out (KO) and wild-type (WT) mice. In the transient model, MMP-13 deficiency reduced the amount of TTC-stained infarct tissue, reduced hemorrhagic events and improved functional outcomes (p<0.01). At two weeks, normal neuroblast (DCX+) migration from the subventricular zone toward the peri-infarct area was observed. However, MMP-13 deficiency significantly reduced the number of newborn neuroblasts (DCX+/BrdU+) in the cortical peri-infarct area (p<0.01). This result occurred in parallel with aberrant cortical vascular remodeling: post-stroke peri-infarct vessel density increased in the WT mice (p<0.01) but this increase was blocked in the MMP-13 KO mice. Prior to these vascular alterations, the levels of pro-angiogenic factors, including G-CSF, VEGF-A and angiopoietin-2, were lower in the ischemic cortex of MMP-13 KO mice than in WT mice (p<0.05). In vitro, gene-silencing of MMP-13 in endothelial progenitor cells (EPCs) confirmed the reduced ability of these cells to build tubulogenic networks in Matrigel™ substrate. Together, our results indicate that MMP-13 is a central protease in infarct development and cortical remodeling during post-stroke neurorepair, which is critical for optimal angiogenic and neurogenic responses.


Assuntos
Ataque Isquêmico Transitório/enzimologia , Metaloproteinase 13 da Matriz/metabolismo , Neuroproteção/fisiologia , Acidente Vascular Cerebral/enzimologia , Animais , Modelos Animais de Doenças , Infarto da Artéria Cerebral Média/metabolismo , Metaloproteinase 13 da Matriz/genética , Camundongos Knockout , Neurogênese/fisiologia
19.
J Cereb Blood Flow Metab ; 35(10): 1547-51, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26219597

RESUMO

Endothelial progenitor cells (EPCs) are being investigated for advanced therapies, and matrix metalloproteinase 9 (MMP9) has an important role in stroke recovery. Our aim was to determine whether tissue MMP9 influences the EPC-induced angiogenesis after ischemia. Wild-type (WT) and MMP9-deficient mice (MMP9/KO) were subjected to cerebral ischemia and treated with vehicle or outgrowth EPCs. After 3 weeks, we observed an increase in the peri-infarct vessel density in WT animals but not in MMP9/KO mice; no differences were found in the vehicle-treated groups. Our data suggest that tissue MMP9 has a crucial role in EPC-induced vascular remodeling after stroke.


Assuntos
Isquemia Encefálica/genética , Córtex Cerebral/patologia , Veias Cerebrais/fisiologia , Células Progenitoras Endoteliais , Metaloproteinase 9 da Matriz/fisiologia , Transplante de Células-Tronco/métodos , Remodelação Vascular , Animais , Isquemia Encefálica/patologia , Isquemia Encefálica/terapia , Infarto Cerebral/patologia , Infarto Cerebral/fisiopatologia , Veias Cerebrais/crescimento & desenvolvimento , Imagem por Ressonância Magnética , Masculino , Metaloproteinase 9 da Matriz/deficiência , Metaloproteinase 9 da Matriz/genética , Camundongos , Camundongos Knockout , Proteínas Associadas aos Microtúbulos/genética , Proteínas Associadas aos Microtúbulos/fisiologia , Neovascularização Fisiológica/genética , Neovascularização Fisiológica/fisiologia , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/fisiologia , Neuropeptídeos/genética , Neuropeptídeos/fisiologia , Proteínas Nucleares/genética , Proteínas Nucleares/fisiologia , Acidente Vascular Cerebral/terapia
20.
Brain Res ; 1623: 150-9, 2015 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-25725381

RESUMO

Brain injury after ischemia induces the mobilization of endothelial progenitor cells (EPCs), a population of bone marrow-derived cells with angio-vasculogenic capabilities. These cells have been also tested in pre-clinical models and proposed for neurorepair therapy aiming to treat patients in the delayed phases of stroke disease. Promising results in the pre-clinical field encourage the translation into a clinical therapeutic approach. In this review, we will describe EPCs actions for enhanced revascularization and neurorepair, which on one hand are by their direct incorporation into new vascular networks/structures or by direct cell-cell interactions with other brain cells, but also to indirect cell-cell communication thorough EPCs secreted growth factors. All these actions contribute to potentiate neurovascular remodeling and neurorepair. The data presented in this review encourages for a deep understanding of the mechanisms of the cross-talks between EPCs and other brain and progenitor cells, which deserves additional investigations and efforts that may lead to new EPCs-based therapies for stroke patients. This article is part of a Special Issue entitled SI: Cell Interactions In Stroke.


Assuntos
Encéfalo/irrigação sanguínea , Encéfalo/fisiopatologia , Diferenciação Celular/fisiologia , Células Progenitoras Endoteliais/fisiologia , Acidente Vascular Cerebral/fisiopatologia , Animais , Comunicação Celular/fisiologia , Humanos , Neovascularização Fisiológica/fisiologia
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