Alzheimer's disease (AD) is a disabling and highly prevalent neurodegenerative condition, for which there are no effective therapies. Soluble oligomers of the amyloid-β peptide (AβOs) are thought to be proximal neurotoxins involved in early neuronal oxidative stress and synapse damage, ultimately leading to neurodegeneration and memory impairment in AD. The aim of the current study was to evaluate the neuroprotective potential of mesenchymal stem cells (MSCs) against the deleterious impact of AβOs on hippocampal neurons. To this end, we established transwell cocultures of rat hippocampal neurons and MSCs. We show that MSCs and MSC-derived extracellular vesicles protect neurons against AβO-induced oxidative stress and synapse damage, revealed by loss of pre- and postsynaptic markers. Protection by MSCs entails three complementary mechanisms: 1) internalization and degradation of AβOs; 2) release of extracellular vesicles containing active catalase; and 3) selective secretion of interleukin-6, interleukin-10, and vascular endothelial growth factor to the medium. Results support the notion that MSCs may represent a promising alternative for cell-based therapies in AD.
BackgroundIschemic stroke causes brain inflammation, which we postulate may result in lung damage. Several studies have focused on stroke-induced immunosuppression and lung infection; however, the possibility that strokes may trigger lung inflammation has been overlooked. We hypothesized that even focal ischemic stroke might induce acute systemic and pulmonary inflammation, thus altering respiratory parameters, lung tissue integrity, and alveolar macrophage behavior.MethodsForty-eight Wistar rats were randomly assigned to ischemic stroke (Stroke) or sham surgery (Sham). Lung function, histology, and inflammation in the lung, brain, bronchoalveolar lavage fluid (BALF), and circulating plasma were evaluated at 24 h. In vitro, alveolar macrophages from naïve rats (unstimulated) were exposed to serum or BALF from Sham or Stroke animals to elucidate possible mechanisms underlying alterations in alveolar macrophage phagocytic capability. Alveolar macrophages and epithelial and endothelial cells of Sham and Stroke animals were also isolated for evaluation of mRNA expression of interleukin (IL)-6 and tumor necrosis factor (TNF)-α.ResultsTwenty-four hours following ischemic stroke, the tidal volume, expiratory time, and mean inspiratory flow were increased. Compared to Sham animals, the respiratory rate and duty cycle during spontaneous breathing were reduced, but this did not affect lung mechanics during mechanical ventilation. Lungs from Stroke animals showed clear evidence of increased diffuse alveolar damage, pulmonary edema, and inflammation markers. This was associated with an increase in ultrastructural damage, as evidenced by injury to type 2 pneumocytes and endothelial cells, cellular infiltration, and enlarged basement membrane thickness. Protein levels of proinflammatory mediators were documented in the lung, brain, and plasma (TNF-α and IL-6) and in BALF (TNF-α). The phagocytic ability of macrophages was significantly reduced. Unstimulated macrophages isolated from naïve rats only upregulated expression of TNF-α and IL-6 following exposure to serum from Stroke rats. Exposure to BALF from Stroke or Sham animals did not change alveolar macrophage behavior, or gene expression of TNF-α and IL-6. IL-6 expression was increased in macrophages and endothelial cells from Stroke animals.ConclusionsIn rats, focal ischemic stroke is associated with brain–lung crosstalk, leading to increased pulmonary damage and inflammation, as well as reduced alveolar macrophage phagocytic capability, which seems to be promoted by systemic inflammation.Electronic supplementary materialThe online version of this article (10.1186/s13054-018-2164-0) contains supplementary material, which is available to authorized users.
Intravascular delivery of cells has been increasingly used in stroke models and clinical trials. We compared the biodistribution and therapeutic effects of bone marrow mononuclear cells (BMMCs) delivered by intra-arterial (IA) or intravenous (IV) injection after cortical ischemia. For the biodistribution analyses, BMMCs were labeled with (99m)Technetium ((99m)Tc). At 2 h, gamma-well counting of the brain and of the other organs evaluated did not show differences between the non-ischemic and ischemic groups or between injection routes, and the organs with the highest uptake were the liver and lungs, with low uptake in the brain. At 24 h, the liver maintained the highest activity, and a marked decrease was seen in pulmonary uptake in all groups. At this time point, although the activity in the brain remained low, the lesioned hemisphere showed greater homing than the contralateral hemisphere, for both the IV and IA ischemic groups. Histological analysis by CellTrace labeling indicated similar homing between both routes in the peri-infarct region 24 h after transplantation and functional recovery was observed in both groups up to 11 weeks after the lesion. In conclusion, transplantation of BMMCs by IA or IV routes may lead to similar brain homing and therapeutic efficacy after experimental stroke.
Global cerebral ischemia (GCI) results in death of the pyramidal neurons in the CA1 layer of the hippocampus. In this study we used the four-vessel occlusion (4VO) model of GCI to investigate a potential neuroprotective role of bone-marrow mononuclear cells (BMMCs) transplantation. BMMCs (3×10(7)) were injected through the carotid artery, 1 or 3 days after ischemia (DAI), and the number of cells undergoing degeneration was investigated in brains at 7 DAI. A significant decrease in the number of dying cells was observed in the treated group, compared to animals treated with saline. Biodistribution of the injected cells (1 or 3 DAI) was investigated by (99m)Technetium labeling of the BMMCs and subsequent image analysis 2h after transplantation. In addition, the presence of CellTrace(™)-labeled BMMCs was investigated in tissue sections of the hippocampal area of these transplanted animals. BMMCs treatment significantly reduced the number of FJ-C positive cells in the hippocampal CA1 layer at 7 DAI. We also observed a decrease in the number of activated microglia/macrophage (ED1-positive cells) in the BMMCs-treated group compared with the untreated group. Our data show that BMMCs are able to modulate the microglial response and reduce neurodegeneration in the CA1 layer.
RESUMO O artigo busca analisar o papel desempenhado pelas relações entre o fundador da Ação Integralista Brasileira, Plínio Salgado, e os editores José Olympio e Augusto Frederico Schmidt na publicação e divulgação dos livros integralistas. Em um primeiro momento, procura-se compreender a importância que o livro teve para o Integralismo, visto que entre os anos de 1933 e 1937 os intelectuais da AIB lançaram quase cinquenta títulos, sendo a maior parte publicada pela editora José Olympio e pela Schmidt Editor. Argumenta-se, em seguida, que a dinâmica entre amizade, interesses (materiais e ideias) e relações de poder construída a partir do relacionamento de Plínio Salgado com aqueles dois editores foi decisiva para a publicação das obras integralistas, garantindo sua presença no mercado editorial brasileiro e a circulação das ideias da AIB. Palavras-chave: Integralismo; Plínio Salgado; José Olympio; Augusto Frederico Schmidt; Livros no Brasil (década de 1930). ABSTRACTThe paper seeks to analyze how conviviality between the founder of the Brazilian Integralist Action (AIB), Plínio Salgado, and the publishers José Olympio and Augusto Frederico Schmidt contributed to the publication of Integralist books. First, it tries to ascertain the relevance of books to Integralism, since the intellectuals from AIB published almost fifty books between 1933 and 1937, most of them through two publishing houses: Editora José Olympio and Schmidt Editor. Then, it argues that the dynamics between friendship (material and ideological), interests, and power relations, built by the Salgado's relationship to those two editors, was crucial to the publication of the Integralist works, assuring their presence within the Brazilian publishing market and, thus, the circulation of AIB's ideas.
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