ABSTRACT
Brain injuries such as trauma and stroke lead to glial scar formation by reactive astrocytes which produce and secret axonal outgrowth inhibitors. Chondroitin sulfate proteoglycans (CSPG) constitute a well-known class of extracellular matrix molecules produced at the glial scar and cause growth cone collapse. The CSPG glycosaminoglycan side chains composed of chondroitin sulfate (CS) are responsible for its inhibitory activity on neurite outgrowth and are dependent on RhoA activation. Here, we hypothesize that CSPG also impairs neural stem cell migration inhibiting their penetration into an injury site. We show that DCX+ neuroblasts do not penetrate a CSPG-rich injured area probably due to Nogo receptor activation and RhoA/ROCK signaling pathway as we demonstrate in vitro with neural stem cells cultured as neurospheres and pull-down for RhoA. Furthermore, CS-impaired cell migration in vitro induced the formation of large mature adhesions and altered cell protrusion dynamics. ROCK inhibition restored migration in vitro as well as decreased adhesion size.
Subject(s)
Cell Movement/drug effects , Chondroitin Sulfates/pharmacology , Neural Stem Cells/cytology , Neural Stem Cells/enzymology , rho-Associated Kinases/metabolism , Animals , Cell Adhesion/drug effects , Cell Surface Extensions/drug effects , Cell Surface Extensions/metabolism , Cells, Cultured , Doublecortin Protein , Enzyme Activation/drug effects , Male , Mice, Inbred C57BL , Neural Stem Cells/drug effects , rho-Associated Kinases/antagonists & inhibitors , rhoA GTP-Binding Protein/metabolismABSTRACT
Brain injuries such as trauma and stroke lead to glial scar formation by reactive astrocytes which produce and secret axonal outgrowth inhibitors. Chondroitin sulfate proteoglycans (CSPG) constitute a well-known class of extracellular matrix molecules produced at the glial scar and cause growth cone collapse. The CSPG glycosaminoglycan side chains composed of chondroitin sulfate (CS) are responsible for its inhibitory activity on neurite outgrowth and are dependent on RhoA activation. Here, we hypothesize that CSPG also impairs neural stem cell migration inhibiting their penetration into an injury site. We show that DCX+ neuroblasts do not penetrate a CSPG-rich injured area probably due to Nogo receptor activation and RhoA/ROCK signaling pathway as we demonstrate in vitro with neural stem cells cultured as neurospheres and pull-down for RhoA. Furthermore, CS-impaired cell migration in vitro induced the formation of large mature adhesions and altered cell protrusion dynamics. ROCK inhibition restored migration in vitro as well as decreased adhesion size.
Subject(s)
Biomedical Research , Genomics , Informed Consent , Research Subjects , Age Factors , Child , Humans , Young AdultABSTRACT
BACKGROUND: Chronic rhinosinusitis (CRS) is a prevalent and disabling paranasal sinus disease, with a likely multifactorial etiology potentially including hazardous occupational and environmental exposures. We completed a systematic review of the occupational and environmental literature to evaluate the quality of evidence of the role that hazardous exposures might play in CRS. METHODS: We searched PubMed for studies of CRS and following exposure categories: occupation, employment, work, industry, air pollution, agriculture, farming, environment, chemicals, roadways, disaster, and traffic. We abstracted information from the final set of articles across 6 primary domains: study design; population; exposures evaluated; exposure assessment; CRS definition; and results. RESULTS: We identified 41 articles from 1080 manuscripts: 37 occupational risk papers, 1 environmental risk paper, and 3 papers studying both categories of exposures. None of the 41 studies used a CRS definition consistent with current diagnostic guidelines. Exposure assessment was generally dependent on self-report or binary measurements of exposure based on industry of employment. Only grain, dairy, and swine operations among farmers were evaluated by more than 1 study using a common approach to defining CRS, but employment in these settings was not consistently associated with CRS. The multiple other exposures did not meet quality standards for reporting associations or were not evaluated by more than 1 study. CONCLUSION: The current state of the literature allows us to make very few conclusions about the role of hazardous occupational or environmental exposures in CRS, leaving a critical knowledge gap regarding potentially modifiable risk factors for disease onset and progression.
Subject(s)
Rhinitis/epidemiology , Sinusitis/epidemiology , Animals , Chronic Disease , Environmental Exposure/adverse effects , Humans , Occupational Exposure/adverse effects , Prevalence , Risk Factors , United StatesABSTRACT
In the Samaritá area of Säo Vicente city, Säo Paulo State, Brazil, a chemical industry discarded for several years, with no environmental protection, a mixture of residues containing 55 to 85 per cent of hexachlorobenzene (HCB) and others in smaller quantities. In order to evaluate the impact of these residues on the health of the local population, blood serum samples taken from 234 people dwelling at several quarters of this area for over two years were analyzed, divided into 6 sectors: A- Quarentenário and neighborhood of the industrial wastes dump at 67 km; B- Jardim Rio Branco; C- Parque das Bandeiras; D- Gleba II; E- Vila Samaritá; F- Vila Ema, Vila Iolanda, Vila Mathias. Ten blood samples from residents of an area considered no exposed from Itanhaém city were collected to provide baseline information and HCB was not found in any of the samples. HCB residues were analysed by gas chromatography with an electron capture detector, with a determination limit of 0,02 ug/dL. The mean of HCB in blood serum for the inhabitants of the affected area presented significant differences (p<0,001) between sector A (0,41 ug/dL) and all the others sectors; B (0,04ug/dL); C (0,04UG/Dl); d(0,03 ug/dL); E (0,04 ug/dL). Although it has not yet been possible to correlate such findings with the presence of diseases among the area inhabitants, this study indicates that the HCB residues are a health risk, as they not only contaminate the environment, but are also present at the biota, including humans
Subject(s)
Environmental Health , Pesticides , Chromatography, Gas , Hexachlorobenzene , Pesticide ResiduesABSTRACT
Estudo transversal controlado, tendo por objetivo sugerir possíveis indicadores de exposiçäo, foi realizado em mulheres expostas a resíduos químicos organoclorados provenientes de indústria química e depositados em lixäo próximo às áreas habitadas de Samaritá, Município de Säo Vicente. Coletou-se e analisou-se 40 amostras de leite materno e soro sanguíneo, sendo 23 de mulheres de Samaritá e 17 de mulheres näo expostas (controle). Näo foram observadas diferenças significativas entre os grupos estudados quanto à idade, número de gestaçöes, número de abortos e tempo de amamentaçäo. As amostras foram analisadas para determinaçäo de resíduos de pesticidas organoclorados, tendo sido utilizados os níveis de Hexaclorobenzeno, o mais importante contaminante do local, para comparar as diferenças entre a populaçäo exposta e näo exposta. Hexaclorobenzeno näo foi encontrado em nenhuma das amostras de soro sanguíneo, embora tenha sido detectado em 20 amostras de leite humano, 14 em Samaritá e em 6 da populaçäo controle. Encontrou-se HCH (Alfa, Beta, ipsilone) e DDT (p-p 'DDE, p-p 'DDD, O-P' E P-P 'DDT) em 90,0 por cento e 100,0 por cento das amostras de leite, respectivamente, e DDT em 42,5 por cento das de soro sanguíneo. Näo foram observadas diferenças estatisticamente significativas entre os grupos estudados, embora os níveis de HCB encontrados em Samaritá sejam mais elevados do que os do grupo controle. O tempo de exposiçäo das mulheres de Samaritá pode ter sido insuficiente para demonstrar estatisticamente as diferenças existentes. O leite materno demonstrou maior sensibilidade para se detectar a presença de organoclorados ambientais, já que mulheres que tiveram níveis elevados dos mesmos no leite, näo apresentaram níveis detectáveis no sangue e, quando isso ocorreu, foi em níveis significativamente inferiores, como no caso do DDT. A avaliaçäo periódica dos níveis de hexaclorobenzeno no leite materno de moradoras de Samaritá poderá indicar se está havendo controle do risco de exposiçäo ambiental a estes resíduos