Les effets des bisphénols sur le métabolisme et les réponses cellulaires des neutrophiles humains

Le bisphénol A (BPA), un composé chimique largement utilisé dans la fabrication de plastiques et de résines époxy, se retrouve dans les fluides humains tels que le sang et l'urine. Il est connu que le BPA affecte, entre autres, les systèmes endocrinien, reproducteur et immunitaire en influençant le métabolisme (glycolyse et respiration mitochondriale) et les fonctions cellulaires. Les préoccupations concernant la sécurité du BPA ont conduit à son remplacement par des substituts tels que le bisphénol S (BPS). Les neutrophiles polymorphonucléaires (PMN), les leucocytes les plus abondants dans le sang, sont des cellules fortement glycolytiques en raison de leur faible nombre de mitochondries et de leur utilisation de l'oxygène pour effectuer des fonctions antimicrobiennes. En raison de cette caractéristique métabolique, nous avons émis l'hypothèse qu'une exposition constante à de faibles doses de bisphénols pourrait altérer le métabolisme énergétique et les fonctions antibactériennes des PMN. Nous avons stimulé les PMN avec le peptide bactérien chimiotactique N-formyl-méthionyl-leucyl-phénylalanine (fMLP) et évalué leur réponse glycolytique en utilisant un analyseur de flux extracellulaire. Nous avons examiné l’impact des bisphénols sur le métabolisme des neutrophiles dans les moments suivant leur isolement du sang de volontaires sains (exposition immédiate) et suite à une exposition de 6h en culture (prolongée). Nous avons observé qu'une exposition immédiate au BPA, au BPS et à leurs métabolites glucuronidés, à des concentrations retrouvées dans le sang, n'avait aucun effet sur la glycolyse basale et la glycolyse induite par le fMLP. Cependant, une exposition prolongée aux bisphénols diminue la glycolyse induite par le fMLP dans les PMN sans affecter la viabilité cellulaire. Ces résultats suggèrent que l'incapacité à répondre correctement aux besoins énergétiques pourrait altérer les fonctions cellulaires des PMN lors d'infections bactériennes. En effet, suite à une exposition prolongée à de faibles concentrations de bisphénols, les neutrophiles activés ont une concentration de CXCL8/IL-8 intracellulaire plus faible que les témoins et une dérégulation de la production de dérivés réactifs de l’oxygène (ROS). La diminution du métabolisme, entraînant une dérégulation de certaines fonctions cellulaires, pourrait contribuer au développement de pathologies ou augmenter la susceptibilité aux infections. Collectivement, ces données supportent les conclusions sur les effets néfastes du BPA et de ses substituts et appuient de nouvelles réglementations concernant leur utilisation au CanadaBisphenol A (BPA), a chemical compound widely used in the fabrication of plastics and epoxy resins, is found in human fluids such as blood and urine. BPA is known to affect the endocrine, reproductive and immune systems by influencing metabolism (glycolysis and mitochondrial respiration) and cellular functions. Concerns about the safety of BPA have led to its replacement with substitutes such as bisphenol S (BPS). Polymorphonuclear neutrophils (PMNs), the most abundant leukocytes in the blood, are highly glycolytic cells due to their low mitochondria count and their use of oxygen to perform anti-microbial functions. Because of this metabolic feature, we hypothesized that constant exposure to low doses of bisphenols could alter energy metabolism and anti-bacterial functions of PMNs. We stimulated PMNs with the chemotactic bacterial peptide N-formyl-methionyl-leucyl-phenylalanine (fMLP) and evaluated their glycolytic response using an extracellular flux analyzer. We examined the impact of bisphenols on neutrophil metabolism in the moments following their isolation from the blood of healthy volunteers (immediate exposure) and following 6h culture exposure (prolonged). We found that an acute exposure to BPA, BPS and their glucuronidated metabolites, at concentrations found in the blood, had no effect on both basal glycolysis and fMLP-induced glycolysis. However, a prolonged exposure to bisphenols reduced the fMLP-induced glycolysis in PMNs without affecting cellular viability. These results suggest that the inability to properly respond to energy requirements could alter the cellular functions of PMNs during bacterial infections. Indeed, following prolonged exposure to low concentrations of bisphenols, activated neutrophils have a lower intracellular CXCL8/IL-8 concentration than the controls and a deregulation of the production of reactive oxygen species (ROS). Decreased metabolism, leading to deregulation of cellular functions, could contribute to the development of pathologies or increase susceptibility to infections. Collectively, these data support conclusions about the adverse effects of BPA and its substitutes and support new regulations regarding their use in Canada

Factors to Improve the Management of Hepatitis C in Drug Users: An Observational Study in an Addiction Centre

Barriers to management of HCV in injection drug users are related to patients, health providers, and facilities. In a primary care drug user's addiction centre we studied access to HCV standard of care before and after using an onsite total care concept provided by a multidisciplinary team and noninvasive liver fibrosis evaluation. A total of 586 patients were seen between 2002 and 2004. The majority, 417 patients, were HCV positive and of these patients 337 were tested positive for HCV RNA. In 2002, patients were sent to the hospital. with the Starting of 2003, patients were offered standard of care HCV management in the center by a team of general practitioners, a consultant hepatologist, psychiatrists, nurses, and a health counsellor. Liver fibrosis was assessed by a non invasive method. In 2002, 6 patients had liver fibrosis assessment at hospital facilities, 4 patients were assessed with liver biopsy and 2 patients with Fibrotest-Actitest. 2 patients were treated for HCV at hospital. In 2003 and 2004, 224 patients were assessed with Fibrotest-Actitest on site. Of these, 85 were treated for HCV. SVR was achieved in 43%. We conclude that the combination of an onsite multidisciplinary team with the use of a noninvasive assessment method led to improved management of HCV infection in drug users' primary care facility

Opposing roles for Hoxa2 and Hoxb2 in hindbrain oligodendrocyte patterning

Oligodendrocytes are the myelin-forming cells of the vertebrate CNS. Little is known about the molecular control of region-specific oligodendrocyte development. Here, we show that oligodendrogenesis in the mouse rostral hindbrain, which is organized in a metameric series of rhombomere-derived (rd) territories, follows a rhombomere-specific pattern, with extensive production of oligodendrocytes in the pontine territory (r4d) and delayed and reduced oligodendrocyte production in the prepontine region (r2d, r3d). We demonstrate that segmental organization of oligodendrocytes is controlled by Hoxgenes, namely Hoxa2 and Hoxb2. Specifically, Hoxa2 loss of function induced a dorsoventral enlargement of the Olig2/Nkx2.2-expressing oligodendrocyte progenitor domain, whereas conditional Hoxa2 overexpression in the Olig2(+) domain inhibited oligodendrogenesis throughout the brain. In contrast, Hoxb2 deletion resulted in a reduction of the pontine oligodendrogenic domain. Compound Hoxa2(-/-)/Hoxb2(-/-) mutant mice displayed the phenotype of Hoxb2(-/-) mutants in territories coexpressing Hoxa2 and Hoxb2 (rd3, rd4), indicating that Hoxb2 antagonizes Hoxa2 during rostral hindbrain oligodendrogenesis. This study provides the first in vivo evidence that Hox genes determine oligodendrocyte regional identity in the mammalian brain

Biciliated ependymal cell proliferation contributes to spinal cord growth

Two neurogenic regions have been described in the adult brain, the lateral ventricle subventricular zone and the dentate gyrus subgranular zone. It has been suggested that neural stem cells also line the central canal of the adult spinal cord. Using transmission and scanning electron microscopy and immunostaining, we describe here the organization and cell types of the central canal epithelium in adult mice. The identity of dividing cells was determined by three-dimensional ultrastructural reconstructions of [3H]thymidine-labeled cells and confocal analysis of bromodeoxyuridine labeling. The most common cell type lining the central canal had two long motile (9+2) cilia and was vimentin+, CD24+, FoxJ1+, Sox2+ and CD133+, but nestin- and glial fibrillary acidic protein (GFAP)-. These biciliated ependymal cells of the central canal (Ecc) resembled E2 cells of the lateral ventricles, but their basal bodies were different from that of E2 or E1 cells. Interestingly, we frequently found Ecc cells with two nuclei and four cilia, suggesting they are formed by incomplete cytokinesis or cell fusion. GFAP+ astrocytes with a single cilium and an orthogonally oriented centriole were also observed. The majority of dividing cells corresponded to biciliated Ecc cells. Central canal proliferation was most common during the active period of spinal cord growth. Pairs of labeled Ecc cells were observed within the central canal in adult mice 2.5 weeks post-labeling. Our work suggests that the vast majority of postnatal dividing cells in the central canal are Ecc cells and their proliferation is associated with the growth of the spinal cord

Age-Related Changes in Astrocytic and Ependymal Cells of the Subventricular Zone

Neurogenesis persists in the adult subventricular zone (SVZ) of the mammalian brain. During aging, the SVZ neurogenic capacity undergoes a progressive decline, which is attributed to a decrease in the population of neural stem cells (NSCs). However, the behavior of the NSCs that remain in the aged brain is not fully understood. Here we performed a comparative ultrastructural study of the SVZ niche of 2-month-old and 24-month-old male C57BL/6 mice, focusing on the NSC population. Using thymidine-labeling, we showed that residual NSCs in the aged SVZ divide less frequently than those in young mice. We also provided evidence that ependymal cells are not newly generated during senescence, as others studies suggest. Remarkably, both astrocytes and ependymal cells accumulated a high number of intermediate filaments and dense bodies during aging, resembling reactive cells. A better understanding of the changes occurring in the neurogenic niche during aging will allow us to develop new strategies for fighting neurological disorders linked to senescence

Basement membrane components are key players in specialized extracellular matrices

More than three decades ago, basement membranes (BMs) were described as membrane-like structures capable of isolating a cell from and connecting a cell to its environment. Since this time, it has been revealed that BMs are specialized extracellular matrices (sECMs) with unique components that support important functions including differentiation, proliferation, migration, and chemotaxis of cells during development. The composition of these sECM is as unique as the tissues to which they are localized, opening the possibility that such matrices can fulfill distinct functions. Changes in BM composition play significant roles in facilitating the development of various diseases. Furthermore, tissues have to provide sECM for their stem cells during development and for their adult life. Here, we briefly review the latest research on these unique sECM and their components with a special emphasis on embryonic and adult stem cells and their niches

Les prises de décision lors des limitations et arrêts des thérapeutiques

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