Accelerated Axonal Loss Following Acute CNS Demyelination in Mice Lacking Protein Tyrosine Phosphatase Receptor Type Z

Protein tyrosine phosphatase receptor type Z (Ptprz) is widely expressed in the mammalian central nervous system and has been suggested to regulate oligodendrocyte survival and differentiation. We investigated the role of Ptprz in oligodendrocyte remyelination after acute, toxin-induced demyelination in Ptprz null mice. We found neither obvious impairment in the recruitment of oligodendrocyte precursor cells, astrocytes, or reactive microglia/macrophage to lesions nor a failure for oligodendrocyte precursor cells to differentiate and remyelinate axons at the lesions. However, we observed an unexpected increase in the number of dystrophic axons by 3 days after demyelination, followed by prominent Wallerian degeneration by 21 days in the Ptprz-deficient mice. Moreover, quantitative gait analysis revealed a deficit of locomotor behavior in the mutant mice, suggesting increased vulnerability to axonal injury. We propose that Ptprz is necessary to maintain central nervous system axonal integrity in a demyelinating environment and may be an important target of axonal protection in inflammatory demyelinating diseases, such as multiple sclerosis and periventricular leukomalacia. (Am J Pathol 2012, 181:1518-1523; http://dx.doi.org/10.1016/j.ajpath.2012.07.011)UK Multiple Sclerosis SocietyMultiple Sclerosis International FederationUniv Cambridge, Dept Vet Med, Cambridge CB3 0ES, EnglandUniv Cambridge, Wellcome Trust & MRC Cambridge Stem Cell Inst, Cambridge CB3 0ES, EnglandUniversidade Federal de São Paulo, Dept Biosci, Santos, BrazilMerck Serono Int, Geneva Res Ctr, Geneva, SwitzerlandUniversidade Federal de São Paulo, Dept Biosci, Santos, BrazilWeb of Scienc

Sox2 Sustains Recruitment of Oligodendrocyte Progenitor Cells following CNS Demyelination and Primes Them for Differentiation during Remyelination.

UNLABELLED: The Sox family of transcription factors have been widely studied in the context of oligodendrocyte development. However, comparatively little is known about the role of Sox2, especially during CNS remyelination. Here we show that the expression of Sox2 occurs in oligodendrocyte progenitor cells (OPCs) in rodent models during myelination and in activated adult OPCs responding to demyelination, and is also detected in multiple sclerosis lesions. In normal adult white matter of both mice and rats, it is neither expressed by adult OPCs nor by oligodendrocytes (although it is expressed by a subpopulation of adult astrocytes). Overexpression of Sox2 in rat OPCs in vitro maintains the cells in a proliferative state and inhibits differentiation, while Sox2 knockout results in decreased OPC proliferation and survival, suggesting that Sox2 contributes to the expansion of OPCs during the recruitment phase of remyelination. Loss of function in cultured mouse OPCs also results in an impaired ability to undergo normal differentiation in response to differentiation signals, suggesting that Sox2 expression in activated OPCs also primes these cells to eventually undergo differentiation. In vivo studies on remyelination following experimental toxin-induced demyelination in mice with inducible loss of Sox2 revealed impaired remyelination, which was largely due to a profound attenuation of OPC recruitment and likely also due to impaired differentiation. Our results reveal a key role of Sox2 expression in OPCs responding to demyelination, enabling them to effectively contribute to remyelination. SIGNIFICANCE STATEMENT: Understanding the mechanisms of CNS remyelination is central to developing effective means by which this process can be therapeutically enhanced in chronic demyelinating diseases such as multiple sclerosis. In this study, we describe the role of Sox2, a transcription factor widely implicated in stem cell biology, in CNS myelination and remyelination. We show how Sox2 is expressed in oligodendrocyte progenitor cells (OPCs) preparing to undergo differentiation, allowing them to undergo proliferation and priming them for subsequent differentiation. Although Sox2 is unlikely to be a direct therapeutic target, these data nevertheless provide more information on how OPC differentiation is controlled and therefore enriches our understanding of this important CNS regenerative process.This work was mainly supported by the UK Multiple Sclerosis Society.This is the final version of the article. It first appeared from the Society for Neuroscience via http://dx.doi.org/10.1523/JNEUROSCI.3655-14.201

The Blood-Brain Barrier Breakdown During Acute Phase of the Pilocarpine Model of Epilepsy Is Dynamic and Time-Dependent

The maintenance of blood-brain barrier (BBB) integrity is essential for providing a suitable environment for nervous tissue function. BBB disruption is involved in many central nervous system diseases, including epilepsy. Evidence demonstrates that BBB breakdown may induce epileptic seizures, and conversely, seizure-induced BBB disruption may cause further epileptic episodes. This study was conducted based on the premise that the impairment of brain tissue during the triggering event may determine the organization and functioning of the brain during epileptogenesis, and that BBB may have a key role in this process. Our purpose was to investigate in rats the relationship between pilocarpine-induced status epilepticus (SE), and BBB integrity by determining the time course of the BBB opening and its subsequent recovery during the acute phase of the pilocarpine model. BBB integrity was assessed by quantitative and morphological methods, using sodium fluorescein and Evans blue (EB) dyes as markers of the increased permeability to micromolecules and macromolecules, respectively. Different time-points of the pilocarpine model were analyzed: 30 min after pilocarpine injection and then 1, 5, and 24 h after the SE onset. Our results show that BBB breakdown is a dynamic phenomenon and time-dependent, i.e., it happens at specific time-points of the acute phase of pilocarpine model of epilepsy, recovering in part its integrity afterwards. Pilocarpine-induced changes on brain tissue initially increases the BBB permeability to micromolecules, and subsequently, around 5 h after SE, the BBB breakdown to macromolecules occurs. After BBB breakdown, EB dye is captured by damaged cells, especially neurons, astrocytes, and oligodendrocytes. Although the BBB permeability to macromolecules is restored 24 h after the start of SE, the leakage of micromolecules persists and the consequences of BBB degradation are widely disseminated in the brain. Our findings reveal the existence of a temporal window of BBB dysfunction in the acute phase of the pilocarpine model that is important for the development of therapeutic strategies that could prevent the epileptogenesis

Educomunicação e suas áreas de intervenção: Novos paradigmas para o diálogo intercultural

oai:omp.abpeducom.org.br:publicationFormat/1O material aqui divulgado representa, em essência, a contribuição do VII Encontro Brasileiro de Educomunicação ao V Global MIL Week, da UNESCO, ocorrido na ECA/USP, entre 3 e 5 de novembro de 2016. Estamos diante de um conjunto de 104 papers executivos, com uma média de entre 7 e 10 páginas, cada um. Com este rico e abundante material, chegamos ao sétimo e-book publicado pela ABPEducom, em seus seis primeiros anos de existência. A especificidade desta obra é a de trazer as “Áreas de Intervenção” do campo da Educomunicação, colocando-as a serviço de uma meta essencial ao agir educomunicativo: o diálogo intercultural, trabalhado na linha do tema geral do evento internacional: Media and Information Literacy: New Paradigms for Intercultural Dialogue

The use of micronucleus assay in exfoliated oral cells in patients undergoing fixed orthodontic therapy: a systematic review with meta-analysis

Abstract The aim of this systematic review was to evaluate published papers regarding the micronucleus assay in oral mucosal cells of patients undergoing orthodontic therapy (OT). A search of the scientific literature was made in the PubMed, Scopus, and Web of Science databases for all data published until November, 2021 using the combination of the following keywords: “fixed orthodontic therapy,” “genetic damage”, “DNA damage,” “genotoxicity”, “mutagenicity”, “buccal cells”, “oral mucosa cells,” and “micronucleus assay”. The systematic review was designed according to the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) guidelines. Nine studies were retrieved. Some authors demonstrated that OT induces cytogenetic damage in oral mucosal cells. Out of the nine studies included, two were classified as strong, five as moderate, and two as weak, according to the quality assessment components of the Effective Public Health Practice Project (EPHPP). Meta-analysis data revealed no relationship between mutagenicity in oral cells and OT in different months of treatment. At one month, the SMD = 0.65 and p = 0.08; after three months of OT, the SMD = 1.21 and p = 0.07; and after six months of OT, the SMD = 0.56 and p = 0.11. In the analyzed months of OT, I2 values were >75%, indicating high heterogeneity. In summary, this review was not able to demonstrate that OT induces genetic damage in oral cells. The study is important for the protection of patients undergoing fixed OT, given that mutagenesis participates in the multi-step process of carcinogenesis

Effects of different fluences of low-level laser therapy in an experimental model of spinal cord injury in rats

The aim of this study was to evaluate the in vivo response of different fluences of low-level laser therapy (LLLT) on the area of the injury, inflammatory markers, and functional recovery using an experimental model of traumatic spinal cord injury (SCI). Thirty two rats were randomly divided into four experimental groups: control group (CG), laser-treated group 500 J/cm(2) (L-500), laser-treated group 750 J/cm(2) (L-750), and laser-treated group 1000 J/cm(2) (L-1000). SCI was performed by an impactor equipment (between the ninth and tenth thoracic vertebrae), with a pressure of 150 kdyn. Afterwards, the injured region was irradiated daily for seven consecutive sessions, using an 808-nm laser, at the respective fluence of each experimental groups. Motor function and tactile sensitivity were performed on days 1 and 7 post-surgery. Animals were euthanized on the eighth day after injury, and the samples were retrieved for histological and immunohistochemistry analyses. Functional evaluation and tactile sensitivity were improved after LLLT, at the higher fluence. Additionally, LLLT, at 750 and 1000 J/cm(2), reduces the lesion volume and modulates the inflammatory process with decrease of CD-68 protein expression. These results suggest that LLLT at higher doses was effective in promoting functional recovery and modulating inflammatory process in the spinal cord of rats after SCI.Univ Fed Sao Paulo, Dept Biosci, R Silva Jardim 136, BR-11015020 Sao Paulo, BrazilUniv Fed Sao Paulo, Dept Biosci, R Silva Jardim 136, BR-11015020 Sao Paulo, BrazilWeb of Scienc

Cytokine Gene Expression In Walker 256: A Comparison Of Variants A (aggressive) And Ar (regressive).

Two variants of this Walker 256 tumor have been previously reported as Walker 256 A and variant AR. The variant A has more aggressive property than variant AR and can induce systemic effects such as anorexia, sodium and water retention, followed by weight loss and death. The mechanisms involved in enhancing tumor regression and progression in this model are still incompletely understood. In the present study, serum and spleen mononuclear cells and tumor cells from animals inoculated with variants A and AR, were isolated to investigate the TGF-beta, IL-12, IFN-gamma and TNF-alpha and relationship with anemia, weight of animals, weight of spleen, volume of tumor and osmotic fragility compared with controls inoculated with Ringer Lactate. Results demonstrate that the group inoculated with variant A, compared to variant AR, shows high levels of TGF-beta gene expression in both tumor tissue and spleen cells, no expression of IFN-gamma and a progressive and higher levels of IL-12 in tumor tissue without inflammatory infiltrate visualized by optical microscopy. These results suggest that the aggressively of variant A is relate to cytokine modulation, facilitating the growth and escape of tumor cells. Furthermore, IL-12 seems to be constitutively expressed in both tumor lineage A and AR.36123-3