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- ItemSomente MetadadadosBiomarcadores periféricos nos transtornos psicóticos: a influência de características clínicas, estágio da doença e tratamento(Universidade Federal de São Paulo (UNIFESP), 2015-10-16) Noto, Cristiano de Souza [UNIFESP]; Brietzke, Elisa Macedo Brietzke [UNIFESP]; Universidade Federal de São Paulo (UNIFESP)INTRODUCTION: Schizophrenia is a chronic disease, with considerable impact on live of individuals and their families. Its origin is related to a complex interaction between genetic and environmental factors during brain development. Despite advances in research, there are no biological markers to confirm the diagnosis, indicate the prognosis, or assist in therapeutic decision. Changes in immune system and oxidation processes have been consistently associated with schizophrenia and markers of these processes emerge as promising biomarkers. However, the current literature is still heterogeneous, and the role of factors such as the use of medication or phenotypic variability remain a challenge to be surmounted. This thesis presents seven studies investigating biomarkers related to inflammation and oxidative stress in different aspects of the disorder. AIMS: To investigate psychotic disorders longitudinally, with a multi-phase and multimodal approach, taking into account clinical heterogeneity. Hence, it was explored the immunological profile and oxidative biomarkers, by evaluating different subgroups of the disease (first episode, drug-naïve patients, the presence of depression, before and after treatment, treatment-resistance). It was also evaluated the relationship between inflammation, oxidative and genetic biomarkers. METHODS: Patients were recruited in their first psychotic episode (FEP), drug-naïve, and followed for an average period of 8 weeks under risperidone. It was also evaluated patients in advanced stages, with more than 1 year of disease. Patients were diagnosed by SCID, with psychopathological evaluation by PANSS and CDSS. RESULTS: FEP patients have increased levels of interleukin (IL)-6, IL-10 and tumor necrosis factor (TNF)-alpha when compared to healthy controls. They also have increased total reactive antioxidant potential (TRAP) and decreased activity of paraoxonase (PON) 1. Those in FEP with depression had higher levels of IL-4 and TNFalfa compared to those without depression, and increased expression of COMT and decrease expression NDEL1. After treatment with risperidone, the three mentioned cytokines, and additionally, IL-4 reduced significantly, and lipid hydroperoxides (LOOH) levels decreased and PON1 activity increased. Next, it was demonstrated that the combination of five biomarkers (sTNF-R1, sTNF-R2, CCL11, IP-10, IL-4) may predict the diagnosis of schizophrenia with a sensitivity of 70.0% and a specificity of 89 4%. Treatment resistance patients showed distinct inflammatory profile, with an increase in increased levels of sTNF-R1, sTNF-R2, and MCP-1. Finally, increased levels of IL-6 was associated with reduced expression of AKT1 and DROSHA, while an increase of IL-10 was associated with increased expression NDEL1, DISC1 and MBP. IL-6 also significantly increased expression of AKT1, DICER1, DROSHA and COMT induced by risperidone. DISCUSSION: It was shown that a disorder in the immune system and oxidative balance is already present from the onset of schizophrenia, before the use of antipsychotic drugs. Moreover, it was suggested that risperidone has antioxidative and anti-inflammatory effects. Features such as depression and treatment resistance also presented a specific immunological profile. Finally, it was showed that inflammatory cytokines play an important role in the regulation of oxidative processes and gene expression. Using an innovative approach and seeking for convergence between different methodologies, the results generated new perspectives in understanding the pathophysiological mechanisms underpinning the neurobiology of schizophrenia.
- ItemAcesso aberto (Open Access)Efeitos da privação de sono paradoxal sobre a implantação e a progressão de metástases experimentais em modelo de melanoma murino(Universidade Federal de São Paulo (UNIFESP), 2015-04-30) Marchioro, Laís de Oliveira [UNIFESP]; Suchecki, Deborah [UNIFESP]; Universidade Federal de São Paulo (UNIFESP)Deprivation of REM sleep (PSP) is a stress induction model because it results in a increased concentrations of glucocorticoids (GCs) in humans (cortisol) and rodents (corticosterone) and others neurotransmitters stress-response-related via activation of the hypothalamic-pituitary-adrenal (HPA) axis, which is able to produce many disorders resulting from prolonged and/or increased secretion of these hormones. Stress is associated with functional reduction of cytotoxic T cells and natural killer cells (NK), processes such as immune surveillance against tumors, the mainly role performed by these populations, genomic stability mechanisms and somatic mutations are affected. Thus, persistent activation of the HPA axis by sleep deprivation (PS) may contribute to the development and progression of some cancers. Melanoma is considered one of the hightest type of angiogenic and aggressive cancers in the world and remains in the lead of deaths from skin cancer in industrialized countries. It has a high capacity to escape from mechanisms that protect the body against it and has a high affinity for vital organs like lungs, liver and brain. Therefore, this study aimed to evaluate the effects of PSP in the development of melanoma lung metastases and the immunological mechanisms involved in the development of this cancer. Therefore, C57BL/6 male mice were inoculated with B16F10 melanoma murine strain cells and subjected to PSP protocol for 72 h after inoculation. Starting at day 8 until day 15 postinoculation, established through pilot experiments the will be show in sequence, the monitoring of metastasis and pulmonary immune populations and the analysis of pulmonary production of interferon gamma (IFN- ?), the main pro-inflammatory cytokine involved in inflammatory processes, and the functional activity of T cells began. Mice from the PSP group had decreased of lung metastases in all the days of evaluation when compared to the control group (CTL), a higher percentage of NK cells and higher concentrations of IFN-?. NK cells are an essential population of killer cells against mutagenic processes and it was the mainly responsible for the restraining metastases in the PSP group showed here. In addition, mice of the CTL group showed a higher percentage of CD8 + CD25 + Foxp3 + lymphocytes (T8reg), which indicated a process of "immune brake" in those animals that had released of metastases. Together, the results point to an important role of NK cells, stimulated by a stressor, presented in greater quantities in the tumor microenvironment of PSP animals.
- ItemAcesso aberto (Open Access)Obesidade e adipocinas inflamatórias: implicações práticas para a prescrição de exercício(Sociedade Brasileira de Medicina do Exercício e do Esporte, 2009-10-01) Prado, Wagner Luiz do [UNIFESP]; Lofrano, Mara Cristina [UNIFESP]; Oyama, Lila Missae [UNIFESP]; Dâmaso, Ana Raimunda [UNIFESP]; UPE Escola Superior de Educação Física; Universidade Federal de São Paulo (UNIFESP)Obesity is a complex disease with a multifaceted etiology with its own physiopathology, co-morbidities and disabiliting capacities. It is crucial that obesity is acknowledged as a disease in order to treat it. Nowadays, the adipose tissue is the main focus of obesity research due to the improvement in the last decade on biological function of this tissue. It is now clear that white adipose tissue release a large amount of bioactive peptides called adipokines (which are proteins synthesized and released by adipose tissue). Thus, the aim of this review was to investigate the relationship between obesity and inflammatory adipokines, trying to discuss the role of physical exercise in the treatment of this pathology. The results have shown that one of the most important recent discoveries is the concept that obesity is characterized by a chronic inflammation state. Among all adipokines, IL-6, TNF- α, leptin (pro-inflammatory) and adiponectin (anti-inflammatory), have received special attention from the specialized literature. High concentration of these adipokines promotes impact in several body functions, which is strongly linked with cardiovascular diseases. Since obesity is considered an inflammatory disease, and exercise directly modulates this process, it is essential that one of the main aims of exercise therapies is the improvement of the inflammatory response of obese individuals.
- ItemAcesso aberto (Open Access)Prebióticos, probióticos e simbióticos na prevenção e tratamento das doenças alérgicas(Sociedade de Pediatria de São Paulo, 2010-03-01) Souza, Fabíola Suano [UNIFESP]; Cocco, Renata Rodrigues [UNIFESP]; Sarni, Roseli Oselka Saccardo [UNIFESP]; Mallozi, Marcia Carvalho [UNIFESP]; Solé, Dirceu [UNIFESP]; Universidade Federal de São Paulo (UNIFESP); Fundação Faculdade de Medicina do ABC Disciplina de PediatriaOBJECTIVE: To review current evidence about the effects of probiotics, prebiotics and symbiotics on the immune development as well as on the prevention of allergic diseases in children. DATA SOURCES: Randomized, double-blind clinical trials in humans published in the last five years, in the Medline database, containing the following keywords: prebiotics (oligosaccharides), probiotics, symbiotics and hypersensitivity. DATA SYNTHESIS: For this review three papers with prebiotics were included, all of them using a mixture of GOS:FOS (9:1) in infant formula for the first months of life; 24 papers with probiotics, where L. rhamnosus GG, B. lactis, L. casei, L. paracasei, L. reuteri, L. acidophilus, B. longum, B. breve and P. freudenreichii sp. were the tested bacterial strains; and two papers about symbiotics. CONCLUSIONS: Although there are some evidence of benefits of early supplementation with some specific probiotic strains, prebiotics and symbiotics for the prevention of atopic eczema in children with high risk of allergy development, and probiotic use for the treatment of IgE-mediated moderate and severe atopic dermatitis, further research is needed in order to extended the evaluation of supplemented individuals, safety aspects and long term effects
- ItemSomente MetadadadosRede transcricional da resposta do hospedeiro à infecção pelo HIV-1(Universidade Federal de São Paulo (UNIFESP), 2014-12-19) Zanoni, Michelle [UNIFESP]; Diaz, Ricardo Sobhie Diaz [UNIFESP]; Universidade Federal de São Paulo (UNIFESP)Host transcriptional network response to HIV-1 infection In this study we investigated 84 transcription network genes in peripheral blood mononuclear cells from 10 antiretroviral naïve individuals experiencing distinct pace of HIV disease progression, and 10 individuals experiencing distinct CD4+ T cells recovery after HAART; all patients belonging to the city of Sao Paulo recent HIV infection Cohort. Investigated genes relate to mechanisms associated to HIV-1 infection susceptibility, natural viral replication control, disease progression rate and immune reconstitution. We evaluated four representative groups of individuals at two distinct time points: antiretroviral naïve elite controllers and rapid progressors evaluated during recent HIV infection period and 1 year after; and immunological responders versus immunological non-responders before HAART initiation and 1 year after. Enhanced dendritic cells cross-presentation to antigen-specific CD8+ T cells evidenced by XCL1 gene upregulation combined with immune activation control (CD4 down-regulation) correlated with natural viremia control during recent infection. In contrast, rapid progressors presented up-regulation of innate immune component (IFNG) added by up-regulation of genes involved in virus transcription activation (CDK9, CCNT1, EP300 and CEBPB) together with remarkable pro-apoptosis signaling (CASP3, TRAIL and TNRF2 and BCL2 lacking) observed 1 year after diagnosis. On the other hand, successfully CD4+ T cell recovery predictors before HAART intervention correlated with ELANE and SLPI upregulation possibly associated to periphery myeloid progenitor cells mobilization and hematopoiesis driven mechanisms added to CD44 up-regulation 1 year after HAART suggesting lymphopoiesis, hematopoieses and CD4+ T cells being driven to Peyer patches. Compared to uninfected controls, immunological non-responders presented 30% of genes differentially expressed (P<0.05) 1 year after HAART, with exception of CD4, CCR4 and RBL2 down-regulation, most of observed transcripts were up-regulated. Lack of satisfactory immune response after HAART also correlated to TGFB1, IL10, STAT3, CEBPB and TNFR2 genes, a scenario probably related to regulatory T cells combined to additional inhibitory effects on dendritic cells maturation status (DCSIGN) associated to sustained chronic innate immune activation (IFNA) with immune senescence and persistence of virus transcription activation (CDK9, CCNT1 and CEBPB). Therefore, the host transcriptional network response to HIV-1 infection described here emerging during early stages of HIV infection or during the course of infection, and before/after HAART initiation can be considered as tools to provide insights into the knowledge of pathogenic mechanisms. Furthermore, these results enables us to develop biomarker tools for disease progression prediction or immune reconstitution after HAART, as well as helping in the development of immune therapies and other interventions that could potentially enable patients to better respond to HIV and HIV treatment.