Sound evidence supports a role for interleukin-17 (IL-17) -producing cd T cells and IL-17-producing helper T (Th17) cells in intestinal homeostasis, especially in intestinal barrier integrity. In the present study, we aimed to evaluate the role of IL-17 cytokine in the regulation of intestinal immunity and obesity-induced metabolic syndrome (MetS) in an experimental murine model. C57BL/6 wild-type (WT) mice and mice lacking the IL-17 cytokine receptor (IL-17RA À/À ) were fed either a control diet (CD) or a high-fat diet (HFD) for 9 weeks. Our data demonstrate that IL-17RA À/À mice are protected against obesity, but develop hyperglycemia, hyperinsulinemia and insulin resistance. In parallel, HFD-fed IL-17RA À/À mice display intense inflammation in the ileum compared with WT mice on the HFD. IL-17RA À/À mice fed the HFD exhibit impaired neutrophil migration to the intestinal mucosa and reduced gene expression of the CXCL-1 chemokine and CXCR-2 receptor in the ileum. Interestingly, the populations of neutrophils (CD11b + Ly6G + ) and anti-inflammatory macrophages (CD11b + CX3CR1 + ) are increased in the mesenteric lymph nodes of these mice. IL-17RA À/À mice on the HFD also display increased commensal bacterial translocation into the bloodstream and elevated lipopolysaccharide (LPS) levels in the visceral adipose tissue (VAT). Metagenomic analysis of bacterial 16S gene revealed increased Proteobacteria and Bacteroidetes phyla, the main representatives of Gram-negative bacteria, and reduced Akkermansia muciniphila in the fecal samples of IL-17RA À/À mice fed the HFD. Together, these data indicate that the IL-17/IL-17R axis drives intestinal neutrophil migration, limits gut dysbiosis and attenuates LPS translocation to VAT, resulting in protection to MetS.
The intestinal microbiome maintains a close relationship with the host immunity. This connection fosters a health state by direct and indirect mechanisms. Direct influences occur mainly through the production of short-chain fatty acids (SCFAs), gastrointestinal hormones and precursors of bioactive molecules. Indirect mechanisms comprise the crosstalk between bacterial products and the host's innate immune system. Conversely, intestinal dysbiosis is a condition found in a large number of chronic intestinal inflammatory diseases, such as ulcerative colitis and Crohn's disease, as well as in diseases associated with low-grade inflammation, such as obesity, type 1 and 2 diabetes mellitus and cardiovascular diseases. NOD-Like receptors (NLRs) are cytoplasmic receptors expressed by adaptive and innate immune cells that form a multiprotein complex, termed the inflammasome, responsible for the release of mature interleukin (IL)-1β and IL-18. NLRs are also involved in the recognition of bacterial components and production of antimicrobial molecules that shape the gut microbiota and maintain the intestinal homeostasis. Recent novel findings show that NLRs may act as positive or negative regulators of inflammation by modulating NF-κB activation. This mini-review presents current and updated evidence on the interplay between NLRs and gut microbiota and their dual role, contributing to progression or conferring protection, in diabetes and other inflammatory diseases.
Pattern recognition receptors (PRRs), such as Nod2, Nlrp3, Tlr2, Trl4, and Tlr9, are directly involved in type 1 diabetes (T1D) susceptibility. However, the role of the cytosolic DNA sensor, AIM2, in T1D pathogenesis is still unknown. Here, we demonstrate that C57BL/6 mice lacking AIM2 (AIM2−/−) are prone to streptozotocin (STZ)-induced T1D, compared to WT C57BL/6 mice. The AIM2−/− mice phenotype is associated with a greater proinflammatory response in pancreatic tissues, alterations in gut microbiota and bacterial translocation to pancreatic lymph nodes (PLNs). These alterations are related to an increased intestinal permeability mediated by tight-junction disruption. Notably, AIM2−/− mice treated with broad-spectrum antibiotics (ABX) are protected from STZ-induced T1D and display a lower pancreatic proinflammatory response. Mechanistically, the AIM2 inflammasome is activated in vivo, leading to an IL-18 release in the ileum at 15 days after an STZ injection. IL-18 favors RegIIIγ production, thus mitigating gut microbiota alterations and reinforcing the intestinal barrier function. Together, our findings show a regulatory role of AIM2, mediated by IL-18, in shaping gut microbiota and reducing bacterial translocation and proinflammatory response against insulin-producing β cells, which ultimately results in protection against T1D onset in an STZ-induced diabetes model.
Histone deacetylases (HDACs) are enzymes that regulate several processes, such as transcription, cell proliferation, differentiation and development. HDACs are classified as either Zn 2+ -dependent or NAD + -dependent enzymes. Over the years, experimental and clinical evidence has demonstrated that HDAC modulation is a critical process in neurodegenerative and psychiatric disorders. Nevertheless, most of the studies have focused on the role of Zn 2+ -dependent HDACs in the development of these diseases, although there is growing evidence showing that the NAD + -dependent HDACs, known as sirtuins, are also very promising targets. This possibility has been strengthened by reports of decreased levels of NAD + in CNS disorders, which can lead to alterations in sirtuin activation and therefore result in increased pathology. In this review, we discuss the role of sirtuins in neurodegenerative and neuropsychiatric disorders as well the possible rationale for them to be considered as pharmacological targets in future therapeutic interventions.LINKED ARTICLES: This article is part of a themed issue on Building Bridges in Neuropharmacology. To view the other articles in this section visit http://onlinelibrary.
Highlights d NLRP1 has a role in both mouse and human autoimmune diabetes d NLRP1 expressed by T cells downregulates the differentiation of Th17 cells d NLRP1, in a STAT3-dependent pathway, suppresses Th17signature genes, such as RORgt d IL-17 levels are decreased in T1D patients carrying a SNP (rs12150220) in the NLRP1 gene
Justificativa e Objetivos: A realização deste trabalho justifica-se pelos elevados índices de casos de câncer a nível global, assim como, as consequências prejudiciais causadas nos indivíduos acometidos pelo mesmo. Em razão da importância da epidemiologia no combate a doenças, como as neoplasias, este estudo teve como objetivo realizar uma analise da prevalência de casos de câncer no município de Santa Amélia, Paraná, entre os anos de 2007 a 2011. Metodologia: Estudo transversal descritivo de abordagem quantitativa. Os dados foram cedidos pelo Departamento de Vigilância Epidemiológica do município de Santa Amélia – PR. Resultados: Os resultados mostraram que no período de 2007 à 2011 houve uma prevalência total de 1.068 casos de câncer, de forma que à maior de tumores foi localizada no aparelho digestório (224 casos), pele (173 casos), mama (143 casos), útero (114 casos) e próstata (111 casos). Conclusão: O município de Santa Amélia – PR apresenta alta prevalência de casos de câncer se levado em consideração o numero total de habitantes. Dessa forma, é de suma importância que seja realizado um programa de conscientização voltado para a população, como forma de prevenção ao mesmo.
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