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Introdução: Os traumas abdominais representam notável importância dentre as causas predominantes de morbi-mortalidade no mundo. Em se tratando de óbitos relacionados a essas lesões, estão na categoria de causas externas, as quais no Brasil representam a segunda causa geral de mortalidade, principalmente na população em idade ativa. Notadamente, traumas estão fortemente relacionados a acidentes automobilísticos, cujas taxas vêm crescendo nos últimos anos. Neles, ocorrem os politraumas, cuja região abdominal é inclusa de forma prevalente. Objetivo: a presente pesquisa tem como objetivo apresentar o perfil de óbitos os quais sejam associados a trauma abdominal e submetido ao Instituto Médico-Legal, entre os anos de 2019 até 2021. Metodologia: estudo retrospectivo, do tipo transversal, de caráter fundamentalmente quantitativo, no qual foram avaliados os laudos de óbitos decorrentes de trauma abdominal necropsiados no IML de Toledo (PR), no período de 2019 a 2021. Foram avaliadas as variáveis sexo, idade, tipo de lesão, circunstância dos óbitos e órgão mais acometido. Resultados e discussão: dos 916 óbitos trazidos à Polícia Científica de Toledo (PR) advindos de causas externas, os inclusos dentre os traumas abdominais representaram um percentual de 51,05% (n=462), no período de 2019 a 2021. Observou-se maior prevalência de óbitos por acidentes automobilísticos (68,61%), cuja causa principal foi o politrauma (37,45%). O sexo masculino fora o mais prevalente, com 84,85% (n=392), cuja faixa etária teve concentração entre os 18 aos 29 anos. Os órgãos mais lesionados foram o fígado (69,31%) e o baço (33,66%). Considerações finais: nesta amostra houve predominância de óbitos por acidentes, principalmente associados ao trauma contuso, em homens na faixa entre 18 e 29 anos, cujo órgão mais lesado fora o fígado. O conhecimento acerca do perfil de óbitos é uma importante ferramenta epidemiológica frente a possíveis intervenções, além de servir como fonte estatística para outros trabalhos do âmbito médico-legal.
Introduction: Trauma represents a notable importance among the predominant causes of morbidity and mortality in the world. When it comes to deaths related to these injuries, they are in the category of external causes, since in Brazil they represent the second general cause of mortality, especially in the working-age population. Notably, traumas are strongly related to car accidents, whose rates have been increasing in recent years. In them, polytraumas occur, whose abdominal region is prevalently included. Objective: this research aims to present the profile of deaths which are associated with abdominal trauma and hospitalized at the Instituto Médico-Legal, between the years 2019 to 2021. Methodology: retrospective, cross-sectional study, fundamentally quantitative, in which the reports of deaths resulting from abdominal trauma necropsied at the IML of Toledo (PR), from 2019 to 2021, were evaluated. The variables were gender, age, type of injury, injuries of the deaths and most affected organ. Results and removal: Of the 916 deaths brought to the Scientific Police of Toledo (PR) from external causes, those included among abdominal traumas represented a percentage of 51.05% (n=462), in the period from 2019 to 2021. there was a higher prevalence of deaths from car accidents (68,61%), whose main cause was polytrauma (37.45%). Males were the most prevalent, with 84.85% (n=392), whose age group was concentrated between 18 and 29 years. The most injured organs were the liver (69.31%) and the spleen (33.66%). Final considerations: in this sample there was a predominance of deaths from accidents, mainly associated with blunt trauma, in men aged between 18 and 29 whose most injured organ outside the liver. Knowledge about the profile of deaths is an important epidemiological tool in the face of possible interventions, in addition to serving as a statistical source for other studies in the medical-legal field.
Introducción: El traumatismo abdominal representa notable importancia entre las causas predominantes de morbimortalidad en el mundo. Cuando se trata de muertes relacionadas con estas lesiones, se encuentran en la categoría de causas externas, que en Brasil representan la segunda causa general de mortalidad, especialmente en la población en edad de trabajar. En particular, el trauma está fuertemente relacionado con los accidentes automovilísticos, cuyas tasas han aumentado en los últimos años. En ellos se producen politraumatismos, cuya región abdominal está predominantemente incluida. Objetivo: esta investigación tiene como objetivo presentar el perfil de las muertes asociadas a traumatismo abdominal y presentadas al Instituto Médico Legal, entre los años 2019 y 2021. Metodología: estudio retrospectivo, transversal, de carácter fundamentalmente cuantitativo, en el que se analizaron los reportes de muertes. resultantes de trauma abdominal autopsiado en el IML de Toledo (PR), de 2019 a 2021. Se evaluaron las variables sexo, edad, tipo de lesión, circunstancias de las muertes y órgano más afectado. Resultados y discusión: de las 916 muertes aportadas a la Policía Científica de Toledo (PR) por causas externas, las incluidas dentro de los traumatismos abdominales representaron un porcentaje del 51,05% (n=462), en el periodo 2019 a 2021. observado- hubo mayor prevalencia de muertes por accidentes automovilísticos (68,61%), cuya principal causa fue el politraumatismo (37,45%). El sexo masculino fue el de mayor prevalencia, con 84,85% (n=392), cuyo grupo etario se concentró entre 18 y 29 años. Los órganos más lesionados fueron el hígado (69,31%) y el bazo (33,66%). Consideraciones finales: en esta muestra hubo predominio de muertes por accidentes, principalmente asociados a traumatismos cerrados, en hombres con edades entre 18 y 29 años, cuyo órgano más lesionado fue el hígado. El conocimiento sobre el perfil de defunciones es una importante herramienta epidemiológica de cara a posibles intervenciones, además de servir como fuente estadística para otros trabajos médico-legales.
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Gut dysbiosis is linked to type 1 diabetes mellitus (T1D). Inulin (INU), a prebiotic, modulates the gut microbiota, promoting beneficial bacteria that produce essential short-chain fatty acids for immune regulation. However, how INU affects T1D remains uncertain. Using a streptozotocin-induced (STZ) mouse model, we studied INU's protective effects. Remarkably, STZ + INU mice resisted T1D, with none developing the disease. They had lower blood glucose, reduced pancreatic inflammation, and normalized serum insulin compared with STZ + SD mice. STZ + INU mice also had enhanced mucus production, abundant Bifidobacterium, Clostridium cluster IV, Akkermansia muciniphila, and increased fecal butyrate. In cecal lymph nodes, we observed fewer CD4+Foxp3+ regulatory T cells expressing CCR4 and more Foxp3+CCR4+ cells in pancreatic islets, with higher CCL17 expression. This phenotype was absent in CCR4-deficient mice on INU. INU supplementation effectively protects against experimental T1D by recruiting CCR4+ regulatory T cells via CCL17 into the pancreas and altering the butyrate-producing microbiota.
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Diabetes Mellitus Tipo 1 , Microbioma Gastrointestinal , Ilhotas Pancreáticas , Camundongos , Animais , Inulina/farmacologia , Prebióticos , Modelos Animais de Doenças , Linfócitos T Reguladores , Butiratos/farmacologia , Fatores de Transcrição ForkheadRESUMO
AIM2 is an interferon-inducible HIN-200 protein family member and is well-documented for its roles in innate immune responses as a DNA sensor. Recent studies have highlighted AIM2's function on regulatory T cells (Treg) and follicular T cells (Tfh). However, its involvement in Th17 cell differentiation remains unclear. This study reveals that AIM2 promotes Th17 cell differentiation. AIM2 deficiency decreases IL-17A production and downregulates key Th17 associated proteins (RORγt, IL-1R1, IL-23R). AIM2 is located in the nucleus of Th17 cells, where it interacts with RORγt, enhancing its binding to the Il17a promoter. The absence of AIM2 hinders naive CD4 T cells from differentiating into functional Th17 cells and from inducing colitis in Rag1-/- mice. This study uncovers AIM2's role as a regulator of Th17 cell transcriptional programming, highlighting its potential as a therapeutic target for Th17 cell-mediated inflammatory diseases.
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Histone deacetylases (HDACs) are enzymes that regulate several processes, such as transcription, cell proliferation, differentiation and development. HDACs are classified as either Zn2+ -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 Zn2+ -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.wiley.com/doi/10.1111/bph.v179.8/issuetoc.
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Sirtuínas , Histona Desacetilases , Humanos , NADRESUMO
Type 1 diabetes (T1D) is an autoimmune disease characterized by the destruction of pancreatic ß cells. We show here that the protein NOD-like receptor family pyrin domain containing 1 (NLRP1) has a key role in the pathogenesis of mouse and human T1D. More specifically, downregulation of NLRP1 expression occurs during T helper 17 (Th17) differentiation, alongside greater expression of several molecules related to Th17 cell differentiation in a signal transducers and activators of transcription 3 (STAT3)-dependent pathway. These changes lead to a consequent increase in interleukin 17 (IL-17) production within the pancreas and higher incidence of diabetes in streptozotocin (STZ)-injected mice. Finally, in patients with T1D and a SNP (rs12150220) in NLRP1, there is a robust decrease in IL-17 levels in serum and in memory Th17 cells from peripheral blood mononuclear cells. Our results demonstrate that NLRP1 acts as a negative regulator of the Th17 cell polarization program, making it an interesting target for intervention during the early stages of T1D.
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Doenças Autoimunes/genética , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Tipo 1/genética , Proteínas NLR/metabolismo , Células Th17/imunologia , Animais , Humanos , Masculino , Camundongos , Camundongos Endogâmicos NOD , RatosRESUMO
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)-1ß 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.
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Disbiose/imunologia , Microbioma Gastrointestinal/imunologia , Inflamação/imunologia , Proteínas NLR/imunologia , Animais , HumanosRESUMO
Type 2 diabetes (T2D) is a metabolic disease characterized by increased inflammation, NOD-like receptors (NLRs) activation and gut dysbiosis. Our research group has recently reported that intestinal Th17 response limits gut dysbiosis and LPS translocation to visceral adipose tissue (VAT), protecting against metabolic syndrome. However, whether NOD2 receptor contributes intestinal Th17 immunity, modulates dysbiosis-driven metabolic tissue inflammation, and obesity-induced T2D remain poorly understood. In this context, we observed that mice lacking NOD2 fed a high-fat diet (HFD) display severe obesity, exhibit greater adiposity, and more hepatic steatosis compared to HFD-fed wild-type (WT) mice. In addition, they develop increased hyperglycemia, worsening of glucose intolerance, and insulin resistance. Notably, the deficiency of NOD2 causes a deviation from M2 macrophage and regulatory T cells (Treg) to M1 macrophage and mast cells into VAT compared to WT mice fed HFD. An imbalance was also observed in Th17/Th1 cell populations, with reduced IL-17 and IL-22 gene expression in the mesenteric lymph nodes (MLNs) and ileum, respectively, of NOD2-deficient mice fed HFD. 16S rRNA sequencing indicates lower richness, alpha diversity, and a depletion of Allobaculum, Lactobacillus, and enrichment with Bacteroides genera in these mice compared to HFD-fed WT mice. These alterations were associated with disrupted tight-junctions expression, augmented serum LPS, and bacterial translocation into VAT. Overall, NOD2 activation is required for a protective Th17 over Th1 immunity in the gut, which seems to decrease gram-negative bacteria outgrowth in gut microbiota, attenuating the endotoxemia, metainflammation, and protecting against obesity-induced T2D.
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Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Diabetes Mellitus Tipo 2/etiologia , Diabetes Mellitus Tipo 2/metabolismo , Inflamação/etiologia , Inflamação/metabolismo , Proteína Adaptadora de Sinalização NOD2/deficiência , Animais , Biomarcadores , Dieta Hiperlipídica , Modelos Animais de Doenças , Microbioma Gastrointestinal/imunologia , Perfilação da Expressão Gênica , Glucose/metabolismo , Imuno-Histoquímica , Insulina/sangue , Insulina/metabolismo , Mucosa Intestinal/imunologia , Mucosa Intestinal/metabolismo , Ilhotas Pancreáticas/metabolismo , Leucócitos/imunologia , Leucócitos/metabolismo , Metabolismo dos Lipídeos , Camundongos , Camundongos Knockout , Obesidade/etiologia , Obesidade/metabolismo , Permeabilidade , Transdução de SinaisRESUMO
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 ß cells, which ultimately results in protection against T1D onset in an STZ-induced diabetes model.
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Proteínas de Ligação a DNA/uso terapêutico , Diabetes Mellitus Experimental/genética , Imunidade Inata/genética , Animais , Homeostase , Humanos , Interleucina-18/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BLRESUMO
Sound evidence supports a role for interleukin-17 (IL-17) -producing γδ 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-/- ) were fed either a control diet (CD) or a high-fat diet (HFD) for 9 weeks. Our data demonstrate that IL-17RA-/- mice are protected against obesity, but develop hyperglycemia, hyperinsulinemia and insulin resistance. In parallel, HFD-fed IL-17RA-/- mice display intense inflammation in the ileum compared with WT mice on the HFD. IL-17RA-/- 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-/- 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-/- 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.