41 research outputs found
Targeting interleukin-1β protects from aortic aneurysms induced by disrupted transforming growth factor β signaling
Aortic aneurysms are life-threatening conditions with effective treatments mainly limited to emergency surgery or trans-arterial endovascular stent grafts, thus calling for the identification of specific molecular targets. Genetic studies have highlighted controversial roles of transforming growth factor β (TGF-β) signaling in aneurysm development. Here, we report on aneurysms developing in adult mice after smooth muscle cell (SMC)-specific inactivation of Smad4, an intracellular transducer of TGF-β. The results revealed that Smad4 inhibition activated interleukin-1β (IL-1β) in SMCs. This danger signal later recruited innate immunity in the adventitia through chemokine (C-C motif) ligand 2 (CCL2) and modified the mechanical properties of the aortic wall, thus favoring vessel dilation. SMC-specific Smad4 deletion in Il1r1- or Ccr2-null mice resulted in milder aortic pathology. A chronic treatment with anti-IL-1β antibody effectively hampered aneurysm development. These findings identify a mechanistic target for controlling the progression of aneurysms with compromised TGF-β signaling, such as those driven by SMAD4 mutations
Theragnostics of TRK-targeting agents (trackins): a challenge that promises reward
Therminologically, theragnostics combines therapeutics and diagnostics. Life at cellular and molecular level is a binary event (e.g., phosphorylation-dephosphorylation of proteins, methylation-demethylations of DNA and acetylation-deacetylation of histones) aimed at the maintenance of a sanogenic phenotype of the homeostasis. Herein, we focus on the neurotrophins with metabotrophic or pathogenic potentials, particularly nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) and their receptors Trk (tyrosine/tropomyosin receptor kinase; pronounced “track”). Accordingly, the term trackins was introduced which stands for Trk-targeting agents influencing agonistically or antagonistically the activity of TrkANGF, TrkBBDNF, and TrkCNT-3 receptor. We argue that multiple diseases may be trackins curable, for instance: (i) agonistic trackins may have therapeutic potentials for cardiometabolic diseases (e.g., atherosclerosis, obesity, T2DM, and metabolic syndrome) and for neurometabolic diseases (e.g., Alzheimer’s disease/T3DM), whereas (ii) antagonistic trackins may be drugs for prostate, breast, gastric, pancreatic and colon cancers, also for pain, and eye, skin and male genitourinary track diseases. Moreover, TrkANGF, TrkBBDNF and TrkCNT-3 receptor may be promising biomarkers for diagnosis and prognosis of these diseases. Altogether, the presented data may be a challenge that promises reward requiring a further pursuit
Oficinas de matemática elementar: resgatando e estruturando o conhecimento / Basic mathematics workshops: rescuing and structuring knowledge
Os altos Ăndices de reprovação e desistĂŞncia em disciplinas de exatas no ensino superior tem sido o principal assunto discutido no FĂłrum das Disciplinas do NĂşcleo Básico dos Bacharelados (ForBas) da Universidade TecnolĂłgica Federal do Paraná (UTFPR). Um ponto em comum, levantado pelos professores dos diversos Campi da UTFPR, está relacionado Ă defasagem na aprendizagem de conteĂşdos básicos da Matemática. Portanto, se torna imprescindĂvel buscar alternativas pedagĂłgicas para atenuar este problema. O projeto oficinas de matemática elementar propõe ofertar conteĂşdos básicos ou pertinentes ao ensino superior para alunos ingressantes pela estratĂ©gia de ensino hĂbrido por meio de oficinas presenciais e o uso de Ambientes Virtuais de Aprendizagem. As oficinas presenciais sĂŁo planejadas e desenvolvidas voluntariamente pelos discentes veteranos do curso de Licenciatura em Matemática e Engenharias, com supervisĂŁo dos professores proponentes do projeto. Desta maneira, busca-se propiciar aos acadĂŞmicos da Licenciatura desenvolvimento da prática pedagĂłgica; aos acadĂŞmicos das Engenharias a troca de experiĂŞncia e a interação “calouro” e “veterano”. Já no ambiente virtual, por meio da plataforma Moodle, os alunos retomam conteĂşdos de matemática elementar utilizando um sistema de trilha de aprendizagem. Neste ambiente o aluno encontra notas de aulas, exemplos resolvidos, exercĂcios, vĂdeos aulas e avaliação, que pode ser acessado sempre que surgirem dĂşvidas. Essa modalidade exige dos alunos uma postura ativa, desenvolvendo a autonomia no processo de estudo. Os resultados tĂŞm mostrado que os alunos participantes do projeto apresentam maior interação nas aulas de Cálculo Diferencial e Integral, desenvolveram rotinas de estudos e melhoraram o desempenho nas avaliações.Â
GDF11 induces mild hepatic fibrosis independent of metabolic health
Background & aims: Growth Differentiation Factor 11 (GDF11) is an anti-aging factor, yet its role in liver diseases is not established. We evaluated the role of GDF11 in healthy conditions and in the transition from non-alcoholic fatty liver disease (NAFLD) to non-alcoholic steatohepatitis (NASH). Results: GDF11 mRNA levels positively correlated with NAFLD activity score and with CPT1, SREBP, PPARÎł and Col1A1 mRNA levels, and associated to portal fibrosis, in morbidly obese patients with NAFLD/NASH. GDF11-treated mice showed mildly exacerbated hepatic collagen deposition, accompanied by weight loss and without changes in liver steatosis or inflammation. GDF11 triggered ALK5-dependent SMAD2/3 nuclear translocation and the pro-fibrogenic activation of HSC. Conclusions: GDF11 supplementation promotes mild liver fibrosis. Even considering its beneficial metabolic effects, caution should be taken when considering therapeutics that regulate GDF11. Methods: We analyzed liver biopsies from a cohort of 33 morbidly obese adults with NAFLD/NASH. We determined the correlations in mRNA expression levels between GDF11 and genes involved in NAFLD-to-NASH progression and with pathological features. We also exposed wild type or obese mice with NAFLD to recombinant GDF11 by daily intra-peritoneal injection and monitor the hepatic pathological changes. Finally, we analyzed GDF11-activated signaling pathways in hepatic stellate cells (HSC)
Emodin Prevents Intrahepatic Fat Accumulation, Inflammation and Redox Status Imbalance During Diet-Induced Hepatosteatosis in Rats
High-fat and/or high-carbohydrate diets may predispose to several metabolic disturbances including liver fatty infiltration (hepatosteatosis) or be associated with necro-inflammation and fibrosis (steatohepatitis). Several studies have emphasized the hepatoprotective effect of some natural agents. In this study, we investigated the potential therapeutic effects of the treatment with emodin, an anthraquinone derivative with anti-oxidant and anti-cancer abilities, in rats developing diet-induced hepatosteatosis and steatohepatitis. Sprague-Dawley rats were fed a standard diet (SD) for 15 weeks, or a high-fat/high-fructose diet (HFD/HF). After 5 weeks, emodin was added to the drinking water of some of the SD and HFD/HF rats. The experiment ended after an additional 10 weeks. Emodin-treated HFD/HF rats were protected from hepatosteatosis and metabolic derangements usually observed in HFD/HF animals. Furthermore, emodin exerted anti-inflammatory activity by inhibiting the HFD/HF-induced increase of tumor necrosis factor (TNF)-α. Emodin also affected the hepatocytes glutathione homeostasis and levels of the HFD/HF-induced increase of glutathionylated/phosphorylated phosphatase and tensin homolog (PTEN). In conclusion, we demonstrated that a natural agent such as emodin can prevent hepatosteatosis, preserving liver from pro-inflammatory and pro-oxidant damage caused by HFD/HF diet. These findings are promising, proposing emodin as a possible hindrance to progression of hepatosteatosis into steatohepatitis
Photoplethysmographic Prediction of the Ankle-Brachial Pressure Index through a Machine Learning Approach
Cardiovascular disease is a leading cause of death. Several markers have been proposed to predict cardiovascular morbidity. The ankle-brachial index (ABI) marker is defined as the ratio between the ankle and the arm systolic blood pressures, and it is generally assessed through sphygmomanometers. An alternative tool for cardiovascular status assessment is Photoplethysmography (PPG). PPG is a non-invasive optical technique that measures volumetric blood changes induced by pulse pressure propagation within arteries. However, PPG does not provide absolute pressure estimation, making assessment of cardiovascular status less direct. The capability of a multivariate data-driven approach to predict ABI from peculiar PPG features was investigated here. ABI was measured using a commercial instrument (Enverdis Vascular Explorer, VE-ABI), and it was then used for a General Linear Model estimation of ABI from multi-site PPG in a supervised learning framework (PPG-ABI). A Receiver Operating Characteristic (ROC) analysis allowed to investigate the capability of PPG-ABI to discriminate cardiovascular impairment as defined by VE-ABI. Findings suggested that ABI can be estimated form PPG (r = 0.79) and can identify pathological cardiovascular status (AUC = 0.85). The advantages of PPG are simplicity, speed and operator-independency, allowing extensive screening of cardiovascular status and associated cardiovascular risks
High prevalence of ALK+/ROS1+ cases in pulmonary adenocarcinoma of adoloscents and young adults
OBJECTIVES: To investigate prevalence and age-distribution of ALK- or ROS1-translocated adenocarcinomas in patients ≤50 years of age.
MATERIALS AND METHODS: Paraffin sections of pulmonary adenocarcinoma were analyzed for ALK (637 cases) and ROS1 (376 cases) translocations using FISH, and for EGFR mutations (789 cases) using mutant-specific Real-Time PCR.
RESULTS: ALK or ROS1 fusions were detected in 55 of 637 cases (8.6%). When patients were stratified for age, it was found that six of six cases (100%) of lung adenocarcinoma diagnosed in patients <30 years of age were translocated for ALK (4 cases) or ROS1 (2 cases). With the increase of age, there was a gradual decrease in the percentage of positive cases. In fact, ALK-translocated or ROS1-translocated cases were 5 of 17 cases (29%) in the 31-40 years age-group, 6 of 46 cases (13%) in the 41-50 years age-group, and 38 of 568 cases (7.0%) in patients older than 50 years. The six patients <30 years of age (5F/1M), including two pediatric patients (≤18 years old), presented with stage IV disease, were never or light smoker, and had no family history of pulmonary tumours. Four of the six patients, were treated with crizotinib and had an objective response.
CONCLUSIONS: Our findings provide evidence that ALK or ROS1 translocations are crucial events in tumourigenesis of pulmonary adenocarcinoma of very young patients, including pediatric patients