Search

Simple Summary: Anaplastic thyroid carcinoma is a rare and very aggressive thyroid carcinoma. Current conventional treatments for anaplastic thyroid carcinoma are not very effective, so there is an urgent need for new types of treatment for this disease. Some molecules known as cardiotonic steroids (e.g., ouabain), which were previously used for the treatment of patients with heart failure, appear to have anti-tumoral effects and cancer therapy potential. The aim of the present work was to analyze the effects of ouabain in human anaplastic thyroid carcinoma, using an anaplastic thyroid cell line (called 8505C) as the model. With this work, we hope to contribute to the study of the potential anti-tumoral roles of ouabain in the search for alternative anaplastic thyroid carcinoma treatments. Anaplastic thyroid carcinoma (ATC) is a rare, but aggressive, carcinoma derived from follicular cells. While conventional treatments may improve patients' survival, the lethality remains high. Therefore, there is an urgent need for more effective ATC treatments. Cardiotonic steroids, such as ouabain, have been shown to have therapeutic potential in cancer treatment. Thus, we aimed to evaluate ouabain's effects in human anaplastic thyroid cells. For this, 8505C cells were cultured in the presence or absence of ouabain. Viability, cell death, cell cycle, colony formation and migratory ability were evaluated in ouabain-treated and control 8505C cells. The expression of differentiation and epithelial-to-mesenchymal transition (EMT) markers, as well as IL-6, TGFb1 and their respective receptors were also quantified in these same cells. Our results showed that ouabain in vitro decreased the number of viable 8505C cells, possibly due to an inhibition of proliferation. A reduction in migration was also observed in ouabain-treated 8505C cells. In contrast, decreased mRNA levels of PAX8 and TTF1 differentiation markers and increased levels of the N-cadherin EMT marker, as well as IL-6 and TGFb1, were found in ouabain-treated 8505C cells. In short, ouabain may have anti-proliferative and anti-migratory effect on 8505C cells, but maintains an aggressive and undifferentiated profile. [ABSTRACT FROM AUTHOR]

Background: Asthma is a chronic disease of the airways and, despite the advances in the knowledge of associated genetic regions in recent years, their mechanisms have yet to be explored. Several genome-wide association studies have been carried out in recent years, but none of these have involved Latin American populations with a high level of miscegenation, as is seen in the Brazilian population. Methods: 1246 children were recruited from a longitudinal cohort study in Salvador, Brazil. Asthma symptoms were identified in accordance with an International Study of Asthma and Allergies in Childhood (ISAAC) questionnaire. Following quality control, 1 877 526 autosomal SNPs were tested for association with childhood asthma symptoms by logistic regression using an additive genetic model. We complemented the analysis with an estimate of the phenotypic variance explained by common genetic variants. Replications were investigated in independent Mexican and US Latino samples. Results: Two chromosomal regions reached genome-wide significance level for childhood asthma symptoms: the 14q11 region flanking the DAD1 and OXA1L genes (rs1999071, MAF 0.32, OR 1.78, 95 % CI 1.45-2.18, p-value 2.83 × 10-8) and 15q22 region flanking the FOXB1 gene (rs10519031, MAF 0.04, OR 3.0, 95 % CI 2.02-4.49, p-value 6.68 × 10-8 and rs8029377, MAF 0.03, OR 2.49, 95 % CI 1.76-3.53, p-value 2.45 × 10-7). eQTL analysis suggests that rs1999071 regulates the expression of OXA1L gene. However, the original findings were not replicated in the Mexican or US Latino samples. Conclusions: We conclude that the 14q11 and 15q22 regions may be associated with asthma symptoms in childhood. [ABSTRACT FROM AUTHOR]

Severe asthma is a multifactorial disorder with marked phenotypic heterogeneity and complex interactions between genetics and environmental risk factors, which could, at least in part, explain why during standard pharmacologic treatment, many patients remain poorly controlled and at an increased risk of airway remodeling and disease progression. The concept of "precision medicine" to better suit individual unique needs is an emerging trend in the management of chronic respiratory diseases. Over the past few years, Genome-Wide Association Studies (GWAS) have revealed novel pharmacogenetic variants related to responses to inhaled corticosteroids and the clinical efficacy of bronchodilators. Optimal clinical response to treatment may vary between racial/ethnic groups or individuals due to genetic differences. It is also plausible to assume that epigenetic factors play a key role in the modulation of gene expression patterns and inflammatory cytokines. Remarkably, specific genetic variants related to treatment effectiveness may indicate promising pathways for novel therapies in severe asthma. In this review, we provide a concise update of genetic determinants of poor response to treatment in severe asthma and future directions in the field. [ABSTRACT FROM AUTHOR]

Background: Asthma is a complex disorder with multiple phenotypes which can influence its severity and response to treatment. The TH17 lymphocytes producing IL-17A and IL17-F cytokines, may have a role on asthma inflammation. The aim of our study was to evaluate the association between genetic variants in IL17 pathway genes with asthma and atopy markers. Materials and methods: Genotyping was performed using a commercial panel in 1245 participants of SCAALA cohort. The study included 91 SNVs in IL-17 pathway genes. Logistic regressions for asthma and atopy markers were performed using PLINK 1.9. In silico analyses were performed using rSNPbase, RegulomeDB, and Gtex portal for in silico gene expression. Results and discussion: The T allele of rs1974226 in IL17A was positively associated with asthma (OR: 1.37; 95% CI 1.02–1.82). Also, the T allele of rs279548 was positively associated with asthma (OR: 1.30; 95% CI 1.02–1.64), atopy (OR: 1.62; 95% CI 1.05–2.50) and increased expression of the IL17RC in lung and whole blood tissues. The others genetic variants in the IL17 pathways genes were associated with both protection and risk for asthma development as well as with IgE levels. Conclusion: The genetic variants in IL-17-related genes are associated with the atopic asthma phenotype and IgE production. [ABSTRACT FROM AUTHOR]

• Variants in the DAD1 and OXA1L genes are linked to asthma and atopy in Brazilian adults. • Significant associations were observed between SNPs in DAD1 and OXA1L with gene expression, cytokines and IgE levels. • Higher DAD1 expression was observed in severe asthmatics compared to moderate cases. • OXA1L expression was higher in severe asthmatics not using corticosteroids. • Future research should focus on understanding the functional impact of these genes to improve asthma management Asthma is a complex disease characterized by reversible and intermittent airway obstruction that has shown a high prevalence and unacceptable mortality in adults. In recent years, several genome-wide association studies (GWAS) have identified variants linked to asthma susceptibility. The DAD1 gene is known for regulating programmed cell death, and OXA1L is described for its involvement in mitochondrial biogenesis and oxidative phosphorylation. The present study aimed to identify variants in the DAD1 and OXA1L genes and to evaluate the association with asthma and atopy markers in adults. 1,084 individuals were divided into mild to moderate asthma, severe asthma, and participants with no asthma (controls). Association analyses were performed using a multivariate logistic regression model adjusted for sex, age, body mass index (BMI), smoking, forced expiratory volume in 1 s (FEV1), and component ancestry master (PC1) using PLINK 1.9 software. This study identified new variants in the DAD1 and OXA1L genes that had never been described before. The C allele of rs200470407 in OXA1L was negatively associated with poor asthma control (OR: 0.32; p-value 0.049) and increased IL-13 (p-value < 0.0001). The alternative allele of rs1681577 was associated with severe asthma (OR: 2.23; p-value 0.01), pulmonary obstruction (OR: 4.12; p-value 0.046), and eosinophilia (OR: 2.42; p-value < 0.001). Our findings demonstrate that variants in the DAD1 and OXA1L genes are linked to asthma and atopy in Brazilian adults. [ABSTRACT FROM AUTHOR]

• Asthma patients who carry the AA/AG genotypes of rs2601796 have a greater chance of having a more severe disease. • Furthermore, patients with moderate to severe asthma with those genotypes have worse lung function and reduced bronchodilator response. • The risk effect of this genetic variant appears to be due to its impact on the expression of the ADCY9 gene. Asthma is a respiratory disease caused by the interaction of genetic and environmental factors. The adenylyl cyclase type 9 (ADCY9) enzyme produces the cyclic-adenosinemonophosphate (cAMP), important mediator involved in bronchodilation and immunomodulatory response. The aim of this study was to investigate if rs2601796 and rs2532019 variants in the ADCY9 gene are associated with asthma and lung function. The study comprised 1,052 subjects. Logistic regressions were done using PLINK 1.9 adjusted by sex, age, BMI, smoke and principal components. Bronchodilator responsiveness was assessed using the percentage of difference in FEV1 before and after the bronchodilator use. The in silico analysis for gene expression was performed in the GTEx Portal. The variant rs2601796 (AA/AG genotype) was positively associated with asthma severity (OR: 1.60 IC95%: 1.08–2.39) and with obstruction in individuals with severe asthma (OR: 3.10, IC95%: 1.11–8.62). Individuals with severe asthma and the AA/AG genotype of rs2601796 had less responsiveness to bronchodilators and also a lower expression of ADCY9 in lung and whole blood. The variant rs2532019 (TT/GT genotype) also downregulated the ADCY9 gene expression, but no significant association with the studied phenotypes was found. Thus, the variant in ADCY9 was associated with worse asthma outcomes, including a lower response to bronchodilators, likely due to the impact on its gene expression rate. This variant may be useful in the future to assist in personalized management of patients with asthma. [ABSTRACT FROM AUTHOR]

Highlights • Genetic variants in the DAD1 and OXA1L genes are significantly associated with asthma and/or allergy markers. • We have demonstrated increased DAD1 expression levels in asthmatic individuals. • These variants are involved in regulatory mechanisms and may impact the occurrence of asthma and allergy in our population. Abstract Atopic asthma, which is characterized by the chronic inflammation and morbidity of airways, is a disease of great complexity, and multiple genetic and environmental factors are involved in its etiology. In the first genome-wide association study (GWAS) conducted in Brazil for asthma, a positive association was found between atopic asthma and a variant (rs1999071), which is located between the DAD1 and OXA1L genes, although neither gene has previously been reported to be associated with asthma or allergies. The DAD1 gene is involved in the regulation of programmed cell death, and OXA1L is involved in biogenesis and mitochondrial oxidative phosphorylation. This study aimed to evaluate how polymorphisms in DAD1 and OXA1L are associated with asthma and markers of atopy in individuals from the Salvador cohort of the SCAALA (Social Change Asthma and Allergy in Latin America) program. The DNA of 1220 individuals was genotyped using the Illumina 2.5 Human Omni Bead chip. Logistic regression analyses were performed with PLINK 1.9 software to verify the association between DAD1 and OXA1L polymorphisms and asthma and atopic markers, adjusted for sex, age, helminth infections and ancestry markers, using an additive model. The DAD1 and OXA1L genes were associated with some of the evaluated phenotypes, such as asthma, skin prick test (SPT), specific IgE for aeroallergens, and Th1/Th2-type cytokine production. Using qPCR, as well as in silico gene expression analysis, we have demonstrated that some of the polymorphisms in both genes are able to affect their respective gene expression levels. In addition, DAD1 was over-expressed in asthmatic patients when compared with controls. Thus, our findings demonstrate that variants in both the DAD1 and OXA1L genes may affect atopy and asthma in a Latin American population with a high prevalence of asthma. [ABSTRACT FROM AUTHOR]

Ethnopharmacological relevance Solanum paniculatum L., popularly known as jurubeba, is a common subtropical plant from Brazil, Paraguay, Bolivia and Argentina, that is used in folk medicine for the treatment of anemia, gastrointestinal disorders and inflammatory conditions in general. In addition to that, an ethnobotanical survey in “Todos os Santos” Bay have pointed out S. paniculatum as an herb to treat asthma. Previous publications have shown that S. paniculatum possesses antibiotic, antioxidant and modulatory effects on gastric acid secretion; however, its anti-inflammatory potential remains unexplored. Aim of the study Herein, we analyzed the S. paniculatum fruits hexane extract ( Sp E) for the presence of stigmasterol and β-sitosterol and investigated the anti-inflammatory effect of Sp E in vitro. Materials and methods Sp E was subjected to high-performance liquid chromatography (HPLC) for standardization and quantification of stigmasterol and β-sitosterol. Spleen cells from BALB/c mice were cultivated and stimulated with pokeweed mitogen and also exposed to 15, 30 and 60 µg/mL of Sp E. Following treatment, levels of IFN-γ, IL-4 and IL-10 in the culture supernatants were assessed by ELISA. We also evaluated nitric oxide (NO) production by murine LPS-stimulated peritoneal macrophages using the Griess technique. In addition, the ability of Sp E to stabilize membranes was assessed using a model of hemolysis induced by heat on murine erythrocytes. Gene expression of Th1-cell-specific Tbx21 transcription factor ( TBET ), zinc-finger transcription factor-3 ( GATA3 ), and nuclear factor-κB ( NFKB ) in murine spleen cells were assessed by quantitative Polymerase Chain Reaction (qRT-PCR). Results Sp E at 15, 30 and 60 µg/mL significantly attenuated cell proliferation, decreased IL-4 release, reduced NO production and improved erythrocyte membrane stabilization in a concentration-dependent manner. Sp E was also able to decrease the release of IFN-γ without altering IL-10 levels. The mechanism whereby Sp E decreased inflammatory markers may be related to the reduction of NFKB , TBET and GATA3 gene expression. Conclusions This study is the first to test the anti-inflammatory action of S. paniculatum . Herein, we provided evidence for the popular use of S. paniculatum in inflammatory conditions. Additional studies must be conducted to further explore the anti-inflammatory potential of Sp E and to elucidate possible clinical applications. [ABSTRACT FROM AUTHOR]

Alternagin-C (ALT-C), a disintegrin-like protein purified from the venom of the Brazilian snake Bothrops alternatus, interacts with the major collagen I receptor, the α2β1 integrin, inhibiting collagen binding. Here we show that ALT-C also inhibits the adhesion of a mouse fibroblast cell line (NIH-3T3) to collagen I (IC50 2.2 μM). In addition, when immobilized on plate wells, ALT-C supports the adhesion of this cell line as well as of human vein endothelial cell (HUVEC). ALT-C (3 μM) does not detach cells that were previously bound to collagen I. ALT-C (5 mM) induces HUVEC proliferation in vitro, and it inhibits the positive effect of vascular endothelial growth factor (VEGF) or FGF-2 on the proliferation of these cells, thus suggesting a common mechanism for these proteins. Gene expression analysis of human fibroblasts growing on ALT-C- or collagen-coated plates showed that ALT-C and collagen I induce a very similar pattern of gene expression. When compared with cells growing on plastic only, ALT-C up-regulates the expression of 45 genes including the VEGF gene and downregulates the expression of 30 genes. Fibroblast VEGF expression was confirmed by RT-PCR and ELISA assay. Up-regulation of the VEGF gene and other growth factors could explain the positive effect on HUVEC proliferation. ALT-C also strongly activates Akt/PKB phosphorylation, a signaling event involved in endothelial survival and angiogenesis. In conclusion, ALT-C acts as a survival factor, promoting adhesion and endothelial cell proliferation. [ABSTRACT FROM AUTHOR]