RESUMO
Argentina is a leading honey producer and honey bees are also critical for pollination services and wild plants. At the same time, it is a major crop producer with significant use of insecticides, posing risks to bees. Therefore, the presence of the highly toxic insecticide chlorpyrifos, and forbidden contaminants (organochlorine pesticides (OCPs), polychlorinated biphenyls (PCBs) and polybrominated diphenyl ethers (PBDEs)) was investigated in honey bee, beebread, wax and honey samples in apiaries from three contrasting regions of Argentina. Chlorpyrifos was detected in all samples with higher levels during period 1 (spring) in contrast to period 2 (fall), agreeing with its season-wise use in different crops, reaching 3.05 ng/g in honey bees. A subsequent first-tier pesticide hazard analysis revealed that it was relevant to honey bee health, mainly due to the high concentrations found in wax samples from two sites, reaching 132.4 ng/g. In addition, wax was found to be the most contaminated matrix with a prevalence of OCPs (∑OCPs 58.23-172.99 ng/g). Beebread samples showed the highest concentrations and diversity of pesticide residues during period 1 (higher temperatures). A predominance of the endosulfan group was registered in most samples, consistent with its intensive past use, especially in Central Patagonia before its prohibition. Among the industrial compounds, lighter PCB congeners dominated, suggesting the importance of atmospheric transport. The spatio-temporal distribution of pesticides shows a congruence with the environmental characteristics of the areas where the fields are located (i.e., land use, type of productive activities and climatic conditions). Sustained monitoring of different pollutants in beekeeping matrices is recommended to characterize chemical risks, assess the health status of honey bee hives and the pollution levels of different agroecosystems. This knowledge will set a precedent for South America and be helpful for actions focused on the conservation of pollination services, apiculture and ecosystems in Argentina.
Assuntos
Monitoramento Ambiental , Poluentes Ambientais , Mel , Abelhas , Argentina , Animais , Mel/análise , Poluentes Ambientais/análise , Bifenilos Policlorados/análise , Ceras/análise , Ceras/química , Éteres Difenil Halogenados/análise , Praguicidas/análise , Estações do Ano , Clorpirifos/análiseRESUMO
The most promising treatment options for severe uncontrolled asthma (SUA) have emerged in recent years with the development of monoclonal antibodies for blocking selective targets responsible for the underlying inflammation, such as mepolizumab and benralizumab. However, there is variability in treatment response that is not fully controlled. The variability of the response to mepolizumab and benralizumab could be influenced by single-nucleotide polymorphisms (SNPs), and it would be useful to detect these and use them as predictive biomarkers of response. We conducted a retrospective observational cohort study of 72 Caucasian patients recruited from a tertiary hospital with severe uncontrolled eosinophilic asthma treated with mepolizumab and benralizumab. Polymorphisms in the IL5 (rs4143832, rs17690122), RAD50 (rs11739623, rs4705959), IL1RL1 (rs1420101, rs17026974, rs1921622), GATA2 (rs4857855), IKZF2 (rs12619285), FCGR2A (rs1801274), FCGR2B (rs3219018, rs1050501), FCGR3A (rs10127939, rs396991), FCER1A (rs2251746, rs2427837), FCER1B (rs1441586, rs573790, rs569108), and ZNF415 (rs1054485) genes were analyzed by real-time polymerase chain reaction (PCR) using Taqman probes. The response was analyzed after 12 months of treatment. In patients under mepolizumab treatment, a treatment response defined as a reduction in exacerbations was associated with ZNF415 rs1054485-T (p = 0.042; OR = 5.33; 95% CI = 1.06-30.02), treatment response defined as a reduction in oral corticosteroids use was associated with the number of exacerbations in the previous year (p = 0.029; OR = 3.89; 95% CI = 1.24-14.92), and treatment response defined as improvement in lung function was associated with the age at the beginning of biological therapy (p = 0.002; OR = 1.10; 95% CI = 1.04-1.18), FCER1B rs569108-AA (p < 0.001; OR = 171.06; 95% CI = 12.94-6264.11), and FCER1A rs2427837-A (p = 0.021; OR = 8.61; 95% CI = 1.71-76.62). On the other hand, in patients under benralizumab treatment, treatment response, defined as a reduction in exacerbations, was associated with ZNF415 rs1054485-T (p = 0.073; OR = 1.3 × 108; 95% CI = 1.8 × 10-19-NA), FCER1B rs569108-AA (p = 0.050; OR = 11.51; 95% CI = 1.19-269.78), allergies (p = 0.045; OR = 4.02; 95% CI = 1.05-16.74), and sex (p = 0.028; OR = 4.78; 95% CI = 1.22-20.63); and treatment response defined as improvement in lung function was associated with polyposis (p = 0.027; OR = 9.16; 95% CI = 1.58-91.4), IKZF2 rs12619285-AA (p = 0.019; OR = 9.1; 95% CI = 1.7-75.78), IL5 rs4143832-T (p = 0.017; OR = 11.1; 95% CI = 1.9-112.17), and FCER1B rs1441586-C (p = 0.045; OR = 7.81; 95% CI = 1.16-73.45). The results of this study show the potential influence of the studied polymorphisms on the response to mepolizumab and benralizumab and the clinical benefit that could be obtained by defining predictive biomarkers of treatment response.
Assuntos
Antiasmáticos , Anticorpos Monoclonais Humanizados , Asma , Polimorfismo de Nucleotídeo Único , Humanos , Asma/tratamento farmacológico , Asma/genética , Feminino , Masculino , Anticorpos Monoclonais Humanizados/uso terapêutico , Pessoa de Meia-Idade , Antiasmáticos/uso terapêutico , Adulto , Estudos Retrospectivos , Biomarcadores , Resultado do Tratamento , IdosoRESUMO
The enzymatic reduction of carbon dioxide presents limited applicability due to denaturation and the impossibility of biocatalyst recovery; disadvantages that can be minimized by its immobilization. Here, a recyclable bio-composed system was constructed by in-situ encapsulation under mild conditions using formate dehydrogenase in a ZIF-8 metalorganic framework (MOF) in the presence of magnetite. The partial dissolution of ZIF-8 in the enzyme's operation medium can be relatively inhibited if the concentration of magnetic support used exceeds 10â mg mL-1 . The bio-friendly environment for immobilization does not harm the integrity of the biocatalyst, and the production of formic acid is improved 3.4-fold compared to the free enzyme because the MOFs act as concentrators of the enzymatic cofactor. Furthermore, the bio-composed system retains 86 % of its activity after a long time of five cycles, thus indicating an excellent magnetic recovery and a good reusability.
Assuntos
Formiato Desidrogenases , Oxirredução , Dióxido de Carbono/química , Formiato Desidrogenases/química , Formiato Desidrogenases/metabolismo , CápsulasRESUMO
Colorectal cancer (CRC) is a highly prevalent form of neoplasm worldwide. Capecitabine, an oral antimetabolite, is widely used for CRC treatment; however, there exists substantial variation in individual therapy response. This may be due to genetic variations in genes involved in capecitabine pharmacodynamics (PD). In this study, we investigated the role of single-nucleotide polymorphisms (SNPs) related to capecitabine's PD on disease-free survival (DFS) in CRC patients under adjuvant treatment. Thirteen SNPs in the TYMS, ENOSF1, MTHFR, ERCC1/2, and XRCC1/3 genes were genotyped in 142 CRC patients using real-time PCR with predesigned TaqMan® probes. A significant association was found between favorable DFS and the ENOSF1 rs2612091-T allele (p = 0.010; HR = 0.34; 95% CI = 0.14-0.83), as well as with the TYMS/ENOSF1 region ACT haplotype (p = 0.012; HR = 0.37; 95% CI = 0.17-0.80). Other factors such as low histological grade (p = 0.009; HR = 0.34; 95% CI = 0.14-0.79) and a family history of cancer (p = 0.040; HR = 0.48; 95% CI = 0.23-0.99) were also linked to improved DFS. Therefore, the SNP ENOSF1 rs2612091 could be considered as a predictive genetic biomarker for survival in CRC patients receiving capecitabine-based adjuvant regimens.
Assuntos
Neoplasias Colorretais , Polimorfismo de Nucleotídeo Único , Humanos , Capecitabina/farmacologia , Capecitabina/uso terapêutico , Terapia Combinada , Alelos , Adjuvantes Imunológicos , Adjuvantes Farmacêuticos , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Proteína 1 Complementadora Cruzada de Reparo de Raio-XRESUMO
Biological therapies only benefit one-third of patients with Crohn's disease (CD). For this reason, a deeper understanding of the mechanisms by which biologics elicit their effect on intestinal mucosa is needed. Increasing evidence points toward the involvement of long noncoding RNAs (lncRNAs) in the pathogenesis of CD, although their role remains poorly studied. We aimed to characterize lncRNA profiles in the ileum and colon from CD patients and evaluate the effect of anti-TNF-α treatment on their transcription. Terminal ileum and left colon samples from 30 patients (active CD = 10, quiescent CD = 10, and healthy controls (HCs) = 10) were collected for RNA-seq. The patients were classified according to endoscopic activity. Furthermore, biopsies were cultured with infliximab, and their transcriptome was determined by Illumina gene expression array. A total of 678 differentially expressed lncRNAs between the terminal ileum and left colon were identified in HCs, 438 in patients with quiescent CD, and 468 in patients with active CD. Additionally, we identified three new lncRNAs in the ileum associated with CD activity. No differences were observed when comparing the effect of infliximab according to intestinal location, presence of disease (CD vs. HC), and activity (active vs. quiescent). The expression profiles of lncRNAs are associated with the location of intestinal tissue, being very different in the ileum and colon. The presence of CD and disease activity are associated with the differential expression of lncRNAs. No modulatory effect of infliximab has been observed in the lncRNA transcriptome.
Assuntos
Doença de Crohn , RNA Longo não Codificante , Humanos , Doença de Crohn/tratamento farmacológico , Doença de Crohn/genética , Doença de Crohn/metabolismo , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Infliximab/farmacologia , Infliximab/uso terapêutico , Inibidores do Fator de Necrose Tumoral/farmacologia , Fator de Necrose Tumoral alfa/metabolismo , Colo/patologia , Íleo/metabolismo , Mucosa Intestinal/metabolismoRESUMO
Severe Uncontrolled Asthma (SUA) counts for more than 25% of cases of severe asthma. The main factors that impair the quality of life of these patients are high doses of oral corticosteroids, the presence of exacerbations, and reduced lung function. The objective of this study was to evaluate, in real life, the clinical improvement of patients with SUA treated with anti-interleukin 5 (IL5) therapies: mepolizumab and benralizumab, together with the search for biomarkers associated with the response. We conducted a retrospective observational cohort study that included patients with severe uncontrolled eosinophilic asthma in a tertiary hospital receiving biological therapies. Three types of response were evaluated: improvement in lung function, reduction in exacerbations, and decrease in the use of oral corticosteroids. After 12 months of treatment, significant reductions were found in the number of exacerbations, the use of oral corticosteroids, and blood eosinophil levels for both biological therapies (p < 0.001). Lung function improved, achieving a significant improvement in %FEV1 (p < 0.001), as well as asthma control, with a significant increase in asthma control test (ACT) scores in both therapies. The markers associated with the corticosteroid-saving effect were the low doses of oral corticosteroids and absence of exacerbations for mepolizumab, and higher blood eosinophilia, absence of chronic obstructive pulmonary disease (COPD), and reduction in oral corticosteroid cycles for benralizumab. The greatest improvement in lung function in both therapies was linked to lower previous FEV1 levels and absence of other respiratory diseases. The reduction in exacerbations was associated with absence of exacerbations the previous year for mepolizumab and never smokers for benralizumab. The results of this real-life study confirm the clinical benefit obtained after the introduction of an anti-IL5 biological therapy and the possible predictive biomarkers of response to treatment.
Assuntos
Antiasmáticos , Asma , Eosinofilia Pulmonar , Humanos , Antiasmáticos/uso terapêutico , Qualidade de Vida , Estudos Retrospectivos , Asma/tratamento farmacológico , Asma/complicações , Corticosteroides/uso terapêutico , BiomarcadoresRESUMO
Biological therapies (BTs) indicated for psoriasis are highly effective; however, not all patients obtain good results, and loss of effectiveness is the main reason for switching. Genetic factors may be involved. The objective of this study was to evaluate the influence of single-nucleotide polymorphisms (SNPs) on the drug survival of tumor necrosis factor inhibitors (anti-TNF) medications and ustekinumab (UTK) in patients diagnosed with moderate-to-severe psoriasis. We conducted an ambispective observational cohort study that included 379 lines of treatment with anti-TNF (n = 247) and UTK (132) in 206 white patients from southern Spain and Italy. The genotyping of the 29 functional SNPs was carried out using real-time polymerase chain reaction (PCR) with TaqMan probes. Drug survival was evaluated with Cox regression and Kaplan-Meier curves. The multivariate analysis showed that the HLA-C rs12191877-T (hazard ratio [HR] = 0.560; 95% CI = 0.40-0.78; p = 0.0006) and TNF-1031 (rs1799964-C) (HR = 0.707; 95% CI = 0.50-0.99; p = 0.048) polymorphisms are associated with anti-TNF drug survival, while TLR5 rs5744174-G (HR = 0.589; 95% CI = 0.37-0.92; p = 0.02), CD84 rs6427528-GG (HR = 0.557; 95% CI = 0.35-0.88; p = 0.013) and PDE3A rs11045392-T together with SLCO1C1 rs3794271-T (HR = 0.508; 95% CI = 0.32-0.79; p = 0.002) are related to UTK survival. The limitations are the sample size and the clustering of anti-TNF drugs; we used a homogeneous cohort of patients from 2 hospitals only. In conclusion, SNPs in the HLA-C, TNF, TLR5, CD84, PDE3A, and SLCO1C1 genes may be useful as biomarkers of drug survival of BTs indicated for psoriasis, making it possible to implement personalized medicine that will reduce financial healthcare costs, facilitate medical decision-making and improve patient quality of life. However, further pharmacogenetic studies need to be conducted to confirm these associations.
Assuntos
Transportadores de Ânions Orgânicos , Psoríase , Humanos , Inibidores do Fator de Necrose Tumoral/uso terapêutico , Antígenos HLA-C , Qualidade de Vida , Receptor 5 Toll-Like , Psoríase/tratamento farmacológico , Psoríase/genética , Psoríase/diagnóstico , Ustekinumab/uso terapêutico , Terapia Biológica/métodos , Adalimumab/uso terapêutico , Fator de Necrose Tumoral alfa/uso terapêutico , Infliximab/uso terapêutico , Família de Moléculas de Sinalização da Ativação LinfocitáriaRESUMO
High blood pressure (HBP) is the leading risk factor for cardiovascular disease (CVD) and all-cause mortality worldwide. The progression of the disease leads to structural and/or functional alterations in various organs and increases cardiovascular risk. Currently, there are significant deficiencies in its diagnosis, treatment, and control. Vitamin D is characterized by its functional versatility and its involvement in countless physiological processes. This has led to the association of vitamin D with many chronic diseases, including HBP and CVD, due to its involvement in the regulation of the renin-angiotensin-aldosterone system. The aim of this study was to evaluate the effect of 13 single nucleotide polymorphisms (SNPs) related to the vitamin D metabolic pathway on the risk of developing HBP. An observational case-control study was performed, including 250 patients diagnosed with HBP and 500 controls from the south of Spain (Caucasians). Genetic polymorphisms in CYP27B1 (rs4646536, rs3782130, rs703842, and rs10877012), CYP2R1 rs10741657, GC rs7041, CYP24A1 (rs6068816, and rs4809957), and VDR (BsmI, Cdx2, FokI, ApaI, and TaqI) were analyzed by real-time PCR using TaqMan probes. Logistic regression analysis, adjusted for body mass index (BMI), dyslipidemia, and diabetes, showed that in the genotypic model, carriers of the GC rs7041 TT genotype were associated with a lower risk of developing HBP than the GG genotype (odds ratio (OR) = 0.44, 95% confidence interval (CI): 0.41-0.77, p = 0.005, TT vs. GG). In the dominant model, this association was maintained; carriers of the T allele showed a lower risk of developing HBP than carriers of the GG genotype (OR = 0.69, 95% CI: 0.47-1.03; TT + TG vs. GG, p = 0.010). Finally, in the additive model, consistent with previous models, the T allele was associated with a lower risk of developing HBP than the G allele (OR = 0.65, 95% CI: 0.40-0.87, p = 0.003, T vs. G). Haplotype analysis revealed that GACATG haplotypes for SNPs rs1544410, rs7975232, rs731236, rs4646536, rs703842, and rs10877012 were associated with a marginally significant lower risk of developing HBP (OR = 0.35, 95% CI: 0.12-1.02, p = 0.054). Several studies suggest that GC 7041 is associated with a lower active isoform of the vitamin D binding protein. In conclusion, the rs7041 polymorphism located in the GC gene was significantly associated with a lower risk of developing HBP. This polymorphism could therefore act as a substantial predictive biomarker of the disease.
Assuntos
Doenças Cardiovasculares , Hipertensão , Humanos , Vitamina D , Polimorfismo de Nucleotídeo Único , Receptores de Calcitriol/genética , Estudos de Casos e Controles , Genótipo , Vitaminas , Fatores de Risco , Redes e Vias Metabólicas , Hipertensão/genética , Predisposição Genética para DoençaRESUMO
Omalizumab is a monoclonal antibody indicated for the treatment of severe uncontrolled asthma with an allergic phenotype. Its effectiveness could be influenced by clinical variables and single nucleotide polymorphisms (SNPs) in one or more of the genes involved in the mechanism of action and process of response to omalizumab, and these could be used as predictive biomarkers of response. We conducted an observational retrospective cohort study that included patients with severe uncontrolled allergic asthma treated with omalizumab in a tertiary hospital. Satisfactory response after 12 months of treatment was defined as (1) Reduction ≥ 50% of exacerbations or no exacerbations, (2) Improvement of lung function ≥ 10% FEV1, and (3) Reduction ≥ 50% of OCS courses or no OCS. Polymorphisms in the FCER1A (rs2251746, rs2427837), FCER1B (rs1441586, rs573790, rs1054485, rs569108), C3 (rs2230199), FCGR2A (rs1801274), FCGR2B (rs3219018, rs1050501), FCGR3A (rs10127939, rs396991), IL1RL1 (rs1420101, rs17026974, rs1921622), and GATA2 (rs4857855) genes were analyzed by real-time polymerase chain reaction (PCR) using TaqMan probes. A total of 110 patients under treatment with omalizumab were recruited. After 12 months of treatment, the variables associated with a reduction in exacerbations were the absence of polyposis (odds ratio [OR] = 4.22; 95% confidence interval [CI] = 0.95-19.63), IL1RL1 rs17026974-AG (OR = 19.07; 95% CI = 1.27-547), and IL1RL1 rs17026974-GG (OR = 16.76; 95% CI = 1.22-438.76). Reduction in oral corticosteroids (OCS) was associated with age of starting omalizumab treatment (OR = 0.95; 95% CI = 0.91-0.99) and blood eosinophil levels > 300 cells/µL (OR = 2.93; 95% CI = 1.01-9.29). Improved lung function showed a relationship to the absence of chronic obstructive pulmonary disease (COPD) (OR = 12.16; 95% CI = 2.45-79.49), FCGR2B rs3219018-C (OR = 8.6; 95% CI = 1.12-117.15), GATA2 rs4857855-T (OR = 15.98; 95% CI = 1.52-519.57) and FCGR2A rs1801274-G (OR = 13.75; 95% CI = 2.14-142.68; AG vs. AA and OR = 7.46; 95% CI = 0.94-89.12; GG vs. AA). Meeting one response criterion was related to FCER1A rs2251746-TT (OR = 24; 95% CI = 0.77-804.57), meeting two to age of asthma diagnosis (OR = 0.93; 95% CI = 0.88-0.99), and meeting all three to body mass index (BMI) < 25 (OR = 14.23; 95% CI = 3.31-100.77) and C3 rs2230199-C (OR = 3; 95% CI = 1.01-9.92). The results of this study show the possible influence of the polymorphisms studied on the response to omalizumab and the clinical benefit that could be obtained by defining predictive biomarkers of treatment response.
Assuntos
Antiasmáticos , Asma , Hipersensibilidade , Humanos , Omalizumab/uso terapêutico , Antiasmáticos/farmacologia , Antiasmáticos/uso terapêutico , Estudos Retrospectivos , Asma/tratamento farmacológico , Asma/genética , Hipersensibilidade/tratamento farmacológico , Fenótipo , Biomarcadores , Resultado do TratamentoRESUMO
Over the past decade, a new family of ceramic matrix composites has been developed from the incorporation of homogeneously dispersed graphene-based fillers (graphene nanoplatelets/GNP, graphene oxide sheets/rGO or graphene nanoribbons/GNR) into the ceramic matrices. These composites have shown a significant increment of their fracture toughness accompanied by other electrical and thermal functionalities, which make them potentially attractive for a wide range of applications. Here, the main methods for testing the fracture toughness of these composites are described, then the principal observations on the reinforcing mechanisms responsible for this improvement are briefly reviewed, and we discuss the relation with graphene platelets type, morphology and alignment. This article is part of the theme issue 'Nanocracks in nature and industry'.
RESUMO
Varroosis is a disease caused by the mite Varroa destructor, and it is considered one of the biggest threats to honey bee populations globally. Mite control is centered on the use of synthetic acaricides, such as amitraz and flumethrine. However, high usage of these chemicals is associated with a wide variety of undesirable effects on bee colonies, including the development of resistance and persistence of harmful residues of acaricides in hive products used by humans. Botanical extracts have been identified as a potentially suitable organic alternative to synthetic acaricides. Essential oils, such as clove, eucalyptus, lemongrass, and oregano, have been found to exhibit acaricidal activity against V. destructor. The main goal of this work was to assess the bioactivity of the Cymbopogon nardus essential oil from two different locations (Argentina and India), and the activity of its major component the monoterpene citronellal. According to our results, complete essential oil from India is more effective in controlling parasitosis than the isolated citronellal component. The essential oil of C. nardus from Argentina demonstrated promise for the control of varroosis, as well as exhibiting low toxicity against bees (LC50 = 11.84 µL/mL). In addition, this essential oil may avoid the problems caused by synthetic acaricides, such as the emergence of resistance foci in Varroa and residues in hive products. Future research needs to investigate the delivery of volatile essentials oils to target mite populations.
Assuntos
Acaricidas , Cymbopogon , Óleos Voláteis , Varroidae , Acaricidas/farmacologia , Monoterpenos Acíclicos , Aldeídos , Animais , Abelhas , Óleos Voláteis/química , Óleos Voláteis/toxicidadeRESUMO
In this research, a compact electronic nose (e-nose) based on a shear horizontal surface acoustic wave (SH-SAW) sensor array is proposed for the NO2 detection, classification and discrimination among some of the most relevant surrounding toxic chemicals, such as carbon monoxide (CO), ammonia (NH3), benzene (C6H6) and acetone (C3H6O). Carbon-based nanostructured materials (CBNm), such as mesoporous carbon (MC), reduced graphene oxide (rGO), graphene oxide (GO) and polydopamine/reduced graphene oxide (PDA/rGO) are deposited as a sensitive layer with controlled spray and Langmuir-Blodgett techniques. We show the potential of the mass loading and elastic effects of the CBNm to enhance the detection, the classification and the discrimination of NO2 among different gases by using Machine Learning (ML) techniques (e.g., PCA, LDA and KNN). The small dimensions and low cost make this analytical system a promising candidate for the on-site discrimination of sub-ppm NO2.
Assuntos
Nariz Eletrônico , Nanoestruturas , Amônia , Gases , Dióxido de NitrogênioRESUMO
Cardiovascular diseases (CVDs) are a group of disorders of the heart and blood vessels. In addition to environmental risk factors, genetic predisposition increases the risk; this includes alterations in the vitamin D receptor gene (VDR). These alterations play a key role in modifying vitamin D uptake, being able to modify its function and increasing susceptibility to cardiovascular disorders. The aim of this study was to evaluate the association of polymorphisms in the VDR gene and risk of CVD in a Caucasian population. A retrospective case-control study was conducted comprising 246 CVD patients and 246 controls of Caucasian origin from Southern Spain. The genetic polymorphisms BsmI (rs1544410), TaqI (rs731236), ApaI (rs7975232), FokI (rs2228570) and Cdx2 (rs11568820) were determined by means of real-time polymerase chain reaction (PCR) for allelic discrimination using TaqMan® probes. The logistic regression analysis adjusted for body mass index and diabetes revealed that the TT genotype was associated with a higher risk of CVD in both the genotypic model (p = 0.0430; OR = 2.30; 95% CI = 1.06-5.37; TT vs. CC) and the recessive model (p = 0.0099; OR = 2.71; 95% CI = 1.31-6.07; TT vs. C). Haplotype analysis revealed that the haplotype GAC (p = 0.047; OR = 0.34; 95% CI = 0.12-0.98) was associated with increased risk of CVD. The VDR polymorphisms FokI (rs2228570) was significantly associated with the development of CVD. No influence was observed of the VDR polymorphisms BsmI (rs1544410), TaqI (rs731236), ApaI (rs7975232) and Cdx2 (rs11568820) on the risk of developing CVD in the patients studied.
Assuntos
Doenças Cardiovasculares , Polimorfismo de Nucleotídeo Único , Biomarcadores , Doenças Cardiovasculares/genética , Estudos de Casos e Controles , Predisposição Genética para Doença , Genótipo , Humanos , Receptores de Calcitriol/genética , Estudos Retrospectivos , Vitamina D , VitaminasRESUMO
Bone morphogenetic protein-9 (BMP-9) is a circulating cytokine that is known to play an essential role in the endothelial homeostasis and the binding of BMP-9 to the receptor activin-like kinase 1 (ALK-1) promotes endothelial cell quiescence. Previously, using an unbiased screen, we identified ALK-1 as a high-capacity receptor for low-density lipoprotein (LDL) in endothelial cells that mediates its transcytosis in a nondegradative manner. Here we examine the crosstalk between BMP-9 and LDL and how it influences their interactions with ALK-1. Treatment of endothelial cells with BMP-9 triggers the extensive endocytosis of ALK-1, and it is mediated by caveolin-1 (CAV-1) and dynamin-2 (DNM2) but not clathrin heavy chain. Knockdown of CAV-1 reduces BMP-9-mediated internalization of ALK-1, BMP-9-dependent signaling and gene expression. Similarly, treatment of endothelial cells with LDL reduces BMP-9-induced SMAD1/5 phosphorylation and gene expression and silencing of CAV-1 and DNM2 diminishes LDL-mediated ALK-1 internalization. Interestingly, BMP-9-mediated ALK-1 internalization strongly re-duces LDL transcytosis to levels seen with ALK-1 deficiency. Thus, BMP-9 levels can control cell surface levels of ALK-1, via CAV-1, to regulate both BMP-9 signaling and LDL transcytosis.
Assuntos
Receptores de Activinas Tipo II/metabolismo , Caveolina 1/metabolismo , Membrana Celular/metabolismo , Endocitose , Endotélio Vascular/fisiologia , Fator 2 de Diferenciação de Crescimento/metabolismo , Lipoproteínas LDL/metabolismo , Receptores de Activinas Tipo II/genética , Caveolina 1/genética , Células Cultivadas , Endotélio Vascular/citologia , Fator 2 de Diferenciação de Crescimento/genética , Humanos , Fosforilação , Transdução de SinaisRESUMO
OBJECTIVES: Multiple sclerosis (MS) is a neurodegenerative chronic inflammatory. Mutations in the vitamin D receptor (VDR) gene can substantially affect serum vitamin D levels or alter its functionality, and can consequently increase susceptibility to developing MS. The objective of this study was to evaluate the association between polymorphisms in the VDR gene and risk of MS in a (Spanish) Caucasian population. PATIENTS AND METHODS: We conducted a retrospective case-control study comprising 209 patients with relapsing-remitting multiple sclerosis (RRMS) and 836 controls of Caucasian origin from southern Spain. The ApaI (rs7975232), BsmI (rs1544410), Cdx2 (rs11568820), FokI (rs2228570), and TaqI (rs731236) gene polymorphisms were determined by allelic discrimination real-time PCR using TaqMan probes. RESULTS: The recessive logical regression model, adjusted for age and sex, revealed that the TT genotype for VDR FokI (rs2228570) polymorphism was associated with higher risk of MS (P = 0.0150; OR = 1.82; 95% CI = 1.12-2.94; TT vs. CT + CC). No association between the other polymorphisms and development of MS was found in any of the models analyzed. The haplotype analysis, adjusted for age, smoking, and sex, did not find any statistically significant association between the haplotypes analyzed and risk of MS. CONCLUSIONS: The VDR FokI (rs2228570) polymorphism was significantly associated with developing MS. We found no influence of the ApaI (rs7975232), BsmI (rs1544410), Cdx2 (rs11568820), FokI (rs2228570), and TaqI (rs731236) gene polymorphisms on the risk of developing MS in our patients.
Assuntos
Estudos de Associação Genética , Predisposição Genética para Doença , Esclerose Múltipla/genética , Polimorfismo de Nucleotídeo Único/genética , Receptores de Calcitriol/genética , Adulto , Alelos , Feminino , Genótipo , Haplótipos/genética , Humanos , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/epidemiologia , Esclerose Múltipla/patologia , Fatores de Risco , Espanha/epidemiologia , População Branca/genéticaRESUMO
OBJECTIVE: Endothelial Cav-1 (caveolin-1) expression plays a relevant role during atherogenesis by controlling NO production, vascular inflammation, LDL (low-density lipoprotein) transcytosis, and extracellular matrix remodeling. Additional studies have identified cholesterol-rich membrane domains as important regulators of autophagy by recruiting ATGs (autophagy-related proteins) to the plasma membrane. Here, we investigate how the expression of Cav-1 in the aortic endothelium influences autophagy and whether enhanced autophagy contributes to the atheroprotective phenotype observed in Cav-1-deficient mice. Approach and Results: To analyze the impact of Cav-1 deficiency on regulation of autophagy in the aortic endothelium during the progression of atherosclerosis, we fed Ldlr-/- and Cav-1-/-Ldlr-/- mice a Western diet and assessed autophagy in the vasculature. We observe that the absence of Cav-1 promotes autophagy activation in athero-prone areas of the aortic endothelium by enhancing autophagic flux. Mechanistically, we found that Cav-1 interacts with the ATG5-ATG12 complex and influences the cellular localization of autophagosome components in lipid rafts, which controls the autophagosome formation and autophagic flux. Pharmacological inhibition of autophagy attenuates the atheroprotection observed in Cav-1-/- mice by increasing endothelial inflammation and macrophage recruitment, identifying a novel molecular mechanism by which Cav-1 deficiency protects against the progression of atherosclerosis. CONCLUSIONS: These results identify Cav-1 as a relevant regulator of autophagy in the aortic endothelium and demonstrate that pharmacological suppression of autophagic flux in Cav-1-deficient mice attenuates the atheroprotection observed in Cav-1-/- mice. Additionally, these findings suggest that activation of endothelial autophagy by blocking Cav-1 might provide a potential therapeutic strategy for cardiovascular diseases including atherosclerosis.
Assuntos
Aterosclerose/prevenção & controle , Autofagia/fisiologia , Caveolina 1/deficiência , Endotélio Vascular/fisiopatologia , Vasculite/prevenção & controle , Adenina/análogos & derivados , Adenina/farmacologia , Animais , Aorta/patologia , Aorta/fisiopatologia , Aorta/ultraestrutura , Aterosclerose/etiologia , Autofagia/efeitos dos fármacos , Caveolina 1/análise , Caveolina 1/fisiologia , Dieta Ocidental , Células Endoteliais/química , Células Endoteliais/fisiologia , Células Endoteliais/ultraestrutura , Endotélio Vascular/química , Endotélio Vascular/ultraestrutura , Feminino , Humanos , Masculino , Microdomínios da Membrana/química , Microdomínios da Membrana/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células NIH 3T3 , Receptores de LDL/deficiênciaRESUMO
BACKGROUND: Adnexal skin tumors are diagnostically challenging with few known molecular signatures. Recently, however, YAP1-MAML2 and YAP1-NUTM1 fusions were identified in poroid adnexal skin tumors. METHODS: Herein, we subjected eight poroid adnexal skin tumors (three poromas and five porocarcinomas) to fusion gene analysis by whole transcriptome sequencing and next-generation DNA sequencing analysis. RESULTS: YAP1 fusions were identified in six cases. YAP1-NUTM1 fusions were identified in two poromas and three porocarcinomas. A single case of porocarcinoma harbored a YAP1-MAML2 fusion. Two cases were negative for gene fusion. All cases that harbored YAP1-NUTM1 fusions showed nuclear protein in testis (NUT) expression by immunohistochemistry, with NUT being negative in the YAP1-MAML2-positive case. In this case series, we provide a detailed histopathologic description of six YAP1-fused poroid skin tumors, which we show harbor reproducible histopathologic features, to include broad, bulbous tumor tongues with admixtures of basaloid, poroid cells punctuated by squamatized cuticles and ductules, with uniform tumor nuclei featuring frequent grooves and pseudonuclear inclusions. CONCLUSIONS: Awareness of the characteristic histopathologic features of YAP1-fused poroid adnexal skin tumor is a step toward a more reproducible classification of adnexal skin tumors as well as a step toward targeted therapy for metastatic and/or unresectable examples of this poroid group of neoplasms.
Assuntos
Porocarcinoma Écrino/genética , Fusão Gênica/genética , Rearranjo Gênico/genética , Poroma/genética , Idoso , Idoso de 80 Anos ou mais , Conscientização , Porocarcinoma Écrino/diagnóstico , Feminino , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Imuno-Histoquímica/métodos , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias , Proteínas Nucleares , Patologia Molecular/métodos , Poroma/diagnóstico , Neoplasias Cutâneas/patologia , Neoplasias das Glândulas Sudoríparas/patologia , Transativadores , Sequenciamento do Exoma/métodos , Proteínas de Sinalização YAPRESUMO
The postharvest deterioration of cherry tomatoes due to diseases caused by fungi is one of the main causes of the loss of this product. The objective of this study was to determine the antagonistic capacity by evaluating the antifungal power of nine strains of lactic acid bacteria (LAB) in vitro against the phytopathogenic fungi Aspergillus niger, Fusarium sp., and Rhizopus stolonifer isolated from cherry tomatoes (Solanum lycopersicum var. cerasiforme) and to measure the biosurfactant production capacity, its antagonism in vivo, and the production of organic acids. The results showed that seven of the nine strains were able to inhibit at least one of the three fungi isolated in the in vitro assay. In eight of nine strains, biosurfactant production was identified, and the strains Weissella confusa and Lactiplantibacillus plantarum A6 showed the highest antifungal activity in vitro and in vivo against the fungi evaluated, with the identification of organic acid production in both strains. LAB demonstrated the ability to inhibit cherry tomato fungi, thus emerging as an alternative to the use of chemical preservatives in the production of this fruit and being projected as a preservation technology for this type of product through the use of strains or their metabolites.
Assuntos
Lactobacillales , Solanum lycopersicum , Weissella , Fungos , RhizopusRESUMO
BACKGROUND: Atherosclerosis is driven by synergistic interactions between pathological, biomechanical, inflammatory, and lipid metabolic factors. Our previous studies demonstrated that absence of caveolin-1 (Cav1)/caveolae in hyperlipidemic mice strongly inhibits atherosclerosis, which was attributed to activation of endothelial nitric oxide (NO) synthase (eNOS) and increased production of NO and reduced inflammation and low-density lipoprotein trafficking. However, the contribution of eNOS activation and NO production in the athero-protection of Cav1 and the exact mechanisms by which Cav1/caveolae control the pathogenesis of diet-induced atherosclerosis are still not clear. METHODS: Triple-knockout mouse lacking expression of eNOS, Cav1, and Ldlr were generated to explore the role of NO production in Cav1-dependent athero-protective function. The effects of Cav1 on lipid trafficking, extracellular matrix remodeling, and vascular inflammation were studied both in vitro and in vivo with a mouse model of diet-induced atherosclerosis. The expression of Cav1 and distribution of caveolae regulated by flow were analyzed by immunofluorescence staining and transmission electron microscopy. RESULTS: We found that absence of Cav1 significantly suppressed atherogenesis in Ldlr-/-eNOS-/- mice, demonstrating that athero-suppression is independent of increased NO production. Instead, we find that the absence of Cav1/caveolae inhibited low-density lipoprotein transport across the endothelium and proatherogenic fibronectin deposition and disturbed flow-mediated endothelial cell inflammation. Consistent with the idea that Cav1/caveolae may play a role in early flow-dependent inflammatory priming, distinct patterns of Cav1 expression and caveolae distribution were observed in athero-prone and athero-resistant areas of the aortic arch even in wild-type mice. CONCLUSIONS: These findings support a role for Cav1/caveolae as a central regulator of atherosclerosis that links biomechanical, metabolic, and inflammatory pathways independently of endothelial eNOS activation and NO production.
Assuntos
Aterosclerose/metabolismo , Caveolina 1/fisiologia , Endotélio Vascular/metabolismo , Lipoproteínas LDL/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Transcitose/fisiologia , Animais , Aterosclerose/patologia , Aterosclerose/prevenção & controle , Células Cultivadas , Cães , Endotélio Vascular/patologia , Ativação Enzimática/fisiologia , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos TransgênicosRESUMO
Insulin resistance (IR) is one of the key contributing factors in the development of type 2 diabetes mellitus (T2DM). However, the molecular mechanisms leading to IR are still unclear. The implication of microRNAs (miRNAs) in the pathophysiology of multiple cardiometabolic pathologies, including obesity, atherosclerotic heart failure and IR, has emerged as a major focus of interest in recent years. Indeed, upregulation of several miRNAs has been associated with obesity and IR. Among them, miR-27b is overexpressed in the liver in patients with obesity, but its role in IR has not yet been thoroughly explored. In this study, we investigated the role of miR-27b in regulating insulin signaling in hepatocytes, both in vitro and in vivo. Therefore, assessment of the impact of miR-27b on insulin resistance through the hepatic tissue is of special importance due to the high expression of miR-27b in the liver together with its known role in regulating lipid metabolism. Notably, we found that miR-27b controls post-transcriptional expression of numerous components of the insulin signaling pathway including the insulin receptor (INSR) and insulin receptor substrate 1 (IRS1) in human hepatoma cells. These results were further confirmed in vivo showing that overexpression and inhibition of hepatic miR-27 enhances and suppresses hepatic INSR expression and insulin sensitivity, respectively. This study identified a novel role for miR-27 in regulating insulin signaling, and this finding suggests that elevated miR-27 levels may contribute to early development of hepatic insulin resistance.