RESUMO

BACKGROUND: Telomeropathies are a group of inherited disorders caused by germline pathogenic variants in genes involved in telomere maintenance, resulting in excessive telomere attrition that affects several tissues, including hematopoiesis. RecQ and RTEL1 helicases contribute to telomere maintenance by unwinding telomeric structures such as G-quadruplexes (G4), preventing replication defects. Germline RTEL1 variants also are etiologic in telomeropathies. METHODS AND RESULTS: Here we investigated the expression of RecQ (RECQL1, BLM, WRN, RECQL4, and RECQL5) and RTEL1 helicase genes in peripheral blood mononuclear cells (PBMCs) from human telomeropathy patients. The mRNA expression levels of all RecQ helicases, but not RTEL1, were significantly downregulated in patients' primary cells. Reduced RecQ expression was not attributable to cell proliferative exhaustion, as RecQ helicases were not attenuated in T cells exhausted in vitro. An additional fifteen genes involved in DNA damage repair and RecQ functional partners also were downregulated in the telomeropathy cells. CONCLUSION: These findings indicate that the expression of RecQ helicases and functional partners involved in DNA repair is downregulated in PBMCs of telomeropathy patients.

Assuntos

Leucócitos Mononucleares , RecQ Helicases , Adulto , Feminino , Humanos , Masculino , DNA Helicases/genética , DNA Helicases/metabolismo , Reparo do DNA/genética , Leucócitos Mononucleares/metabolismo , RecQ Helicases/genética , RecQ Helicases/metabolismo , Telômero/metabolismo , Telômero/genética , Homeostase do Telômero/genética

RESUMO

Polycystic ovary syndrome (PCOS) is a multifactorial disorder and obesity occurs in 38% to 88% of these women. Although hyperandrogenism may contribute to telomere lengthening, increased body mass index (BMI) is associated with telomere erosion. We sought to compare leukocyte telomere length (LTL) in PCOS women with normal, overweight, and obese BMI. We evaluated the relationship between LTL and clinical variables of PCOS and inflammatory biomarkers independent of BMI. A total of 348 women (243 PCOS and 105 non-PCOS) were evaluated for anthropometric measures, total testosterone, androstenedione, estradiol (E2), follicle-stimulating hormone (FSH), luteinizing hormone (LH), sex hormone-binding globulin (SHBG), free androgen index (FAI), fasting insulin and glycemia, lipid profile, homocysteine, C-reactive protein (CRP) and homeostatic model of insulin resistance (HOMA-IR). LTL was measured by qPCR. The PCOS group presented higher weight, waist circumference, BMI, testosterone, LH, fasting insulin, FAI, and HOMA-IR, and lower E2, SHBG, and fasting glycemia measures compared with the non-PCOS. When stratified by BMI, LTL was increased in all subgroups in PCOS compared to non-PCOS. However, in the PCOS group, LTL was lower in overweight (P = 0.0187) and obese (P = 0.0018) compared to normal-weight women. The generalized linear model showed that BMI, androstenedione, homocysteine, and CRP were associated with telomere biology. Women with PCOS had longer LTL, however, overweight or obesity progressively contributes to telomere shortening and may affect reproductive outcomes of PCOS, while androstenedione may increase LTL.

Assuntos

Índice de Massa Corporal , Obesidade , Síndrome do Ovário Policístico , Encurtamento do Telômero , Humanos , Síndrome do Ovário Policístico/genética , Síndrome do Ovário Policístico/sangue , Síndrome do Ovário Policístico/metabolismo , Feminino , Obesidade/genética , Obesidade/sangue , Adulto , Adulto Jovem , Resistência à Insulina , Telômero/metabolismo , Leucócitos/metabolismo , Biomarcadores/sangue

RESUMO

ABSTRACTObjectives: The aim of this study was thus to evaluate the effect of Cr supplementation on morphological changes and expression of pro-inflammatory cytokines in the hippocampus and on developmental parameters. Methods: Male Wistar rat pups were submitted to an experimental model of CP. Cr was administered via gavage from the 21st to the 28th postnatal day, and in water after the 28th, until the end of the experiment. Body weight (BW), food consumption (FC), muscle strength, and locomotion were evaluated. Expression of interleukin-1ß (IL-1ß), interleukin-6 (IL-6), and tumor necrosis factor α (TNF-α) were assessed in the hippocampus by quantitative real-time polymerase chain reaction. Iba1 immunoreactivity was assessed by immunocytochemistry in the hippocampal hilus. Results: Experimental CP caused increased density and activation of microglial cells, and overexpression of IL-6. The rats with CP also presented abnormal BW development and impairment of strength and locomotion. Cr supplementation was able to reverse the overexpression of IL-6 in the hippocampus and mitigate the impairments observed in BW, strength, and locomotion. Discussion: Future studies should evaluate other neurobiological characteristics, including changes in neural precursor cells and other cytokines, both pro- and anti-inflammatory.

Assuntos

Paralisia Cerebral , Células-Tronco Neurais , Ratos , Animais , Masculino , Interleucina-6/genética , Interleucina-6/metabolismo , Creatina/metabolismo , Ratos Wistar , Hipocampo/metabolismo , Citocinas/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Microglia/metabolismo , Modelos Teóricos , Suplementos Nutricionais

RESUMO

OBJECTIVES: This study aims to assess the effect of neonatal treatment with kaempferol on neuromotor development, proliferation of neural precursor cells, the microglia profile, and antioxidant enzyme gene expression in the hippocampus. METHODS: A rat model of cerebral palsy was established using perinatal anoxia and sensorimotor restriction of hindlimbs during infancy. Kaempferol (1 mg/ kg) was intraperitoneally administered during the neonatal period. RESULTS: Neonatal treatment with kaempferol reduces the impact of the cerebral palsy model on reflex ontogeny and on the maturation of physical features. Impairment of locomotor activity development and motor coordination was found to be attenuated by kaempferol treatment during the neonatal period in rats exposed to cerebral palsy. Neonatal treatment of kaempferol in cerebral palsy rats prevents a substantial reduction in the number of neural precursor cells in the dentate gyrus of the hippocampus, an activated microglia profile, and increased proliferation of microglia in the sub-granular zone and in the granular cell layer. Neonatal treatment with kaempferol increases gene expression of superoxide dismutase and catalase in the hippocampus of rats submitted to the cerebral palsy model. DISCUSSION: Kaempferol attenuates the impact of cerebral palsy on neuromotor behavior development, preventing altered hippocampal microglia activation and mitigating impaired cell proliferation in a neurogenic niche in these rats. Neonatal treatment with kaempferol also increases antioxidant defense gene expression in the hippocampus of rats submitted to the cerebral palsy model.

Assuntos

Paralisia Cerebral , Células-Tronco Neurais , Gravidez , Feminino , Animais , Ratos , Antioxidantes/farmacologia , Microglia , Quempferóis/farmacologia , Quempferóis/metabolismo , Hipocampo , Proliferação de Células

RESUMO

TERRA (telomeric repeat-containing RNA) is a class of long noncoding RNAs transcribed from subtelomeric and telomeric regions. TERRA binds to the subtelomeric and telomeric DNA-forming R-loops (DNA-RNA hybrids), which are involved in telomere maintenance and telomerase function, but the role of TERRA in human cells is not well characterized. Here, we comprehensively investigated for the first time TERRA expression in primary human hematopoietic cells from an exploratory cohort of patients with acute myeloid leukemia (AML), patients with acute lymphoblastic leukemia (ALL), patients with telomere biology disorder (TBD), and healthy subjects. TERRA expression was repressed in primary human hematopoietic cells, including healthy donors, patients with ALL, and patients with TBD, irrespective of their telomere length, except for AML. A second cohort comprising 88 patients with AML showed that TERRA was overexpressed in an AML subgroup also characterized by higher R-loop formation, low TERT and RNAseH2 expression, and a paucity of somatic splicing factor mutations. Telomere length did not correlate with TERRA expression levels. To assess the role of TERRA R-loops in AML, we induced R-loop depletion by increasing RNAseH1 expression in 2 AML cell lines. Decreased TERRA R-loops in AML cell lines resulted in increased chemosensitivity to cytarabine. Our findings indicate that TERRA is uniformly repressed in primary human hematopoietic cells but abnormally expressed in an AML subset with low telomerase.

Assuntos

Leucemia Mieloide Aguda , Leucemia-Linfoma Linfoblástico de Células Precursoras , RNA Longo não Codificante , Telomerase , Humanos , Leucemia Mieloide Aguda/genética , Linhagem Celular , DNA

RESUMO

OBJECTIVE: to analyze the trend of incompleteness of the maternal schooling and race/skin color variables held on the Brazilian Live Birth Information System (SINASC) between 2012 and 2020. METHODS: this was an ecological time series study of the incompleteness of maternal schooling and race/skin color data for Brazil, its regions and Federative Units, by means of joinpoint regression and calculation of annual percentage change (APC) and average annual percentage change. RESULTS: a total of 26,112,301 births were registered in Brazil in the period; incompleteness of maternal schooling data decreased for Brazil (APC = -8.1%) and the Southeast (APC = -19.5%) and Midwest (APC = -17.6%) regions; as for race/skin color, there was a downward trend for Brazil (APC = -8.2%) and all regions, except the Northeast region, while nine Federative Units and the Federal District showed a stationary trend. CONCLUSION: there was an improvement in filling out these variables on the SINASC, but with regional disparities, mainly for race/skin color.

Assuntos

Escolaridade , Nascido Vivo , Feminino , Humanos , Gravidez , Brasil , Gravidez Múltipla , Pigmentação da Pele , Bases de Dados Factuais/normas , Bases de Dados Factuais/estatística & dados numéricos , Sistemas de Informação em Saúde , Grupos Raciais

RESUMO

Androgens have been reported to elongate telomeres in retrospective and prospective trials with patients with telomeropathies, mainly with bone marrow failure. In our single-arm prospective clinical trial (clinicaltrials gov. Identifier: NCT02055456), 17 patients with short telomeres and/or germline pathogenic variants in telomere biology genes associated with at least one cytopenia and/or radiologic diagnosis of interstitial lung disease were treated with 5 mg/kg of intramuscular nandrolone decanoate every 15 days for 2 years. Ten of 13 evaluable patients (77%) showed telomere elongation at 12 months by flow-fluorescence in situ hybridization (average increase, 0.87 kb; 95% confidence interval: 0.20-1.55 kb; P=0.01). At 24 months, all ten evaluable patients showed telomere elongation (average increase, 0.49 kb; 95% confidence interval: 0.24-1.23 kb; P=0.18). Hematologic response was achieved in eight of 16 patients (50%) with marrow failure at 12 months, and in ten of 16 patients (63%) at 24 months. Seven patients had interstitial lung disease at baseline, and two and three had pulmonary response at 12 and 24 months, respectively. Two patients died due to pulmonary failure during treatment. In the remaining evaluable patients, the pulmonary function remained stable or improved, but showed consistent decline after cessation of treatment. Somatic mutations in myeloid neoplasm-related genes were present in a minority of patients and were mostly stable during drug treatment. The most common adverse events were elevations in liver function test levels in 88%, acne in 59%, and virilization in 59%. No adverse events grade ≥4 was observed. Our findings indicate that nandrolone decanoate elongates telomeres in patients with telomeropathies, which correlated with clinical improvement in some cases and tolerable adverse events.

Assuntos

Doenças Pulmonares Intersticiais , Humanos , Hibridização in Situ Fluorescente , Decanoato de Nandrolona , Estudos Prospectivos , Estudos Retrospectivos , Telômero

RESUMO

Cerebral palsy (CP) is characterized by brain damage at a critical period of development of the central nervous system, and, as a result, motor, behavioural and learning deficits are observed in those affected. Flavonoids such as kaempferol have demonstrated potential anti-inflammatory and neuroprotective properties for neurological disorders. This study aimed to assess the effects of neonatal treatment with kaempferol on the body development, grip strength, gait performance and morphological and biochemical phenotype of skeletal muscle in rats subjected to a model of CP. The groups were formed by randomly allocating male Wistar rats after birth to four groups as follows: C = control treated with vehicle, K = control treated with kaempferol, CP = CP treated with vehicle and CPK = CP treated with kaempferol. The model of CP involved perinatal anoxia and sensorimotor restriction of the hind paws during infancy, from the second to the 28th day of postnatal life. Treatment with kaempferol (1 mg/kg) was performed intraperitoneally during the neonatal period. Body weight and length, muscle strength, gait kinetics and temporal and spatial parameters were evaluated in the offspring. On the 36th day of postnatal life, the animals were euthanized for soleus muscle dissection. The muscle fibre phenotype was assessed using the myofibrillar ATPase technique, and the muscle protein expression was measured using the Western blot technique. A reduction in the impact of CP on body phenotype was observed, and this also attenuated deficits in muscle strength and gait. Treatment also mitigated the impact on muscle phenotype by preventing a reduction in the proportion of oxidative fibres and in the histomorphometric parameters in the soleus muscle of rats in the CP group. The results demonstrate that neonatal treatment with kaempferol attenuated gait deficits and impaired muscle strength and muscle maturation in rats subjected to a model of CP.

Assuntos

Paralisia Cerebral , Gravidez , Feminino , Animais , Ratos , Masculino , Animais Recém-Nascidos , Ratos Wistar , Quempferóis/farmacologia , Quempferóis/uso terapêutico , Quempferóis/metabolismo , Marcha/fisiologia , Músculo Esquelético/metabolismo , Fenótipo , Força Muscular

RESUMO

Objective: to analyze the trend of incompleteness of the maternal schooling and race/skin color variables held on the Brazilian Live Birth Information System (SINASC) between 2012 and 2020. Methods: this was an ecological time series study of the incompleteness of maternal schooling and race/skin color data for Brazil, its regions and Federative Units, by means of joinpoint regression and calculation of annual percentage change (APC) and average annual percentage change. Results: a total of 26,112,301 births were registered in Brazil in the period; incompleteness of maternal schooling data decreased for Brazil (APC = -8.1%) and the Southeast (APC = -19.5%) and Midwest (APC = -17.6%) regions; as for race/skin color, there was a downward trend for Brazil (APC = -8.2%) and all regions, except the Northeast region, while nine Federative Units and the Federal District showed a stationary trend. Conclusion: there was an improvement in filling out these variables on the SINASC, but with regional disparities, mainly for race/skin color.

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Objetivo: analizar la tendencia de incompletitud de educación y raza/color de piel materna en el Sistema de Información de Nacidos Vivo (Sinasc), Brasil, entre 2012-2020. Métodos: estudio ecológico de serie temporal sobre la incompletitud de la educación y raza/color de piel materna para Brasil, regiones y Unidades de la Federación (UF), a través de regresión de joinpoint y cálculo de cambio porcentual anual (APC) y cambio porcentual anual promedio Resultados: se registraron 26.112.301 nacimientos en Brasil en el período. Brasil (APC = -8,1%) y regiones Sudeste (APC = -19,5%) y Centro-Oeste (APC = -17,6%) disminuirán la incompletud de la educación materna. En cuanto a raza/color de piel, hubo un descenso para Brasil (APC = -8,2%) y todas las regiones, excepto Nordeste, y nueve UF y Distrito Federal presentaron tendencia estacionaria. Conclusión: e llenado das variables en el Sinasc ha mejorado, pero con disparidades regionales, principalmente por raza/color de piel.

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Objetivo: analisar a tendência da incompletude das variáveis escolaridade e raça/cor da pele da mãe no Sistema de Informações sobre Nascidos Vivos (Sinasc), Brasil, entre 2012 e 2020. Métodos: estudo ecológico de série temporal sobre a incompletude da escolaridade e da raça/cor da pele da mãe para o Brasil, suas macrorregiões e Unidades da Federação, pela regressão por joinpoint, e cálculo da variação percentual anual (VPA) e da variação percentual anual média. Resultados: foram registrados 26.112.301 nascimentos no Brasil, no período; no país (VPA = -8,1%) e em suas regiões Sudeste (VPA = -19,5%) e Centro-Oeste (VPA = -17,6%), houve redução da incompletude da escolaridade materna; quanto à raça/cor da pele da mãe, observou-se queda para o Brasil (VPA = -8,2%) e todas as suas regiões, exceto o Nordeste, e nove UFs e o Distrito Federal com tendência estável. Conclusão: o preenchimento das variáveis no Sinasc melhorou, porém com disparidades regionais, principalmente quanto à raça/cor da pele.

Assuntos

Humanos , Feminino , Adulto , Sistemas de Informação/estatística & dados numéricos , Declaração de Nascimento , Grupos Raciais/estatística & dados numéricos , Escolaridade , Brasil/epidemiologia , Estudos de Séries Temporais , Nascido Vivo/epidemiologia

RESUMO

Diets high in bioactive compounds, such as polyphenols, have been used to mitigate metabolic syndrome (MetS). Polyphenols are a large group of naturally occurring bioactive compounds, classified into two main classes: non-flavonoids and flavonoids. Flavonoids are distributed in foods, such as fruits, vegetables, tea, red wine, and cocoa. Studies have already demonstrated the benefits of flavonoids on the cardiovascular and nervous systems, as well as cancer cells. The present review summarizes the results of clinical studies that evaluated the effects of flavonoids on the components of the MetS and associated complications when offered as supplements over the long term. The results show that flavonoids can significantly modulate several metabolic parameters, such as lipid profile, blood pressure, and blood glucose. Only theaflavin and catechin were unable to affect metabolic parameters. Moreover, only body weight and body mass index were unaltered. Thus, the evidence presented in this systematic review offers bases in support of a flavonoid supplementation, held for at least 3 weeks, as a strategy to improve several metabolic parameters and, consequently, reduce the risk of diseases associated with MetS. This fact becomes stronger due to the rare side effects reported with flavonoids.

Assuntos

Flavonoides , Síndrome Metabólica , Antioxidantes , Dieta , Flavonoides/farmacologia , Flavonoides/uso terapêutico , Humanos , Síndrome Metabólica/tratamento farmacológico , Polifenóis

RESUMO

In acquired immune aplastic anemia (AA), pathogenic cytotoxic Th1 cells are activated and expanded, driving an immune response against the hematopoietic stem and progenitor cells (HSPCs) that provokes cell depletion and causes bone marrow failure. However, additional HSPC defects may contribute to hematopoietic failure, reflecting on disease outcomes and response to immunosuppression. Here we derived induced pluripotent stem cells (iPSCs) from peripheral blood (PB) erythroblasts obtained from patients diagnosed with immune AA using non-integrating plasmids to model the disease. Erythroblasts were harvested after hematologic response to immunosuppression was achieved. Patients were screened for germline pathogenic variants in bone marrow failure-related genes and no variant was identified. Reprogramming was equally successful for erythroblasts collected from the three immune AA patients and the three healthy subjects. However, the hematopoietic differentiation potential of AA-iPSCs was significantly reduced both quantitatively and qualitatively as compared to healthy-iPSCs, reliably recapitulating disease: differentiation appeared to be more severely affected in cells from the two patients with partial response as compared to the one patient with complete response. Telomere elongation and the telomerase machinery were preserved during reprogramming and differentiation in all AA-iPSCs. Our results indicate that iPSCs are a reliable platform to model immune AA and recapitulate clinical phenotypes. We propose that the immune attack may cause specific epigenetic changes in the HSPCs that limit adequate proliferation and differentiation.

Assuntos

Anemia Aplástica , Células-Tronco Pluripotentes Induzidas , Anemia Aplástica/genética , Anemia Aplástica/patologia , Transtornos da Insuficiência da Medula Óssea , Diferenciação Celular , Células-Tronco Hematopoéticas/patologia , Humanos

RESUMO

Asthma is a chronic and heterogeneous disease of the airways that begins in childhood and persists, in many cases, into adulthood. The disease is the result of environmental, epigenetic and genetic interactions. This work aims to review the polymorphisms described in the literature in the IL-4 gene associated with susceptibility or protection to the development of asthma. This is a systematic literature review, carried out in PubMed, MEDLINE and Science Direct databases in the time frame from 2000 to July 2021, revealing the following key points: IL-4, Polymorphisms and Asthma. The search resulted in 29 articles, all in English. Despite some divergent studies, the SNP rs2243250, which was the most studied in populations from different countries, was also the one that found the most correlations of susceptibility with the disease. It is concluded that although there is controversial data on IL-4 SNPs related to the disease, the association of pangenomic studies has brought a list of genes and their variations associated with the risk of developing asthma, such as the rs2243250 SNP that was well related in populations of several countries analyzed. (AU)

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A asma é uma doença crônica e heterogênea das vias aéreas que tem início na infância e persiste em muitos casos até a vida adulta. A doença é resultado de interações ambientais, epigenéticas e genéticas. Este trabalho tem como objetivo revisar sobre os polimorfismos descritos na literatura no gene IL-4 associados à susceptibilidade ou proteção ao desenvolvimento da asma. Trata-se de uma revisão sistemática da literatura, feita nos bancos de dados PubMed, MEDLINE e Science Direct no corte temporal de 2000 a julho de 2021, ressaltando os seguintes pontos-chave: IL-4, Polimorfismos e Asma. A pesquisa resultou em 29 artigos, sendo em sua totalidade em língua inglesa. Apesar de alguns estudos divergentes, o SNP rs2243250, que foi o mais estudado em populações de diversos países, também foi o que mais encontrou correlações de susceptibilidade com a doença. Conclui-se que, apesar de haver dados controversos sobre os SNPs de IL-4 relacionados à doença, a associação dos estudos pangenômicos tem trazido uma lista de genes e variações deles associados com o risco de desenvolver a asma, como o SNP rs2243250 que foi bem relacionado em populações de vários países analisados (AU).

Assuntos

Polimorfismo Genético , Asma , Interleucina-4 , Revisão Sistemática

RESUMO

Serotonin (5-hydroxytryptamine, 5-HT) is a neurotransmitter that regulates multiple psychophysiological functions. An imbalance of 5-HT in the brain can modulate emotional behavior such as depression and anxiety. Substances, such as flavonols, naturally found in some plants and foods have beneficial effects on psychiatric disorders, have been studied. The aim of this systematic review was to investigate the effects of flavonols on morphological, physiological, and cellular aspects of the serotonergic system as well as on some behaviors modulated by this system. Literature searches were performed in the LILACS, Web of Science, Scopus, PubMed and Sigle via Open Grey databases, from which 1725 studies were found. Using a predefined protocol registered on the CAMARADES website, 18 studies were chosen for qualitative synthesis. Internal validity was assessed using the SYRCLE's risk of bias tool. The Kappa index was also measured to analyze agreement among the reviewers. The results of this systematic review showed that flavonols have been reported to modify physiological aspects of the serotonergic system, increasing levels of serotonin and decreasing levels of its metabolite, 5-hydroxyindoleacetic acid (5-HIAA) and promoting antioxidant effects in encephalic regions. Moreover, the results showed that flavonols can also modulate of the serotonergic system, being associated with antidepressant and anxiolytic activities. Additionally, flavonols were found to not have psychostimulant effect; they can, however, reverse damage to locomotor activity.

Assuntos

Ansiedade , Flavonóis , Antidepressivos , Ansiedade/tratamento farmacológico , Ansiedade/psicologia , Flavonóis/farmacologia , Humanos , Ácido Hidroxi-Indolacético/metabolismo , Serotonina/metabolismo

RESUMO

Metabolic and hormonal outcomes of polycystic ovary syndrome (PCOS) have implications on telomere biology and physical activity may prevent telomere erosion. We sought to observe the effects of continuous (CAT) and intermittent (IAT) aerobic training on telomere length, inflammatory biomarkers, and its correlation with metabolic, hormonal, and anthropometric parameters of PCOS. This randomized controlled clinical trial study included 87 PCOS randomly stratified according to body mass index (BMI) in CAT (n = 28), IAT (n = 29) and non-training control group (CG, n = 30). The exercises were carried out on a treadmill, three times per week for 16 weeks. The participants' anthropometric characteristics and biochemical and hormonal concentrations were measured before and after aerobic training or observation period, as the telomere length that was evaluated using quantitative real-time PCR. Four months of aerobic exercises (CAT or IAT) did not alter telomere length and inflammatory biomarkers in PCOS women. Obesity index as BMI and waist circumference (WC), and inflammatory biomarkers negatively affect telomeres. The hyper-andro-genism measured by testosterone levels was reduced after both exercises (CAT, p ≤ 0.001; IAT, p = 0.019). In particular, the CAT reduced WC (p = 0.045), hip circumference (p = 0.032), serum cholesterol (p ≤ 0.001), and low-density lipoprotein (p = 0.030). Whereas, the IAT decreased WC (p = 0.014), waist-to-hip ratio (p = 0.012), free androgen index (FAI) (p = 0.037). WC (p = 0.049) and body fat (p = 0.015) increased in the non-training group while total cholesterol was reduced (p = 0.010). Booth exercises reduced obesity indices and hyperandrogenism on PCOS women without changes in telomere length or inflammatory biomarkers.

Assuntos

Resistência à Insulina , Síndrome do Ovário Policístico , Índice de Massa Corporal , Exercício Físico , Feminino , Humanos , Obesidade , Telômero , Testosterona

RESUMO

BACKGROUND: Human T-lymphotropic virus 1 (HTLV-1) is etiologically associated with the chronic inflammatory neurodegenerative disease HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) Annexin A1 (AnxA1) is an anti-inflammatory protein with proposed neuroprotective and anti-neuroinflammatory functions. We hypothesized that ANXA1 gene expression may be dysregulated in HTLV-1-infected HAM/TSP patients. METHODS: This study involved 37 individuals infected with HTLV-1, including 21 asymptomatic (AS) carriers and 16 with HAM/TSP, and a control group of 30 individuals negative for HTLV-1 and HTLV-2. For AS HTLV-1-positive and HAM/TSP patients, ANXA1 and formyl peptide receptor (FPR1, FPR2 and FPR3) expression and HTLV-1 proviral load (PVL) in peripheral blood cells were evaluated by real-time quantitative PCR (qPCR), and plasma AnxA1 levels were determined by enzyme-linked immunosorbent assay (ELISA). RESULTS: ANXA1 gene expression was increased in the AS group compared with the HAM/TSP and control groups, but the differences were not statistically significant. FPR1 gene expression was higher in patients with HTLV-1 than in controls (AS, p = 0.0032; HAM/TSP, p < 0.0001). Plasma AnxA1 levels were higher in the AS group than in the HAM/TSP group (p = 0.0045), and PVL was higher in patients with HAM/TSP than in AS individuals (p = 0.0162). The use of a combined ROC curve using Annexin 1 levels and proviral load significantly increased the sensitivity and specificity to predict progression to HAM/TSP (AUC = 0.851 and AUC = 0.937, respectively, to AUC = 1000). CONCLUSIONS: Our results suggest that AnxA1 may be dysregulated in HAM/TSP patients. Serological detection of AnxA1 in association with proviral load may provide a prognostic biomarker for HTLV-1-associated neurodegenerative disease.

Assuntos

Anexina A1/sangue , Vírus Linfotrópico T Tipo 1 Humano/isolamento & purificação , Paraparesia Espástica Tropical/diagnóstico , Adulto , Anexina A1/genética , Biomarcadores/sangue , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Paraparesia Espástica Tropical/sangue , Paraparesia Espástica Tropical/virologia , Prognóstico , Curva ROC , Sensibilidade e Especificidade , Carga Viral

RESUMO

Purpose Children with cerebral palsy (CP) often exhibit difficulties in feeding resulting from deficits in chewing. This study investigates the therapeutic potential of L-tryptophan (TRI) to reduce deficits in chewing in rats subjected to an experimental model of CP.Methods A total of 80 Wistar albino rats were used. Pups were randomly assigned to 4 experimental groups: Control Saline, Control TRI, CP Saline, and CP TRI groups. The experimental model of CP was based on the combination of perinatal anoxia associated with postnatal sensorimotor restriction of the hind limbs. TRI was administered subcutaneously during the lactation period. Anatomical and behavioral parameters were evaluated during maturation, including body weight gain, food intake, chewing movements, relative weight and the distribution of the types of masseter muscle fibers.Results The induction of CP limited body weight gain, decreased food intake and led to impairment in the morphological and functional parameters of chewing. Moreover, for a comparable amount of food ingested, CP TRI animals grew the most. In addition, supplementation with TRI improved the number of chewing movements, and increased the weight and proportion of type IIB fibers of the masseter in rats subjected to CP.Conclusion These results demonstrate that experimental CP impaired the development of mastication and that TRI supplementation increased masticatory maturation in animals subjected to CP.

Assuntos

Paralisia Cerebral/fisiopatologia , Mastigação/efeitos dos fármacos , Mastigação/fisiologia , Triptofano/uso terapêutico , Animais , Paralisia Cerebral/tratamento farmacológico , Modelos Animais de Doenças , Ingestão de Alimentos , Músculo Masseter/efeitos dos fármacos , Músculo Masseter/fisiopatologia , Fenótipo , Ratos , Ratos Wistar , Aumento de Peso/efeitos dos fármacos

RESUMO

Chronic stress is related to the acceleration of telomere shortening. Recent work showed a correlation between chronic psychosocial stress and reduced telomere length in certain cells. The exposure of T lymphocytes to cortisol promoted a significant reduction in telomerase activity. Although stress can promote changes in telomere length, whether increased glucocorticoid concentrations alter telomere length in brain tissue cells is unclear. In addition to modulating the activity of the stress system, estrogen also influences telomere length. The objective of this study was to verify whether chronic exposure to glucocorticoids promotes changes in the telomere length of encephalic areas involved in the control of HPA axis activity and whether estrogen affects these changes. Wistar rats were ovariectomized and treated with estradiol cypionate [(50 or 100 µg/kg, subcutaneously)] or oil and 20 mg/kg corticosterone or vehicle (isotonic saline with 2% Tween 80, subcutaneously) for 28 days. On the day after the end of the hormonal treatment, the animals were euthanized for collection of blood, brain and pituitary gland samples. Estrogen modulated the activity of the HPA axis. CRH, AVP and POMC mRNA levels were reduced by estrogen. At least in doses and treatment time used, there was no correlation between effects of exposure to glucocorticoids and estrogen on telomere length in the brain areas of female rats. However, estrogen treatment reduced the telomere length in the central amygdala and dorsal hippocampus, but not in the PVN, indicating a variation of reaction of telomeres for estrogen in different brain areas.

Assuntos

Corticosterona/farmacologia , Estrogênios/farmacologia , Homeostase do Telômero/fisiologia , Hormônio Adrenocorticotrópico/metabolismo , Tonsila do Cerebelo/efeitos dos fármacos , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Corticosterona/metabolismo , Hormônio Liberador da Corticotropina/metabolismo , Estrogênios/metabolismo , Feminino , Hipocampo/efeitos dos fármacos , Sistema Hipotálamo-Hipofisário/metabolismo , Núcleo Hipotalâmico Paraventricular/efeitos dos fármacos , Sistema Hipófise-Suprarrenal/metabolismo , Ratos , Estresse Fisiológico , Telômero/efeitos dos fármacos , Telômero/metabolismo , Telômero/fisiologia , Homeostase do Telômero/efeitos dos fármacos

RESUMO

Eltrombopag has been added to first-line treatment of immune aplastic anaemia (AA), resulting in higher responses. We analysed marrow samples of AA patients who responded to immunosuppressive therapy (IST) alone or in combination with eltrombopag for the composition of the haematopoietic stem and progenitor cell (HSPC) compartment. The number of CD34+ cells and multipotent progenitors was higher in patients treated with eltrombopag (P < 0·005; P < 0·05; respectively), but not the number of stem cells. No aberrant phenotype was observed. These results indicate that eltrombopag augments CD34+ cells in vivo and preferentially expands multipotent progenitors, but not stem cells.

Assuntos

Anemia Aplástica/tratamento farmacológico , Benzoatos/farmacologia , Células-Tronco Hematopoéticas/efeitos dos fármacos , Hidrazinas/farmacologia , Células-Tronco Multipotentes/efeitos dos fármacos , Pirazóis/farmacologia , Receptores de Trombopoetina/agonistas , Adolescente , Adulto , Antígenos CD34/efeitos dos fármacos , Benzoatos/administração & dosagem , Biópsia por Agulha/métodos , Células da Medula Óssea/citologia , Células da Medula Óssea/efeitos dos fármacos , Células da Medula Óssea/patologia , Brasil/epidemiologia , Feminino , Citometria de Fluxo/métodos , Células-Tronco Hematopoéticas/citologia , Humanos , Hidrazinas/administração & dosagem , Imunossupressores/uso terapêutico , Masculino , Pessoa de Meia-Idade , Células-Tronco Multipotentes/citologia , Pirazóis/administração & dosagem

RESUMO

There is a concern about early life exposure to Selective Serotonin Reuptake Inhibitors (SSRI) in child development and motor system maturation. Little is known, however, about the interaction of environmental factors, such as maternal nutrition, associated with early exposure to SSRI. The increased maternal consumption of high-fat diets is worrisome and affects serotonin system development with repercussions in body phenotype. This study aimed to assess the short- and long-term effects of neonatal fluoxetine treatment on the body and skeletal muscle phenotype of rats exposed to a maternal lard-based high-fat (H) diet during the perinatal period. A maternal lard-based high-fat diet causes reduced birth weight, a short-term reduction in type IIA fibers in the soleus muscle, and in type IIB fibers in the Extensor Digitorum Longus (EDL) muscle, reducing Lactate Dehydrogenase (LDH) activity in both muscles. In the long-term, the soleus showed reduced muscle weight, smaller area and perimeter of muscle fibers, while the EDL muscle showed reduced Citrate Synthase (CS) activity in offspring from the rats on the maternal lard-based high-fat diet. Early-life exposure to fluoxetine reduced body weight and growth and reduced soleus weight and enzymatic activity in young rats. Exposure to neonatal fluoxetine in adult rats caused a decreased body mass index, less food intake, and reduced muscle weight with reduced CS and LDH activity. Neonatal fluoxetine in young rats exposed to a maternal lard-based high-fat diet caused reduced body weight and growth, reduced soleus weight as well as area and perimeter of type I muscle fibers. In adulthood, there was a reduction in food intake, increased proportion of IIA type fibers, reduced area and perimeter of type IIB, and reduction in levels of CS activity in EDL muscle. Neonatal fluoxetine treatment in rats exposed to a maternal lard-based, high-fat diet induces a reduction in muscle weight, an increase in the proportion of oxidative fibers and greater oxidative enzymatic activity in adulthood.

Assuntos

Dieta Hiperlipídica , Fluoxetina/farmacologia , Músculo Esquelético/efeitos dos fármacos , Efeitos Tardios da Exposição Pré-Natal , Animais , Animais Recém-Nascidos , Peso Corporal/efeitos dos fármacos , Citrato (si)-Sintase/metabolismo , Gorduras na Dieta , Ingestão de Alimentos/efeitos dos fármacos , Feminino , Hidroliases/metabolismo , Masculino , Fibras Musculares Esqueléticas/efeitos dos fármacos , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Fenótipo , Gravidez , Ratos , Ratos Wistar

RESUMO

INTRODUCTION: HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a chronic progressive myelopathy associated with an inflammation of the central nervous system (CNS), being characterized by perivascular infiltration of inflammatory cells. HTLV-1-infected cells have the capacity to migrate through endothelial layers by enhancing adhesion receptor expression and corresponding ligands. T cells interact with the extracellular matrix via integrin receptors and these interactions affect both cell migration and proliferation. The importance of these interactions in retrovirus-induced diseases, however, remains less clear. METHODS: Herein we studied the expression of 3 integrin alpha chains (CD49d, CD49e, and CD49f) on the membrane of T-cell subsets in patients infected by HTLV-1, both HAM/TSP patients and oligo/asymptomatic subjects who were asymptomatic or presented slight manifestations related to the virus infection. RESULTS: We observed higher peripheral blood frequency of CD49dhiCD4+ and CD49dhiCD8+ T cells in HTLV-1-infected patients. CONCLUSION: Our findings suggest that the increased expression of adhesion molecules, such as CD49d on T lymphocytes from HTLV-1-infected patients may contribute to the pathogenesis of the disease, in both oligo/asymptomatic and HAM/TSP-infected subjects. Accordingly, it is conceivable that there is a potential use of CD49d as target for a therapeutic approach aiming at blocking migration of activated T cells from HTLV-1-infected patients into the CNS, thus avoiding the progression to HAM/TSP.

Assuntos

Vírus Linfotrópico T Tipo 1 Humano , Paraparesia Espástica Tropical , Sistema Nervoso Central , Humanos , Inflamação , Subpopulações de Linfócitos T