Clonal landscape and clinical outcomes of telomere biology disorders: somatic rescuing and cancer mutations.

Telomere biology disorders (TBD), caused by pathogenic germline variants in telomere-related genes, present with multi-organ disease and a predisposition to cancer. Clonal hematopoiesis (CH) as a marker of cancer development and survival in TBD is poorly understood. Here, we characterized the clonal landscape of a large cohort of 207 TBD patients with a broad range of age and phenotype. CH occurred predominantly in symptomatic patients and in signature genes typically associated with cancers: PPM1D, POT1, TERT promoter (TERTp), U2AF1S34, and/or TP53. Chromosome 1q gain (Chr1q+) was the commonest karyotypic abnormality. Clinically, multiorgan involvement and CH in TERTp, TP53, and splicing factor genes associated with poorer overall survival. Chr1q+, and splicing factor or TP53 mutations significantly increased the risk of hematologic malignancies, regardless of the clonal burden. Chr1q+ and U2AF1S34 mutated clones were pre-malignant events associated with the secondary acquisition of mutations in genes related to hematologic malignancies. Like known effects of Chr1q+ and TP53-CH, functional studies demonstrated that U2AF1S34 mutations primarily compensated for aberrant upregulation of TP53 and interferon pathways in telomere-dysfunctional hematopoietic stem cells, highlighting the TP53 pathway as a canonical route of malignancy in TBD. In contrast, somatic POT1/PPM1D/TERTp-CH had distinct trajectories unrelated to cancer development. With implications beyond TBD, our data show that telomere dysfunction is a strong selective pressure for CH. In TBD, CH is a poor prognostic marker associated with worse overall survival. The identification of key regulatory pathways that drive clonal transformation in TBD allows the identification of patients at a higher risk of cancer development.

RecQ helicase expression in patients with telomeropathies.

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.

Obesity contributes to telomere shortening in polycystic ovary syndrome.

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.

Creatine supplementation increases postnatal growth and strength and prevents overexpression of pro-inflammatory interleukin 6 in the hippocampus in an experimental model of cerebral palsy.

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.

Neonatal kaempferol exposure attenuates impact of cerebral palsy model on neuromotor development, cell proliferation, microglia activation, and antioxidant enzyme expression in the hippocampus of rats.

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.

Telomeric repeat-containing RNA is dysregulated in acute myeloid leukemia.

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.

Motor deficits are associated with increased glial cell activation in the hypothalamus and cerebellum of young rats subjected to cerebral palsy.

Cerebral palsy (CP) is a syndrome characterized by a wide range of sensory and motor damage, associated with behavioral and cognitive deficits. The aim of the present study was to investigate the potential of a model of CP using a combination of perinatal anoxia and sensorimotor restriction of hind paws to replicate motor, behavioral and neural deficits. A total of 30 of male Wistar rats were divided into Control (C, n = 15), and CP (CP, n = 15) groups. The potential of the CP model was assessed by evaluating food intake, the behavioral satiety sequence, performance on the CatWalk and parallel bars, muscle strength, and locomotor activity. The weight of the encephalon, soleus, and extensor digitorum longus (EDL) muscles, and the activation of glial cells (microglia and astrocytes) were also measured. The CP animals showed delayed satiety, impaired locomotion on the CatWalk and open field test, reduced muscle strength, and reduced motor coordination. CP also reduced the weight of the soleus and muscles, brain weight, liver weight, and quantity of fat in various parts of the body. There was also found to be an increase in astrocyte and microglia activation in the cerebellum and hypothalamus (arcuate nucleus, ARC) of animals subjected to CP.

Trend of incompleteness of maternal schooling and race/skin color variables held on the Brazilian Live Birth Information System, 2012-2020.

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.

Differential diagnosis of bone marrow failure syndromes guided by machine learning.

The choice to postpone treatment while awaiting genetic testing can result in significant delay in definitive therapies in patients with severe pancytopenia. Conversely, the misdiagnosis of inherited bone marrow failure (BMF) can expose patients to ineffectual and expensive therapies, toxic transplant conditioning regimens, and inappropriate use of an affected family member as a stem cell donor. To predict the likelihood of patients having acquired or inherited BMF, we developed a 2-step data-driven machine-learning model using 25 clinical and laboratory variables typically recorded at the initial clinical encounter. For model development, patients were labeled as having acquired or inherited BMF depending on their genomic data. Data sets were unbiasedly clustered, and an ensemble model was trained with cases from the largest cluster of a training cohort (n = 359) and validated with an independent cohort (n = 127). Cluster A, the largest group, was mostly immune or inherited aplastic anemia, whereas cluster B comprised underrepresented BMF phenotypes and was not included in the next step of data modeling because of a small sample size. The ensemble cluster A-specific model was accurate (89%) to predict BMF etiology, correctly predicting inherited and likely immune BMF in 79% and 92% of cases, respectively. Our model represents a practical guide for BMF diagnosis and highlights the importance of clinical and laboratory variables in the initial evaluation, particularly telomere length. Our tool can be potentially used by general hematologists and health care providers not specialized in BMF, and in under-resourced centers, to prioritize patients for genetic testing or for expeditious treatment.

Effects of nandrolone decanoate on telomere length and clinical outcome in patients with telomeropathies: a prospective trial.

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.

Neonatal kaempferol exposure attenuates gait and strength deficits and prevents altered muscle phenotype in a rat model of cerebral palsy.

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.

Tendência da incompletude das variáveis escolaridade e raça/cor da pele da mãe no Sistema de Informações sobre Nascidos Vivos do Brasil, 2012-2020 / Tendencia de incompletitud de las variables escolaridad y raza/color de piel materno en el sistema de información sobre nacidos vivos en Brasil, 2012-2020 / Trend of incompleteness of maternal schooling and race/skin color variables held on the Brazilian Live Birth Information System, 2012-2020

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.

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.

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.

Effects of the Treatment with Flavonoids on Metabolic Syndrome Components in Humans: A Systematic Review Focusing on Mechanisms of Action.

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.

Defective hematopoietic differentiation of immune aplastic anemia patient-derived iPSCs.

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.

The relationship between IL-4 polymorphisms and asthma: a systematic review / A relação entre polimorfismos de IL-4 e asma: uma revisão sistemática

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)

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).

Effects of flavonols on emotional behavior and compounds of the serotonergic system: A preclinical systematic review.

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.

Short-Term Aerobic Exercise Did Not Change Telomere Length While It Reduced Testosterone Levels and Obesity Indexes in PCOS: A Randomized Controlled Clinical Trial Study.

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.

Low Annexin A1 level in HTLV-1 infected patients is a potential biomarker for the clinical progression and diagnosis of HAM/TSP.

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.

Treatment with the essential amino acid L-tryptophan reduces masticatory impairments in experimental cerebral palsy.

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.

Effects chronic administration of corticosterone and estrogen on HPA axis activity and telomere length in brain areas of female rats.

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.