Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 229
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
BMC Pulm Med ; 19(1): 115, 2019 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-31238942

RESUMO

BACKGROUND: We aimed to evaluate whether serum activin-A levels are elevated and have any value in predicting severity and prognosis in acute respiratory distress syndrome (ARDS). METHODS: Retrospective cohort study was performed with patients who were admitted to MICU with diagnosis of ARDS and have serum samples stored within 48 h of Intensive care unit (ICU) admission between March 2013 and December 2016 at a single tertiary referral hospital. Serum activin-A levels were measured with ELISA kit, and were compared with those of normal healthy control and non-ARDS sepsis patients. RESULTS: Total 97 ARDS patients were included for the study. Levels of Activin-A were elevated in ARDS patients compared to those of healthy controls (Log-transformed activin-A levels 2.89 ± 0.36 vs. 2.34 ± 0.11, p < 0.001, absolute activin-A levels 1525.6 ± 1060.98 vs. 225.9 ± 30.1, p = 0.016) and non-ARDS sepsis patients (Log-transformed activin-A levels 2.89 ± 0.36 vs. 2.73 ± 0.34, p = 0.002, Absolute activin-A levels 1525.6 ± 1060.98 vs. 754.8 ± 123.5 pg/mL, p = 0.036). When excluding five outliers with extremely high activin-A levels, activin-A showed statistically significant correlation with in-hospital mortalities (In-hospital survivors 676.2 ± 407 vs. non-survivors 897.9 ± 561.9 pg/mL, p = 0.047). In predicting in-hospital mortality, serum activin-A concentrations showed superior area under curve compared to that of Acute physiologic and chronic health evaluation II scores (0.653; 95% CI [0541, 0.765] vs. 0.591, 95% CI [0.471, 0.710]). With cut-off level of 708 pg/mL, those with high serum activin-A levels had more than twofold increased risk of in-hospital mortalities. However, those relations were missing when outliers were in. CONCLUSIONS: Serum activin-A levels in ARDS patients are elevated. However, its levels are weakly associated with ARDS outcomes.


Assuntos
Ativinas/sangue , Síndrome do Desconforto Respiratório do Adulto/sangue , Síndrome do Desconforto Respiratório do Adulto/diagnóstico , Idoso , Biomarcadores/sangue , Feminino , Mortalidade Hospitalar , Humanos , Unidades de Terapia Intensiva , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Valor Preditivo dos Testes , Prognóstico , Curva ROC , República da Coreia , Síndrome do Desconforto Respiratório do Adulto/mortalidade , Estudos Retrospectivos , Sepse/sangue , Sepse/diagnóstico , Análise de Sobrevida
2.
Ann Hematol ; 98(7): 1583-1592, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31041514

RESUMO

Despite the advances in the management of hemoglobinopathies, further insight into disease pathophysiology is necessary to improve our therapeutic approach. Activin-A has emerged as a regulator of erythropoiesis and bone turnover in malignant disorders; however, clinical data in hemoglobinopathies are currently scarce. Thus, we aimed to investigate the role of activin-A among hemoglobinopathy patients and evaluate the rationale of its targeting. Circulating levels of activin-A were measured in patients (n = 227) with beta-thalassemia major (TM) (n = 58), beta-thalassemia intermedia (TI) (n = 43), double heterozygous sickle cell/beta-thalassemia (HbS/beta-thal) (n = 109), or homozygous sickle cell disease (n = 17), and we explored possible correlations with clinical and laboratory data. Seventeen age- and gender-matched, healthy individuals served as controls. Bone marrow density (BMD) was determined using dual-energy X-ray absorptiometry. TM and HbS/beta-thal patients had elevated activin-A compared to controls (p = 0.041 and p = 0.038, respectively). In TM patients, high circulating activin-A showed strong correlations with hemolysis markers, namely reticulocyte count (p = 0.011) and high lactate dehydrogenase (LDH; p = 0.024). Similarly, in HbS/beta-thal patients, activin-A showed positive correlations with indirect bilirubin (p < 0.001), ferritin (p = 0.005), and LDH (p = 0.044). High activin-A correlated with low Z-score of both lumbar spine BMD in TI patients (p < 0.01) and femoral neck BMD in TM patients (p < 0.01). Serum activin-A is elevated in patients with TM and HbS/beta-thal and correlates with markers of hemolysis and low BMD. These data support a role of activin-A in the biology of these disorders and provide further rationale for the broader clinical development of activin-A inhibitors in this setting.


Assuntos
Ativinas/sangue , Anemia Falciforme , Densidade Óssea , Hemólise , Heterozigoto , Talassemia beta , Ativinas/genética , Adulto , Idoso , Anemia Falciforme/sangue , Anemia Falciforme/genética , Biomarcadores/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Contagem de Reticulócitos , Talassemia beta/sangue , Talassemia beta/genética
3.
Clin Nephrol ; 91(4): 222-230, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30862350

RESUMO

INTRODUCTION: Renal osteodystrophy (ROD) develops early in chronic kidney disease (CKD) and progresses with loss of kidney function. While intact parathyroid hormone (PTH), 1,25-dihydroxyvitamin D3 (1,25D), and fibroblast growth factor-23 (FGF-23) levels are usually considered the primary abnormalities in ROD development, the role of serum activin A elevations in CKD and its relationships to ROD have not been explored. The aims of this study were to evaluate serum activin A at different CKD stages, and to establish the relationships between activin A, bone biomarkers, and bone histomorphometric parameters. MATERIALS AND METHODS: 104 patients with CKD stages 2 - 5D underwent bone biopsies. We measured in the serum activin A, BSAP, DKK1, FGF-23, α-Klotho, intact PTH, sclerostin, TRAP-5b, and 1,25D. Biochemical results were compared across CKD stages and with 19 age-matched controls with normal kidney function. RESULTS: Median activin A levels were increased in all stages of CKD compared to controls from 544 pg/mL in CKD 2 (431 - 628) to 1,135 pg/mL in CKD 5D (816 - 1,456), compared to 369 pg/mL in controls (316 - 453, p < 0.01). The increase of activin A in CKD 2 (p = 0.016) occurred before changes in the other measured biomarkers. Activin A correlated with intact PTH and FGF-23 (r = 0.65 and 0.61; p < 0.01) and with histomorphometric parameters of bone turnover (BFR/BS, Acf, ObS/BS and OcS/BS; r = 0.47 - 0.52; p < 0.01). These correlations were comparable to those found with intact PTH and FGF-23. CONCLUSION: Serum activin A levels increase starting at CKD 2 before elevations in intact PTH and FGF-23. Activin A correlates with bone turnover similar to intact PTH and FGF-23. These findings suggest a role for activin A in early development of ROD.


Assuntos
Ativinas/sangue , Distúrbio Mineral e Ósseo na Doença Renal Crônica/sangue , Insuficiência Renal Crônica/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Proteínas Morfogenéticas Ósseas/sangue , Remodelação Óssea , Estudos de Casos e Controles , Distúrbio Mineral e Ósseo na Doença Renal Crônica/etiologia , Distúrbio Mineral e Ósseo na Doença Renal Crônica/fisiopatologia , Feminino , Fatores de Crescimento de Fibroblastos/sangue , Marcadores Genéticos , Taxa de Filtração Glomerular , Glucuronidase/sangue , Humanos , Subunidades beta de Inibinas , Peptídeos e Proteínas de Sinalização Intercelular/sangue , Falência Renal Crônica/sangue , Masculino , Pessoa de Meia-Idade , Fator de Transcrição PAX5/sangue , Hormônio Paratireóideo/sangue , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/fisiopatologia , Índice de Gravidade de Doença , Fosfatase Ácida Resistente a Tartarato/sangue , Vitamina D/análogos & derivados , Vitamina D/sangue
5.
J Clin Endocrinol Metab ; 104(2): 349-358, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30388235

RESUMO

Context: Breast cancer is the most common malignancy in women. Noninvasive biomarkers are needed for its early diagnosis and/or prognosis. Objective: The aim of this case-control study was the comparison of serum activins, follistatins, and members of the IGF family levels in women with benign vs malignant breast neoplasms vs apparently healthy controls. Design and Patients: Women with breast benign (n = 100) or malignant tumors (n = 145) and disease-free controls (n = 100) were recruited. Women with breast cancer were subsequently subdivided into recently diagnosed/treatment-naive (n = 112) and chemotherapy-treated (n = 33). Anthropometric, demographic, biochemical, and histological data were recorded. Setting: A breast cancer clinic in Thessaloniki, Greece. Main Outcome Measures: Serum levels of activin A, activin B, follistatin, follistatin-like (FSTL)-3, total IGF-1, total and intact insulin-like growth factor binding protein (IGFBP)-4 and pregnancy-associated plasma protein-A (PAPP-A) were measured with highly specific ELISA kits. Results: In adjusted comparisons, substantial differences in FSTL-3, total and intact IGFBP-4, PAPP-A, and total IGF-1 were observed between groups. In logistic regression analysis, primarily total IGFBP-4 levels were independently associated with the overall presence of breast malignancy. FSTL-3 was the only variable that could distinguish between a benign vs malignant breast mass. In linear regression analysis, FSTL-3 was independently associated with tumor size. Conclusions: We showed that members of the IGF-1/IGFBP-4/PAPP-A axis and FSTL-3 may serve as surrogate markers in breast cancer. Future mechanistic and longitudinal studies and/or clinical trials are needed to explore the efficacy of these molecules as noninvasive biomarkers and their possible therapeutic potential in breast cancer.


Assuntos
Biomarcadores Tumorais/sangue , Neoplasias da Mama/diagnóstico , Ativinas/sangue , Adulto , Fatores Etários , Idoso , Neoplasias da Mama/sangue , Estudos de Casos e Controles , Feminino , Folistatina/sangue , Proteínas Relacionadas à Folistatina/sangue , Humanos , Proteína 4 de Ligação a Fator de Crescimento Semelhante à Insulina/sangue , Fator de Crescimento Insulin-Like I/análise , Pessoa de Meia-Idade , Proteína Plasmática A Associada à Gravidez/análise
6.
Drug Test Anal ; 10(11-12): 1714-1721, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30285318

RESUMO

Therapeutic proteins are a continuously growing class of pharmaceuticals and comprise several drug candidates with potential performance-enhancing properties. In particular, activin receptor competitors, such as the ActRII-Fc fusion proteins Sotatercept (ActRIIA-Fc) and Luspatercept (modified ActRIIB-Fc), have the potential for being misused as doping agents in sports as they were found to inhibit negative regulators of late-stage erythropoiesis. Within this study, ammonium sulfate precipitation, immunoaffinity purification, tryptic digestion, and liquid chromatography-tandem mass spectrometry (LC-MS/MS) were employed to develop an assay for the combined detection of Sotatercept and Luspatercept in doping control serum samples. The assay was optimized, comprehensively characterized, and found to be fit-for-purpose for application to sports drug testing. It complements existing tests for ActRII-Fc fusion proteins and expands the range of available detection methods for novel protein therapeutics.


Assuntos
Ativinas/sangue , Cromatografia Líquida de Alta Pressão/métodos , Fragmentos Fc das Imunoglobulinas/sangue , Imunoprecipitação/métodos , Proteínas Recombinantes de Fusão/sangue , Espectrometria de Massas em Tandem/métodos , Receptores de Activinas Tipo II , Ativinas/análise , Ativinas/isolamento & purificação , Precipitação Química , Humanos , Fragmentos Fc das Imunoglobulinas/análise , Fragmentos Fc das Imunoglobulinas/isolamento & purificação , Limite de Detecção , Substâncias para Melhoria do Desempenho/sangue , Proteólise , Proteínas Recombinantes de Fusão/análise , Proteínas Recombinantes de Fusão/isolamento & purificação , Detecção do Abuso de Substâncias/métodos , Tripsina/química
7.
Drug Test Anal ; 10(11-12): 1708-1713, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30203930

RESUMO

We recently published two protocols for the detection of Sotatercept (ACE-011, ACVR2A-Fc) and Luspatercept (ACE-536, ACVR2B-Fc) in human serum. Both methods used covalently immobilized antibodies on agarose beads for immunoprecipitation and SAR-PAGE/Western blotting for detection. Disadvantages were the relatively high amount of antibody required per sample (10 µg) and the need of a secondary antibody for the final detection. The updated protocols overcome these limitations by antigen-antibody complex formation in solution followed by capture of the complex with anti-antibody-coated magnetic beads. They also omit the secondary antibody incubation step by usage of biotinylated primary antibodies, which can be directly incubated with streptavidin-HRP. Thus, the new protocols are faster, simpler, and cheaper and offer comparable sensitivities.


Assuntos
Ativinas/sangue , Fragmentos Fc das Imunoglobulinas/sangue , Proteínas Recombinantes de Fusão/sangue , Receptores de Activinas Tipo II , Ativinas/isolamento & purificação , Anticorpos Imobilizados/química , Biotinilação , Western Blotting/métodos , Eletroforese em Gel de Poliacrilamida/métodos , Humanos , Fragmentos Fc das Imunoglobulinas/isolamento & purificação , Imunoprecipitação/métodos , Proteínas Recombinantes de Fusão/isolamento & purificação
8.
J Musculoskelet Neuronal Interact ; 18(3): 320-322, 2018 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-30179208

RESUMO

BACKGROUND: Activin A plays as an anticatabolic autocrine cytokine in articular cartilage. Thus, this study aims to evaluate whether activin Aconcentration is correlated with the occurrence and severity of knee osteoarthritis (OA). METHODS: A total of 210 knee OA patients and 150 healthy controls were enrolled in this cross-sectional study, to evaluate the severity of OA by Kellgren-Lawrence (KL) grading method. RESULTS: It was found that the concentration of activin A in knee OA group was higher than that in healthy subjects. Furthermore, results of of activin A concentration in serum and synovial fluid (SF) suggested that activin A concentration was the highest in Kellgren-Lawrence (KL) grade 4, and the lowest in KL grade 2. Concentrations of activin A in serum and SF showed significant correlation with disease severity measured by KL grading criteria. CONCLUSIONS: It was indicated that concentrations of activin A in serum and SF showed a positive correlation with the occurrence and severity of knee OA.


Assuntos
Ativinas/metabolismo , Articulação do Joelho/diagnóstico por imagem , Osteoartrite do Joelho/metabolismo , Líquido Sinovial/metabolismo , Ativinas/sangue , Idoso , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Osteoartrite do Joelho/sangue , Osteoartrite do Joelho/diagnóstico por imagem , Radiografia , Índice de Gravidade de Doença
9.
Physiol Rep ; 6(17): e13823, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30178598

RESUMO

Loss of muscle mass and function are a well-defined aspect of human aging from the 3rd decade of life, which result in reduced independence and increased mortality. The activin family of peptides contains several endocrine factors (activin A, myostatin, growth and differentiation factor 11 [GDF11]) that may play roles in changes in muscle mass and the aging process, however, it may be simplistic to consider aging as a result of a single peptides changes. Thus, we aimed to examine changes in activin family members across a cohort of healthy individuals of various ages, hypothesizing that these would aid predictive models of age and functional measures of age. Healthy participants (n = 88) were recruited and resting metabolic rate, body composition, grip strength, walking speed, and circulating plasma concentrations of myostatin (total and free), activin A, follistatin-like binding protein (FLRG), and GDF11 quantified. Simple regressions between circulating factors and chronological age, grip strength, and walking speed were examined. Multiple stepwise regressions for age, grip strength, and walking speed are also reported. Age negatively correlated with total myostatin (P = 0.032, r2  = 0.053), grip strength positively with activin A (P = 0.046, r2  = 0.048), whereas walking speed showed no simple regression relationships. Stepwise regressions suggested a role of total myostatin and activin A in models of age, whereas GDF11 contributed to the model of grip strength. Here we suggest a role for myostatin, activin A, and GDF11 in normal human aging that mirrors animal studies to date. Further interventional studies are required to elicitate the physiological role of these changes in the normal human aging process, and indeed if offsetting these changes can promote successful aging.


Assuntos
Ativinas/sangue , Envelhecimento/sangue , Proteínas Morfogenéticas Ósseas/sangue , Proteínas Relacionadas à Folistatina/sangue , Fatores de Diferenciação de Crescimento/sangue , Músculo Esquelético/fisiologia , Miostatina/sangue , Adolescente , Adulto , Idoso , Envelhecimento/fisiologia , Metabolismo Basal , Feminino , Força da Mão , Humanos , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/crescimento & desenvolvimento , Velocidade de Caminhada
10.
Exp Gerontol ; 111: 197-202, 2018 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-30071284

RESUMO

Cardiovascular disease imposes substantial burdens of morbidity and mortality that increase with population aging. Estimating cardiometabolic risk accurately and expediently is challenging, and no single biomarker is satisfactory; hence, we investigated the potential of serum activin A for this purpose. Study data were collected from 433 community-dwelling adults age ≥53 years from Yilan County, Taiwan. Data included: demographics and medical history; physical measurements (blood pressure, body mass index, waist circumference); comprehensive functional assessments (frailty, cognitive function, depressive symptoms, nutritional status); fasting blood biochemistry (glucose, high-density lipoprotein cholesterol, triglycerides, high-sensitivity C-reactive protein, insulin-like growth factor-1, activin A, stratified into high, medium and low tertiles, and others); and dual-energy X-ray absorptiometry. Metabolic syndrome was considered a proxy for overall cardiometabolic risk. Subjects mean age was 69.3 ±â€¯9.2 years, 48.3% were males. Compared to women, men had higher systolic blood pressure, education levels, relative appendicular skeletal muscle mass, waist circumference, physical activity, walking speed, free androgen index, and levels of serum uric acid, alanine aminotransferase, and dehydroepiandrosterone sulfate. High activin A was significantly associated with age, relative appendicular skeletal muscle mass in both gender, waist circumference in women, current alcohol drinking, hypertension, and Charlson Comorbidity Index. There were dose-dependent relationships (low to high) between serum activin A and frailty, cognitive impairment, malnutrition, metabolic syndrome, uric acid, and high-sensitivity C-reactive protein. Logistic regression analyses showed older age, serum uric acid, and metabolic syndrome were significantly associated with medium and high activin-A status, whereas, skeletal muscle mass, insulin-like growth factor-1 and dehydroepiandrosterone sulphate were associated with high, but not medium, serum activin A. This discovery of a dose-dependent association between serum activin A levels, age, and metabolic syndrome, suggests activin A may be a biomarker of overall cardiometabolic risk; however, further studies are needed to evaluate its potential applications in assessing and managing cardiometabolic risk.


Assuntos
Ativinas/sangue , Envelhecimento/metabolismo , Doenças Cardiovasculares/sangue , Diabetes Mellitus/sangue , Síndrome Metabólica/sangue , Absorciometria de Fóton , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Índice de Massa Corporal , Proteína C-Reativa/metabolismo , Feminino , Humanos , Fator de Crescimento Insulin-Like I , Modelos Logísticos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Proteínas Recombinantes/sangue , Fatores de Risco , Taiwan , Ácido Úrico/sangue
11.
J Clin Endocrinol Metab ; 103(10): 3890-3899, 2018 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-30085147

RESUMO

Context: Clinical trials are evaluating the efficacy of inhibitors of the myostatin pathway in neuromuscular and metabolic diseases. Activins and follistatins are major regulators of the myostatin pathway, but their physiology in relation to metabolic and anthropometric variables and in response to exercise remains to be fully elucidated in humans. Objective: We investigated whether concentrations of circulating activin A, activin B, follistatin, and follistatin-like 3 (FSTL3) are associated with anthropometric and metabolic variables and whether they are affected by exercise. Design: Activin A, activin B, follistatin, and FSTL3 were measured in (1) 80 subjects divided according to age (young vs old) and fitness status (active vs sedentary) before and after exercise at 70% maximal oxygen consumption (VO2max), followed by 90% of VO2max until exhaustion; and (2) 23 subjects [9 healthy and 14 with metabolic syndrome (MetS)] who completed four sessions: no exercise, high-intensity interval exercise, continuous moderate-intensity exercise, and resistance exercise for up to 45 minutes. Results: At baseline, follistatin and FSTL3 concentrations were positively associated with age, fat percentage, and body mass index (P < 0.001). Follistatin was positively associated with serum cholesterol (P = 0.005), low-density lipoprotein cholesterol (P = 0.01), triglycerides (P = 0.033), and blood pressure (P = 0.019), whereas activin A and activin B were higher in physically active participants (P = 0.056 and 0.029, respectively). All exercise types increased the levels of all hormones ∼10% to 21% (P = 0.034 for activin B, P < 0.001 for the others) independent of the presence of MetS. Conclusion: Concentrations of circulating activins and follistatins are associated with metabolic parameters and increase after 45 minutes of exercise.


Assuntos
Ativinas/fisiologia , Exercício/fisiologia , Folistatina/fisiologia , Ativinas/sangue , Adiposidade/fisiologia , Adolescente , Adulto , Idoso , Envelhecimento/sangue , Envelhecimento/fisiologia , Antropometria/métodos , Composição Corporal/fisiologia , Folistatina/sangue , Proteínas Relacionadas à Folistatina/sangue , Proteínas Relacionadas à Folistatina/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade , Aptidão Física/fisiologia , Comportamento Sedentário , Adulto Jovem
12.
Sci Rep ; 8(1): 9957, 2018 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-29967428

RESUMO

Activin A and its binding protein follistatin may be crucial in glucose homeostasis, as multifunctional proteins mediating inflammatory and anti-inflammatory effects. However, clinical data on the activin A level in prediabetes, and the association between the circulating activin A level and carotid intima-media thickness (cIMT), are lacking. We aimed to investigate activin A and follistatin levels and their associations with cIMT. In total, 470 inhabitants of I-Lan county (235 men; mean age 69 ± 9 years) with measurements of serum activin A and follistatin levels were included. Patients with prediabetes and diabetes had significantly increased activin A concentrations compared with those in the normal glycemic group (both p < 0.001). A multivariable logistic regression model demonstrated that the circulating activin A level was associated with prediabetes and diabetes independently of other risk factors. Moreover, the circulating activin A levels were associated positively with cIMT in prediabetes (rs = 0.264, p = 0.001). In conclusion, activin A level, but not follistatin, was elevated independent of demographic variables with borderline significance and was correlated positively with cIMT in prediabetes. Activin A and follistatin levels were elevated in diabetes. In addition, elevated activin A was an independent risk factor for prediabetes and diabetes.


Assuntos
Ativinas/sangue , Espessura Intima-Media Carotídea , Estado Pré-Diabético/sangue , Idoso , Aterosclerose/sangue , Biomarcadores/sangue , Estudos Transversais , Diabetes Mellitus/sangue , Diabetes Mellitus/fisiopatologia , Feminino , Folistatina/sangue , Humanos , Modelos Logísticos , Masculino , Estado Pré-Diabético/fisiopatologia , Taiwan
13.
Metabolism ; 85: 240-249, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29752954

RESUMO

BACKGROUND: We have previously demonstrated that the adipose tissue derived hormone leptin controls reproductive function by regulating the hypothalamic-pituitary-gonadal axis in response to energy deficiency. Here, we evaluate the activins-follistatins-inhibins (AFI) axis during acute (short-term fasting in healthy people) and chronic energy deficiency (women with hypothalamic amenorrhea due to strenuous exercise [HA]) and investigate their relation to leptin and reproductive function in healthy subjects and subjects with HA. METHODS: The AFI axis was investigated in: a) A double-blinded study in healthy subjects having three randomly assigned admissions, each time for four days: in the isocaloric fed state, complete fasting with placebo treatment, complete fasting with leptin replacement, b) A case-control study comparing women with HA vs healthy controls, c) An open-label interventional study investigating leptin treatment in women with HA over a period of up to three months, d) A randomized interventional trial investigating leptin treatment vs placebo in women with HA for nine months. RESULTS: The circulating levels of activin A, activin B, follistatin and follistatin-like 3 change robustly in response to acute and chronic energy deficiency. Leptin replacement in acute energy deprivation does not affect the levels of these hormones suggesting an independent regulation by these two hormonal pathways. In chronic energy deficiency, leptin replacement restores only activin B levels, which are in turn associated with an increase in the number of dominant follicles. CONCLUSIONS: We demonstrate for the first time that the AFI axis is affected both by acute and chronic energy deficiency. Partial restoration of a component of the axis, i.e. activin B only, through leptin replacement is associated with improved reproductive function in women with HA.


Assuntos
Ativinas/sangue , Jejum/sangue , Proteínas Relacionadas à Folistatina/sangue , Folistatina/sangue , Reprodução/fisiologia , Adulto , Estudos de Casos e Controles , Método Duplo-Cego , Metabolismo Energético/fisiologia , Feminino , Humanos , Leptina/farmacologia , Masculino , Adulto Jovem
14.
Hypertension ; 72(1): 188-193, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29844146

RESUMO

Women with hypertensive disorders of pregnancy have an increased risk of subsequent heart failure and cardiovascular disease when compared with women with normotensive pregnancies. Although the mechanisms underlying these findings are unclear, elevated levels of the biomarker activin A are associated with myocardial dysfunction and may have predictive value. We hypothesized that elevated levels of antepartum activin A levels would correlate with postpartum cardiac dysfunction in women with hypertensive disorders of pregnancy. We prospectively studied 85 women to determine whether increased antepartum activin A levels were associated with cardiac dysfunction at 1 year postpartum as measured by global longitudinal strain. Thirty-two patients were diagnosed with preeclampsia, 28 were diagnosed with gestational or chronic hypertension, and the remainder were nonhypertensive controls. Activin A levels were measured with ELISA both in the third antepartum trimester and at 1 year postpartum. Comprehensive echocardiograms including measurement of global longitudinal strain were also performed at enrollment and at 1 year postpartum. Antepartum activin A levels correlated with worsening antepartum global longitudinal strain (r=0.70; P=0.0001). Across the entire cohort, elevated antepartum activin A levels were associated with the development of abnormal global longitudinal strain at 1 year (C statistic 0.74; P=0.004). This association remained significant after multivariable adjustment for clinically relevant confounders (C statistic 0.93; P=0.01). Postpartum activin A levels also correlated with increasing left ventricular mass index (P=0.02), increasing mean arterial pressures (P=0.02), and decreasing E' values (P=0.01). Activin A may be a useful tool for identifying and monitoring patients at risk for postpartum development of cardiovascular disease.


Assuntos
Ativinas/sangue , Pressão Sanguínea/fisiologia , Ventrículos do Coração/diagnóstico por imagem , Hipertensão Induzida pela Gravidez/fisiopatologia , Período Pós-Parto , Disfunção Ventricular Esquerda/sangue , Função Ventricular Esquerda/fisiologia , Adulto , Biomarcadores/sangue , Estudos de Casos e Controles , Ecocardiografia , Feminino , Ventrículos do Coração/fisiopatologia , Humanos , Gravidez , Terceiro Trimestre da Gravidez , Estudos Prospectivos , Disfunção Ventricular Esquerda/diagnóstico , Disfunção Ventricular Esquerda/fisiopatologia
15.
J Immunol ; 201(1): 41-52, 2018 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-29743313

RESUMO

IVIg is an approved therapy for immunodeficiency and for several autoimmune and inflammatory diseases. However, the molecular basis for the IVIg anti-inflammatory activity remains to be fully explained and cannot be extrapolated from studies on animal models of disease. We now report that IVIg impairs the generation of human monocyte-derived anti-inflammatory macrophages by inducing JNK activation and activin A production and limits proinflammatory macrophage differentiation by inhibiting GM-CSF-driven STAT5 activation. In vivo, IVIg provokes a rapid increase in peripheral blood activin A, CCL2, and IL-6 levels, an effect that can be recapitulated in vitro on human monocytes. On differentiating monocytes, IVIg promotes the acquisition of altered transcriptional and cytokine profiles, reduces TLR expression and signaling, and upregulates negative regulators of TLR-initiated intracellular signaling. In line with these effects, in vivo IVIg infusion induces a state tolerant toward subsequent stimuli that results in reduced inflammatory cytokine production after LPS challenge in human peripheral blood and significant protection from LPS-induced death in mice. Therefore, IVIg conditions human macrophages toward the acquisition of a state of cross-tolerance against inflammatory stimuli, an effect that correlates with the net anti-inflammatory action of IVIg in vivo.


Assuntos
Anti-Inflamatórios/imunologia , Tolerância Imunológica/imunologia , Imunoglobulinas Intravenosas/imunologia , Imunoglobulinas Intravenosas/farmacologia , Macrófagos/imunologia , Fator de Transcrição STAT5/metabolismo , Ativinas/sangue , Animais , Células Cultivadas , Quimiocina CCL2/sangue , Ativação Enzimática , Fator Estimulador de Colônias de Granulócitos e Macrófagos/metabolismo , Humanos , Inflamação/imunologia , Interleucina-6/sangue , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Lipopolissacarídeos/imunologia , Camundongos , Monócitos/citologia , Monócitos/imunologia
16.
J Transl Med ; 16(1): 97, 2018 04 12.
Artigo em Inglês | MEDLINE | ID: mdl-29650052

RESUMO

BACKGROUND: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is clinically defined and characterised by persistent disabling tiredness and exertional malaise, leading to functional impairment. METHODS: This study introduces the weighted standing time (WST) as a proxy for ME/CFS severity, and investigates its behaviour in an Australian cohort. WST was calculated from standing time and subjective standing difficulty data, collected via orthostatic intolerance assessments. The distribution of WST for healthy controls and ME/CFS patients was correlated with the clinical criteria, as well as pathology and cytokine markers. Included in the WST cytokine analyses were activins A and B, cytokines causally linked to inflammation, and previously demonstrated to separate ME/CFS from healthy controls. Forty-five ME/CFS patients were recruited from the CFS Discovery Clinic (Victoria) between 2011 and 2013. Seventeen healthy controls were recruited concurrently and identically assessed. RESULTS: WST distribution was significantly different between ME/CFS participants and controls, with six diagnostic criteria, five analytes and one cytokine also significantly different when comparing severity via WST. On direct comparison of ME/CFS to study controls, only serum activin B was significantly elevated, with no significant variation observed for a broad range of serum and urine markers, or other serum cytokines. CONCLUSIONS: The enhanced understanding of standing test behaviour to reflect orthostatic intolerance as a ME/CFS symptom, and the subsequent calculation of WST, will encourage the greater implementation of this simple test as a measure of ME/CFS diagnosis, and symptom severity, to the benefit of improved diagnosis and guidance for potential treatments.


Assuntos
Síndrome de Fadiga Crônica/complicações , Síndrome de Fadiga Crônica/fisiopatologia , Intolerância Ortostática/complicações , Intolerância Ortostática/fisiopatologia , Postura , Índice de Gravidade de Doença , Ativinas/sangue , Adolescente , Adulto , Idoso , Biomarcadores/sangue , Biomarcadores/urina , Estudos de Casos e Controles , Estudos de Coortes , Síndrome de Fadiga Crônica/sangue , Síndrome de Fadiga Crônica/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Intolerância Ortostática/sangue , Intolerância Ortostática/patologia , Fatores de Tempo , Adulto Jovem
17.
Sci Rep ; 8(1): 5176, 2018 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-29581558

RESUMO

Acute kidney injury (AKI) is a common but complex condition that is associated with increased morbidity and mortality. In the present study, we examined whether urinary activin A, a member of the TGF-beta superfamily, is present in mice with ischemia-reperfusion injury and in humans with AKI, as well as its potential as a biomarker for AKI. Expression of activin A was markedly increased in ischemic mouse kidneys. In situ hybridization demonstrated that activin mRNA was expressed in tubular cells of ischemic kidneys but not of normal kidneys. Immunoreactive activin A, which was absent in normal kidneys, was detected in the cytoplasm of proximal tubular cells in ischemic kidneys. Activin A was undetectable in the urine of normal mice. In contrast, activin A was significantly increased in the urine of ischemic mice at 3 h after reperfusion. Urinary activin A levels increased according to the period of ischemia. In humans, urinary activin A was almost undetectable in healthy volunteers and in patients with pre-renal AKI, but was significantly increased in patients with renal AKI. There was no significant correlation between urinary activin A and serum activin A. Collectively, urinary activin A might be a useful biomarker reflecting the severity of AKI.


Assuntos
Ativinas/urina , Lesão Renal Aguda/urina , Biomarcadores/urina , Traumatismo por Reperfusão/urina , Ativinas/sangue , Lesão Renal Aguda/fisiopatologia , Animais , Biomarcadores/sangue , Regulação da Expressão Gênica , Humanos , Rim/metabolismo , Rim/patologia , Camundongos , Traumatismo por Reperfusão/fisiopatologia
18.
Mol Cell Endocrinol ; 470: 188-198, 2018 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-29111388

RESUMO

Regionalised interaction of the activins, follistatin and inhibin was investigated in the male reproductive tract of mice lacking the inhibin α-subunit (Inha-/-). Serum and intratesticular activin B, although not activin A and follistatin, were increased in Inha-/- mice at 25 days of age, but all three proteins were elevated at 56 days. None of these proteins were altered within the epididymis and vas deferens at either age. At 25 days, histology of the epididymis and vas deferens was similar to wild-type. At 56 days, the testis contained extensive somatic cell tumours, leading to Leydig cell regression and testosterone deficiency. The epididymis and vas deferens showed epithelial regression and increased prominence of the interstitial stroma. Immunoregulatory and fibrotic gene expression in the epididymis and vas deferens were unchanged. Thus, absence of the inhibin α-subunit has marginal effects on activins in the epididymis and vas deferens, and regression of these tissues is associated with androgen deficiency.


Assuntos
Ativinas/metabolismo , Androgênios/deficiência , Inibinas/genética , Testículo/metabolismo , Testículo/patologia , Ativinas/sangue , Ativinas/genética , Envelhecimento/patologia , Animais , Epididimo/patologia , Folistatina/sangue , Folistatina/genética , Regulação da Expressão Gênica , Inibinas/deficiência , Inibinas/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Fenótipo , Células Estromais/metabolismo , Células Estromais/patologia , Neoplasias Testiculares/metabolismo , Neoplasias Testiculares/patologia , Ducto Deferente/patologia
19.
Theriogenology ; 105: 135-141, 2018 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-28965025

RESUMO

The use of genomic testing in the cattle industries has renewed an interest in hastening bull puberty. In prepubertal males, FSH facilitates Sertoli cell proliferation and testis maturation. The aim of this study was to determine the effect of prepubertal administration of a timed-release FSH (delivered in a hyaluronan solution) on hormone secretion, puberty attainment, and mature sperm production in Holstein bulls in an AI center. Bulls (n = 29) were randomly assigned to one of two treatment groups based on birth date and pedigree. Beginning at 62 days of age (Day 62), bulls were injected im every 3.5 days with either 30 mg FSH (Folltropin-V; NIH-FSH-P1 units) in a 2% hyaluronan solution (FSH-HA, n = 17) or saline (control, n = 12) until Day 170.5. Blood samples to assess FSH, activin A, and testosterone were collected prior to each treatment. Scrotal circumference (SC) and BW were measured monthly. Puberty assessment (ability to ejaculate 5 × 107 sperm, 10% motile) was initiated at Day 244. Average mature daily sperm production (3× wk collection, combined 2 ejaculates) was assessed from Day 571-627. In blood collected every 3.5 days, FSH concentrations within FSH-HA bulls were increased (P < 0.05) over initial Day 62 concentration from Day 93.5-170.5. Concentrations of FSH did not differ between treatments from Day 62-93.5, but were greater (P < 0.05) in FSH-HA than control bulls from Day 97-170.5. Concentrations of activin A assessed for Day 62, 86.5, 107.5, 139, and 170.5 were greater (P < 0.05) in FSH-HA than control bulls on Day 86.5 and 107.5. Treatments did not differ (P > 0.1) in testosterone, BW, or SC. FSH-HA bulls attained puberty at a younger age than control bulls (278 ± 7.7 vs. 303 ± 9.1 days of age, P < 0.05), but mature daily sperm production was not different when measured from Day 571-627 (average 5.84 ± 0.11 billion cells/day, P = 0.5). In summary, FSH administration every 3.5 days from Day 62-170.5 resulted in an increase in FSH concentration beginning at 97 days of age and a hastened age of puberty. We propose this exogenous FSH delivered in hyaluronan initiates a positive feedback loop that includes an increase in activin A production observed on Day 86.5 and 107.5. However, differences in mature sperm production were not realized in this experiment.


Assuntos
Bovinos/crescimento & desenvolvimento , Hormônio Foliculoestimulante/farmacologia , Maturidade Sexual/efeitos dos fármacos , Espermatogênese/efeitos dos fármacos , Ativinas/sangue , Ativinas/metabolismo , Animais , Preparações de Ação Retardada , Hormônio Foliculoestimulante/administração & dosagem , Masculino , Testosterona/sangue , Testosterona/metabolismo , Ganho de Peso
20.
Theriogenology ; 105: 142-149, 2018 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-28965026

RESUMO

In prepubertal males, FSH facilitates Sertoli cell proliferation and testis maturation. The study aimed to determine the effect of an exogenous FSH treatment on hormone secretion and testis development in Angus bulls. Bulls (n = 22) weaned at 53 ± 3.8 days of age were randomized into two treatment groups based on age and pedigree. Beginning at Day 59, bulls were injected im every 3.5 days with either 30 mg FSH (Folltropin-V; NIH-FSH-P1 units) in a 2% hyaluronan solution (FSH-HA, n = 11) or saline (control, n = 11) until Day 167.5. Blood samples to assess FSH, activin A, and testosterone were collected prior to each treatment. To determine how FSH profiles surrounding treatment were affected, three intensive blood sampling periods, each encompassing two treatment administrations, began at Day 66, 108, and 157, and blood was collected at 0, 6, 12, 18, 24, 36, 60, and 84 h respective to time of treatment. Scrotal circumference (SC) and BW were measured monthly. Bulls were castrated at Day 170 to measure testis size, seminiferous tubule diameter, and the number of Sertoli and germ cells per tubule cross-section. During intensive FSH sampling, FSH-HA bulls experienced an increase (P < 0.05) in FSH over control bulls for at least 18 h post-injection in all instances. In blood collected every 3.5 days, FSH concentrations in FSH-HA bulls were increased (P < 0.05) over initial Day 59 concentration from Day 97.5-167.5. FSH concentrations did not differ between treatments from Day 59-90.5, but were greater (P < 0.05) in FSH-HA from Day 94-167.5. Concentrations of activin A assessed for Day 59, 83.5, 94, 129, and 167.5 were greater (P < 0.05) in FSH-HA than control bulls on Day 83.5 and 94. The treatments did not differ (P > 0.1) in testosterone, BW, SC, testis size, tubule diameter, or number of germ cells per tubule. However, the number of Sertoli cells per tubule was greater in FSH-HA than control bulls (45.2 ± 1.4 vs. 41.6 ± 0.9 cells, P < 0.05). In summary, FSH-HA treatment every 3.5 days from Day 59-167.5 maintained elevated FSH for a minimum of 18 h post-injection, likely attributable to the addition of HA. We propose the exogenous FSH-HA treatment initiates a positive feedback loop that includes an increased density of Sertoli cells per tubule cross-section, which is related to increased activin A concentrations on Day 83.5 and 94. Furthermore, this activin A increase preceded an increase in endogenous FSH from Day 94-167.5 in FSH-HA bulls.


Assuntos
Bovinos/crescimento & desenvolvimento , Hormônio Foliculoestimulante/farmacologia , Maturidade Sexual/efeitos dos fármacos , Espermatogênese/efeitos dos fármacos , Testículo/crescimento & desenvolvimento , Ativinas/sangue , Ativinas/metabolismo , Animais , Preparações de Ação Retardada , Hormônio Foliculoestimulante/administração & dosagem , Masculino , Escroto/crescimento & desenvolvimento , Testosterona/análogos & derivados , Testosterona/sangue , Testosterona/metabolismo , Ganho de Peso
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA