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1.
Life Sci ; 274: 119346, 2021 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-33713667

RESUMO

AIMS: Fibroblast growth factor 21 (FGF21) has been identified as the master hormonal regulator of energy balance, its elevation is observed in a series of metabolic and cardiovascular diseases. Studies have implicated the role of FGF21 signaling in the pathogenesis of abdominal aortic aneurysm (AAA). We will investigate the association of FGF21 and AAA development. MATERIALS AND METHODS: In this study, we assayed plasma levels of FGF21 in 82 patients with AAA and 44 control subjects, then analyzed their relationship with clinical, biochemical and histological phenotypes. The expression of ß-klotho, an essential co-receptor of FGF21, was assessed with IHC staining and RT-qPCR. Machine learning models incorporate a combination of FGF21 and clinical data were utilized in the prediction of AAA occurrence. KEY FINDINGS: FGF21 was statistically higher in patients with AAA (781 pg/ml [533, 1213]) than in control subjects (567 pg/ml [324, 939]). After adjustment for age and BMI, we found a positive association of FGF21 levels with AAA diameters, hypertension rate and hsCRP, and a negative correlation between FGF21 levels and HDL-c. Furthermore, the protein levels of ß-klotho in abdominal aorta of AAA were found significantly lower than in control group indicating the presence of FGF21 resistance. Combining FGF21 levels with four clinical characteristics significantly improved the stratification of AAA and control groups with an AUC of 0.778. SIGNIFICANCE: Combining detection of plasma FGF21 and clinical characteristics may be reliable for identifying the presence of AAA. The role of FGF21 as a therapeutic target of AAA warrants further investigation.


Assuntos
Aneurisma da Aorta Abdominal/diagnóstico , Biomarcadores/sangue , Fatores de Crescimento de Fibroblastos/sangue , Proteínas de Membrana/metabolismo , Idoso , Aneurisma da Aorta Abdominal/sangue , Aneurisma da Aorta Abdominal/patologia , Estudos de Casos e Controles , Feminino , Fatores de Crescimento de Fibroblastos/genética , Humanos , Masculino , Proteínas de Membrana/genética , Prognóstico
2.
PLoS Negl Trop Dis ; 14(9): e0008711, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32997666

RESUMO

Environmental enteric dysfunction (EED) is an intestinal disorder common among children in low-resource settings and is associated with increased risk of growth stunting, cognitive deficits, and reduced oral vaccine immunogenicity. The Micronutrient and EED Assessment Tool (MEEDAT) is a multiplexed immunoassay that measures biomarkers previously associated with child growth faltering and/or oral vaccine immunogenicity: intestinal fatty acid-binding protein (I-FABP), soluble CD14 (sCD14), insulin-like growth factor 1 (IGF-1), and fibroblast growth factor 21 (FGF21). MEEDAT also measures systemic inflammation (α1-acid glycoprotein, C-reactive protein), ferritin, soluble transferrin receptor, retinol binding protein 4, thyroglobulin, and Plasmodium falciparum antigenemia (histidine-rich protein 2). The performance of MEEDAT was compared with commercially available enzyme-linked immunosorbent assays (ELISAs) using 300 specimens from Malian infant clinical trial participants. Regression methods were used to test if MEEDAT biomarkers were associated with seroconversion to meningococcal A conjugate vaccine (MenAV), yellow fever vaccine (YFV), and pentavalent rotavirus vaccine (PRV) after 28 days, or with growth faltering over 12 weeks. The Pearson correlations between the MEEDAT and ELISA results were 0.97, 0.86, 0.80, and 0.97 for serum I-FABP, sCD14, IGF-1, and FGF21, respectively. There were significant associations between I-FABP concentration and the probability of PRV IgG seroconversion and between IGF-1 concentration and the probability of YFV seroconversion. In multivariable models neither association remained significant, however there was a significant negative association between AGP concentration and YFV seroconversion. GLP-2 and sCD14 concentrations were significantly negatively associated with 12-week change in weight-for-age z-score and weight-for-height z-score in multivariable models. MEEDAT performed well in comparison to commercially-available ELISAs for the measurement of four analytes for EED and growth hormone resistance. Adoption of MEEDAT in low-resource settings could help accelerate the identification of interventions that prevent or treat child stunting and interventions that boost the immunogenicity of child vaccinations.


Assuntos
Imunogenicidade da Vacina/imunologia , Enteropatias/imunologia , Micronutrientes/imunologia , Vacinas/imunologia , Vacina contra Febre Amarela/imunologia , Febre Amarela/imunologia , Febre Amarela/prevenção & controle , Biomarcadores/sangue , Método Duplo-Cego , Ensaio de Imunoadsorção Enzimática , Proteínas de Ligação a Ácido Graxo , Feminino , Ferritinas/sangue , Fatores de Crescimento de Fibroblastos/sangue , Humanos , Lactente , Inflamação , Fator de Crescimento Insulin-Like I/metabolismo , Intestino Delgado , Receptores de Lipopolissacarídeos , Masculino , Mali , Proteínas Plasmáticas de Ligação ao Retinol , Fatores de Risco , Vacinação
3.
PLoS One ; 15(8): e0235557, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32756564

RESUMO

AIM: Fibroblast growth factor 21 (FGF21) has recently been implicated in thirst in rodent models. The mechanisms for this are currently uncertain, and it is unclear whether hydration status can alter FGF21 concentrations, potentially providing an additional mechanism by which hypohydration induces thirst. The aim of this study is therefore to understand whether hydration status can alter circulating FGF21 in humans. METHODS: Using a heat tent and fluid restriction, we induced hypohydration (1.9% body mass loss) in 16 healthy participants (n = 8 men), and compared their glycaemic regulation to a rehydration protocol (heat tent and fluid replacement) in a randomised crossover design. RESULTS: After the hypohydration procedure, urine specific gravity, urine and serum osmolality, and plasma copeptin (as a marker for arginine vasopressin) increased as expected, with no change after the rehydration protocol. In the fasted state, the median paired difference in plasma FGF21 concentrations from the rehydrated to hypohydrated trial arm was -37 (interquartile range -125, 10) pg∙mL-1(P = 0.278), with average concentrations being 458 ± 462 pg∙mL-1 after hypohydration and 467 ± 438 pg∙mL-1 after rehydration; mean difference -9 ± 173 pg∙mL-1. CONCLUSION: To our knowledge, these are the first causal data in humans investigating hydration and FGF21, demonstrating that an acute bout of hypohydration does not impact fasted plasma FGF21 concentrations. These data may suggest that whilst previous research has found FGF21 administration can induce thirst and drinking behaviours, a physiological state implicated in increased thirst (hypohydration) does not appear to impact plasma FGF21 concentrations in humans.


Assuntos
Desidratação/sangue , Fatores de Crescimento de Fibroblastos/sangue , Adulto , Estudos Cross-Over , Desidratação/fisiopatologia , Desidratação/terapia , Comportamento de Ingestão de Líquido , Jejum/sangue , Feminino , Hidratação , Humanos , Masculino , Sede , Adulto Jovem
4.
PLoS One ; 15(6): e0235077, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32569271

RESUMO

Proteinuria and hyperphosphatemia are risk factors for cardiovascular disease in patients with chronic kidney disease (CKD). Although the interaction between proteinuria and the serum phosphate level is well established, the mechanistic link between the two, particularly the extent to which this interaction is mediated by phosphate-regulating factors, remains poorly understood. In this study, we examined the association between proteinuria and the serum phosphate level, as well as potential mediators, including circulating fibroblast growth factor (FGF23)/klotho, the 24-h urinary phosphate excretion rate to glomerular filtration rate ratio (EP/GFR), and the 24-h tubular phosphate reabsorption rate to GFR ratio (TRP/GFR). The analyses were performed with data from 1793 patients in whom 24-h urine protein and phosphate, serum phosphate, FGF23, and klotho levels were measured simultaneously, obtained from the KoreaN cohort study for Outcome in patients With Chronic Kidney Disease (KNOW-CKD). Multivariable linear regression and mediation analyses were performed. Total, direct, and indirect effects were also estimated. Patients with high serum phosphate levels were found to be more likely to exhibit greater proteinuria, higher FGF23 levels, and lower klotho levels. The 24-h EP/GFR increased and the 24-h TRP/GFR decreased with increasing proteinuria and CKD progression. Simple mediation analyses showed that 15.4% and 67.9% of the relationship between proteinuria and the serum phosphate level were mediated by the FGF23/klotho ratio and 24-h EP/GFR, respectively. Together, these two factors accounted for 73.1% of the relationship between serum markers. These findings suggest that proteinuria increases the 24-h EP/GFR via the FGF23/klotho axis as a compensatory mechanism for the increased phosphate burden well before the reduction in renal function is first seen.


Assuntos
Fosfatos/sangue , Proteinúria/sangue , Insuficiência Renal Crônica/sangue , Estudos de Coortes , Feminino , Fatores de Crescimento de Fibroblastos/sangue , Taxa de Filtração Glomerular , Glucuronidase/sangue , Humanos , Túbulos Renais/metabolismo , Túbulos Renais/patologia , Masculino , Pessoa de Meia-Idade , Análise de Regressão , Insuficiência Renal Crônica/fisiopatologia , República da Coreia , Resultado do Tratamento
5.
PLoS One ; 15(6): e0235362, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32584895

RESUMO

OBJECTIVE: Cardiovascular disease is a leading cause of death worldwide. Obesity-related metabolic disorders including dyslipidemia cause impaired collateralization under ischemic conditions, thereby resulting in exacerbated cardiovascular dysfunction. Pemafibrate is a novel selective PPARα modulator, which has been reported to improve atherogenic dyslipidemia, in particular, hypertriglyceridemia and low HDL-cholesterol. Here, we investigated whether pemafibrate modulates the revascularization process in a mouse model of hindlimb ischemia. METHODS AND RESULTS: Male wild-type (WT) mice were randomly assigned to two groups, normal diet or pemafibrate admixture diet from the ages of 6 weeks. After 4 weeks, mice were subjected to unilateral hindlimb surgery to remove the left femoral artery and vein. Pemafibrate treatment enhanced blood flow recovery and capillary formation in ischemic limbs of mice, which was accompanied by enhanced phosphorylation of endothelial nitric oxide synthase (eNOS). Treatment of cultured endothelial cells with pemafibrate resulted in increased network formation and migratory activity, which were blocked by pretreatment with the NOS inhibitor NG-nitro-L-arginine methyl ester (L-NAME). Pemafibrate treatment also increased plasma levels of the PPARα-regulated gene, fibroblast growth factor (FGF) 21 in WT mice. Systemic administration of adenoviral vectors expressing FGF21 (Ad-FGF21) to WT mice enhanced blood flow recovery, capillary density and eNOS phosphorylation in ischemic limbs. Treatment of cultured endothelial cells with FGF21 protein led to increases in endothelial cell network formation and migration, which were canceled by pretreatment with L-NAME. Furthermore, administration of pemafibrate or Ad-FGF21 had no effects on blood flow in ischemic limbs in eNOS-deficient mice. CONCLUSION: These data suggest that pemafibrate can promote revascularization in response to ischemia, at least in part, through direct and FGF21-mediated modulation of endothelial cell function. Thus, pemafibrate could be a potentially beneficial drug for ischemic vascular disease.


Assuntos
Benzoxazóis/farmacologia , Butiratos/farmacologia , Isquemia/patologia , Neovascularização Fisiológica/efeitos dos fármacos , Óxido Nítrico Sintase Tipo III/metabolismo , Animais , Diferenciação Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Fatores de Crescimento de Fibroblastos/sangue , Fatores de Crescimento de Fibroblastos/genética , Fatores de Crescimento de Fibroblastos/metabolismo , Vetores Genéticos/genética , Vetores Genéticos/metabolismo , Membro Posterior/irrigação sanguínea , Células Endoteliais da Veia Umbilical Humana , Humanos , Masculino , Camundongos , Camundongos Knockout , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico Sintase Tipo III/antagonistas & inibidores , PPAR alfa/química , PPAR alfa/metabolismo , Fosforilação/efeitos dos fármacos
6.
Medicine (Baltimore) ; 99(22): e20399, 2020 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-32481431

RESUMO

Cytokeratin 18 (CK18) and fibroblast growth factor 21 (FGF21) are elevated in patients with nonalcoholic fatty liver disease (NAFLD) and are useful markers for identifying or monitoring outcomes. Exercise therapy is one of the established treatments for NAFLD; however, few studies have investigated the effectiveness of exercise therapy on CK18 and FGF21 levels. Therefore, the aim of the present study was to assess the effects of 12 weeks of simple resistance exercise on CK18 and FGF21 levels in patients with NAFLD.Fifty patients with NAFLD were assigned to a resistance exercise group (n = 23) or a control group (n = 27) for a trial period of 12 weeks. During the study, the resistance exercise group performed two exercises (push-ups and squats) three times a week on nonconsecutive days, whereas the control group proceeded with regular physical activities under a restricted diet. We then compared serum levels of CK18 fragments (M65) and FGF21 between groups just before and after the 12-week period.Serum M65 levels (880.0 ±â€Š503.6 vs 648.9 ±â€Š450.2 U/L; P < .01) were significantly decreased in the exercise group. However, no significant differences were observed in body mass index or skeletal muscle. The decreases in serum M65 (-231.1 ±â€Š354.7 vs 56.2 ±â€Š375.0 U/L; P = .02), and FGF21 levels (-41.7 ±â€Š98.2 vs. 33.2 ±â€Š127.6 pg/mL; P = .03) were significantly greater in the exercise than in the control group. Changes in M65 levels in the exercise group were significantly correlated with changes in alanine aminotransferase levels (r = 0.618, P < .01).Simple resistance exercise reduced CK18 and FGF21 levels in patients with NAFLD. These findings suggest that resistance exercise consisting of push-ups and squats helps prevent the progression of NAFLD.


Assuntos
Fatores de Crescimento de Fibroblastos/sangue , Queratina-18/sangue , Hepatopatia Gordurosa não Alcoólica/terapia , Treinamento de Resistência/métodos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/sangue , Hepatopatia Gordurosa não Alcoólica/metabolismo , Estudos Retrospectivos
7.
Sci Rep ; 10(1): 7216, 2020 04 29.
Artigo em Inglês | MEDLINE | ID: mdl-32350388

RESUMO

GPRC6A is a widely expressed G-protein coupled receptor that regulates energy metabolism. Global deletion of Gprc6a in mice is reported to result in a metabolic syndrome-like phenotype and conditional deletion of Gprc6a in pancreatic ß-cell and skeletal muscle respectively impair insulin secretion and glucose uptake. In the current study, we explore the hepatic functions of GPRC6A by conditionally deleting Gprc6a in hepatocytes by cross breeding Alb-Cre and Gprc6aflox/flox mice to obtain Gprc6aLiver-cko mice. Gprc6aLiver-cko mice on a normal diet showed excessive hepatic fat accumulation and glycogen depletion. These mice also exhibit impaired glucose and pyruvate tolerance, but normal insulin sensitivity. Decreased circulating FGF-21 levels and FGF-21 message expression in the liver were found in Gprc6aLiver-cko mice. Hepatic transcriptome analysis identified alterations in multiple pathways regulating glucose, fat and glycogen metabolism in Gprc6aLiver-cko mice. Taken together, our studies suggest that GPRC6A directly regulates hepatic metabolism as well as regulates the production and release of FGF-21 to control systemic energy homeostasis. GPRC6A's unique regulation of ß-cell, skeletal muscle and hepatic function may represent a new therapeutic target for treating disordered energy metabolism metabolic syndrome and type 2 diabetes.


Assuntos
Metabolismo Energético , Fígado/metabolismo , Receptores Acoplados a Proteínas-G/metabolismo , Animais , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Fatores de Crescimento de Fibroblastos/sangue , Glucose/genética , Glucose/metabolismo , Fígado/patologia , Síndrome Metabólica/genética , Síndrome Metabólica/metabolismo , Síndrome Metabólica/patologia , Camundongos , Camundongos Knockout , Receptores Acoplados a Proteínas-G/genética
8.
Nature ; 583(7814): 122-126, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32461692

RESUMO

The cellular NADH/NAD+ ratio is fundamental to biochemistry, but the extent to which it reflects versus drives metabolic physiology in vivo is poorly understood. Here we report the in vivo application of Lactobacillus brevis (Lb)NOX1, a bacterial water-forming NADH oxidase, to assess the metabolic consequences of directly lowering the hepatic cytosolic NADH/NAD+ ratio in mice. By combining this genetic tool with metabolomics, we identify circulating α-hydroxybutyrate levels as a robust marker of an elevated hepatic cytosolic NADH/NAD+ ratio, also known as reductive stress. In humans, elevations in circulating α-hydroxybutyrate levels have previously been associated with impaired glucose tolerance2, insulin resistance3 and mitochondrial disease4, and are associated with a common genetic variant in GCKR5, which has previously been associated with many seemingly disparate metabolic traits. Using LbNOX, we demonstrate that NADH reductive stress mediates the effects of GCKR variation on many metabolic traits, including circulating triglyceride levels, glucose tolerance and FGF21 levels. Our work identifies an elevated hepatic NADH/NAD+ ratio as a latent metabolic parameter that is shaped by human genetic variation and contributes causally to key metabolic traits and diseases. Moreover, it underscores the utility of genetic tools such as LbNOX to empower studies of 'causal metabolism'.


Assuntos
Fígado/metabolismo , NAD/metabolismo , Estresse Fisiológico , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Citosol/metabolismo , Modelos Animais de Doenças , Fatores de Crescimento de Fibroblastos/sangue , Variação Genética , Teste de Tolerância a Glucose , Humanos , Resistência à Insulina , Lactobacillus brevis/enzimologia , Lactobacillus brevis/genética , Masculino , Camundongos , Complexos Multienzimáticos/genética , Complexos Multienzimáticos/metabolismo , NADH NADPH Oxirredutases/genética , NADH NADPH Oxirredutases/metabolismo , Oxirredução , Triglicerídeos/sangue
9.
Am J Physiol Renal Physiol ; 318(5): F1188-F1198, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32249611

RESUMO

Caloric restriction (CR) is known to have multiple beneficial effects on health and longevity. To study the effect of CR on phosphorus metabolism and vascular calcification (VC), rats were fed normal or restricted calories (67% of normal). The phosphorus content of the diets was adjusted to provide equal phosphorus intake independent of the calories ingested. After 50 days of CR, rats had negative phosphorus balance, lower plasma phosphorus, glucose, triglycerides, and leptin, and higher adiponectin than rats fed normal calories. Uremia was induced by 5/6 nephrectomy (Nx). After Nx, rats were treated with calcitriol (80 ng/kg ip every other day) and high-phosphorus diets (1.2% and 1.8%). No differences in aortic calcium content were observed between rats that ate normal or restricted calories before Nx in either rats that received 1.2% phosphorus (11.5 ± 1.7 vs. 10.9 ± 2.1 mg/g tissue) or in rats that received 1.8% phosphorus (12.5 ± 2.3 vs. 12.0 ± 2.9 mg/g of tissue). However, mortality was significantly increased in rats subjected to CR before Nx in both the 1.2% phosphorus groups (75% vs. 25%, P = 0.019) and 1.8% phosphorus groups (100% vs. 45%, P < 0.001). After calcitriol administration was stopped and phosphorus intake was normalized, VC regressed rapidly, but no significant differences in aortic calcium were detected between rats that ate normal or restricted calories during the regression phase (5.7 ± 2.7 and 5.2 ± 1.5 mg/g tissue). In conclusion, CR did not prevent or ameliorate VC and increased mortality in uremic rats.


Assuntos
Aorta/metabolismo , Doenças da Aorta/prevenção & controle , Restrição Calórica , Rim/metabolismo , Fósforo na Dieta/metabolismo , Uremia/dietoterapia , Calcificação Vascular/prevenção & controle , Animais , Aorta/patologia , Doenças da Aorta/etiologia , Doenças da Aorta/metabolismo , Doenças da Aorta/patologia , Calcitriol , Modelos Animais de Doenças , Progressão da Doença , Metabolismo Energético , Feminino , Fatores de Crescimento de Fibroblastos/sangue , Glucuronidase/metabolismo , Rim/patologia , Nefrectomia , Ratos Wistar , Fatores de Tempo , Uremia/etiologia , Uremia/metabolismo , Calcificação Vascular/etiologia , Calcificação Vascular/metabolismo , Calcificação Vascular/patologia
10.
Arch Endocrinol Metab ; 64(4): 479-482, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32267352

RESUMO

Objective Fibroblast growth factor 21 (FGF21) is among the activators that can stimulate thermogenesis in the white adipose tissue and brown adipose tissue. People with obesity have elevated blood levels of FGF21, but also develop resistance to its action, impairing its beneficial role. Inversely, clinical treatments to weight loss has been pointed out as an important therapy for increasing and recovering sensitivity to FGF21. The aim was to analyse the effect of long-term weight loss interdisciplinary intervention on FGF21 and body composition. Subjects and methods Eighty-six post-pubertal obese adolescents (14-19 years-old), were submitted to 20 weeks of weight loss therapy (clinical, nutritional, psychological and physical exercise support). Anthropometric measures, body composition and rest metabolic rate (RMR) by bioelectrical impedance, and serum FGF21 sample by ELISA were evaluated. The adolescents were grouped according to FGF21 individual delta variations after therapy: Higher Increase (HI); lower increase (LI); lower decrease (LD); higher decrease (HD). Results All groups present weight loss. Only in FGF21 ≥ 76,5 pg/mL variation the free-fat-mass and rest metabolic rate were preserved and to others group these variables were significantly reduced. Conclusion High increase in FGF21 can contribute to preservation of FFM and RMR after weight loss therapy, could have important implications for energy balance regulation. Future studies are necessary to continue determining the role of magnitude effects of FGF21 levels in obesity to improve clinical practice, especially in paediatrics population.


Assuntos
Fatores de Crescimento de Fibroblastos/sangue , Obesidade , Perda de Peso , Tecido Adiposo Branco , Adolescente , Metabolismo Energético , Humanos
11.
Ann Palliat Med ; 9(2): 368-374, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32268770

RESUMO

BACKGROUND: This study aimed to investigate the relationship between serum level of fibroblast growth factor 21 (FGF-21) and long-term prognosis in patients with both diabetes mellitus (DM) and coronary artery calcification (CAC). METHODS: The study included 1,132 patients with DM and CAC according to inclusion and exclusion criteria. Based on the baseline serum level of FGF-21, patients were divided into four groups (283 in each group): low-FGF-21 group (LFG), lower-medium-FGF-21 group (LMFG), higher-medium-FGF-21 group (HMFG), and high-FGF-21 group (HFG). Major adverse cardiovascular events (MACEs), including coronary revascularization, acute coronary syndrome (ACS), heart failure (HF), malignant arrhythmia, and sudden cardiac death (SCD), were recorded. Renal function, serum level of NT-proBNP, and left ventricular function were watched and observed during follow-up. RESULTS: All patients were followed up for 1.5-5.1 (2.7±2.2) years. The range of baseline serum level of FGF-21 was 67.5-314.7 pg/mL. The serum level of FGF-21 was ≤103.8 pg/mL in LFG, 108.6-184.9 pg/mL in LMFG, 199.3-271.2 pg/mL in LHFG, and >276.1 pg/mL in HFG. The baseline CAC score (CACS) was 83.2-524.9 and the mean CACS was 124.6±37.5, 186.8±51.9, 271.3±62.7, and 349.2±80.6, respectively. During follow-up, 481 patients underwent percutaneous coronary intervention (PCI) with 71, 107, 141, and 162 in subgroups, respectively. Malignant arrhythmia occurred in 89 patients, HF in 127, and SCD in 9. At the end of the 1-year follow-up, the average eGFR, NT-proBNP, and left ventricular ejection fraction (LVEF) differed significantly among groups. CONCLUSIONS: Lower baseline serum level of FGF-21 is a prediction for a better long-term prognosis.


Assuntos
Doença da Artéria Coronariana/sangue , Diabetes Mellitus Tipo 2/sangue , Fatores de Crescimento de Fibroblastos/sangue , Placa Aterosclerótica/sangue , Insuficiência Renal Crônica/sangue , Adulto , Idoso , Biomarcadores/sangue , Progressão da Doença , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Fatores de Risco , Índice de Gravidade de Doença
12.
Nefrología (Madrid) ; 40(2): 171-179, mar.-abr. 2020. ilus, tab, graf
Artigo em Espanhol | IBECS | ID: ibc-199105

RESUMO

ANTECEDENTES: La principal causa de morbimortalidad en el paciente con enfermedad renal crónica (ERC) es la cardiovascular. La inflamación y las alteraciones en el metabolismo óseo-mineral en estos pacientes conllevan aumento del riesgo cardiovascular. OBJETIVOS: Valorar el papel de paricalcitol sobre distintos parámetros séricos relacionados con inflamación, fibrosis y enfermedad óseo-mineral en la ERC. MATERIAL Y MÉTODOS: Estudio prospectivo, no controlado en 46 pacientes con ERC estadios III-V sin diálisis, con niveles elevados de paratohormona, según su estadio de ERC, por lo que se introdujo tratamiento con el análogo de vitamina D paricalcitol. Durante 4 meses de tratamiento valoramos los parámetros clásicos y novedosos del metabolismo óseo-mineral en suero (calcio, fósforo, paratohormona, factor de crecimiento fibroblástico-23 [FGF-23], Klotho y calcidiol) y parámetros relacionados con el proceso de inflamación-fibrosis y anticalcificantes (interleucina-6 y 10, factor de necrosis tumoral alfa [TNF-a], factor de crecimiento transformante beta [TGF-b], proteína ósea morfogénica-7 [BMP-7], y fetuína-A). RESULTADOS: Tras el uso de paricalcitol los niveles de Klotho aumentaron (p = 0,001) y los de FGF-23 se mantuvieron estables al igual que los de calcio y fósforo; calcidiol aumentó de forma significativa (p = 0,010) y paratohormona descendió (p = 0,002). Los parámetros de inflamación, fibrosis y calcificación mostraron una regulación benigna con descenso significativo de interleucina-6 (p = 0,001), TNF-alfa (p = 0,005) y TGF-β (p = 0,001) y aumento de BMP-7 (p = 0,001), fetuína-A (p = 0,001) e interleucina-10 (p = 0,001). El filtrado glomerular y la proteinuria se mantuvieron estables. CONCLUSIONES: El tratamiento con paricalcitol en el paciente renal sin diálisis parece ser beneficioso en la regulación de los parámetros inflamatorios y anticalcificantes, preservando la función renal y el eje óseo-mineral. Los marcadores elegidos en nuestro estudio podrían indicarnos un efecto positivo de paricalcitol a nivel vascular


BACKWARD: Cardiovascular events are the major cause of morbidity and mortality in patients with chronic kidney disease (CKD). Inflammation and mineral-bone disorder are pathological conditions that have been associated with an increased cardiovascular risk. OBJECTIVE: Show paricalcitol regulation overinflammatory, fibrotic and mineral disorder parameters in CKD. MATERIAL AND METHODS: Prospective Study in 46 CKD stages III-V patients without dialysis patients whith elevated parathormone in which we introduced paricalcitol. We evaluated classic and newest mineral and bone metabolism serum parameters (calcium, phosphorus, parathormone, fibroblast growth factor-23 [FGF-23], Klotho, calcidiol), inflammatory-fibrosis and anticalcifying parameters (interleukin-6 and 10, tumor necrosis factor-a [TNF- alfa], transforming growth factor-b [TGF-β],bone morphogenic protein-7 [BMP-7] and fetuin-A) for four months. RESULTS: At the end of study soluble Klotho increased (p = .001), FGF-23 remained stable, calcium and phosphorus levels were not increased, calcidiol increased (p = .010) and PTH decreased (p = .002). Inflammation-fibrosis and calcification parameters showed positive regulation after paricalcitol treatment: interleukin-6 decreased significantly (p = .001) and also TNF-alfa did (p = .005), on the contrary, interleukin-10 and fetuin-A increased (p = .001 for both). Anti-fibrosis marker BMP-7 increased (p = .001) and TGF-b decreased (p = .001). We did not find significant changes in renal function. CONCLUSIONS: Paricalcitol treatment might be profitable in regulating inflammatory and anticalcificant parameters, unmodified calcium or phosphorus seric levels and preserving kidney function in renal patients with no dialysis. Our selected parameters could indicate paricalcitol effects in mineral and endothelial disorder related to renal disease


Assuntos
Humanos , Masculino , Feminino , Idoso , Conservadores da Densidade Óssea/uso terapêutico , Ergocalciferóis/uso terapêutico , Insuficiência Renal Crônica/tratamento farmacológico , Proteína Morfogenética Óssea 7/sangue , Calcifediol/sangue , Cálcio/sangue , Fatores de Crescimento de Fibroblastos/sangue , Taxa de Filtração Glomerular , Glucuronidase/sangue , Interleucina-10/sangue , Interleucina-6/sangue , Hormônio Paratireóideo/sangue , Fósforo/sangue , Estudos Prospectivos , Proteinúria/metabolismo , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/terapia , Fator de Crescimento Transformador beta/sangue , Fator de Necrose Tumoral alfa/sangue , Calcificação Vascular/etiologia , Calcificação Vascular/prevenção & controle , alfa-2-Glicoproteína-HS/análise
13.
Int J Mol Sci ; 21(5)2020 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-32121294

RESUMO

Obesity remodels bone and increases bone marrow adipocytes (BMAT), which negatively regulate hematopoiesis and bone. Reduced BMAT could restore altered hematopoiesis and bone features. We analyzed the potential of erythropoietin (EPO), the cytokine required for erythropoiesis, to inhibit BMAT in C57BL6/J mice fed four weeks of a high-fat diet (HFD). Acute EPO administration markedly decreased BMAT in regular chow diet (RCD) and HFD-fed mice, without affecting whole body fat mass. Micro-CT analysis showed EPO reduced trabecular bone in RCD- and HFD-fed mice, but EPO-treated HFD-fed mice maintained cortical bone mineral density and cortical bone volume, which was reduced on RCD. Despite achieving similar increased hematocrits with BMAT loss in RCD- and HFD-fed mice treated with EPO, decreased bone marrow cellularity was only observed in RCD-fed mice concomitant with an increasing percentage of bone marrow erythroid cells. In contrast, in HFD-fed mice, EPO increased endothelial cells and stromal progenitors with a trend toward the normalization of marrow homeostasis. EPO administration increased c-terminal FGF23 and intact serum FGF23 only in HFD-fed mice. These data demonstrate the distinct EPO responses of bone and marrow in normal and obese states, accompanying EPO-induced loss of BMAT.


Assuntos
Medula Óssea/patologia , Osso e Ossos/patologia , Dieta Hiperlipídica , Eritropoetina/farmacologia , Obesidade/patologia , Tecido Adiposo/patologia , Animais , Medula Óssea/efeitos dos fármacos , Osso e Ossos/efeitos dos fármacos , Osso Esponjoso/efeitos dos fármacos , Osso Esponjoso/patologia , Modelos Animais de Doenças , Eritropoetina/administração & dosagem , Feminino , Fatores de Crescimento de Fibroblastos/sangue , Camundongos Endogâmicos C57BL , Obesidade/sangue , Osteoblastos/efeitos dos fármacos , Osteoblastos/metabolismo , Osteoblastos/patologia , Osteoclastos/efeitos dos fármacos , Osteoclastos/metabolismo , Osteoclastos/patologia , Osteócitos/efeitos dos fármacos , Osteócitos/patologia , Periósteo/patologia
14.
Biol Sex Differ ; 11(1): 9, 2020 03 10.
Artigo em Inglês | MEDLINE | ID: mdl-32156311

RESUMO

Fibroblast growth factors (FGFs) belong to a large family comprising 22 FGF polypeptides that are widely expressed in tissues. Most of the FGFs can be secreted and involved in the regulation of skeletal muscle function and structure. However, the role of fasting on FGF expression pattern in skeletal muscles remains unknown. In this study, we combined bioinformatics analysis and in vivo studies to explore the effect of 24-h fasting on the expression of Fgfs in slow-twitch soleus and fast-twitch tibialis anterior (TA) muscle from male and female C57BL/6 mice. We found that fasting significantly affected the expression of many Fgfs in mouse skeletal muscle. Furthermore, skeletal muscle fibre type and sex also influenced Fgf expression and response to fasting. We observed that in both male and female mice fasting reduced Fgf6 and Fgf11 in the TA muscle rather than the soleus. Moreover, fasting reduced Fgf8 expression in the soleus and TA muscles in female mice rather than in male mice. Fasting also increased Fgf21 expression in female soleus muscle and female and male plasma. Fasting reduced Fgf2 and Fgf18 expression levels without fibre-type and sex-dependent effects in mice. We further found that fasting decreased the expression of an FGF activation marker gene-Flrt2 in the TA muscle but not in the soleus muscle in both male and female mice. This study revealed the expression profile of Fgfs in different skeletal muscle fibre types and different sexes and provides clues to the interaction between the skeletal muscle and other organs, which deserves future investigations.


Assuntos
Jejum/metabolismo , Fatores de Crescimento de Fibroblastos/metabolismo , Fibras Musculares Esqueléticas/metabolismo , Caracteres Sexuais , Animais , Biologia Computacional , Feminino , Fatores de Crescimento de Fibroblastos/sangue , Masculino , Camundongos Endogâmicos C57BL
15.
Artigo em Inglês | MEDLINE | ID: mdl-32188054

RESUMO

Recent evidence has indicated that fibroblast growth factor 21 (FGF21) regulates longitudinal bone growth, with increased FGF21 levels leading to bone loss. The present study evaluated the relationship between bone mineral density (BMD) and serum FGF21 levels in patients undergoing hemodialysis (HD). We analyzed blood samples from 95 patients undergoing HD and measured BMD using dual-energy X-ray absorptiometry of the lumbar vertebrae (L2-L4). Serum FGF21 concentrations were determined using a commercially available enzyme-linked immunosorbent assay kit. Thirteen (11.6%) patients were found to have osteoporosis, 27 (28.4%) osteopenia, and 57 patients had normal BMD. Advanced age and decreased body mass index, height, body weight, waist circumference, and triglyceride level were associated with lower lumbar T-scores, as were increased alkaline phosphatase, urea reduction rate, fractional clearance index for urea, and FGF21 levels. Low log-FGF21, increased body mass index, increased pre-HD body weight, and increased logarithmically transformed triglycerides (log-TG) were found to be significantly and independently associated with lumbar BMD by multivariate forward stepwise linear regression analysis with adjustment for significant confounders. We conclude that high serum FGF21 level is negatively associated with BMD in patients undergoing HD.


Assuntos
Densidade Óssea , Fatores de Crescimento de Fibroblastos , Vértebras Lombares , Diálise Renal , Absorciometria de Fóton , Idoso , Densidade Óssea/fisiologia , Feminino , Fatores de Crescimento de Fibroblastos/sangue , Humanos , Masculino , Pessoa de Meia-Idade
16.
Horm Metab Res ; 52(3): 194-201, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32215890

RESUMO

Derangements in phosphate and calcium homeostasis are common in patients with beta-thalassemia. Fibroblast growth factor 23 (FGF23) is among the main hormones regulating phosphate levels, while several studies underline an interplay between iron (Fe) and FGF23. Herein, we investigated, for the first time, the serum intact molecule (iFGF23) and the carboxyl-terminal fragment (C-FGF23) and Klotho levels simultaneously in patients with beta-thalassemia major receiving iron chelation regimens in comparison to healthy control subjects. We also correlated them with the body iron burden. The observational case-control study included 81 subjects (40 thalassemic patients and 41 healthy controls). Serum iFGF23, C-FGF23 and Κlotho were measured by ELISA. Parathormone, 25-hydroxycholecalciferol, calcium, and phosphorus were measured in blood and/or urine. The degree of hemosiderosis was evaluated by assessing the serum ferritin levels and performing T2* MRI measurements. Serum C-FGF23 levels were significantly lower in patients compared to control subjects (p=0.04), while iFGF23 and Klotho levels did not differ. Serum C-FGF23 levels were negatively correlated with ferritin (r=-0,421, p=0.018), whereas there were no significant correlations of each of the three factors with the iron chelation therapy. Decreased serum C-FGF23 levels were found in ßTh patients which may be attributed to inhibition of proteolytic cleavage of iFGF23. Further studies in a greater number of patients will shed more light on the disturbances of the iFGF23, Klotho and C-FGF23 in thalassemia and their possible role in bone disease of such patients.


Assuntos
Fatores de Crescimento de Fibroblastos/sangue , Glucuronidase/sangue , Talassemia beta/sangue , Adolescente , Adulto , Feminino , Ferritinas/sangue , Fatores de Crescimento de Fibroblastos/genética , Humanos , Ferro/sangue , Quelantes de Ferro/administração & dosagem , Masculino , Pessoa de Meia-Idade , Adulto Jovem , Talassemia beta/tratamento farmacológico
17.
Eur J Endocrinol ; 182(5): R83-R99, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32069220

RESUMO

Fibrous dysplasia/McCune-Albright Syndrome (FD/MAS), arising from gain-of-function mutations in Gαs, and cutaneous skeletal hypophosphatemia syndrome (CSHS), arising from gain-of-function mutations in the Ras/MAPK pathway, are strikingly complex, mosaic diseases with overlapping phenotypes. Both disorders are defined by mosaic skin and bone involvement, and both are complicated by increased FGF23 production. These similarities have frequently led to mis-diagnoses, primarily in patients with CSHS who are often assumed to have FD/MAS. The intriguing similarities in skeletal involvement in these genetically distinct disorders have led to novel insights into FGF23 physiology, making an understanding of FD/MAS and CSHS relevant to both clinicians and researchers interested in bone and endocrine disorders. This review will give an overview of FD/MAS and CSHS, focusing on the roles of mosaicism and FGF23 in the pathogenesis and clinical presentation of these disorders.


Assuntos
Fatores de Crescimento de Fibroblastos/sangue , Displasia Fibrosa Poliostótica/diagnóstico , Hipofosfatemia/diagnóstico , Displasia Fibrosa Poliostótica/sangue , Displasia Fibrosa Poliostótica/genética , Humanos , Hipofosfatemia/sangue , Hipofosfatemia/genética , Mosaicismo , Mutação , Transdução de Sinais/genética
18.
Nutrients ; 12(2)2020 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-32069846

RESUMO

Nutrient excess enhances glucose-dependent insulinotropic polypeptide (GIP) secretion, which may in turn contribute to the development of liver steatosis. We hypothesized that elevated GIP levels in obesity may affect markers of liver injury through microRNAs. The study involved 128 subjects (body mass index (BMI) 25-40). Fasting and postprandial GIP, glucose, insulin, and lipids, as well as fasting alanine aminotransferase (ALT), γ-glutamyltransferase (GGT), cytokeratin-18, fibroblast growth factor (FGF)-19, and FGF-21 were determined. TaqMan low density array was used for quantitative analysis of blood microRNAs. Fasting GIP was associated with ALT [ß = 0.16 (confidence interval (CI): 0.01-0.32)], triglycerides [ß = 0.21 (95% CI: 0.06-0.36], and FGF-21 [ß = 0.20 (95%CI: 0.03-0.37)]; and postprandial GIP with GGT [ß = 0.17 (95%CI: 0.03-0.32)]. The odds ratio for elevated fatty liver index (>73%) was 2.42 (95%CI: 1.02-5.72) for high GIP versus low GIP patients. The miRNAs profile related to a high GIP plasma level included upregulated miR-136-5p, miR-320a, miR-483-5p, miR-520d-5p, miR-520b, miR-30e-3p, and miR-571. Analysis of the interactions of these microRNAs with gene expression pathways suggests their potential contribution to the regulation of the activity of genes associated with insulin resistance, fatty acids metabolism, and adipocytokines signaling. Exaggerated fasting and postprandial secretion of GIP in obesity are associated with elevated liver damage markers as well as FGF-21 plasma levels. Differentially expressed microRNAs suggest additional, epigenetic factors contributing to the gut-liver cross-talk.


Assuntos
Fígado Gorduroso/sangue , Polipeptídeo Inibidor Gástrico/sangue , MicroRNAs/sangue , Obesidade/sangue , Adipocinas/sangue , Adulto , Idoso , Biomarcadores/sangue , Índice de Massa Corporal , Epigênese Genética , Jejum/sangue , Ácidos Graxos/sangue , Fígado Gorduroso/etiologia , Fígado Gorduroso/genética , Feminino , Fatores de Crescimento de Fibroblastos/sangue , Humanos , Insulina/sangue , Fígado/patologia , Masculino , Pessoa de Meia-Idade , Obesidade/complicações , Obesidade/genética , Razão de Chances , Período Pós-Prandial , Transdução de Sinais/genética
19.
Sci Rep ; 10(1): 1795, 2020 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-32020002

RESUMO

To test the hypothesis that fibroblast growth factor 23 (FGF23) is directly regulated by energy intake, in vivo and in vitro experiments were conducted. Three groups of rats were fed diets with high (HC), normal (NC) and low (LC) caloric content that resulted in different energy intake. In vitro, UMR106 cells were incubated in high (HG, 4.5 g/l) or low glucose (LG, 1 g/l) medium. Additional treatments included phosphorus (P), mannitol, rapamycin and everolimus. Intestinal absorption of P and plasma P concentrations were similar in the three groups of rats. As compared with NC, plasma FGF23 concentrations were increased in HC and decreased in the LC group. A significant correlation between energy intake and plasma FGF23 concentrations was observed. In vitro, mRNA FGF23 was significantly higher in UMR106 cells cultured in HG than in LG. When exposed to high P, mRNA FGF23 increased but only when cells were cultured in HG. Cells incubated with HG and mechanistic target of rapamycin (mTOR) inhibitors expressed low mRNA FGF23, similar to the values obtained in LG. In conclusion, this study shows a direct regulation of FGF23 production by energy availability and demonstrates that the mTOR signaling pathway plays a central role in this regulatory system.


Assuntos
Ingestão de Energia/fisiologia , Fatores de Crescimento de Fibroblastos/metabolismo , Glucose/farmacologia , Fósforo/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Animais , Linhagem Celular Tumoral , Feminino , Fatores de Crescimento de Fibroblastos/sangue , Ratos , Ratos Wistar
20.
Intern Med ; 59(3): 345-355, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32009088

RESUMO

Objective To prolong the health expectancy, it is important to prevent age-related diseases, such as osteoporosis and cerebrovascular disease, which are major causes of a bedridden state. Early predictable biomarkers for these diseases are urgently required in the clinical setting. Three members of the fibroblast growth factor (FGF) family - FGF19, FGF21, and FGF23 - are designated as endocrine FGFs and play crucial roles in various metabolic processes. We tried to clarify the clinical utility of endocrine FGFs as biomarkers for age-related diseases in elderly patients. Methods We examined the serum endocrine FGF levels and analyzed their association with various clinical parameters in 73 outpatients >60 years old as a single-center cross-sectional study. Results In a multivariable linear regression analysis, FGF19 was associated with ALT, a history of cardiovascular disease, and medication with active vitamin D3. FGF21 was associated with the estimated glomerular filtration rate (eGFR), triglyceride level, and hypertension. FGF23 was associated with the eGFR and the serum levels of 1,25-dihydroxy vitamin D3 and TRACP5b. In addition, a receiver operating characteristics analysis revealed that the measurement of FGF21 and FGF23 was useful for detecting chronic kidney disease (CKD) and its complications, including cardiovascular disease and metabolic bone disorder. Conclusion The measurement of FGF21 and FGF23 may be useful for evaluating CKD and its complications. Using serum endocrine FGFs as biomarkers for age-related conditions may help prevent elderly patients from entering a bedridden state.


Assuntos
Biomarcadores/sangue , Fatores de Crescimento de Fibroblastos/sangue , Doenças Metabólicas/etiologia , Doenças Metabólicas/fisiopatologia , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/fisiopatologia , Idoso , Idoso de 80 Anos ou mais , Estudos Transversais , Feminino , Humanos , Japão , Masculino , Pessoa de Meia-Idade
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