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1.
Biomed Res Int ; 2021: 5567666, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34497849

RESUMO

Background: Fracture risk assessment tool (FRAX) index was developed for estimating of the 10-year risk of major or hip osteoporotic fracture. To date, there is insufficient information regarding the correlation between FRAX and serum bone turnover markers (BTMs), such as soluble ligand of receptor activator of nuclear factor-κB (sRANKL), osteoprotegerin (OPG), and other molecules related with secondary osteoporosis in rheumatoid arthritis (RA). Therefore, this study is aimed at assessing the correlation between the FRAX and serum levels of sRANKL, OPG, sRANKL/OPG ratio, Dickkopf-1 (DKK-1), and sclerostin (SOST) in RA. Methods: Cross-sectional study included 156 postmenopausal women with RA. Bone mineral density (BMD) was measured at lumbar spine (L1-L4) and total hip using dual-energy X-ray absorptiometry (DXA). RA patients were divided into (A) RA + osteoporosis and (B) RA without osteoporosis. FRAX scores were calculated including the total hip BMD. Serum sRANKL, OPG, DKK-1, and SOST levels were measured by ELISA. Pearson tests were used for assessing the correlation between serum levels of these molecules and FRAX scores in RA. Results: The RA + osteoporosis group had elevated sRANKL levels (p = 0.005), higher sRANKL/OPG ratio (p = 0.017), decreased DKK-1 (p = 0.028), and lower SOST levels (p < 0.001). Low total hip BMD correlated with high sRANKL (p = 0.001) and sRANKL/OPG ratio (p = 0.005). Total hip and lumbar spine BMD correlated with DKK-1 (p = 0.009 and p = 0.05, respectively) and SOST levels (p < 0.001 and p < 0.001, respectively). Higher sRANKL levels and sRANKL/OPG ratio correlated with estimated 10-year risk of a major osteoporotic fractures (p = 0.003 and p = 0.003, respectively) and hip fracture (p = 0.002 and p = 0.006, respectively). High serum SOST levels were associated with a low estimated 10-year risk of a major osteoporotic fracture (p = 0.003) and hip fracture (p = 0.009). Conclusion: High sRANKL levels and sRANKL/OPG ratio can be useful to detect a subgroup of RA patients who has an increased 10-year risk of major and hip osteoporotic fractures.


Assuntos
Artrite Reumatoide/sangue , Remodelação Óssea/fisiologia , Osteoporose/sangue , Fraturas por Osteoporose/diagnóstico , Osteoprotegerina/sangue , Ligante RANK/sangue , Artrite Reumatoide/complicações , Artrite Reumatoide/patologia , Biomarcadores/sangue , Densidade Óssea , Estudos Transversais , Feminino , Humanos , Pessoa de Meia-Idade , Osteoporose/etiologia , Osteoporose/patologia , Fraturas por Osteoporose/sangue , Fraturas por Osteoporose/etiologia , Pós-Menopausa/sangue , Prognóstico
2.
Breast Cancer Res Treat ; 190(3): 463-475, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34570303

RESUMO

PURPOSE: Emerging evidence suggests that the progesterone-mediated receptor activator of nuclear factor κB (RANK)/soluble RANK ligand (sRANKL)/osteoprotegerin (OPG) pathway plays an important role in mammary carcinogenesis and is hyperactivated in germline (g)BRCA1/2 mutation carriers. We analyzed the effects of a 3-month intensive lifestyle intervention within the LIBRE-1 study on the serum levels of OPG and sRANKL and hypothesized that the intervention program provides a beneficial impact on the biomarkers by increasing OPG and reducing sRANKL serum concentrations. METHODS: Serum levels of OPG and sRANKL of 49 gBRCA1/2 mutation carriers were quantified using enzyme-linked immunosorbent assays. We used previously collected blood samples from participants of the prospective LIBRE-1 study, who were randomized into an intervention group (IG), increasing physical activity and adherence to the Mediterranean diet (MedD) through supervised sessions from study entry to the first study visit after 3 months and a usual-care control group (CG). Differences in biomarker levels before and after the 3-month intervention were tested within and between study groups. RESULTS: The lifestyle intervention resulted in a significant increase in OPG for participants in both the IG (q = 0.022) and CG (q = 0.002). sRANKL decreased significantly in the IG (q = 0.0464) and seemed to decrease in the CG (q = 0.5584). An increase in the intake of Omega-3 polyunsaturated fatty acids was significantly associated with an increase in OPG (r = 0.579, q = 0.045). Baseline serum levels of sRANKL were a strong predictor for the change of sRANKL in the course of the intervention (ß-estimate = - 0.70; q = 0.0018). Baseline physical fitness (assessed as VO2peak) might predict the change of OPG in the course of the intervention program (ß-estimate = 0.133 pg/ml/ml/min/kg; p = 0.0319; q = 0.2871). CONCLUSION: Findings from this pilot study seem to confirm our hypothesis by showing an increase in OPG and decrease in sRANKL over a 3-month lifestyle intervention and suggest that increased physical activity and adherence to the MedD are potent modulators of the biomarkers OPG and potentially sRANKL.


Assuntos
Proteína BRCA1 , Neoplasias da Mama , Dieta Mediterrânea , Osteoprotegerina , Estudos Prospectivos , Proteína BRCA1/genética , Proteína BRCA2/genética , Exercício Físico , Feminino , Humanos , Estilo de Vida , Mutação , Osteoprotegerina/sangue , Osteoprotegerina/genética , Projetos Piloto , Ligante RANK/sangue , Ligante RANK/genética , Ensaios Clínicos Controlados Aleatórios como Assunto
3.
Sci Rep ; 11(1): 16156, 2021 08 09.
Artigo em Inglês | MEDLINE | ID: mdl-34373519

RESUMO

We investigated the effects of single and repeated exposures to whole-body cryotherapy on biomarkers of bone remodeling and osteo-immune crosstalk: sclerostin, osteocalcin (OC), C-terminal cross-linked telopeptide of type I collagen (CTx-I), osteoprotegerin (OPG) and free soluble receptor activator for nuclear factor κ B ligand (sRANKL). The study included 22 healthy males, grouped in high physical fitness level (HPhL) and low physical fitness level (LPhL), all undergone 10 consecutive sessions in a cryogenic chamber (- 110 °C). We observed a significant time-effect on sclerostin (p < 0.05), OC (p < 0.01), CTx-I (p < 0.001), OC/CTx-I (p < 0.05), and significant differences in sRANKL between the groups (p < 0.05) after the 1st cryostimulation; a significant time-effect on OC (p < 0.001) and OC/CTx-I (p < 0.001) after the 10th cryostimulation, and a significant time-effect on CTx-I (p < 0.001) and OC/CTx-I (p < 0.01) after 10 sessions of WBC. In conclusion, in young men, the first exposure to extreme cold induced significant changes in serum sclerostin. The changes in sRANKL, between groups, suggest that fitness level may modify the body's response to cold. The effects of the first stimulus and the whole session are not identical, probably due to the physiological development of habituation to cold.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/sangue , Remodelação Óssea/fisiologia , Crioterapia/métodos , Aptidão Física/fisiologia , Biomarcadores/sangue , Osso e Ossos/metabolismo , Colágeno Tipo I/sangue , Metabolismo Energético , Humanos , Masculino , Osteocalcina/sangue , Osteoprotegerina/sangue , Peptídeos/sangue , Ligante RANK/sangue , Adulto Jovem
4.
RMD Open ; 7(2)2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34112702

RESUMO

OBJECTIVES: Our knowledge about the effect of tocilizumab (TCZ) on the synovium in rheumatoid arthritis (RA) is limited. The aim of this study was to investigate the effect of TCZ on citrullination and on inflammation in the synovial tissue and in the peripheral blood. METHODS: 15 patients with RA underwent synovial biopsy before and 8 weeks after TCZ initiation. Clinical evaluation was performed at baseline and at 8 weeks. Using immunohistochemistry, we evaluated the expression of CD68, CD3, CD20, osteoprotegerin (OPG) and receptor activator for nuclear factor-κB ligand (RANKL) before and after treatment with TCZ. We also analysed the expression of protein arginine deiminase (PAD)-2 and PAD-4 enzymes in the synovial tissue and protein citrullination patterns with the help of anticitrullinated protein antibody (ACPA) clones 1325:04C03 and 1325:01B09. Serum levels of interleukin-6 (IL-6), IL-8, RANKL, OPG and C-terminal crosslinked telopeptide type II collagen were measured by ELISA. Paired-wise Wilcoxon signed-rank test was used to compare median values before and after treatment. RESULTS: Disease activity in patients was reduced from baseline to 8 weeks. Although PAD-2 and PAD-4 expressions remained unchanged after TCZ treatment, the binding of one ACPA clone decreased in the synovial tissue. TCZ did not affect the number of CD68+ macrophages or CD20+ B cells but induced significant decrease in the number of CD3+ T cells. RANKL and OPG expression remained unchanged in the synovial tissue. A significant increase in the levels of IL-6 and RANKL was observed in the serum. This increase was statistically significant in patients who responded to TCZ (achieving Clinical Disease Activity Index low disease activity or remission) but not in non-responders. CONCLUSIONS: TCZ reduced synovial T-cell counts but not macrophages. A significant increase of serum IL-6 was observed in responders.


Assuntos
Artrite Reumatoide , Interleucina-6 , Ligante RANK , Anticorpos Monoclonais Humanizados , Artrite Reumatoide/tratamento farmacológico , Humanos , Interleucina-6/sangue , Macrófagos , Ligante RANK/sangue , Receptor Ativador de Fator Nuclear kappa-B , Membrana Sinovial , Linfócitos T
5.
J Clin Endocrinol Metab ; 106(7): e2647-e2655, 2021 06 16.
Artigo em Inglês | MEDLINE | ID: mdl-33710302

RESUMO

PURPOSE: To examine the association of maternal bone markers [sclerostin, soluble receptor activator of nuclear factor-κB ligand (sRANKL), osteocalcin, 25-hydroxyvitamin D3] with fetal intra-abdominal and subcutaneous adipose tissue deposition and birthweight during normal pregnancy. METHODS: One hundred pregnant women (aged 30.4 ±â€…5.6 years, mean ±â€…SD) with prepregnancy body mass index = 24.1 ±â€…4.6 kg/m2 were seen prospectively during each trimester. At each visit they were submitted to anthropometric measurements, a fasting blood sampling, a 75-g oral glucose tolerance test, and a fetal ultrasonogram. At birth, neonates had birth weight measurement. RESULTS: In the second trimester, maternal sclerostin concentrations correlated positively with fetal abdominal circumference and birth weight; maternal sRANKL concentrations correlated positively with fetal abdominal subcutaneous fat thickness, sagittal abdominal diameter, and abdominal circumference. Fetuses born to mothers with greater (>254 ng/mL), compared to fetuses born to mothers with lower (≤254ng/mL), sRANKL concentrations had greater abdominal circumference, sagittal diameter, and abdominal subcutaneous fat thickness. Maternal serum sclerostin concentrations were the best positive predictors of birth weight. In the third trimester maternal sclerostin concentrations correlated positively with fetal sagittal abdominal diameter; maternal sRANKL concentrations positively correlated with fetal abdominal circumference and fetal abdominal sagittal diameter. CONCLUSIONS: Maternal bone markers sclerostin and sRANKL may relate to fetal intra-abdominal adipose tissue deposition through as yet unknown direct or indirect mechanisms, thus contributing to birthweight.


Assuntos
Gordura Abdominal/embriologia , Adiposidade , Feto/metabolismo , Segundo Trimestre da Gravidez/sangue , Ultrassonografia Pré-Natal , Abdome/diagnóstico por imagem , Abdome/embriologia , Gordura Abdominal/diagnóstico por imagem , Proteínas Adaptadoras de Transdução de Sinal/sangue , Adulto , Biomarcadores/sangue , Peso ao Nascer , Índice de Massa Corporal , Calcifediol/sangue , Feminino , Feto/diagnóstico por imagem , Feto/embriologia , Humanos , Recém-Nascido , Osteocalcina/sangue , Gravidez , Trimestres da Gravidez/sangue , Estudos Prospectivos , Ligante RANK/sangue , Circunferência da Cintura
6.
Mol Med ; 27(1): 19, 2021 02 26.
Artigo em Inglês | MEDLINE | ID: mdl-33637048

RESUMO

BACKGROUND: Osteoporosis is a common phenomenon in HIV patients on tenofovir treatment, but its underlying mechanisms remain to be explored. METHODS: Quantitative real-time PCR was performed to analyze the expression of miR-302, miR-101, miR-145 and osteoclast-specific genes in the serum of HIV patients treated with tenofovir and ZOL. ELISA was used to evaluate the expression of RANKL, SMAD3 and PRKACB in the serum of these patients. Luciferase assay was carried out to explore the inhibitory effects of miR-302, miR-101 and miR-145 on the expression of PRKACB, RANKL and SMAD3, respectively. Western blot was used to examine the expression of genes involved in NF­κB and JNK signaling pathways. RESULTS: ZOL treatment significantly suppressed the expression of CTx and osteocalcin in HIV patients treated with tenofovir. The BMD loss of HIV patients treated with tenofovir was effectively hindered by ZOL treatment. Mechanistically, the expression of miR-302, miR-101, miR-145, RANKL, SMAD3 and PRKACB in the serum was remarkably activated by ZOL treatment. Luciferase assays showed that miR-302, miR-101 and miR-145 effectively suppressed the expression of PRKACB, RANKL and SMAD3, respectively, through binding to their 3' UTR. Furthermore, ZOL treatment notably restored the normal expression of osteoclast­specific genes while activating NF­κB and JNK signaling pathways. CONCLUSION: The findings of this study demonstrated that administration of ZOL suppressed the expression of RANKL via modulating signaling pathways of miR-101-3p/RANKL, miR-302/PRKACB/RANKL and miR-145/SMAD3/RANKL. Furthermore, down-regulated expression of RANKL by ZOL treatment alleviated osteoporosis in HIV-positive subjects treated with tenofovir.


Assuntos
Conservadores da Densidade Óssea/uso terapêutico , Infecções por HIV/tratamento farmacológico , Osteogênese/efeitos dos fármacos , Osteoporose/tratamento farmacológico , Ligante RANK/metabolismo , Ácido Zoledrônico/uso terapêutico , Adulto , Antirretrovirais/efeitos adversos , Densidade Óssea/efeitos dos fármacos , Conservadores da Densidade Óssea/farmacologia , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Subunidades Catalíticas da Proteína Quinase Dependente de AMP Cíclico/sangue , Feminino , Infecções por HIV/sangue , Infecções por HIV/metabolismo , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , MicroRNAs/sangue , Pessoa de Meia-Idade , Osteoclastos/efeitos dos fármacos , Osteoporose/sangue , Osteoporose/metabolismo , Ligante RANK/sangue , Proteína Smad3/sangue , Tenofovir/efeitos adversos , Ácido Zoledrônico/farmacologia
7.
Medicine (Baltimore) ; 100(5): e24562, 2021 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-33592912

RESUMO

ABSTRACT: We previously identified E26 transformation specific sequence 1 (ETS1) rs73013527 single nucleotide polymorphism associated with RA susceptibility and disease activity. In the present study, we aims to further investigate the association between ETS1 rs73013527 and receptor activator of nuclear factor kappa B ligand (RANKL), an index related to bone destruction and was reported to elevate in RA.We determined genotypes of ETS1 rs73013527, serum RANKL concentration, clinical characteristics (disease duration, disease activity score for 28 painful/swollen joints), and laboratory markers (rheumatoid factor, anti-citrullinated protein antibody, anti-keratin antibody, c-reactive protein, erythrocyte sedimentation rate) of 254 RA cases. Univariate and multivariate analysis were employed to explore the association between ETS1 rs73013527 and serum RANKL levels in RA patients.Univariate and multivariate analysis indicated no association of serum RANKL levels with patient age, gender, clinical characteristics, and laboratory markers. Univariate analysis, not multivariate analysis indicated genotype CT/TT of ETS1 rs73013527 was significantly associated with elevated RANKL levels in RA patients.ETS1 rs73013527 is in relation to serum RANKL levels among patients with RA. ETS1 probably might be an indirect factors involved in RANKL regulation in RA.


Assuntos
Artrite Reumatoide/genética , Artrite Reumatoide/fisiopatologia , Proteína Proto-Oncogênica c-ets-1/genética , Ligante RANK/sangue , Adulto , Idoso , Artrite Reumatoide/sangue , Biomarcadores , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único
8.
Ecotoxicol Environ Saf ; 211: 111897, 2021 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-33493719

RESUMO

Chronic cadmium (Cd) toxicity is a significant health concern, and the mechanism of long-term low-dose Cd exposure on bone has not been fully elucidated yet. This study aimed to assess the association between long-term environmental Cd exposure and bone remodeling in women who aged over 50. A total of 278 non-smoking subjects from Cd-polluted group (n = 191) and non-Cd polluted group (n = 87) were investigated. Bone mineral density (BMD), the levels of three bone turnover markers (BTMs), including total procollagen type 1 amino-terminal propeptide (P1NP), collagen type 1 cross-linked C-telopeptide (ß-CTX), bone-specific alkaline phosphatase (BALP), together with serum soluble receptor activator of nuclear factor-κB ligand (sRANKL) and osteoprotegerin (OPG) were determined. Early markers of renal dysfunction were measured as well. Urinary Cd concentrations ranged from 0.41 to 87.31 µg/g creatinine, with a median of 4.91 µg/g creatinine. Age, BMD, T-score, and prevalence of osteoporosis showed no statistical differences among the quartiles of urinary Cd concentrations, while serum levels of P1NP, ß-CTX, and OPG were higher in the upper quartiles. Multivariate linear regression models indicated significantly positive associations of urinary Cd concentration with serum levels of P1NP, ß-CTX, BALP, sRANKL, and OPG. A ridge regression analysis with T-score and the three BTMs, sRANKL, and OPG, adjusted for age and body mass index (BMI), indicated that except for age and Cd exposure, ß-CTX was a predictor of T-score. These findings demonstrated that Cd may directly accelerate bone remodeling. Serum ß-CTX might be an appropriate biochemical marker for evaluating and monitoring Cd-related bone loss. Capsule: Cadmium (Cd) may directly accelerate bone remodeling and serum ß-CTX is a valuable biochemical marker for evaluating Cd-related bone loss.


Assuntos
Remodelação Óssea , Cádmio/sangue , Exposição Ambiental/estatística & dados numéricos , Poluentes Ambientais/sangue , Adulto , Idoso , Fosfatase Alcalina , Biomarcadores/sangue , Índice de Massa Corporal , Densidade Óssea , Osso e Ossos , Colágeno Tipo I , Feminino , Humanos , Pessoa de Meia-Idade , Osteoporose/sangue , Osteoprotegerina , Peptídeos , Ligante RANK/sangue
9.
Nat Commun ; 11(1): 6335, 2020 12 10.
Artigo em Inglês | MEDLINE | ID: mdl-33303745

RESUMO

Most breast cancers exhibit low immune infiltration and are unresponsive to immunotherapy. We hypothesized that inhibition of the receptor activator of nuclear factor-κB (RANK) signaling pathway may enhance immune activation. Here we report that loss of RANK signaling in mouse tumor cells increases leukocytes, lymphocytes, and CD8+ T cells, and reduces macrophage and neutrophil infiltration. CD8+ T cells mediate the attenuated tumor phenotype observed upon RANK loss, whereas neutrophils, supported by RANK-expressing tumor cells, induce immunosuppression. RANKL inhibition increases the anti-tumor effect of immunotherapies in breast cancer through a tumor cell mediated effect. Comparably, pre-operative single-agent denosumab in premenopausal early-stage breast cancer patients from the Phase-II D-BEYOND clinical trial (NCT01864798) is well tolerated, inhibits RANK pathway and increases tumor infiltrating lymphocytes and CD8+ T cells. Higher RANK signaling activation in tumors and serum RANKL levels at baseline predict these immune-modulatory effects. No changes in tumor cell proliferation (primary endpoint) or other secondary endpoints are observed. Overall, our preclinical and clinical findings reveal that tumor cells exploit RANK pathway as a mechanism to evade immune surveillance and support the use of RANK pathway inhibitors to prime luminal breast cancer for immunotherapy.


Assuntos
Neoplasias da Mama/imunologia , Linfócitos T CD8-Positivos/imunologia , Imunidade , Receptor Ativador de Fator Nuclear kappa-B/metabolismo , Transdução de Sinais , Adulto , Animais , Neoplasias da Mama/sangue , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Quimiocinas/metabolismo , Denosumab/farmacologia , Denosumab/uso terapêutico , Feminino , Humanos , Imunossupressão , Imunoterapia , Mediadores da Inflamação/metabolismo , Linfócitos do Interstício Tumoral/imunologia , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Modelos Biológicos , Células Mieloides/imunologia , Estadiamento de Neoplasias , Neutrófilos/imunologia , Ligante RANK/sangue , Ligante RANK/metabolismo
11.
Med Sci Monit ; 26: e926171, 2020 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-33128539

RESUMO

BACKGROUND The aim of this study is to investigate the effects of Drynaria total flavonoids (DTF) on mandible microarchitecture, serum estrogen (E2), osteoprotegerin (OPG), and receptor activator of nuclear factor kappa-B ligand (RANKL) levels in an ovariectomy-induced osteoporosis rat model. MATERIAL AND METHODS Thirty female Sprague-Dawley rats were divided into 5 groups (n=6 per group): sham surgery, ovariectomy (OVX), and low-dose, middle-dose, and high-dose DTF. Mandibular osteoporosis was induced by ovariectomy; an equal amount of ovary-sized fat tissue was removed from the sham group. The DTF-treated groups were given DTF gavage at different doses for 12 weeks; the sham and OVX groups were given saline. After the treatment phase, the effects of DTF on the microarchitecture of the mandible were evaluated by measuring bone density, maximum load, morphometric parameters, and histopathological alterations. Serum E2, OPG, and RANKL levels were measured. RESULTS The OVX group showed obvious osteoporosis in the mandible and decreased serum E2 levels and OPG/RANKL ratio. The low-dose group did not show significant improvement in mandibular microstructure. The middle-dose group showed significantly ameliorated osteoporosis. The high-dose group had further improvement in bone microstructures and increase of OPG/RANKL over the middle-dose group. Furthermore, ovariectomy significantly decreased serum E2, but DTF treatment failed to restore serum E2 levels. CONCLUSIONS Ovariectomy can cause significant bone loss in the rat mandible and a decrease in serum E2 and OPG/RANKL. DTF significantly improved the mandibular microstructure and restored OPG/RANKL balance, but it did not restore the decreased serum E2 concentration following ovariectomy.


Assuntos
Densidade Óssea/efeitos dos fármacos , Flavonoides/farmacologia , Mandíbula/efeitos dos fármacos , Osteoporose/tratamento farmacológico , Extratos Vegetais/farmacologia , Polypodiaceae/química , Animais , Biomarcadores/sangue , Estrogênios/sangue , Feminino , Mandíbula/patologia , Osteoprotegerina/sangue , Ovariectomia , Ligante RANK/sangue , Ratos , Ratos Sprague-Dawley
12.
Cardiovasc Diabetol ; 19(1): 140, 2020 09 18.
Artigo em Inglês | MEDLINE | ID: mdl-32948184

RESUMO

BACKGROUND: Lower limb arterial calcification is a frequent, underestimated but serious complication of diabetes. The DIACART study is a prospective cohort study designed to evaluate the determinants of the progression of lower limb arterial calcification in 198 patients with type 2 diabetes. METHODS: Lower limb arterial calcification scores were determined by computed tomography at baseline and after a mean follow up of 31.20 ± 3.86 months. Serum RANKL (Receptor Activator of Nuclear factor kB Ligand) and bone remodeling, inflammatory and metabolic parameters were measured at baseline. The predictive effect of these markers on calcification progression was analyzed by a multivariate linear regression model. RESULTS: At baseline, mean ± SD and median lower limb arterial calcification scores were, 2364 ± 5613 and 527 respectively and at the end of the study, 3739 ± 6886 and 1355 respectively. Using multivariate analysis, the progression of lower limb arterial log calcification score was found to be associated with (ß coefficient [slope], 95% CI, p-value) baseline log(calcification score) (1.02, 1.00-1.04, p < 0.001), triglycerides (0.11, 0.03-0.20, p = 0.007), log(RANKL) (0.07, 0.02-0.11, p = 0.016), previous ischemic cardiomyopathy (0.36, 0.15-0.57, p = 0.001), statin use (0.39, 0.06-0.72, p = 0.023) and duration of follow up (0.04, 0.01-0.06, p = 0.004). CONCLUSION: In patients with type 2 diabetes, lower limb arterial calcification is frequent and can progress rapidly. Circulating RANKL and triglycerides are independently associated with this progression. These results open new therapeutic perspectives in peripheral diabetic calcifying arteriopathy. Trial registration NCT02431234.


Assuntos
Diabetes Mellitus Tipo 2/sangue , Angiopatias Diabéticas/sangue , Extremidade Inferior/irrigação sanguínea , Ligante RANK/sangue , Triglicerídeos/sangue , Calcificação Vascular/sangue , Idoso , Estudos de Coortes , Angiopatias Diabéticas/diagnóstico por imagem , Angiopatias Diabéticas/epidemiologia , Progressão da Doença , Feminino , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Masculino , Pessoa de Meia-Idade , Isquemia Miocárdica/epidemiologia , Estudos Prospectivos , Tomografia Computadorizada por Raios X , Calcificação Vascular/diagnóstico por imagem , Calcificação Vascular/epidemiologia
13.
Artif Cells Nanomed Biotechnol ; 48(1): 1036-1046, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32667225

RESUMO

This study is focussed on evaluating and comparing two mediators of osteoclast, osteoprotegerin (OPG) and nuclear factor-κB ligand (RANKL), in plasma and tissue levels in patients with steroid-induced osteonecrosis of femoral head (SIONFH). Subjects were included in this cross-sectional case-control study in 2016. Bone histomorphology, immunohistochemistry, Western blotting, OPG and RANKL plasma levels, post-hoc statistical power and receiver-operating characteristic (ROC) curves were evaluated. Eighty-six patients diagnosed with SIONFH and 51 healthy subjects were included. OPG expression levels in bone samples increased with ARCO stage, and RANKL expression levels decreased with ARCO stages. Plasma OPG and RANKL levels were significantly higher in the SIONFH group compared with the healthy control group. The plasma OPG level and ratio of OPG and RANKL were positively associated with ARCO stages and significantly higher in stages III and IV. Plasma RANKL levels were negatively associated with ARCO stage and were significantly higher in ARCO stages II and III. Plasma OPG and RANKL may represent potential biomarkers during SIONFH at different stages. Higher plasma OPG levels indicated late-stage SIONFH, and higher plasma RANKL levels indicated early stage. Our findings may provide a clue for the development of diagnostic tools and therapies for SIONFH.


Assuntos
Necrose da Cabeça do Fêmur/induzido quimicamente , Necrose da Cabeça do Fêmur/patologia , Osteoclastos/efeitos dos fármacos , Osteoclastos/patologia , Esteroides/efeitos adversos , Adolescente , Adulto , Idoso , Feminino , Necrose da Cabeça do Fêmur/sangue , Necrose da Cabeça do Fêmur/diagnóstico por imagem , Humanos , Masculino , Pessoa de Meia-Idade , Osteoprotegerina/sangue , Ligante RANK/sangue , Microtomografia por Raio-X , Adulto Jovem
14.
Int J Mol Sci ; 21(11)2020 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-32485823

RESUMO

BACKGROUND: It has been shown that sex affects immunity, including cytokine production. Given that atherosclerosis is an inflammatory disease promoted by specific cytokines, such as interleukin (IL)-1ß, IL-6, and tumor necrosis factor (TNF)-α, we aimed at evaluating whether sex could affect the levels of these proatherogenic cytokines in a group of healthy adults. In this analysis, we also included other cytokines and peptides that have been implicated in atherosclerosis development and progression. METHODS: A total of 104 healthy adults were recruited; we measured circulating levels of IL-1ß, IL-6, TNF-α, angiotensins and angiotensin-converting enzyme-2 (ACE2), as well as osteoprotegerin and receptor activator of nuclear factor κB ligand (RANKL). RESULTS: IL-1ß, IL-6, and TNF-α were significantly higher in men as compared to women. They were all associated with testosterone and the testosterone/estradiol ratio. They remained significantly associated with sex (but not with hormones) after being tested for potential confounders. CONCLUSIONS: Sex seems to influence the levels of proatherogenic cytokines. This is consistent not only with sex differences in vulnerability to infections but also with the higher cardiovascular risk exhibited by the male gender as compared to the female gender. Nevertheless, this association is only partly explained by hormone levels.


Assuntos
Aterosclerose/epidemiologia , Interleucinas/sangue , Ligante RANK/sangue , Fator de Necrose Tumoral alfa/sangue , Adulto , Enzima de Conversão de Angiotensina 2/sangue , Aterosclerose/sangue , Biomarcadores/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores Sexuais
15.
Dis Markers ; 2020: 8641749, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32377274

RESUMO

Background: Patients undergoing hemodialysis experience a greater risk of cognitive impairment than the general population, but limited data elucidates the biomarkers on this. We evaluated the association of bone turnover markers on cognitive function among 251 prevalent hemodialysis enrollees in a cross-sectional study. Methods: 251 hemodialysis patients (median age = 57.8, 55% men) and 37 control subjects (mean age = 61.2, 56% men) without a prior stroke or dementia diagnosis were enrolled. Serum concentrations of 8 bone markers were analyzed as the association of cognitive function (Montreal Cognitive Assessment (MoCA) and Cognitive Abilities Screening Instrument (CASI)) using linear regression analysis. Results: A lower cognitive function was noted in hemodialysis patients compared to control subjects. The receptor activator of nuclear factor kappa-B ligand (RANKL) was the only bone marker found to be associated with cognitive function (MoCA and CASI tests) in hemodialysis patients without a prior stroke or dementia diagnosis. In stepwise multiple linear regression analysis, the association remained significant in MoCA (ß = 1.14, 95% CI 0.17 to 2.11) and CASI (ß = 3.06, 95% CI 0.24 to 5.88). Short-term memory (ß = 0.52, 95% CI 0.01 to 1.02), mental manipulation (ß = 0.51, 95% CI 0.05 to 0.96), and abstract thinking (ß = 0.57, 95% CI 0.06 to 1.09) were the significant subdomains in the CASI score related to RANKL. Conclusions: Serum RANKL levels were potentially associated with better cognitive function in hemodialysis patients. Further large-scale and prospective studies are needed to confirm our findings.


Assuntos
Disfunção Cognitiva/sangue , Diálise Renal/efeitos adversos , Idoso , Biomarcadores/sangue , Disfunção Cognitiva/epidemiologia , Disfunção Cognitiva/etiologia , Feminino , Fatores de Crescimento de Fibroblastos/sangue , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/sangue , Leptina/sangue , Masculino , Pessoa de Meia-Idade , Osteocalcina/sangue , Osteopontina/sangue , Osteoprotegerina/sangue , Ligante RANK/sangue
16.
Clin Chim Acta ; 507: 219-223, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32371216

RESUMO

Vitamin D status is involved in the risk of many chronic diseases including cancer, inflammatory and autoimmune disease. The RANK/RANKL/OPG system is also implicated in the orchestration of immune functions. We aimed to investigate the expression of RANKL, OPG and markers of inflammation and immune activation in peripheral blood mononuclear cells (PBMC) from healthy subjects with different 25(OH)D3 plasma levels. The 25(OH)D3 plasma concentrations were assessed by HPLC. The gene expression was evaluated by qRT-PCR. The expression of CYP27B1 was lower in subjects with 25(OH)D3 levels below 50 nmol/L (deficiency) than subjects with both insufficient and sufficient levels of 25(OH)D3. In subjects with deficiency, we observed the up-regulation of RANKL, TNF-α, IFN-γ, ICAM and LFA-1, and a reduction of the anti-inflammatory cytokines IL-13 and IL-4 in comparison to other subjects. Finally, we found a negative correlation between RANKL mRNA levels and 25(OH)D3 and between 25(OH)D3 and ICAM mRNA levels. A positive correlation between ICAM and RANKL was observed. Our results give evidence of the modulatory effects of circulating 25(OH)D3 levels on gene expression of biomarkers of immune activation in PBMC, suggesting the possible use of PBMC as ex-vivo model to characterize molecular mechanisms of immune/inflammatory response in hypovitaminosis conditions.


Assuntos
Inflamação/sangue , Leucócitos Mononucleares/metabolismo , Ligante RANK/sangue , Vitamina D/análogos & derivados , Biomarcadores/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Ligante RANK/genética , RNA Mensageiro/sangue , RNA Mensageiro/genética , Vitamina D/sangue
17.
Artigo em Inglês | MEDLINE | ID: mdl-32418417

RESUMO

INTRODUCTION: Type 1 diabetes (T1D) may be associated with numerous complications including bone metabolism disorders. The aim of the study was to evaluate the bone metabolism markers twice in children with a newly diagnosed T1D and after an average of seven months of its duration in relation to parameters of the clinical course of diabetes. MATERIAL AND METHODS: In 100 T1D patients and 52 control subjects, the following bone turnover markers were evaluated: osteocalcin - OC, osteoprotegerin - OPG, sRANKL, and deoxypyridoline in urine - DPD and DXA examination was also performed. RESULTS: Lower OC concentration at T1D onset in comparison to controls (p < 0.001) and its increase during follow-up (p < 0.001) was ob-served. The OPG concentration was elevated at T1D onset as compared to the control group (p = 0.024) and decreased thereafter (p < 0.001). The s-RANKL level increased during follow-up (p < 0.001) and was lower than in controls (p < 0.001). Urine DPD con-centration also increased during follow-up in the T1D patient group (p < 0.001) and was higher in comparison to the control group (p = 0.021). BMD-TBLH was higher in the control group as compared to patients both at T1D onset (p = 0.025) and in follow-up ob-servation (p = 0.034). Moreover, OPG correlated positively with glycated haemoglobin (HbA1c) (p = 0.004) and negatively with fasting C-peptide level (p = 0.046) and BMI Z-score (p = 0.003), whereas s-RANKL correlated positively with both fasting (p < 0.001) and stimulated C-peptide levels (p < 0.001). CONCLUSIONS: Bone metabolism disorders observed at T1D onset in children and modified after reaching the metabolic control of the disease seem to be most strongly associated with preserved insulin secretion.


Assuntos
Diabetes Mellitus Tipo 1/sangue , Secreção de Insulina , Osteocalcina/sangue , Osteoprotegerina/sangue , Ligante RANK/sangue , Adolescente , Densidade Óssea , Criança , Pré-Escolar , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 1/fisiopatologia , Feminino , Humanos , Masculino
18.
Inflamm Res ; 69(8): 765-777, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32444883

RESUMO

Inflammation plays a negative role in the growth and development of bone. However, the underlining mechanisms of inflammation caused abnormal bone development and even bone disease are still poorly understood, especially in chickens. In this study, we explored the influence of inflammation on bone formation in broilers for the first time by using lipopolysaccharide (LPS) to establish systemic inflammatory models in chickens with tibia as the research object. The measurements of production and tibial parameters showed an inefficient production performance and lower growth rate in LPS group. We also found a large amount of platelets, inflammatory cells in chickens' blood and higher levels of inflammatory factors in serum after LPS injection, meanwhile, increase in thrombus, chondrocyte nucleolysis, and osteoclasts and a reduction in blood vessels were observed in growth plate through histological observation. The qPCR analysis showed that the mRNA expression levels of NF-κB, TLR4, TF, TPO, and its receptor C-MPL enhanced, while VEGFA was inhibited in LPS group. In addition, in OPG/RANKL system, OPG was decreased while RANKL enhanced. It was also observed that the mRNA levels of MMP-9 and its inducing factor CD147 enhanced in LPS group. The western blot results were basically in consistent with mRNA test. Thus, we infer that inflammation can inhibit bone modeling and remodeling by affecting angiogenesis and osteogenesis, and result in negative effect on bone formation furtherly.


Assuntos
Inibidores da Angiogênese/farmacologia , Remodelação Óssea/efeitos dos fármacos , Inflamação/fisiopatologia , Lipopolissacarídeos/farmacologia , Osteogênese/efeitos dos fármacos , Animais , Galinhas , Inflamação/induzido quimicamente , Inflamação/complicações , Interleucina-6/sangue , Metaloproteinase 9 da Matriz/análise , Ligante RANK/sangue
19.
Asian Pac J Cancer Prev ; 21(2): 355-361, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-32102511

RESUMO

OBJECTIVES: Searching for sensitive, minimally invasive biomarkers that represent tumor-associated changes in the peripheral blood might enable the early diagnosis of breast cancer (BC) and monitoring of tumor progression. METHODS: Herein, we investigated the association of some circulating biomarkers with the risk of metastasis. In the current study, 115 BC patients which were subdivided into two groups: nonmetastatic breast cancer patients (NMBC) (n=83) and metastatic breast cancer patients (MBC) (n=32), and 79 apparently healthy controls were recruited. Serum protein levels of lysosomal protein transmembrane 4 beta (LAPTM4B), receptor activator of nuclear factor-kappa b (NF-Kb) ligand (RANKL), osteoprotegerin (OPG), vitamin D (VIT D), chitinase-3-like protein 1 (also known as YKL-40), and sirtuin 1 (SIRT1) were assessed in blood samples using ELISA technique. RESULTS: The results showed that RANKL and OPG had the highest diagnostic potential for MBC detection, with area under the curve values of 0.97 and 0.94, respectively. Moreover, logistic regression analysis showed that RANKL had the highest differentiation power in the discrimination of MBC from NMBC. CONCLUSION: The study highlighted that measuring RANKL and OPG may be helpful in the early detection of metastasis in Egyptian patients with BC.


Assuntos
Biomarcadores Tumorais/sangue , Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/secundário , Carcinoma Lobular/secundário , Osteoprotegerina/sangue , Ligante RANK/sangue , Adulto , Idoso , Neoplasias da Mama/sangue , Neoplasias da Mama/epidemiologia , Carcinoma Ductal de Mama/sangue , Carcinoma Ductal de Mama/epidemiologia , Carcinoma Lobular/sangue , Carcinoma Lobular/epidemiologia , Estudos de Casos e Controles , Egito/epidemiologia , Feminino , Seguimentos , Humanos , Metástase Linfática , Pessoa de Meia-Idade , Invasividade Neoplásica , Prognóstico , Curva ROC , Adulto Jovem
20.
Sci Rep ; 10(1): 1288, 2020 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-31992773

RESUMO

Receptor-activator of nuclear-factor -κB-ligand (RANKL) and its receptor RANK have been recently identified as key players in breast cancer bone metastases. Since Circulating Tumor Cells (CTCs) are considered a crucial step of metastatic process, we explored RANK expression on CTCs in metastatic breast cancer (MBC), and the predictive value of RANK-positive CTCs in monitoring patients during treatment with denosumab (anti-RANKL antibody). To this purpose, we developed a novel CTC assay to quantify RANK-positive CTCs in forty-two bone MBC patients, candidates to denosumab treatment. Companion algorithms ΔAUC and Slope were developed, and correlated with time to first skeletal-related-events (SRE), time to bone metastasis progression and time to visceral metastasis progression. Twenty-seven patients had at least one CTC at baseline and, among these, nineteen (70%) had one or more RANK-positive CTCs. Notably, the baseline total CTCs, but not the RANK-positive, were associated with Time-to-first-SRE, Time-to-Bone-Metastasis-Progression and Time-to-Visceral-Metastasis-Progression. Conversely, during treatment monitoring, positive ΔAUC value, expression of RANK-positive CTCs persistence, correlated with longer Time-to-first-SRE (p = 0.0002) and Time-to-Bone-Metastasis-Progression (p = 0.0012). Furthermore, the early increase at second day, in RANK-positive CTCs (Positive-Slope) was associated with delay in time-to-first-SRE (p = 0.0038) and Time-to-Bone-Metastasis-Progression (p = 0.0024). We demonstrate, for the first time, the expression of RANK on CTCs in MBC patients and that the persistence of RANK expression determines denosumab effectiveness.


Assuntos
Neoplasias da Mama , Denosumab/administração & dosagem , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Proteínas de Neoplasias/sangue , Células Neoplásicas Circulantes/metabolismo , Ligante RANK/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/sangue , Neoplasias da Mama/tratamento farmacológico , Feminino , Humanos , Pessoa de Meia-Idade , Metástase Neoplásica , Projetos Piloto
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