Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 1.505
Filtrar
1.
Gynecol Oncol ; 153(3): 639-650, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30928020

RESUMO

OBJECTIVE: To test whether platelets could increase invasion potential and initiate EMT in ovarian cancer cells via a TGF-ß signaling pathway. METHODS: Blood samples were collected in 69 patients with ovarian cancer, 16 patients with benign ovarian tumor and 64 healthy donors. SK-OV-3 and OVCAR-3 ovarian cancer cells were treated with platelets. Transwell assays were used to analyze the invasive capacity, and EMT was assessed by microarray analysis, quantitative real-time PCR (qPCR) and Western blotting. Activation of TGF-ß pathway was examined by ELISA and Western blotting. TGF-ß type I receptor (TßR I) inhibitor A83-01 was used to confirm the role of TGF-ß pathway in vitro and in vivo. RESULTS: Clinical data showed ovarian cancer patients with elevated platelet counts had a higher incidence of advanced stages. Treatment with platelets increased the invasive properties of both cell lines. Mesenchymal markers (snail family transcriptional repressor-1, vimentin, neural cadherin, fibronectin-1 and matrix metalloproteinase-2) were up-regulated in platelet-treated cells, while the epithelial marker (epithelial cadherin) was down-regulated. Higher TGF-ß level was observed in patients with elevated platelet counts when compared to the subjects. Higher levels of TGF-ß were also found in culture medium treated with platelets, and cells treated with platelets also showed increased phosphorylation of Smad2. TßR I inhibitor A83-01 reversed the EMT-like alterations and inhibited platelet-induced invasion in vitro and in vivo. CONCLUSION: Platelet increased invasion potential and induced EMT in ovarian cancer cells in a TGF-ß dependent pathway. Platelet-derived TGF-ß may be useful as a new target treatment for ovarian cancer.


Assuntos
Plaquetas , Transição Epitelial-Mesenquimal , Neoplasias Ovarianas/sangue , Fator de Crescimento Transformador beta/metabolismo , Adulto , Animais , Caderinas/genética , Caderinas/metabolismo , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Técnicas de Cocultura , Transição Epitelial-Mesenquimal/genética , Feminino , Fibronectinas/genética , Expressão Gênica , Voluntários Saudáveis , Humanos , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 2 da Matriz/metabolismo , Camundongos , Pessoa de Meia-Idade , Invasividade Neoplásica , Transplante de Neoplasias , Neoplasias Ovarianas/patologia , Contagem de Plaquetas , Pirazóis/farmacologia , Receptor do Fator de Crescimento Transformador beta Tipo I/antagonistas & inibidores , Transdução de Sinais , Proteínas Smad/metabolismo , Fatores de Transcrição da Família Snail/genética , Tiossemicarbazonas/farmacologia , Fator de Crescimento Transformador beta/sangue , Regulação para Cima , Vimentina/genética
2.
Transl Res ; 210: 8-25, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30953609

RESUMO

Type 1 diabetes (T1D) is a chronic metabolic disease of unknown etiology that results from ß-cell destruction. The onset of the disease, which arises after a long asymptomatic period of autoimmune attack, may be followed by a relapsing and remitting progression, a phenomenon that is most evident during the partial remission phase (PR). This stage lasts for a few months, shows minor requirements of exogenous insulin and could be explained by a recovery of immunological tolerance. This study aims to identify new biomarkers at early stages of pediatric T1D that reflect immunoregulatory changes. To that end, pediatric patients with T1D (n = 52) and age-related control subjects (n = 30) were recruited. Immune response-related molecules and lymphocyte subsets were determined starting at T1D onset and until the second year of progression. Results showed that circulating TGF-ß levels decreased during PR, and that betatrophin concentration was increased in all the considered stages without differing among studied checkpoints. Moreover, an increase of regulatory T, B and NK subsets was found during T1D progression, probably reflecting an attempt to restore self-tolerance. By contrast, a reduction in monocyte levels was observed at the early stages of diabetes. The results reveal significant changes in immunological parameters during the different early stages of T1D in children, which could ultimately serve as potential biomarkers to characterize the progression of T1D.


Assuntos
Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 1/patologia , Proteínas Semelhantes a Angiopoietina/sangue , Biomarcadores/sangue , Índice de Massa Corporal , Estudos de Casos e Controles , Criança , Diabetes Mellitus Tipo 1/sangue , Progressão da Doença , Feminino , Humanos , Memória Imunológica , Subpopulações de Linfócitos/metabolismo , Masculino , Monócitos/metabolismo , Hormônios Peptídicos/sangue , Projetos Piloto , Indução de Remissão , Fator de Crescimento Transformador beta/sangue
3.
Clin Exp Rheumatol ; 37(6): 963-975, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30943147

RESUMO

OBJECTIVES: The aim of the study was to explore whether TGF-ß and IL-6 gene polymorphisms may be associated with SLE and assess the frequency of HLA-DRB1 alleles in Polish systemic lupus erythematosus (SLE) patients. METHODS: 216 SLE patients and 552 healthy individuals were examined for TGF-ß rs1800469 and rs1800470 by TaqMan SNP genotyping assay and for and IL-6(rs2069827 and rs1800795 using the PCR- RFLP method. RESULTS: An increased frequency of TT genotype and T allele of the TGF ß -509 C/T was found in SLE patients (p=0.02). The TGF-ß 869 C allele was more frequent in SLE patients. The genotype-phenotype analysis showed association between the TGF ß -509 C/T and mean value of CRP, ESR, haemoglobin, APTT, Pt and INR (p=0.05, p=0.03, p<0.001, p=0.03, p=0.03 and p=0.05, respectively) as well as anti-SSA and anti-Sm presence (p=0.04 and p=0.03, respectively); the TGF- ß 869 T/C and mean value of APTT and INR (p=0.01 and p=0.05, respectively); the IL-6 -174 G/C and SLICC (p=0.05), anti-SSA (p=0.05) and anti-SSB (p=0.05). A higher TGF-ß and IL-6 serum level were found in SLE patients compared to controls (both p<0.0001). In SLE patients with the TGF-ß -509 TT genotype have shown positive association with the TGF-ß serum levels. Polish SLE patients have strong positive association with HLA-DRB1*52.1, and negative with the HLA-DRB1*07:01 allele. HLA-DRB1*52.1 was also associated with higher TGF-ß serum levels in the Polish population. CONCLUSIONS: Our results suggested that the TGF ß -509 C/T variant may be considered as a genetic marker for SLE in the Polish population.


Assuntos
Interleucina-6 , Lúpus Eritematoso Sistêmico , Polimorfismo Genético , Fator de Crescimento Transformador beta , Alelos , Estudos de Casos e Controles , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Cadeias HLA-DRB1 , Humanos , Interleucina-6/sangue , Interleucina-6/genética , Lúpus Eritematoso Sistêmico/genética , Polônia , Fator de Crescimento Transformador beta/sangue , Fator de Crescimento Transformador beta/genética
4.
J Cancer Res Ther ; 15(Supplement): S135-S139, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30900635

RESUMO

Context: There are plenty of evidence that suggest that the potential high doses of radiation result in severe health effects to exposed individuals, although there is no consensus about the health impact of low dose of ionizing radiation (IR). Aims: This study aimed to discuss the effect a range of IR doses on the changes of gene expression and serum protein levels of two immune factors transforming growth factor-ß (TGF-ß) and interferon gamma (IFN-γ) in rats. Findings from this study can be useful to develop a suitable biomarker for biological dosimetry applications. Subjects and Methods: After 24 h of irradiation of rats with the doses of 1000, 500, 100, 50, and 20 mGy, the gene expression of TGF-ß and IFN-γ in lymphocytes was assessed using quantitative polymerase chain reaction. Besides, the protein level of these two factors in blood plasma was determined by enzyme-linked immunosorbent assay (ELISA) kits. Statistical Analysis Used: One-way analysis of variance Tukey-Kramer Multiple Comparisons Test was used. P <0.05 was considered statistically significant. Results: Significant increases in the expression levels of TGF-ß and IFN-γ genes were observed by increasing the dose from 100 to 500 mGy and then 1000 mGy compared to the control (P < 0.05). The ELISA tests showed significant differences in the serum level of TGF-ß cytokine in the dose of 1000 mGy, while the serum level of IFN-γ cytokine showed significant differences in doses of 20 mGy and 1000 mGy compared to the control (P < 0.05). Conclusions: The results of this study showed the changes in the expression of TGF-ß and IFN-γ genes after irradiation more than 100 mGy in lymphocytes compared to the control group; the changes in the serum levels of these cytokines only occurred in the specific doses compared to the control group.


Assuntos
Raios gama/efeitos adversos , Regulação da Expressão Gênica/efeitos da radiação , Interferon gama/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Irradiação Corporal Total/efeitos adversos , Animais , Biomarcadores/sangue , Biomarcadores/metabolismo , Relação Dose-Resposta à Radiação , Exposição Ambiental/efeitos adversos , Interferon gama/sangue , Linfócitos/metabolismo , Linfócitos/efeitos da radiação , Masculino , Modelos Animais , Exposição Ocupacional/efeitos adversos , Ratos , Fator de Crescimento Transformador beta/sangue
5.
Nutrients ; 11(3)2019 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-30841605

RESUMO

Glomerular fibrosis is caused by an accumulation of intercellular spaces containing mesangial matrix proteins through either diffused or nodular changes. Dianthus superbus has been used in traditional medicine as a diuretic, a contraceptive, and an anti-inflammatory agent. The aim of this study was to investigate the effects of Dianthus superbus-EtOAc soluble fraction (DS-EA) on glomerular fibrosis and renal dysfunction, which has been implicated in diabetic nephropathy in human renal mesangial cells and db/db mice. DS-EA was administered to db/db mice at 10 or 50 mg/kg/day for 8 weeks. DS-EA treatment significantly ameliorated blood glucose, insulin, the homeostasis model assessment of insulin resistance (HOMA-IR) index, and HbA1c in diabetic mice. DS-EA decreased albumin excretion, creatinine clearance (Ccr), and plasma creatinine levels. DS-EA also ameliorated the levels of kidney injury molecules-1 (KIM-1) and C-reactive protein. DS-EA reduced the periodic acid-Schiff (PAS) staining intensity and basement membrane thickening in glomeruli of the diabetic nephropathy model. In addition, DS-EA suppressed transforming growth factor-ß (TGF-ß)/Smad signaling. Collagen type IV, a glomerular fibrosis biomarker, was significantly decreased upon DS-EA administration. DS-EA pretreatment attenuated levels of inflammation factors such as intracellular cell adhesion molecule-1 (ICAM-1) and monocyte chemoattractant protein-1 (MCP-1). DS-EA inhibited the translocation of nuclear factor kappa B (NF-κB) in Angiotensin II (Ang II)-stimulated mesangial cells. These findings suggest that DS-EA has a protective effect against renal inflammation and fibrosis. Therefore, DS-EA may serve as a potential therapeutic agent targeting glomerulonephritis and glomerulosclerosis, which lead to diabetic nephropathy.


Assuntos
Nefropatias Diabéticas/tratamento farmacológico , Dianthus , Fitoterapia , Extratos Vegetais/farmacologia , Substâncias Protetoras/farmacologia , Animais , Glicemia/efeitos dos fármacos , Quimiocina CCL2/sangue , Colágeno Tipo IV/sangue , Diabetes Mellitus Experimental/complicações , Nefropatias Diabéticas/sangue , Nefropatias Diabéticas/etiologia , Modelos Animais de Doenças , Fibrose , Humanos , Inflamação , Insulina/sangue , Resistência à Insulina/fisiologia , Molécula 1 de Adesão Intercelular/sangue , Rim/efeitos dos fármacos , Rim/patologia , Rim/fisiopatologia , Células Mesangiais , Camundongos , Transdução de Sinais , Fator de Crescimento Transformador beta/sangue
6.
BMC Immunol ; 20(1): 10, 2019 03 04.
Artigo em Inglês | MEDLINE | ID: mdl-30832584

RESUMO

BACKGROUND: Previously, we demonstrated up-regulated activated CD4+ and CD8+ T lymphocytes as well as up-regulated cytotoxic NK cells in the blood of patients with idiopathic recurrent miscarriage. In the present study, we tried to identify deficiencies in counter-regulating immune mechanisms of these patients. METHOD: Cytokines were determined in NK cells and in plasma samples of 35 healthy controls, 33 patients with idiopathic recurrent miscarriage, 34 patients with end stage renal disease, 10 transplant patients early and 37 transplant patients late post-transplant using flow-cytometry and luminex. In addition, cytokines were studied in supernatants of cell cultures with peripheral blood mononuclear cells stimulated in-vitro with tumor cell line K562. RESULTS: Patients with idiopathic recurrent miscarriage exhibited the highest absolute cell counts of circulating TGFß1+ NK, NKT and T lymphocytes and the lowest TGFß1 plasma levels of all study groups (for all p < 0.050). In-vitro, peripheral blood mononuclear cells of patients with idiopathic recurrent miscarriage showed high spontaneous TGFß1 production that could not be further increased by stimulation with K562, indicating increased consumption of TGFß1 by activated cells in the cell culture. Moreover, patients with idiopathic recurrent miscarriage had abnormally high IL4+ as well as abnormally high IFNy+ NK cells (p < 0.010) but similar IL10+ NK cell numbers as female healthy controls and showed the lowest plasma levels of IL10, TGFß3, IL1RA, IL1ß, IL5, IL6, IL8, IL17, TNFα, GM-CSF, TPO and VEGF and the highest plasma levels of G-CSF, FGF-basic, CCL3 and CXCL5 as compared to female HC and female transplant recipients (for all p < 0.050). CONCLUSIONS: Patients with idiopathic recurrent miscarriage show an activated immune system that can hardly be stimulated further and cannot be efficiently down-regulated by up-regulated TGFß1+ and IL4+ NK, NKT and T lymphocytes which are present concomitantly in these patients. The strongly decreased TGFß and IL10 plasma levels indicate deficient down-regulation and reflect a dysbalance of the immune system in patients with idiopathic recurrent miscarriage. These findings may be relevant for explaining the pathogenesis of idiopathic recurrent miscarriage.


Assuntos
Aborto Habitual/sangue , Aborto Habitual/imunologia , Células Matadoras Naturais/imunologia , Contagem de Linfócitos , Células T Matadoras Naturais/imunologia , Subpopulações de Linfócitos T/imunologia , Fator de Crescimento Transformador beta/sangue , Biomarcadores , Citocinas/metabolismo , Feminino , Citometria de Fluxo , Humanos , Imunofenotipagem , Células Matadoras Naturais/metabolismo , Células T Matadoras Naturais/metabolismo , Receptores de Citocinas/metabolismo , Subpopulações de Linfócitos T/metabolismo
7.
Scand J Immunol ; 89(4): e12754, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30729559

RESUMO

Regulatory T cells (Tregs) play a critical role in the maintenance of a pregnancy. While the kinetics of the number of peripheral blood Tregs has been satisfactorily described in mouse models, analysis of these cell populations in human pregnancy is complicated by high variability in the quantity of Tregs and inconsistencies in the markers used for detecting different types of Treg. In the light of this, we set out to investigate the kinetics of various types of Treg, including CD45RA, GARP and PD-1(+) Tregs, in the peripheral blood of pregnant women in the first, second and third trimester, and at the time of delivery. Tregs, defined as a CD4(+)CD25(++)CD127(dim)Foxp3(+) population of leucocytes, were detected using flow cytometry. Natural thymus-derived Tregs and induced Tregs in the peripheral blood were distinguished by the expression or absence of a Helios marker, respectively. Our results showed that during normal pregnancy the sizes of various Treg subpopulations varied across women and also in an individual woman did not remain constant but varied significantly, most notable being the decrease observed at the time of delivery. Helios(-) cells were significantly less frequent in the peripheral blood of healthy pregnant women than Helios(+) cells, and the majority of Tregs were Helios(+)PD-1(+) Tregs.


Assuntos
Gravidez/imunologia , Subpopulações de Linfócitos T/imunologia , Linfócitos T Reguladores/imunologia , Timo/imunologia , Diferenciação Celular , Células Cultivadas , Feminino , Citometria de Fluxo , Fatores de Transcrição Forkhead/metabolismo , Voluntários Saudáveis , Humanos , Fator de Transcrição Ikaros/metabolismo , Imunofenotipagem , Contagem de Linfócitos , Fator de Crescimento Transformador beta/sangue
8.
Clin Transl Oncol ; 21(10): 1343-1347, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30788838

RESUMO

OBJECTIVE: In this study, we aimed to discuss the clinical significance of CD4+CD25hiCD127low regulatory T cells (Tregs) in the peripheral blood of patients with non-small cell lung cancer (NSCLC). METHODS: Sixty patients with NSCLC and 35 healthy controls were studied. Peripheral blood CD4+CD25hiCD127lowTregs, CD4+CD25hiT cells, and CD4+T cells were measured with flow cytometric analysis, and results were compared between the groups. RESULTS: Compared with healthy people, CD4+CD25hiCD127low Tregs and CD4+CD25hi T cells significantly increased in patients with NSCLC, while CD4+ T cell proportions decreased. CONCLUSIONS: CD4+CD25 hi CD127low Treg detection in the peripheral blood of NSCLC patients is highly significant, in that it provides additional knowledge to guide the selection of individualized treatment plans for patients with NSCLC.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/sangue , Neoplasias Pulmonares/sangue , Linfócitos T Reguladores , Linfócitos T CD4-Positivos , Carcinoma Pulmonar de Células não Pequenas/imunologia , Estudos de Casos e Controles , Feminino , Citometria de Fluxo , Humanos , Interleucina-10/sangue , Neoplasias Pulmonares/imunologia , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Fator de Crescimento Transformador beta/sangue , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral
9.
Front Immunol ; 10: 65, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30800121

RESUMO

Background: Immunosenescence contributes to reduced vaccine response in elderly persons, and is worsened by deficiencies in nutrients such as Vitamin (Vit-D). The immune system is a well-known target of Vit-D, which can both potentiate the innate immune response and inhibit the adaptive system, and so modulate vaccination response. Objective: This randomized placebo-controlled double-blind trial investigated whether Vit-D supplementation in deficient elderly persons could improve influenza seroprotection and immune response. Design: Deficient volunteers (Vit-D serum <30 ng/mL) were assigned (V1) to receive either 100,000 IU/15 days of cholecalciferol (D, n = 19), or a placebo (P, n = 19), over a 3 month period. Influenza vaccination was performed at the end of this period (V2), and the vaccine response was evaluated 28 days later (V3). At each visit, serum cathelicidin, immune response to vaccination, plasma cytokines, lymphocyte phenotyping, and phagocyte ROS production were assessed. Results: Levels of serum 25-(OH)D increased after supplementation (D group, V1 vs. V2: 20.7 ± 5.7 vs. 44.3 ± 8.6 ng/mL, p < 0.001). No difference was observed for serum cathelicidin levels, antibody titers, and ROS production in D vs. P groups at V3. Lower plasma levels of TNFα (p = 0.040) and IL-6 (p = 0.046), and higher ones for TFGß (p = 0.0028) were observed at V3. The Th1/Th2 ratio was lower in the D group at V2 (D: 0.12 ± 0.05 vs. P: 0.18 ± 0.05, p = 0.039). Conclusions: Vit-D supplementation promotes a higher TGFß plasma level in response to influenza vaccination without improving antibody production. This supplementation seems to direct the lymphocyte polarization toward a tolerogenic immune response. A deeper characterization of metabolic and molecular pathways of these observations will aid in the understanding of Vit-D's effects on cell-mediated immunity in aging. This clinical trial was registered at clinicaltrials.gov as NCT01893385.


Assuntos
Vacinas contra Influenza/imunologia , Influenza Humana/imunologia , Orthomyxoviridae/fisiologia , Células Th1/imunologia , Células Th2/imunologia , Deficiência de Vitamina D/imunologia , Vitamina D/administração & dosagem , Idoso , Suplementos Nutricionais , Método Duplo-Cego , Feminino , Humanos , Tolerância Imunológica , Masculino , Efeito Placebo , Equilíbrio Th1-Th2 , Fator de Crescimento Transformador beta/sangue , Vacinação
10.
PLoS One ; 14(1): e0209158, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30650075

RESUMO

INTRODUCTION: Epoxyeicosatrienoic acids (EETs) are able to enhance angiogenesis and regulate inflammation that is especially important in wound healing under ischemic conditions. Thus, we evaluated the effect of local EET application on ischemic wounds in mice. METHODS: Ischemia was induced by cautherization of two of the three supplying vessels to the mouse ear. Wounding was performed on the ear three days later. Wounds were treated either with 11,12 or 14,15 EET and compared to untreated control and normal wounds. Epithelialization was measured every second day. VEGF, TNF-α, TGF-ß, matrix metalloproteinases (MMP), tissue inhibitors of metalloproteinases (TIMP), Ki67, and SDF-1α were evaluated immunohistochemically in wounds on day 3, 6, and 9. RESULTS: Ischemia delayed wound closure (12.8 days ± 1.9 standard deviation (SD) for ischemia and 8.0 days ± 0.94 SD for control). 11,12 and14,15 EET application ameliorated deteriorated wound healing on ischemic ears (7.6 ± 1.3 SD for 11,12 EET and 9.2 ± 1.4 SD for 14,15 EET). Ischemia did not change VEGF, TNF-α, TGF-ß, SDF-1α, TIMP, MMP7 or MMP9 level significantly compared to control. Local application of 11,12 as well as 14,15 EET induced a significant elevation of VEGF, TGF-ß, and SDF-1α expression as well as proliferation during the whole phase of wound healing compared to control and ischemia alone. CONCLUSION: In summary, EET improve impaired wound healing caused by ischemia as they enhance neovascularization and alter inflammatory response in wounds. Thus elevating lipid mediator level as 11,12 and 14,15 EET in wounds might be a successful strategy for amelioration of deranged wound healing under ischemia.


Assuntos
Eicosanoides/uso terapêutico , Isquemia/tratamento farmacológico , Cicatrização/efeitos dos fármacos , Animais , Quimiocina CXCL12/sangue , Modelos Animais de Doenças , Isquemia/sangue , Metaloproteinase 7 da Matriz/sangue , Metaloproteinase 9 da Matriz/sangue , Camundongos , Inibidor Tecidual de Metaloproteinase-1/sangue , Fator de Crescimento Transformador beta/sangue , Fator de Necrose Tumoral alfa/sangue , Fator A de Crescimento do Endotélio Vascular/sangue
11.
Nanomedicine ; 16: 34-44, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30529791

RESUMO

Glucocorticosteroids are the most efficacious anti-inflammatory agents and the gold standard treatment in Duchenne muscular dystrophy (DMD). However, their chronic use may lead to severe side effects. We evaluated the use of a novel injectable steroidal nano-drug in mdx mouse model of DMD by comparing the efficacy of nano-liposomes remotely loaded with the steroid prodrug, methylprednisolone hemisuccinate (MPS) with the same steroid as-is, in short (4-weeks) and long-term (58-weeks) treatments. Liposomal-MPS was selectively targeted to the mouse diaphragm, the most dystrophic muscle at early stage of the disease. The bioactivity of the steroidal nano-drug was evidenced by a significant decreased serum TGF-ß and reduced diaphragm macrophage infiltration after short-term treatment. In the long-term, the treatment with liposomal-MPS not only demonstrated improved muscle strength and mobility it also induced lower tibia and lumbar vertebrae osteoporosis indicating much lower bone related adverse effects.


Assuntos
Lipossomos/química , Distrofia Muscular de Duchenne/tratamento farmacológico , Esteroides/uso terapêutico , Animais , Creatina Quinase/metabolismo , Modelos Animais de Doenças , Imuno-Histoquímica , Inflamação/sangue , Inflamação/tratamento farmacológico , Masculino , Camundongos , Camundongos Endogâmicos mdx , Força Muscular/efeitos dos fármacos , Distrofia Muscular de Duchenne/sangue , Esteroides/química , Fator de Crescimento Transformador beta/sangue
12.
J Med Virol ; 91(2): 265-271, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-29611873

RESUMO

Indoleamine-2,3-dioxygenase (IDO) is an enzyme that catalyzes tryptophan to kynurenine and studies have revealed that IDO play a vital role in regulation of liver immunity and inflammation activities. This study investigated the association between plasma IDO and disease severity and the possible marker role of IDO in the inflammatory process of hepatitis C. In this study, 80 individuals with HCV infection were retrospectively selected. Plasma levels of IDO, IL-10, and TGF-ß were assayed by ELISA. Clinical characteristics of patients, including the levels of ALT, AST, and total bilirubin (TBil) were collected from clinical databases. HCV-related liver cirrhosis (HC-Cirr) and HCV-related Hepatocellular carcinoma (HCV-HCC) had significantly high plasma levels of IDO compared to other patient groups and healthy controls. Plasma IL-10 level were significantly greater in all chronic liver disease groups and with respect to TGF-ß, the level was high in all the selected patients with HCV infection compare with controls. Moreover, HCV-HCC patients showed highest values for both IL-10 and TGF-ß, with significant difference compared with other groups. In addition, plasma IDO was positively correlated with TGF-ß among all patients with HCV infection (r = 0.4509, P < 0.0001), with IL-10 in CHC patients (r = 0.4787, P = 0.0047), with TBil in HCV-Cirr patients (r = 0.4671; P = 0.0093). High level of IDO and TGF-ß is associated with hepatocyte necrosis and intrahepatic inflammation, and may be used as an index of disease progression for patients with chronic HCV infection.


Assuntos
Carcinoma Hepatocelular/patologia , Hepatite C Crônica/patologia , Indolamina-Pirrol 2,3,-Dioxigenase/sangue , Interleucina-10/sangue , Cirrose Hepática/patologia , Neoplasias Hepáticas/patologia , Fator de Crescimento Transformador beta/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Alanina Transaminase/sangue , Aspartato Aminotransferases/sangue , Bilirrubina/sangue , Ensaio de Imunoadsorção Enzimática , Feminino , Hepatite C Crônica/complicações , Humanos , Cirrose Hepática/complicações , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
13.
Clin Exp Hypertens ; 41(5): 434-443, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30192645

RESUMO

Pitavastatin inhibits 3 hydroxy 3 methyl glutaryl coenzyme A (HMGCoA) reductase enzyme, preventing cholesterol synthesis along with elevating high density apolipoprotein A1 (Apo-A1). The present study was designed to evaluate cardioprotective potential of pitavastatin at 1 mg/kg/day and 3 mg/kg/day dose for 14 days in low dose isoproterenol (ISO) (5 mg/kg/day for 7 consecutive days) induced myocardial damage. ISO administration induced significant reduction in endogenous antioxidant enzymes like reduced glutathione (GSH), superoxide dismutase (SOD), catalase (CAT) and raised thiobarbituric acid reactive substances (TBARS) indicating activated lipid peroxidation. Along with this, a significant increase in level of cardiac injury biomarkers vie, creatine kinase (CK-MB), lactate dehydrogenase (LDH), aspartate amino transferase (AST), tumor necrosis factor (TNF-α) and transforming growth factor (TGF-ß) as well as brain natriuretic peptide (BNP). Histological examination also revealed marked myocardial tissue damage in ISO treated rats. However, pretreatment with pitavastatin (3 mg/kg/day) significantly maintained nearly normal levels of cardiac biomarkers and oxidant antioxidant status as well as lipid peroxidation in ISO induced MI rats. Cardiac histological assessment and infarct size assessment also showed marked reduction in myocardial architecture alteration including infarct size as well as collagen deposition by pitavastatin that strongly supported biochemical findings. These observations strongly corroborate that pitavastatin prevents myocardial damages via up regulation of endogenous oxidants along with its hypocholesterolemic activity.


Assuntos
Radicais Livres/metabolismo , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Infarto do Miocárdio/sangue , Infarto do Miocárdio/patologia , Miocárdio/patologia , Quinolinas/uso terapêutico , Animais , Antioxidantes/farmacologia , Aspartato Aminotransferases/sangue , Catalase/metabolismo , Colágeno/metabolismo , Creatina Quinase Forma MB/sangue , Glutationa/metabolismo , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Inflamação/sangue , Inflamação/prevenção & controle , Isoproterenol , L-Lactato Desidrogenase/sangue , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Infarto do Miocárdio/induzido quimicamente , Peptídeo Natriurético Encefálico/sangue , Quinolinas/administração & dosagem , Ratos , Ratos Wistar , Superóxido Dismutase/metabolismo , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismo , Fator de Crescimento Transformador beta/sangue , Fator de Necrose Tumoral alfa/sangue
14.
Eur J Gastroenterol Hepatol ; 31(1): 43-46, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30134384

RESUMO

BACKGROUND: We sought to explore the interplay of multiple serum biomarkers of fibrosis and extracellular matrix remodeling with the results of liver histology in patients with nonalcoholic fatty liver disease (NAFLD). PATIENTS AND METHODS: Venous blood samples were collected from 80 patients with biopsy-proven NAFLD and 59 age-matched and sex-matched healthy controls. Serum levels of transforming growth factor (TGF)-ß1, TGF-ß2, matrix metalloproteinases (MMP)-1, MMP-2, MMP-7, MMP-9, MMP-10, tissue inhibitors of metalloproteinase (TIMP)-1, and TIMP-2 were determined by using the Luminex MagPix technology on a MAGPIX analyzer. RESULTS: We documented significant differences in the levels of TGF-ß1, TGF-ß2, MMP-2, MMP-7, MMP-9, TIMP-1, and TIMP-2 between NAFLD patients and controls. However, none of these biomarkers was able to distinguish between nonalcoholic steatohepatitis and nonalcoholic fatty liver. TIMP-1 levels were significantly higher in patients with significant fibrosis (fibrosis stage ≥2; 2624±1261 pg/ml) than in those without (fibrosis stage 0-1; 2096±906 pg/ml; P=0.03). Moreover, serum levels of TIMP-1 were identified as the only independent predictor of histological fibrosis (ß=0.298, t=2.7, P=0.007). CONCLUSION: Our study provides insights into the association of multiple serum biomarkers of fibrosis and extracellular matrix remodeling with NAFLD histology. Notably, serum levels of TIMP-1 were identified as a clinically useful marker for distinguishing NAFLD patients with and without significant fibrosis.


Assuntos
Matriz Extracelular/metabolismo , Cirrose Hepática/sangue , Fígado/metabolismo , Hepatopatia Gordurosa não Alcoólica/sangue , Inibidor Tecidual de Metaloproteinase-1/sangue , Adulto , Biomarcadores/sangue , Biópsia , Estudos de Casos e Controles , Matriz Extracelular/patologia , Feminino , Humanos , Fígado/patologia , Cirrose Hepática/etiologia , Cirrose Hepática/patologia , Masculino , Metaloproteinases da Matriz/sangue , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/patologia , Valor Preditivo dos Testes , Fator de Crescimento Transformador beta/sangue , Regulação para Cima
15.
Can J Cardiol ; 34(12): 1606-1612, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30527148

RESUMO

BACKGROUND: Patients with acute coronary syndrome show an inflammatory response that is known to affect platelet aggregation. We aimed to clarify the relationship between the inflammation severity and the effect of antiplatelet therapy after percutaneous coronary intervention (PCI) for ST-elevation myocardial infarction (STEMI). METHODS: This retrospective, single-center study included 203 patients with STEMI who underwent primary PCI and were stratified on the basis of the antiplatelet therapy on admission (clopidogrel vs ticagrelor). Inflammation levels were defined as low, intermediate, and high, based on the tertiles of the distribution of high-specificity C-reactive protein levels pre-PCI. Platelet aggregation function during hospitalization and follow-up was quantified as residual adenosine diphosphate-induced platelet reactivity on light transmittance aggregometry. Inflammation markers were measured on admission and at 1 year post-PCI. RESULTS: At intermediate and high levels of inflammation, residual adenosine diphosphate-induced platelet aggregation was significantly higher among clopidogrel users than among ticagrelor users. In the clopidogrel group, statistically significant differences in platelet aggregation function were observed among the 3 levels of inflammation. At 1 year post-PCI, ticagrelor users had significantly lower levels of interleukin-1ß and higher levels of interleukin-35 and transforming growth factor-ß. CONCLUSION: At different inflammation levels, ticagrelor provides more potent platelet inhibition than clopidogrel, suggesting that ticagrelor might exert a more stable antiplatelet effect at higher levels of systemic inflammation. Furthermore, ticagrelor is associated with reduced indices of inflammation on follow-up after PCI, suggesting that anti-inflammatory effects might play a role in the clinical benefit observed with antiplatelet therapy, which would provide an additional rationale for using ticagrelor in patients with STEMI undergoing primary PCI.


Assuntos
Clopidogrel/uso terapêutico , Intervenção Coronária Percutânea , Agregação Plaquetária/efeitos dos fármacos , Infarto do Miocárdio com Supradesnível do Segmento ST/terapia , Ticagrelor/uso terapêutico , Biomarcadores/sangue , Proteína C-Reativa/análise , Feminino , Humanos , Interleucina-1beta/sangue , Interleucinas/sangue , Masculino , Pessoa de Meia-Idade , Inibidores da Agregação de Plaquetas/uso terapêutico , Estudos Retrospectivos , Infarto do Miocárdio com Supradesnível do Segmento ST/sangue , Fator de Crescimento Transformador beta/sangue , Fator de Necrose Tumoral alfa/sangue
16.
BMC Musculoskelet Disord ; 19(1): 434, 2018 Dec 06.
Artigo em Inglês | MEDLINE | ID: mdl-30522483

RESUMO

BACKGROUND: Axial spondyloarthritis (axSpA) is characterized by significant bone loss caused by dysregulation of physiological bone turnover, possibly resulting from intensified differentiation of osteoclasts. The aim of this study was to reevaluate the levels of osteoclastogenesis-mediating factors: soluble RANKL, M-CSF, OPG and other cytokines in sera of untreated, with sDMARDs and/or bDMARDs, axSpA patients and to test whether these sera influence differentiation of healthy monocytes towards osteoclast lineage. METHODS: Bone remodeling molecules (RANKL, M-CSF, OPG, IL-6, OSM, IL-17A, TGFß, and TNFα) were evaluated in 27 patients with axSpA and 23 age and sex-matched controls. Disease activity (BASDAI, ASDAS) and inflammatory markers (ESR, CRP) were assessed. Monocytes obtained from healthy individuals were cultured in vitro in presence of sera from 11 randomly chosen axSpA patients and 10 controls, with addition of exogenous M-CSF and/or RANKL or without. Osteoclastic differentiation was assessed analyzing osteoclast markers (cathepsin K and RANK at mRNA level) and with osteoclast-specific staining. RESULTS: axSpA patients' sera levels of soluble RANKL were significantly lower and M-CSF, IL-6, OSM, IL-17A and TNFα significantly higher in comparison to controls, whereas of OPG and TGFß were comparable in both groups. Numbers of generated in vitro osteoclasts and cathepsin K mRNA levels did not differ between cultures supplemented with sera of healthy and axSpA patients, both in the absence and presence of M-CSF. Instead, addition of exogenous RANKL boosted osteoclastogenesis, which was significantly higher in cultures with axSpA sera. Furthermore, sera from axSpA patients induced substantially higher levels of RANK mRNA, independently of M-CSF and RANKL stimulation. CONCLUSION: We show that, paradoxically, serum levels of soluble RANKL observed in axSpA are in fact significantly lower in comparison to healthy blood donors. Our results indicate that sera of axSpA patients - in contrary to healthy subjects - contain circulating, soluble factors (presumably IL-6, OSM, IL-17A, TNFα and others) able to stimulate healthy monocytes responsiveness to even relative low RANKL serum levels, by inducing high RANK mRNA expression and - as a net effect - boosting their osteoclastogenic potential. We suggest also that locally produced RANKL in axSpA may induce overactive osteoclasts from their precursors.


Assuntos
Monócitos/fisiologia , Osteogênese/fisiologia , Ligante RANK/sangue , Espondilartrite/sangue , Adulto , Biomarcadores/sangue , Catepsina K/sangue , Diferenciação Celular , Células Cultivadas , Citocinas/sangue , Feminino , Humanos , Interleucina-17/sangue , Fator Estimulador de Colônias de Macrófagos/sangue , Masculino , Osteoclastos/citologia , Osteoprotegerina/sangue , RNA Mensageiro/sangue , Fosfatase Ácida Resistente a Tartarato/sangue , Fator de Crescimento Transformador beta/sangue , Fator de Necrose Tumoral alfa/sangue , Regulação para Cima
17.
JCI Insight ; 3(22)2018 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-30429363

RESUMO

BACKGROUND: Inflammation helps regulate normal growth and tissue repair. Although bone morphogenetic proteins (BMPs) and inflammation are known contributors to abnormal bone formation, how these pathways interact in ossification remains unclear. METHODS: We examined this potential link in patients with fibrodysplasia ossificans progressiva (FOP), a genetic condition of progressive heterotopic ossification caused by activating mutations in the Activin A type I receptor (ACVR1/ALK2). FOP patients show exquisite sensitivity to trauma, suggesting that BMP pathway activation may alter immune responses. We studied primary blood, monocyte, and macrophage samples from control and FOP subjects using multiplex cytokine, gene expression, and protein analyses; examined CD14+ primary monocyte and macrophage responses to TLR ligands; and assayed BMP, TGF-ß activated kinase 1 (TAK1), and NF-κB pathways. RESULTS: FOP subjects at baseline without clinically evident heterotopic ossification showed increased serum IL-3, IL-7, IL-8, and IL-10. CD14+ primary monocytes treated with the TLR4 activator LPS showed increased CCL5, CCR7, and CXCL10; abnormal cytokine/chemokine secretion; and prolonged activation of the NF-κB pathway. FOP macrophages derived from primary monocytes also showed abnormal cytokine/chemokine secretion, increased TGF-ß production, and p38MAPK activation. Surprisingly, SMAD phosphorylation was not significantly changed in the FOP monocytes/macrophages. CONCLUSIONS: Abnormal ACVR1 activity causes a proinflammatory state via increased NF-κB and p38MAPK activity. Similar changes may contribute to other types of heterotopic ossification, such as in scleroderma and dermatomyositis; after trauma; or with recombinant BMP-induced bone fusion. Our findings suggest that chronic antiinflammatory treatment may be useful for heterotopic ossification.


Assuntos
Receptores de Ativinas Tipo I/sangue , Inflamação/complicações , Miosite Ossificante/complicações , NF-kappa B/sangue , Ossificação Heterotópica/etiologia , Quimiocinas/sangue , Citocinas/sangue , Humanos , Inflamação/sangue , Macrófagos/metabolismo , Monócitos/metabolismo , Miosite Ossificante/sangue , Miosite Ossificante/imunologia , Ossificação Heterotópica/sangue , Ossificação Heterotópica/imunologia , Transdução de Sinais , Fator de Crescimento Transformador beta/sangue , Proteínas Quinases p38 Ativadas por Mitógeno/sangue
18.
PLoS One ; 13(10): e0205329, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30356307

RESUMO

BACKGROUND: Myocardial infarction is the most common cause of heart failure. MI has been intricately linked to ventricular remodeling, subsequently leading to the reduction in the cardiac ejection fraction causing HF. The cumulative line of evidence suggests an important role of several biomarkers in modulating the cardiac vasculature, further contributing towards the progression of post-MI complications. Studies have demonstrated, yet not fully established, that an important biomarker, IL-10, has a causal relationship with MI and associated cardiac dysfunction. HYPOTHESIS: This study aims to establish the role of IL-10 as a prognostic marker for the cardiovascular outcomes and to develop a panel of biomarkers and circulating miRNAs that could potentially result in the early detection of HF resulting from MI, allowing for early intervention strategies. METHODS AND RESULTS: Blood was withdrawn and echocardiography assessment was performed on a total of 43 patients that were enrolled, within 24 hours of the incidence of MI. Patients were divided in three main groups, based on the ejection fraction measurement from echocardiography: control (n = 14), MI with normal EF (MI+NEF, n = 13) and MI with low EF (MI+LEF, n = 16). Our results showed that TGFß-1, TNF-α, IL-6 and MMP-9 were upregulated significantly in MI+NEF group and more so in MI+LEF group, as compared to control group (p<0.01). The circulating levels of miR-34a, miR-208b and miR-126 were positively correlated and showed elevated levels in the MI+NEF group, even higher in MI+LEF group, while levels of miR-24 and miR-29a were reduced in MI+NEF, and much lower in MI+LEF, as compared to the control group (p<0.01). Our results also demonstrated a direct correlation of IL-10 with the ejection fraction in patients with MI: IL-10 was elevated in MI+NEF group, however, the levels were significantly low in MI+LEF group suggesting an important role of IL-10 in predicting heart failure. Importantly, our study confirmed the correlation of IL-10 with EF by our follow-up echocardiography assessment that was performed 2 months after the incidence of MI. CONCLUSION: Our results support the clinical application of these serum biomarkers to develop a panel for appropriate prognosis and management of adverse cardiac remodeling and development of heart failure post-myocardial infarction.


Assuntos
Biomarcadores/sangue , Insuficiência Cardíaca/sangue , Interleucina-10/sangue , Infarto do Miocárdio/sangue , Idoso , Ecocardiografia , Feminino , Regulação da Expressão Gênica/genética , Insuficiência Cardíaca/diagnóstico por imagem , Insuficiência Cardíaca/epidemiologia , Insuficiência Cardíaca/patologia , Humanos , Interleucina-10/genética , Masculino , Metaloproteinase 9 da Matriz/sangue , MicroRNAs/sangue , Pessoa de Meia-Idade , Infarto do Miocárdio/diagnóstico por imagem , Infarto do Miocárdio/genética , Infarto do Miocárdio/patologia , Prognóstico , Volume Sistólico/genética , Fator de Crescimento Transformador beta/sangue , Fator de Necrose Tumoral alfa/sangue , Função Ventricular Esquerda/genética , West Virginia/epidemiologia
19.
J Interferon Cytokine Res ; 38(10): 457-462, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30328796

RESUMO

The study aimed to determine effect of extremely low frequency (50 Hz) electromagnetic fields (ELF-EMFs) exposure on serum levels of interleukin-17 (IL-17) and transforming growth factor-ß (TGF-ß) as signature cytokines of Th17 and regulatory T (Treg) cells, respectively. Retinoid-related orphan receptor γT and transcription factor forkhead box P3 (Foxp3) expression levels as lineage defining of Th17 and Treg cells were also assessed in the spleen and thymus. Eighty male rats were separated into 4 exposed groups (1, 100, 500, and 2,000 µT magnetic flux intensities) and a control. All rats were immunized by human serum albumin after 1 month of the exposure and the experiment was continued in the same manner for 1 month more. The results demonstrated that the weight of thymuses was significantly declined at intensity of 2,000 µT. At the preimmunization phase, the serum levels of IL-17 and TGF-ß were significantly decreased at intensities of 1 and 100 µT. The expression of Foxp3 was also downregulated at intensities of 1 and 100 µT. In conclusion, low intensities of ELF-EMF may reduce the serum levels of IL-17 and TGF-ß and downregulate the expression of Foxp3 in spleen.


Assuntos
Regulação para Baixo , Campos Eletromagnéticos , Fatores de Transcrição Forkhead/biossíntese , Interleucina-17/sangue , Baço/metabolismo , Fator de Crescimento Transformador beta/sangue , Animais , Fatores de Transcrição Forkhead/genética , Humanos , Masculino , Ratos , Ratos Wistar , Reação em Cadeia da Polimerase em Tempo Real , Albumina Sérica Humana/metabolismo
20.
Acta Biomed ; 89(3): 365-369, 2018 10 08.
Artigo em Inglês | MEDLINE | ID: mdl-30333460

RESUMO

BACKGROUND AND AIM: Nowadays there is a strong necessity in identifying patients who may be exposed to the risk for future cardiovascular events like progressive atherosclerotic disease. Biomarkers are valuable tools for this purpose. Coronary artery calcification (CAC) is utilized as an important tool for the global risk assessment of cardiovascular events in individuals with intermediate risk. Decorin (DCN) is a small leucine-rich proteoglycan that induces calcification of arterial smooth muscle cell and localizes to mineral deposition in human atherosclerotic plaque. The main purpose of this clinical study was to find out the correlation between Decorin serum concentration and CAC in human for the first time. METHODS: In this study 84 patients with coronary artery disease who fulfilled inclusion and exclusion criteria, entered the study. For all patients a questionnaire consisting demographic data and traditional cardiovascular risk factors were completed. CT-Angiography was carried out to determine coronary artery calcium score and ELISA method was used for measuring DCN serum concentrations. RESULTS: No significant correlation between DCN serum concentration and total CAC score and also CAC of left anterior descending, right coronary artery, left main coronary artery and circumflex was found in the study population (P>0.05). CONCLUSIONS: On the basis of our results DCN serum concentration is not a suitable biomarker of coronary artery disease. However, more studies with higher sample size are necessary for its confirmation.


Assuntos
Doença da Artéria Coronariana/diagnóstico , Decorina/sangue , Idoso , Biomarcadores , Calcinose/sangue , Calcinose/diagnóstico , Comorbidade , Angiografia por Tomografia Computadorizada , Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/diagnóstico por imagem , Feminino , Humanos , Lipídeos/sangue , Masculino , Pessoa de Meia-Idade , Isquemia Miocárdica/prevenção & controle , Projetos Piloto , Fatores de Risco , Inquéritos e Questionários , Fator de Crescimento Transformador beta/sangue
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA