RESUMO
BACKGROUND: Human T-lymphotropic virus 1 (HTLV-1) is etiologically associated with the chronic inflammatory neurodegenerative disease HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) Annexin A1 (AnxA1) is an anti-inflammatory protein with proposed neuroprotective and anti-neuroinflammatory functions. We hypothesized that ANXA1 gene expression may be dysregulated in HTLV-1-infected HAM/TSP patients. METHODS: This study involved 37 individuals infected with HTLV-1, including 21 asymptomatic (AS) carriers and 16 with HAM/TSP, and a control group of 30 individuals negative for HTLV-1 and HTLV-2. For AS HTLV-1-positive and HAM/TSP patients, ANXA1 and formyl peptide receptor (FPR1, FPR2 and FPR3) expression and HTLV-1 proviral load (PVL) in peripheral blood cells were evaluated by real-time quantitative PCR (qPCR), and plasma AnxA1 levels were determined by enzyme-linked immunosorbent assay (ELISA). RESULTS: ANXA1 gene expression was increased in the AS group compared with the HAM/TSP and control groups, but the differences were not statistically significant. FPR1 gene expression was higher in patients with HTLV-1 than in controls (AS, p = 0.0032; HAM/TSP, p < 0.0001). Plasma AnxA1 levels were higher in the AS group than in the HAM/TSP group (p = 0.0045), and PVL was higher in patients with HAM/TSP than in AS individuals (p = 0.0162). The use of a combined ROC curve using Annexin 1 levels and proviral load significantly increased the sensitivity and specificity to predict progression to HAM/TSP (AUC = 0.851 and AUC = 0.937, respectively, to AUC = 1000). CONCLUSIONS: Our results suggest that AnxA1 may be dysregulated in HAM/TSP patients. Serological detection of AnxA1 in association with proviral load may provide a prognostic biomarker for HTLV-1-associated neurodegenerative disease.
Assuntos
Anexina A1/sangue , Vírus Linfotrópico T Tipo 1 Humano/isolamento & purificação , Paraparesia Espástica Tropical/diagnóstico , Adulto , Anexina A1/genética , Biomarcadores/sangue , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Paraparesia Espástica Tropical/sangue , Paraparesia Espástica Tropical/virologia , Prognóstico , Curva ROC , Sensibilidade e Especificidade , Carga ViralRESUMO
Chronic inflammation contributes to neuronal death in Alzheimer's disease (AD) and frontotemporal dementia (FTD). Here we evaluated inflammatory and pro-resolving mediators in AD and behavioural variant of FTD (bvFTD) patients compared with controls, since neuroinflamamtion is a common feature in both diseases. Ninety-eight subjects were included in this study, divided into AD (nâ¯=â¯32), bvFTD (nâ¯=â¯30), and control (nâ¯=â¯36) groups. The levels of hsCRP, IL-1ß, IL-6, TNF, and TGF-ß1, as well as annexin A1 (AnxA1) and lipoxin A4 (LXA4) were measured in blood and cerebrospinal fluid (CSF). The expression profile of AnxA1 was evaluated in peripheral blood mononuclear cells (PBMCs) as well the distribution of ANXA1 rs2611228 polymorphism. We found reduced peripheral levels of hsCRP and TNF in AD compared with bvFTD patients and controls, and increased levels of TGF-ß1 in AD compared to controls. Moreover, reduced plasma levels of AnxA1 were observed in bvFTD compared to AD and controls. There was a significant cleavage of AnxA1 in PBMCs in both dementia groups. The results suggest differential regulation of inflammatory and pro-resolving mediators in bvFTD and AD, while AnxA1 cleavage may impair pro-resolving mechanisms in both groups.
Assuntos
Doença de Alzheimer/metabolismo , Anexina A1/metabolismo , Citocinas/metabolismo , Demência Frontotemporal/metabolismo , Lipoxinas/metabolismo , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/imunologia , Anexina A1/sangue , Anexina A1/líquido cefalorraquidiano , Citocinas/sangue , Citocinas/líquido cefalorraquidiano , Diagnóstico Diferencial , Feminino , Demência Frontotemporal/imunologia , Genótipo , Voluntários Saudáveis , Humanos , Inflamação , Lipoxinas/sangue , Lipoxinas/líquido cefalorraquidiano , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Preeclampsia (PE) is a disease characterized by excessive maternal inflammatory response. Early studies suggested that brain-derived neurotrophic factor (BDNF) modulates inflammation. The main objective of this study was to investigate BDNF plasma concentrations in PE women and to compare with BDNF concentrations from normotensive pregnant women. We also investigated the association among the plasma concentrations of BDNF and inflammatory mediators, and maternal clinical features. METHODS: BDNF plasma concentrations were measured by ELISA in 38 PE women (17 early onset and 21 late onset) and in 20 normotensive pregnant women (Norm) matched for gestational age (Norm<34weeks: n=8; Norm≥34weeks: n=12). Correlation analyses between laboratory parameters and clinical characteristics were evaluated through Spearman's coefficients. RESULTS: BDNF concentration was lower in PE women than in normotensive pregnant women, but no difference was detected between the subgroups of PE women and normotensive pregnant women. BDNF correlated negatively with annexin A1, and positively with body mass index and diastolic blood pressure. No correlation was significant in normotensive pregnant women. CONCLUSIONS: Lower BDNF plasma concentrations and cross-talk between BDNF and AnxA1 signaling pathways might be involved in PE pathogenesis.
Assuntos
Fator Neurotrófico Derivado do Encéfalo/sangue , Pré-Eclâmpsia/sangue , Adulto , Anexina A1/sangue , Feminino , Humanos , Pré-Eclâmpsia/patologia , Gravidez , Receptores Tipo I de Fatores de Necrose Tumoral/sangue , Transdução de Sinais , Adulto JovemRESUMO
Sickle cell disease (SCD) is an inherited hemolytic anemia whose pathophysiology is driven by polymerization of the hemoglobin S (Hb S), leading to hemolysis and vaso-occlusive events. Inflammation is a fundamental component in these processes and a continuous inflammatory stimulus can lead to tissue damages. Thus, pro-resolving pathways emerge in order to restore the homeostasis. For example there is the annexin A1 (ANXA1), an endogenous anti-inflammatory protein involved in reducing neutrophil-endothelial interactions, accelerating neutrophil apoptosis and stimulating macrophage efferocytosis. We investigated the expression of ANXA1 in plasma of SCD patients and its relation with anemic, hemolytic and inflammatory parameters of the disease. Three SCD genotypes were considered: the homozygous inheritance for Hb S (Hb SS) and the association between Hb S and the hemoglobin variants D-Punjab (Hb SD) and C (Hb SC). ANXA1 and proinflammatory cytokines were quantified by ELISA in plasma of SCD patients and control individuals without hemoglobinopathies. Hematological and biochemical parameters were analyzed by flow cytometry and spectrophotometer. The plasma levels of ANXA1 were about three-fold lesser in SCD patients compared to the control group, and within the SCD genotypes the most elevated levels were found in Hb SS individuals (approximately three-fold higher). Proinflammatory cytokines were higher in SCD groups than in the control individuals. Anemic and hemolytic markers were higher in Hb SS and Hb SD genotypes compared to Hb SC patients. White blood cells and platelets count were higher in Hb SS genotype and were positively correlated to ANXA1 levels. We found that ANXA1 is down-regulated and differentially expressed within the SCD genotypes. Its expression seems to depend on the inflammatory, hemolytic and vaso-occlusive characteristics of the diseased. These data may lead to new biological targets for therapeutic intervention in SCD.
Assuntos
Anemia Falciforme/sangue , Anemia Falciforme/genética , Anexina A1/sangue , Anexina A1/genética , Regulação para Baixo , Adolescente , Adulto , Anemia Falciforme/complicações , Anemia Falciforme/imunologia , Biomarcadores/sangue , Criança , Feminino , Genótipo , Hemoglobina Falciforme/genética , Hemólise , Homozigoto , Humanos , Inflamação/complicações , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
BACKGROUND: Preeclampsia (PE) is a pregnancy disease associated with exacerbated inflammatory response. Annexin A1 (AnxA1) is a glucocorticoid-regulated protein endowed with anti-inflammatory and proresolving properties that has been much studied in various animal models of inflammation but poorly studied in the context of human inflammatory diseases. The main objective of this study was to measure AnxA1 levels in PE women and to compare those levels in normotensive pregnant and non-pregnant women. We evaluated the association among AnxA1, ultrasensitive C reactive protein (us-CRP) and soluble tumor necrosis factor alpha receptor type 1 (sTNF-R1) plasma levels of the study participants. METHODS: This study included 40 non-pregnant, 38 normotensive pregnant and 51 PE women. PE women were stratified in early (N = 23) and late (N = 28) subgroups, according to gestational age (GA) at onset of clinical symptoms. Protein AnxA1 and us-CRP plasma levels were determined by ELISA and immunoturbidimetric assays, respectively. Transcript levels of AnxA1 in peripheral blood mononuclear cells (PBMC) were measured by real time RT-PCR. RESULTS: Increased levels of AnxA1 coincided with higher us-CRP levels in the plasma of PE women. Pregnant women with early PE had higher levels of AnxA1 and us-CRP than normotensive pregnant women with GA <34 weeks. No significant difference was found for AnxA1 and us-CRP, comparing late PE and normotensive pregnant women with GA ≥ 34 weeks. AnxA1 mRNA levels in PBMC were similar among the studied groups. AnxA1 was positively correlated with sTNF-R1, but not with us-CRP. CONCLUSIONS: Our data show that increased AnxA1 levels were associated with a systemic inflammatory phenotype in PE, suggesting AnxA1 deregulation in PE pathogenesis. However, more studies are needed to clarify the role of AnxA1 and other proresolving molecules in the context of the systemic inflammatory response in this intriguing disease.
Assuntos
Anexina A1/sangue , Pré-Eclâmpsia/sangue , Adulto , Anexina A1/genética , Proteína C-Reativa/metabolismo , Feminino , Idade Gestacional , Humanos , Gravidez , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores Tipo I de Fatores de Necrose Tumoral/sangue , Adulto JovemRESUMO
BACKGROUND: Development of inflammatory bowel disease (IBD) involves the interplay of environmental and genetic factors with the host immune system. Mechanisms contributing to immune dysregulation in IBD are not fully defined. Development of novel therapeutic strategies is focused on controlling aberrant immune response in IBD. Current IBD therapy utilizes a combination of immunomodulators and biologics to suppress pro-inflammatory effectors of IBD. However, the role of immunomodulatory factors such as annexin A1 (ANXA1) is not well understood. The goal of this study was to examine the association between ANXA1 and IBD, and the effects of anti-TNF-α, Infliximab (IFX), therapy on ANXA1 expression. METHODS: ANXA1 and TNF-α transcript levels in PBMC were measured by RT PCR. Clinical follow up included the administration of serial ibdQs. ANXA1 expression in the gut mucosa was measured by IHC. Plasma ANXA1 levels were measured by ELISA. RESULTS: We found that the reduction in ANXA1 protein levels in plasma coincided with a decrease in the ANXA1 mRNA expression in peripheral blood of IBD patients. ANXA1 expression is upregulated during IFX therapy in patients with a successful intervention but not in clinical non-responders. The IFX therapy also modified the cellular immune activation in the peripheral blood of IBD patients. Decreased expression of ANXA1 was detected in the colonic mucosa of IBD patients with incomplete resolution of inflammation during continuous therapy, which correlated with increased levels of TNF-α transcripts. Gut mucosal epithelial barrier disruption was evident by increased plasma bacterial 16S levels. CONCLUSION: Loss of ANXA1 expression may support inflammation during IBD and can serve as a biomarker of disease progression. Changes in ANXA1 levels may be predictive of therapeutic efficacy.
Assuntos
Anexina A1/genética , Anexina A1/metabolismo , Doença de Crohn/metabolismo , Progressão da Doença , Regulação da Expressão Gênica , Adulto , Idoso , Anexina A1/sangue , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Doença de Crohn/sangue , Doença de Crohn/tratamento farmacológico , Doença de Crohn/imunologia , DNA Bacteriano/sangue , DNA Ribossômico/sangue , Feminino , Humanos , Inflamação/genética , Inflamação/metabolismo , Infliximab , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Ativação Linfocitária/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Resultado do Tratamento , Fator de Necrose Tumoral alfa/genética , Adulto JovemRESUMO
Several studies have been suggesting annexin A1 protein as an active player in tumorigenesis of many organs. Nevertheless, its tumor biomarker role has been mainly studied in tissues by immunohistochemistry or cell culture. Hence, in this investigation, the peripheral blood from 27 oral squamous cell carcinoma (OSCC) patients and 25 negative control individuals were examined by quantitative real-time PCR. Down-regulated ANXA1 expression at mRNA level was observed in OSCC samples (p=0.026). Significantly diminished mRNA levels correlated to age, sex and the anatomical site of the tumor lesion were observed. Moreover, the ROC curve analysis revealed the performance of ANXA1 expression as a suitable biomarker for patients with oral cavity cancer, especially those with 60years of age or older and/or women. For the first time, ANXA1 mRNA is revealed as blood-based biomarker, and its adoption for complementary non-invasive diagnosis of OSCC is suggested. These results suggest that, beyond the anti-inflammatory function, annexin A1 may also play a tumor suppressor role in peripheral blood cells, such as leukocytes.