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1.
Invest Ophthalmol Vis Sci ; 61(5): 62, 2020 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-32462202

RESUMO

Purpose: Fibrosis or scarring is a pathological outcome of wound healing and is characterized by terminally differentiated myofibroblasts. Heavy chain-hyaluronic acid/pentraxin 3 (HC-HA/PTX3) is a unique matrix component purified from amniotic membrane that exerts an anti-inflammatory effect. Herein, we investigate whether HC-HA/PTX3 can also exert an antiscarring effect. Methods: Human corneal fibroblasts and myofibroblasts were seeded on plastic, immobilized HA or HC-HA/PTX3 or on plastic with or without soluble HA and HC-HA/PTX3 in DMEM+10% FBS, with or without AMD3100 or SB431542 in DMEM+ITS with or without transforming growth factor-ß1 (TGF-ß1). Transcript expression of keratocyte and signaling markers was determined by RT-qPCR. Immunostaining was performed to monitor cytolocalization of signaling markers and α-SMA. Western blotting was used to measure relative protein level. Results: Human corneal fibroblasts and myofibroblasts cultured in or on HC-HA/PTX3, but not HA, were refrained from cytoplasmic expression of αSMA and nuclear translocation of pSMAD2/3 when challenged with exogenous TGF-ß1. Such an antiscarring action by suppressing canonical TGF-ß1 signaling was surprisingly accompanied by phenotypic reversal to keratocan-expressing keratocytes through activation of BMP signaling. Further investigation disclosed that such phenotypic reversal was initiated by cell aggregation mediated by SDF1-CXCR4 signaling highlighted by nuclear translocation of CXCR4 and upregulation of CXCR4 transcript and protein followed by activation of canonical BMP signaling. Conclusions: These findings collectively provide mechanistic understanding explaining how amniotic membrane transplantation exerts an antiscarring action. In addition, HC-HA/PTX3 and derivatives may be developed into a new biologic to treat corneal blindness caused by stromal scar or opacity in the future.


Assuntos
Proteínas Morfogenéticas Ósseas/fisiologia , Proteína C-Reativa/isolamento & purificação , Proteína C-Reativa/fisiologia , Diferenciação Celular , Córnea/citologia , Ceratócitos da Córnea/citologia , Fibroblastos/citologia , Ácido Hialurônico/fisiologia , Miofibroblastos/citologia , Componente Amiloide P Sérico/isolamento & purificação , Componente Amiloide P Sérico/fisiologia , Âmnio/química , Humanos , Transdução de Sinais
2.
J Minim Invasive Gynecol ; 27(2): 541-547, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31479751

RESUMO

STUDY OBJECTIVE: To evaluate the clinical parameters of hospitalized patients with pelvic inflammatory disease (PID) for the presence of tubo-ovarian abscess (TOA) and predict the need for intervention. DESIGN: A prospective cohort study. SETTING: A tertiary care university medical center. PATIENTS: Ninety-four patients were diagnosed with complicated PID and hospitalized between 2015 and 2017. INTERVENTIONS: Patients with PID were treated with parenteral antibiotics according to Centers for Disease Control guidelines. Demographic, clinical, sonographic, and laboratory data for patients with PID were analyzed. Inflammatory markers including C-reactive protein (CRP), white blood cells (WBCs), erythrocyte sedimentation rate (ESR), and clinical parameters were collected at admission and during hospitalization. MEASUREMENTS AND MAIN RESULTS: Forty-eight of 94 patients (51.1%) hospitalized with complicated PID were diagnosed with TOA sonographically. CRP levels were the strongest predictor of TOA, followed by WBC count, ESR, and fever on admission. The areas under the receiver operating characteristic (ROC) curve for CRP, WBC, ESR, and fever were .92, .75, .73 and .62, respectively. CRP specificity was 93.4% and sensitivity was 85.4% for predicting TOA, with cutoff value of 49.3 mg/L. Twelve patients (25%) failed conservative management and underwent surgical intervention including laparoscopy (n = 7), computed tomography (CT)-guided drainage (n = 4), and laparotomy (n = 1). In this group, CRP levels significantly increased from admission to day 1 and day 2 during hospitalization (128.26, 173.75, and 214.66 mg/L, respectively; p < .05 for both). In the conservative management group, CRP levels showed a plateau from admission to day 1 and then a decrease until day 3 (110, 120.49, 97.52, and 78.45 mg/L, respectively). CONCLUSION: CRP is a sensitive, specific inflammatory marker for predicting TOA in patients with complicated PID, and levels >49.3 mg/L suggest the presence of TOA. In the TOA group, CRP level trends correlated well with success or failure of conservative management. Increasing CRP levels during treatment may be used as an indicator of the need for invasive intervention, and daily CRP measurements can help predict the need for invasive intervention.


Assuntos
Abscesso/diagnóstico , Proteína C-Reativa/análise , Doenças das Tubas Uterinas/diagnóstico , Procedimentos Cirúrgicos em Ginecologia , Doenças Ovarianas/diagnóstico , Doença Inflamatória Pélvica/diagnóstico , Abscesso Abdominal/sangue , Abscesso Abdominal/diagnóstico , Abscesso Abdominal/cirurgia , Abscesso/sangue , Abscesso/complicações , Abscesso/cirurgia , Adulto , Biomarcadores/sangue , Proteína C-Reativa/fisiologia , Estudos de Coortes , Doenças das Tubas Uterinas/sangue , Doenças das Tubas Uterinas/complicações , Doenças das Tubas Uterinas/cirurgia , Feminino , Procedimentos Cirúrgicos em Ginecologia/métodos , Humanos , Laparotomia/métodos , Pessoa de Meia-Idade , Doenças Ovarianas/sangue , Doenças Ovarianas/complicações , Doenças Ovarianas/cirurgia , Doença Inflamatória Pélvica/sangue , Doença Inflamatória Pélvica/complicações , Doença Inflamatória Pélvica/cirurgia , Valor Preditivo dos Testes , Prognóstico , Estudos Prospectivos , Estudos Retrospectivos , Fatores de Risco , Sensibilidade e Especificidade
3.
Curr Pharm Des ; 26(1): 37-43, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31840602

RESUMO

C-reactive Protein (CRP) is an acute phase reactant, belonging to the pentraxin family of proteins. Its level rises up to 1000-fold in response to acute inflammation. High sensitivity CRP level is utilized as an independent biomarker of inflammation and cardiovascular disease. The accumulating data suggests that CRP has two distinct forms. It is predominantly produced in the liver in a native pentameric form (nCRP). At sites of local inflammation and tissue injury it may bind to phosphocholine-rich membranes of activated and apoptotic cells and their microparticles, undergoing irreversible dissociation to five monomeric subunits, termed monomeric CRP (mCRP). Through dissociation, CRP deposits into tissues and acquires distinct proinflammatory properties. It activates both classic and alternative complement pathways, binding complement component C1q and factor H. mCRP actively participates in the development of endothelial dysfunction. It activates leukocytes, inducing cytokine release and monocyte recruitment. It may also play a role in the polarization of monocytes and T cells into proinflammatory phenotypes. It may be involved in low-density lipoproteins (LDL) opsonization and uptake by macrophages. mCRP deposits were detected in samples of atherosclerotic lesions from human aorta, carotid, coronary and femoral arteries. mCRP may also induce platelet aggregation and thrombus formation, thus contributing in multiple ways in the development of atherosclerosis and atherothrombosis. In this mini-review, we will provide an insight into the process of conformational rearrangement of nCRP, leading to dissociation, and describe known effects of mCRP. We will provide a rationalization for mCRP involvement in the development of atherosclerosis and atherothrombosis.


Assuntos
Aterosclerose/fisiopatologia , Proteína C-Reativa/fisiologia , Trombose/fisiopatologia , Endotélio Vascular/fisiopatologia , Humanos , Inflamação/fisiopatologia , Lipoproteínas LDL
4.
Front Immunol ; 10: 2628, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31787987

RESUMO

The innate immune system is equipped with a number of germ-line encoded soluble pattern recognition molecules (PRMs) that collectively mediate the humoral host response to infection and damage in cooperation with cells and tissues of the immune and non-immune compartments. Despite the impressive diversity in structure, source, and regulation across PRMs, these all share remarkably similar functions inasmuch as they recognize microbes and damaged tissues, activate complement, exert opsono-phagocytic activities, and regulate inflammation. The long pentraxin 3 (PTX3) is a prototypic soluble PRM. Long known as a major player in innate immunity, inflammation and matrix remodeling, only recently has PTX3 emerged as a mediator of bone homeostasis in rodents and humans. Ptx3-targeted mice exhibit reduced trabecular volume during bone development, and impaired callus mineralization following experimental fracture. The murine gene is expressed in vivo by non-hematopoietic periosteal cells in the early phases of fracture healing, and in vitro by maturing osteoblasts. Human osteoblasts do express the PTX3 protein, whose levels positively correlate with bone density in vivo and osteoblast proliferation and maturation in vitro, thus pointing to a role in bone deposition. Contrasting evidence, however, suggest osteoclastogenesis-promoting effects of PTX3, where its expression has been associated with periodontitis, arthritis, and bone metastasis, conditions hallmarked by inflammation and bone resorption. Here, we review past and recent literature on the functions exerted by this long pentraxin in bone biology, with major emphasis on physiological skeletal remodeling, fracture healing, and chronic diseases of the bone.


Assuntos
Osso e Ossos/fisiologia , Proteína C-Reativa/fisiologia , Componente Amiloide P Sérico/fisiologia , Animais , Doenças Ósseas/metabolismo , Doenças Ósseas/patologia , Osso e Ossos/patologia , Proteína C-Reativa/genética , Doença Crônica , Consolidação da Fratura , Homeostase , Humanos , Componente Amiloide P Sérico/genética
5.
Psychoneuroendocrinology ; 109: 104388, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31398588

RESUMO

BACKGROUND: Chronotype influences several physiological systems, including the immune system and the hypothalamus-pituitary-adrenal (HPA)-axis. Previous research has shown that evening chronotype is associated with adverse metabolic health outcomes and obesity. However, the exact mechanisms underlying the observed differences in metabolic function between "morning" and "evening" types remain to be explored. OBJECTIVE: To investigate the relationship of chronotype with inflammatory and neuroendocrine stress markers and to explore their mediating and moderating roles in the association between chronotype and body mass index (BMI). METHODS: Twenty-eight healthy young adults (50% women), mean age 23.8 ±â€¯3.3 (SD) years, underwent a standardized laboratory stress test (Trier Social Stress Test, TSST). Concentrations of plasma C-reactive protein (CRP) at baseline and of salivary cortisol before and after the onset of the stressor were analyzed. Heart rate was measured continuously. Chronotype was assessed with the Morningness-Eveningness Questionnaire (MEQ). RESULTS: Lower MEQ scores (i.e. evening tendency) were associated with higher BMI (r = -.40, p < .05), elevated CRP concentrations (r = -.42, p < .05) and higher cortisol responses to acute stress (r = -.53, p < .01). The relationship between MEQ score and BMI was mediated by CRP concentrations (b = -0.03, CI 95%: -0.08 to -0.007, p < .05). In addition, we observed a moderating effect of the cortisol stress response on this mediated relationship (b = 0.005, CI 95%: 0.0002 to 0.01, p < .05), such that the mediated relationship was stronger in individuals with a higher cortisol response. CONCLUSION: Enhanced pro-inflammatory state and a higher cortisol response to stress may underlie the effect of evening chronotype on obesity risk and adverse metabolic health outcomes.


Assuntos
Ritmo Circadiano/fisiologia , Sono/fisiologia , Estresse Psicológico/metabolismo , Adulto , Índice de Massa Corporal , Proteína C-Reativa/metabolismo , Proteína C-Reativa/fisiologia , Feminino , Humanos , Hidrocortisona/metabolismo , Masculino , Obesidade/metabolismo , Fatores de Risco , Saliva/química , Inquéritos e Questionários , Adulto Jovem
6.
Medicina (Kaunas) ; 55(7)2019 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-31284487

RESUMO

Background and Objectives: Ischaemic stroke (IS) is the leading cause of death and disability worldwide. All stages of cerebral ischaemia, but especially acute phase, are associated with inflammatory response. Recent studies showed that neutrophil-to-lymphocyte ratio (NLR) and lymphocyte-to-monocyte ratio (LMR) may be used to assess inflammation in IS. To test whether there is a relationship between these parameters and type of stroke treatment, we analysed NLR and LMR in IS patients treated with three different modalities. Materials and Methods: The study included 58 adults with acute IS. A total of 28 patients received intravenous thrombolysis. In another 10 patients, the thrombolytic therapy was followed by thrombectomy and 20 patients did not undergo causal treatment. Blood samples were obtained within 24 h of the stroke diagnosis to calculate NLR and LMR. Next, NLR and LMR of the study subgroups were compared. Results: Our study revealed that NLR was significantly higher in patients treated with thrombectomy following thrombolysis, compared to no causal treatment. Statistical analysis demonstrated that patients with high National Institutes of Health Stroke Scale (NIHSS) scores presented higher NLR than in those with low NIHSS scores. Additionally, patients with high-sensitivity C-reactive protein (hs-CRP) ≥ 3 mg/L presented with significantly higher NLR and significantly lower LMR than the group of patients with lower hs-CRP (<3 mg/L). Conclusions: The main finding of this pilot study was that NLR in IS patients treated using thrombectomy following thrombolysis was markedly higher than that in other treatment groups, which was associated with increased severity of the disease in these patients. Therefore, patients with higher NLR may be expected to have more severe stroke. The link between stroke severity and NLR deserves further study.


Assuntos
Inflamação/classificação , Linfócitos/fisiologia , Monócitos/fisiologia , Neutrófilos/fisiologia , Acidente Vascular Cerebral/sangue , Idoso , Contagem de Células Sanguíneas/métodos , Isquemia Encefálica/sangue , Isquemia Encefálica/classificação , Proteína C-Reativa/análise , Proteína C-Reativa/fisiologia , Distribuição de Qui-Quadrado , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Polônia , Estudos Prospectivos , Índice de Gravidade de Doença , Acidente Vascular Cerebral/classificação
7.
Oncogene ; 38(30): 5873-5889, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31253871

RESUMO

Cutaneous melanoma is one of the most aggressive cancers characterized by a high plasticity, a propensity for metastasis, and drug resistance. Melanomas are composed of phenotypically diverse subpopulations of tumor cells with heterogeneous molecular profiles that reflect intrinsic invasive abilities. In an attempt to identify novel factors of the melanoma invasive cell state, we previously investigated the nature of the invasive secretome by using a comparative proteomic approach. Here, we have extended this analysis to show that PTX3, an acute phase inflammatory glycoprotein, is one such factor secreted by invasive melanoma to promote tumor cell invasiveness. Elevated PTX3 production was observed in the population of MITFlow invasive cells but not in the population of MITFhigh differentiated melanoma cells. Consistently, MITF knockdown increased PTX3 expression in MITFhigh proliferative and poorly invasive cells. High levels of PTX3 were found in tissues and blood of metastatic melanoma patients, and in BRAF inhibitor-resistant melanoma cells displaying a mesenchymal invasive MITFlow phenotype. Genetic silencing of PTX3 in invasive melanoma cells dramatically impaired migration and invasion in vitro and in experimental lung extravasation assay in xenografted mice. In contrast, addition of melanoma-derived or recombinant PTX3, or expression of PTX3 enhanced motility of low migratory cells. Mechanistically, autocrine production of PTX3 by melanoma cells triggered an IKK/NFκB signaling pathway that promotes migration, invasion, and expression of the EMT factor TWIST1. Finally, we found that TLR4 and MYD88 knockdown inhibited PTX3-induced melanoma cell migration, suggesting that PTX3 functions through a TLR4-dependent pathway. Our work reveals that tumor-derived PTX3 contributes to melanoma cell invasion via targetable inflammation-related pathways. In addition to providing new insights into the biology of melanoma invasive behavior, this study underscores the notion that secreted PTX3 represents a potential biomarker and therapeutic target in a subpopulation of MITFlow invasive and/or refractory melanoma.


Assuntos
Proteína C-Reativa/fisiologia , Melanoma/metabolismo , NF-kappa B/metabolismo , Metástase Neoplásica/fisiopatologia , Componente Amiloide P Sérico/fisiologia , Transdução de Sinais , Neoplasias Cutâneas/metabolismo , Receptor 4 Toll-Like/metabolismo , Animais , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral , Xenoenxertos , Humanos , Melanoma/patologia , Camundongos , Invasividade Neoplásica , Neoplasias Cutâneas/patologia , Regulação para Cima
8.
Infect Immun ; 87(8)2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31109949

RESUMO

Nontypeable Haemophilus influenzae (NTHi) colonizes the human upper respiratory tract without causing disease symptoms, but it is also a major cause of upper and lower respiratory tract infections in children and elderly, respectively. NTHi synthesizes various molecules to decorate its lipooligosaccharide (LOS), which modulates the level of virulence. The presence of phosphorylcholine (PCho) on NTHi LOS increases adhesion to epithelial cells, which is an advantage for the bacterium enabling nasopharyngeal colonization. However, when PCho is incorporated on the LOS of NTHi, it is recognized by the acute-phase C-reactive protein (CRP) and PCho-specific antibodies, both potent initiators of the classical pathway of complement activation. We determined the presence of PCho and binding of IgG and IgM to the bacterial surface for 319 NTHi strains collected from the nasopharynx/oropharynx, middle ear, and lower respiratory tract. PCho detection was higher for NTHi strains collected from the nasopharynx/oropharynx, which was associated with increased binding of IgM and IgG to the bacterial surface. Binding of CRP and IgM to the bacterial surface of PChohigh NTHi strains increased complement-mediated killing, which was largely dependent on PCho-specific IgM. The levels of PCho-specific IgM varied in sera from 12 healthy individuals, and higher PCho-specific IgM levels were associated with increased complement-mediated killing of a PChohigh NTHi strain. In conclusion, incorporation of PCho on the LOS of NTHi marks the bacterium for binding of CRP and IgM, resulting in complement-mediated killing. Therefore, having a lower PCho might be beneficial in situations where sufficient PCho-specific antibodies and complement are present.


Assuntos
Proteína C-Reativa/fisiologia , Proteínas do Sistema Complemento/imunologia , Citotoxicidade Imunológica , Haemophilus influenzae/imunologia , Imunoglobulina M/fisiologia , Fosforilcolina/metabolismo , Aderência Bacteriana , Humanos , Lipopolissacarídeos/metabolismo , Nasofaringe/microbiologia , Orofaringe/microbiologia
9.
Cell Death Dis ; 10(3): 217, 2019 03 04.
Artigo em Inglês | MEDLINE | ID: mdl-30833544

RESUMO

Accumulating evidence from clinical and epidemiological studies has highlighted the close correlation between the individual risk of cancer and nervous system diseases. The expression of neuronal pentraxin 2 (NPTX2) is absent in Alzheimer's disease, anxiety, and depression. Herein, we found that NPTX2 mRNA and protein expression was significantly upregulated in colorectal carcinoma (CRC). NPTX2 expression level gradually increased with CRC progression and was closely associated with poor prognosis. In vitro and in vivo studies demonstrated that NPTX2 promoted CRC proliferation and metastasis through the activation of the Wnt/ß-catenin signaling pathway. As NPTX2 receptors are absent on CRC cells, NPTX2 was shown to physically interact with frizzled class receptor 6 (FZD6) to promote ß-catenin translocation into the cell nucleus, resulting in an increase in the expression of MYC, cyclin D1, snail, and N-cadherin along with a decrease in the expression of E-cadherin. Knockdown of FZD6 expression with a small-interfering RNA almost completely reversed the proliferative effects of NPTX2 on CRC development. In conclusion, NPTX2, a molecule related to nervous system diseases, promotes CRC cell proliferation and metastasis through the activation of the Wnt/ß-catenin pathway via direct interaction with FZD6.


Assuntos
Proteína C-Reativa/fisiologia , Neoplasias Colorretais/patologia , Receptores Frizzled/metabolismo , Neoplasias Hepáticas/secundário , Proteínas do Tecido Nervoso/fisiologia , Via de Sinalização Wnt , Proteína C-Reativa/metabolismo , Neoplasias Colorretais/metabolismo , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Proteínas do Tecido Nervoso/metabolismo , Regulação para Cima
10.
Front Immunol ; 10: 240, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30858847

RESUMO

Pentraxin-3 (PTX3) and C-reactive protein (CRP) have been shown to regulate complement activation in vitro, but their role has not been investigated in complement consumption in vivo. Thrombotic microangiopathies (TMA) are often accompanied by complement overactivation and consumption, therefore we analyzed the relation of the systemic pentraxin levels to the complement profile, laboratory parameters and clinical outcome of TMA patients. We determined the PTX3 and CRP levels, complement factor and activation product concentrations in blood samples of 171 subjects with the diagnosis of typical hemolytic uremic syndrome (STEC-HUS) (N = 34), atypical HUS (aHUS) (N = 44), secondary TMA (N = 63), thrombotic thrombocytopenic purpura (TTP) (N = 30) and 69 age-matched healthy individuals. Clinical data, blood count and chemistry were collected from medical records. To determine the in vitro effect of PTX3 on alternative pathway (AP) activation, sheep red blood cell-based hemolytic assay and AP activity ELISA were used. We found that PTX3 levels were elevated in the acute phase of STEC-HUS, aHUS and secondary TMA, whereas PTX3 elevation was exceptional is TTP. Conversely, a significantly higher median CRP was present in all patient groups compared to controls. PTX3, but not CRP was associated with signs of complement consumption in vivo, and PTX3 significantly decreased the AP hemolytic activity in vitro. Our results provide a detailed description of acute phase-TMA patients' complement profile linked to changes in the systemic pentraxin levels that may support further molecular studies on the function of PTX3 in disease pathogenesis and add to the laboratory assessment of complement consumption in TMA.


Assuntos
Proteína C-Reativa/análise , Ativação do Complemento , Componente Amiloide P Sérico/análise , Microangiopatias Trombóticas/imunologia , Adolescente , Adulto , Síndrome Hemolítico-Urêmica Atípica/imunologia , Proteína C-Reativa/fisiologia , Criança , Via Alternativa do Complemento , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Púrpura Trombocitopênica Trombótica/imunologia , Componente Amiloide P Sérico/fisiologia , Microangiopatias Trombóticas/mortalidade , Adulto Jovem
11.
Clin Nutr ; 38(3): 996-1011, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30314925

RESUMO

BACKGROUND & AIM: The results of studies about the effect of soy products on serum highly sensitive C-reactive protein (hs-CRP) are inconsistent. The aim of this systematic review and meta-analysis of randomized clinical trials (RCTs) was to investigate the effect of soy products intake on serum hs-CRP concentration. METHODS: We searched PubMed, EMBASE, Science Direct, ISI Web of Science, Google Scholar and Cochrane Central Register of Controlled Trials up to December 2016 without language restrictions. Random-effect model was used for quantitative data synthesis. RESULTS: Thirty-six studies were included in our analyses. A meta-analysis revealed a non-significant reduction in serum hs-CRP concentrations following soy products consumption, -0.19 (mg/L) (95% CI: -0.49 to 0.09; I2 = 95.6%). Subgroup analyses suggested that natural soya products may reduce plasma levels of CRP by -0.18 mg/L (95% CI: -0.28 to -0.08; I2: 11.6) in comparison to other source of isoflavones (soya extracts, supplements). Moreover, the effect was stronger among subjects with baseline hs-CRP concentrations of less than 2.52 mg/L, -0.15 (95% CI: -0.27 to -0.02; I2: 34.6). A meta-regression analysis revealed that dosage of isoflavones seems to be a strong predictor of the effect of soya on serum hs-CRP levels. CONCLUSION: Present review of RCTs published up to December 2016 did not provide strong evidence regarding the beneficial effect of soya products consumption on blood hs-CRP concentrations. However, it appears that natural soya products may reduce plasma levels of hs-CRP in comparison to other source of isoflavones. Large and well-designed studies are recommended to confirm this conclusion. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42018069371.


Assuntos
Proteína C-Reativa , Isoflavonas , Alimentos de Soja , Soja , Adulto , Idoso , Proteína C-Reativa/análise , Proteína C-Reativa/metabolismo , Proteína C-Reativa/fisiologia , Feminino , Humanos , Inflamação/metabolismo , Masculino , Pessoa de Meia-Idade , Adulto Jovem
12.
Osteoarthritis Cartilage ; 27(1): 118-128, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30248505

RESUMO

OBJECTIVE: C-reactive protein (CRP) levels can be elevated in osteoarthritis (OA) patients. In addition to indicating systemic inflammation, it is suggested that CRP itself can play a role in OA development. Obesity and metabolic syndrome are important risk factors for OA and also induce elevated CRP levels. Here we evaluated in a human CRP (hCRP)-transgenic mouse model whether CRP itself contributes to the development of 'metabolic' OA. DESIGN: Metabolic OA was induced by feeding 12-week-old hCRP-transgenic males (hCRP-tg, n = 30) and wild-type littermates (n = 15) a 45 kcal% high-fat diet (HFD) for 38 weeks. Cartilage degradation, osteophytes and synovitis were graded on Safranin O-stained histological knee joint sections. Inflammatory status was assessed by plasma lipid profiling, flow cytometric analyses of blood immune cell populations and immunohistochemical staining of synovial macrophage subsets. RESULTS: Male hCRP-tg mice showed aggravated OA severity and increased osteophytosis compared with their wild-type littermates. Both classical and non-classical monocytes showed increased expression of CCR2 and CD86 in hCRP-tg males. HFD-induced effects were evident for nearly all lipids measured and indicated a similar low-grade systemic inflammation for both genotypes. Synovitis scores and synovial macrophage subsets were similar in the two groups. CONCLUSIONS: Human CRP expression in a background of HFD-induced metabolic dysfunction resulted in the aggravation of OA through increased cartilage degeneration and osteophytosis. Increased recruitment of classical and non-classical monocytes might be a mechanism of action through which CRP is involved in aggravating this process. These findings suggest interventions selectively directed against CRP activity could ameliorate metabolic OA development.


Assuntos
Artrite Experimental/etiologia , Proteína C-Reativa/fisiologia , Dieta Hiperlipídica/efeitos adversos , Osteoartrite/etiologia , Animais , Artrite Experimental/imunologia , Artrite Experimental/metabolismo , Artrite Experimental/patologia , Humanos , Metabolismo dos Lipídeos/fisiologia , Macrófagos/imunologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Monócitos/imunologia , Osteoartrite/imunologia , Osteoartrite/metabolismo , Osteoartrite/patologia , Osteófito/etiologia , Osteófito/fisiopatologia , Índice de Gravidade de Doença
13.
EMBO J ; 38(1)2019 01 03.
Artigo em Inglês | MEDLINE | ID: mdl-30396995

RESUMO

Control of synapse number and function in the developing central nervous system is critical to the formation of neural circuits. Astrocytes play a key role in this process by releasing factors that promote the formation of excitatory synapses. Astrocyte-secreted thrombospondins (TSPs) induce the formation of structural synapses, which however remain post-synaptically silent, suggesting that completion of early synaptogenesis may require a two-step mechanism. Here, we show that the humoral innate immune molecule Pentraxin 3 (PTX3) is expressed in the developing rodent brain. PTX3 plays a key role in promoting functionally-active CNS synapses, by increasing the surface levels and synaptic clustering of AMPA glutamate receptors. This process involves tumor necrosis factor-induced protein 6 (TSG6), remodeling of the perineuronal network, and a ß1-integrin/ERK pathway. Furthermore, PTX3 activity is regulated by TSP1, which directly interacts with the N-terminal region of PTX3. These data unveil a fundamental role of PTX3 in promoting the first wave of synaptogenesis, and show that interplay of TSP1 and PTX3 sets the proper balance between synaptic growth and synapse function in the developing brain.


Assuntos
Proteína C-Reativa/fisiologia , Matriz Extracelular/metabolismo , Integrina beta1/metabolismo , Proteínas do Tecido Nervoso/fisiologia , Receptores de AMPA/metabolismo , Sinapses/fisiologia , Animais , Astrócitos/metabolismo , Encéfalo/crescimento & desenvolvimento , Encéfalo/metabolismo , Proteína C-Reativa/genética , Células CHO , Células Cultivadas , Cricetinae , Cricetulus , Matriz Extracelular/genética , Camundongos , Camundongos Endogâmicos C57BL , Proteínas do Tecido Nervoso/genética , Plasticidade Neuronal/genética , Transporte Proteico/genética , Trombospondina 1/metabolismo
14.
Arch Dis Child Educ Pract Ed ; 104(3): 150-153, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30026267

RESUMO

A 3-month-old baby is brought to the paediatric emergency department by their parents because of a fever. You decide to check their inflammatory markers. Their C-reactive protein (CRP) level comes back as 20 mg/L. Does this affect whether or not you start antibiotic therapy? Does it influence your decision to admit or discharge the patient? CRP is a commonly used biochemical test and yet its use is constantly debated and challenged. We look at the current evidence and suggest the best way to use this test in clinical practice.


Assuntos
Proteína C-Reativa/análise , Tomada de Decisão Clínica , Antibacterianos/uso terapêutico , Infecções Bacterianas/sangue , Infecções Bacterianas/diagnóstico , Infecções Bacterianas/tratamento farmacológico , Biomarcadores/sangue , Proteína C-Reativa/fisiologia , Febre/etiologia , Humanos , Inflamação/diagnóstico , Pediatria
15.
J Endod ; 44(12): 1826-1831, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30477668

RESUMO

INTRODUCTION: Pentraxin 3 (PTX3) has been suggested as a novel inflammatory biomarker in inflammation-associated diseases. The aim of this study was to examine the role of PTX3 in the inflammatory response of human dental pulp cells (HDPCs). METHODS: HDPCs were treated with tumor necrosis factor alpha (TNF-α), and total RNA and protein were extracted. PTX3 messenger RNA and protein expression levels were analyzed using reverse transcription polymerase chain reaction and Western blotting, respectively. For PTX3 knockdown, HDPCs were transfected with a small interfering RNA against human PTX3. Macrophage chemotaxis after PTX3 silencing in HDPCs was assessed by transwell migration assays. RESULTS: TNF-α increased PTX3 messenger RNA and protein levels in HDPCs. TNF-α-induced PTX3 expression was mediated by extracellular signal-regulated kinase 1/2 and nuclear factor kappa B. PTX3 knockdown decreased the expression levels of interleukin 6, interleukin 8, and monocyte chemoattractant protein 1 after stimulation with TNF-α in HDPCs. Moreover, PTX3 silencing in HDPCs significantly decreased the chemotactic migration of macrophages. CONCLUSIONS: Our findings indicate PTX3 plays a critical role in the regulation of pulp inflammatory processes and reveal its underlying molecular mechanism.


Assuntos
Proteína C-Reativa/genética , Proteína C-Reativa/fisiologia , Polpa Dentária/citologia , Polpa Dentária/patologia , Terapia de Alvo Molecular , Pulpite/genética , Pulpite/terapia , Componente Amiloide P Sérico/genética , Componente Amiloide P Sérico/fisiologia , Proteína C-Reativa/metabolismo , Células Cultivadas , Citocinas/metabolismo , Expressão Gênica , Técnicas de Silenciamento de Genes , Inativação Gênica , Humanos , Mediadores da Inflamação/metabolismo , Proteína Quinase 1 Ativada por Mitógeno , Proteína Quinase 3 Ativada por Mitógeno , NF-kappa B , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA Interferente Pequeno , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Componente Amiloide P Sérico/metabolismo , Fator de Necrose Tumoral alfa
16.
J Mol Med (Berl) ; 96(12): 1319-1332, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30315331

RESUMO

Restoration of cerebral blood flow (CBF) and upregulation of angiogenesis are crucial for brain repair and functional recovery after cerebral ischaemia. Pentraxin 3 (PTX3) is a key regulator of angiogenesis and is emerging as a promising target for cerebrovascular repair after stroke. Here, we investigated for the first time the role of PTX3 in long-term CBF, angiogenesis, and neuronal viability after ischaemic stroke induced by transient middle cerebral artery occlusion (MCAo). Lack of PTX3 had no effect on early brain damage, but significantly impaired restoration of CBF, 14 and 28 days after MCAo, compared to wild-type (WT) mice. Immunohistochemical analysis revealed that PTX3 KO mice have significantly greater neuronal loss, significantly decreased vessel diameter, vessel proliferation, vascular density, and reactive astrocytes and decreased expression of vascular endothelial growth factor receptor 2 (VEGR2), vascular extracellular matrix (ECM)-proteins (collagen IV, laminin), and integrin-ß, in the ipsilateral (stroke) hemisphere compared to WT mice, 28 days after MCAo. Therefore, PTX3 promotes sustained long-term recovery of CBF, angiogenesis, and neuronal viability after cerebral ischaemia. Collectively, these findings demonstrate the potential and clinical relevance of PTX3 as a promising therapeutic target, providing sustained long-term post-stroke neurovascular repair and reducing the loss of neurons. KEY MESSAGES: Pentraxin 3 (PTX3) is a key regulator of angiogenesis and is emerging as a promising target for cerebrovascular repair after stroke. Restoration of cerebral blood flow (CBF) and angiogenesis are crucial for brain repair and functional recovery after cerebral ischaemia. PTX3 promotes sustained long-term recovery of CBF, angiogenesis, and neuronal viability after cerebral ischaemia.


Assuntos
Proteína C-Reativa/fisiologia , Circulação Cerebrovascular , Infarto da Artéria Cerebral Média/fisiopatologia , Neovascularização Fisiológica , Componente Amiloide P Sérico/fisiologia , Animais , Encéfalo/fisiologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neurônios/fisiologia
17.
Front Immunol ; 9: 2327, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30349543

RESUMO

Angiogenesis, the process of new blood vessel formation from pre-existing ones, plays a key role in various physiological and pathological conditions. Alteration of the angiogenic balance, consequent to the deranged production of angiogenic growth factors and/or natural angiogenic inhibitors, is responsible for angiogenesis-dependent diseases, including cancer. Fibroblast growth factor-2 (FGF2) represents the prototypic member of the FGF family, able to induce a complex "angiogenic phenotype" in endothelial cells in vitro and a potent neovascular response in vivo as the consequence of a tight cross talk between pro-inflammatory and angiogenic signals. The soluble pattern recognition receptor long pentraxin-3 (PTX3) is a member of the pentraxin family produced locally in response to inflammatory stimuli. Besides binding features related to its role in innate immunity, PTX3 interacts with FGF2 and other members of the FGF family via its N-terminal extension, thus inhibiting FGF-mediated angiogenic responses in vitro and in vivo. Accordingly, PTX3 inhibits the growth and vascularization of FGF-dependent tumors and FGF2-mediated smooth muscle cell proliferation and artery restenosis. Recently, the characterization of the molecular bases of FGF2/PTX3 interaction has allowed the identification of NSC12, the first low molecular weight pan-FGF trap able to inhibit FGF-dependent tumor growth and neovascularization. The aim of this review is to provide an overview of the impact of PTX3 and PTX3-derived molecules on the angiogenic, inflammatory, and tumorigenic activity of FGF2 and their potential implications for the development of more efficacious anti-FGF therapeutic agents to be used in those clinical settings in which FGFs play a pathogenic role.


Assuntos
Proteína C-Reativa/fisiologia , Fator 2 de Crescimento de Fibroblastos/metabolismo , Componente Amiloide P Sérico/fisiologia , Animais , Humanos , Inflamação , Neovascularização Fisiológica
18.
Brain Behav Immun ; 73: 717-724, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30102967

RESUMO

Prior studies suggest that the inflammatory biomarker c-reactive protein (CRP) holds promise for predicting antidepressant response in patients with major depressive disorder. The objective of this study was to evaluate whether CRP might similarly predict antidepressant responses to lurasidone in patients with bipolar I depression. Serum CRP concentration was measured prior to, and following, 6 weeks of treatment in 485 outpatients with bipolar I depression. Patients were randomized to receive monotherapy with lurasidone 20-60 mg/day (N = 161), lurasidone 80-120 mg/day (N = 162) or placebo (N = 162). CRP was assessed using the wide-range CRP assay (wr-CRP). The primary efficacy endpoint was change from baseline to week 6 in Montgomery-Åsberg Depression Rating Scale (MADRS) score. Mixed models and statistical interaction tests were applied to investigate the moderating effects of pre-treatment wr-CRP on clinical endpoints. CRP was evaluated as a log-transformed continuous variable and by clinically-relevant cut-points. Increasing pre-treatment wr-CRP level predicted a larger overall antidepressant response to lurasidone, as well as an increased response for a number of individual depressive symptoms. These moderating effects of pre-treatment wr-CRP remained significant after adjustment for potential confounds (e.g. baseline BMI and weight change). Treatment with lurasidone did not affect serum concentrations of CRP compared to placebo during the study. Elevated CRP level prior to treatment was associated with an enhanced clinical response to lurasidone in patients with bipolar I depression. If confirmed in future studies, CRP may represent a clinically useful diagnostic and predictive biomarker supporting a precision medicine approach to the treatment of bipolar depression.


Assuntos
Transtorno Bipolar/tratamento farmacológico , Proteína C-Reativa/metabolismo , Cloridrato de Lurasidona/farmacologia , Adulto , Antidepressivos/uso terapêutico , Antimaníacos/uso terapêutico , Biomarcadores Farmacológicos/sangue , Biomarcadores Farmacológicos/metabolismo , Transtorno Bipolar/fisiopatologia , Proteína C-Reativa/análise , Proteína C-Reativa/fisiologia , Transtorno Depressivo Maior/tratamento farmacológico , Método Duplo-Cego , Feminino , Humanos , Cloridrato de Lurasidona/metabolismo , Masculino , Pessoa de Meia-Idade , Pacientes Ambulatoriais , Escalas de Graduação Psiquiátrica , Resultado do Tratamento
19.
Brain Behav Immun ; 73: 85-114, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29928963

RESUMO

One of the most common inflammatory markers examined in depression is C-reactive protein (CRP). However, the magnitude of the association between CRP and depression when controlling for potentially confounding factors such as age, sex, socio-economic status, body mass index, medication and other substance use, and medical illness, is unclear. Inconsistencies in other methodological practices, such as sample collection, assaying, and data cleaning and transformation, may contribute to variations in results. We aggregate studies that examined the association between CRP and depression in two ways. First, a systematic review summarizes how studies of CRP and depression have reported on methodological issues. Second, a tiered meta-analysis aggregates studies that have adhered to various levels of methodological rigor. Findings from the systematic review indicate a lack of protocol detail provided. The effect between depression and CRP was small, but highly significant across all stages of the meta-analysis (p < 0.01). The effect size in the most methodologically rigorous stage of the meta-analysis, which included studies controlling for age, sex, obesity, medical conditions and substance, medication, or psychosocial factors, was small (r = 0.05). There were also only 26 articles in this stage (13% of studies from the systematic review), suggesting that more studies that consistently account for these confounding factors are needed. Additionally, an a priori quality score of methodological rigor was a significant moderator in this stage of the meta-analysis. The effect size was strikingly attenuated (r = 0.005) and non-significant in studies with higher quality scores. We describe a set of recommended guidelines for future research to consider, including sample collection and assaying procedures, data cleaning and statistical methods, and control variables to assess.


Assuntos
Proteína C-Reativa/metabolismo , Proteína C-Reativa/fisiologia , Depressão/metabolismo , Biomarcadores/sangue , Proteína C-Reativa/análise , Comorbidade , Fatores de Confusão Epidemiológicos , Transtorno Depressivo/metabolismo , Feminino , Humanos , Inflamação/sangue , Inflamação/metabolismo , Masculino , Reprodutibilidade dos Testes
20.
Brain Behav Immun ; 71: 133-141, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29627531

RESUMO

OBJECTIVE: Heart failure (HF) is a complex medical condition with a multitude of genetic and other factors being involved in the pathogenesis. Emerging evidence points to an involvement of inflammatory mechanisms at least in subgroups of patients. The same is true for depression and depressive symptoms, which have a high prevalence in HF patients and are risk factors for the development and outcomes of cardiovascular disease. METHODS: In 936 patients of the Interdisciplinary Network Heart Failure (INH) program, CRP and IL-6 protein blood levels were measured and genetic variants (single nucleotide polymorphisms) of the CRP and IL6 gene analyzed regarding their influence on mortality. RESULTS: Less common recessive genotypes of two single nucleotide polymorphisms in the CRP gene (rs1800947 and rs11265263) were associated with significantly higher mortality risk (p < 0.006), higher CRP levels (p = 0.029, p = 0.006) and increased depressive symptoms in the PHQ-9 (p = 0.005, p = 0.003). Variants in the IL-6 gene were not associated with mortality. CONCLUSION: Our results hint towards an association of less common CRP genetic variants with increased mortality risk, depressive symptoms and peripheral CRP levels in this population of HF patients thereby suggesting a possible role of the inflammatory system as link between poor prognosis in HF and depressive symptoms.


Assuntos
Proteína C-Reativa/genética , Transtorno Depressivo/genética , Insuficiência Cardíaca/genética , Idoso , Proteína C-Reativa/metabolismo , Proteína C-Reativa/fisiologia , Doença Crônica , Depressão/sangue , Depressão/genética , Depressão/fisiopatologia , Transtorno Depressivo/sangue , Transtorno Depressivo/fisiopatologia , Feminino , Predisposição Genética para Doença/genética , Variação Genética/genética , Genótipo , Insuficiência Cardíaca/mortalidade , Insuficiência Cardíaca/psicologia , Humanos , Interleucina-6/sangue , Interleucina-6/genética , Interleucina-6/fisiologia , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco
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