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1.
Front Immunol ; 11: 574593, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33072117

RESUMO

Familial Mediterranean Fever (FMF) and COVID-19 show a remarkable overlap of clinical symptoms and similar laboratory findings. Both are characterized by fever, abdominal/chest pain, elevation of C-reactive protein, and leukocytosis. In addition, colchicine and IL-1 inhibitors treatments that are effective in controlling inflammation in FMF patients have recently been proposed for off-label use in COVID-19 patients. Thus, FMF may resemble a milder recapitulation of the cytokine storm that is a hallmark of COVID-19 patients progressing to severe disease. We analyzed the sequence of the MEFV-encoded Pyrin protein - whose mutations cause FMF- in mammals, bats and pangolin. Intriguingly, although Pyrin is extremely conserved in species that are considered either a reservoir or intermediate hosts for SARS-CoV-2, some of the most common FMF-causing variants in humans are present as wildtype residues in these species. We propose that in humans, Pyrin may have evolved to fight highly pathogenic infections.


Assuntos
Betacoronavirus , Colchicina/uso terapêutico , Infecções por Coronavirus , Febre Familiar do Mediterrâneo , Mutação , Pandemias , Pneumonia Viral , Pirina , Animais , Betacoronavirus/genética , Betacoronavirus/imunologia , Proteína C-Reativa/genética , Proteína C-Reativa/imunologia , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/genética , Infecções por Coronavirus/imunologia , Febre Familiar do Mediterrâneo/tratamento farmacológico , Febre Familiar do Mediterrâneo/epidemiologia , Febre Familiar do Mediterrâneo/genética , Febre Familiar do Mediterrâneo/imunologia , Humanos , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/epidemiologia , Pneumonia Viral/genética , Pneumonia Viral/imunologia , Pirina/genética , Pirina/imunologia
2.
Artigo em Inglês | MEDLINE | ID: mdl-32933066

RESUMO

Because elevated circulating C-reactive protein (CRP) and low socio-economic status (SES), have both been implicated in cardiovascular disease development, we investigated whether SES factors associate with and interact with CRP polymorphisms in relation to the phenotype. Included in the study were 1569 black South Africans for whom CRP concentrations, 12 CRP single nucleotide polymorphisms (SNPs), cardiovascular health markers, and SES factors were known. None of the investigated SES aspects was found to associate with CRP concentrations when measured individually; however, in adjusted analyses, attaining twelve or more years of formal education resulted in a hypothetically predicted 18.9% lower CRP concentration. We also present the first evidence that active smokers with a C-allele at rs3093068 are at an increased risk of presenting with elevated CRP concentrations. Apart from education level, most SES factors on their own are not associated with the elevated CRP phenotype observed in black South Africans. However, these factors may collectively with other environmental, genetic, and behavioral aspects such as smoking, contribute to the elevated inflammation levels observed in this population. The gene-smoking status interaction in relation to inflammation observed here is of interest and if replicated could be used in at-risk individuals to serve as an additional motivation to quit.


Assuntos
Grupo com Ancestrais do Continente Africano , Proteína C-Reativa , Fumar , Adulto , Grupo com Ancestrais do Continente Africano/genética , Proteína C-Reativa/análise , Proteína C-Reativa/genética , Feminino , Humanos , Inflamação , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Fumar/efeitos adversos
3.
Gene ; 762: 145056, 2020 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-32805313

RESUMO

BACKGROUND: Abdominal aortic aneurysm (AAA) is a disease characterized by weakening arterial wall and permanent expansion with high mortality once rupture, which was involved with immune system activation. However, owing to technical difficulties, previous research has limited the impact of one or limited immune cells on AAA. METHODS: We analyzed the composition of immune cells using the CIBERSORT algorithm through transcriptome sequencing data from patients with stable (eAAA) and ruptured aneurysms (rAAA). The whole transcriptome sequencing data, including 17 patients with ruptured AAA and 31 patients with stable AAA were downloaded from Gene Expression Omnibus (GEO, GSE98278). After normalizing and data processing, five rAAA and seventeen eAAA patients entered the follow-up analysis. We performed Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis to identify several pathways that were significantly enriched in rAAA compared to eAAA tissues. RESULTS: We demonstrated that the compositions of infiltrative immune cell in eAAA and rAAA were different. Naïve B cells, both resting and activated CD4+ memory T cells were found significantly higher in ruptured AAA, while memory B cells and activated mast cells were much less in ruptured AAA than that in stable AAA. Besides, PTX3 was significantly highly expressed in rAAA, which might be associated with the complement system and polarization of macrophages. Finally, differentially expressed genes and the related immune cells were mapped in a network to reveal the relationship between gene expression and infiltrative immune cells. CONCLUSION: We identified the infiltrated immune cell profile of eAAA and rAAA patients, which might be the potential target of AAA treatment.


Assuntos
Aneurisma da Aorta Abdominal/genética , Ruptura Aórtica/genética , Linfócitos B/metabolismo , Linfócitos T/metabolismo , Transcriptoma , Animais , Aneurisma da Aorta Abdominal/metabolismo , Aneurisma da Aorta Abdominal/patologia , Ruptura Aórtica/metabolismo , Ruptura Aórtica/patologia , Proteína C-Reativa/genética , Proteína C-Reativa/metabolismo , Células Dendríticas/metabolismo , Humanos , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Componente Amiloide P Sérico/genética , Componente Amiloide P Sérico/metabolismo
4.
Cardiovasc Ther ; 2020: 9397109, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32821285

RESUMO

Chronic systemic inflammation contributes to cardiovascular disease (CVD) and correlates with the abundance of acute phase response (APR) proteins in the liver and plasma. Bromodomain and extraterminal (BET) proteins are epigenetic readers that regulate inflammatory gene transcription. We show that BET inhibition by the small molecule apabetalone reduces APR gene and protein expression in human hepatocytes, mouse models, and plasma from CVD patients. Steady-state expression of serum amyloid P, plasminogen activator inhibitor 1, and ceruloplasmin, APR proteins linked to CVD risk, is reduced by apabetalone in cultured hepatocytes and in humanized mouse liver. In cytokine-stimulated hepatocytes, apabetalone reduces the expression of C-reactive protein (CRP), alpha-2-macroglobulin, and serum amyloid P. The latter two are also reduced by apabetalone in the liver of endotoxemic mice. BET knockdown in vitro also counters cytokine-mediated induction of the CRP gene. Mechanistically, apabetalone reduces the cytokine-driven increase in BRD4 BET occupancy at the CRP promoter, confirming that transcription of CRP is BET-dependent. In patients with stable coronary disease, plasma APR proteins CRP, IL-1 receptor antagonist, and fibrinogen γ decrease after apabetalone treatment versus placebo, resulting in a predicted downregulation of the APR pathway and cytokine targets. We conclude that CRP and components of the APR pathway are regulated by BET proteins and that apabetalone counters chronic cytokine signaling in patients.


Assuntos
Anti-Inflamatórios/farmacologia , Proteína C-Reativa/metabolismo , Doenças Cardiovasculares/tratamento farmacológico , Citocinas/metabolismo , Endotoxemia/tratamento farmacológico , Epigênese Genética/efeitos dos fármacos , Proteínas Nucleares/metabolismo , Quinazolinonas/farmacologia , Fatores de Transcrição/metabolismo , Animais , Sítios de Ligação , Proteína C-Reativa/genética , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/metabolismo , Células Cultivadas , Ceruloplasmina/genética , Ceruloplasmina/metabolismo , Citocinas/genética , Modelos Animais de Doenças , Endotoxemia/genética , Endotoxemia/metabolismo , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Proteínas Nucleares/genética , Inibidor 1 de Ativador de Plasminogênio/metabolismo , Regiões Promotoras Genéticas , Componente Amiloide P Sérico/metabolismo , Transdução de Sinais , Fatores de Transcrição/genética , alfa-Macroglobulinas/genética , alfa-Macroglobulinas/metabolismo
5.
J Steroid Biochem Mol Biol ; 202: 105722, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32565247

RESUMO

PTX3, a member of the pentraxin protein family, plays important roles in ovulation as a marker of cumulus cell-oocyte complex expansion. However, the expression and function of PTX3 in goat ovarian GCs remain unclear. We isolated GCs from small and large follicles and found that PTX3 expression was significantly decreased and miR-29 mRNA expression was significantly increased during the growth of antral follicles. MiR-29 decreased PTX3 expression by targeting its 3' untranslated. Furthermore, miR-29 promoted GC proliferation, suppressed steroidogenesis and apoptosis by targeting PTX3 via the activation of the PI3K/AKT/mTOR and Erk1/2 signaling pathways. Treatment with inhibitors also verified these results. Meanwhile, we found that PI3K/AKT/mTOR and Erk1/2 signaling pathways had different role in secretion of E2 and P4 by regulating differently various steroidogenic enzyme (CYP19A1, CYP11A1, StAR and HSD3B) expression. These outcomes indicate the potential role of PTX3 in goat follicular growth and atresia.


Assuntos
Proteína C-Reativa/metabolismo , Células da Granulosa/metabolismo , MicroRNAs/genética , Componente Amiloide P Sérico/metabolismo , Animais , Apoptose , Proteína C-Reativa/genética , Proliferação de Células , Estradiol/metabolismo , Feminino , Cabras , Células HEK293 , Humanos , Sistema de Sinalização das MAP Quinases , Fosfatidilinositol 3-Quinases/metabolismo , Progesterona/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Componente Amiloide P Sérico/genética , Serina-Treonina Quinases TOR/metabolismo
6.
Gene ; 753: 144808, 2020 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-32470505

RESUMO

OBJECTIVE: C-reactive protein (CRP) is increased in Parkinson's disease (PD). The CRP +1444C/T (rs1130864) polymorphism is located in the 3' untranslated region (3'-UTR) and is associated with serum CRP concentrations. We explored the relationship between the CRP +1444C/T polymorphism and susceptibility to PD. METHODS: A total of 1000 subjects from a Chinese population were recruited into this case-control study, including 500 PD patients and 500 healthy controls. The genotype of the CRP +1444C/T polymorphism was tested by Sanger sequencing, and the Hardy-Weinberg equilibrium (HWE) was assessed in the groups. The odds ratios and 95% confidence intervals were calculated to evaluate the strength of any correlations in allelic, dominant, recessive, and additive genetic models. RESULTS: The genotypic distribution of the CRP +1444C/T polymorphism was consistent with HWE in controls, and markedly different with cases. The CRP +1444C/T polymorphism was associated with increased PD risk in allelic and dominant models in the overall and male population, but not the female subgroup. CONCLUSION: The presence of a CRP +1444C/T polymorphism may be associated with an increased risk of PD in our Chinese population. Given the missing support for a role of this SNP in PD in the pre-existing GWAS, the SNP may not be genuinely associated with PD despite some positive candidate gene studies.


Assuntos
Proteína C-Reativa/genética , Doença de Parkinson/genética , Regiões 3' não Traduzidas/genética , Adulto , Idoso , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Casos e Controles , China , Suscetibilidade a Doenças , Feminino , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único
7.
Nat Commun ; 11(1): 2487, 2020 05 19.
Artigo em Inglês | MEDLINE | ID: mdl-32427938

RESUMO

Cancer stem-like cells (CSCs) are the tumorigenic cell subpopulation and contribute to cancer recurrence and metastasis. However, the understanding of CSC regulatory mechanisms remains incomplete. By transcriptomic analysis, we identify a scaffold protein SH3RF3 (also named POSH2) that is upregulated in CSCs of breast cancer clinical tumors and cancer cell lines, and enhances the CSC properties of breast cancer cells. Mechanically, SH3RF3 interacts with the c-Jun N-terminal kinase (JNK) in a JNK-interacting protein (JIP)-dependent manner, leading to enhanced phosphorylation of JNK and activation of the JNK-JUN pathway. Further the JNK-JUN signaling expands CSC subpopulation by transcriptionally activating the expression of Pentraxin 3 (PTX3). The functional role of SH3RF3 in CSCs is validated with patient-derived organoid culture, and supported by clinical cohort analyses. In conclusion, our work elucidates the role and molecular mechanism of SH3RF3 in CSCs of breast cancer, and might provide opportunities for CSC-targeting therapy.


Assuntos
Neoplasias da Mama/genética , Proteína C-Reativa/genética , Proteínas Quinases JNK Ativadas por Mitógeno/genética , Células-Tronco Neoplásicas/metabolismo , Componente Amiloide P Sérico/genética , Ubiquitina-Proteína Ligases/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Proteína C-Reativa/metabolismo , Linhagem Celular , Linhagem Celular Tumoral , Ativação Enzimática , Feminino , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Sistema de Sinalização das MAP Quinases/genética , Fosforilação , Componente Amiloide P Sérico/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Regulação para Cima
8.
Cryobiology ; 94: 100-106, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32289283

RESUMO

In recent years, the prevalence of obesity has increased dramatically and has become a 21st century epidemic. Obesity is associated with the development of many diseases, and therefore treatments that can reduce body mass are actively sought. The aim of this study was to examine the effect of 20 cryostimulation sessions on body composition in obese/high body mass (HBM, n = 12) males and normal body mass (NBM, n = 9) controls. The HBM group had a mean age = 29.08 ± 4.19 years, body fat percentage = 32.08 ± 6.16%, body mass index = 36.23 ± 8.13 kg/m2) and NBM group had a mean age = 22.00 ± 2.45 years, body fat percentage = 12.14 ± 4.93%, body mass index = 23.58 ± 2.00 kg/m2. Kilocalorie intake was similar for both groups. All participants received 20 sessions of systemic cryostimulation at -120°C for 2-3 min in a cryochamber. Blood samples were collected before the first session, 1 h after the 10th session, and 1 h after the 20th cryostimulation session. C-reactive protein (CRP) plasma concentrations, and expression of the heat shock protein genes (HSPA1A, HSPB1) and CRP mRNA in leukocytes were evaluated after 10 and 20 cryostimulation sessions. In both groups, 20 sessions were associated with a significant decrease in body mass, fat mass and the percentage of body fat. CRP concentrations were significantly higher in obese people before the first session and after 10 treatments, but not at the end of study. Expression of HSPA1A and HSPB1 mRNA gradually decreased with the number of cryostimulation sessions. A significant difference in HSPA1A expression was found after 20 sessions (NBM > HBM) and for HSPB1 at baseline and after 20 sessions (HBM > NBM). Our results show that cryostimulation influences body composition and that cryostimulation-induced HSP genes expression depends on the number of cryosessions and baseline body mass, and is differentially altered in HBM individuals. Further research on the interaction between body mass and cold adaptation is warranted.


Assuntos
Composição Corporal , Proteína C-Reativa/genética , Crioterapia/métodos , Proteínas de Choque Térmico HSP70/genética , Proteínas de Choque Térmico/genética , Chaperonas Moleculares/genética , Obesidade/terapia , Adulto , Proteína C-Reativa/análise , Proteínas de Choque Térmico HSP70/sangue , Proteínas de Choque Térmico/sangue , Humanos , Leucócitos/metabolismo , Masculino , Chaperonas Moleculares/sangue , Obesidade/sangue , Obesidade/genética , Adulto Jovem
9.
Int J Mol Sci ; 21(8)2020 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-32294882

RESUMO

Human C-reactive protein (CRP) and lactate dehydrogenase are important markers in clinical laboratory testing-the former is used to detect in vivo inflammation, and the latter is used to detect cell necrosis and tissue destruction. We developed aptamers that bind to human CRP and human lactate dehydrogenase-5 (LDH-5) with high affinities (dissociation constants of 6.2 pM and 235 pM, respectively), applying the systematic evolution of ligands by exponential enrichment (SELEX) method, and by using a modified DNA library containing the following base-appended base modifications: analog adenine derivative at the fifth position of uracil (Uad), analog guanine derivative at the fifth position of uracil (Ugu), and analog adenine derivative at the seventh position of adenine (Aad). A potential application of these aptamers as sensor elements includes high-sensitivity target detection in point-of-care testing.


Assuntos
Aptâmeros de Nucleotídeos/genética , Proteína C-Reativa/genética , Lactato Desidrogenase 5/genética , Aptâmeros de Nucleotídeos/química , Sequência de Bases , DNA de Cadeia Simples , Biblioteca Gênica , Humanos , Estrutura Molecular , Técnica de Seleção de Aptâmeros
10.
Eur J Immunol ; 50(5): 624-642, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32246830

RESUMO

Maintenance of homeostasis at body barriers that are constantly challenged by microbes, toxins and potentially bioactive (macro)molecules requires complex, highly orchestrated mechanisms of protection. Recent discoveries in respiratory research have shed light on the unprecedented role of airway epithelial cells (AEC), which, besides immune cells homing to the lung, also significantly contribute to host defence by expressing membrane-bound and soluble pattern recognition receptors (sPRR). Recent evidence suggests that distinct, evolutionary ancient, sPRR secreted by AEC might become activated by usually innocuous proteins, commonly referred to as allergens. We here provide a systematic overview on sPRR detectable in the mucus lining of AEC. Some of them become actively produced and secreted by AECs (like the pentraxins C-reactive protein and pentraxin 3; the collectins mannose binding protein and surfactant proteins A and D; H-ficolin; serum amyloid A; and the complement components C3 and C5). Others are elaborated by innate and adaptive immune cells such as monocytes/macrophages and T cells (like the pentraxins C-reactive protein and pentraxin 3; L-ficolin; serum amyloid A; and the complement components C3 and C5). Herein we discuss how sPRRs may contribute to homeostasis but sometimes also to overt disease (e.g. airway hyperreactivity and asthma) at the alveolar-air interface.


Assuntos
Asma/imunologia , Hiper-Reatividade Brônquica/imunologia , Proteína C-Reativa/imunologia , Homeostase/imunologia , Receptores de Reconhecimento de Padrão/imunologia , Mucosa Respiratória/imunologia , Alérgenos/administração & dosagem , Animais , Asma/genética , Asma/patologia , Hiper-Reatividade Brônquica/genética , Hiper-Reatividade Brônquica/patologia , Proteína C-Reativa/genética , Colectinas/genética , Colectinas/imunologia , Complemento C3/genética , Complemento C3/imunologia , Complemento C5/genética , Complemento C5/imunologia , Células Epiteliais/imunologia , Células Epiteliais/patologia , Regulação da Expressão Gênica , Homeostase/genética , Humanos , Lectinas/genética , Lectinas/imunologia , Receptores de Reconhecimento de Padrão/genética , Mucosa Respiratória/patologia , Proteína Amiloide A Sérica/genética , Proteína Amiloide A Sérica/imunologia , Componente Amiloide P Sérico/genética , Componente Amiloide P Sérico/imunologia
11.
J Cancer Res Clin Oncol ; 146(4): 897-907, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32146565

RESUMO

INTRODUCTION: Pancreatic ductal adenocarcinoma (PDAC) is a very aggressive cancer. There are various sub-cellular events (both genetic and epigenetic) that get dysregulated leading to tumorigenesis. Methylation in promoters of tumor suppressor genes is one of these epigenetic phenomena contributing to the pathogenesis of cancer. Genes analyzed for promoter methylation status in this study namely SPARC (Secreted Protein Acidic and Rich in Cysteine, UCHL1 (ubiquitin carboxy-terminal hydrolase L1), NPTX2 (neuronal pentraxin 2), PENK (proenkephalin) had been studied in pancreatic cancer, but there is a need to check methylation in these genes as circulatory non-invasive markers. This study analyzed the absolute quantification of methylation levels of SPARC, UCHL1, PENK, and NPTX2 genes promoters in PDAC patients as well as in chronic pancreatitis (CP) patients and healthy subjects (HC) and evaluated its clinical significance in PDAC. MATERIALS AND METHODS: The study included 65 PDAC patients, 25 CP patients, and 25 healthy controls. DNA was extracted from their plasma samples and subsequently given bisulfite treatment. Absolute quantization of methylated and unmethylated copies of gene promoters of all the four genes was performed using real-time PCR (SYBR green) by the standard curve method. Methylation levels were expressed as methylation index (MI) for each gene in each patient. MI was calculated from absolute copy numbers as follows: MI-methylated copy number/methylated copy number + unmethylated copy number). These indices were used to compare gene methylation levels within different groups and to correlate with clinicopathological features and survival of pancreatic cancer patients. An appropriate statistical analysis was applied. RESULTS: Methylation indices for all the four genes in PDAC cases were found to be significantly higher as compared to that in healthy individuals. SPARC MI values were found to differentiate early-stage PDAC patients from CP patients. PDAC patients with the metastasized disease and stage IV disease were found to have high MI for the SPARC gene as well as for the NPTX2 gene, while a higher UCHL1 methylation index was found to correlate with an advanced stage of the disease. Higher MI values for SPARC and NPTX2 genes were found to associate with poor survival in patients with PDAC. CONCLUSION: Methylation load in the form of MI for each of the four genes assessed in plasma may emerge as a non-invasive biomarker to differentiate pancreatic cancer from healthy individuals. But only SPARC and NPTX2 hypermethylation were able to distinguish pancreatic cancer from chronic pancreatitis. Association of aberrant methylation in SPARC and NPTX2 gene with metastasis and poor survival of patients suggest the role of methylation in these genes as prognostic markers.


Assuntos
Carcinoma Ductal Pancreático/genética , DNA Tumoral Circulante/genética , Metilação de DNA , Genes Supressores de Tumor , Neoplasias Pancreáticas/genética , Proteína C-Reativa/genética , Carcinoma Ductal Pancreático/sangue , Estudos de Casos e Controles , Diferenciação Celular/genética , DNA Tumoral Circulante/sangue , Encefalinas/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas do Tecido Nervoso/genética , Osteonectina/genética , Neoplasias Pancreáticas/sangue , Pancreatite Crônica/sangue , Pancreatite Crônica/genética , Regiões Promotoras Genéticas , Precursores de Proteínas/genética , Ubiquitina Tiolesterase/genética
12.
Arq Bras Cardiol ; 114(2): 268-272, 2020 02.
Artigo em Inglês, Português | MEDLINE | ID: mdl-32215496

RESUMO

BACKGROUND: Periodontitis and coronary artery disease (CAD) share an inflammatory etiology; there is a recent concern regarding the investigation of an association between these two conditions. Current theories indicate that cytokines and proteins have an important role in this process. C-reactive protein and interleukin-6 are inflammatory derivatives produced in the presence of periodontitis and in the pathophysiology of coronary disease. The polymorphisms of CRP + 1444 C > T and IL6-174 G > C are recognized in the literature as being related to CAD. OBJECTIVE: This study investigates the association between periodontitis and coronary artery disease, through the presence of PCR and IL-6 polymorphisms. METHODS: We selected 80 patients who underwent diagnostic catheterization in the HU of UFSM. The presence of periodontitis was determined by the Community Periodontal Index, whereas the CAD was established by the medical report. DNA was collected from a saliva sample and the presence of polymorphism was determined by PCR and restriction enzymes. A significance level of 5% was adopted. RESULTS: The mean age of all participants (p = 0.035, OR 2.65; 95%CI: (1.02-6.87) male gender (p = 0.012, OR 3.37; 95% CI: (1.28- (p = 0.013, OR 3.66; 95% CI: (1.27-10.5)), PCR polymorphism + 1444C > T (p = 0.001, OR 6.37; 95% CI:, (2.25-17.9)) and IL6 -174 G > C polymorphism (p = 0.025, OR 2.87, 95% CI: (1.09-7.55)) were statistically associated with the presence of CAD. Age > 60 years and presence of the PCR +1444 C > T polymorphism remained independently associated with CAD after adjustment by logistic regression. CONCLUSIONS: The presence of the PCR + 1444 C > T polymorphism in this study was independently associated with the presence of coronary artery disease.


Assuntos
Proteína C-Reativa/genética , Doença da Artéria Coronariana/complicações , Doença da Artéria Coronariana/genética , Interleucina-6/genética , Periodontite/complicações , Periodontite/genética , Polimorfismo de Nucleotídeo Único , Fatores Etários , Idoso , Alelos , Brasil , Proteína C-Reativa/análise , Feminino , Humanos , Interleucina-6/análise , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Fatores de Risco , Fatores Sexuais
13.
PLoS One ; 15(3): e0230715, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32214403

RESUMO

Evidence suggests the existence of association between a large panel of modifiable biomarkers representing inflammation, coagulation, paraoxonase, and endothelial activation pathways and carotid atherosclerosis. Thus, this study investigated whether CRP, FGA, FGB, FGG, PON1, and EDNRA gene variants affected plasma hs-CRP, fibrinogen levels, and thickness of carotid intima media thickness (IMT). Nineteen single-nucleotide polymorphisms of CRP, FGA, FGB, FGG, PON1, and EDNRA genes were examined in 480 participants from 160 families. Carotid IMT was measured by ultrasound. Generalized linear models with generalized estimating equation were utilized to consider the dependence of subjects within families. In the recessive model, homozygotes for the minor alleles of rs1800789, rs1800790 and rs4220 SNPs in FGB gene indicated a reduced risk of IMT (Exp. ß = 0.89, 0.89, 0.88), which remained significant after adjustment for confounding factors. Significant interaction effects between CRP SNP rs1130864 and rs3093059 and gender for IMT were observed with a significant association in men only. Men carrying minor-minor genotype of CRP SNP rs1130864 and rs3093059 had 0.70- and 0.78-fold lower IMT than men carrying minor-major/major-major genotype. We also observed that the interaction of CRP SNP rs1130864 and rs3093059 with obesity on IMT, hs-CRP and fibrinogen levels. These results support the hypothesis that inflammatory genes are involved in atherosclerosis, most likely via complex gene-gender and gene-obesity interactions.


Assuntos
Espessura Intima-Media Carotídea , Vida Independente , Polimorfismo de Nucleotídeo Único , Arildialquilfosfatase/genética , Proteína C-Reativa/genética , Proteína C-Reativa/metabolismo , Feminino , Fibrinogênio/genética , Fibrinogênio/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Receptor de Endotelina A/genética
14.
Medicine (Baltimore) ; 99(3): e18740, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32011454

RESUMO

To investigate the interaction between the single nucleotide polymorphism of the 3' untranslated region (3'UTR) of the pentraxin 3 (PTX3) gene, as well as environmental factors and the preeclampsia risk in a Chinese Han population.Sanger sequencing was used to analyze rs5853783 and rs73158510 loci of the PTX3 gene 3'UTR from 235 patients with preeclampsia and 235 control subjects. The plasma PTX3 protein level was measured by enzyme-linked immunosorbent assay (ELISA).The risk of preeclampsia in the PTX3 gene rs5853783 locus D allele carriers was 0.72 times higher than that of the I allele carriers (95% CI: 0.60-0.84, P < .001). The risk of preeclampsia in the PTX3 gene rs73158510 locus A allele carriers was 1.36 times higher than in the G allele carriers (95% CI: 1.16-1.55, P < .001). The area under the ROC curve (AUC) for the diagnosis of preeclampsia by plasma PTX3 protein levels was 0.906 (P < .001). The PTX3 gene rs5853783 and rs73158510 single nucleotide polymorphisms (SNPs) were associated with plasma PTX3 protein levels. The AUC of plasma PTX3 protein level diagnosis of preeclampsia in PTX3 gene rs5853783 locus II genotype subjects was up to 0.9371, followed by the ID genotype (AUC = 0.8586); the DD genotype was the lowest (AUC = 0.8154). The AUC of plasma PTX3 protein level diagnosis of preeclampsia in rs73158510 locus GG genotype subjects was 0.9102, GA genotype was 0.8766, and AA genotype was 0.8750.The rs5853783 and rs73158510 SNPs in the 3'UTR region of the PTX3 gene are associated with the risk of preeclampsia in a Chinese Han population.


Assuntos
Regiões 3' não Traduzidas/genética , Proteína C-Reativa/genética , Polimorfismo de Nucleotídeo Único , Pré-Eclâmpsia/genética , Componente Amiloide P Sérico/genética , Adolescente , Adulto , Alelos , Grupo com Ancestrais do Continente Asiático , China/etnologia , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Pré-Eclâmpsia/etnologia , Gravidez , Fatores de Risco
15.
Sci Rep ; 10(1): 566, 2020 01 17.
Artigo em Inglês | MEDLINE | ID: mdl-31953490

RESUMO

In the present work, the mechanisms involved in the recently reported antiviral activity of zebrafish C-reactive protein-like protein (CRP1-7) against the spring viraemia of carp rhabdovirus (SVCV) in fish are explored. The results neither indicate blocking of the attachment or the binding step of the viral replication cycle nor suggest the direct inhibition of G protein fusion activity or the stimulation of the host's interferon system. However, an antiviral state in the host is induced. Further results showed that the antiviral protection conferred by CRP1-7 was mainly due to the inhibition of autophagic processes. Thus, given the high affinity of CRPs for cholesterol and the recently described influence of the cholesterol balance in lipid rafts on autophagy, both methyl-ß-cyclodextrin (a cholesterol-complexing agent) and 25-hydroxycholesterol (a cholesterol molecule with antiviral properties) were used to further describe CRP activity. All the tested compounds exerted antiviral activity by affecting autophagy in a similar manner. Further assays indicate that CRP reduces autophagy activity by initially disturbing the cholesterol ratios in the host cellular membranes, which in turn negatively affects the intracellular regulation of reactive oxygen species (ROS) and increases lysosomal pH as a consequence. Ultimately, here we propose that such pH changes exert an inhibitory direct effect on SVCV replication by disrupting the pH-dependent membrane-fusogenic ability of the viral glycoprotein G, which allows the release of the virus from endosomes into cytoplasm during its entry phase.


Assuntos
Proteína C-Reativa/farmacologia , Membrana Celular/química , Colesterol/metabolismo , Infecções por Rhabdoviridae/prevenção & controle , Rhabdoviridae/fisiologia , Peixe-Zebra/virologia , Animais , Autofagia , Proteína C-Reativa/genética , Linhagem Celular , Concentração de Íons de Hidrogênio/efeitos dos fármacos , Hidroxicolesteróis/metabolismo , Isoformas de Proteínas/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Rhabdoviridae/efeitos dos fármacos , Infecções por Rhabdoviridae/metabolismo , Replicação Viral/efeitos dos fármacos , Peixe-Zebra/genética , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/farmacologia , beta-Ciclodextrinas/metabolismo
16.
Eur J Epidemiol ; 35(2): 139-146, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31900758

RESUMO

Serum C-reactive protein (CRP), an important inflammatory marker, has been associated with age-related macular degeneration (AMD) in observational studies; however, the findings are inconsistent. It remains unclear whether the association between circulating CRP levels and AMD is causal. We used two-sample Mendelian randomization (MR) to evaluate the potential causal relationship between serum CRP levels and AMD risk. We derived genetic instruments for serum CRP levels in 418,642 participants of European ancestry from UK Biobank, and then conducted a genome-wide association study for 12,711 advanced AMD cases and 14,590 controls of European descent from the International AMD Genomics Consortium. Genetic variants which predicted elevated serum CRP levels were associated with advanced AMD (odds ratio [OR] for per standard deviation increase in serum CRP levels: 1.31, 95% confidence interval [CI]: 1.19-1.44, P = 5.2 × 10-8). The OR for the increase in advanced AMD risk when moving from low (< 3 mg/L) to high (> 3 mg/L) CRP levels is 1.29 (95% CI: 1.17-1.41). Our results were unchanged in sensitivity analyses using MR models which make different modelling assumptions. Our findings were broadly similar across the different forms of AMD (intermediate AMD, choroidal neovascularization, and geographic atrophy). We used multivariable MR to adjust for the effects of other potential AMD risk factors including smoking, body mass index, blood pressure and cholesterol; this did not alter our findings. Our study provides strong genetic evidence that higher circulating CRP levels lead to increases in risk for all forms of AMD. These findings highlight the potential utility for using circulating CRP as a biomarker in future trials aimed at modulating AMD risk via systemic therapies.


Assuntos
Proteína C-Reativa/genética , Degeneração Macular/sangue , Degeneração Macular/genética , Análise da Randomização Mendeliana , Idoso , Idoso de 80 Anos ou mais , Proteína C-Reativa/metabolismo , Estudos de Casos e Controles , Feminino , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Degeneração Macular/epidemiologia , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Fatores de Risco
17.
Am J Hum Genet ; 106(1): 112-120, 2020 01 02.
Artigo em Inglês | MEDLINE | ID: mdl-31883642

RESUMO

Whole-genome sequencing (WGS) can improve assessment of low-frequency and rare variants, particularly in non-European populations that have been underrepresented in existing genomic studies. The genetic determinants of C-reactive protein (CRP), a biomarker of chronic inflammation, have been extensively studied, with existing genome-wide association studies (GWASs) conducted in >200,000 individuals of European ancestry. In order to discover novel loci associated with CRP levels, we examined a multi-ancestry population (n = 23,279) with WGS (∼38× coverage) from the Trans-Omics for Precision Medicine (TOPMed) program. We found evidence for eight distinct associations at the CRP locus, including two variants that have not been identified previously (rs11265259 and rs181704186), both of which are non-coding and more common in individuals of African ancestry (∼10% and ∼1% minor allele frequency, respectively, and rare or monomorphic in 1000 Genomes populations of East Asian, South Asian, and European ancestry). We show that the minor (G) allele of rs181704186 is associated with lower CRP levels and decreased transcriptional activity and protein binding in vitro, providing a plausible molecular mechanism for this African ancestry-specific signal. The individuals homozygous for rs181704186-G have a mean CRP level of 0.23 mg/L, in contrast to individuals heterozygous for rs181704186 with mean CRP of 2.97 mg/L and major allele homozygotes with mean CRP of 4.11 mg/L. This study demonstrates the utility of WGS in multi-ethnic populations to drive discovery of complex trait associations of large effect and to identify functional alleles in noncoding regulatory regions.


Assuntos
Grupo com Ancestrais do Continente Africano/genética , Grupo com Ancestrais do Continente Asiático/genética , Proteína C-Reativa/genética , Grupo com Ancestrais do Continente Europeu/genética , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Sequenciamento Completo do Genoma/métodos , Estudos de Coortes , Frequência do Gene , Estudo de Associação Genômica Ampla , Humanos , Desequilíbrio de Ligação
18.
Int J Mol Sci ; 20(23)2019 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-31795454

RESUMO

: (1) Background: Age-related macular degeneration (AMD) is closely related with retinal pigment epithelial (RPE) cell dysfunction. Although the exact pathogenesis of AMD remains largely unknown, oxidative stress-induced RPE damage is believed to be one of the primary causes. We investigated the molecular mechanisms of pentraxin 3 (PTX3) expression and its biological functions during oxidative injury. (2) Methods: Using enzyme-linked immunosorbent assays and real-time reverse transcription-polymerase chain reaction, we analyzed mRNA and protein levels of PTX3 in the presence or absence of oxidative stress inducer, sodium iodate (NaIO3), in primary human H-RPE and ARPE-19 cells. Furthermore, we assessed cell death, antioxidant enzyme expression, and AMD-associated gene expression to determine the biological functions of PTX3 under oxidative stress. (3) Results: NaIO3 increased PTX3 expression, in a dose- and time-dependent manner, in H-RPE and ARPE-19 cells. We found phosphorylated Akt, a downstream target of the PI3 kinase pathway, phosphor- mitogen-activated protein kinase kinase 1/2 (ERK), and intracellular reactive oxygen species (ROS) were predominantly induced by NaIO3. NaIO3-induced PTX3 expression was decreased in the presence of phosphoinositide 3 (PI3) kinase inhibitors, ERK inhibitors, and ROS scavengers. Furthermore, NaIO3 enhanced mRNA expression of antioxidant enzymes such as glucose-6-phosphate dehydrogenase (G6PDH), catalase (CAT), and glutathione S-reductase (GSR) in the control shRNA expressing RPE cells, but not in hPTX3 shRNA expressing RPE cells. Interestingly, NaIO3 did not induce mRNA expression of AMD marker genes, such as complement factor I (CFI), complement factor H (CFH), apolipoprotein E (APOE), and toll-like receptor 4 (TLR4) in hPTX3 shRNA expressing RPE cells. 4) Conclusions: These results suggest that PTX3 accelerates RPE cell death and might be involved in AMD development in the presence of oxidative stress.


Assuntos
Proteína C-Reativa/metabolismo , Degeneração Macular/metabolismo , Estresse Oxidativo , Epitélio Pigmentado da Retina/metabolismo , Componente Amiloide P Sérico/metabolismo , Proteína C-Reativa/genética , Morte Celular , Linhagem Celular , Humanos , Sistema de Sinalização das MAP Quinases , Degeneração Macular/genética , Degeneração Macular/patologia , Espécies Reativas de Oxigênio/metabolismo , Epitélio Pigmentado da Retina/patologia , Componente Amiloide P Sérico/genética , Regulação para Cima
19.
Sensors (Basel) ; 19(24)2019 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-31842479

RESUMO

The integration of several controlled parameters within a single test system is experiencing increased demand. However, multiplexed test systems typically require complex manufacturing. Here, we describe a multiplexed immunochromatographic assay that incorporates a conventional nitrocellulose membrane, which is used together with microspot printing, to construct adjacent microfluidic "tracks" for multiplexed detection. The 1 mm distance between tracks allows for the detection of up to four different analytes. The following reagents are applied in separate zones: (a) gold nanoparticle conjugates with antibodies against each analyte, (b) other antibodies against each analyte, and (c) antispecies antibodies. The immersion of the test strip in the sample initiates the lateral flow, during which reagents of different specificities move along their tracks without track erosion or reagent mixing. An essential advantage of the proposed assay is its extreme rapidity (1-1.5 min compared with 10 min for common test strips). This assay format was applied to the detection of cardiac and inflammatory markers (myoglobin, D-dimer, and C-reactive protein) in human blood, and was characterized by high reproducibility (8%-15% coefficient of variation) with stored working ranges of conventional tests. The universal character of the proposed approach will facilitate its use for various analytes.


Assuntos
Anticorpos/isolamento & purificação , Técnicas Biossensoriais , Técnicas de Diagnóstico Cardiovascular , Imunoensaio/métodos , Anticorpos/genética , Proteína C-Reativa/genética , Proteína C-Reativa/isolamento & purificação , Cromatografia de Afinidade , Produtos de Degradação da Fibrina e do Fibrinogênio/genética , Produtos de Degradação da Fibrina e do Fibrinogênio/isolamento & purificação , Ouro/química , Humanos , Nanopartículas Metálicas/química , Mioglobina/sangue , Mioglobina/isolamento & purificação , Fitas Reagentes/química
20.
Int J Mol Sci ; 20(22)2019 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-31744201

RESUMO

Pentraxin-3 (PTX3) is recognized as a modulator of inflammation and a mediator of tissue repair. In this study, we characterized the role of PTX3 on some biological functions of human dental pulp stem cells (HDPSCs). The expression level of PTX3 significantly increased during osteogenic/odontogenic differentiation of HDPSCs, whereas the knockdown of PTX3 decreased this differentiation. Silencing of PTX3 in HDPSCs inhibited their migration and C-X-C chemokine receptor type 4 (CXCR4) expression. Our present study indicates that PTX3 is involved in osteogenic/odontogenic differentiation and migration of HDPSCs, and may contribute to the therapeutic potential of HDPSCs for regeneration and repair.


Assuntos
Proteína C-Reativa/metabolismo , Diferenciação Celular , Movimento Celular , Odontogênese/fisiologia , Osteogênese/fisiologia , Componente Amiloide P Sérico/metabolismo , Proteína C-Reativa/genética , Polpa Dentária/crescimento & desenvolvimento , Polpa Dentária/fisiologia , Técnicas de Silenciamento de Genes , Humanos , Receptores CXCR4/metabolismo , Componente Amiloide P Sérico/genética , Células-Tronco/fisiologia
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