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1.
J Clin Pathol ; 73(1): 7-13, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31422373

RESUMO

AIMS: Hereditary protein S (PS) deficiency is one of the natural anticoagulant deficiencies causing thrombophilia. We herein described a young male with recurrent deep venous thrombosis, who was diagnosed as type I PS deficiency with compound heterozygous mutations of PROS1 gene. We aimed to analyse the relationship between the genotype and phenotype detection and investigate the pathological mechanisms of PROS1 mutations causing PS deficiency. METHODS: Genetic analysis of PROS1 gene was carried out by direct sequencing. Thrombin generation potential and the inhibition function of thrombin generation by plasma PS were detected by thrombin generation test (TGT). The mRNA transcription level of mutant PS in vitro was measured by real-time PCR, while the protein level was evaluated by western blot and ELISA. Cellular distribution of the protein was further analysed by immunofluorescence. RESULTS: Compound heterozygous mutations (PROS1 c.1551_1552delinsG, p.Thr518Argfs*39 and PROS1 c.1681C>T, p.Arg561Trp) were identified in the propositus, and the former one was a novel small indel mutation. TGT results showed impaired inhibition of thrombin generation with the addition of activated protein C in his parents with certain heterozygous mutations. In vitro expression study, p.Thr518Argfs*39 mutant produced truncated protein retained in the cytoplasm, while p.Arg561Trp mutant partially affected the secretion of PS. Both mutations are located in C-terminal sex hormone-binding globulin (SHBG)-like domain of PS. CONCLUSIONS: Compound heterozygous mutations identified in the study have strong detrimental effect, causing severe type I PS deficiency in the propositus. SHBG-like domain of PS might play an important role in PS secretion system.


Assuntos
Coagulação Sanguínea/genética , Proteínas Sanguíneas/genética , Heterozigoto , Mutação , Deficiência de Proteína S/genética , Trombose Venosa/genética , Adulto , Proteínas Sanguíneas/metabolismo , Feminino , Predisposição Genética para Doença , Células HEK293 , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Deficiência de Proteína S/sangue , Deficiência de Proteína S/diagnóstico , Recidiva , Via Secretória , Índice de Gravidade de Doença , Trombina/metabolismo , Trombose Venosa/sangue , Trombose Venosa/diagnóstico
2.
Nat Med ; 25(12): 1851-1857, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31792462

RESUMO

Proteins are effector molecules that mediate the functions of genes1,2 and modulate comorbidities3-10, behaviors and drug treatments11. They represent an enormous potential resource for personalized, systemic and data-driven diagnosis, prevention, monitoring and treatment. However, the concept of using plasma proteins for individualized health assessment across many health conditions simultaneously has not been tested. Here, we show that plasma protein expression patterns strongly encode for multiple different health states, future disease risks and lifestyle behaviors. We developed and validated protein-phenotype models for 11 different health indicators: liver fat, kidney filtration, percentage body fat, visceral fat mass, lean body mass, cardiopulmonary fitness, physical activity, alcohol consumption, cigarette smoking, diabetes risk and primary cardiovascular event risk. The analyses were prospectively planned, documented and executed at scale on archived samples and clinical data, with a total of ~85 million protein measurements in 16,894 participants. Our proof-of-concept study demonstrates that protein expression patterns reliably encode for many different health issues, and that large-scale protein scanning12-16 coupled with machine learning is viable for the development and future simultaneous delivery of multiple measures of health. We anticipate that, with further validation and the addition of more protein-phenotype models, this approach could enable a single-source, individualized so-called liquid health check.


Assuntos
Proteínas Sanguíneas/genética , Composição Corporal/genética , Exercício , Medicina de Precisão , Tecido Adiposo/metabolismo , Composição Corporal/fisiologia , Feminino , Humanos , Gordura Intra-Abdominal/metabolismo , Estilo de Vida , Fígado/metabolismo , Masculino , Fatores de Risco
3.
Nat Med ; 25(12): 1843-1850, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31806903

RESUMO

Aging is a predominant risk factor for several chronic diseases that limit healthspan1. Mechanisms of aging are thus increasingly recognized as potential therapeutic targets. Blood from young mice reverses aspects of aging and disease across multiple tissues2-10, which supports a hypothesis that age-related molecular changes in blood could provide new insights into age-related disease biology. We measured 2,925 plasma proteins from 4,263 young adults to nonagenarians (18-95 years old) and developed a new bioinformatics approach that uncovered marked non-linear alterations in the human plasma proteome with age. Waves of changes in the proteome in the fourth, seventh and eighth decades of life reflected distinct biological pathways and revealed differential associations with the genome and proteome of age-related diseases and phenotypic traits. This new approach to the study of aging led to the identification of unexpected signatures and pathways that might offer potential targets for age-related diseases.


Assuntos
Envelhecimento/sangue , Proteínas Sanguíneas/genética , Longevidade/genética , Proteoma/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/genética , Animais , Doença Crônica , Feminino , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Fatores de Risco , Adulto Jovem
4.
Cancer Immunol Immunother ; 68(9): 1537-1545, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31482306

RESUMO

PURPOSE: To evaluate the clinical-pathological and prognostic significance of the circulating PD-L1 level in patients with surgically treated NSCLC, by combining data for PD-L1 expression with other immune-related markers and tumor metabolism. METHODS: Overall, 40 patients with resected NSCLC (stage Ia-IIIa) who had preoperative blood storage and underwent staging PET/CT were enrolled for the study. In all cases, we determined plasma levels of PD-L1 (pg/ml), immune-reactive areas (IRA %) covered by CD3, CD68, CD20, CD8, PD-1, and PD-L1 in the tumor specimen, and metabolic parameters on PET, i.e., SUVmax, SUVpeak, metabolic tumor volume (MTV), and total lesion glycolysis (TLG). Variables were statistically analyzed to establish their association with disease-free survival (DFS). RESULTS: The circulating levels of PD-L1 in the bloodstream could be determined in 38/40 (95%) samples. The mean and median expression levels were 34.86 pg/ml and 24.83 pg/ml, respectively. We did not find any statistically significant correlation between circulating PD-L1 and tissue expression of PD-L1/PD-1. Some mild degree of positive correlation was determined between tissue PD-L1 and SUVmax (ρ = 0.390; p = 0.0148). Hierarchical clustering combining circulating, tissue, and metabolic parameters identified clusters with high metabolic tumor burden or high expression of plasma PD-L1 levels (Z score ≥ 2) as having a poor DFS (p = 0.033). The multivariate analysis detected stage and metabolism (i.e., SUVmax and SUVpeak) as independent prognostic factors for DFS. CONCLUSION: Plasma levels of PD-L1 are independent of the expression of PD-1/PD-L1 in NSCLC tumor tissue and, when combined with other clinical-pathological parameters, allow for the identification of clusters with different outcomes.


Assuntos
Antígeno B7-H1/metabolismo , Proteínas Sanguíneas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Neoplasias Pulmonares/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígeno B7-H1/genética , Proteínas Sanguíneas/genética , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Feminino , Regulação Neoplásica da Expressão Gênica , Glicólise , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Análise de Sobrevida , Resultado do Tratamento , Carga Tumoral
5.
Fish Shellfish Immunol ; 93: 841-850, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31430558

RESUMO

Bactericidal permeability-increasing protein (BPI) is an antimicrobial protein with potent endotoxin-neutralising activity and plays a crucial role in innate immunity against bacterial infection. In the present study, a bpi (designed as rpbpi) was identified and characterized from manila clam Ruditapes philippinarum. Multiple alignments and phylogenetic analysis suggested that rpbpi was a new member of the bpis family. In non-stimulated clams, rpbpi transcripts were ubiquitously expressed in all tested tissues with the highest expression level in hemocytes. After Vibrio anguillarum challenge, the expression levels of rpbpi mRNA in hemocytes were up-regulated significantly at 3 h and 48 h compared with that in the control, which were 4.01- and 19.10-fold (P < 0.05), respectively. The recombinant RpBPI (rRpBPI) showed high antibacterial activities against Gram-negative bacteria Escherichia coli and V. anguillarum, but not Staphylococcus aureus. Moreover, membrane integrity analysis revealed that rRpBPI increased the membrane permeability of Gram-negative bacteria, and then resulted in cell death. Overall, our results suggested that RpBPI played an important role in the elimination of invaded bacteria through membrane-disruptive activity.


Assuntos
Peptídeos Catiônicos Antimicrobianos/genética , Peptídeos Catiônicos Antimicrobianos/imunologia , Bivalves/genética , Bivalves/imunologia , Proteínas Sanguíneas/genética , Proteínas Sanguíneas/imunologia , Regulação da Expressão Gênica/imunologia , Imunidade Inata/genética , Sequência de Aminoácidos , Animais , Antibacterianos/metabolismo , Peptídeos Catiônicos Antimicrobianos/química , Sequência de Bases , Proteínas Sanguíneas/química , Perfilação da Expressão Gênica , Bactérias Gram-Negativas/fisiologia , Filogenia , Alinhamento de Sequência
6.
Blood ; 134(12): 911-923, 2019 09 19.
Artigo em Inglês | MEDLINE | ID: mdl-31366617

RESUMO

There is increasing recognition that platelets have a functional role in the pathophysiology of sepsis, though this role has not been precisely defined. Whether sepsis alters the human platelet transcriptome and translational landscape has never been established. We used parallel techniques of RNA sequencing and ribosome footprint profiling to interrogate the platelet transcriptome and translatome in septic patients and healthy donors. We identified 1806 significantly differentially expressed (false discovery rate <0.05) transcripts in platelets from septic patients. Platelet translational events during sepsis were also upregulated. To explore the relevance of a murine model of sepsis, cecal ligation and puncture (CLP), we compared sepsis-induced changes in platelet gene expression between septic patients and mice subjected to CLP. Platelet transcriptional (ρ = 0.42, P = 3.2 × 10-285) and translational (ρ = 0.65, P = 1.09 × 10-56) changes were significantly correlated between septic patients and mice. We focused on ITGA2B, tracking and validating the expression, regulation, and functional impact of changes in ITGA2B during sepsis. Increased ITGA2B was identified in bone marrow megakaryocytes within 24 hours of sepsis onset. Subsequent increases in ITGA2B were seen in circulating platelets, suggesting dynamic trafficking of the messenger RNA. Transcriptional changes in ITGA2B were accompanied by de novo protein synthesis of αIIb and integrin αIIbß3 activation. Increased αIIb was associated with mortality in humans and mice. These findings provide previously unrecognized evidence that human and murine sepsis similarly alters the platelet transcriptional and translational landscape. Moreover, ITGA2B is upregulated and functional in sepsis due to trafficking from megakaryocytes and de novo synthesis in platelets and is associated with increased mortality.


Assuntos
Plaquetas/metabolismo , Sepse/genética , Sepse/metabolismo , Animais , Plaquetas/patologia , Proteínas Sanguíneas/análise , Proteínas Sanguíneas/genética , Proteínas Sanguíneas/metabolismo , Estudos de Casos e Controles , Feminino , Perfilação da Expressão Gênica , Humanos , Masculino , Camundongos , Biossíntese de Proteínas , Proteoma/análise , Proteômica , Sepse/sangue , Sepse/patologia , Índice de Gravidade de Doença , Transcrição Genética , Transcriptoma
7.
Nat Commun ; 10(1): 3160, 2019 07 18.
Artigo em Inglês | MEDLINE | ID: mdl-31320639

RESUMO

Although plasma proteins may serve as markers of neurological disease risk, the molecular mechanisms responsible for inter-individual variation in plasma protein levels are poorly understood. Therefore, we conduct genome- and epigenome-wide association studies on the levels of 92 neurological proteins to identify genetic and epigenetic loci associated with their plasma concentrations (n = 750 healthy older adults). We identify 41 independent genome-wide significant (P < 5.4 × 10-10) loci for 33 proteins and 26 epigenome-wide significant (P < 3.9 × 10-10) sites associated with the levels of 9 proteins. Using this information, we identify biological pathways in which putative neurological biomarkers are implicated (neurological, immunological and extracellular matrix metabolic pathways). We also observe causal relationships (by Mendelian randomisation analysis) between changes in gene expression (DRAXIN, MDGA1 and KYNU), or DNA methylation profiles (MATN3, MDGA1 and NEP), and altered plasma protein levels. Together, this may help inform causal relationships between biomarkers and neurological diseases.


Assuntos
Biomarcadores/sangue , Proteínas Sanguíneas/análise , Proteínas Sanguíneas/genética , Doenças do Sistema Nervoso/sangue , Doenças do Sistema Nervoso/genética , Idoso , Ilhas de CpG/genética , Metilação de DNA/genética , Epigênese Genética/genética , Feminino , Genoma Humano/genética , Estudo de Associação Genômica Ampla , Humanos , Masculino , Locos de Características Quantitativas/genética , Escócia
8.
Ann Hematol ; 98(8): 1827-1834, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31190133

RESUMO

In this study, we aimed to investigate the pattern and association of genetic mutations occurring within the alpha hemoglobin-stabilizing protein (AHSP) gene among HbE beta thalassemia patients with varying phenotypic expressions. Fifty-four diagnosed cases of HbE beta thalassemia (transfusion dependent and independent) were included in the study. Among them, 38 patients with similar genotypes (IVS 1-5, alpha gene deletion and triplication, Xmn polymorphism) were selected for further analysis. AHSP gene sequencing was done for these 38 samples to study associated mutations in AHSP gene. HbE beta thalassemia patients with similar genotypes but different phenotypic expressions were found to have mutations in the AHSP gene. There were five mutations found most prevalent among the samples analyzed for AHSP gene sequencing. Among these, two mutations were from intron 1 region of AHSP and three mutations were found in exon 3. The most prevalent mutation was found at the Oct binding site at intron 1 of AHSP. The mutations in exon 3 were more prevalent among the TDT groups. A mutation in exon 3 changing the amino acid (33rd) from serine to phenylalanine was found to be associated with only TDT group. This study documents that among the HbE beta thalassemia patients with varying severity, an exon mutation in AHSP is significantly prevalent only among the TDT group. Further understanding of the mechanism will shed light upon the impact of AHSP in modifying the disease severity in thalassemia.


Assuntos
Proteínas Sanguíneas/genética , Deleção de Genes , Duplicação Gênica , Hemoglobina E/genética , Chaperonas Moleculares/genética , Talassemia beta/genética , Adolescente , Adulto , Sequência de Bases , Proteínas Sanguíneas/metabolismo , Transfusão de Sangue/estatística & dados numéricos , Criança , Pré-Escolar , Análise Mutacional de DNA , Eritrócitos/metabolismo , Eritrócitos/patologia , Éxons , Feminino , Expressão Gênica , Genótipo , Hemoglobina E/metabolismo , Humanos , Íntrons , Masculino , Pessoa de Meia-Idade , Modelos Moleculares , Chaperonas Moleculares/metabolismo , Fenótipo , Estrutura Secundária de Proteína , Índice de Gravidade de Doença , Talassemia beta/metabolismo , Talassemia beta/patologia , Talassemia beta/terapia
9.
Rinsho Ketsueki ; 60(3): 171-183, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31068512

RESUMO

Protein S (PS) gene (PROS1) is found on chromosome 3 (3q11.1). To date, the reported detection rate of causative gene mutations in patients suspected of PS deficiency is only approximately 50%. To improve the detection rate of causative mutations, an exhaustive analysis of PROS1 was attempted using the next-generation sequencing method (NGS) to analyze the entire nucleotide sequence of PROS1 without analyzing those affected by pseudogenes. A total of 10 different mutations (three males and six females (52.9%) out of 17 patients (3 males and 14 females) with clinical PS deficiency were identified in this study. Remarkable improvements in the detection rate of causative mutations could not be obtained even with NGS analysis. These results suggested that the rate of diagnosis did not improve even after performing an exhaustive genetic analysis in patients clinically diagnosed with low PS antigen level and/or low PS activity. Although no reports were found on the gender gap in the rate of gene diagnosis for PS deficiency, the fluctuation of estrogen levels especially in women might cause a lower rate of diagnosis.


Assuntos
Proteínas Sanguíneas/genética , Sequenciamento de Nucleotídeos em Larga Escala , Mutação , Deficiência de Proteína S/genética , Análise Mutacional de DNA , Feminino , Humanos , Masculino
10.
Folia Histochem Cytobiol ; 57(2): 43-55, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31099889

RESUMO

Biological membranes are organized in various microdomains, one of the best known being called membrane rafts. The major function of these is thought to organize signaling partners into functional complexes. An important protein found in membrane raft microdomains of erythroid and other blood cells is MPP1 (membrane palmitoylated protein 1)/p55. MPP1 (p55) belongs to the MAGUK (membrane-associated guanylate kinase homolog) family and it is a major target of palmitoylation in the red blood cells (RBCs) membrane. The well-known function of this protein is to participate in formation of the junctional complex of the erythrocyte mem-brane skeleton. However, its function as a "raft organizer" is not well understood. In this review we focus on recent reports concerning MPP1 participation in membrane rafts organization in erythroid cells, including its role in signal transduction. Currently it is not known whether MPP1 could have a similar role in cell types other than erythroid lineage. We present also preliminary data regarding the expression level of MPP1 gene in several non-erythroid cell lines.


Assuntos
Proteínas Sanguíneas/metabolismo , Membrana Celular/metabolismo , Eritrócitos/metabolismo , Microdomínios da Membrana/metabolismo , Proteínas de Membrana/metabolismo , Proteínas Sanguíneas/genética , Colesterol/metabolismo , Humanos , Fluidez de Membrana/fisiologia , Lipídeos de Membrana/metabolismo , Proteínas de Membrana/genética , Ligação Proteica
11.
J Diabetes Res ; 2019: 2310235, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31089471

RESUMO

Measurements of fasting glucose (FG) or glycated hemoglobin A1c (HbA1c) are two clinically approved approaches commonly used to determine glycemia, both of which are influenced by genetic factors. Obtaining accurate measurements of FG or HbA1c is not without its challenges, though. Measuring glycated serum protein (GSP) offers an alternative approach for assessing glycemia. The aim of this study was to estimate the heritability of GSP and GSP expressed as a percentage of total serum albumin (%GA) using a variance component approach and localize genomic regions (QTLs) that harbor genes likely to influence GSP and %GA trait variation in a large extended multigenerational pedigree from Jiri, Nepal (n = 1,800). We also performed quantitative bivariate analyses to assess the relationship between GSP or %GA and several cardiometabolic traits. Additive genetic effects significantly influence variation in GSP and %GA levels (p values: 1.15 × 10-5 and 3.39 × 10-5, respectively). We localized a significant (LOD score = 3.18) and novel GSP QTL on chromosome 11q, which has been previously linked to type 2 diabetes. Two common (MAF > 0.4) SNPs within the chromosome 11 QTL were associated with GSP (adjusted pvalue < 5.87 × 10-5): an intronic variant (rs10790184) in the DSCAML1 gene and a 3'UTR variant (rs8258) in the CEP164 gene. Significant positive correlations were observed between GSP or %GA and blood pressure, and lipid traits (p values: 0.0062 to 1.78 × 10-9). A significant negative correlation was observed between %GA and HDL cholesterol (p = 1.12 × 10-5). GSP is influenced by genetic factors and can be used to assess glycemia and diabetes risk. Thus, GSP measurements can facilitate glycemic studies when accurate FG and/or HbA1c measurements are difficult to obtain. GSP can also be measured from frozen blood (serum) samples, which allows the prospect of retrospective glycemic studies using archived samples.


Assuntos
Glicemia/análise , Proteínas Sanguíneas/genética , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/diagnóstico , Diabetes Mellitus/sangue , Diabetes Mellitus/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/metabolismo , Pressão Sanguínea , Índice de Massa Corporal , HDL-Colesterol/sangue , Saúde da Família , Feminino , Predisposição Genética para Doença , Genótipo , Hemoglobina A Glicada/genética , Glicosilação , Humanos , Hiperglicemia , Hipoglicemia/sangue , Lipídeos/sangue , Lipídeos/química , Escore Lod , Masculino , Pessoa de Meia-Idade , Nepal , Linhagem , Fenótipo , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Estudos Retrospectivos , Fatores de Risco , Albumina Sérica/análise , Adulto Jovem
12.
Cell Mol Life Sci ; 76(18): 3515-3523, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31089746

RESUMO

Cytokine-like protein 1 (Cytl1), also named Protein C17 or C4orf4 is located on human chromosome 4p15-p16 and encodes a polypeptide of 126 amino acid residues that displays characteristics of a secretory protein. Cytl1 is expressed by a sub-population of CD34+ human mononuclear cells from bone marrow and cord blood, and by chondrocytes (cartilage-forming cells). In this review, we explore evidence suggesting that Cytl1 may be involved in the regulation of chondrogenesis, cartilage homeostasis and osteoarthritis progression, accompanied by the modulation of Sox9 and insulin-like growth factor 1 expression. In addition, Cytl1 exhibits chemotactic and pro-angiogenic biological effects. Interestingly, CCR2 (C-C chemokine receptor type 2) has been identified as a likely receptor for Cytl1, which mediates the ERK signalling pathway. Cytl1 also appears to mediate the TGF-beta-Smad signalling pathway, which is hypothetically independent of the CCR2 receptor. More recently, studies have also potentially linked Cytl1 with a variety of conditions including cardiac fibrosis, smoking, alcohol dependence risk, and tumours such as benign prostatic hypertrophy, lung squamous cell carcinoma, neuroblastoma and familial colorectal cancer. Defining the molecular structure of Cytl1 and its role in disease pathogenesis will help us to design therapeutic approaches for Cytl1-associated pathological conditions.


Assuntos
Proteínas Sanguíneas/metabolismo , Cartilagem/metabolismo , Citocinas/metabolismo , Proteínas Sanguíneas/química , Proteínas Sanguíneas/genética , Condrócitos/citologia , Condrócitos/metabolismo , Condrogênese , Citocinas/química , Citocinas/genética , Humanos , Osteoartrite/metabolismo , Osteoartrite/patologia , Receptores CCR2/metabolismo , Transdução de Sinais
13.
Nat Med ; 25(5): 805-813, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31011203

RESUMO

Chronic inflammation is postulated to be involved in the development of end-stage renal disease in diabetes, but which specific circulating inflammatory proteins contribute to this risk remain unknown. To study this, we examined 194 circulating inflammatory proteins in subjects from three independent cohorts with type 1 and type 2 diabetes. In each cohort, we identified an extremely robust kidney risk inflammatory signature (KRIS), consisting of 17 proteins enriched in tumor necrosis factor-receptor superfamily members, that was associated with a 10-year risk of end-stage renal disease. All these proteins had a systemic, non-kidney source. Our prospective study findings provide strong evidence that KRIS proteins contribute to the inflammatory process underlying end-stage renal disease development in both types of diabetes. These proteins point to new therapeutic targets and new prognostic tests to identify subjects at risk of end-stage renal disease, as well as biomarkers to measure responses to treatment of diabetic kidney disease.


Assuntos
Nefropatias Diabéticas/sangue , Nefropatias Diabéticas/etiologia , Falência Renal Crônica/sangue , Falência Renal Crônica/etiologia , Adulto , Idoso , Biomarcadores/sangue , Proteínas Sanguíneas/genética , Proteínas Sanguíneas/metabolismo , Estudos de Coortes , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/genética , Nefropatias Diabéticas/genética , Progressão da Doença , Feminino , Humanos , Mediadores da Inflamação/sangue , Falência Renal Crônica/genética , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Proteômica , Receptores do Fator de Necrose Tumoral/sangue , Receptores do Fator de Necrose Tumoral/genética , Fatores de Risco
14.
Gene ; 702: 143-147, 2019 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-30935919

RESUMO

The genetic defects of a 12-year-old patient with factor XIII deficiency (FXIIID) and eight pedigree members suspected with FXIIID were studied. Clinical diagnosis, pedigree investigation, phenotypic study and genetic analysis were performed. DNA sequence analysis revealed that the proband had a novel deletion mutation of F13A1 gene (NM_000129: exon 12: c.1652delC: p.Thr551LysfsTer26) which he inherited from both the parents who were heterozygous for the same 1652delC deletion. This frameshift (p.Thr551LysfsTer26) led in homozygous form to severe FXIIID. Additionally, a homozygous missense mutation of NBEAL2 gene (NM_015175: exon 13: c.1367C > T: p.Ala456Val) was identified in the proband. Again, the mutation was inherited from both the parents who were heterozygous for the same c.1367C > T novel mutation. Other members of the pedigree were also revealed to be heterozygous for the same proband's F13A1 and NBEAL2 genes mutations. We first report a pedigree with pathogenic F13A1 gene mutation and a novel mutant NBEAL2 gene.


Assuntos
Proteínas Sanguíneas/genética , Deficiência do Fator XIII/genética , Fator XIII/genética , Mutação de Sentido Incorreto , Deleção de Sequência , Adulto , Idoso , Plaquetas/ultraestrutura , Criança , Deficiência do Fator XIII/congênito , Deficiência do Fator XIII/diagnóstico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem
15.
Methods Mol Biol ; 1964: 45-57, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30929234

RESUMO

Differential scanning calorimetry (DSC) has been used for several decades to characterize thermal stability of macromolecules such as proteins and DNA. It allows to determine the denaturation temperature and enthalpy of individual domains of proteins, thus giving new insights into their domain organization and ligand interaction. Over the past decade, it has been shown that this technique can also be used to study biofluids such as plasma or cerebrospinal fluid to obtain denaturation profiles. An increasing number of studies demonstrated that such profiles obtained from patients were significantly different from profiles obtained using biofluids of healthy individuals. This opens interesting perspectives for new diagnostics and monitoring tools for a large number of diseases. Nevertheless, the extensive studies of plasma samples from patients with different pathologies as well as the development of standardized methods of data analysis are necessary to reach the promising diagnostic potential of this methodology. Using plasma samples from healthy individuals and glioblastoma patients, we outline the steps necessary to obtain a plasmatic calorimetric profile with VP-DSC instrument and describe a cluster analysis of obtained data.


Assuntos
Proteínas Sanguíneas/química , Varredura Diferencial de Calorimetria/métodos , Proteínas do Líquido Cefalorraquidiano/química , Glioblastoma/genética , Proteínas Sanguíneas/genética , Proteínas do Líquido Cefalorraquidiano/genética , DNA/química , DNA/genética , Glioblastoma/sangue , Glioblastoma/líquido cefalorraquidiano , Humanos , Ligantes , Desnaturação Proteica , Temperatura Ambiente , Termodinâmica
18.
Fish Shellfish Immunol ; 87: 499-506, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30731212

RESUMO

Bactericidal permeability-increasing protein (BPI) and lipopolysaccharide-binding protein (LBP) play important roles in host antimicrobial defense. In the present study, we identified one isoform of BPI/LBP gene from turbot (Scophthalmus maximus), designated as SmBPI/LBP1. The full-length cDNA sequence of SmBPI/LBP1 was 1826 bp, which encoding one secreted protein with 480 amino acid residues. Structurally, the SmBPI/LBP1 showed high similarity to its homologs from other vertebrates or invertebrates, which all contained a signal peptide, a BPI/LBP/CETP N-terminal with a LPS-binding domain, and a BPI/LBP/CETP C-terminal domain. The deduced amino acid sequences of SmBPI/LBP1 shared significant similarity to BPI/LBP of Seriola lalandi dorsalis (71%) and Paralichthys olivaceus (69%). Phylogentic analysis further supported that SmBPI/LBP1 act as a new member of vertebrate BPI/LBP family. SmBPI/LBP1 was ubiquitously expressed in all tested tissues, with the highest expression level in spleen tissue. The mRNA expression of SmBPI/LBP1 in spleen and kidney were significantly up-regulated after Vibrio vulnificus challenge. Finally, the recombinant SmBPI/LBP1 showed high affinity to lipopolysaccharide, followed by peptidoglycan and lipoteichoic acid, which is the ubiquitous component of Gram-negative or Gram-positive bacteria. These results indicated that SmBPI/LBP1 probably played important roles in immune response against bacteria infection.


Assuntos
Doenças dos Peixes/imunologia , Proteínas de Peixes/genética , Proteínas de Peixes/imunologia , Linguados/genética , Linguados/imunologia , Regulação da Expressão Gênica/imunologia , Imunidade Inata/genética , Proteínas da Fase Aguda/química , Proteínas da Fase Aguda/genética , Proteínas da Fase Aguda/imunologia , Sequência de Aminoácidos , Animais , Peptídeos Catiônicos Antimicrobianos/química , Peptídeos Catiônicos Antimicrobianos/genética , Peptídeos Catiônicos Antimicrobianos/imunologia , Sequência de Bases , Proteínas Sanguíneas/química , Proteínas Sanguíneas/genética , Proteínas Sanguíneas/imunologia , Proteínas de Transporte/química , Proteínas de Transporte/genética , Proteínas de Transporte/imunologia , Proteínas de Peixes/química , Perfilação da Expressão Gênica/veterinária , Lipopolissacarídeos/fisiologia , Glicoproteínas de Membrana/química , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/imunologia , Peptidoglicano , Filogenia , Alinhamento de Sequência/veterinária , Ácidos Teicoicos , Vibrioses/imunologia , Vibrioses/veterinária , Vibrio vulnificus/fisiologia
19.
Biomed Res Int ; 2019: 5653424, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30792993

RESUMO

Most multidrug-resistant tuberculosis (MDR-TB) patients fail to receive a timely diagnosis and treatment. Therefore, we explored the differentially expressed peptides in MDR-TB compared with drug-susceptible tuberculosis (DS-TB) patients using LC-MS/MS and Ingenuity Pathway Analysis (IPA) to analyse the potential significance of these differentially expressed peptides. A total of 301 peptides were differentially expressed between MDR-TB and DS-TB groups. Of these, 24 and 16 peptides exhibited presented high (fold change ≥ 2.0, P < 0.05) and low (fold change ≤ -2.0, P < 0.05) levels in MDR-TB. Significant canonical pathways included the prothrombin activation system, coagulation system, and complement system. In the network of differentially expressed precursor proteins, lipopolysaccharide (LPS) regulates many precursor proteins, including four proteins correlated with organism survival. These four important differentially expressed proteins are prothrombin (F2), complement receptor type 2 (CR2), collagen alpha-2(V) chain (COL5A2), and inter-alpha-trypsin inhibitor heavy chain H4 (ITIH4). After addition of CR2 peptide, IL-6 mRNA expression in THP-1 cells decreased significantly in dose- and time-dependent manners. Cumulatively, our study proposes potential biomarkers for MDR-TB diagnosis and enables a better understanding of the pathogenesis of MDR-TB. The functions of differentially expressed peptides, especially CR2, in MDR-TB require further investigation.


Assuntos
Biomarcadores , Peptídeos/genética , Proteômica , Tuberculose Resistente a Múltiplos Medicamentos/genética , Adulto , Proteínas Sanguíneas/genética , Cromatografia Líquida , Colágeno Tipo V/genética , Feminino , Regulação da Expressão Gênica/genética , Glicoproteínas/genética , Humanos , Masculino , Mycobacterium tuberculosis/patogenicidade , Proteínas Secretadas Inibidoras de Proteinases/genética , Protrombina/genética , Receptores de Complemento 3d/genética , Transdução de Sinais , Espectrometria de Massas em Tandem , Tuberculose Resistente a Múltiplos Medicamentos/microbiologia , Tuberculose Resistente a Múltiplos Medicamentos/patologia
20.
J Vet Med Sci ; 81(3): 418-424, 2019 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-30674748

RESUMO

Equine Glandular Gastric Disease (EGGD) is a common disease in sport horses. This disease might be associated with usage of nonsteroidal anti-inflammatory drugs (NSAIDs) for treating inflammatory diseases. Although gastroscopy has been an effective method for diagnosis, but a less invasive, and inexpensive method is preferred. This study used proteomic technology to identify candidate serum proteins that might be used as markers of NSAIDs induced EGGD. Five Thoroughbred horses were given high doses of NSAID, phenylbutazone to treat lameness. The experiment was divided into three periods: (i) Pre-EGGD period, (ii) during EGGD period, and (iii) Post-EGGD period. Gastroscopy were used to diagnose EGGD, serum was collected to perform gel electrophoresis (1D SDS-PAGE) and mass spectrometry (LC-MS) in order to identify serum proteins in each group. The candidate serum proteins were computationally predicted for the interaction between phenylbutazone and proteins, tissue specific expression, and association to gastric ulceration. After EGGD induction, all horses showed clinical signs of colic with marked congestion and erosion appearing in the mucosa of the glandular stomach whereas no change was observed in the mucosa of non-glandular stomach. Our proteomic results identified 14 proteins that might be used as EGGD markers. These proteins were highly expressed in the glandular stomach and some proteins were associated with phenylbutazone or ulcer development. However, confirmation of these candidate marker proteins is required with specific antibodies in the larger horse population before they can be considered for application in the field.


Assuntos
Anti-Inflamatórios não Esteroides/toxicidade , Proteínas Sanguíneas/metabolismo , Doenças dos Cavalos/induzido quimicamente , Fenilbutazona/toxicidade , Gastropatias/induzido quimicamente , Animais , Proteínas Sanguíneas/genética , Cavalos , Masculino
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