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1.
Immunity ; 55(3): 542-556.e5, 2022 03 08.
Artigo em Inglês | MEDLINE | ID: mdl-35151371

RESUMO

Some patients hospitalized with acute COVID-19 suffer respiratory symptoms that persist for many months. We delineated the immune-proteomic landscape in the airways and peripheral blood of healthy controls and post-COVID-19 patients 3 to 6 months after hospital discharge. Post-COVID-19 patients showed abnormal airway (but not plasma) proteomes, with an elevated concentration of proteins associated with apoptosis, tissue repair, and epithelial injury versus healthy individuals. Increased numbers of cytotoxic lymphocytes were observed in individuals with greater airway dysfunction, while increased B cell numbers and altered monocyte subsets were associated with more widespread lung abnormalities. A one-year follow-up of some post-COVID-19 patients indicated that these abnormalities resolved over time. In summary, COVID-19 causes a prolonged change to the airway immune landscape in those with persistent lung disease, with evidence of cell death and tissue repair linked to the ongoing activation of cytotoxic T cells.


Assuntos
Linfócitos B/imunologia , COVID-19/imunologia , Monócitos/imunologia , Transtornos Respiratórios/imunologia , Sistema Respiratório/imunologia , SARS-CoV-2/fisiologia , Linfócitos T Citotóxicos/imunologia , Adulto , Idoso , COVID-19/complicações , Feminino , Seguimentos , Humanos , Imunidade Celular , Imunoproteínas , Masculino , Pessoa de Meia-Idade , Proteoma , Transtornos Respiratórios/etiologia , Sistema Respiratório/patologia
2.
Front Immunol ; 13: 832533, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35178051

RESUMO

Immunoproteomics has emerged as a versatile tool for analyzing the antibody repertoire in various disease contexts. Until recently, characterization of antibody molecules in biological fluids was limited to bulk serology, which identifies clinically relevant features of polyclonal antibody responses. The past decade, however, has seen the rise of mass-spectrometry-enabled proteomics methods that have allowed profiling of the antibody response at the molecular level, with the disease-specific serological repertoire elucidated in unprecedented detail. In this review, we present an up-to-date survey of insights into the disease-specific immunological repertoire by examining how quantitative proteomics-based approaches have shed light on the humoral immune response to infection and vaccination in pathogenic illnesses, the molecular basis of autoimmune disease, and the tumor-specific repertoire in cancer. We address limitations of this technology with a focus on emerging potential solutions and discuss the promise of high-resolution immunoproteomics in therapeutic discovery and novel vaccine design.


Assuntos
Anticorpos/análise , Imunoproteínas/análise , Proteômica/métodos , Animais , Doenças Autoimunes/imunologia , Humanos , Espectrometria de Massas , Neoplasias/imunologia , Vacinas/imunologia
3.
JAMA Netw Open ; 4(8): e2119132, 2021 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-34342651

RESUMO

Importance: Host immune dysregulation is associated with initiation and development of osteosarcoma. In addition, immunotherapy for osteosarcomas requires some knowledge of the immune state of patients. Objective: To perform an immunogenomic landscape analysis based on The Cancer Genome Atlas (TCGA) project, which provides osteosarcoma samples with clinical information. Design, Setting, and Participants: This genetic association study was conducted from July 20, 2020, to September 20, 2020, as a secondary analysis of public data. Cox regression and risk score analyses were used to construct signatures of immune-related genes (IRGs) in 84 patients with osteosarcoma from TCGA with corresponding clinical information. Patients were divided into high- and low-risk groups with 42 individuals in each group according to their risk scores. Data were analyzed from July 20 to September 20, 2020. Main Outcomes and Measures: Differentially expressed genes (DEGs) were analyzed between groups, and potential molecular mechanisms, expression regulation, and immune cell infiltration were also explored using bioinformation methods. A prognostic model based on independent risk factors selected from multivariate Cox hazard ratio regression was established to estimate 1-year overall survival. Results: In this genetic association study based on 84 samples from patients with osteosarcoma from TCGA (mean [SD] age, 15.0 [4.8] years; 47 [56.0%] men; mean [SD] follow-up time, 4.1 [2.8] years), a total of 14 survival-associated IRGs were identified. Patients assigned to the high-risk group had worse survival than patients from the low-risk group (1 death [2.4%] vs 26 deaths [61.9%%]; P < .001). The protein digestion and absorption pathway was one of the associated pathways in the functional enrichment analysis (gene ratio, 2:8; P < .001). The prognostic model based on metastases at diagnosis and risk score performed well in 1-year overall survival estimations (area under the curve, 0.947; 95% CI, 0.832-0.972). The risk score was correlated with immune cell infiltration (B cells: r = 0.331; P = .002; macrophages: r = 0.410; P < .001; CD8 T cells: r = 0.230; P = .04). Conclusions and Relevance: This genetic association study developed a prognostic modeling tool for osteosarcoma based on IRG expression profiles, which could result in improved survival rates through more individualized therapies. Further research on IRG expression profiles could provide potential targets for future studies on immune treatment for osteosarcoma.


Assuntos
Neoplasias Ósseas/genética , Regulação Neoplásica da Expressão Gênica/genética , Predisposição Genética para Doença/genética , Imunoproteínas/genética , Osteossarcoma/genética , Adolescente , Neoplasias Ósseas/mortalidade , Biologia Computacional , Feminino , Estudos de Associação Genética , Humanos , Masculino , Osteossarcoma/mortalidade , Prognóstico , Modelos de Riscos Proporcionais , Fatores de Risco , Taxa de Sobrevida , Adulto Jovem
4.
J Head Trauma Rehabil ; 36(5): E322-E328, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33656476

RESUMO

OBJECTIVE: To define clinical, radiographic, and blood-based biomarker features to be incorporated into a classification model of progression of intracranial hemorrhage (PICH), and to provide a pilot assessment of those models. METHODS: Patients with hemorrhage on admission head computed tomography were identified from a prospectively enrolled cohort of subjects with traumatic brain injury. Initial and follow-up images were interpreted both by 2 independent readers, and disagreements adjudicated. Admission plasma samples were analyzed and principal components (PCs) composed of the immune proteins (IPs) significantly associated with the outcome of interest were selected for further evaluation. A series of logistic regression models were constructed based on (1) clinical variables (CV) and (2) clinical variables + immune proteins (CV+IP). Error rates of these models for correct classification of PICH were estimated; significance was set at P < .05. RESULTS: We identified 106 patients, 36% had PICH. Dichotomized admission Glasgow Coma Scale (P = .004), Marshall score (P = .004), and 3 PCs were significantly associated with PICH. For the CV only model, sensitivity was 1.0 and specificity was 0.29 (95% CI, 0.07-0.67). The CV+IP model performed significantly better, with a sensitivity of 0.93 (95% CI, 0.64-0.99) and a specificity of 1.0 (P = .008). Adjustments to refine the definition of PICH and better define radiographic predictors of PICH did not significantly improve the models' performance. CONCLUSIONS: In this pilot investigation, we observed that composites of IPs may improve PICH classification models when combined with CVs. However, overall model performance must be further optimized; results will inform feature inclusion included in follow-up models.


Assuntos
Lesões Encefálicas Traumáticas , Lesões Encefálicas Traumáticas/complicações , Lesões Encefálicas Traumáticas/diagnóstico , Escala de Coma de Glasgow , Humanos , Imunoproteínas , Hemorragias Intracranianas/diagnóstico por imagem , Estudos Retrospectivos
5.
Medicine (Baltimore) ; 100(2): e24263, 2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-33466212

RESUMO

BACKGROUND: Laryngeal squamous cell carcinoma (LSCC) is one of the most common malignant tumors of the head and neck in the world. At present, the treatment methods include surgery, radiotherapy, and chemotherapy, but the 5-year survival rate is still not ideal and the quality of life of the patients is low. Due to the relative lack of immunotherapy methods, this study aims to build a risk prediction model of related immune genes, which can be used to effectively predict the prognosis of laryngeal cancer patients, and provide targets for subsequent immunotherapy. METHODS: We collected the 111 cases of laryngeal squamous cell carcinoma and 12 matched normal samples in the The Cancer Genome Atlas Database (TCGA) gene expression quantification database. The differentially expressed related immune genes were screened by R software version 3.5.2. The COX regression model of immune related genes was constructed, and the sensitivity and specificity of the model were evaluated. The risk value was calculated according to the model, and the risk curve was drawn to verify the correlation between related immune genes, risk score, and clinical traits. RESULTS: We selected 8 immune-related genes that can predict the prognosis of LSCC in a COX regression model and plotted the Kaplan-Meier survival curve. The 5-year survival rate of the high-risk group was 16.5% (95% CI: 0.059-0.459), and that of the low-risk group was 72.9% (95% CI: 0.555-0.956). The area under the receiver operating characteristic (ROC) curve was used to confirm the accuracy of the model (AUG = 0.887). After univariate and multivariate regression analysis, the risk score can be used as an independent risk factor for predicting prognosis. The risk score (P = .021) was positively correlated with the clinical Stage classification. CONCLUSION: We screened out 8 immune genes related to prognosis: RBP1, TLR2, AQP9, BTC, EPO, STC2, ZAP70, and PLCG1 to construct risk value models, which can be used to speculate the prognosis of the disease and provide new targets for future immunotherapy.


Assuntos
Imunoproteínas/análise , Peptídeos e Proteínas de Sinalização Intercelular/análise , Neoplasias Laríngeas/genética , Modelos de Riscos Proporcionais , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Aquaporinas/análise , Betacelulina/análise , Biomarcadores Tumorais , Bases de Dados Genéticas , Eritropoetina/análise , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Glicoproteínas/análise , Humanos , Neoplasias Laríngeas/mortalidade , Masculino , Fosfolipase C gama/análise , Prognóstico , Proteínas Celulares de Ligação ao Retinol/análise , Medição de Risco , Fatores de Risco , Sensibilidade e Especificidade , Carcinoma de Células Escamosas de Cabeça e Pescoço/mortalidade , Taxa de Sobrevida , Receptor 2 Toll-Like/análise
6.
Pharmacol Ther ; 217: 107662, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32805297

RESUMO

Immune checkpoint inhibitor therapy activates tumor-killing T-cells by releasing the brake of anti-tumor immunity. It has been approved as first- or second-line therapy in many cancer types. Unfortunately, a majority of immune checkpoint inhibitor recipients are refractory to the therapy. Recent investigations of the peripheral blood and tumor microenvironment of cancer patients indicate that high neutrophil content is associated with poor response rates, suggesting an opportunity for synergistic therapy. In the current review, we discuss the mechanisms of neutrophil-mediated immunosuppression in cancer and recent findings suggesting that neutrophil antagonism will improve the efficacy of immune checkpoint inhibitor therapy.


Assuntos
Resistencia a Medicamentos Antineoplásicos/imunologia , Inibidores de Checkpoint Imunológico/farmacologia , Neoplasias/imunologia , Neutrófilos/imunologia , Microambiente Tumoral/imunologia , Animais , Antígeno B7-H1/imunologia , Humanos , Inibidores de Checkpoint Imunológico/uso terapêutico , Imunoproteínas/metabolismo , Neoplasias/tratamento farmacológico , Receptor de Morte Celular Programada 1/imunologia , Espécies Reativas de Oxigênio/imunologia
7.
BMC Genomics ; 21(1): 606, 2020 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-32883205

RESUMO

BACKGROUND: Immune-response (IR) genes have an important role in the defense against highly variable pathogens, and therefore, diversity in these genomic regions is essential for species' survival and adaptation. Although current genome assemblies from Old World camelids are very useful for investigating genome-wide diversity, demography and population structure, they have inconsistencies and gaps that limit analyses at local genomic scales. Improved and more accurate genome assemblies and annotations are needed to study complex genomic regions like adaptive and innate IR genes. RESULTS: In this work, we improved the genome assemblies of the three Old World camel species - domestic dromedary and Bactrian camel, and the two-humped wild camel - via different computational methods. The newly annotated dromedary genome assembly CamDro3 served as reference to scaffold the NCBI RefSeq genomes of domestic Bactrian and wild camels. These upgraded assemblies were then used to assess nucleotide diversity of IR genes within and between species, and to compare the diversity found in immune genes and the rest of the genes in the genome. We detected differences in the nucleotide diversity among the three Old World camelid species and between IR gene groups, i.e., innate versus adaptive. Among the three species, domestic Bactrian camels showed the highest mean nucleotide diversity. Among the functionally different IR gene groups, the highest mean nucleotide diversity was observed in the major histocompatibility complex. CONCLUSIONS: The new camel genome assemblies were greatly improved in terms of contiguity and increased size with fewer scaffolds, which is of general value for the scientific community. This allowed us to perform in-depth studies on genetic diversity in immunity-related regions of the genome. Our results suggest that differences of diversity across classes of genes appear compatible with a combined role of population history and differential exposures to pathogens, and consequent different selective pressures.


Assuntos
Camelus/genética , Imunoproteínas/genética , Polimorfismo de Nucleotídeo Único , Animais , Camelus/imunologia , Mapeamento de Sequências Contíguas , Anotação de Sequência Molecular , Locos de Características Quantitativas
8.
Hypertension ; 76(3): 985-996, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32713273

RESUMO

Pulmonary arterial hypertension (PAH) is a fatal disease characterized by increased mean pulmonary arterial pressure. Elevated plasma and lung concentrations of oxidized lipids, including 15-hydroxyeicosatetraenoic acid (15-HETE), have been demonstrated in patients with PAH and animal models. We previously demonstrated that feeding mice with 15-HETE is sufficient to induce pulmonary hypertension, but the mechanisms remain unknown. RNA sequencing data from the mouse lungs on 15-HETE diet revealed significant activation of pathways involved in both antigen processing and presentation and T cell-mediated cytotoxicity. Analysis of human microarray from patients with PAH also identified activation of identical pathways compared with controls. We show that in both 15-HETE-fed mice and patients with PAH, expression of the immunoproteasome subunit 5 is significantly increased, which was concomitant with an increase in the number of CD8/CD69 (cluster of differentiation 8 / cluster of differentiation 69) double-positive cells, as well as pulmonary arterial endothelial cell apoptosis in mice. Human pulmonary arterial endothelial cells cultured with 15-HETE were more prone to apoptosis when exposed to CD8 cells. Cultured intestinal epithelial cells secreted more oxidized lipids in response to 15-HETE, which is consistent with accumulation of circulating oxidized lipids in 15-HETE-fed mice. Administration of an apoA-I (apolipoprotein A-I) mimetic peptide, Tg6F (transgenic 6F), which is known to prevent accumulation of circulating oxidized lipids, not only inhibited pulmonary arterial endothelial cell apoptosis but also prevented and rescued 15-HETE-induced pulmonary hypertension in mice. In conclusion, our results suggest that (1) 15-HETE diet induces pulmonary hypertension by a mechanism that involves oxidized lipid-mediated T cell-dependent pulmonary arterial endothelial cell apoptosis and (2) Tg6F administration may be a novel therapy for treating PAH.


Assuntos
Apoptose , Células Endoteliais , Ácidos Hidroxieicosatetraenoicos/metabolismo , Hipertensão Pulmonar/metabolismo , Peptídeos/farmacologia , Artéria Pulmonar , Animais , Apoptose/efeitos dos fármacos , Apoptose/imunologia , Diferenciação Celular , Proliferação de Células , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Hipertensão Pulmonar/prevenção & controle , Fatores Imunológicos/farmacologia , Imunoproteínas , Metabolismo dos Lipídeos/efeitos dos fármacos , Camundongos , Complexo de Endopeptidases do Proteassoma , Artéria Pulmonar/metabolismo , Artéria Pulmonar/patologia , Linfócitos T
9.
Med Sci Monit ; 26: e923621, 2020 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-32680979

RESUMO

BACKGROUND The ubiquitin-proteasome pathway (UPP) is closely associated with the occurrence and progression of cancer, and the 5i immunoproteasome subunit is an important antitumor target in UPP. This study aimed to characterize the regulation of the immunoproteasome subunit ß5i (PSMB8) in JHU-011 laryngeal carcinoma cells and FaDu hypopharyngeal carcinoma cells to explore a new target for the treatment of laryngeal and hypopharyngeal carcinomas. MATERIAL AND METHODS JHU-011 and FaDu cells were used as effector cells in this study. By means of 6°Co γ-irradiation, the construction of stable cell lines of the silenced proto-oncogene c-Abl, and the addition of exogenous tyrosine kinase inhibitor (TKI) and activator, the transcription and protein expression levels of PSMB8 and its alternatively spliced isoforms in both cell lines were detected by real-time fluorescence quantitative polymerase chain reaction (RT-PCR) and Western blot. RESULTS Ionizing radiation upregulated the transcription level of the alternatively spliced isoform of PSMB8, E2, in both cell lines, thereby upregulating the mRNA and protein levels of PSMB8. The silencing of the proto-oncogene c-Abl and the activation and inhibition of its kinetic kinase product can affect the transcription and protein levels of PSMB8. CONCLUSIONS Ionizing radiation can significantly upregulate the mRNA and protein levels of PSMB8, which happens through the upregulation of its splicing isoform E2. The proto-oncogene c-Abl and its kinetic kinase protein product can regulate the transcription and protein expression levels of PSMB8 and its alternatively spliced isoforms.


Assuntos
Neoplasias Hipofaríngeas/metabolismo , Neoplasias Laríngeas/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Carcinoma/genética , Carcinoma/metabolismo , Linhagem Celular Tumoral , Expressão Gênica/genética , Humanos , Neoplasias Hipofaríngeas/genética , Imunoproteínas/metabolismo , Neoplasias Laríngeas/genética , Complexo de Endopeptidases do Proteassoma/genética , Proto-Oncogene Mas
10.
J Med Chem ; 63(5): 1841-1858, 2020 03 12.
Artigo em Inglês | MEDLINE | ID: mdl-31670954

RESUMO

The immunoproteasome (iCP) is an isoform of the 20S proteasome that is expressed when cells are stressed or receive an inflammatory signal. The primary role of the iCP is to hydrolyze proteins into peptides that are compatible with being loaded into a MHC-I complex. When the activity of the iCP is dysregulated or highly expressed, it can lead to unwanted cell death. Some cancer types express the iCP rather than the standard proteasome, and selective inhibitors have been developed to exploit this difference. Here, we describe diseases known to be influenced by iCP activity and the current status for targeting the iCP to elicit a therapeutic response. We also describe a variety of chemical tools that have been developed to monitor the activity of the iCP in cells. Finally, we present the future outlook for targeting the iCP in a variety of disease types and with mechanisms besides inhibition.


Assuntos
Doenças Autoimunes/metabolismo , Sistemas de Liberação de Medicamentos/métodos , Neoplasias/metabolismo , Doenças do Sistema Nervoso/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Inibidores de Proteassoma/metabolismo , Animais , Doenças Autoimunes/tratamento farmacológico , Doenças Autoimunes/imunologia , Sistemas de Liberação de Medicamentos/tendências , Humanos , Imunoproteínas/antagonistas & inibidores , Imunoproteínas/imunologia , Imunoproteínas/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Doenças do Sistema Nervoso/tratamento farmacológico , Doenças do Sistema Nervoso/imunologia , Complexo de Endopeptidases do Proteassoma/imunologia , Inibidores de Proteassoma/administração & dosagem , Estrutura Secundária de Proteína
11.
Curr Protoc Immunol ; 126(1): e87, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31483107

RESUMO

Polymorphonuclear cells (PMNs or neutrophils) are the most abundant leukocyte in humans and represent an essential component of the innate immune system. The ability of neutrophils to initiate an immediate and non-specific host response against invading microbial species is the key to determining the outcome of infection. Neutrophils produce and secrete a plethora of immunomodulatory proteins, including major granule proteins and cytokines, as well as various enzymes, which regulate adherence, phagocytosis, chemotaxis, and cell survival. Historically, characterization of neutrophils and their roles during infection have relied on genetic and phenotypic analyses, as well as biochemical assays. However, recent advances in mass spectrometry-based proteomic workflows and technological platforms have supported the comprehensive profiling of neutrophil-associated immune responses in consideration of cellular factors and secreted proteins. Given the critical role of neutrophils in maintaining and regulating innate immune function, comprehensive profiling of their response to infection is imperative to ensuring host survival. Here, we briefly discuss the role of neutrophils in host-defense and describe methods to purify neutrophils from murine samples and comprehensively profile their proteomes. © 2019 by John Wiley & Sons, Inc.


Assuntos
Espectrometria de Massas/métodos , Neutrófilos/metabolismo , Proteômica/métodos , Animais , Citocinas/metabolismo , Humanos , Imunidade Inata , Fatores Imunológicos/metabolismo , Imunoproteínas/metabolismo , Camundongos , Neutrófilos/citologia
13.
Neuron ; 101(6): 1003-1015, 2019 03 20.
Artigo em Inglês | MEDLINE | ID: mdl-30897353

RESUMO

Immunoproteostasis is a term used to reflect interactions between the immune system and the proteinopathies that are presumptive "triggers" of many neurodegenerative disorders. The study of immunoproteostasis is bolstered by several observations. Mutations or rare variants in genes expressed in microglial cells, known to regulate immune functions, or both can cause, or alter risk for, various neurodegenerative disorders. Additionally, genetic association studies identify numerous loci harboring genes that encode proteins of known immune function that alter risk of developing Alzheimer's disease (AD) and other neurodegenerative proteinopathies. Further, preclinical studies reveal beneficial effects and liabilities of manipulating immune pathways in various neurodegenerative disease models. Although there are concerns that manipulation of the immune system may cause more harm than good, there is considerable interest in developing immune modulatory therapies for neurodegenerative disorders. Herein, I highlight the promise and challenges of harnessing immunoproteostasis to treat neurodegenerative proteinopathies.


Assuntos
Doença de Alzheimer/imunologia , Imunoproteínas/imunologia , Inflamação/imunologia , Microglia/imunologia , Doença de Alzheimer/genética , Doença de Alzheimer/terapia , Animais , Predisposição Genética para Doença , Humanos , Imunoproteínas/genética , Camundongos , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/imunologia , Doenças Neurodegenerativas/terapia , Proteostase
14.
Genomics ; 111(3): 242-250, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30458273

RESUMO

To understand the precise mechanism and the pathways activated by thermal stress in fish, we sampled livers from juvenile Megalobrama amblycephala exposed to control (25 °C) and test (35 °C) conditions, and performed short read (100 bp) next-generation RNA sequencing (RNA-seq). Using reads from different temperature, expression analysis identified a total of 440 differentially-expressed genes. These genes were related to oxidative stress, apoptosis, immune responses and so on. We used quantitative real-time reverse transcriptase PCR to assess the differential mRNA expression of selected genes that encode antioxidant enzymes and heat shock proteins in response to thermal stress. Fish exposed to thermal stress also showed liver damage associated with serum biochemical parameter changes. The set of genes identified showed regulatory modulation at different temperatures, and therefore could be further studied to determine how thermal stress damages M. amblycephala livers and the possible roles of reactive oxygen species in this process.


Assuntos
Cyprinidae/genética , Resposta ao Choque Térmico , Fígado/metabolismo , Transcriptoma , Animais , Apoptose , Cyprinidae/metabolismo , Proteínas de Peixes/genética , Proteínas de Peixes/metabolismo , Proteínas de Choque Térmico/genética , Proteínas de Choque Térmico/metabolismo , Imunoproteínas/genética , Imunoproteínas/metabolismo , Fígado/citologia , Estresse Oxidativo
15.
Hypertension ; 73(1): 92-101, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30571551

RESUMO

Atrial fibrillation (AF) is the most common type of cardiac arrhythmia and increases the risk of stroke, heart failure, and death. Ang II (angiotensin II) triggers AF, mainly through stimulation of the AT1R (Ang II type I receptor). The immunoproteasome is a highly efficient proteolytic machine derived from the constitutive proteasome, but the role it plays in regulating AT1R activation and triggering AF remains unknown. Here, we show that among the catalytic subunits, ß5i (PSMB8) expression, and chymotrypsin-like activity were the most significantly upregulated in atrial tissue of Ang II-infused mice or serum from patients with AF. ß5i KO (ß5i knockout) in mice markedly attenuated Ang II-induced AF incidence, atrial fibrosis, inflammatory response, and oxidative stress compared with WT (wild type) animals, but injection with recombinant adeno-associated virus serotype 9-ß5i increased these effects. Moreover, we found that ATRAP (AT1R-associated protein) was a target of ß5i. Overexpression of ATRAP significantly attenuated Ang II-induced atrial remodeling and AF in recombinant adeno-associated virus serotype 9-ß5i-injected mice. Mechanistically, Ang II upregulated ß5i expression to promote ATRAP degradation, which resulted in activation of AT1R-mediated NF-κB signaling, increased NADPH oxidase activity, increased TGF (transforming growth factor)-ß1/Smad signaling, and altered the expression of Kir2.1 and CX43 (connexin 43) in the atria, thereby affecting atrial remodeling and AF. In summary, this study identifies ß5i as a negative regulator of ATRAP stability that contributes to AT1R activation and to AF, highlighting that targeting ß5i activity may represent a potential therapeutic approach for the treatment of hypertensive AF.


Assuntos
Angiotensina II , Fibrilação Atrial , Átrios do Coração , Complexo de Endopeptidases do Proteassoma/metabolismo , Receptor Tipo 1 de Angiotensina/metabolismo , Angiotensina II/metabolismo , Angiotensina II/farmacologia , Animais , Fibrilação Atrial/metabolismo , Fibrilação Atrial/patologia , Fibrilação Atrial/fisiopatologia , Remodelamento Atrial/efeitos dos fármacos , Modelos Animais de Doenças , Fibrose , Átrios do Coração/metabolismo , Átrios do Coração/patologia , Imunoproteínas/metabolismo , Camundongos , Estresse Oxidativo/efeitos dos fármacos
16.
J Neuroinflammation ; 15(1): 329, 2018 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-30477534

RESUMO

BACKGROUND: Few studies have suggested a relationship between inflammation and cerebral venous thrombosis (CVT). This retrospective study aimed to explore the changes in inflammation in different CVT stages and the correlation between inflammation and severity and outcome of CVT. METHODS: In total, 95 suitable patients with CVT and 41 controls were compared. Patients with CVT were divided into three groups. The inflammatory factors studied included hypersensitive C-reactive protein (Hs-CRP), interleukin-6 (IL-6), and neutrophil-to-lymphocyte ratio (NLR) in the peripheral blood and immunoglobulin A (IgA), immunoglobulin M (IgM), and immunoglobulin G (IgG) in the cerebrospinal fluid (CSF). The severity of CVT was evaluated with the modified Rankin Scale (mRS), the National Institutes of Health Stroke Scale (NIHSS), fundus condition, intracranial pressure (ICP), and complications on admission. The short-term outcome was evaluated with the mRS at discharge. RESULTS: The following results were obtained: (1) Inflammatory factor levels in patients with CVT were higher than those in the controls. (2) Inflammatory factor levels in the acute and subacute stages were significantly higher than those in the chronic stage (all P < 0.05). (3) Serum NLR and CSF IgM levels were positively related to baseline degree of disability (odds ratio [OR], 1.279, 95% confidence interval [CI] 1.009-1.621, P = 0.042; OR 1.402, 95% CI 1.036-1.896, P = 0.028). The Hs-CRP level was positively correlated with the baseline occurrence of seizure (OR 1.040, 95% CI 1.001-1.080, P = 0.043). The baseline serum NLR (r = 0.244, P = 0.017), CSF IgA (r = 0.615, P < 0.001), CSF IgM (r = 0.752, P < 0.001), and CSF IgG (r = 0.248, P = 0.015) levels were positively associated with NIHSS. (4) The baseline NLR was significantly associated with high risk of poor outcome at discharge (OR 1.339, 95% CI 1.097-1.784, P = 0.007). Moreover, the ROC showed that NLR ≥ 4.205 could better predict the poor outcome at discharge. The data were analyzed using SPSS. CONCLUSIONS: Inflammation may develop after CVT and gradually decrease during the course. Inflammation was significantly correlated with severity on admission and short-term poor outcome at discharge in CVT.


Assuntos
Inflamação/etiologia , Trombose Intracraniana/complicações , Trombose Venosa/complicações , Adulto , Proteína C-Reativa , Estudos de Casos e Controles , Feminino , Humanos , Imunoglobulinas/líquido cefalorraquidiano , Imunoproteínas , Inflamação/líquido cefalorraquidiano , Inflamação/diagnóstico por imagem , Interleucina-6/líquido cefalorraquidiano , Pressão Intracraniana/fisiologia , Trombose Intracraniana/líquido cefalorraquidiano , Trombose Intracraniana/diagnóstico por imagem , Linfócitos/patologia , Masculino , Pessoa de Meia-Idade , Neuroimagem , Neutrófilos/patologia , Curva ROC , Estudos Retrospectivos , Índice de Gravidade de Doença , Trombose Venosa/líquido cefalorraquidiano , Trombose Venosa/diagnóstico por imagem , Adulto Jovem
17.
Oncol Rep ; 39(5): 2413-2421, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29498409

RESUMO

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy characterized by early invasiveness and resistance to treatment. Surgery in early stages is the only effective treatment, thus finding new biomarkers for the early detection of PDAC remains a major challenge. The present study aimed to compare the immunoproteome between PDAC patients and healthy controls using serological proteome analysis method. Firstly, cell lysates from two different pancreatic cancer cell lines were separated by two dimensional (2D) gels, and then transferred onto membranes probed with sera from 20 PDAC patients and 10 healthy controls. Proteins differentially reacting with autoantibodies in PDAC patients and control groups and were identified using mass spectrometry. This process led to the identification of 18 pancreatic immunoreactive antigens such as laminin, superoxide dismutase, ATP synthase, Rho GDP-dissociation inhibitor II, septin, glyceraldehyde 3-phosphate-dehydrogenase, phosphoglycerate mutase B, tubulin ß8 channel and prohibit in. In the present study, we identified 18 immunoreactive proteins in PDAC. While the identified proteins were critically involved in PDAC pathogenesis, further investigation in a large scale population will determine the applicability of these potential biomarkers for the early diagnosis or treatment of the disease.


Assuntos
Autoanticorpos/metabolismo , Carcinoma Ductal Pancreático/imunologia , Imunoproteínas/análise , Neoplasias Pancreáticas/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/imunologia , Linhagem Celular Tumoral , Feminino , Humanos , Immunoblotting , Imunoproteínas/imunologia , Masculino , Pessoa de Meia-Idade , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz
18.
Biochem Biophys Res Commun ; 496(3): 961-966, 2018 02 12.
Artigo em Inglês | MEDLINE | ID: mdl-29355526

RESUMO

The natural small molecule piperlongumine A is toxic selectively to cancer cells in vitro and in vivo. This toxicity has been correlated with cancer cell ROS, DNA damage and apoptotic cell death increases. We demonstrate here a new mechanistic property of piperlongumine: it inhibits selectively human immunoproteasome with no noticeable inhibition of human constitutive proteasome. This result suggests that immunoproteasome inhibition, a mechanism independent of ROS elevation, may also partly play a role in the anticancer effects observed with piperlongumine. Structure-activity relationships of piperlongumine analogs suggest that the lactam (piperidonic) ring of piperlongumine A may be replaced by the linear olefin -NHCO-CH2=CH2 to improve both in vitro inhibitory efficiency against immunoproteasome and cellular toxicity.


Assuntos
Apoptose/imunologia , Dioxolanos/química , Dioxolanos/imunologia , Imunoproteínas/química , Imunoproteínas/imunologia , Complexo de Endopeptidases do Proteassoma/química , Complexo de Endopeptidases do Proteassoma/imunologia , Apoptose/efeitos dos fármacos , Dioxolanos/administração & dosagem , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Células HeLa , Humanos , Ligação Proteica , Resultado do Tratamento
19.
Am J Reprod Immunol ; 79(2)2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29286179

RESUMO

PROBLEM: Fluctuating hormones regulate reproductive processes in the female genital tract. Consequent changes in the local immunological environment are likely to affect cellular interaction with infectious agents and the assessment of therapies that target mucosal infections. METHOD OF STUDY: We compared Softcup and Weck-Cel sampling protocols and assessed the changes in the concentrations of 39 soluble proteins with menstrual cycle progression in the mucosal and peripheral compartments. RESULTS: We demonstrate that the mucosal immunological profile is distinct from serum with inflammatory and migratory signatures that are localized throughout the cycle. The analytes highlighted in the mucosal compartment were generally highest at the follicular phase with a tendency to fall as the cycle progressed through ovulation to the luteal phase. CONCLUSION: Our results underscore the need to consider these localized cyclical differences in studies aimed at assessing the outcome of disease and the efficacy of mucosal vaccines and other therapies.


Assuntos
Genitália Feminina/imunologia , Infecções por HIV/imunologia , HIV-1/fisiologia , Imunoproteínas/metabolismo , Ciclo Menstrual/imunologia , Membrana Mucosa/imunologia , Periodicidade , Adolescente , Adulto , Boranos/metabolismo , Feminino , Hormônios Esteroides Gonadais/metabolismo , Humanos , Pessoa de Meia-Idade , Adulto Jovem
20.
Cytokine ; 106: 114-124, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29089178

RESUMO

Diagnosis of complex disease and response to treatment is often associated with multiple indicators, both clinical and laboratorial. With the use of biomarkers, various mechanisms have been unraveled which can lead to better and faster diagnosis, predicting and monitoring of response to treatment and new drug development. With the introduction of multiplex technology for immunoassays and the growing awareness of the role of immune-monitoring during new therapeutic interventions it is now possible to test large numbers of soluble mediators in small sample volumes. However, standardization of sample collection and laboratory assessments remains suboptimal. We developed a multiplex immunoassay for detection of 162 immune related proteins in human serum and plasma. The assay was split in panels depending on natural occurring concentrations with a maximum of 60 proteins. The aim of this study was to evaluate precision, accuracy, reproducibility and stability of proteins when repeated freeze-thaw cycles are performed of this in-house developed panel, as well as assessing the protein signature in plasma and serum using various anticoagulants. Intra-assay variance of each mediator was <10%. Inter-assay variance ranged between 1.6 and 37% with an average of 12.2%. Recoveries were similar for all mediators (mean 99.8 ± 2.6%) with a range between 89-107%. Next we measured all mediators in serum, EDTA plasma and sodium heparin plasma of 43 healthy control donors. Of these markers only 19 showed similar expression profiles in the 3 different matrixes. Only 5 mediators were effected by multiple freeze-thawing cycles. Principal component analysis revealed different coagulants cluster separately and that sodium heparin shows the most consistent profile.


Assuntos
Anticoagulantes/farmacologia , Voluntários Saudáveis , Imunoproteínas/metabolismo , Adulto , Ácido Edético/farmacologia , Feminino , Congelamento , Heparina/farmacologia , Humanos , Imunoensaio , Limite de Detecção , Masculino , Pessoa de Meia-Idade , Estabilidade Proteica , Padrões de Referência , Reprodutibilidade dos Testes
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