Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 1.611
Filtrar
1.
Mol Cell Proteomics ; 19(11): 1749-1759, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32788344

RESUMO

Coronavirus disease 2019 (COVID-19) is a highly contagious infection and threating the human lives in the world. The elevation of cytokines in blood is crucial to induce cytokine storm and immunosuppression in the transition of severity in COVID-19 patients. However, the comprehensive changes of serum proteins in COVID-19 patients throughout the SARS-CoV-2 infection is unknown. In this work, we developed a high-density antibody microarray and performed an in-depth proteomics analysis of serum samples collected from early COVID-19 (n = 15) and influenza (n = 13) patients. We identified a large set of differentially expressed proteins (n = 132) that participate in a landscape of inflammation and immune signaling related to the SARS-CoV-2 infection. Furthermore, the significant correlations of neutrophil and lymphocyte with the CCL2 and CXCL10 mediated cytokine signaling pathways was identified. These information are valuable for the understanding of COVID-19 pathogenesis, identification of biomarkers and development of the optimal anti-inflammation therapy.


Assuntos
Proteínas Sanguíneas/imunologia , Infecções por Coronavirus/imunologia , Tosse/imunologia , Síndrome da Liberação de Citocina/imunologia , Febre/imunologia , Cefaleia/imunologia , Influenza Humana/imunologia , Mialgia/imunologia , Pneumonia Viral/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Betacoronavirus/patogenicidade , Proteínas Sanguíneas/genética , Criança , Infecções por Coronavirus/genética , Infecções por Coronavirus/fisiopatologia , Infecções por Coronavirus/virologia , Tosse/genética , Tosse/fisiopatologia , Tosse/virologia , Síndrome da Liberação de Citocina/genética , Síndrome da Liberação de Citocina/fisiopatologia , Síndrome da Liberação de Citocina/virologia , Citocinas/genética , Citocinas/imunologia , Feminino , Febre/genética , Febre/fisiopatologia , Febre/virologia , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Cefaleia/genética , Cefaleia/fisiopatologia , Cefaleia/virologia , Humanos , Influenza Humana/genética , Influenza Humana/fisiopatologia , Influenza Humana/virologia , Masculino , Pessoa de Meia-Idade , Mialgia/genética , Mialgia/fisiopatologia , Mialgia/virologia , Orthomyxoviridae/patogenicidade , Pandemias , Pneumonia Viral/genética , Pneumonia Viral/fisiopatologia , Pneumonia Viral/virologia , Análise Serial de Proteínas , Proteoma/genética , Proteoma/imunologia , Receptores de Citocinas/genética , Receptores de Citocinas/imunologia , Transdução de Sinais/imunologia
2.
J Toxicol Sci ; 45(8): 435-447, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32741896

RESUMO

The imbalance of testosterone to estradiol ratio has been related to the development of prostate diseases. Although rat models of prostate diseases induced by endocrine-disrupting chemicals (EDCs) and/or hormone exposure are commonly used to analyze gene expression profiles in the prostate, most studies utilize a single endpoint. In this study, microarray analysis was used for gene expression profiling in rat prostate tissue after exposure to EDCs and sex hormones over multiple time points (prepubertal through adulthood). We used dorsolateral prostate tissues from Sprague-Dawley rats (male offspring) and postnatally administered estradiol benzoate (EB) on postnatal days (PNDs) 1, 3, and 5, followed by treatment with additional hormones [estradiol (E) and testosterone (T)] on PNDs 90-200, as described by Ho et al. Microarray analysis was performed for gene expression profiling in the dorsolateral prostate, and the results were validated via qRT-PCR. The genes in cytokine-cytokine receptor interaction, cell adhesion molecules, and chemokines were upregulated in the EB+T+E group on PNDs 145 and 200. Moreover, early-stage downregulation of anti-inflammatory gene: bone morphogenetic protein 7 gene was observed. These findings suggest that exposure to EB, T, and E activates multiple pathways and simultaneously downregulates anti-inflammatory genes. Interestingly, these genes are reportedly expressed in prostate cancer tissues/cell lines. Further studies are required to elucidate the mechanism, including analyses using human prostate tissues.


Assuntos
Disruptores Endócrinos/toxicidade , Estradiol/análogos & derivados , Estradiol/toxicidade , Perfilação da Expressão Gênica/métodos , Expressão Gênica , Próstata/metabolismo , Puberdade , Testosterona/toxicidade , Transcriptoma , Fatores Etários , Animais , Proteína Morfogenética Óssea 7/genética , Proteína Morfogenética Óssea 7/metabolismo , Moléculas de Adesão Celular/genética , Moléculas de Adesão Celular/metabolismo , Quimiocinas/genética , Quimiocinas/metabolismo , Disruptores Endócrinos/efeitos adversos , Estradiol/efeitos adversos , Inflamação/genética , Masculino , Análise em Microsséries , Ratos Sprague-Dawley , Receptores de Citocinas/genética , Receptores de Citocinas/metabolismo , Testosterona/efeitos adversos
3.
DNA Cell Biol ; 39(9): 1678-1684, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32716219

RESUMO

Coronary artery disease (CAD) is the main cause of death worldwide. Atherosclerosis, the leading underlying cause of CAD, is a progressive inflammatory disease. miRNAs play a substantial role in inflammation. The aim of this study was to investigate the associations of peripheral blood mononuclear cells (PBMCs) gene expression of IP10 and miRNA 296-a and serum levels of IP10 and serum inflammatory cytokines interleukin-6 (IL-6) in CAD patients and controls. This is a case-control study conducted on 82 angiography confirmed CAD patients and 82 controls. PBMC expressions of miR-296a and IP10 were evaluated by real-time method, and serum concentrations of IL-6 and TNF-α were evaluated by enzyme-linked immunosorbent assay in the study population. A significant increase was found for serum IP10, IL-6, and TNF-α levels, and PBMC expression of IP10 and miRNA 296-a genes expression of CAD as comparison with controls. No significant correlation was found between IP10 gene expression and miRNA 296-a. A significant positive correlation was found between PBMC gene expression level of IP10 and serum concentrations of IP10 and cytokines IL-6 and TNF-α levels. Taking together, in PBMC of CAD patients, the IP10 and 296-a miRNA genes expression levels were increased significantly than controls. IP10, IL-6, and TNF-α levels in CAD patients were more than those in controls significantly. Concerning positive relationship between miRNA 296-a gene expression level and serum concentrations of IL-6 and TNF-α in CAD patients, it is proposed that IL-6 and TNF-α inhibitor could be the main targets of miRNA 296a and, thereby the IL-6 and TNF-α levels were increased; however, further study is needed.


Assuntos
Doença da Artéria Coronariana/sangue , MicroRNAs/sangue , Receptores de Citocinas/sangue , Idoso , Biomarcadores/sangue , Doença da Artéria Coronariana/patologia , Feminino , Humanos , Interleucina-6/sangue , Masculino , MicroRNAs/genética , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Monócitos/metabolismo , Receptores de Citocinas/genética , Receptores de Citocinas/metabolismo , Fator de Necrose Tumoral alfa/sangue
4.
Arterioscler Thromb Vasc Biol ; 40(6): 1559-1573, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32321307

RESUMO

OBJECTIVE: Excessive prostaglandin E2 production is a hallmark of abdominal aortic aneurysm (AAA). Enhanced expression of prostaglandin E2 receptor EP4 (prostaglandin E receptor 4) in vascular smooth muscle cells (VSMCs) has been demonstrated in human AAAs. Although moderate expression of EP4 contributes to vascular homeostasis, the roles of excessive EP4 in vascular pathology remain uncertain. We aimed to investigate whether EP4 overexpression in VSMCs exacerbates AAAs. Approach and Results: We constructed mice with EP4 overexpressed selectively in VSMCs under an SM22α promoter (EP4-Tg). Most EP4-Tg mice died within 2 weeks of Ang II (angiotensin II) infusion due to AAA, while nontransgenic mice given Ang II displayed no overt phenotype. EP4-Tg developed much larger AAAs than nontransgenic mice after periaortic CaCl2 application. In contrast, EP4fl/+;SM22-Cre;ApoE-/- and EP4fl/+;SM22-Cre mice, which are EP4 heterozygous knockout in VSMCs, rarely exhibited AAA after Ang II or CaCl2 treatment, respectively. In Ang II-infused EP4-Tg aorta, Ly6Chi inflammatory monocyte/macrophage infiltration and MMP-9 (matrix metalloprotease-9) activation were enhanced. An unbiased analysis revealed that EP4 stimulation positively regulated the genes binding cytokine receptors in VSMCs, in which IL (interleukin)-6 was the most strongly upregulated. In VSMCs of EP4-Tg and human AAAs, EP4 stimulation caused marked IL-6 production via TAK1 (transforming growth factor-ß-activated kinase 1), NF-κB (nuclear factor-kappa B), JNK (c-Jun N-terminal kinase), and p38. Inhibition of IL-6 prevented Ang II-induced AAA formation in EP4-Tg. In addition, EP4 stimulation decreased elastin/collagen cross-linking protein LOX (lysyl oxidase) in both human and mouse VSMCs. CONCLUSIONS: Dysregulated EP4 overexpression in VSMCs promotes inflammatory monocyte/macrophage infiltration and attenuates elastin/collagen fiber formation, leading to AAA exacerbation.


Assuntos
Aneurisma da Aorta Abdominal/etiologia , Inflamação/etiologia , Músculo Liso Vascular/metabolismo , Receptores de Prostaglandina E Subtipo EP4/fisiologia , Transdução de Sinais/fisiologia , Angiotensina II/administração & dosagem , Animais , Aorta/efeitos dos fármacos , Aorta/metabolismo , Aorta/patologia , Aneurisma da Aorta Abdominal/patologia , Cloreto de Cálcio/administração & dosagem , Expressão Gênica , Regulação da Expressão Gênica/fisiologia , Humanos , Interleucina-6/genética , Macrófagos/patologia , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Knockout para ApoE , Camundongos Transgênicos , Monócitos/patologia , Músculo Liso Vascular/química , Miócitos de Músculo Liso/metabolismo , Proteína-Lisina 6-Oxidase/análise , Proteína-Lisina 6-Oxidase/genética , Receptores de Citocinas/genética , Receptores de Prostaglandina E Subtipo EP4/genética
5.
Int J Mol Sci ; 21(6)2020 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-32235787

RESUMO

Philadelphia (Ph)-like acute lymphoblastic leukemia (ALL) is a high-risk B-cell Acute Lymphoblastic Leukemia (B-ALL) characterized by a gene expression profile similar to Ph-positive B-ALL but lacking the BCR-ABL1 translocation. The molecular pathogenesis of Ph-like B-ALL is heterogenous and involves aberrant genomics, receptor overexpression, kinase fusions, and mutations leading to kinase signaling activation, leukemogenic cellular proliferation, and differentiation blockade. Testing for the Ph-like signature, once only a research technique, is now available to the clinical oncologist. The plethora of data pointing to poor outcomes for this ALL subset has triggered investigations into the role of targeted therapies, predominantly involving tyrosine kinase inhibitors that are showing promising results.


Assuntos
Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Transcriptoma , Animais , Proteínas de Fusão bcr-abl/genética , Regulação Leucêmica da Expressão Gênica , Genômica , Humanos , Fator de Transcrição Ikaros/genética , Fator de Transcrição PAX5/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Receptores de Citocinas/genética
6.
Int J Mol Sci ; 21(7)2020 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-32235353

RESUMO

Cells within the hematopoietic stem cell compartment selectively express receptors for cytokines that have a lineage(s) specific role; they include erythropoietin, macrophage colony-stimulating factor, granulocyte colony-stimulating factor, granulocyte/macrophage colony-stimulating factor and the ligand for the fms-like tyrosine kinase 3. These hematopoietic cytokines can instruct the lineage fate of hematopoietic stem and progenitor cells in addition to ensuring the survival and proliferation of cells that belong to a particular cell lineage(s). Expression of the receptors for macrophage colony-stimulating factor and granulocyte colony-stimulating factor is positively autoregulated and the presence of the cytokine is therefore likely to enforce a lineage bias within hematopoietic stem cells that express these receptors. In addition to the above roles, macrophage colony-stimulating factor and granulocyte/macrophage colony-stimulating factor are powerful chemoattractants. The multiple roles of some hematopoietic cytokines leads us towards modelling hematopoietic stem cell decision-making whereby these cells can 'choose' just one lineage fate and migrate to a niche that both reinforces the fate and guarantees the survival and expansion of cells as they develop.


Assuntos
Diferenciação Celular/genética , Linhagem da Célula/genética , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/metabolismo , Nicho de Células-Tronco , Animais , Citocinas/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Hematopoese/genética , Humanos , Modelos Biológicos , Receptores de Citocinas/genética , Receptores de Citocinas/metabolismo , Nicho de Células-Tronco/genética
7.
BMC Genomics ; 21(1): 123, 2020 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-32019511

RESUMO

BACKGROUND: Duck hepatitis A virus type 3 (DHAV-3) is one of the most harmful pathogens in the duck industry. However, the molecular mechanism underlying DHAV-3 infection in ducklings remains poorly understood. To study the genetic regulatory network for miRNA-mRNA and the signaling pathways involved in DHAV-3 infection in ducklings, we conducted global miRNA and mRNA expression profiling of duckling liver tissues infected with lethal DHAV-3 by high-throughput sequencing. RESULTS: We found 156 differentially expressed miRNAs (DEMs) and 7717 differentially expressed genes (DEGs) in livers of mock-infected and DHAV-3-infected duckling. A total of 19,606 miRNA-mRNA pairs with negatively correlated expression patterns were identified in miRNA-mRNA networks constructed on the basis of these DEMs and DEGs. Moreover, immune-related pathways, including the cytokine-cytokine receptor interaction, apoptosis, Toll-like receptor, Jak-STAT, and RIG-I-like receptor signaling pathway, were significantly enriched through analyzing functions of mRNAs in the network in response to DHAV-3 infection. Furthermore, apl-miR-32-5p, apl-miR-125-5p, apl-miR-128-3p, apl-miR-460-5p, and novel-m0012-3p were identified as potential regulators in the immune-related signaling pathways during DHAV-3 infection. And some host miRNAs were predicted to target the DHAV-3 genome. CONCLUSIONS: This is the first integrated analysis of miRNA and mRNA in DHAV-3-infected ducklings. The results indicated the important roles of miRNAs in regulating immune response genes and revealed the immune related miRNA-mRNA regulation network in the DHAV-3-infected duckling liver. These findings increase our knowledge of the roles of miRNAs and their target genes in DHAV-3 replication and pathogenesis. They also aid in the understanding of host-virus interactions.


Assuntos
Patos/genética , Patos/virologia , Redes Reguladoras de Genes/genética , Vírus da Hepatite do Pato/genética , Fígado/virologia , MicroRNAs/genética , RNA Mensageiro/genética , Animais , Citocinas/genética , Genoma Viral/genética , Doenças das Aves Domésticas/virologia , Receptores de Citocinas/genética , Transdução de Sinais/genética
8.
PLoS Negl Trop Dis ; 14(2): e0008080, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32078636

RESUMO

Schistosoma mansoni adaptive success is related to regulation of replication, transcription and translation inside and outside the intermediate and definitive host. We hypothesize that S. mansoni alters its epigenetic state in response to the mammalian host immune system, reprogramming gene expression and altering the number of eggs. In response, a change in the DNA methylation profile of hepatocytes could occurs, modulating the extent of hepatic granuloma. To investigate this hypothesis, we used the EBi3-/- murine (Mus musculus) model of S. mansoni infection and evaluated changes in new and maintenance DNA methylation profiles in the liver after 55 days of infection. We evaluated expression of epigenetic genes and genes linked to histone deubiquitination in male and female S. mansoni worms. Comparing TET expression with DNMT expression indicated that DNA demethylation exceeds methylation in knockout infected and uninfected mice and in wild-type infected and uninfected mice. S. mansoni infection provokes activation of demethylation in EBi3-/-I mice (knockout infected). EBi3-/-C (knockout uninfected) mice present intrinsically higher DNA methylation than WTC (control uninfected) mice. EBi3-/-I mice show decreased hepatic damage considering volume and reduced number of granulomas compared to WTI mice; the absence of IL27 and IL35 pathways decreases the Th1 response resulting in minor liver damage. S. mansoni males and females recovered from EBi3-/-I mice have reduced expression of a deubiquitinating enzyme gene, orthologs of which target histones and affect chromatin state. SmMBD and SmHDAC1 expression levels are downregulated in male and female parasites recovered from EBi3-/-, leading to epigenetic gene downregulation in S. mansoni. Changes to the immunological background thus induce epigenetic changes in hepatic tissues and alterations in S. mansoni gene expression, which attenuate liver symptoms in the acute phase of schistosomiasis.


Assuntos
Epigênese Genética , Antígenos de Histocompatibilidade Menor/genética , Receptores de Citocinas/genética , Esquistossomose mansoni/imunologia , Animais , Metilação de DNA , Feminino , Regulação da Expressão Gênica/imunologia , Fígado/metabolismo , Fígado/parasitologia , Masculino , Camundongos , Camundongos Knockout , MicroRNAs , RNA de Helmintos/genética , RNA de Helmintos/metabolismo , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Schistosoma mansoni/imunologia , Esquistossomose mansoni/parasitologia
9.
Cytogenet Genome Res ; 160(1): 18-21, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32008001

RESUMO

Multiple isodicentric Y chromosomes [idic(Y)] is a rare cytogenetic abnormality, most exclusively described in constitutional karyotypes. Only recently has this entity been reported in hematologic neoplasms such as myeloid disorders, albeit these cases remain very scarce. The possible involvement of increasing copies of potential proto-oncogenes located on the multiple idic(Y) led to consider one of them, CRLF2, as a target for kinase inhibitors. We report here, to our knowledge, the first case of multiple idic(Y) in a patient with myelofibrosis secondary to essential thrombocythemia. The patient received ruxolitinib therapy with initial good clinical response.


Assuntos
Cromossomos Humanos Y/genética , Mielofibrose Primária/complicações , Aberrações dos Cromossomos Sexuais , Trombocitemia Essencial/complicações , Idoso , Alelos , Humanos , Hibridização in Situ Fluorescente , Cariótipo , Cariotipagem , Masculino , Mosaicismo , Contagem de Plaquetas , Mielofibrose Primária/genética , Prognóstico , Pirazóis/uso terapêutico , Receptores de Citocinas/genética , Trombocitemia Essencial/genética
10.
PLoS Negl Trop Dis ; 14(1): e0008021, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31961868

RESUMO

Domestic dogs are the main reservoir of Leishmania infantum, a causative agent of visceral leishmaniasis (VL). The number of human disease cases is associated with the rate of canine infection. Currently available drugs are not efficient at treating canine leishmaniasis (CanL) and months after the treatment most dogs show disease relapse, therefore the development of new drugs or new therapeutic strategies should be sought. In CanL, dogs lack the ability to mount a specific cellular immune response suitable for combating the parasite and manipulation of cytokine signaling pathway has the potential to form part of effective immunotherapeutic methods. In this study, recombinant canine cytokines (rcaIL-12, rcaIL-2, rcaIL-15 and rcaIL-7) and soluble receptor IL-10R1 (rcasIL-10R1), with antagonistic activity, were evaluated for the first time in combination (rcaIL-12/rcaIL-2, rcaIL-12/rcaIL-15, rcaIL-12/rcasIL-10R1, rcaIL-15/rcaIL-7) or alone (rcasIL-10R1) to evaluate their immunomodulatory capacity in peripheral blood mononuclear cells (PBMCs) from dogs with leishmaniasis. All the combinations of recombinant proteins tested were shown to improve lymphoproliferative response. Further, the combinations rcaIL-12/rcaIL-2 and rcaIL-12/rcaIL-15 promoted a decrease in programmed cell death protein 1 (PD-1) expression in lymphocytes. These same combinations of cytokines and rcaIL-12/rcasIL-10R1 induced IFN-γ and TNF-α production in PBMCs. Furthermore, the combination IL-12/IL-15 led to an increased in T-bet expression in lymphocytes. These findings are encouraging and indicate the use of rcaIL-12 and rcaIL-15 in future in vivo studies aimed at achieving polarization of cellular immune responses in dogs with leishmaniasis, which may contribute to the development of an effective treatment against CanL.


Assuntos
Doenças do Cão/tratamento farmacológico , Doenças do Cão/imunologia , Interleucina-12/administração & dosagem , Interleucina-15/administração & dosagem , Leishmaniose Visceral/imunologia , Animais , Doenças do Cão/genética , Doenças do Cão/parasitologia , Cães , Imunidade Celular , Interferon gama/genética , Interferon gama/imunologia , Interleucina-12/genética , Interleucina-12/imunologia , Interleucina-15/genética , Interleucina-15/imunologia , Leishmania infantum/fisiologia , Leishmaniose Visceral/tratamento farmacológico , Leishmaniose Visceral/parasitologia , Leishmaniose Visceral/veterinária , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/parasitologia , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/imunologia , Receptores de Citocinas/genética , Receptores de Citocinas/imunologia
11.
Cell Mol Life Sci ; 77(23): 5017-5030, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31955243

RESUMO

Ulcerative colitis (UC) is characterized by relapsing-remitting inflammatory episodes paralleled by varying cytokine levels, suggesting that switching epigenetic processes might be involved. However, the epigenetic impact on cytokine levels in colitis is mostly unexplored. The heterodimeric interleukin (IL)-12 cytokine family have various functions in both pro- and anti-inflammatory processes. The family member IL-35 (EBI3/IL-12p35) was recently reported to play an anti-inflammatory role in UC. Therefore, we aimed to investigate a possible epigenetic regulation of the IL-35 subunits in vitro and in vivo, and to examine the epigenetic targeting of EBI3 expression as a therapeutic option for UC. Exposure to either the pro-inflammatory TNFα or to histone deacetylase inhibitors (HDACi) significantly increased EBI3 expression in Human Colon Epithelial Cells (HCEC) generated from healthy tissue. When applied in combination, a drastic upregulation of EBI3 expression occurred, suggesting a synergistic mechanism. Consequently, IL-35 was increased as well. In vivo, the intestines of HDACi-treated wild-type mice exhibited reduced pathological signs of colitis compared to non-treated colitic mice. However, the improvement by HDACi treatment was completely lost in Ebi3-deficient mice (Ebi3-/-). In fact, HDACi appeared to exacerbate the disease phenotype in Ebi3-/-. In conclusion, our results reveal that under inflammatory conditions, EBI3 is upregulated by the epigenetic mechanism of histone acetylation. The in vivo data show that the deficiency of EBI3 plays a key role in colitis manifestation. Concordantly, our data suggest that conditions promoting histone acetylation, such as upon HDACi application, improve colitis by a mechanism involving the local formation of the anti-inflammatory cytokine IL-35.


Assuntos
Epigênese Genética , Histonas/metabolismo , Doenças Inflamatórias Intestinais/genética , Interleucinas/metabolismo , Antígenos de Histocompatibilidade Menor/metabolismo , Receptores de Citocinas/metabolismo , Animais , Complexo CD3/metabolismo , Caspase 3/metabolismo , Colite/induzido quimicamente , Colite/patologia , Sulfato de Dextrana , Epigênese Genética/efeitos dos fármacos , Inibidores de Histona Desacetilases/farmacologia , Humanos , Inflamação/patologia , Interleucina-12/metabolismo , Interleucinas/genética , Camundongos Endogâmicos C57BL , Antígenos de Histocompatibilidade Menor/genética , Fenótipo , Ligação Proteica/efeitos dos fármacos , Receptores de Citocinas/genética , Transdução de Sinais/efeitos dos fármacos , Fator de Necrose Tumoral alfa/farmacologia , Vorinostat/farmacologia
12.
Cell Mol Biol Lett ; 24: 63, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31827539

RESUMO

Background: The participation of long noncoding RNAs (lncRNAs) in myocardial infarction has recently been noted. However, their underlying roles in the border zone of myocardial infarction remain unclear. This study uses microarrays to determine the profiles of lncRNAs and mRNAs in the border zone. Methods: Bioinformatics methods were employed to uncover their underlying roles. Highly dysregulated lncRNAs was further validated via PCR. Results: Four hundred seven lncRNAs and 752 mRNAs were upregulated, while 132 lncRNAs and 547 mRNAs were downregulated in the border zone of myocardial infarction. A circos graph was constructed to visualize the chromosomal distribution and classification of the dysregulated lncRNAs and mRNAs. The upregulated mRNAs in the border zone were most highly enriched in cytokine activity, binding, cytokine receptor binding and related processes, as ascertained through Go analysis. Pathway analysis of the upregulated mRNAs showed the most significant changes were in the TNF signaling pathway, cytokine-cytokine receptor interaction and chemokine signaling pathway and similar pathways and interactions. An lncRNA-mRNA co-expression network was established to probe into the underlying functions of the 10 most highly dysregulated lncRNAs based on their co-expressed mRNAs. In the co-expression network, we found 16 genes directly involved in myocardial infarction, including Alox5ap, Itgb2 and B4galt1. The lncRNAs AY212271, EF424788 and MRAK088538, among others, might be associated with myocardial infarction. BC166504 is probably a key lncRNA in the border zone of myocardial infarction. Conclusions: The results may have revealed some aberrantly expressed lncRNAs and mRNAs that contribute to the underlying pathophysiological mechanisms of myocardial infarction.


Assuntos
Regulação da Expressão Gênica , Redes Reguladoras de Genes , Infarto do Miocárdio/genética , RNA Longo não Codificante/genética , RNA Mensageiro/genética , Proteínas Ativadoras de 5-Lipoxigenase/genética , Proteínas Ativadoras de 5-Lipoxigenase/metabolismo , Animais , Aorta Torácica/cirurgia , Antígenos CD18/genética , Antígenos CD18/metabolismo , Biologia Computacional/métodos , Citocinas/genética , Citocinas/metabolismo , Modelos Animais de Doenças , Galactosiltransferases/genética , Galactosiltransferases/metabolismo , Perfilação da Expressão Gênica , Ontologia Genética , Ligadura , Masculino , Anotação de Sequência Molecular , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/fisiopatologia , Análise de Sequência com Séries de Oligonucleotídeos , RNA Longo não Codificante/classificação , RNA Longo não Codificante/metabolismo , RNA Mensageiro/classificação , RNA Mensageiro/metabolismo , Ratos , Ratos Wistar , Receptores de Citocinas/genética , Receptores de Citocinas/metabolismo , Transdução de Sinais
13.
PLoS One ; 14(12): e0224652, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31830053

RESUMO

It has been reported that overexpression of the CRLF2 gene is associated with poor outcomes in pediatric B cell acute lymphoblastic leukemia (B-ALL), but the incidence rates, clinical characteristics and outcomes of CRLF2 gene overexpression in pediatric T cell ALL (T-ALL) have not been systematically analyzed. In this study, CRLF2 mRNA expression levels and clinical and laboratory parameters in 63 pediatric T-ALL patients were detected at the Children's Hospital of Chongqing Medical University and Children's Hospital of Xianyang between February 2015 and June 2018. The patients were treated according to the modified St. Jude TXV ALL protocol, and early treatment responses (bone marrow smear and MRD level) and prognoses in the enrolled patients were assessed. CRLF2 overexpression was detected in 21/63 (33.33%) patients. Statistical differences were not found for clinical or laboratory parameters (including sex, age, initial WBC count, incidence mediastinal involvement, abnormal karyotype and fusion genes) between patients with high CRLF2 expression and patients with low expression of CRLF2 (P>0.05). One patient died of tumor lysis syndrome and renal failure, and the treatment response was monitored on day 19 (TP1) of remission in 62 patients. One patient quit treatment because of family decisions, and 61 patients underwent treatment response evaluation on day 46 (TP2) of remission. Significant differences were not found between patients with high CRLF2 expression and patients with low CRLF2 expression in terms of the treatment responses at TP1 or TP2 (P>0.05). Following October 2018, 12 patients among the 61 evaluable patients relapsed (relapse rate: 19.67%), 3 patients died from chemotherapy, and the treatment-related mortality (TRM) rate was 4.92%. Secondary tumors occurred in 1 patient. The 3-year prospective EFS rate was 54.1±11.2% and 77.7±6.6% for the 61 evaluable patients and 58 patients without TRM. Patients with low CRLF2 expression had longer EFS durations than patients with high CRLF2 expression (61 evaluable patients: 35.91± 2.38 months vs 23.43± 2.57 months; 58 patients without TRM: 37.86± 2.08 months vs 24.55±2.43 months, P<0.05). CRLF2 expression levels were also monitored in 13 patients at TP1 and TP2, and the MRD level did not vary with the CRLF2 expression level. Our data suggest that clinical features, laboratory findings and treatment responses in the pediatric T-ALL population do not vary based on the overexpression of CRLF2 but that CRLF2 overexpression can contribute to a high risk of relapse in pediatric T-ALL. Thus, CRLF2 expression levels should not be used as biomarkers for monitoring MRD.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/metabolismo , Recidiva Local de Neoplasia/patologia , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patologia , Receptores de Citocinas/metabolismo , Adolescente , Biomarcadores Tumorais/genética , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Lactente , Masculino , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/metabolismo , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/metabolismo , Prognóstico , Estudos Prospectivos , Receptores de Citocinas/genética
14.
Biomed Res Int ; 2019: 1545680, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31781593

RESUMO

Colorectal cancer (CRC) is one of the most common malignant tumors. The aim of the present study was to identify key genes and pathways to improve the understanding of the mechanism of CRC. GSE87211, including 203 CRC samples and 160 control samples, was screened to identify differentially expressed genes (DEGs). In total, 853 DEGs were obtained, including 363 upregulated genes and 490 downregulated genes. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis of DEGs were performed to obtain enrichment datasets. GO analysis showed that DEGs were significantly enriched in the extracellular region, cell-cell signaling, hormone activity, and cytokine activity. KEGG pathway analysis revealed that the DEGs were mainly enriched in the cytokine-cytokine receptor interaction, drug metabolism, androgen and estrogen metabolism, and neuroactive ligand-receptor interaction. The Protein-Protein Interaction (PPI) network of DEGs was constructed by using Search Tool for the Retrieval of Interacting Genes (STRING). The app MCODE plugged in Cytoscape was used to explore the key modules involved in disease development. 43 key genes involved in the top two modules were identified. Six hub genes (CXCL2, CXCL3, PTGDR2, GRP, CXCL11, and AGTR1) were statistically associated with patient overall survival or disease-free survival. The functions of six hub genes were mainly related to the hormone and chemokine activities. In conclusion, the present study may help understand the molecular mechanisms of CRC development.


Assuntos
Neoplasias Colorretais/genética , Proteína Semelhante a ELAV 2/genética , Transdução de Sinais/genética , Biologia Computacional/métodos , Citocinas/genética , Intervalo Livre de Doença , Regulação para Baixo/genética , Regulação Neoplásica da Expressão Gênica/genética , Ontologia Genética , Redes Reguladoras de Genes/genética , Humanos , Mapeamento de Interação de Proteínas/métodos , Receptores de Citocinas/genética , Regulação para Cima/genética
15.
PLoS One ; 14(11): e0223955, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31725732

RESUMO

African swine fever (ASF) is a swine disease caused by a large, structurally complex, double-stranded DNA virus, African swine fever virus (ASFV). In domestic pigs, acute infection by highly virulent ASF viruses causes hemorrhagic fever and death. Previous work has suggested that ASFV pathogenesis is primarily mediated by host cytokines produced by infected monocytes and macrophages. To better understand molecular mechanisms mediating virus pathogenesis and immune evasion, we used transcriptome analysis to identify gene expression changes after ASFV infection in ex vivo swine macrophages. Our results suggest that the cytokines of TNF family including FASLG, LTA, LTB, TNF, TNFSF4, TNFSF10, TNFSF13B and TNFSF18 are the major causative cytokine factors in ASF pathogenesis via inducing apoptosis. Other up-regulated proinflammatory cytokines (IL17F and interferons) and down-regulated anti-inflammatory cytokine (IL10) may also significantly contribute to ASF pathogenesis and cause excessive tissue inflammatory responses. The differential expression of genes also indicates that ASFV could evade both the innate and adaptive immune responses by (i) inhibiting MHC Class II antigen processing and presentation, (ii) avoiding CD8+ T effector cells and neutrophil extracellular traps via decreasing expression of neutrophil/CD8+ T effector cell-recruiting chemokines, (iii) suppressing M1 activation of macrophages, (iv) inducing immune suppressive cytokines, and (v) inhibiting the processes of macrophage autophagy and apoptosis. These results provide novel information to further investigate and better understand the mechanism of pathogenesis and immune evasion of this devastating swine disease.


Assuntos
Vírus da Febre Suína Africana/patogenicidade , Febre Suína Africana/imunologia , Evasão da Resposta Imune , Macrófagos/imunologia , Macrófagos/virologia , Imunidade Adaptativa/genética , Febre Suína Africana/genética , Febre Suína Africana/virologia , Vírus da Febre Suína Africana/imunologia , Animais , Apresentação do Antígeno/genética , Proteínas Relacionadas à Autofagia/genética , Células Cultivadas , Quimiocinas/genética , Citocinas/genética , Regulação para Baixo , Perfilação da Expressão Gênica , Evasão da Resposta Imune/genética , Imunidade Inata/genética , Ativação de Macrófagos/genética , Ativação de Macrófagos/imunologia , Receptores de Citocinas/genética , Transdução de Sinais/genética , Sus scrofa , Suínos , Regulação para Cima
16.
Dermatology ; 235(6): 445-455, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31454825

RESUMO

BACKGROUND: Acne is the most common skin inflammatory condition. The pathogenesis of acne is not fully understood. AIMS: We performed weighted gene co-expression network analysis (WGCNA) to select acne-associated genes and pathways. METHODS: GSE53795 and GSE6475 datasets including data from lesional and nonlesional skin of acne patients were downloaded from the NCBI Gene Expression Omnibus. Differentially expressed genes (DEGs) in lesions were identified following a false discovery rate <0.05 and | log2 fold change | ≥0.5. DEG-associated biological processes and pathways were identified. WGCNA analysis was performed to identify acne-associated modules. DEGs in the acne-associated modules were used for protein-protein interaction (PPI) network construction and Gene Set Enrichment Analysis (GSEA). Acne-associated candidate DEGs and pathways were identified together with items in the Comparative Toxicogenomics Database (CTD). RESULTS: A total of 2,140 and 1,190 DEGs were identified in GSE53795 and GSE6475 datasets, respectively, including 716 overlapping DEGs with similar expression profiles in the two datasets, which were clustered into 10 consensus modules. Two modules (brown and turquoise, 359 genes) were associated with acne phenotype. Of these 359 DEGs, 254 were enrolled in the PPI network. GSEA showed that these DEGs were associated with chemokine signaling pathway, cytokine-cytokine receptor interaction, and natural killer cell-mediated cytotoxicity. After identification in CTD, one pathway Cytokine-cytokine receptor interaction and 24 acne-associated DEGs, including IL1R1, CXCL1, CXCR4, CCR1, CXCL2 and IL1ß, were identified as candidates associated with acne. CONCLUSION: Our results highlight the important roles of the proinflammatory cytokines including IL1ß, CXCL1, CXCL2, CXCR4, and CCR1 in acne pathogenesis or therapeutic management.


Assuntos
Acne Vulgar/genética , Acne Vulgar/metabolismo , Biologia Computacional , Expressão Gênica , Biologia Computacional/métodos , Citocinas/genética , Bases de Dados Genéticas , Conjuntos de Dados como Assunto , Regulação para Baixo , Humanos , Redes e Vias Metabólicas/genética , Mapas de Interação de Proteínas , Receptores de Citocinas/genética , Transdução de Sinais/genética , Regulação para Cima
17.
PLoS One ; 14(7): e0220026, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31318944

RESUMO

Philadelphia chromosome-like (Ph-like) acute lymphoblastic leukemia (ALL) is a genetically heterogeneous subtype of B-cell ALL characterized by chromosomal rearrangements and mutations that result in aberrant cytokine receptor and kinase signaling. In particular, chromosomal rearrangements resulting in the overexpression of cytokine receptor-like factor 2 (CRLF2) occur in 50% of Ph-like ALL cases. CRLF2 overexpression is associated with particularly poor clinical outcomes, though the molecular basis for this is currently unknown. Glucocorticoids (GCs) are integral to the treatment of ALL and GC resistance at diagnosis is an important negative prognostic factor. Given the importance of GCs in ALL therapy and the poor outcomes for patients with CRLF2 overexpression, we hypothesized that the aberrant signal transduction associated with CRLF2 overexpression might mediate intrinsic GC insensitivity. To test this hypothesis, we exposed Ph-like ALL cells from patient-derived xenografts to GCs and found that CRLF2 rearranged (CRLF2R) leukemias uniformly demonstrated reduced GC sensitivity in vitro. Furthermore, targeted inhibition of signal transduction with the MEK inhibitor trametinib and the Akt inhibitor MK2206, but not the JAK inhibitor ruxolitinib, was sufficient to augment GC sensitivity. These data suggest that suboptimal GC responses may in part underlie the poor clinical outcomes for patients with CRLF2 overexpression and provide rationale for combination therapy involving GCs and signal transduction inhibitors as a means of enhancing GC efficacy.


Assuntos
Resistencia a Medicamentos Antineoplásicos/genética , Rearranjo Gênico , Glucocorticoides/farmacologia , MAP Quinase Quinase Quinases/antagonistas & inibidores , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Receptores de Citocinas/genética , Linhagem Celular Tumoral , Regulação Leucêmica da Expressão Gênica , Glucocorticoides/uso terapêutico , Humanos , Cromossomo Filadélfia , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Inibidores de Proteínas Quinases/uso terapêutico , Transdução de Sinais/efeitos dos fármacos
18.
Curr Stem Cell Res Ther ; 14(7): 591-597, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31120000

RESUMO

Combination antiretroviral therapy (cART) has significantly reduced the mortality rate and morbidity, and has increased the life expectancy of the human immunodeficiency virus (HIV) infected patients. However, the current cART is incapable of eradicating viruses from the human body, and HIV remains one of the most notorious viruses mankind has ever faced. HIV-1 enters target cells through the binding of gp120 viral protein to a CD4 receptor and then to a coreceptor, C-C chemokine receptor 5 (CCR5) or C-X-C chemokine receptor type 4 (CXCR4). Individuals homozygous for a 32-bp deletion in the CCR5 allele, CCR5Δ32, are almost completely resistant to HIV-1 acquisition. Moreover, several of natural CXCR4 mutants which have been identified can reduce HIV-1 entry without impairing either ligand binding or signaling. In order to get rid of indefinite treatment for HIV patients, there is a growing interest in creating an HIV-resistant immune system through the use of CCR5 and CXCR4-modified hematopoietic stem cells (HSCs). Proof of concept for this approach has been provided in the instance of "Berlin patient" transplanted with allogeneic stem cells from a donor with homozygosity for the CCR5Δ32 deletion. Here, we review the progress of coreceptor-based HSC gene therapy for HIV disease and present new strategies.


Assuntos
Terapia Genética/métodos , Infecções por HIV/terapia , HIV-1/fisiologia , Transplante de Células-Tronco Hematopoéticas/métodos , Células-Tronco Hematopoéticas/citologia , Receptores de Citocinas/genética , Receptores de HIV/genética , Terapia Combinada , Infecções por HIV/genética , Infecções por HIV/metabolismo , Humanos
19.
Immunity ; 50(4): 778-795, 2019 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-30995499

RESUMO

Forty years after its naming, interleukin-1 (IL-1) is experiencing a renaissance brought on by the growing understanding of its context-dependent roles and advances in the clinic. Recent studies have identified important roles for members of the IL-1 family-IL-18, IL-33, IL-36, IL-37, and IL-38-in inflammation and immunity. Here, we review the complex functions of IL-1 family members in the orchestration of innate and adaptive immune responses and their diversity and plasticity. We discuss the varied roles of IL-1 family members in immune homeostasis and their contribution to pathologies, including autoimmunity and auto-inflammation, dysmetabolism, cardiovascular disorders, and cancer. The trans-disease therapeutic activity of anti-IL-1 strategies argues for immunity and inflammation as a metanarrative of modern medicine.


Assuntos
Imunidade Adaptativa/imunologia , Citocinas/fisiologia , Imunidade Inata/imunologia , Inflamação/imunologia , Interleucina-1/fisiologia , Animais , Doenças Cardiovasculares/imunologia , Citocinas/genética , Citocinas/imunologia , Gastroenteropatias/imunologia , Hematopoese/imunologia , Humanos , Interleucina-1/imunologia , Linfócitos/imunologia , Camundongos , Camundongos Knockout , Família Multigênica , Neoplasias/imunologia , Doenças Neurodegenerativas/imunologia , Receptores de Citocinas/genética , Receptores de Citocinas/imunologia
20.
Cancer Sci ; 110(6): 1931-1946, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30974024

RESUMO

Activating mutations in cytokine receptors and transcriptional regulators govern aberrant signal transduction in T-cell lineage acute lymphoblastic leukemia (T-ALL). However, the roles played by suppressors of cytokine signaling remain incompletely understood. We examined the regulatory roles of suppressor of cytokine signaling 5 (SOCS5) in T-ALL cellular signaling networks and leukemia progression. We found that SOCS5 was differentially expressed in primary T-ALL and its expression levels were lowered in HOXA-deregulated leukemia harboring KMT2A gene rearrangements. Here, we report that SOCS5 expression is epigenetically regulated by DNA methyltransferase-3A-mediated DNA methylation and methyl CpG binding protein-2-mediated histone deacetylation. We show that SOCS5 negatively regulates T-ALL cell growth and cell cycle progression but has no effect on apoptotic cell death. Mechanistically, SOCS5 silencing induces activation of JAK-STAT signaling, and negatively regulates interleukin-7 and interleukin-4 receptors. Using a human T-ALL murine xenograft model, we show that genetic inactivation of SOCS5 accelerates leukemia engraftment and progression, and leukemia burden. We postulate that SOCS5 is epigenetically deregulated in T-ALL and serves as an important regulator of T-ALL cell proliferation and leukemic progression. Our results link aberrant downregulation of SOCS5 expression to the enhanced activation of the JAK-STAT and cytokine receptor-signaling cascade in T-ALL.


Assuntos
Epigênese Genética , Janus Quinases/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Fatores de Transcrição STAT/genética , Proteínas Supressoras da Sinalização de Citocina/genética , Animais , Linhagem Celular , Linhagem Celular Tumoral , DNA (Citosina-5-)-Metiltransferases/genética , DNA (Citosina-5-)-Metiltransferases/metabolismo , Progressão da Doença , Perfilação da Expressão Gênica , Humanos , Janus Quinases/metabolismo , Células Jurkat , Camundongos Endogâmicos NOD , Camundongos Knockout , Camundongos SCID , Leucemia-Linfoma Linfoblástico de Células T Precursoras/metabolismo , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patologia , Terapêutica com RNAi/métodos , Receptores de Citocinas/genética , Receptores de Citocinas/metabolismo , Fatores de Transcrição STAT/metabolismo , Transdução de Sinais/genética , Proteínas Supressoras da Sinalização de Citocina/metabolismo , Análise de Sobrevida , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA