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1.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 28(2): 695-699, 2020 Apr.
Artigo em Chinês | MEDLINE | ID: mdl-32319419

RESUMO

Abstract  Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL or BCR-ABL1-like ALL) is a kind of acute leukemia which has the similar gene expression profiles and manifests the biological behavior same to Ph-positive ALL, but lacks the BCR-ABL1 fusion gene. Ph-like ALL was involved in multiple abnormal changes of genomes, activating kinase and cytokine receptor signaling. This review focuses on the progress of classical genetic abnormalities of PH-like ALL in the JAK-STAT signaling, ABL kinase activation, TKI resistance in Ph-like ALL, SH2B3 gene inactivating mutation and IKZF1 gene abnormality. Besides, also summarizes the frontier progress of novel gene mutation (ATF7IP exon 9 fused with PDGFRB exon 11, PDGFRBC843G mutation caused by fusion of exon 11-23 of PDGFRB with exon 1-6 of AGGF1 gene) in recent years.


Assuntos
Leucemia-Linfoma Linfoblástico de Células Precursoras , Proteínas de Fusão bcr-abl , Humanos , Mutação , Cromossomo Filadélfia , Receptor beta de Fator de Crescimento Derivado de Plaquetas , Receptores de Citocinas
2.
PLoS One ; 15(4): e0230804, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32236103

RESUMO

Cytokine signaling is transmitted by cell surface receptors which act as natural biological switches to control cellular functions such as immune reactions. Recently, we have designed synthetic cytokine receptors (SyCyRs) consisting of green fluorescent protein (GFP)- and mCherry-nanobodies fused to the transmembrane and intracellular domains of cytokine receptors. Following stimulation with homo- and heterodimeric GFP-mCherry fusion proteins, the resulting receptors phenocopied signaling induced by physiologically occurring cytokines. GFP and mCherry fusion proteins were produced in E. coli or CHO-K1 cells, but the overall yield and stability was low. Therefore, we applied two alternative multimerization strategies and achieved immunoglobulin Fc-mediated dimeric and coiled-coil GCN4pII-mediated trimeric assemblies. GFP- and/or mCherry-Fc homodimers activated synthetic gp130 cytokine receptors, which naturally respond to Interleukin 6 family cytokines. Activation of these synthetic gp130 receptors resulted in STAT3 and ERK phosphorylation and subsequent proliferation of Ba/F3-gp130 cells. Half-maximal effective concentrations (EC50) of 8.1 ng/ml and 0.64 ng/ml were determined for dimeric GFP-Fc and mCherry-Fc, respectively. This is well within the expected EC50 range of the native cytokines. Moreover, we generated tetrameric and hexameric GFP-mCherry-Fc fusion proteins, which were also biologically active. This highlighted the importance of close juxtaposition of two cytokine receptors for efficient receptor activation. Finally, we used a trimeric GCN4pII motif to generate homo-trimeric GFP and mCherry complexes. These synthetic cytokines showed improved EC50 values (GFP3: 0.58 ng/ml; mCherrry3: 0.37 ng/ml), over dimeric Fc fused variants. In conclusion, we successfully generated highly effective and stable multimeric synthetic cytokine receptor ligands for activation of synthetic cytokine receptors.


Assuntos
Multimerização Proteica , Receptores Artificiais/síntese química , Receptores de Citocinas/metabolismo , Animais , Antígenos CD/metabolismo , Células CHO , Linhagem Celular , Cricetinae , Cricetulus , Receptor gp130 de Citocina/metabolismo , Humanos , Interleucina-6/metabolismo , Ligantes , Modelos Teóricos , Receptores Artificiais/metabolismo , Receptores de Interleucina-6/metabolismo , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais
3.
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
4.
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
5.
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
6.
Cell Host Microbe ; 27(1): 129-139.e4, 2020 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-31901521

RESUMO

Bacteria masterfully co-opt and subvert host signal transduction. As a paradigmatic example, Salmonella uses two type-3 secretion systems to inject effector proteins that facilitate Salmonella entry, establishment of an intracellular niche, and modulation of immune responses. We previously demonstrated that the Salmonella anti-inflammatory response activator SarA (Stm2585, GogC, PagJ, SteE) activates the host transcription factor STAT3 to drive expression of immunomodulatory STAT3-targets. Here, we demonstrate-by sequence, function, and biochemical measurement-that SarA mimics the cytoplasmic domain of glycoprotein 130 (gp130, IL6ST). SarA is phosphorylated at a YxxQ motif, facilitating binding to STAT3 with greater affinity than gp130. Departing from canonical gp130 signaling, SarA function is JAK-independent but requires GSK-3, a key regulator of metabolism and development. Our results reveal that SarA undergoes host phosphorylation to recruit a STAT3-activating complex, circumventing cytokine receptor activation. Effector mimicry of gp130 suggests GSK-3 can regulate normal cytokine signaling, potentially enabling metabolic and immune crosstalk.


Assuntos
Proteínas de Bactérias/metabolismo , Quinase 3 da Glicogênio Sintase/metabolismo , Mimetismo Molecular/imunologia , Fator de Transcrição STAT3/metabolismo , Transativadores/metabolismo , Linhagem Celular , Receptor gp130 de Citocina/metabolismo , Citocinas/metabolismo , Humanos , Imunidade Inata , Receptores de Citocinas/metabolismo , Fator de Transcrição STAT3/imunologia , Salmonella , Transdução de Sinais
7.
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
8.
J Orthop Res ; 38(2): 336-347, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31424111

RESUMO

The objective of this study was to define the effects of osteoarthritic (OA) milieu on good manufactured practice-adipose-derived mesenchymal stromal cells (GMP-ASC) that are commonly utilized in cell therapies. Two different OA milieu: OA synovial fluid (SF) and OA-conditioned medium (CM) from synoviocytes were used to treat GMP-ASC both in normoxia or hypoxia. GMP-ASC were tested for cell migration, proliferation, cytokine receptors expression (CXCR1, CXCR2, CXCR3, CXCR4, CXCR7, CCR1, CCR2, CCR3, CCR5, IL6R), and cytokines (CXCL8/IL8, CXCL10/IP10, CXCL12/SDF-1, CCL2/MCP1, CCL3/MIP1α, CCL4/MIP1ß, CCL5/RANTES, IL6) release. Healthy SF was used as controls. We demonstrated that GMP-ASC show an increase in proliferation, migration, and modulation of CXCR1, CXCR3, CCR1, and CCR5 receptors in hypoxic condition. Moreover, GMP-ASC migration increased 15-fold when treated either with OA-SF or OA-CM compared with healthy SF both in normoxia and hypoxia. GMP-ASC treated in both OA milieu showed an increase in CXCR3, CCR3, and IL6R and a decrease in CCR1 and CCR2 receptors. In OA-SF, we detected higher amount of CXCL10/IP10 than in OA-CM, while CCL2/MCP1 and CCL4/MIP1ß were higher in OA-CM compared with OA-SF. CXCL10/IP10 was the only chemokine of the OA milieu, which was down-modulated after treatment with GMP-ASC. In conclusion, we demonstrated specific effects of OA milieu on both GMP-ASC proliferation, migration, and cytokine receptor expression that were strictly dependent on the inflammatory and hypoxic environment. The use of characterized OA milieu is crucial to define the therapeutic effect of GMP-ASC and indicates that CXCL10/IP10-CXCR3 axis is partially involved in the GMP-ASC effect on synovial macrophages. © 2019 The Authors. Journal of Orthopaedic Research® published by Wiley Periodicals, Inc. on behalf of Orthopaedic Research Society. J Orthop Res 38:336-347, 2020.


Assuntos
Células-Tronco Mesenquimais/fisiologia , Osteoartrite/metabolismo , Líquido Sinovial/fisiologia , Movimento Celular , Meios de Cultivo Condicionados , Humanos , Hipóxia/metabolismo , Cultura Primária de Células , Receptores de Citocinas/metabolismo
9.
Life Sci ; 240: 117063, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31734262

RESUMO

BACKGROUND: Network pharmacology uses bioinformatics to broaden our understanding of drug actions and thereby advance drug discovery. Here we apply network pharmacology to generate testable hypotheses about the multi-target mechanism of celastrol against systemic lupus erythematosus (SLE). METHODS: We reconstructed drug-target pathways and networks to predict the likely protein targets of celastrol and the main interactions between those targets and the drug. Then we validated our predictions of candidate targets by performing docking studies with celastrol. RESULTS: The results suggest that celastrol acts against SLE by regulating the function of several signaling proteins, such as interleukin 10, tumor necrosis factor, and matrix metalloprotein 9, which regulate signaling pathways involving mitogen-activated protein kinase and tumor necrosis factor as well as apoptosis pathways. Celastrol is predicted to affect networks involved mainly in cytokine activity, cytokine receptor binding, receptor ligand activity, receptor regulator activity, and cofactor binding. Molecular docking analysis showed that hydrogen bonding and π-π stacking were the main forms of interaction. CONCLUSIONS: This network pharmacology strategy may be useful for discovery of multi-target drugs against complex diseases, specifically, it provides protein targets associated with SLE that may be further tested for therapeutic potential by celastrol.


Assuntos
Lúpus Eritematoso Sistêmico/tratamento farmacológico , Simulação de Acoplamento Molecular , Transdução de Sinais/efeitos dos fármacos , Triterpenos/uso terapêutico , Citocinas/metabolismo , Sistemas de Liberação de Medicamentos , Humanos , Ligação de Hidrogênio/efeitos dos fármacos , Lúpus Eritematoso Sistêmico/genética , Receptores de Citocinas/efeitos dos fármacos
10.
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
11.
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
12.
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
13.
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
14.
Nat Immunol ; 20(12): 1603-1609, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31745338

RESUMO

The cytokine TSLP has been shown to be a key factor in maintaining immune homeostasis and regulating inflammatory responses at mucosal barriers. While the role of TSLP in type 2 immune responses has been investigated extensively, recent studies have found an expanding role for TSLP in inflammatory diseases and cancer. In this Review, we will highlight major recent advances in TSLP biology, along with results from emerging clinical trials of anti-TSLP agents used for the treatment of a variety of inflammatory conditions.


Assuntos
Citocinas/metabolismo , Hipersensibilidade/metabolismo , Inflamação/imunologia , Neoplasias/metabolismo , Isoformas de Proteínas/metabolismo , Receptores de Citocinas/metabolismo , Animais , Ensaios Clínicos como Assunto , Homeostase , Humanos , Interleucina-7/metabolismo , Linfopoese
15.
Adv Exp Med Biol ; 1172: 1-19, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31628649

RESUMO

The common γ chain (γc) family of hematopoietic cytokines consists of six distinct four α-helix bundle soluble ligands that signal through receptors which include the shared γc subunit to coordinate a wide range of physiological processes, in particular, those related to innate and adaptive immune function. Since the first crystallographic structure of a γc family cytokine/receptor signaling complex (the active Interleukin-2 [IL-2] quaternary complex) was determined in 2005 [1], tremendous progress has been made in the structural characterization of this protein family, transforming our understanding of the molecular mechanisms underlying immune activity. Although many conserved features of γc family cytokine complex architecture have emerged, distinguishing details have been observed for individual cytokine complexes that rationalize their unique functional properties. Much work remains to be done in the molecular characterization of γc family signaling, particularly with regard to intracellular activation events, and looking forward, new technologies in structural biophysics will offer further insight into the biology of cytokine signaling to inform the design of targeted therapeutics for treatment of immune-linked diseases such as cancer, infection, and autoimmune disorders.


Assuntos
Subunidade gama Comum de Receptores de Interleucina , Transdução de Sinais , Animais , Humanos , Subunidade gama Comum de Receptores de Interleucina/química , Subunidade gama Comum de Receptores de Interleucina/fisiologia , Interleucina-2/química , Interleucina-2/fisiologia , Receptores de Citocinas/metabolismo , Transdução de Sinais/fisiologia
16.
Int J Mol Sci ; 20(19)2019 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-31597273

RESUMO

There is increasing evidence of a correlation between interferon-inducible protein 10 (IP-10) and disease activity of systemic lupus erythematosus (SLE) and lupus nephritis (LN). We conducted a comprehensive search on IP-10 using MEDLINE, Scopus, and Cochrane electronic databases from the beginning to the end of December 2017. All studies that compared serum and/or urine IP-10 between active SLE/LN patients and any control groups were identified and included in this systematic review and meta-analysis. The mean difference (MD) of IP-10 level among active SLE and LN patients, as well as the correlation of IP-10 with disease activity, were meta-analyzed using a random-effects model. From 23 eligible studies, 15 provided adequate data for meta-analysis. Serum IP-10 was significantly elevated in patients with active SLE compared to non-active SLE patients (MD 356.5 pg/mL, 95% CI 59.6 to 653.4, p = 0.019). On the other hand, the levels of serum IP-10 was not different between active LN and non-active LN. However, serum IP-10 was positively correlated with disease activity like SLE disease activity index (SLEDAI) (pooled r = 0.29, 95% CI 0.22 to 0.35, p < 0.001). Furthermore, urine IP-10 tended to be higher in patients with active LN compared to non-active LN patients but this did not reach statistical significance (MD 3.47 pg/mgCr × 100, 95% CI -0.18 to 7.12, p = 0.06). Nevertheless, urine IP-10 was positively correlated with renal SLEDAI (pooled r = 0.29, 95% CI 0.05 to 0.50, p = 0.019). In conclusion, serum and urine IP-10 levels may be useful in monitoring the disease activity of SLE and LN. Serum IP-10 was correlated with systemic disease whereas urine IP-10 was a useful biomarker for detecting active LN.


Assuntos
Quimiocina CXCL10/sangue , Lúpus Eritematoso Sistêmico/sangue , Lúpus Eritematoso Sistêmico/diagnóstico , Nefrite Lúpica/sangue , Nefrite Lúpica/diagnóstico , Biomarcadores , Quimiocina CXCL10/urina , Humanos , Lúpus Eritematoso Sistêmico/complicações , Nefrite Lúpica/etiologia , Prognóstico , Curva ROC , Receptores de Citocinas/sangue , Índice de Gravidade de Doença
17.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 27(4): 1058-1063, 2019 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-31418357

RESUMO

OBJECTIVE: To detect the expression of CRLF2 in bone marrow mononuclear cells from children with newly diagnosed acute lymphoblastic leukemia(ALL) and to explore its clinical significance in pediatric ALL. METHODS: A total of 218 children with newly diagnosed ALL who achieveal the complete remission and had the complete follow-up information were selected, and the expression level of CRLF2 in bone marrow mononuclear cells of these children was detected by real-time fluorescent quantitative PCR, and the significance of CRLF2 expression level in clinical prognosis of ALL children was analyzed by using statistical method. RESULTS: 28 cases in 218 children with complete data showed high expression of CRLF2. The cumulative recurrence rate in the CRLF2 high expression group was significantly higher than that in the low expression group (53.6% vs 12.6%) (P<0.01). The predicted 5-year recurrence-free survival rate (RFS) of ALL children with CRLF2 high expression was significantly higher than that of low expression group (P<0.01). There was no significant difference in the predicted 5-year RFS between ALL children with CRLF2 low and high expression in the standard-risk(SR) group (P>0.05). The predicted 5-year RFS of ALL children with CRLF2 low expression was higher than that of ALL children with CRLF2 high expression in the intermediate-risk (IR) and high-risk (HR) groups. (P<0.05). Cox analysis showed that CRLF2 high expression is an independent risk factor for the relapse of children with ALL. CONCLUSION: The recurrence rate of pediatric ALL with CRLF2 high expression is high, and CRLF2 high expression is an important prognostic factor for high risk of relapse in ALL children with IR and HR. It is necessary to use CRLF2 expression as an indicator of risk stratification in pediatric ALL.


Assuntos
Medula Óssea , Leucemia-Linfoma Linfoblástico de Células Precursoras , Receptores de Citocinas/metabolismo , Criança , Humanos , Prognóstico , Recidiva , Fatores de Risco
18.
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
19.
World Neurosurg ; 132: 138-147, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31470153

RESUMO

BACKGROUND: The infliction of a traumatic spinal cord injury (SCI) propagates damage that occurs in 2 stages. The first phase of trauma develops from the initial mechanical insult. The second phase involves the degradation of nervous tissue but is likely not affected by the initial insult. Thus, therapeutic targets with a high specificity for these secondary injury processes have been of increasing interest. We reviewed the pathophysiologic cascades of inflammation after SCI and potential therapeutic targets. METHODS: The PubMed and EMBASE databases were queried using appropriate medical subject headings for studies involving tumor necrosis factor (TNF)-α), nuclear factor (NF)-κB, inducible nitric oxide synthase (iNOS), interleukin (IL)-1ß, and/or Fas ligand (FasL) targets. The relevant studies found were graded into 3 levels (i.e., A, B, C) according to the quality of evidence. RESULTS: We have summarized the basis of the neurological damage for TNF-α, NF-κB, iNOS, IL-1ß, and FasL after SCI. A total of 17 studies were rated, each of which had reported histological, biochemical, physiological, and behavioral outcomes according to the treatment that had focused on TNF-α, NF-κB, iNOS, IL-1ß, and FasL. CONCLUSION: The TNF-α, iNOS, NF-κB, IL-1ß, and FasL will become active within minutes after SCI. The adverse effects from the activity of these receptors include inflammation and other important neurological damage. Each of these targets can be modulated by specific agents with differing degrees of efficacy according to the reported data.


Assuntos
Anti-Inflamatórios/uso terapêutico , Inflamação/tratamento farmacológico , Inflamação/etiologia , Traumatismos da Medula Espinal/complicações , Traumatismos da Medula Espinal/tratamento farmacológico , Animais , Citocinas/metabolismo , Humanos , Receptores de Citocinas/efeitos dos fármacos
20.
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
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