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[PMID]:28877989
[Au] Autor:Madireddi S; Eun SY; Mehta AK; Birta A; Zajonc DM; Niki T; Hirashima M; Podack ER; Schreiber TH; Croft M
[Ad] Endereço:Division of Immune Regulation, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037.
[Ti] Título:Regulatory T Cell-Mediated Suppression of Inflammation Induced by DR3 Signaling Is Dependent on Galectin-9.
[So] Source:J Immunol;199(8):2721-2728, 2017 Oct 15.
[Is] ISSN:1550-6606
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Stimulation of several TNF receptor family proteins has been shown to dampen inflammatory disease in murine models through augmenting the number and/or activity of regulatory T cells (Tregs). We recently found that one molecule, 4-1BB, used binding to Galectin-9 to exert its immunosuppressive effects and drive expansion of CD8 Foxp3 Tregs. We now show that ligation of another TNFR family molecule, DR3, which has previously been found to strongly expand CD4 Foxp3 Tregs and suppress inflammation, also requires Galectin-9. We found that the extracellular region of DR3 directly binds to Galectin-9, and that Galectin-9 associates with DR3 in Tregs. From studies in vitro with Galectin-9 CD4 T cells and Tregs, we found that stimulatory activity induced by ligating DR3 was in part dependent on Galectin-9. In vivo, in a model of experimental autoimmune encephalomyelitis, we show that an agonist of DR3 suppressed disease, correlating with expansion of CD4 Foxp3 Tregs, and this protective effect was lost in Galectin-9 mice. Similar results were seen in an allergic lung inflammation model. Thus, we demonstrate a novel function of Galectin-9 in facilitating activity of DR3 related to Treg-mediated suppression.
[Mh] Termos MeSH primário: Encefalomielite Autoimune Experimental/imunologia
Galectinas/metabolismo
Inflamação/imunologia
Esclerose Múltipla/imunologia
Subpopulações de Linfócitos T/imunologia
Linfócitos T Reguladores/imunologia
Membro 9 da Superfamília de Receptores de Fatores de Necrose Tumoral/metabolismo
[Mh] Termos MeSH secundário: Animais
Proliferação Celular
Células Cultivadas
Fatores de Transcrição Forkhead/metabolismo
Galectinas/genética
Seres Humanos
Tolerância Imunológica
Ativação Linfocitária
Camundongos
Camundongos Endogâmicos C57BL
Camundongos Knockout
Ligação Proteica
Membro 25 de Receptores de Fatores de Necrose Tumoral/metabolismo
Transdução de Sinais
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Forkhead Transcription Factors); 0 (Foxp3 protein, mouse); 0 (Galectins); 0 (Receptors, Tumor Necrosis Factor, Member 25); 0 (Tnfrsf25 protein, mouse); 0 (Tumor Necrosis Factor Receptor Superfamily, Member 9); 0 (galectin 9, mouse)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170908
[St] Status:MEDLINE
[do] DOI:10.4049/jimmunol.1700575


  2 / 222 MEDLINE  
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[PMID]:28827283
[Au] Autor:Mitchell AM; Kaiser Y; Falta MT; Munson DJ; Landry LG; Eklund A; Nakayama M; Slansky JE; Grunewald J; Fontenot AP
[Ad] Endereço:Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045.
[Ti] Título:Shared αß TCR Usage in Lungs of Sarcoidosis Patients with Löfgren's Syndrome.
[So] Source:J Immunol;199(7):2279-2290, 2017 Oct 01.
[Is] ISSN:1550-6606
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Sarcoidosis is a granulomatous disease that primarily affects the lungs and is characterized by an accumulation of CD4 T cells in the bronchoalveolar lavage (BAL). Previous work has indicated that HLA-DRB1*03:01 (DR3 ) patients diagnosed with the acute form of the disease, Löfgren's syndrome (LS), have an accumulation of CD4 T cells bearing TCRs using TRAV12-1 (formerly AV2S3). However, the importance of these α-chains in disease pathogenesis and the paired TCRß-chain remains unknown. This study aimed to identify expanded αßTCR pairs expressed on CD4 T cells derived from the BAL of DR3 LS patients. Using a deep-sequencing approach, we determined TCRα- and TCRß-chain usage, as well as αßTCR pairs expressed on BAL CD4 T cells from LS patients. TRAV12-1 and TRBV2 (formerly BV22) were the most expanded V region gene segments in DR3 LS patients relative to control subjects, and TRAV12-1 and TRBV2 CDR3 motifs were shared among multiple DR3 LS patients. When assessing αßTCR pairing, TRAV12-1 preferentially paired with TRBV2, and these TRAV12-1/TRBV2 TCRs displayed CDR3 homology. These findings suggest that public CD4 TCR repertoires exist among LS patients and that these T cells are recognizing the putative sarcoidosis-associated Ag(s) in the context of DR3.
[Mh] Termos MeSH primário: Líquido da Lavagem Broncoalveolar/citologia
Pulmão/imunologia
Receptores de Antígenos de Linfócitos T alfa-beta/imunologia
Sarcoidose Pulmonar/imunologia
[Mh] Termos MeSH secundário: Doença Aguda
Adulto
Idoso
Líquido da Lavagem Broncoalveolar/imunologia
Linfócitos T CD4-Positivos/imunologia
Feminino
Cadeias HLA-DRB1/genética
Cadeias HLA-DRB1/imunologia
Sequenciamento de Nucleotídeos em Larga Escala
Seres Humanos
Masculino
Meia-Idade
Receptores de Antígenos de Linfócitos T alfa-beta/genética
Receptores de Antígenos de Linfócitos T alfa-beta/metabolismo
Membro 25 de Receptores de Fatores de Necrose Tumoral/genética
Membro 25 de Receptores de Fatores de Necrose Tumoral/imunologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (HLA-DRB1 Chains); 0 (HLA-DRB1*03:01 antigen); 0 (Receptors, Antigen, T-Cell, alpha-beta); 0 (Receptors, Tumor Necrosis Factor, Member 25); 0 (TNFRSF25 protein, human)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171109
[Lr] Data última revisão:
171109
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170823
[St] Status:MEDLINE
[do] DOI:10.4049/jimmunol.1700570


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[PMID]:28817719
[Au] Autor:Pham OH; O'Donnell H; Al-Shamkhani A; Kerrinnes T; Tsolis RM; McSorley SJ
[Ad] Endereço:Center for Comparative Medicine and Department of Anatomy, Physiology and Cell Biology, School of Veterinary Medicine, University of California Davis, Davis, California, United States of America.
[Ti] Título:T cell expression of IL-18R and DR3 is essential for non-cognate stimulation of Th1 cells and optimal clearance of intracellular bacteria.
[So] Source:PLoS Pathog;13(8):e1006566, 2017 Aug.
[Is] ISSN:1553-7374
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Th1 cells can be activated by TCR-independent stimuli, but the importance of this pathway in vivo and the precise mechanisms involved require further investigation. Here, we used a simple model of non-cognate Th1 cell stimulation in Salmonella-infected mice to examine these issues. CD4 Th1 cell expression of both IL-18R and DR3 was required for optimal IFN-γ induction in response to non-cognate stimulation, while IL-15R expression was dispensable. Interestingly, effector Th1 cells generated by immunization rather than live infection had lower non-cognate activity despite comparable IL-18R and DR3 expression. Mice lacking T cell intrinsic expression of MyD88, an important adapter molecule in non-cognate T cell stimulation, exhibited higher bacterial burdens upon infection with Salmonella, Chlamydia or Brucella, suggesting that non-cognate Th1 stimulation is a critical element of efficient bacterial clearance. Thus, IL-18R and DR3 are critical players in non-cognate stimulation of Th1 cells and this response plays an important role in protection against intracellular bacteria.
[Mh] Termos MeSH primário: Infecções Bacterianas/imunologia
Ativação Linfocitária/imunologia
Receptores de Interleucina-18/biossíntese
Membro 25 de Receptores de Fatores de Necrose Tumoral/biossíntese
Células Th1/imunologia
[Mh] Termos MeSH secundário: Animais
Modelos Animais de Doenças
Ensaio de Imunoadsorção Enzimática
Citometria de Fluxo
Interleucina-18/metabolismo
Camundongos
Análise de Sequência com Séries de Oligonucleotídeos
Receptores de Interleucina-18/imunologia
Membro 25 de Receptores de Fatores de Necrose Tumoral/imunologia
Células Th1/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Interleukin-18); 0 (Receptors, Interleukin-18); 0 (Receptors, Tumor Necrosis Factor, Member 25); 0 (Tnfrsf25 protein, mouse)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171002
[Lr] Data última revisão:
171002
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170818
[St] Status:MEDLINE
[do] DOI:10.1371/journal.ppat.1006566


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[PMID]:28686297
[Au] Autor:Bittner S; Ehrenschwender M
[Ad] Endereço:Institute of Clinical Microbiology and Hygiene, University Hospital Regensburg, Germany.
[Ti] Título:Multifaceted death receptor 3 signaling-promoting survival and triggering death.
[So] Source:FEBS Lett;591(17):2543-2555, 2017 Sep.
[Is] ISSN:1873-3468
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Death Receptor 3 (DR3) and its cognate ligand TL1A belong to the tumor necrosis factor superfamily (TNFSF). This sophisticated network of receptor-ligand systems controls innumerable biological processes. For many (if not all) TNFSF ligands and receptors, a role in conditions such as inflammation, tissue development, proliferation, and cell death has been firmly established. However, relatively little is known about DR3 and TL1A. Here, we review novel aspects of DR3 signaling and DR3-associated signaling pathways before summarizing the function of DR3 in the immune system. The emerging role of DR3 in disease will be addressed before we finally critically discuss the potential therapeutic exploitation of this receptor-ligand pair.
[Mh] Termos MeSH primário: Morte Celular
Membro 25 de Receptores de Fatores de Necrose Tumoral/metabolismo
Transdução de Sinais
[Mh] Termos MeSH secundário: Animais
Sobrevivência Celular
Seres Humanos
Sistema Imunitário/citologia
Inflamação/imunologia
Inflamação/patologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Receptors, Tumor Necrosis Factor, Member 25)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171004
[Lr] Data última revisão:
171004
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170708
[St] Status:MEDLINE
[do] DOI:10.1002/1873-3468.12747


  5 / 222 MEDLINE  
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[PMID]:28493878
[Au] Autor:Opoku-Acheampong AB; Henningson JN; Beck AP; Lindshield BL
[Ad] Endereço:Department of Food, Nutrition, Dietetics and Health, Kansas State University, Manhattan, KS, United States of America.
[Ti] Título:5α-reductase 1 mRNA levels are positively correlated with TRAMP mouse prostate most severe lesion scores.
[So] Source:PLoS One;12(5):e0175874, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: The contribution of 5α-reductase 1 and 5α-reductase 2 to prostate cancer development and progression is not clearly understood. TRAMP mice are a common prostate cancer model, in which 5α-reductase 1 and 5α-reductase 2 expression levels, along with prostate lesions scores, have not been investigated at different time points to further understand prostate carcinogenesis. METHOD/PRINCIPAL FINDINGS: To this end, 8-, 12-, 16-, and 20-week-old male C57BL/6TRAMP x FVB mice prostate most severe and most common lesion scores, 5α-reductase 1 and 5α-reductase 2 in situ hybridization expression, and Ki-67, androgen receptor, and apoptosis immunohistochemistry levels were measured. Levels of these markers were quantified in prostate epithelium, hyperplasia, and tumors sections. Mice developed low- to high-grade prostatic intraepithelial neoplasia at 8 weeks as the most severe and most common lesions, and moderate- and high-grade prostatic intraepithelial neoplasia at 12 and 16 weeks as the most severe lesion in all lobes. Moderately differentiated adenocarcinoma was observed at 20 weeks in all lobes. Poorly differentiated carcinoma was not observed in any lobe until 12-weeks-old. 5α-reductase 1 and 5α-reductase 2 were not significantly decreased in tumors compared to prostate epithelium and hyperplasia in all groups, while proliferation, apoptosis, and androgen receptor were either notably or significantly decreased in tumors compared with prostate epithelium and hyperplasia in most or all groups. Prostate 5αR1 levels were positively correlated with adjusted prostate most severe lesion scores. CONCLUSION: Downregulation of androgen receptor and 5α-reductase 2, along with upregulation of 5α-reductase 1 in tumors may promote prostatic intraepithelial neoplasia and prostate cancer development in TRAMP mice.
[Mh] Termos MeSH primário: Colestenona 5 alfa-Redutase/genética
Neoplasia Prostática Intraepitelial/genética
Neoplasias da Próstata/genética
Receptores Androgênicos/genética
[Mh] Termos MeSH secundário: Animais
Colestenona 5 alfa-Redutase/biossíntese
Progressão da Doença
Regulação Neoplásica da Expressão Gênica
Seres Humanos
Masculino
Camundongos
Hiperplasia Prostática/genética
Hiperplasia Prostática/patologia
Neoplasia Prostática Intraepitelial/patologia
Neoplasias da Próstata/patologia
RNA Mensageiro/biossíntese
Membro 25 de Receptores de Fatores de Necrose Tumoral/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (AR protein, mouse); 0 (RNA, Messenger); 0 (Receptors, Androgen); 0 (Receptors, Tumor Necrosis Factor, Member 25); 0 (Tnfrsf25 protein, mouse); EC 1.3.1.22 (Cholestenone 5 alpha-Reductase)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170911
[Lr] Data última revisão:
170911
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170512
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0175874


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[PMID]:28337757
[Au] Autor:Bittner S; Knoll G; Ehrenschwender M
[Ad] Endereço:Institute of Clinical Microbiology and Hygiene, University Hospital Regensburg, Germany.
[Ti] Título:Death receptor 3 signaling enhances proliferation of human regulatory T cells.
[So] Source:FEBS Lett;591(8):1187-1195, 2017 Apr.
[Is] ISSN:1873-3468
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Exploiting regulatory T cells (Tregs) to control aberrant immune reactions is a promising therapeutic approach, but is hampered by their relative paucity. In mice, activation of death receptor 3 (DR3), a member of the TNF-receptor superfamily (TNFRSF), increases Treg frequency and efficiently controls exuberant immune activation. For human Tregs, neither DR3 expression nor potential functions have been described. Here, we show that human Tregs express DR3 and demonstrate DR3-mediated activation of p38, ERK, and NFκB. DR3 stimulation enhances Treg expansion ex vivo while retaining their suppressive capacity. In summary, our results establish a functional role for DR3 signaling in human Tregs and could potentially help to tailor Treg-based therapies.
[Mh] Termos MeSH primário: Sistema de Sinalização das MAP Quinases
Subunidade p52 de NF-kappa B/agonistas
Membro 25 de Receptores de Fatores de Necrose Tumoral/agonistas
Transdução de Sinais
Linfócitos T Reguladores/metabolismo
Membro 15 da Superfamília de Ligantes de Fatores de Necrose Tumoral/metabolismo
Regulação para Cima
[Mh] Termos MeSH secundário: Proliferação Celular/efeitos dos fármacos
Células Cultivadas
Seres Humanos
Imunossupressores/farmacologia
Ligantes
Sistema de Sinalização das MAP Quinases/efeitos dos fármacos
Subunidade p52 de NF-kappa B/metabolismo
Fragmentos de Peptídeos/química
Fragmentos de Peptídeos/genética
Fragmentos de Peptídeos/metabolismo
Fosforilação/efeitos dos fármacos
Domínios e Motivos de Interação entre Proteínas
Isoformas de Proteínas/química
Isoformas de Proteínas/genética
Isoformas de Proteínas/metabolismo
Processamento de Proteína Pós-Traducional/efeitos dos fármacos
Membro 25 de Receptores de Fatores de Necrose Tumoral/química
Membro 25 de Receptores de Fatores de Necrose Tumoral/genética
Membro 25 de Receptores de Fatores de Necrose Tumoral/metabolismo
Receptores Tipo II do Fator de Necrose Tumoral/química
Receptores Tipo II do Fator de Necrose Tumoral/genética
Receptores Tipo II do Fator de Necrose Tumoral/metabolismo
Proteínas Recombinantes de Fusão/química
Proteínas Recombinantes de Fusão/metabolismo
Transdução de Sinais/efeitos dos fármacos
Sirolimo/farmacologia
Linfócitos T Reguladores/citologia
Linfócitos T Reguladores/efeitos dos fármacos
Linfócitos T Reguladores/imunologia
Membro 15 da Superfamília de Ligantes de Fatores de Necrose Tumoral/química
Membro 15 da Superfamília de Ligantes de Fatores de Necrose Tumoral/genética
Regulação para Cima/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Immunosuppressive Agents); 0 (Ligands); 0 (NF-kappa B p52 Subunit); 0 (NFKB2 protein, human); 0 (Peptide Fragments); 0 (Protein Isoforms); 0 (Receptors, Tumor Necrosis Factor, Member 25); 0 (Receptors, Tumor Necrosis Factor, Type II); 0 (Recombinant Fusion Proteins); 0 (TNFRSF1B protein, human); 0 (TNFRSF25 protein, human); 0 (TNFSF15 protein, human); 0 (Tumor Necrosis Factor Ligand Superfamily Member 15); W36ZG6FT64 (Sirolimus)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170808
[Lr] Data última revisão:
170808
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170325
[St] Status:MEDLINE
[do] DOI:10.1002/1873-3468.12632


  7 / 222 MEDLINE  
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[PMID]:28324007
[Au] Autor:Pu H; Begemann DE; Kyprianou N
[Ad] Endereço:Department of Urology, University of Kentucky College of Medicine, Lexington, Kentucky 40536.
[Ti] Título:Aberrant TGF-ß Signaling Drives Castration-Resistant Prostate Cancer in a Male Mouse Model of Prostate Tumorigenesis.
[So] Source:Endocrinology;158(6):1612-1622, 2017 Jun 01.
[Is] ISSN:1945-7170
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The androgen receptor (AR) plays a critical role as a driver of castration-resistant prostate cancer (CRPC). Our previous studies demonstrated that disruption of transforming growth factor-ß (TGF-ß) signaling via introduction of dominant-negative transforming growth factor-ß type II receptor (DNTGFßRII) in the prostate epithelium of transgenic adenocarcinoma of the prostate mice accelerated tumor. This study investigated the consequences of disrupted TGF-ß signaling on prostate tumor growth under conditions of castration-induced androgen deprivation in the preclinical model of DNTGFßRII. Our results indicate that in response to androgen deprivation therapy (ADT) the proliferative index in prostate tumors from DNTGFßRII mice was higher compared with prostate tumors from TGFßRII wild-type (WT) mice, whereas there was a reduced incidence of apoptosis in tumors from DNTGFßRII. Protein and gene expression profiling revealed that tumors from DNTGFßRII mice exhibit a strong nuclear AR localization among the prostate tumor epithelial cells and increased AR messenger RNA after ADT. In contrast, TGFßRII WT mice exhibited a marked loss in nuclear AR in prostate tumor acini (20 weeks), followed by a downregulation of AR and transmembrane protease serine 2 messenger RNA. There was a significant increase in nuclear AR and activity in prostate tumors from castrate DNTGFßRII compared with TGFßRII WT mice. Consequential to aberrant TGF-ß signaling, ADT enhanced expression and nuclear localization of Smad4 and ß-catenin. Our findings support that under castrate conditions, aberrant TGF-ß signaling leads to AR activation and ß-catenin nuclear localization, an adaptation mechanism contributing to emergence of CRPC. The work defines a potentially significant new targeting platform for overcoming therapeutic resistance in CRPC.
[Mh] Termos MeSH primário: Transformação Celular Neoplásica/patologia
Neoplasias de Próstata Resistentes à Castração/patologia
Fator de Crescimento Transformador beta/farmacologia
[Mh] Termos MeSH secundário: Animais
Transformação Celular Neoplásica/genética
Transformação Celular Neoplásica/metabolismo
Modelos Animais de Doenças
Seres Humanos
Masculino
Camundongos
Camundongos Endogâmicos C57BL
Camundongos Transgênicos
Neoplasias de Próstata Resistentes à Castração/genética
Neoplasias de Próstata Resistentes à Castração/metabolismo
Proteínas Serina-Treonina Quinases/genética
Proteínas Serina-Treonina Quinases/metabolismo
Receptores de Fatores de Crescimento Transformadores beta/genética
Receptores de Fatores de Crescimento Transformadores beta/metabolismo
Membro 25 de Receptores de Fatores de Necrose Tumoral/genética
Transdução de Sinais/efeitos dos fármacos
Fator de Crescimento Transformador beta/metabolismo
beta Catenina/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Receptors, Transforming Growth Factor beta); 0 (Receptors, Tumor Necrosis Factor, Member 25); 0 (Tnfrsf25 protein, mouse); 0 (Transforming Growth Factor beta); 0 (beta Catenin); EC 2.7.11.1 (Protein-Serine-Threonine Kinases); EC 2.7.11.30 (transforming growth factor-beta type II receptor)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170907
[Lr] Data última revisão:
170907
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170322
[St] Status:MEDLINE
[do] DOI:10.1210/en.2017-00086


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[PMID]:28278297
[Au] Autor:Levin I; Zaretsky M; Aharoni A
[Ad] Endereço:The National Institute for Biotechnology in the Negev (NIBN), Ben-Gurion University of the Negev, Be'er Sheva, Israel.
[Ti] Título:Directed evolution of a soluble human DR3 receptor for the inhibition of TL1A induced cytokine secretion.
[So] Source:PLoS One;12(3):e0173460, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:TNF-like 1A (TL1A) is a cytokine belonging to the TNF superfamily that promotes inflammation in autoimmune diseases. Inhibiting the interaction of TL1A with the endogenous death-domain receptor 3 (DR3) offers a therapeutic approach for treating TL1A-induced autoimmune diseases. Here, we generated improved DR3 variants showing increased TL1A binding affinity and stability using a directed evolution approach. Given the high cysteine content and post-translational modification of DR3, we employed yeast surface display and expression in mammalian cell lines for screening, expression and characterization of improved DR3 variants. A cell-based assay performed with the human TF-1 cell line and CD4+ T cells showed that two improved DR3 mutants efficiently inhibited TL1A-induced cell death and secretion of IFN-γ, respectively. These DR3 mutants can be used as drug candidates for the treatment of inflammatory bowel diseases and for other autoimmune diseases, including rheumatic arthritis and asthma.
[Mh] Termos MeSH primário: Evolução Molecular Direcionada
Membro 25 de Receptores de Fatores de Necrose Tumoral/química
Membro 25 de Receptores de Fatores de Necrose Tumoral/metabolismo
Membro 15 da Superfamília de Ligantes de Fatores de Necrose Tumoral/metabolismo
[Mh] Termos MeSH secundário: Apoptose/genética
Linhagem Celular
Células HEK293
Seres Humanos
Mutação
Membro 25 de Receptores de Fatores de Necrose Tumoral/genética
Solubilidade
Linfócitos T/citologia
Linfócitos T/secreção
Membro 15 da Superfamília de Ligantes de Fatores de Necrose Tumoral/secreção
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Receptors, Tumor Necrosis Factor, Member 25); 0 (TNFSF15 protein, human); 0 (Tumor Necrosis Factor Ligand Superfamily Member 15)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170831
[Lr] Data última revisão:
170831
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170310
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0173460


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[PMID]:28249898
[Au] Autor:Ibrahim-Hashim A; Robertson-Tessi M; Enriquez-Navas PM; Damaghi M; Balagurunathan Y; Wojtkowiak JW; Russell S; Yoonseok K; Lloyd MC; Bui MM; Brown JS; Anderson ARA; Gillies RJ; Gatenby RA
[Ad] Endereço:Department of Cancer Imaging and Metabolism, H. Lee Moffitt Cancer Center, Tampa, Florida.
[Ti] Título:Defining Cancer Subpopulations by Adaptive Strategies Rather Than Molecular Properties Provides Novel Insights into Intratumoral Evolution.
[So] Source:Cancer Res;77(9):2242-2254, 2017 May 01.
[Is] ISSN:1538-7445
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Ongoing intratumoral evolution is apparent in molecular variations among cancer cells from different regions of the same tumor, but genetic data alone provide little insight into environmental selection forces and cellular phenotypic adaptations that govern the underlying Darwinian dynamics. In three spontaneous murine cancers (prostate cancers in TRAMP and PTEN mice, pancreatic cancer in KPC mice), we identified two subpopulations with distinct niche construction adaptive strategies that remained stable in culture: (i) invasive cells that produce an acidic environment via upregulated aerobic glycolysis; and (ii) noninvasive cells that were angiogenic and metabolically near-normal. Darwinian interactions of these subpopulations were investigated in TRAMP prostate cancers. Computer simulations demonstrated invasive, acid-producing (C2) cells maintain a fitness advantage over noninvasive, angiogenic (C3) cells by promoting invasion and reducing efficacy of immune response. Immunohistochemical analysis of untreated tumors confirmed that C2 cells were invariably more abundant than C3 cells. However, the C2 adaptive strategy phenotype incurred a significant cost due to inefficient energy production (i.e., aerobic glycolysis) and depletion of resources for adaptations to an acidic environment. Mathematical model simulations predicted that small perturbations of the microenvironmental extracellular pH (pHe) could invert the cost/benefit ratio of the C2 strategy and select for C3 cells. , 200 mmol/L NaHCO added to the drinking water of 4-week-old TRAMP mice increased the intraprostatic pHe by 0.2 units and promoted proliferation of noninvasive C3 cells, which remained confined within the ducts so that primary cancer did not develop. A 0.2 pHe increase in established tumors increased the fraction of C3 cells and signficantly diminished growth of primary and metastatic tumors. In an experimental tumor construct, MCF7 and MDA-MB-231 breast cancer cells were coinjected into the mammary fat pad of SCID mice. C2-like MDA-MB-231 cells dominated in untreated animals, but C3-like MCF7 cells were selected and tumor growth slowed when intratumoral pHe was increased. Overall, our data support the use of mathematical modeling of intratumoral Darwinian interactions of environmental selection forces and cancer cell adaptive strategies. These models allow the tumor to be steered into a less invasive pathway through the application of small but selective biological force. .
[Mh] Termos MeSH primário: Neoplasias da Mama/genética
Evolução Molecular
Neoplasias Pancreáticas/genética
Neoplasias da Próstata/genética
Seleção Genética/genética
[Mh] Termos MeSH secundário: Animais
Neoplasias da Mama/patologia
Linhagem da Célula/genética
Proliferação Celular/genética
Simulação por Computador
Feminino
Seres Humanos
Células MCF-7
Masculino
Camundongos
Modelos Teóricos
PTEN Fosfo-Hidrolase/genética
Neoplasias Pancreáticas/patologia
Neoplasias da Próstata/patologia
Membro 25 de Receptores de Fatores de Necrose Tumoral/genética
Microambiente Tumoral
Ensaios Antitumorais Modelo de Xenoenxerto
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Receptors, Tumor Necrosis Factor, Member 25); 0 (Tnfrsf25 protein, mouse); EC 3.1.3.67 (PTEN Phosphohydrolase); EC 3.1.3.67 (Pten protein, mouse)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170912
[Lr] Data última revisão:
170912
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170303
[St] Status:MEDLINE
[do] DOI:10.1158/0008-5472.CAN-16-2844


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[PMID]:28197639
[Au] Autor:Nasser MI; Masood M; Wei W; Li X; Zhou Y; Liu B; Li J; Li X
[Ad] Endereço:The Key Laboratory of Molecular Epigenetics of MOE, Institute of Genetics and Cytology, Northeast Normal University, Changchun, Jilin 130024, P.R. China.
[Ti] Título:Cordycepin induces apoptosis in SGC­7901 cells through mitochondrial extrinsic phosphorylation of PI3K/Akt by generating ROS.
[So] Source:Int J Oncol;50(3):911-919, 2017 Mar.
[Is] ISSN:1791-2423
[Cp] País de publicação:Greece
[La] Idioma:eng
[Ab] Resumo:Medicinal plants are affluent sources of several effectual natural drugs. Among them cordycepin which is extracted from Cordyceps militaris is a hopeful chemotherapy agent due to its extensive anti-inflammatory, anti-proliferative, antioxidant, and antitumor characteristics. This study investigated the efficacy of cordycepin in the context of human gastric cancer SGC­7901 and searched for the cell death procedure. Cordycepin incorporates mitochondrial-mediated apoptosis in SGC­7901 cells with the help of regulating mitochondrial extrinsic pathways by inhibition of A3AR and drive activation of DR3, which promote the activation of PI3K/Akt protein expression as well as collapse of mitochondrial membrane potential (MMP). In addition, phosphorylation of PI3K/Akt and DNA damage by cordycepin induced the production of reactive oxygen species (ROS), and mediates SGC­7901 cell cycle cessation at S phase. Collectively, this study suggests that cordycepin might be effective as a modern chemotherapy drug for gastric cancer.
[Mh] Termos MeSH primário: Anti-Inflamatórios/farmacologia
Antineoplásicos/farmacologia
Desoxiadenosinas/farmacologia
Potencial da Membrana Mitocondrial/efeitos dos fármacos
Fosfatidilinositol 3-Quinases/metabolismo
Proteínas Proto-Oncogênicas c-akt/metabolismo
Espécies Reativas de Oxigênio/metabolismo
Neoplasias Gástricas/tratamento farmacológico
[Mh] Termos MeSH secundário: Apoptose/efeitos dos fármacos
Linhagem Celular Tumoral
Proliferação Celular/efeitos dos fármacos
Seres Humanos
Mitocôndrias/metabolismo
Fosforilação/efeitos dos fármacos
Membro 25 de Receptores de Fatores de Necrose Tumoral/metabolismo
Pontos de Checagem da Fase S do Ciclo Celular/efeitos dos fármacos
Transdução de Sinais/efeitos dos fármacos
Neoplasias Gástricas/patologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anti-Inflammatory Agents); 0 (Antineoplastic Agents); 0 (Deoxyadenosines); 0 (Reactive Oxygen Species); 0 (Receptors, Tumor Necrosis Factor, Member 25); 0 (TNFRSF25 protein, human); EC 2.7.1.- (Phosphatidylinositol 3-Kinases); EC 2.7.11.1 (Proto-Oncogene Proteins c-akt); GZ8VF4M2J8 (cordycepin)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170613
[Lr] Data última revisão:
170613
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170216
[St] Status:MEDLINE
[do] DOI:10.3892/ijo.2017.3862



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