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[PMID]:27773809
[Au] Autor:Jung B; Staudacher JJ; Beauchamp D
[Ad] Endereço:University of Illinois at Chicago, Chicago, Illinois. Electronic address: bjung@uic.edu.
[Ti] Título:Transforming Growth Factor ß Superfamily Signaling in Development of Colorectal Cancer.
[So] Source:Gastroenterology;152(1):36-52, 2017 Jan.
[Is] ISSN:1528-0012
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Transforming growth factor (TGF)-ß cytokines signal via a complex network of pathways to regulate proliferation, differentiation, adhesion, migration, and other functions in many cell types. A high percentage of colorectal tumors contain mutations that disrupt TGF-ß family member signaling. We review how TGF-ß family member signaling is altered during development of colorectal cancer, models of study, interaction of pathways, and potential therapeutic strategies.
[Mh] Termos MeSH primário: Neoplasias Colorretais/genética
Neoplasias Colorretais/metabolismo
Receptores de Fatores de Crescimento Transformadores beta/genética
Transdução de Sinais
Proteínas Smad/genética
Fator de Crescimento Transformador beta/genética
Fator de Crescimento Transformador beta/metabolismo
[Mh] Termos MeSH secundário: Ativinas/metabolismo
Animais
Proteínas Morfogenéticas Ósseas/metabolismo
Neoplasias Colorretais/imunologia
Mutação em Linhagem Germinativa
Homeostase
Seres Humanos
Camundongos
Camundongos Knockout
Receptores de Fatores de Crescimento Transformadores beta/imunologia
Proteínas Smad/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Bone Morphogenetic Proteins); 0 (Receptors, Transforming Growth Factor beta); 0 (Smad Proteins); 0 (Transforming Growth Factor beta); 104625-48-1 (Activins)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:180307
[Lr] Data última revisão:
180307
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:161025
[St] Status:MEDLINE


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[PMID]:29378560
[Au] Autor:Kuai L; Zhang JT; Deng Y; Xu S; Xu XZ; Wu MF; Guo DJ; Chen Y; Wu RJ; Zhao XQ; Nian H; Li B; Li FL
[Ad] Endereço:Department of Dermatology of Yueyang Hospital, Shanghai University of TCM, Shanghai, 200437, China.
[Ti] Título:Sheng-ji Hua-yu formula promotes diabetic wound healing of re-epithelization via Activin/Follistatin regulation.
[So] Source:BMC Complement Altern Med;18(1):32, 2018 Jan 29.
[Is] ISSN:1472-6882
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Sheng-ji Hua-yu(SJHY) formula is one of the most useful Traditional Chinese medicine (TCM) in the treatment of the delayed diabetic wound. However, elucidating the related molecular biological mechanism of how the SJHY Formula affects excessive inflammation in the process of re-epithelialization of diabetic wound healing is a task urgently needed to be fulfilled. The objectives of this study is to evaluate the effect of antagonisic expression of pro-/anti-inflammatory factors on transforming growth factor-ß(TGF-ß) superfamily (activin and follistatin) in the process of re-epithelialization of diabetic wound healing in vivo, and to characterize the involvement of the activin/follistatin protein expression regulation, phospho-Smad (pSmad2), and Nuclear factor kappa B p50 (NF-kB) p50 in the diabetic wound healing effects of SJHY formula. METHODS: SJHY Formula was prepared by pharmaceutical preparation room of Yueyang Hospital of Integrated Traditional Chinese and Western Medicine. Diabetic wound healing activity was evaluated by circular excision wound models. Wound healing activity was examined by macroscopic evaluation. Activin/follistatin expression regulation, protein expression of pSmad2 and NF-kB p50 in skin tissue of wounds were analyzed by Real Time PCR, Western blot, immunohistochemistry and hematoxylin and eosin (H&E) staining. RESULTS: Macroscopic evaluation analysis showed that wound healing of diabetic mice was delayed, and SJHY Formula accelerated wound healing time of diabetic mice. Real Time PCR analysis showed higher mRNA expression of activin/follistatin in diabetic delayed wound versus the wound in normal mice. Western Blot immunoassay analysis showed reduction of activin/follistatin proteins levels by SJHY Formula treatment 15 days after injury. Immunohistochemistry investigated the reduction of pSmad2 and NF-kB p50 nuclear staining in the epidermis of diabetic SJHY versus diabetic control mice on day 15 after wounding. H&E staining revealed that SJHY Formula accelerated re-epithelialization of diabetic wound healing. CONCLUSION: The present study found that diabetic delayed wound healing time is closely related to the high expression level of activin/follistatin, which leads to excessive inflammation in the process of re-epithelization. SJHY Formula accelerates re-epithelialization and healing time of diabetic wounds through decreasing the high expression of activin/follistatin.
[Mh] Termos MeSH primário: Ativinas/metabolismo
Diabetes Mellitus Experimental/metabolismo
Medicamentos de Ervas Chinesas/farmacologia
Folistatina/metabolismo
Reepitelização/efeitos dos fármacos
[Mh] Termos MeSH secundário: Animais
Diabetes Mellitus Experimental/complicações
Medicamentos de Ervas Chinesas/uso terapêutico
Feminino
Camundongos
Camundongos Endogâmicos C57BL
Úlcera/tratamento farmacológico
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Drugs, Chinese Herbal); 0 (Follistatin); 104625-48-1 (Activins)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180305
[Lr] Data última revisão:
180305
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180131
[St] Status:MEDLINE
[do] DOI:10.1186/s12906-017-2074-8


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[PMID]:29480835
[Au] Autor:Li L; Tong M; Zhao YT; He Y; Zhou HY; Zhang GF; Zhang YJ
[Ad] Endereço:Department of Orthopedics, Traditional Chinese Medical Hospital of Xinjiang Uygur Autonomous Region, Urumqi.
[Ti] Título:Membrane translocation of Bruton kinase in multiple myeloma cells is associated with osteoclastogenic phenotype in bone metastatic lesions.
[So] Source:Medicine (Baltimore);97(2):e9482, 2018 Jan.
[Is] ISSN:1536-5964
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Using bone biopsy samples, we examined whether osteolytic cytokine profile is changed in situ in bone samples of metastatic multiple myeloma, and whether this creates an environment of lysis within the bone to which it has spread. This also produces the clinical features of increased circulating plasma calcium, and deleterious effects on the kidney.Using multiple myeloma biopsy and cell extracts from bone metastatic lesions, Bruton kinase, a tyrosine kinase, was demonstrated to be translocated to the membrane. Several transcription factors were upregulated included activin A, inflammatory transcription activator like such as nuclear factor kappa B, and specific bone lytic factor such as receptor activator of nuclear factor kappa-B ligand that is known to drive osteoclastogenesis as opposed to a osteogenic environment. The transcript for Bruton kinase was also elevated in its expression.Cytokines that support osteolytic activity such as a proliferation-inducing ligand, RANTES (regulated on activation, normal T cell expressed and secreted), interleukin-8, and activin A were upregulated. Tartrate resistant acid phosphatase (TRAP)-positive osteoclastic enzymatic activity was significantly elevated in the bone microenvironment in metastatic multiple myeloma. Several tyrosine kinase inhibitors, including inhibitors for Bruton kinase such as ibrutinib have been developed. The results of the present study provide evidence that multiple myeloma possess signal transduction mechanisms to support a bone lytic environment.The results provide a preliminary molecular basis to design specific inhibitors for management of bone metastasis of multiple myeloma.
[Mh] Termos MeSH primário: Neoplasias Ósseas/enzimologia
Neoplasias Ósseas/secundário
Membrana Celular/enzimologia
Mieloma Múltiplo/enzimologia
Osteogênese/fisiologia
Proteínas Tirosina Quinases/metabolismo
[Mh] Termos MeSH secundário: Ativinas/metabolismo
Idoso
Quimiocina CCL5/metabolismo
Seres Humanos
Masculino
Meia-Idade
NF-kappa B/metabolismo
RNA Mensageiro/metabolismo
Fosfatase Ácida Resistente a Tartarato/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (CCL5 protein, human); 0 (Chemokine CCL5); 0 (NF-kappa B); 0 (RNA, Messenger); 0 (activin A); 104625-48-1 (Activins); EC 2.7.10.1 (Agammaglobulinaemia tyrosine kinase); EC 2.7.10.1 (Protein-Tyrosine Kinases); EC 3.1.3.2 (Tartrate-Resistant Acid Phosphatase)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180302
[Lr] Data última revisão:
180302
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:180227
[St] Status:MEDLINE
[do] DOI:10.1097/MD.0000000000009482


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[PMID]:29269485
[Au] Autor:Estarás C; Hsu HT; Huang L; Jones KA
[Ad] Endereço:Regulatory Biology Laboratory, The Salk Institute for Biological Studies, La Jolla, California 92037, USA.
[Ti] Título:YAP repression of the gene controls hESC differentiation along the cardiac mesoderm lineage.
[So] Source:Genes Dev;31(22):2250-2263, 2017 11 15.
[Is] ISSN:1549-5477
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Activin/SMAD signaling in human embryonic stem cells (hESCs) ensures expression and stem cell pluripotency. In the presence of Wnt ligand, the Activin/SMAD transcription network switches to cooperate with Wnt/ß-catenin and induce mesendodermal (ME) differentiation genes. We show here that the Hippo effector YAP binds to the gene enhancer and prevents the gene from being induced by Activin in proliferating hESCs. ChIP-seq (chromatin immunoprecipitation [ChIP] combined with high-throughput sequencing) data show that YAP impairs SMAD recruitment and the accumulation of P-TEFb-associated RNA polymerase II (RNAPII) C-terminal domain (CTD)-Ser7 phosphorylation at the gene. CRISPR/ knockout of YAP in hESCs enables Activin to induce Wnt3 expression and stabilize ß-catenin, which then synergizes with Activin-induced SMADs to activate a subset of ME genes that is required to form cardiac mesoderm. Interestingly, exposure of YAP hESCs to Activin induces cardiac mesoderm markers ( and ) without activating Wnt-dependent cardiac inhibitor genes ( and ). Moreover, canonical Wnt target genes are up-regulated only modestly, if at all, under these conditions. Consequently, YAP-null hESCs exposed to Activin differentiate precisely into beating cardiomyocytes without further treatment. We conclude that YAP maintains hESC pluripotency by preventing expression in response to Activin, thereby blocking a direct route to embryonic cardiac mesoderm formation.
[Mh] Termos MeSH primário: Células-Tronco Embrionárias/metabolismo
Regulação da Expressão Gênica no Desenvolvimento
Miócitos Cardíacos/metabolismo
Proteínas Nucleares/fisiologia
Proteínas Repressoras/fisiologia
Fatores de Transcrição/fisiologia
Proteína Wnt3/genética
[Mh] Termos MeSH secundário: Ativinas/fisiologia
Fator de Transcrição CDX2/genética
Diferenciação Celular/genética
Linhagem da Célula
Células Cultivadas
Cromatina/metabolismo
Células-Tronco Embrionárias/citologia
Elementos Facilitadores Genéticos
Coração/embriologia
Seres Humanos
Mesoderma/citologia
Proteínas Nucleares/genética
Regiões Promotoras Genéticas
Proteínas Repressoras/genética
Transdução de Sinais
Proteínas Smad/antagonistas & inibidores
Elongação da Transcrição Genética
Fatores de Transcrição/genética
beta Catenina/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (CDX2 Transcription Factor); 0 (CDX2 protein, human); 0 (Chromatin); 0 (Nuclear Proteins); 0 (Repressor Proteins); 0 (Smad Proteins); 0 (Transcription Factors); 0 (WNT3 protein, human); 0 (Wnt3 Protein); 0 (YY1AP1 protein, human); 0 (beta Catenin); 104625-48-1 (Activins)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180202
[Lr] Data última revisão:
180202
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171223
[St] Status:MEDLINE
[do] DOI:10.1101/gad.307512.117


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[PMID]:28945231
[Au] Autor:Anderson KGV; Hamilton WB; Roske FV; Azad A; Knudsen TE; Canham MA; Forrester LM; Brickman JM
[Ad] Endereço:The Novo Nordisk Foundation Center for Stem Cell Biology - DanStem, University of Copenhagen, 3B Blegdamsvej, DK-2200 Copenhagen N, Denmark.
[Ti] Título:Insulin fine-tunes self-renewal pathways governing naive pluripotency and extra-embryonic endoderm.
[So] Source:Nat Cell Biol;19(10):1164-1177, 2017 Oct.
[Is] ISSN:1476-4679
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Signalling downstream of Activin/Nodal (ActA) and Wnt can induce endoderm differentiation and also support self-renewal in pluripotent cells. Here we find that these apparently contradictory activities are fine-tuned by insulin. In the absence of insulin, the combination of these cytokines supports endoderm in a context-dependent manner. When applied to naive pluripotent cells that resemble peri-implantation embryos, ActA and Wnt induce extra-embryonic primitive endoderm (PrE), whereas when applied to primed pluripotent epiblast stem cells (EpiSC), these cytokines induce gastrulation-stage embryonic definitive endoderm. In naive embryonic stem cell culture, we find that insulin complements LIF signalling to support self-renewal; however, when it is removed, LIF, ActA and Wnt signalling not only induce PrE differentiation, but also support its expansion. Self-renewal of these PrE cultures is robust and, on the basis of gene expression, these cells resemble early blastocyst-stage PrE, a naive endoderm state able to make both visceral and parietal endoderm.
[Mh] Termos MeSH primário: Diferenciação Celular/efeitos dos fármacos
Autorrenovação Celular/efeitos dos fármacos
Células-Tronco Embrionárias/efeitos dos fármacos
Endoderma/efeitos dos fármacos
Insulina/farmacologia
Células-Tronco Pluripotentes/efeitos dos fármacos
[Mh] Termos MeSH secundário: Ativinas/farmacologia
Animais
Linhagem Celular
Linhagem da Célula
Técnicas de Cultura Embrionária
Células-Tronco Embrionárias/metabolismo
Endoderma/citologia
Endoderma/metabolismo
Regulação da Expressão Gênica no Desenvolvimento
Idade Gestacional
Fator Inibidor de Leucemia/farmacologia
Camundongos Endogâmicos C57BL
Proteína Nodal/farmacologia
Células-Tronco Pluripotentes/metabolismo
Fatores de Tempo
Transfecção
Via de Sinalização Wnt/efeitos dos fármacos
Proteína Wnt3A/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; VIDEO-AUDIO MEDIA
[Nm] Nome de substância:
0 (Insulin); 0 (Leukemia Inhibitory Factor); 0 (Nodal Protein); 0 (Nodal protein, mouse); 0 (Wnt3A Protein); 0 (activin A); 104625-48-1 (Activins)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171024
[Lr] Data última revisão:
171024
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170926
[St] Status:MEDLINE
[do] DOI:10.1038/ncb3617


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[PMID]:28870615
[Au] Autor:Platzbecker U; Germing U; Götze KS; Kiewe P; Mayer K; Chromik J; Radsak M; Wolff T; Zhang X; Laadem A; Sherman ML; Attie KM; Giagounidis A
[Ad] Endereço:Universitätsklinikum "Carl Gustav Carus" der Technischen Universität Dresden, Dresden, Germany. Electronic address: uwe.platzbecker@uniklinikum-dresden.de.
[Ti] Título:Luspatercept for the treatment of anaemia in patients with lower-risk myelodysplastic syndromes (PACE-MDS): a multicentre, open-label phase 2 dose-finding study with long-term extension study.
[So] Source:Lancet Oncol;18(10):1338-1347, 2017 Oct.
[Is] ISSN:1474-5488
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Myelodysplastic syndromes are characterised by ineffective erythropoiesis. Luspatercept (ACE-536) is a novel fusion protein that blocks transforming growth factor beta (TGF ß) superfamily inhibitors of erythropoiesis, giving rise to a promising new investigative therapy. We aimed to assess the safety and efficacy of luspatercept in patients with anaemia due to lower-risk myelodysplastic syndromes. METHODS: In this phase 2, multicentre, open-label, dose-finding study (PACE-MDS), with long-term extension, eligible patients were aged 18 years or older, had International Prognostic Scoring System-defined low or intermediate 1 risk myelodysplastic syndromes or non-proliferative chronic myelomonocytic leukaemia (white blood cell count <13 000/µL), and had anaemia with or without red blood cell transfusion support. Enrolled patients were classified as having low transfusion burden, defined as requiring less than 4 red blood cell units in the 8 weeks before treatment (and baseline haemoglobin <10 g/dL), or high transfusion burden, defined as requiring 4 or more red blood cell units in the 8 weeks before treatment. Patients received luspatercept subcutaneously once every 21 days at dose concentrations ranging from 0·125 mg/kg to 1·75 mg/kg bodyweight for five doses (over a maximum of 12 weeks). Patients in the expansion cohort were treated with 1·0 mg/kg luspatercept; dose titration up to 1·75 mg/kg was allowed, and patients could be treated with luspatercept for a maximum of 5 years. Patients in the base study were assessed for response and safety after 12 weeks in order to be considered for enrolment into the extension study. The primary endpoint was the proportion of patients achieving modified International Working Group-defined haematological improvement-erythroid (HI-E), defined as a haemoglobin concentration increase of 1·5 g/dL or higher from baseline for 14 days or longer in low transfusion burden patients, and a reduction in red blood cell transfusion of 4 or more red blood cell units or a 50% or higher reduction in red blood cell units over 8 weeks versus pre-treatment transfusion burden in high transfusion burden patients. Patient data were subcategorised by: luspatercept dose concentrations (0·125-0·5 mg/kg vs 0·75-1·75 mg/kg); pre-study transfusion burden (high transfusion burden vs low transfusion burden, defined as ≥4 vs <4 red blood cell units per 8 weeks); pre-study serum erythropoietin concentration (<200 IU/L, 200-500 IU/L, and >500 IU/L); presence of 15% or more ring sideroblasts; and presence of SF3B1 mutations. Efficacy analyses were carried out on the efficacy evaluable and intention-to-treat populations. This trial is currently ongoing. This study is registered with ClinicalTrials.gov, numbers NCT01749514 and NCT02268383. FINDINGS: Between Jan 21, 2013, and Feb 12, 2015, 58 patients with myelodysplastic syndromes were enrolled in the 12 week base study at nine treatment centres in Germany; 27 patients were enrolled in the dose-escalation cohorts (0·125-1·75 mg/kg) and 31 patients in the expansion cohort (1·0-1·75 mg/kg). 32 (63% [95% CI 48-76]) of 51 patients receiving higher dose luspatercept concentrations (0·75-1·75 mg/kg) achieved HI-E versus two (22% [95% CI 3-60]) of nine receiving lower dose concentrations (0·125-0·5 mg/kg). Three treatment-related grade 3 adverse events occurred in one patient each: myalgia (one [2%]), increased blast cell count (one [2%]), and general physical health deterioration (one [2%]). Two of these treatment-related grade 3 adverse events were reversible serious grade 3 adverse events: one patient (2%) had myalgia and one patient (2%) had general physical health deterioration. INTERPRETATION: Luspatercept was well tolerated and effective for the treatment of anaemia in lower-risk myelodysplastic syndromes and so could therefore provide a novel therapeutic approach for the treatment of anaemia associated with lower-risk myelodysplastic syndromes; further studies are ongoing. FUNDING: Acceleron Pharma.
[Mh] Termos MeSH primário: Ativinas/administração & dosagem
Anemia/tratamento farmacológico
Anemia/etiologia
Fragmentos Fc das Imunoglobulinas/administração & dosagem
Síndromes Mielodisplásicas/complicações
Síndromes Mielodisplásicas/tratamento farmacológico
Proteínas Recombinantes de Fusão/administração & dosagem
[Mh] Termos MeSH secundário: Ativinas/efeitos adversos
Adulto
Idoso
Anemia/mortalidade
Intervalo Livre de Doença
Relação Dose-Resposta a Droga
Esquema de Medicação
Feminino
Alemanha
Seres Humanos
Fragmentos Fc das Imunoglobulinas/efeitos adversos
Estimativa de Kaplan-Meier
Masculino
Dose Máxima Tolerável
Meia-Idade
Síndromes Mielodisplásicas/diagnóstico
Síndromes Mielodisplásicas/mortalidade
Prognóstico
Modelos de Riscos Proporcionais
Estudos Prospectivos
Proteínas Recombinantes de Fusão/efeitos adversos
Medição de Risco
Índice de Gravidade de Doença
Análise de Sobrevida
Fatores de Tempo
Resultado do Tratamento
[Pt] Tipo de publicação:CLINICAL TRIAL, PHASE II; JOURNAL ARTICLE; MULTICENTER STUDY
[Nm] Nome de substância:
0 (Immunoglobulin Fc Fragments); 0 (Recombinant Fusion Proteins); 0 (luspatercept); 104625-48-1 (Activins)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171012
[Lr] Data última revisão:
171012
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170906
[St] Status:MEDLINE


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[PMID]:28864263
[Au] Autor:Esebanmen GE; Langridge WHR
[Ad] Endereço:Department of Earth and Biological Sciences, Loma Linda University School of Medicine, Loma Linda, CA, USA; Center for Health Disparities and Molecular Medicine, Loma Linda University School of Medicine, Mortensen Hall, Loma Linda, CA, USA.
[Ti] Título:Mechanism of chimeric vaccine stimulation of indoleamine 2,3-dioxygenase biosynthesis in human dendritic cells is independent of TGF-ß signaling.
[So] Source:Cell Immunol;319:43-52, 2017 Sep.
[Is] ISSN:1090-2163
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Cholera toxin B subunit fusion to autoantigens such as proinsulin (CTB-INS) down regulate dendritic cell (DC) activation and stimulate synthesis of DC immunosuppressive cytokines. Recent studies of CTB-INS induction of immune tolerance in human DCs indicate that increased biosynthesis of indoleamine 2,3-dioxygenase (IDO1) may play an important role in CTB-INS vaccine suppression of DC activation. Studies in murine models suggest a role for transforming growth factor beta (TGF-ß) in the stimulation of IDO1 biosynthesis, for the induction of tolerance in DCs. Here, we investigated the contribution of TGF-ß superfamily proteins to CTB-INS induction of IDO1 biosynthesis in human monocyte-derived DCs (moDCs). We show that CTB-INS upregulates the level of TGF-ß1, activin-A and the TGF-ß activator, integrin αvß8 in human DCs. However, inhibition of endogenous TGF-ß, activin-A or addition of biologically active TGF-ß1, and activin-A, did not inhibit or stimulate IDO1 biosynthesis in human DCs treated with CTB-INS. While inhibition with the kinase inhibitor, RepSox, blocked SMAD2/3 phosphorylation and diminished IDO1 biosynthesis in a concentration dependent manner. Specific blocking of the TGF-ß type 1 kinase receptor with SB-431542 did not arrest IDO1 biosynthesis, suggesting the involvement of a different kinase pathway other than TGF-ß type 1 receptor kinase in CTB-INS induction of IDO1 in human moDCs. Together, our experimental findings identify additional immunoregulatory proteins induced by the CTB-INS fusion protein, suggesting CTB-INS may utilize multiple mechanisms in the induction of tolerance in human moDCs.
[Mh] Termos MeSH primário: Células Dendríticas/efeitos dos fármacos
Regulação da Expressão Gênica/efeitos dos fármacos
Indolamina-Pirrol 2,3,-Dioxigenase/biossíntese
Proteínas Recombinantes de Fusão/farmacologia
Fator de Crescimento Transformador beta1/genética
[Mh] Termos MeSH secundário: Ativinas/genética
Ativinas/imunologia
Animais
Diferenciação Celular
Toxina da Cólera/genética
Toxina da Cólera/imunologia
Clonagem Molecular
Células Dendríticas/citologia
Células Dendríticas/imunologia
Escherichia coli/genética
Escherichia coli/metabolismo
Seres Humanos
Indolamina-Pirrol 2,3,-Dioxigenase/genética
Indolamina-Pirrol 2,3,-Dioxigenase/imunologia
Integrinas/genética
Integrinas/imunologia
Camundongos
Monócitos/citologia
Monócitos/efeitos dos fármacos
Monócitos/imunologia
Cultura Primária de Células
Proinsulina/genética
Proinsulina/imunologia
Proteínas Serina-Treonina Quinases/genética
Proteínas Serina-Treonina Quinases/imunologia
Pirazóis/farmacologia
Piridinas/farmacologia
Receptores de Fatores de Crescimento Transformadores beta/genética
Receptores de Fatores de Crescimento Transformadores beta/imunologia
Proteínas Recombinantes de Fusão/genética
Proteínas Recombinantes de Fusão/imunologia
Transdução de Sinais
Proteína Smad2/genética
Proteína Smad2/imunologia
Proteína Smad3/genética
Proteína Smad3/imunologia
Fator de Crescimento Transformador beta1/imunologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Indoleamine-Pyrrole 2,3,-Dioxygenase); 0 (Integrins); 0 (Pyrazoles); 0 (Pyridines); 0 (Receptors, Transforming Growth Factor beta); 0 (Recombinant Fusion Proteins); 0 (RepSox); 0 (SMAD2 protein, human); 0 (SMAD3 protein, human); 0 (Smad2 Protein); 0 (Smad3 Protein); 0 (Transforming Growth Factor beta1); 0 (activin A); 0 (integrin alphavbeta8); 104625-48-1 (Activins); 9012-63-9 (Cholera Toxin); 9035-68-1 (Proinsulin); EC 2.7.1.11 (TGF-beta type I receptor); EC 2.7.11.1 (Protein-Serine-Threonine Kinases)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171003
[Lr] Data última revisão:
171003
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170903
[St] Status:MEDLINE


  8 / 3346 MEDLINE  
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[PMID]:28758906
[Au] Autor:Hino K; Horigome K; Nishio M; Komura S; Nagata S; Zhao C; Jin Y; Kawakami K; Yamada Y; Ohta A; Toguchida J; Ikeya M
[Ad] Endereço:Department of Cell Growth and Differentiation, Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan.
[Ti] Título:Activin-A enhances mTOR signaling to promote aberrant chondrogenesis in fibrodysplasia ossificans progressiva.
[So] Source:J Clin Invest;127(9):3339-3352, 2017 Sep 01.
[Is] ISSN:1558-8238
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Fibrodysplasia ossificans progressiva (FOP) is a rare and intractable disease characterized by extraskeletal bone formation through endochondral ossification. Patients with FOP harbor point mutations in ACVR1, a type I receptor for BMPs. Although mutated ACVR1 (FOP-ACVR1) has been shown to render hyperactivity in BMP signaling, we and others have uncovered a mechanism by which FOP-ACVR1 mistransduces BMP signaling in response to Activin-A, a molecule that normally transduces TGF-ß signaling. Although Activin-A evokes enhanced chondrogenesis in vitro and heterotopic ossification (HO) in vivo, the underlying mechanisms have yet to be revealed. To this end, we developed a high-throughput screening (HTS) system using FOP patient-derived induced pluripotent stem cells (FOP-iPSCs) to identify pivotal pathways in enhanced chondrogenesis that are initiated by Activin-A. In a screen of 6,809 small-molecule compounds, we identified mTOR signaling as a critical pathway for the aberrant chondrogenesis of mesenchymal stromal cells derived from FOP-iPSCs (FOP-iMSCs). Two different HO mouse models, an FOP model mouse expressing FOP-ACVR1 and an FOP-iPSC-based HO model mouse, revealed critical roles for mTOR signaling in vivo. Moreover, we identified ENPP2, an enzyme that generates lysophosphatidic acid, as a linker of FOP-ACVR1 and mTOR signaling in chondrogenesis. These results uncovered the crucial role of the Activin-A/FOP-ACVR1/ENPP2/mTOR axis in FOP pathogenesis.
[Mh] Termos MeSH primário: Ativinas/metabolismo
Condrogênese
Miosite Ossificante/metabolismo
Transdução de Sinais
Serina-Treonina Quinases TOR/metabolismo
[Mh] Termos MeSH secundário: Animais
Diferenciação Celular
Condrócitos/citologia
Células-Tronco Embrionárias/citologia
Feminino
Seres Humanos
Células-Tronco Pluripotentes Induzidas/citologia
Concentração Inibidora 50
Lisofosfolipídeos/metabolismo
Masculino
Células Mesenquimais Estromais/metabolismo
Camundongos
Camundongos Endogâmicos C3H
Camundongos Endogâmicos C57BL
Camundongos Transgênicos
Análise de Sequência com Séries de Oligonucleotídeos
Diester Fosfórico Hidrolases/metabolismo
Mutação Puntual
Proteínas Recombinantes/metabolismo
Fator de Crescimento Transformador beta/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Lysophospholipids); 0 (Recombinant Proteins); 0 (Transforming Growth Factor beta); 0 (activin A); 104625-48-1 (Activins); EC 2.7.1.1 (TOR Serine-Threonine Kinases); EC 2.7.1.1 (mTOR protein, mouse); EC 3.1.4.- (Phosphoric Diester Hydrolases); EC 3.1.4.39 (alkylglycerophosphoethanolamine phosphodiesterase); PG6M3969SG (lysophosphatidic acid)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171024
[Lr] Data última revisão:
171024
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170801
[St] Status:MEDLINE


  9 / 3346 MEDLINE  
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[PMID]:28732565
[Au] Autor:Anastasilakis AD; Koulaxis D; Kefala N; Polyzos SA; Upadhyay J; Pagkalidou E; Economou F; Anastasilakis CD; Mantzoros CS
[Ad] Endereço:Department of Endocrinology, 424 General Military Hospital, Thessaloniki, Greece. Electronic address: a.anastasilakis@gmail.com.
[Ti] Título:Circulating irisin levels are lower in patients with either stable coronary artery disease (CAD) or myocardial infarction (MI) versus healthy controls, whereas follistatin and activin A levels are higher and can discriminate MI from CAD with similar to CK-MB accuracy.
[So] Source:Metabolism;73:1-8, 2017 Aug.
[Is] ISSN:1532-8600
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Several myokines are produced by cardiac muscle. We investigated changes in myokine levels at the time of acute myocardial infarction (MI) and following reperfusion in relation to controls. METHODS: Patients with MI (MI Group, n=31) treated with percutaneous coronary intervention (PCI) were compared to patients with stable coronary artery disease (CAD) subjected to scheduled PCI (CAD Group, n=40) and controls with symptoms mimicking CAD without stenosis in angiography (Control Group, n=43). The number and degree of stenosis were recorded. Irisin, follistatin, follistatin-like 3, activin A and B, ALT, AST, CK and CK-MB were measured at baseline and 6 or 24h after the intervention. RESULTS: MI and CAD patients had lower irisin than controls (p<0.001). MI patients had higher follistatin, activin A, CK, CK-MB and AST than CAD patients and controls (all p≤0.001). None of the myokines changed following reperfusion. Circulating irisin was associated with the degree of stenosis in all patients (p=0.05). Irisin was not inferior to CK-MB in predicting MI while folistatin and activin A could discriminate MI from CAD patients with similar to CK-MB accuracy. None of these myokines was altered following PCI in contrast to CK-MB. CONCLUSIONS: Irisin levels are lower in MI and CAD implying that their production may depend on myocadial blood supply. Follistatin and activin A are higher in MI than in CAD suggesting increased release due to myocardial necrosis. They can predict MI with accuracy similar to CK-MB and their role in the diagnosis of MI remains to be confirmed by prospective large clinical studies.
[Mh] Termos MeSH primário: Ativinas/sangue
Doença da Artéria Coronariana/diagnóstico
Creatina Quinase Forma MB/sangue
Fibronectinas/sangue
Folistatina/sangue
Infarto do Miocárdio/diagnóstico
[Mh] Termos MeSH secundário: Idoso
Estudos de Casos e Controles
Constrição Patológica/sangue
Constrição Patológica/diagnóstico por imagem
Angiografia Coronária
Doença da Artéria Coronariana/sangue
Diagnóstico Diferencial
Feminino
Seres Humanos
Masculino
Meia-Idade
Infarto do Miocárdio/sangue
Intervenção Coronária Percutânea
[Pt] Tipo de publicação:CLINICAL TRIAL; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (FNDC5 protein, human); 0 (Fibronectins); 0 (Follistatin); 104625-48-1 (Activins); EC 2.7.3.2 (Creatine Kinase, MB Form)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171003
[Lr] Data última revisão:
171003
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170723
[St] Status:MEDLINE


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[PMID]:28662143
[Au] Autor:Fung RSK; Bai J; Yuen KWY; Wong AOL
[Ad] Endereço:School of Biological Sciences, the University of Hong Kong, Pokfulam Road, Hong Kong, China.
[Ti] Título:Activin/follistatin system in grass carp pituitary cells: - Regulation by local release of growth hormone and luteinizing hormone and its functional role in growth hormone synthesis and secretion.
[So] Source:PLoS One;12(6):e0179789, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Gonadotrophin regulation by activin/follistatin system is well-documented, but the corresponding effect on growth hormone (GH) has not been fully characterized and with little information available in lower vertebrates, especially in fish models. In grass carp, local interactions of GH and luteinizing hormone (LH) can induce GH release and gene expression at pituitary level via autocrine/paracrine mechanisms. To shed light on the role of activin/follistatin system in GH regulation by local actions of GH and LH, grass carp activin ßA and ßB were cloned, shown to be single-copy genes expressed in the pituitary, and confirmed to encode activin proteins capable of transactivating promoter with activin-responsive elements. In grass carp pituitary cells, activin A and B were effective in reducing GH secretion and GH cell content with concurrent drop in GH mRNA level whereas the opposite was true for follistatin, the activin-binding protein known to neutralize the effects of endogenous activin. Treatment with activin A and B not only could suppress basal but also inhibit GH mRNA expression induced by GH and human chorionic gonadotropin (hCG), a functional analogue of LH in fish model. Apparently, down-regulation of GH mRNA by activin was mediated by reducing GH transcript stability with concurrent inhibition on GH promoter activity via the SMAD pathway. In reciprocal experiments, GH treatment was found to up-regulate activin ßA, activin ßB and follistatin mRNA levels in carp pituitary cells but the opposite was noted by removing endogenous GH with GH antiserum. Interestingly, parallel treatment with hCG could also inhibit basal as well as GH-induced activin ßA, activin ßB and follistatin gene expression. These results, as a whole, indicate that the pituitary activin/follistatin system can serve as a regulatory target for local interactions of GH and LH and contribute to GH regulation by autocrine/paracrine mechanisms in the carp pituitary.
[Mh] Termos MeSH primário: Ativinas/fisiologia
Folistatina/fisiologia
Hormônio do Crescimento/metabolismo
Hormônio Luteinizante/metabolismo
Hipófise/fisiologia
[Mh] Termos MeSH secundário: Ativinas/genética
Animais
Carpas
Clonagem Molecular
Feminino
Folistatina/genética
Hormônio do Crescimento/secreção
Masculino
Hipófise/citologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Follistatin); 104625-48-1 (Activins); 9002-67-9 (Luteinizing Hormone); 9002-72-6 (Growth Hormone)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170928
[Lr] Data última revisão:
170928
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170630
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0179789



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