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[PMID]:28867579
[Au] Autor:Sheng M; Huang Z; Pan L; Yu M; Yi C; Teng L; He L; Gu C; Xu C; Li J
[Ad] Endereço:Department of Intensive Care Unit (ICU), the People's Hospital of Three Gorges University/the First People's Hospital of Yichang, Yichang 443000, China.
[Ti] Título:SOCS2 exacerbates myocardial injury induced by ischemia/reperfusion in diabetic mice and H9c2 cells through inhibiting the JAK-STAT-IGF-1 pathway.
[So] Source:Life Sci;188:101-109, 2017 Nov 01.
[Is] ISSN:1879-0631
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:AIMS: This study aimed to investigate potential candidates and molecular mechanisms of myocardial ischemia/reperfusion (I/R) injury (MIRI) in type 2 diabetes mellitus. MAIN METHODS: Type 2 diabetic and myocardial I/R mouse models were established with a high fat-diet (HFD) for 24weeks and subjecting to global ischemia/reperfusion for 1h/3h, respectively. Microarray analysis was applied to screen differentially expressed genes (DEGs) in the hearts of these mice. Moreover, H9c2 cells were treated with high glucose (HG) and/or hypoxia and reoxygenation (H/R). Subsequently, the expression of suppressor of cytokine signaling 2 (SOCS2) was knocked down by siRNA followed by the above treatments. Then, the cell lipid peroxidation and apoptosis-related indicators (malondialdehyde, MDA, and lactate dehydrogenase, LDH, cleaved-caspase-3; glucose-regulated protein 78, GRP78;), Janus kinase (JAK)/signal transducers and activators of transcription (STAT) signaling pathway-related proteins (p-JAK2 and p-STAT5b) and insulin-like growth factor-1 (IGF-1) were detected. KEY FINDINGS: The mRNA levels of selected DEGs, such as Angptl4, Gadd45b, Rnf122 and SOCS2, showed a high degree of correlation with the microarray data. In addition, the levels of SOCS2, caspase-3, GRP78, LDH and MDA were increased, while the IGF-1 level was down-regulated in cells treated with HG and/or H/R compared to untreated cells (p<0.05). However, SOCS2 knockdown elevated the expression levels of IGF-1, p-JAK2 and p-STAT5b, as well as caspase-3, GRP78, LDH and MDA. SIGNIFICANCE: This research suggests that overexpressed SOCS2 might exacerbates MIRI in type 2 diabetes mellitus by inhibiting the expression of IGF-1 via the JAK-STAT signaling pathway.
[Mh] Termos MeSH primário: Diabetes Mellitus Experimental/metabolismo
Fator de Crescimento Insulin-Like I/metabolismo
Janus Quinase 2/metabolismo
Traumatismo por Reperfusão Miocárdica/metabolismo
Fator de Transcrição STAT5/metabolismo
Transdução de Sinais
Proteínas Supressoras da Sinalização de Citocinas/metabolismo
[Mh] Termos MeSH secundário: Animais
Caspase 3/metabolismo
Linhagem Celular
Diabetes Mellitus Experimental/complicações
Diabetes Mellitus Experimental/genética
Dieta Hiperlipídica
Expressão Gênica
Proteínas de Choque Térmico/metabolismo
L-Lactato Desidrogenase/metabolismo
Masculino
Malondialdeído/metabolismo
Análise em Microsséries
Traumatismo por Reperfusão Miocárdica/complicações
Traumatismo por Reperfusão Miocárdica/genética
Miocárdio/metabolismo
RNA Interferente Pequeno/farmacologia
Ratos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Heat-Shock Proteins); 0 (Hspa5 protein, rat); 0 (RNA, Small Interfering); 0 (STAT5 Transcription Factor); 0 (Socs2 protein, rat); 0 (Stat5b protein, rat); 0 (Suppressor of Cytokine Signaling Proteins); 4Y8F71G49Q (Malondialdehyde); 67763-96-6 (Insulin-Like Growth Factor I); EC 1.1.1.27 (L-Lactate Dehydrogenase); EC 2.7.10.2 (Jak2 protein, rat); EC 2.7.10.2 (Janus Kinase 2); EC 3.4.22.- (Caspase 3)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170929
[Lr] Data última revisão:
170929
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170905
[St] Status:MEDLINE


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[PMID]:28800960
[Au] Autor:Chean J; Chen CJ; Shively JE
[Ad] Endereço:Department of Molecular Immunology, Beckman Research Institute of City of Hope, 1450 E. Duarte Road, Duarte, CA 91010, USA.
[Ti] Título:ETS transcription factor ELF5 induces lumen formation in a 3D model of mammary morphogenesis and its expression is inhibited by Jak2 inhibitor TG101348.
[So] Source:Exp Cell Res;359(1):62-75, 2017 Oct 01.
[Is] ISSN:1090-2422
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The loss of expression of a single gene can revert normal tissue to a malignant phenotype. For example, while normal breast has high lumenal expression of CEACAM1, the majority of breast cancers exhibit the early loss of this gene with the concurrent loss of their lumenal phenotype. MCF7 cells that lack CEACAM1 expression and fail to form lumena in 3D culture, regain the normal phenotype when transfected with CEACAM1. In order to probe the mechanism of this gain of function, we treated these cells with the clinically relevant Jak2 inhibitor TG101348 (TG), expecting that disruption of the prolactin receptor signaling pathway would interfere with the positive effects of transfection of MCF7 cells with CEACAM1. Indeed, lumen formation was inhibited, resulting in the down regulation of a set of genes, likely involved in the complex process of lumen formation. As expected, inhibition of the expression of many of these genes also inhibited lumen formation, confirming their involvement in a single pathway. Among the genes identified by the inhibition assay, ETS transcription factor ELF5 stood out, since it has been identified as a master regulator of mammary morphogenesis, and is associated with prolactin receptor signaling. When ELF5 was transfected into the parental MCF7 cells that lack CEACAM1, lumen formation was restored, indicating that ELF5 can replace CEACAM1 in this model system of lumenogenesis. We conclude that the event(s) that led to the loss of expression of CEACAM1 is epistatic in that multiple genes associated with a critical pathway were affected, but that restoration of the normal phenotype can be achieved with reactivation of certain genes at various nodal points in tissue morphogenesis.
[Mh] Termos MeSH primário: Janus Quinase 2/antagonistas & inibidores
Glândulas Mamárias Humanas/crescimento & desenvolvimento
Modelos Biológicos
Morfogênese/efeitos dos fármacos
Inibidores de Proteínas Quinases/farmacologia
Proteínas Proto-Oncogênicas c-ets/metabolismo
Pirrolidinas/farmacologia
Sulfonamidas/farmacologia
[Mh] Termos MeSH secundário: Células Acinares/efeitos dos fármacos
Células Acinares/metabolismo
Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos
Seres Humanos
Janus Quinase 2/metabolismo
Células MCF-7
Glândulas Mamárias Humanas/efeitos dos fármacos
Proteínas de Neoplasias/genética
Proteínas de Neoplasias/metabolismo
Interferência de RNA
RNA Antissenso/metabolismo
RNA Mensageiro/genética
RNA Mensageiro/metabolismo
Fator de Transcrição STAT5/metabolismo
Análise de Sequência de RNA
Proteínas Supressoras da Sinalização de Citocinas/metabolismo
Proteínas Supressoras de Tumor/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (ELF5 protein, human); 0 (Neoplasm Proteins); 0 (Protein Kinase Inhibitors); 0 (Proto-Oncogene Proteins c-ets); 0 (Pyrrolidines); 0 (RNA, Antisense); 0 (RNA, Messenger); 0 (SOCS2 protein, human); 0 (STAT5 Transcription Factor); 0 (STAT5A protein, human); 0 (Sulfonamides); 0 (Suppressor of Cytokine Signaling Proteins); 0 (TG101348); 0 (Tumor Suppressor Proteins); EC 2.7.10.2 (Janus Kinase 2)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171016
[Lr] Data última revisão:
171016
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170813
[St] Status:MEDLINE


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[PMID]:28666115
[Au] Autor:Nirschl CJ; Suárez-Fariñas M; Izar B; Prakadan S; Dannenfelser R; Tirosh I; Liu Y; Zhu Q; Devi KSP; Carroll SL; Chau D; Rezaee M; Kim TG; Huang R; Fuentes-Duculan J; Song-Zhao GX; Gulati N; Lowes MA; King SL; Quintana FJ; Lee YS; Krueger JG; Sarin KY; Yoon CH; Garraway L; Regev A; Shalek AK; Troyanskaya O; Anandasabapathy N
[Ad] Endereço:Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
[Ti] Título:IFNγ-Dependent Tissue-Immune Homeostasis Is Co-opted in the Tumor Microenvironment.
[So] Source:Cell;170(1):127-141.e15, 2017 Jun 29.
[Is] ISSN:1097-4172
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Homeostatic programs balance immune protection and self-tolerance. Such mechanisms likely impact autoimmunity and tumor formation, respectively. How homeostasis is maintained and impacts tumor surveillance is unknown. Here, we find that different immune mononuclear phagocytes share a conserved steady-state program during differentiation and entry into healthy tissue. IFNγ is necessary and sufficient to induce this program, revealing a key instructive role. Remarkably, homeostatic and IFNγ-dependent programs enrich across primary human tumors, including melanoma, and stratify survival. Single-cell RNA sequencing (RNA-seq) reveals enrichment of homeostatic modules in monocytes and DCs from human metastatic melanoma. Suppressor-of-cytokine-2 (SOCS2) protein, a conserved program transcript, is expressed by mononuclear phagocytes infiltrating primary melanoma and is induced by IFNγ. SOCS2 limits adaptive anti-tumoral immunity and DC-based priming of T cells in vivo, indicating a critical regulatory role. These findings link immune homeostasis to key determinants of anti-tumoral immunity and escape, revealing co-opting of tissue-specific immune development in the tumor microenvironment.
[Mh] Termos MeSH primário: Interferon gama/imunologia
Melanoma/imunologia
Monócitos/imunologia
Metástase Neoplásica/patologia
Neoplasias Cutâneas/imunologia
Proteínas Supressoras da Sinalização de Citocinas/metabolismo
Microambiente Tumoral
[Mh] Termos MeSH secundário: Animais
Diferenciação Celular
Células Dendríticas/imunologia
Homeostase
Seres Humanos
Melanoma/genética
Melanoma/patologia
Camundongos
Monócitos/patologia
Análise de Sequência de RNA
Análise de Célula Única
Neoplasias Cutâneas/genética
Neoplasias Cutâneas/patologia
Transcriptoma
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (IFNG protein, human); 0 (SOCS2 protein, human); 0 (Suppressor of Cytokine Signaling Proteins); 82115-62-6 (Interferon-gamma)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170914
[Lr] Data última revisão:
170914
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170701
[St] Status:MEDLINE


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[PMID]:28652396
[Au] Autor:Ye J; Wang Y; Liu X; Li L; Opejin A; Hsueh EC; Luo H; Wang T; Hawiger D; Peng G
[Ad] Endereço:Division of Infectious Diseases, Allergy, and Immunology, Department of Internal Medicine, Saint Louis University School of Medicine, St. Louis, MO 63104.
[Ti] Título:TLR7 Signaling Regulates Th17 Cells and Autoimmunity: Novel Potential for Autoimmune Therapy.
[So] Source:J Immunol;199(3):941-954, 2017 Aug 01.
[Is] ISSN:1550-6606
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Innate regulation through TLR signaling has been shown to be important for promoting T cell subset development and function. However, limited information is known about whether differential TLR signaling can selectively inhibit Th17 and/or Th1 cells, which are important for controlling excessive inflammation and autoimmune responses. In this article, we demonstrate that activation of TLR7 signaling in T cells can inhibit Th17 cell differentiation from naive T cells and IL-17 production in established Th17 cells. We further report that downregulation of STAT3 signaling is responsible for TLR7-mediated inhibition of Th17 cells due to induction of suppressor of cytokine signaling 3 and 5. TLR7-mediated suppression of Th17 cells does not require dendritic cell involvement. In addition, we show that TLR7 signaling can suppress Th1 cell development and function through a mechanism different from Th17 cell suppression. Importantly, our complementary in vivo studies demonstrate that treatment with the TLR7 ligand imiquimod can inhibit Th1 and Th17 cells, resulting in the prevention of, and an immunotherapeutic reduction in, experimental autoimmune encephalomyelitis. These studies identify a new strategy to manipulate Th17/Th1 cells through TLR7 signaling, with important implications for successful immunotherapy against autoimmune and inflammatory diseases.
[Mh] Termos MeSH primário: Autoimunidade/imunologia
Glicoproteínas de Membrana/metabolismo
Transdução de Sinais/imunologia
Células Th17/imunologia
Receptor 7 Toll-Like/metabolismo
[Mh] Termos MeSH secundário: Aminoquinolinas/administração & dosagem
Animais
Diferenciação Celular
Modelos Animais de Doenças
Encefalomielite Autoimune Experimental/imunologia
Encefalomielite Autoimune Experimental/fisiopatologia
Encefalomielite Autoimune Experimental/prevenção & controle
Encefalomielite Autoimune Experimental/terapia
Seres Humanos
Imunoterapia
Inflamação/terapia
Interleucina-17/biossíntese
Interleucina-17/imunologia
Glicoproteínas de Membrana/genética
Glicoproteínas de Membrana/imunologia
Camundongos
Fator de Transcrição STAT3/metabolismo
Proteínas Supressoras da Sinalização de Citocinas/genética
Proteínas Supressoras da Sinalização de Citocinas/imunologia
Células Th1/efeitos dos fármacos
Células Th1/imunologia
Células Th17/efeitos dos fármacos
Receptor 7 Toll-Like/genética
Receptor 7 Toll-Like/imunologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Aminoquinolines); 0 (Interleukin-17); 0 (Membrane Glycoproteins); 0 (STAT3 Transcription Factor); 0 (Suppressor of Cytokine Signaling Proteins); 0 (TLR7 protein, human); 0 (Tlr7 protein, mouse); 0 (Toll-Like Receptor 7); P1QW714R7M (imiquimod)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171010
[Lr] Data última revisão:
171010
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170628
[St] Status:MEDLINE
[do] DOI:10.4049/jimmunol.1601890


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[PMID]:28549582
[Au] Autor:You T; Wang Y; Li K; Zhang D; Wei H; Luo Y; Li H; Lu Y; Su X; Kuang Z
[Ad] Endereço:Department of Cell Biology and Institute of Biomedicine, Jinan University, Guangzhou 510632, China; Guangdong Provincial Key Laboratory of Bioengineering Medicine, National Engineering Research Center of Genetic Medicine, Guangzhou 510632, China.
[Ti] Título:Crystal structure of SPSB2 in complex with a rational designed RGD-containing cyclic peptide inhibitor of SPSB2-iNOS interaction.
[So] Source:Biochem Biophys Res Commun;489(3):346-352, 2017 Jul 29.
[Is] ISSN:1090-2104
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:SPRY domain-containing SOCS box protein 2 (SPSB2) is a negative regulator of inducible nitric oxide synthase (iNOS) that modulates the lifetime of iNOS and thus the levels of nitric oxide (NO) production. Inhibitors that can disrupt the endogenous SPSB2-iNOS interaction and augment NO production have potential as novel antimicrobial and anticancer drugs. In this study, we have designed a cyclic peptide (cR8), containing an RGD motif and the SPSB2 binding motif (DINNNV). ITC and chemical shift perturbation showed that cR8 binds to the iNOS binding site on SPSB2 with a K of 671 nM, and saturation transfer difference NMR showed that cR8 binds to α ß integrin-expressing cells. Moreover, we determined the crystal structure of SPSB2 in complex with cR8, at a resolution of 1.34 Å. cR8 forms extensive hydrogen bonding with SPSB2 residues, but loss of an intramolecular hydrogen bond that is present in SPSB2-bound iNOS peptide may destabilize the bound conformation of cR8 and lead to a gentle reduction in SPSB2 binding affinity. These results serve as a useful basis for designing site-directed SPSB2 inhibitors in the future.
[Mh] Termos MeSH primário: Desenho de Drogas
Óxido Nítrico Sintase Tipo II/metabolismo
Oligopeptídeos/farmacologia
Peptídeos Cíclicos/química
Peptídeos Cíclicos/farmacologia
Proteínas Supressoras da Sinalização de Citocinas/química
Proteínas Supressoras da Sinalização de Citocinas/metabolismo
[Mh] Termos MeSH secundário: Cristalização
Cristalografia
Seres Humanos
Modelos Moleculares
Conformação Molecular
Oligopeptídeos/química
Peptídeos Cíclicos/síntese química
Ligação Proteica/efeitos dos fármacos
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Oligopeptides); 0 (Peptides, Cyclic); 0 (SPSB2 protein, human); 0 (Suppressor of Cytokine Signaling Proteins); 78VO7F77PN (arginyl-glycyl-aspartic acid); EC 1.14.13.39 (Nitric Oxide Synthase Type II)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170925
[Lr] Data última revisão:
170925
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170528
[St] Status:MEDLINE


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[PMID]:28437072
[Au] Autor:Chittoor B; Krishnarjuna B; Morales RAV; MacRaild CA; Sadek M; Leung EWW; Robinson SD; Pennington MW; Norton RS
[Ad] Endereço:Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University , Parkville, Victoria 3052, Australia.
[Ti] Título:The Single Disulfide-Directed ß-Hairpin Fold. Dynamics, Stability, and Engineering.
[So] Source:Biochemistry;56(19):2455-2466, 2017 May 16.
[Is] ISSN:1520-4995
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Grafting bioactive peptide sequences onto small cysteine-rich scaffolds is a promising strategy for enhancing their stability and value as novel peptide-based therapeutics. However, correctly folded disulfide-rich peptides can be challenging to produce by either recombinant or synthetic means. The single disulfide-directed ß-hairpin (SDH) fold, first observed in contryphan-Vc1, provides a potential alternative to complex disulfide-rich scaffolds. We have undertaken recombinant production of full-length contryphan-Vc1 (rCon-Vc1[Z1Q]) and a truncated analogue (rCon-Vc1 [Z1Q]), analyzed the backbone dynamics of rCon-Vc1[Z1Q], and probed the conformational and proteolytic stability of these peptides to evaluate the potential of contryphan-Vc1 as a molecular scaffold. Backbone N relaxation measurements for rCon-Vc1[Z1Q] indicate that the N-terminal domain of the peptide is ordered up to Thr19, whereas the remainder of the C-terminal region is highly flexible. The solution structure of truncated rCon-Vc1 [Z1Q] was similar to that of the full-length peptide, indicating that the flexible C-terminus does not have any effect on the structured domain of the peptide. Contryphan-Vc1 exhibited excellent proteolytic stability against trypsin and chymotrypsin but was susceptible to pepsin digestion. We have investigated whether contryphan-Vc1 can accept a bioactive epitope while maintaining the structure of the peptide by introducing peptide sequences based on the DINNN motif of inducible nitric oxide synthase. We show that sCon-Vc1 [NNN ] binds to the iNOS-binding protein SPSB2 with an affinity of 1.3 µM while maintaining the SDH fold. This study serves as a starting point in utilizing the SDH fold as a peptide scaffold.
[Mh] Termos MeSH primário: Conotoxinas/química
Peptídeos Cíclicos/química
Engenharia de Proteínas
Proteínas Supressoras da Sinalização de Citocinas/química
[Mh] Termos MeSH secundário: Conotoxinas/genética
Conotoxinas/metabolismo
Cisteína/química
Cistina/química
Epitopos
Seres Humanos
Cinética
Isótopos de Nitrogênio
Oxirredução
Fragmentos de Peptídeos/química
Fragmentos de Peptídeos/genética
Fragmentos de Peptídeos/metabolismo
Peptídeos Cíclicos/genética
Peptídeos Cíclicos/metabolismo
Conformação Proteica em Folha beta
Dobramento de Proteína
Estabilidade Proteica
Proteólise
Proteínas Recombinantes de Fusão/química
Proteínas Recombinantes de Fusão/metabolismo
Proteínas Recombinantes/química
Proteínas Recombinantes/metabolismo
Solubilidade
Proteínas Supressoras da Sinalização de Citocinas/genética
Proteínas Supressoras da Sinalização de Citocinas/metabolismo
Ressonância de Plasmônio de Superfície
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Conotoxins); 0 (Epitopes); 0 (Nitrogen Isotopes); 0 (Peptide Fragments); 0 (Peptides, Cyclic); 0 (Recombinant Fusion Proteins); 0 (Recombinant Proteins); 0 (SPSB2 protein, human); 0 (Suppressor of Cytokine Signaling Proteins); 0 (alpha-conotoxin Vc1.1); 0 (contryphan); 48TCX9A1VT (Cystine); K848JZ4886 (Cysteine)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170623
[Lr] Data última revisão:
170623
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170425
[St] Status:MEDLINE
[do] DOI:10.1021/acs.biochem.7b00120


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[PMID]:28423484
[Au] Autor:Rontauroli S; Norfo R; Pennucci V; Zini R; Ruberti S; Bianchi E; Salati S; Prudente Z; Rossi C; Rosti V; Guglielmelli P; Barosi G; Vannucchi A; Tagliafico E; Manfredini R
[Ad] Endereço:Centre for Regenerative Medicine, Life Sciences Department, University of Modena and Reggio Emilia, Modena, Italy.
[Ti] Título:miR-494-3p overexpression promotes megakaryocytopoiesis in primary myelofibrosis hematopoietic stem/progenitor cells by targeting SOCS6.
[So] Source:Oncotarget;8(13):21380-21397, 2017 Mar 28.
[Is] ISSN:1949-2553
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Primary myelofibrosis (PMF) is a chronic Philadelphia-negative myeloproliferative neoplasm characterized by hematopoietic stem cell-derived clonal myeloproliferation, involving especially the megakaryocyte lineage. To better characterize how the altered expression of microRNAs might contribute to PMF pathogenesis, we have previously performed the integrative analysis of gene and microRNA expression profiles of PMF hematopoietic stem/progenitor cells (HSPCs), which allowed us to identify miR-494-3p as the upregulated microRNA predicted to target the highest number of downregulated mRNAs.To elucidate the role of miR-494-3p in hematopoietic differentiation, in the present study we demonstrated that miR-494-3p enforced expression in normal HSPCs promotes megakaryocytopoiesis. Gene expression profiling upon miR-494-3p overexpression allowed the identification of genes commonly downregulated both after microRNA overexpression and in PMF CD34+ cells. Among them, suppressor of cytokine signaling 6 (SOCS6) was confirmed to be a miR-494-3p target by luciferase assay. Western blot analysis showed reduced level of SOCS6 protein as well as STAT3 activation in miR-494-3p overexpressing cells. Furthermore, transient inhibition of SOCS6 expression in HSPCs demonstrated that SOCS6 silencing stimulates megakaryocytopoiesis, mimicking the phenotypic effects observed upon miR-494-3p overexpression. Finally, to disclose the contribution of miR-494-3p upregulation to PMF pathogenesis, we performed inhibition experiments in PMF HSPCs, which showed that miR-494-3p silencing led to SOCS6 upregulation and impaired megakaryocyte differentiation.Taken together, our results describe for the first time the role of miR-494-3p during normal HSPC differentiation and suggest that its increased expression, and the subsequent downregulation of its target SOCS6, might contribute to the megakaryocyte hyperplasia commonly observed in PMF patients.
[Mh] Termos MeSH primário: Células-Tronco Hematopoéticas/patologia
MicroRNAs/biossíntese
Mielofibrose Primária/patologia
Proteínas Supressoras da Sinalização de Citocinas/metabolismo
Trombopoese/genética
[Mh] Termos MeSH secundário: Western Blotting
Eletroporação
Perfilação da Expressão Gênica
Regulação Neoplásica da Expressão Gênica/genética
Células-Tronco Hematopoéticas/metabolismo
Seres Humanos
Imunofenotipagem
Reação em Cadeia da Polimerase
Mielofibrose Primária/genética
Mielofibrose Primária/metabolismo
Transcriptoma
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (MIRN494 microRNA, human); 0 (MicroRNAs); 0 (SOCS6 protein, human); 0 (Suppressor of Cytokine Signaling Proteins)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171010
[Lr] Data última revisão:
171010
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170421
[St] Status:MEDLINE
[do] DOI:10.18632/oncotarget.15226


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[PMID]:28378729
[Au] Autor:Sorokina LN; Mineev VN; Lim VV
[Ad] Endereço:I.P. Pavlov First Saint Petersburg State Medical University, Ministry of Health of Russia, Saint Petersburg, Russia.
[Ti] Título:[Role of negative regulators of SOCS1, SOCS3, and SOCS5 gene transcription in the negative cell signaling regulation system in asthma].
[Ti] Título:Rol' negativnykh regulyatorov transkriptsii genov SOCS1, SOCS3 i SOCS5 v sisteme negativnoi regulyatsii kletochnoi signalizatsii pri bronkhial'noi astme..
[So] Source:Ter Arkh;89(3):43-47, 2017.
[Is] ISSN:0040-3660
[Cp] País de publicação:Russia (Federation)
[La] Idioma:rus
[Ab] Resumo:AIM: To conduct a comprehensive study of the components of negative cell signaling regulation in different types of asthma. SUBJECTS AND METHODS: A total of 171 people, including 80 patients with allergic asthma (AA), 60 patients with non-allergic asthma (NAA), and 31 apparently healthy individuals, were examined. SOCS5 mRNA expression was assessed by reverse-transcription polymerase chain reaction. The expression of SOCS1 and SOCS3 proteins was investigated by immunoblotting. The concentration of total serum IgE was determined by enzyme immunoassay; the level of cytokines was measured according to the standard protocol using a Bio-Plex fluorometer. RESULTS: The findings show that the patients with AA generally display more marked changes in the expression of all three investigated SOCSes (SOCS1, SOCS3, and SOCS5) at baseline and when interleukin 4 (IL-4) acts. In NAA, there are pronounced changes in the expression of SOCS3 only and, to a lesser extent, SOCS5. The results of investigating the concentrations of IL-4 in the examined groups demonstrate its significant decrease in the AA group, whereas in the NAA group, it is similar to those in healthy individuals. On the contrary, IL-10 concentrations in AA tend towards those in the control group, but much exceed in NAA. CONCLUSION: The findings allow one to consider the complexity of regulatory disorders arising at various levels of cell signaling in the context of the multifunctional nature of the molecules from the family of negative regulators of transcription of the SOCS1, SOCS3, and SOCS5 genes, which provide the comprehensive control of cytokine signaling simultaneously in different signal pathways.
[Mh] Termos MeSH primário: Asma
Interleucina-4/metabolismo
Proteína 1 Supressora da Sinalização de Citocina/metabolismo
Proteína 3 Supressora da Sinalização de Citocinas/metabolismo
Proteínas Supressoras da Sinalização de Citocinas/metabolismo
[Mh] Termos MeSH secundário: Adulto
Asma/diagnóstico
Asma/etiologia
Asma/metabolismo
Asma/fisiopatologia
Feminino
Perfilação da Expressão Gênica/métodos
Seres Humanos
Hipersensibilidade/metabolismo
Interleucina-10/metabolismo
Masculino
Transdução de Sinais/fisiologia
Transcrição Genética/fisiologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (IL10 protein, human); 0 (IL4 protein, human); 0 (SOCS1 protein, human); 0 (SOCS3 protein, human); 0 (SOCS5 protein, human); 0 (Suppressor of Cytokine Signaling 1 Protein); 0 (Suppressor of Cytokine Signaling 3 Protein); 0 (Suppressor of Cytokine Signaling Proteins); 130068-27-8 (Interleukin-10); 207137-56-2 (Interleukin-4)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170713
[Lr] Data última revisão:
170713
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170406
[St] Status:MEDLINE
[do] DOI:10.17116/terarkh201789343-47


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[PMID]:28328845
[Au] Autor:Zhao R; Chen K; Zhou J; He J; Liu J; Guan P; Li B; Qin Y
[Ad] Endereço:aDepartment of Liver Surgery and Liver Transplantation Center bDepartment of Medical Oncology, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University cDepartment of Biochemistry and Molecular Biology dDepartment of Forensic Pathology, West China School of Preclinical and Forensic Medicine, Sichuan University, Chengdu, China.
[Ti] Título:The prognostic role of BORIS and SOCS3 in human hepatocellular carcinoma.
[So] Source:Medicine (Baltimore);96(12):e6420, 2017 Mar.
[Is] ISSN:1536-5964
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Brother of regulator of imprinted sites (BORIS) is a DNA-binding protein that is normally expressed in the testes. However, aberrant expression of BORIS is observed in various carcinomas, indicating a malignant role for this protein. Furthermore, abolishment or reduction of suppressor of cytokine signaling 3 (SOCS3) expression directed by promoter methylation is considered significant in hepatocellular carcinoma (HCC) carcinogenesis. This study aims to investigate BORIS and SOCS3 expression in HCC specimens and assess the prognostic significance of these proteins.BORIS and SOCS3 expression was examined using immunohistochemistry in HCC tissues, along with corresponding paracarcinomatous, cirrhosis, hepatitis, and normal liver tissues. The expression levels of these 2 proteins in HCC were evaluated for their association with clinicopathological parameters. Survival analysis was performed using Kaplan-Meier curves, the log-rank test, and multivariate Cox regression analysis.BORIS expression was significantly higher in HCC tissues than in normal liver tissues. In contrast, SOCS3 expression was dramatically lower in HCC tissues. BORIS expression was associated with tumor size, differentiation grade, satellite lesions, and recurrence while SOCS3 expression correlated with differentiation grade, vascular invasion, and recurrence. A significant negative correlation between BORIS and SOCS3 was observed. Patients with high BORIS expression and/or low SOCS3 expression had poorer postoperative survival. Patients with both these characteristics had the poorest prognostic outcome.BORIS and SOCS3 are promising as valuable indicators for predicting HCC prognosis.
[Mh] Termos MeSH primário: Carcinoma Hepatocelular/patologia
Proteínas de Ligação a DNA/biossíntese
Neoplasias Hepáticas/patologia
Proteínas Supressoras da Sinalização de Citocinas/biossíntese
[Mh] Termos MeSH secundário: Biomarcadores Tumorais
Feminino
Seres Humanos
Estimativa de Kaplan-Meier
Fígado/fisiopatologia
Masculino
Meia-Idade
Recidiva Local de Neoplasia
Prognóstico
Carga Tumoral
[Pt] Tipo de publicação:JOURNAL ARTICLE; OBSERVATIONAL STUDY
[Nm] Nome de substância:
0 (Biomarkers, Tumor); 0 (CTCFL protein, human); 0 (DNA-Binding Proteins); 0 (Suppressor of Cytokine Signaling Proteins)
[Em] Mês de entrada:1704
[Cu] Atualização por classe:170410
[Lr] Data última revisão:
170410
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170323
[St] Status:MEDLINE
[do] DOI:10.1097/MD.0000000000006420


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[PMID]:28270450
[Au] Autor:Shi W; Vu T; Boucher D; Biernacka A; Nde J; Pandita RK; Straube J; Boyle GM; Al-Ejeh F; Nag P; Jeffery J; Harris JL; Bain AL; Grzelak M; Skrzypczak M; Mitra A; Dojer N; Crosetto N; Cloonan N; Becherel OJ; Finnie J; Skaar JR; Walkley CR; Pandita TK; Rowicka M; Ginalski K; Lane SW; Khanna KK
[Ad] Endereço:QIMR Berghofer Medical Research Institute, Herston, QLD, Australia.
[Ti] Título:Ssb1 and Ssb2 cooperate to regulate mouse hematopoietic stem and progenitor cells by resolving replicative stress.
[So] Source:Blood;129(18):2479-2492, 2017 May 04.
[Is] ISSN:1528-0020
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Hematopoietic stem and progenitor cells (HSPCs) are vulnerable to endogenous damage and defects in DNA repair can limit their function. The 2 single-stranded DNA (ssDNA) binding proteins SSB1 and SSB2 are crucial regulators of the DNA damage response; however, their overlapping roles during normal physiology are incompletely understood. We generated mice in which both and were constitutively or conditionally deleted. Constitutive double knockout (DKO) caused early embryonic lethality, whereas conditional double knockout (cDKO) in adult mice resulted in acute lethality due to bone marrow failure and intestinal atrophy featuring stem and progenitor cell depletion, a phenotype unexpected from the previously reported single knockout models of or Mechanistically, cDKO HSPCs showed altered replication fork dynamics, massive accumulation of DNA damage, genome-wide double-strand breaks enriched at Ssb-binding regions and CpG islands, together with the accumulation of -loops and cytosolic ssDNA. Transcriptional profiling of cDKO HSPCs revealed the activation of p53 and interferon (IFN) pathways, which enforced cell cycling in quiescent HSPCs, resulting in their apoptotic death. The rapid cell death phenotype was reproducible in in vitro cultured cDKO-hematopoietic stem cells, which were significantly rescued by nucleotide supplementation or after depletion of p53. Collectively, Ssb1 and Ssb2 control crucial aspects of HSPC function, including proliferation and survival in vivo by resolving replicative stress to maintain genomic stability.
[Mh] Termos MeSH primário: Proliferação Celular/fisiologia
Quebras de DNA de Cadeia Dupla
Instabilidade Genômica/fisiologia
Células-Tronco Hematopoéticas/metabolismo
Proteínas Supressoras da Sinalização de Citocinas/metabolismo
[Mh] Termos MeSH secundário: Animais
Sobrevivência Celular/fisiologia
Ilhas de CpG/fisiologia
Células-Tronco Hematopoéticas/citologia
Camundongos
Camundongos Knockout
Proteínas Supressoras da Sinalização de Citocinas/genética
Proteína Supressora de Tumor p53/genética
Proteína Supressora de Tumor p53/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (SSB-1 protein, mouse); 0 (SSB-4 protein, mouse); 0 (Suppressor of Cytokine Signaling Proteins); 0 (Tumor Suppressor Protein p53)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170901
[Lr] Data última revisão:
170901
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170309
[St] Status:MEDLINE
[do] DOI:10.1182/blood-2016-06-725093



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