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[PMID]: 29286858 [Au] Autor: Ritchie AI; Singanayagam A; Wiater E; Edwards MR; Montminy M; Johnston SL [Ad] Endereço: 1 National Heart and Lung Institute, Imperial College London, United Kingdom. [Ti] Título: ß -Agonists Enhance Asthma-Relevant Inflammatory Mediators in Human Airway Epithelial Cells. [So] Source: Am J Respir Cell Mol Biol;58(1):128-132, 2018 01. [Is] ISSN: 1535-4989 [Cp] País de publicação: United States [La] Idioma: eng [Mh] Termos MeSH primário: Agonistas de Receptores Adrenérgicos beta 2/farmacologia Asma/metabolismo Brônquios/metabolismo Células Epiteliais/metabolismo Mediadores da Inflamação/metabolismo [Mh] Termos MeSH secundário: Asma/patologia Fator Neurotrófico Derivado do Encéfalo/biossíntese Brônquios/patologia Linhagem Celular Células Epiteliais/patologia Seres Humanos Interleucina-11/biossíntese Interleucina-6/biossíntese [Pt] Tipo de publicação: LETTER [Nm] Nome de substância: 0 (Adrenergic beta-2 Receptor Agonists); 0 (Brain-Derived Neurotrophic Factor); 0 (IL11 protein, human); 0 (IL6 protein, human); 0 (Inflammation Mediators); 0 (Interleukin-11); 0 (Interleukin-6); 0 (brain-derived neurotrophic factor, human) [Em] Mês de entrada: 1802 [Cu] Atualização por classe: 180221 [Lr] Data última revisão: 180221 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 171230 [St] Status: MEDLINE [do] DOI: 10.1165/rcmb.2017-0315LE

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[PMID]: 28854223 [Au] Autor: Yu Y; Song EM; Lee KE; Joo YH; Kim SE; Moon CM; Kim HY; Jung SA; Jo I [Ad] Endereço: Department of Molecular Medicine, College of Medicine, Ewha Womans University, Seoul, South Korea. [Ti] Título: Therapeutic potential of tonsil-derived mesenchymal stem cells in dextran sulfate sodium-induced experimental murine colitis. [So] Source: PLoS One;12(8):e0183141, 2017. [Is] ISSN: 1932-6203 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: The therapeutic potential of tonsil-derived mesenchymal stem cells (TMSC) prepared from human tonsillar tissue has been studied in animal models for several diseases such as hepatic injury, hypoparathyroidism, diabetes and muscle dystrophy. In this study, we examined the therapeutic effects of TMSC in a dextran sulfate sodium (DSS)-induced colitis model. TMSC were injected in DSS-induced colitis mice via intraperitoneal injection twice (TMSC[x2]) or four times (TMSC[x4]). Control mice were injected with either phosphate-buffered saline or human embryonic kidney 293 cells. Body weight, stool condition and disease activity index (DAI) were examined daily. Colon length, histologic grading, and mRNA expression of pro-inflammatory cytokines, interleukin 1ß (IL-1ß), IL-6, IL-17 and tumor necrosis factor α, and anti-inflammatory cytokines, IL-10, IL-11 and IL-13, were also measured. Our results showed a significant improvement in survival rates and body weight gain in colitis mice injected with TMSC[x2] or TMSC[x4]. Injection with TMSC also significantly decreased DAI scores throughout the experimental period; at the end of experiment, almost complete reversal of DAI scores to normal was found in colitis mice treated with TMSC[x4]. Colon length was also significantly recovered in colitis mice treated with TMSC[x4]. However, histopathological alterations induced by DSS treatment were not apparently improved by injection with TMSC. Finally, treatment with TMSC[x4] significantly reversed the mRNA levels of IL-1ß and IL-6, although expression of all pro-inflammatory cytokines tested was induced in colitis mice. Under our experimental conditions, however, no apparent alterations in the mRNA levels of all the anti-inflammatory cytokines tested were found. In conclusion, our findings demonstrate that multiple injections with TMSC produced a therapeutic effect in a mouse model of DSS-induced colitis. [Mh] Termos MeSH primário: Terapia Baseada em Transplante de Células e Tecidos/métodos Colite/terapia Transplante de Células-Tronco Mesenquimais Células Mesenquimais Estromais/citologia Tonsila Palatina/citologia [Mh] Termos MeSH secundário: Animais Peso Corporal Criança Colite/induzido quimicamente Colite/imunologia Colite/patologia Sulfato de Dextrana Modelos Animais de Doenças Regulação da Expressão Gênica Células HEK293 Seres Humanos Injeções Intraperitoneais Interleucina-10/genética Interleucina-10/imunologia Interleucina-11/genética Interleucina-11/imunologia Interleucina-13/genética Interleucina-13/imunologia Interleucina-17/genética Interleucina-17/imunologia Interleucina-1beta/genética Interleucina-1beta/imunologia Interleucina-6/genética Interleucina-6/imunologia Masculino Células Mesenquimais Estromais/fisiologia Camundongos Camundongos Endogâmicos C57BL Tonsila Palatina/fisiologia Tonsila Palatina/cirurgia Recuperação de Função Fisiológica/fisiologia Análise de Sobrevida Resultado do Tratamento Fator de Necrose Tumoral alfa/genética Fator de Necrose Tumoral alfa/imunologia [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (IL10 protein, mouse); 0 (IL1B protein, mouse); 0 (Interleukin-11); 0 (Interleukin-13); 0 (Interleukin-17); 0 (Interleukin-1beta); 0 (Interleukin-6); 0 (Tumor Necrosis Factor-alpha); 0 (interleukin-6, mouse); 130068-27-8 (Interleukin-10); 9042-14-2 (Dextran Sulfate) [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: 170831 [St] Status: MEDLINE [do] DOI: 10.1371/journal.pone.0183141

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[PMID]: 28735867 [Au] Autor: Lokau J; Flynn CM; Garbers C [Ad] Endereço: Institute of Biochemistry, Kiel University, 24118 Kiel, Germany. [Ti] Título: Cleavage of the Interleukin-11 receptor induces processing of its C-terminal fragments by the gamma-secretase and the proteasome. [So] Source: Biochem Biophys Res Commun;491(2):296-302, 2017 Sep 16. [Is] ISSN: 1090-2104 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: The cytokine Interleukin-11 (IL-11) signals through the membrane-bound IL-11 receptor (IL-11R), which is expressed in a cell-type specific manner. We have recently shown that the metalloprotease ADAM10 can cleave the IL-11R. The liberated soluble IL-11R (sIL-11R) ectodomain can bind its ligand, and the resulting IL-11/sIL-11R complex can activate cells that do not express the IL-11R (trans-signaling). In this study, we show that the remaining C-terminal fragment (CTF1) after ADAM10-mediated cleavage is subsequently cleaved within the membrane by the gamma-secretase complex, and that the resulting shorter CTF2 is further degraded by the proteasome. In contrast to other transmembrane receptors, e.g. Notch, we find no evidence that the IL-11R CTF can translocate into the nucleus to act as a transcription factor, suggesting that regulated intramembrane proteolysis of the IL-11R CTF acts as a mechanism to clear the plasma membrane from remaining protein fragments after cleavage of its ectodomain. [Mh] Termos MeSH primário: Proteína ADAM10/metabolismo Secretases da Proteína Precursora do Amiloide/metabolismo Interleucina-11/metabolismo Proteínas de Membrana/metabolismo Células Precursoras de Linfócitos B/metabolismo Complexo de Endopeptidases do Proteassoma/metabolismo Receptores de Interleucina-11/metabolismo [Mh] Termos MeSH secundário: Proteína ADAM10/genética Proteína ADAM10/imunologia Secretases da Proteína Precursora do Amiloide/genética Secretases da Proteína Precursora do Amiloide/imunologia Animais Linhagem Celular Tumoral Membrana Celular/imunologia Membrana Celular/metabolismo Expressão Gênica Interleucina-11/genética Interleucina-11/imunologia Ligantes Proteínas de Membrana/genética Proteínas de Membrana/imunologia Camundongos Fragmentos de Peptídeos/genética Fragmentos de Peptídeos/imunologia Fragmentos de Peptídeos/metabolismo Células Precursoras de Linfócitos B/citologia Células Precursoras de Linfócitos B/imunologia Ligação Proteica Proteólise Receptores de Interleucina-11/genética Receptores de Interleucina-11/imunologia Transdução de Sinais [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Interleukin-11); 0 (Ligands); 0 (Membrane Proteins); 0 (Peptide Fragments); 0 (Receptors, Interleukin-11); EC 3.4.- (Amyloid Precursor Protein Secretases); EC 3.4.24.81 (ADAM10 Protein); EC 3.4.24.81 (Adam10 protein, mouse); EC 3.4.25.1 (Proteasome Endopeptidase Complex) [Em] Mês de entrada: 1708 [Cu] Atualização por classe: 170824 [Lr] Data última revisão: 170824 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170725 [St] Status: MEDLINE

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[PMID]: 28708884 [Au] Autor: Murakami K; Kobayashi Y; Uehara S; Suzuki T; Koide M; Yamashita T; Nakamura M; Takahashi N; Kato H; Udagawa N; Nakamura Y [Ad] Endereço: Department of Orthopedic Surgery, Shinshu University School of Medicine, Matsumoto, Nagano, Japan. [Ti] Título: A Jak1/2 inhibitor, baricitinib, inhibits osteoclastogenesis by suppressing RANKL expression in osteoblasts in vitro. [So] Source: PLoS One;12(7):e0181126, 2017. [Is] ISSN: 1932-6203 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: The Janus kinases (Jaks) are hubs in the signaling process of more than 50 cytokine or hormone receptors. However, the function of Jak in bone metabolism remains to be elucidated. Here, we showed that the inhibition of Jak1 and/or Jak2 in osteoblast-lineage cells led to impaired osteoclastogenesis due to the reduced expression of receptor activator of nuclear factor-κB ligand (RANKL). Murine calvaria-derived osteoblasts induced differentiation of bone marrow cells into osteoclasts in the presence of 1,25-dihydroxyvitamin D3 (1,25D3) and prostaglandin E2 (PGE2) in vitro. However, treatment with the Jak1/2 inhibitor, baricitinib, markedly inhibited osteoclastogenesis in the co-culture. On the other hand, baricitinib did not inhibit RANKL-induced osteoclast differentiation of bone marrow macrophages. These results indicated that baricitinib acted on osteoblasts, but not on bone marrow macrophages. Baricitinib suppressed 1,25D3 and PGE2-induced up-regulation of RANKL in osteoblasts, but not macrophage colony-stimulating factor expression. Moreover, the addition of recombinant RANKL to co-cultures completely rescued baricitinib-induced impairment of osteoclastogenesis. shRNA-mediated knockdown of Jak1 or Jak2 also suppressed RANKL expression in osteoblasts and inhibited osteoclastogenesis. Finally, cytokine array revealed that 1,25D3 and PGE2 stimulated secretion of interleukin-6 (IL-6), IL-11, and leukemia inhibitory factor in the co-culture. Hence, Jak1 and Jak2 represent novel therapeutic targets for osteoporosis as well as inflammatory bone diseases including rheumatoid arthritis. [Mh] Termos MeSH primário: Azetidinas/farmacologia Regulação para Baixo/efeitos dos fármacos Janus Quinase 1/antagonistas & inibidores Janus Quinase 2/antagonistas & inibidores Osteogênese/efeitos dos fármacos Ligante RANK/metabolismo Sulfonamidas/farmacologia [Mh] Termos MeSH secundário: Animais Células da Medula Óssea/citologia Células da Medula Óssea/efeitos dos fármacos Células da Medula Óssea/metabolismo Diferenciação Celular/efeitos dos fármacos Sobrevivência Celular/efeitos dos fármacos Colecalciferol/farmacologia Técnicas de Cocultura Dinoprostona/farmacologia Interleucina-11/metabolismo Interleucina-11/secreção Interleucina-6/metabolismo Interleucina-6/secreção Janus Quinase 1/genética Janus Quinase 1/metabolismo Janus Quinase 2/genética Janus Quinase 2/metabolismo Fator Estimulador de Colônias de Macrófagos/metabolismo Masculino Camundongos Osteoblastos/citologia Osteoblastos/efeitos dos fármacos Osteoblastos/metabolismo Ligante RANK/genética Ligante RANK/farmacologia Interferência de RNA Proteínas Recombinantes/biossíntese Proteínas Recombinantes/isolamento & purificação Proteínas Recombinantes/farmacologia [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Azetidines); 0 (Interleukin-11); 0 (Interleukin-6); 0 (RANK Ligand); 0 (Recombinant Proteins); 0 (Sulfonamides); 1C6V77QF41 (Cholecalciferol); 81627-83-0 (Macrophage Colony-Stimulating Factor); EC 2.7.10.2 (Janus Kinase 1); EC 2.7.10.2 (Janus Kinase 2); ISP4442I3Y (baricitinib); K7Q1JQR04M (Dinoprostone) [Em] Mês de entrada: 1709 [Cu] Atualização por classe: 170926 [Lr] Data última revisão: 170926 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170715 [St] Status: MEDLINE [do] DOI: 10.1371/journal.pone.0181126

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[PMID]: 28686677 [Au] Autor: Hennenberg EM; Eyking A; Reis H; Cario E [Ad] Endereço: Experimental Gastroenterology, Department of Gastroenterology and Hepatology, University Hospital Essen, Essen, Germany. [Ti] Título: MDR1A deficiency restrains tumor growth in murine colitis-associated carcinogenesis. [So] Source: PLoS One;12(7):e0180834, 2017. [Is] ISSN: 1932-6203 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Patients with Ulcerative Colitis (UC) have an increased risk to develop colitis-associated colorectal cancer (CAC). Here, we found that protein expression of ABCB1 (ATP Binding Cassette Subfamily B Member 1) / MDR1 (multidrug resistance 1) was diminished in the intestinal mucosa of patients with active UC with or without CAC, but not in non-UC patients with sporadic colon cancer. We investigated the consequences of ABCB1/MDR1 loss-of-function in a common murine model for CAC (AOM/DSS). Mice deficient in MDR1A (MDR1A KO) showed enhanced intratumoral inflammation and cellular damage, which were associated with reduced colonic tumor size and decreased degree of dysplasia, when compared to wild-type (WT). Increased cell injury correlated with reduced capacity for growth of MDR1A KO tumor spheroids cultured ex-vivo. Gene expression analysis by microarray demonstrated that MDR1A deficiency shaped the inflammatory response towards an anti-tumorigenic microenvironment by downregulating genes known to be important mediators of cancer progression (PTGS2 (COX2), EREG, IL-11). MDR1A KO tumors showed increased gene expression of TNFSF10 (TRAIL), a known inducer of cancer cell death, and CCL12, a strong trigger of B cell chemotaxis. Abundant B220+ B lymphocyte infiltrates with interspersed CD138+ plasma cells were recruited to the MDR1A KO tumor microenvironment, concomitant with high levels of immunoglobulin light chain genes. In contrast, MDR1A deficiency in RAG2 KO mice that lack both B and T cells aggravated colonic tumor progression. MDR1A KO CD19+ B cells, but not WT CD19+ B cells, suppressed growth of colonic tumor-derived spheroids from AOM/DSS-WT mice in an ex-vivo co-culture system, implying that B-cell regulated immune responses contributed to delayed tumor development in MDR1A deficiency. In conclusion, we provide first evidence that loss of ABCB1/MDR1 function may represent an essential tumor-suppressive host defense mechanism in CAC. [Mh] Termos MeSH primário: Subfamília B de Transportador de Cassetes de Ligação de ATP/imunologia Linfócitos B/imunologia Colite Ulcerativa/imunologia Neoplasias Colorretais/imunologia Regulação Neoplásica da Expressão Gênica [Mh] Termos MeSH secundário: Subfamília B de Transportador de Cassetes de Ligação de ATP/deficiência Subfamília B de Transportador de Cassetes de Ligação de ATP/genética Animais Linfócitos B/patologia Carcinogênese/genética Carcinogênese/imunologia Carcinogênese/patologia Quimiotaxia Colite Ulcerativa/complicações Colite Ulcerativa/genética Colite Ulcerativa/patologia Neoplasias Colorretais/complicações Neoplasias Colorretais/genética Neoplasias Colorretais/patologia Ciclo-Oxigenase 2/genética Ciclo-Oxigenase 2/imunologia Proteínas de Ligação a DNA/deficiência Proteínas de Ligação a DNA/genética Proteínas de Ligação a DNA/imunologia Modelos Animais de Doenças Epirregulina/genética Epirregulina/imunologia Genes de Cadeia Leve de Imunoglobulina/genética Seres Humanos Interleucina-11/genética Interleucina-11/imunologia Mucosa Intestinal/imunologia Mucosa Intestinal/patologia Antígenos Comuns de Leucócito/genética Antígenos Comuns de Leucócito/imunologia Masculino Camundongos Camundongos Knockout Proteínas Quimioatraentes de Monócitos/genética Proteínas Quimioatraentes de Monócitos/imunologia Transdução de Sinais Ligante Indutor de Apoptose Relacionado a TNF/genética Ligante Indutor de Apoptose Relacionado a TNF/imunologia [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (ATP Binding Cassette Transporter, Sub-Family B); 0 (Ccl12 protein, mouse); 0 (DNA-Binding Proteins); 0 (Epiregulin); 0 (Ereg protein, mouse); 0 (Interleukin-11); 0 (Monocyte Chemoattractant Proteins); 0 (Rag2 protein, mouse); 0 (TNF-Related Apoptosis-Inducing Ligand); 0 (Tnfsf10 protein, mouse); 0 (multidrug resistance protein 3); EC 1.14.99.- (Ptgs2 protein, mouse); EC 1.14.99.1 (Cyclooxygenase 2); EC 3.1.3.48 (Leukocyte Common Antigens) [Em] Mês de entrada: 1709 [Cu] Atualização por classe: 171116 [Lr] Data última revisão: 171116 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170708 [St] Status: MEDLINE [do] DOI: 10.1371/journal.pone.0180834

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[PMID]: 28447514 [Au] Autor: Sanadgol N; Golab F; Tashakkor Z; Taki N; Moradi Kouchi S; Mostafaie A; Mehdizadeh M; Abdollahi M; Taghizadeh G; Sharifzadeh M [Ad] Endereço: a Department of Pharmacology and Toxicology, Pharmaceutical Sciences Research Center, Faculty of Pharmacy , Tehran University of Medical Sciences , Tehran , Iran. [Ti] Título: Neuroprotective effects of ellagic acid on cuprizone-induced acute demyelination through limitation of microgliosis, adjustment of CXCL12/IL-17/IL-11 axis and restriction of mature oligodendrocytes apoptosis. [So] Source: Pharm Biol;55(1):1679-1687, 2017 Dec. [Is] ISSN: 1744-5116 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: CONTEXT: Ellagic acid (EA) is a natural phenol antioxidant with various therapeutic activities. However, the efficacy of EA has not been examined in neuropathologic conditions. OBJECTIVE: In vivo neuroprotective effects of EA on cuprizone (cup)-induced demyelination were evaluated. MATERIAL AND METHODS: C57BL/6 J mice were fed with chow containing 0.2% cup for 4 weeks to induce oligodendrocytes (OLGs) depletion predominantly in the corpus callosum (CC). EA was administered at different doses (40 or 80 mg/kg body weight/day/i.p.) from the first day of cup diet. Oligodendrocytes apoptosis [TUNEL assay and myelin oligodendrocyte glycoprotein (MOG )/caspase-3 cells), gliosis (H&E staining, glial fibrillary acidic protein (GFAP ) and macrophage-3 (Mac-3 ) cells) and inflammatory markers (interleukin 17 (IL-17), interleukin 11 (IL-11) and stromal cell-derived factor 1 α (SDF-1α) or CXCL12] during cup intoxication were examined. RESULTS: High dose of EA (EA-80) increased mature oligodendrocytes population (MOG cells, p < 0.001), and decreased apoptosis (p < 0.05) compared with the cup mice. Treatment with both EA doses did not show any considerable effects on the expression of CXCL12, but significantly down-regulated the expression of IL-17 and up-regulated the expression of IL-11 in mRNA levels compared with the cup mice. Only treatment with EA-80 significantly decreased the population of active macrophage (MAC-3 cells, p < 0.001) but not reactive astrocytes (GFAP cells) compared with the cup mice. DISCUSSION AND CONCLUSION: In this model, EA-80 effectively reduces lesions via reduction of neuroinflammation and toxic effects of cup on mature OLGs. EA is a suitable therapeutic agent for moderate brain damage in neurodegenerative diseases such as multiple sclerosis. [Mh] Termos MeSH primário: Cuprizona/toxicidade Doenças Desmielinizantes/prevenção & controle Ácido Elágico/farmacologia Fármacos Neuroprotetores/farmacologia [Mh] Termos MeSH secundário: Animais Apoptose/efeitos dos fármacos Astrócitos/efeitos dos fármacos Astrócitos/metabolismo Quimiocina CXCL12/metabolismo Corpo Caloso/efeitos dos fármacos Corpo Caloso/metabolismo Modelos Animais de Doenças Relação Dose-Resposta a Droga Regulação para Baixo/efeitos dos fármacos Ácido Elágico/administração & dosagem Marcação In Situ das Extremidades Cortadas Interleucina-11/metabolismo Interleucina-17/metabolismo Masculino Camundongos Camundongos Endogâmicos C57BL Fármacos Neuroprotetores/administração & dosagem Oligodendroglia/efeitos dos fármacos Oligodendroglia/metabolismo RNA Mensageiro/metabolismo Regulação para Cima/efeitos dos fármacos [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Chemokine CXCL12); 0 (Interleukin-11); 0 (Interleukin-17); 0 (Neuroprotective Agents); 0 (RNA, Messenger); 19YRN3ZS9P (Ellagic Acid); 5N16U7E0AO (Cuprizone) [Em] Mês de entrada: 1710 [Cu] Atualização por classe: 171030 [Lr] Data última revisão: 171030 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170428 [St] Status: MEDLINE [do] DOI: 10.1080/13880209.2017.1319867

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[PMID]: 28098860 [Au] Autor: Winship A; Van Sinderen M; Heffernan-Marks A; Dimitriadis E [Ad] Endereço: Centre for Reproductive Health, The Hudson Institute of Medical Research, Clayton, 3168 VIC, Australia. [Ti] Título: Chondroitin sulfate proteoglycan protein is stimulated by interleukin 11 and promotes endometrial epithelial cancer cell proliferation and migration. [So] Source: Int J Oncol;50(3):798-804, 2017 Mar. [Is] ISSN: 1791-2423 [Cp] País de publicação: Greece [La] Idioma: eng [Ab] Resumo: Endometrial cancer is the most common gynecological cancer. We identified interleukin 11 (IL11) as a critical mediator of endometrial tumourigenesis and demonstrated that IL11 regulates chondroitin sulfate proteoglycan (CSPG4) in human placental trophoblasts. CSPG4 is a cell membrane protein overexpressed in numerous human cancers, although its role in endometrial cancer has not been investigated. We examined CSPG4 expression and localization in primary human type I endometrioid grade (G) 1-3 tumours by qPCR and immunohistochemistry and determined whether IL11 stimulated CSPG4. IL11 upregulated CSPG4 mRNA in HEC1A (G2-derived endometrial epithelial cancer cell line) cells. IL11 administration to BALB/c nude mice enhanced HEC1A xenograft tumour growth and increased CSPG4 protein in tumours. CSPG4 mRNA was unchanged between human G1-3 endometrial cancer and control tissues. CSPG4 protein levels were elevated in the epithelium of G2 and G3 endometrial cancer and in the tumour-associated stroma of G3 tumour tissues compared to proliferative phase or post-menopausal endometrium. CSPG4 knockdown by siRNA reduced HEC1A proliferation and migration in vitro and reduced gene expression of the key epithelial-to-mesenchymal transition (EMT) regulator SNAIL. Our data suggest that CSPG4 inhibition may impair endometrial cancer progression by reducing cancer cell proliferation, migration and potentially EMT. [Mh] Termos MeSH primário: Proteoglicanas de Sulfatos de Condroitina/metabolismo Neoplasias do Endométrio/patologia Endométrio/patologia Transição Epitelial-Mesenquimal/genética Interleucina-11/metabolismo Proteínas de Membrana/metabolismo [Mh] Termos MeSH secundário: Animais Linhagem Celular Tumoral Movimento Celular/genética Proliferação Celular/genética Proteoglicanas de Sulfatos de Condroitina/genética Endométrio/citologia Feminino Seres Humanos Proteínas de Membrana/genética Camundongos Camundongos Endogâmicos BALB C Camundongos Nus Transplante de Neoplasias Interferência de RNA RNA Mensageiro/biossíntese RNA Interferente Pequeno/genética Fatores de Transcrição da Família Snail/genética Fatores de Transcrição da Família Snail/metabolismo Transplante Heterólogo [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (CSPG4 protein, human); 0 (Chondroitin Sulfate Proteoglycans); 0 (IL11 protein, human); 0 (Interleukin-11); 0 (Membrane Proteins); 0 (RNA, Messenger); 0 (RNA, Small Interfering); 0 (Snail Family Transcription Factors) [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: 170119 [St] Status: MEDLINE [do] DOI: 10.3892/ijo.2017.3848

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[PMID]: 27884519 [Au] Autor: Sano E; Takei T; Ueda T; Tsumoto K [Ad] Endereço: Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, 5-1-5 Kashiwanoha, Kashiwa-shi, Chiba 277-8562, Japan. Electronic address: sano_e@mgs.k.u-tokyo.ac.jp. [Ti] Título: Production and characterization of genetically modified human IL-11 variants. [So] Source: Biochim Biophys Acta;1861(2):205-217, 2017 02. [Is] ISSN: 0006-3002 [Cp] País de publicação: Netherlands [La] Idioma: eng [Ab] Resumo: Interleukin-11 (IL-11) has been expected as a drug on severe thrombocytopenia caused by myelo-suppressive chemotherapy. Whereas, development of IL-11 inhibitor is also expected for a treatment against IL-11 related cancer progression. Here, we will demonstrate the creation of various kinds of genetically modified hIL-11s. Modified vectors were constructed by introducing N- or O-glycosylation site on the region of hIL-11 that does not belong to the core α-helical motif based on the predicted secondary structure. N-terminal (N: between 22 to 23 aa), the first loop (M1:70 to 71 aa), the second loop (M2:114-115 aa), the third loop (M3:160-161 aa) and C-terminal (C: 200- aa) were selected for modification. A large scale production system was established and the characteristics of modified hIL-11s were evaluated. The structure was analyzed by amino acid sequence and composition analysis and CD-spectra. Glycan was assessed by monosaccharide composition analysis. Growth promoting activity and biological stability were analyzed by proliferation of T1165 cells. N-terminal modified proteins were well glycosylated and produced. Growth activity of 3NN with NASNASNAS sequence on N-terminal was about tenfold higher than wild type (WT). Structural and biological stabilities of 3NN were also better than WT and residence time in mouse blood was longer than WT. M1 variants lacked growth activity though they are well glycosylated and secondary structure is very stable. Both of 3NN and OM1 with AAATPAPG on M1 associated with hIL-11R strongly. These results indicate N-terminal and M1 variants will be expected for practical use as potent agonists or antagonists of hIL-11. [Mh] Termos MeSH primário: Interleucina-11/genética Interleucina-11/metabolismo [Mh] Termos MeSH secundário: Sequência de Aminoácidos Animais Linhagem Celular Tumoral Proliferação Celular/genética Glicosilação Seres Humanos Camundongos Polissacarídeos/genética Polissacarídeos/metabolismo Estrutura Secundária de Proteína Homologia de Sequência de Aminoácidos Relação Estrutura-Atividade [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T [Nm] Nome de substância: 0 (IL11 protein, human); 0 (Interleukin-11); 0 (Polysaccharides) [Em] Mês de entrada: 1710 [Cu] Atualização por classe: 171019 [Lr] Data última revisão: 171019 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 161126 [St] Status: MEDLINE

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MEDLINE

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[PMID]: 27872193 [Au] Autor: Nishina T; Deguchi Y; Miura R; Yamazaki S; Shinkai Y; Kojima Y; Okumura K; Kumagai Y; Nakano H [Ad] Endereço: From the Department of Biochemistry, Toho University School of Medicine, 5-21-16 Omori-Nishi, Ota-ku, Tokyo 143-8540. [Ti] Título: Critical Contribution of Nuclear Factor Erythroid 2-related Factor 2 (NRF2) to Electrophile-induced Interleukin-11 Production. [So] Source: J Biol Chem;292(1):205-216, 2017 Jan 06. [Is] ISSN: 1083-351X [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Nuclear factor erythroid 2-related factor 2 (NRF2) is a transcription factor that plays a crucial role in protection of cells from electrophile-induced toxicity through up-regulating phase II detoxifying enzymes and phase III transporters. We previously reported that oxidative stress induces up-regulation of interleukin-11 (IL-11), a member of the IL-6 family that ameliorates acetaminophen-induced liver toxicity. However, a role for IL-11 in protection of cells from electrophile-induced toxicity remains unclear. Here we show that an environmental electrophile, 1,2-naphthoquinone (1,2-NQ), but not 15d-prostaglandin J (PGJ ) or tert-butylhydroxyquinone (tBHQ), induced IL-11 production. Consistent with a crucial role for prolonged ERK activation in H O -induced IL-11 production, 1,2-NQ, but not 15d-PGJ or tBHQ, elicited prolonged ERK activation. Conversely, inhibition of the ERK pathway by a MEK inhibitor completely blocked 1,2-NQ-induced IL-11 production at both protein and mRNA levels, further substantiating an intimate cross-talk between ERK activation and 1,2-NQ-induced IL-11 production. Promoter analysis of the Il11 gene revealed that two AP-1 sites were essential for 1,2-NQ-induced promoter activities. Among various members of the AP-1 family, Fra-1 was up-regulated by 1,2-NQ, and its up-regulation was blocked by a MEK inhibitor. Although NRF2 was not required for H O -induced IL11 up-regulation, NRF2 was essential for 1,2-NQ-induced IL11 up-regulation by increasing Fra-1 proteins possibly through promoting mRNA translation of FOSL1 Finally, intraperitoneal administration of 1,2-NQ induced body weight loss in wild-type mice, which was further exacerbated in Il11ra1 mice compared with Il11ra1 mice. Together, both Fra-1 and NRF2 play crucial roles in IL-11 production that protects cells from 1,2-NQ intestinal toxicity. [Mh] Termos MeSH primário: Interleucina-11/biossíntese Enteropatias/prevenção & controle Fator 2 Relacionado a NF-E2/metabolismo Naftoquinonas/toxicidade Peritonite/prevenção & controle Prostaglandina D2/análogos & derivados [Mh] Termos MeSH secundário: Animais Antineoplásicos/toxicidade Células Cultivadas Regulação da Expressão Gênica/efeitos dos fármacos Células HEK293 Células Hep G2 Seres Humanos Peróxido de Hidrogênio/farmacologia Subunidade alfa de Receptor de Interleucina-11/fisiologia Enteropatias/induzido quimicamente Enteropatias/metabolismo Enteropatias/patologia Sistema de Sinalização das MAP Quinases Camundongos Camundongos Endogâmicos C57BL Camundongos Knockout Fator 2 Relacionado a NF-E2/genética Oxidantes/farmacologia Estresse Oxidativo/efeitos dos fármacos Peritonite/induzido quimicamente Peritonite/metabolismo Peritonite/patologia Prostaglandina D2/toxicidade Espécies Reativas de Oxigênio/metabolismo [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (15-deoxyprostaglandin J2); 0 (Antineoplastic Agents); 0 (Il11ra1 protein, mouse); 0 (Interleukin-11); 0 (Interleukin-11 Receptor alpha Subunit); 0 (NF-E2-Related Factor 2); 0 (Naphthoquinones); 0 (Oxidants); 0 (Reactive Oxygen Species); 60203-57-8 (9-deoxy-delta-9-prostaglandin D2); 804K62F61Q (1,2-naphthoquinone); BBX060AN9V (Hydrogen Peroxide); RXY07S6CZ2 (Prostaglandin D2) [Em] Mês de entrada: 1706 [Cu] Atualização por classe: 170602 [Lr] Data última revisão: 170602 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 161123 [St] Status: MEDLINE [do] DOI: 10.1074/jbc.M116.744755

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[PMID]: 26726132 [Au] Autor: Kazakov AS; Sokolov AS; Vologzhannikova AA; Permyakova ME; Khorn PA; Ismailov RG; Denessiouk KA; Denesyuk AI; Rastrygina VA; Baksheeva VE; Zernii EY; Zinchenko DV; Glazatov VV; Uversky VN; Mirzabekov TA; Permyakov EA; Permyakov SE [Ad] Endereço: a Institute for Biological Instrumentation of the Russian Academy of Sciences , Institutskaya str., 7, Pushchino, Moscow Region 142290 , Russia. [Ti] Título: Interleukin-11 binds specific EF-hand proteins via their conserved structural motifs. [So] Source: J Biomol Struct Dyn;35(1):78-91, 2017 Jan. [Is] ISSN: 1538-0254 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: Interleukin-11 (IL-11) is a hematopoietic cytokine engaged in numerous biological processes and validated as a target for treatment of various cancers. IL-11 contains intrinsically disordered regions that might recognize multiple targets. Recently we found that aside from IL-11RA and gp130 receptors, IL-11 interacts with calcium sensor protein S100P. Strict calcium dependence of this interaction suggests a possibility of IL-11 interaction with other calcium sensor proteins. Here we probed specificity of IL-11 to calcium-binding proteins of various types: calcium sensors of the EF-hand family (calmodulin, S100B and neuronal calcium sensors: recoverin, NCS-1, GCAP-1, GCAP-2), calcium buffers of the EF-hand family (S100G, oncomodulin), and a non-EF-hand calcium buffer (α-lactalbumin). A specific subset of the calcium sensor proteins (calmodulin, S100B, NCS-1, GCAP-1/2) exhibits metal-dependent binding of IL-11 with dissociation constants of 1-19 µM. These proteins share several amino acid residues belonging to conservative structural motifs of the EF-hand proteins, 'black' and 'gray' clusters. Replacements of the respective S100P residues by alanine drastically decrease its affinity to IL-11, suggesting their involvement into the association process. Secondary structure and accessibility of the hinge region of the EF-hand proteins studied are predicted to control specificity and selectivity of their binding to IL-11. The IL-11 interaction with the EF-hand proteins is expected to occur under numerous pathological conditions, accompanied by disintegration of plasma membrane and efflux of cellular components into the extracellular milieu. [Mh] Termos MeSH primário: Proteínas de Transporte/química Sequência Conservada Motivos EF Hand Interleucina-11/química Modelos Moleculares Domínios e Motivos de Interação entre Proteínas [Mh] Termos MeSH secundário: Animais Proteínas de Ligação ao Cálcio/química Proteínas de Ligação ao Cálcio/metabolismo Seres Humanos Interleucina-11/metabolismo Metais/química Proteínas de Neoplasias/química Proteínas de Neoplasias/metabolismo Ligação Proteica Domínios Proteicos [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Calcium-Binding Proteins); 0 (Carrier Proteins); 0 (Interleukin-11); 0 (Metals); 0 (Neoplasm Proteins); 0 (S100P protein, human) [Em] Mês de entrada: 1703 [Cu] Atualização por classe: 170817 [Lr] Data última revisão: 170817 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 160105 [St] Status: MEDLINE [do] DOI: 10.1080/07391102.2015.1132392

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