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Pesquisa : D02.455.526.728 [Categoria DeCS]
Referências encontradas : 556 [refinar]
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[PMID]:28922425
[Au] Autor:Shrestha P; Davis DA; Veeranna RP; Carey RF; Viollet C; Yarchoan R
[Ad] Endereço:HIV and AIDS Malignancy Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, United States of America.
[Ti] Título:Hypoxia-inducible factor-1 alpha as a therapeutic target for primary effusion lymphoma.
[So] Source:PLoS Pathog;13(9):e1006628, 2017 Sep.
[Is] ISSN:1553-7374
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Primary effusion lymphoma (PEL) is an aggressive B-cell lymphoma with poor prognosis caused by Kaposi's sarcoma-associated herpesvirus (KSHV). Previous studies have revealed that HIF-1α, which mediates much of the cellular response to hypoxia, plays an important role in life cycle of KSHV. KSHV infection promotes HIF-1α activity, and several KSHV genes are in turn activated by HIF-1α. In this study, we investigated the effects of knocking down HIF-1α in PELs. We observed that HIF-1α knockdown in each of two PEL lines leads to a reduction in both aerobic and anaerobic glycolysis as well as lipid biogenesis, indicating that HIF-1α is necessary for maintaining a metabolic state optimal for growth of PEL. We also found that HIF-1α suppression leads to a substantial reduction in activation of lytic KSHV genes, not only in hypoxia but also in normoxia. Moreover, HIF-1α knockdown led to a decrease in the expression of various KSHV latent genes, including LANA, vCyclin, kaposin, and miRNAs, under both normoxic and hypoxic conditions. These observations provide evidence that HIF-1α plays an important role in PEL even in normoxia. Consistent with these findings, we observed a significant inhibition of growth of PEL in normoxia upon HIF-1α suppression achieved by either HIF-1α knockdown or treatment with PX-478, a small molecule inhibitor of HIF-1α. These results offer further evidence that HIF-1α plays a critical role in the pathogenesis of PEL, and that inhibition of HIF-1α can be a potential therapeutic strategy in this disease.
[Mh] Termos MeSH primário: Antígenos Virais/genética
Regulação Viral da Expressão Gênica/efeitos dos fármacos
Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo
Linfoma de Efusão Primária/virologia
Sarcoma de Kaposi/virologia
[Mh] Termos MeSH secundário: Antígenos Virais/imunologia
Hipóxia Celular
Seres Humanos
Subunidade alfa do Fator 1 Induzível por Hipóxia/genética
Linfoma de Efusão Primária/tratamento farmacológico
MicroRNAs/metabolismo
Compostos de Mostarda/farmacologia
Fenilpropionatos/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (2-amino-3-(4'-N,N-bis(2-chloroethyl)amino)phenylpropionic acid N-oxide); 0 (Antigens, Viral); 0 (Hypoxia-Inducible Factor 1, alpha Subunit); 0 (MicroRNAs); 0 (Mustard Compounds); 0 (Phenylpropionates)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171026
[Lr] Data última revisão:
171026
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170919
[St] Status:MEDLINE
[do] DOI:10.1371/journal.ppat.1006628


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[PMID]:28052321
[Au] Autor:Zhang F; Hao M; Jin H; Yao Z; Lian N; Wu L; Shao J; Chen A; Zheng S
[Ad] Endereço:Department of Pharmacology, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China.
[Ti] Título:Canonical hedgehog signalling regulates hepatic stellate cell-mediated angiogenesis in liver fibrosis.
[So] Source:Br J Pharmacol;174(5):409-423, 2017 Mar.
[Is] ISSN:1476-5381
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND AND PURPOSE: Hepatic stellate cells (HSCs) are liver-specific pericytes regulating angiogenesis during liver fibrosis. We aimed to elucidate the mechanisms by which hedgehog signalling regulated HSC angiogenic properties and to validate the therapeutic implications. EXPERIMENTAL APPROACH: Rats and mice were treated with carbon tetrachloride for in vivo evaluation of hepatic angiogenesis and fibrotic injury. Diversified molecular approaches including real-time PCR, Western blot, luciferase reporter assay, chromatin immunoprecipitation, electrophoretic mobility shift assay and co-immunoprecipitation were used to investigate the underlying mechanisms in vitro. KEY RESULTS: Angiogenesis was concomitant with up-regulation of Smoothened (SMO) and hypoxia inducible factor-1α (HIF-1α) in rat fibrotic liver. The SMO inhibitor cyclopamine and Gli1 inhibitor GANT-58 reduced expression of VEGF and angiopoietin 1 in HSCs and suppressed HSC tubulogenesis capacity. HIF-1α inhibitor PX-478 suppressed HSC angiogenic behaviour, and inhibition of hedgehog decreased HIF-1α expression. Furthermore, heat shock protein 90 (HSP90) was characterized as a direct target gene of canonical hedgehog signalling in HSCs. HSP90 inhibitor 17-AAG reduced HSP90 binding to HIF-1α, down-regulated HIF-1α protein abundance and decreased HIF-1α binding to DNA. 17-AAG also abolished 1-stearoyl-2-arachidonoyl-sn-glycerol (SAG) (a SMO agonist)-enhanced HSC angiogenic properties. Finally, the natural compound ligustrazine was found to inhibit canonical hedgehog signalling leading to suppressed angiogenic properties of HSCs in vitro and ameliorated liver fibrosis and sinusoidal angiogenesis in mice. CONCLUSION AND IMPLICATIONS: We have provided evidence that the canonical hedgehog pathway controlled HSC-mediated liver angiogenesis. Selective inhibition of HSC hedgehog signalling could be a promising therapeutic approach for hepatic fibrosis.
[Mh] Termos MeSH primário: Proteínas Hedgehog/metabolismo
Células Estreladas do Fígado/metabolismo
Cirrose Hepática/fisiopatologia
Neovascularização Patológica/patologia
[Mh] Termos MeSH secundário: Animais
Benzoquinonas/farmacologia
Tetracloreto de Carbono/toxicidade
Modelos Animais de Doenças
Proteínas de Choque Térmico HSP90/metabolismo
Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo
Lactamas Macrocíclicas/farmacologia
Cirrose Hepática/tratamento farmacológico
Masculino
Camundongos
Camundongos Endogâmicos ICR
Compostos de Mostarda/farmacologia
Neovascularização Patológica/tratamento farmacológico
Fenilpropionatos/farmacologia
Pirazinas/farmacologia
Ratos
Ratos Sprague-Dawley
Transdução de Sinais/efeitos dos fármacos
Receptor Smoothened/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (2-amino-3-(4'-N,N-bis(2-chloroethyl)amino)phenylpropionic acid N-oxide); 0 (Benzoquinones); 0 (HSP90 Heat-Shock Proteins); 0 (Hedgehog Proteins); 0 (Hypoxia-Inducible Factor 1, alpha Subunit); 0 (Lactams, Macrocyclic); 0 (Mustard Compounds); 0 (Phenylpropionates); 0 (Pyrazines); 0 (Smo protein, mouse); 0 (Smo protein, rat); 0 (Smoothened Receptor); 4GY0AVT3L4 (tanespimycin); CL2T97X0V0 (Carbon Tetrachloride); V80F4IA5XG (tetramethylpyrazine)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170728
[Lr] Data última revisão:
170728
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170105
[St] Status:MEDLINE
[do] DOI:10.1111/bph.13701


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[PMID]:27497816
[Au] Autor:Kheshtchin N; Arab S; Ajami M; Mirzaei R; Ashourpour M; Mousavi N; Khosravianfar N; Jadidi-Niaragh F; Namdar A; Noorbakhsh F; Hadjati J
[Ad] Endereço:Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
[Ti] Título:Inhibition of HIF-1α enhances anti-tumor effects of dendritic cell-based vaccination in a mouse model of breast cancer.
[So] Source:Cancer Immunol Immunother;65(10):1159-67, 2016 Oct.
[Is] ISSN:1432-0851
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:Considerable evidence shows that the tumor microenvironment is an active participant in preventing immunosurveillance and limiting the efficacy of anticancer therapies. Hypoxia is a prominent characteristic of the solid tumor microenvironment. The transcription factor hypoxia-inducible factor-1α (HIF-1α) is an important mediator of hypoxic response of tumor cells that modulates the expression of specific genes involved in tumor immunosuppression. Using a 4T1 breast cancer model, we show that in vivo administration of PX-478, an inhibitor of oxygen-sensitive HIF-1α, led to reduced expression of Foxp3 and VEGF transcript and/or protein, molecules that are directly controlled by HIF-1. When combined with dendritic cell (DC)-based vaccination, HIF-1α inhibition resulted in an augmented cytotoxic T lymphocyte effector function, improved proliferation status of T cells, increased production of inflammatory cytokine IFN-γ, as well as reduced regulatory function of T cells in association with slower tumor growth. Taken together, our findings indicate that the use of HIF-1α inhibition provides an immune adjuvant activity, thereby improves the efficacy of tumor antigen-based DC vaccine.
[Mh] Termos MeSH primário: Antineoplásicos/uso terapêutico
Neoplasias da Mama/terapia
Vacinas Anticâncer/imunologia
Células Dendríticas/imunologia
Subunidade alfa do Fator 1 Induzível por Hipóxia/antagonistas & inibidores
Imunoterapia Adotiva/métodos
Neoplasias Mamárias Animais/terapia
Compostos de Mostarda/uso terapêutico
Fenilpropionatos/uso terapêutico
Linfócitos T Citotóxicos/imunologia
[Mh] Termos MeSH secundário: Animais
Proliferação Celular
Células Cultivadas
Terapia Combinada
Células Dendríticas/transplante
Feminino
Fatores de Transcrição Forkhead/genética
Fatores de Transcrição Forkhead/metabolismo
Seres Humanos
Interferon gama/metabolismo
Camundongos
Camundongos Endogâmicos BALB C
Carga Tumoral
Fator A de Crescimento do Endotélio Vascular/genética
Fator A de Crescimento do Endotélio Vascular/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (2-amino-3-(4'-N,N-bis(2-chloroethyl)amino)phenylpropionic acid N-oxide); 0 (Antineoplastic Agents); 0 (Cancer Vaccines); 0 (Forkhead Transcription Factors); 0 (Foxp3 protein, mouse); 0 (Hif1a protein, mouse); 0 (Hypoxia-Inducible Factor 1, alpha Subunit); 0 (Mustard Compounds); 0 (Phenylpropionates); 0 (Vascular Endothelial Growth Factor A); 82115-62-6 (Interferon-gamma)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170803
[Lr] Data última revisão:
170803
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160808
[St] Status:MEDLINE
[do] DOI:10.1007/s00262-016-1879-5


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[PMID]:27212442
[Au] Autor:Lang M; Wang X; Wang H; Dong J; Lan C; Hao J; Huang C; Li X; Yu M; Yang Y; Yang S; Ren H
[Ad] Endereço:National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.
[Ti] Título:Arsenic trioxide plus PX-478 achieves effective treatment in pancreatic ductal adenocarcinoma.
[So] Source:Cancer Lett;378(2):87-96, 2016 08 10.
[Is] ISSN:1872-7980
[Cp] País de publicação:Ireland
[La] Idioma:eng
[Ab] Resumo:Arsenic trioxide (ATO) has been selected as a promising treatment not only in leukemia but also in solid tumors. Previous studies showed that the cytotoxicity of ATO mainly depends on the induction of reactive oxygen species. However, ATO has only achieved a modest effect in pancreatic ductal adenocarcinoma, suggesting that the existing radical scavenging proteins, such as hypoxia inducible factor-1, attenuate the effect. The goal of this study is to investigate the effect of combination treatment of ATO plus PX-478 (hypoxia-inducible factor-1 inhibitor) and its underlying mechanism. Here, we showed that PX-478 robustly strengthened the anti-growth and pro-apoptosis effect of ATO on Panc-1 and BxPC-3 pancreatic cancer cells in vitro. Meanwhile, in vivo mouse xenograft models also showed the synergistic effect of ATO plus PX-478 compared with any single agent. Further studies showed that the anti-tumor effect of ATO plus PX-478 was derived from the reactive oxygen species-induced apoptosis. We next confirmed that Hypoxia-inducible factor-1 cleared reactive oxygen species by its downstream target, forkhead box O transcription factors, and this effect may justify the strategy of ATO plus PX-478 in the treatment of pancreatic cancer.
[Mh] Termos MeSH primário: Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia
Arsenicais/farmacologia
Carcinoma Ductal Pancreático/tratamento farmacológico
Compostos de Mostarda/farmacologia
Óxidos/farmacologia
Neoplasias Pancreáticas/tratamento farmacológico
Fenilpropionatos/farmacologia
[Mh] Termos MeSH secundário: Animais
Apoptose/efeitos dos fármacos
Sítios de Ligação
Carcinoma Ductal Pancreático/genética
Carcinoma Ductal Pancreático/metabolismo
Carcinoma Ductal Pancreático/patologia
Linhagem Celular
Proliferação Celular/efeitos dos fármacos
Relação Dose-Resposta a Droga
Sinergismo Farmacológico
Proteína Forkhead Box O1/genética
Proteína Forkhead Box O1/metabolismo
Regulação Neoplásica da Expressão Gênica
Proteínas de Choque Térmico/genética
Proteínas de Choque Térmico/metabolismo
Seres Humanos
Subunidade alfa do Fator 1 Induzível por Hipóxia/antagonistas & inibidores
Subunidade alfa do Fator 1 Induzível por Hipóxia/genética
Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo
Camundongos Nus
Estresse Oxidativo/efeitos dos fármacos
Neoplasias Pancreáticas/genética
Neoplasias Pancreáticas/metabolismo
Neoplasias Pancreáticas/patologia
Regiões Promotoras Genéticas
Interferência de RNA
Espécies Reativas de Oxigênio/metabolismo
Transdução de Sinais/efeitos dos fármacos
Fatores de Tempo
Ativação Transcricional
Transfecção
Ensaios Antitumorais Modelo de Xenoenxerto
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (2-amino-3-(4'-N,N-bis(2-chloroethyl)amino)phenylpropionic acid N-oxide); 0 (Arsenicals); 0 (FOXO1 protein, human); 0 (Forkhead Box Protein O1); 0 (HIF1A protein, human); 0 (Heat-Shock Proteins); 0 (Hypoxia-Inducible Factor 1, alpha Subunit); 0 (Mustard Compounds); 0 (Oxides); 0 (Phenylpropionates); 0 (Reactive Oxygen Species); 0 (SESN3 protein, human); S7V92P67HO (arsenic trioxide)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:171028
[Lr] Data última revisão:
171028
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160524
[St] Status:MEDLINE


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[PMID]:27076683
[Au] Autor:Bakirtzi K; Law IK; Xue X; Iliopoulos D; Shah YM; Pothoulakis C
[Ad] Endereço:Inflammatory Bowel Disease Center, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095;
[Ti] Título:Neurotensin Promotes the Development of Colitis and Intestinal Angiogenesis via Hif-1α-miR-210 Signaling.
[So] Source:J Immunol;196(10):4311-21, 2016 05 15.
[Is] ISSN:1550-6606
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Neurotensin (NT) via its receptor 1 (NTR1) modulates the development of colitis, decreases HIF-1α/PHD2 interaction, stabilizes and increases HIF-1α transcriptional activity, and promotes intestinal angiogenesis. HIF-1α induces miR-210 expression, whereas miR-210 is strongly upregulated in response to NT in NCM460 human colonic epithelial cells overexpressing NTR1 (NCM460-NTR1). In this study, we examined whether NT activates a NTR1-HIF-1α-miR-210 cascade using in vitro (NCM460-NTR1 cells) and in vivo (transgenic mice overexpressing [HIF-1α-OE] or lacking HIF-1α [HIF-1α-knockout (KO)] in intestinal epithelial cells and mice lacking NTR1 [NTR1-KO]) models. Pretreatment of NCM460-NTR1 cells with the HIF-1α inhibitor PX-478 or silencing of HIF-1α (small interfering HIF-1α) attenuated miR-210 expression in response to NT. Intracolonic 2,4,6-trinitrobenzenesulfonic acid (TNBS) administration (2-d model) increased colonic miR-210 expression that was significantly reduced in NTR1-KO, HIF-1α-KO mice, and wild-type mice pretreated intracolonically with locked nucleic acid anti-miR-210. In contrast, HIF-1α-OE mice showed increased miR-210 expression at baseline that was further increased following TNBS administration. HIF-1α-OE mice had also exacerbated TNBS-induced neovascularization compared with TNBS-exposed wild-type mice. TNBS-induced neovascularization was attenuated in HIF-1α-KO mice, or mice pretreated intracolonically with anti-miR-210. Intracolonic anti-miR-210 also reduced colitis in response to TNBS (2 d). Importantly, miR-210 expression was increased in tissue samples from ulcerative colitis patients. We conclude that NT exerts its proinflammatory and proangiogenic effects during acute colitis via a NTR1-prolyl hydroxylase 2/HIF-1α-miR-210 signaling pathway. Our results also demonstrate that miR-210 plays a proinflammatory role in the development of colitis.
[Mh] Termos MeSH primário: Colite Ulcerativa/metabolismo
Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo
MicroRNAs/metabolismo
Neovascularização Patológica/metabolismo
Neurotensina/metabolismo
[Mh] Termos MeSH secundário: Animais
Linhagem Celular Tumoral
Colo/irrigação sanguínea
Colo/patologia
Células Epiteliais/metabolismo
Seres Humanos
Mucosa Intestinal/metabolismo
Masculino
Camundongos
Camundongos Endogâmicos C57BL
Camundongos Knockout
Compostos de Mostarda/administração & dosagem
NF-kappa B/metabolismo
Fenilpropionatos/administração & dosagem
Receptores de Neurotensina/genética
Receptores de Neurotensina/metabolismo
Transdução de Sinais
Ácido Trinitrobenzenossulfônico
Regulação para Cima/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (2-amino-3-(4'-N,N-bis(2-chloroethyl)amino)phenylpropionic acid N-oxide); 0 (HIF1A protein, human); 0 (Hypoxia-Inducible Factor 1, alpha Subunit); 0 (MIRN210 microRNA, human); 0 (MicroRNAs); 0 (Mustard Compounds); 0 (NF-kappa B); 0 (Phenylpropionates); 0 (Receptors, Neurotensin); 0 (neurotensin type 1 receptor); 39379-15-2 (Neurotensin); 8T3HQG2ZC4 (Trinitrobenzenesulfonic Acid)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:171109
[Lr] Data última revisão:
171109
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:160415
[St] Status:MEDLINE
[do] DOI:10.4049/jimmunol.1501443


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[PMID]:26721400
[Au] Autor:Agarwal S; Loder S; Brownley C; Cholok D; Mangiavini L; Li J; Breuler C; Sung HH; Li S; Ranganathan K; Peterson J; Tompkins R; Herndon D; Xiao W; Jumlongras D; Olsen BR; Davis TA; Mishina Y; Schipani E; Levi B
[Ad] Endereço:Department of Surgery, University of Michigan, Ann Arbor, MI 48109;
[Ti] Título:Inhibition of Hif1α prevents both trauma-induced and genetic heterotopic ossification.
[So] Source:Proc Natl Acad Sci U S A;113(3):E338-47, 2016 Jan 19.
[Is] ISSN:1091-6490
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Pathologic extraskeletal bone formation, or heterotopic ossification (HO), occurs following mechanical trauma, burns, orthopedic operations, and in patients with hyperactivating mutations of the type I bone morphogenetic protein receptor ACVR1 (Activin type 1 receptor). Extraskeletal bone forms through an endochondral process with a cartilage intermediary prompting the hypothesis that hypoxic signaling present during cartilage formation drives HO development and that HO precursor cells derive from a mesenchymal lineage as defined by Paired related homeobox 1 (Prx). Here we demonstrate that Hypoxia inducible factor-1α (Hif1α), a key mediator of cellular adaptation to hypoxia, is highly expressed and active in three separate mouse models: trauma-induced, genetic, and a hybrid model of genetic and trauma-induced HO. In each of these models, Hif1α expression coincides with the expression of master transcription factor of cartilage, Sox9 [(sex determining region Y)-box 9]. Pharmacologic inhibition of Hif1α using PX-478 or rapamycin significantly decreased or inhibited extraskeletal bone formation. Importantly, de novo soft-tissue HO was eliminated or significantly diminished in treated mice. Lineage-tracing mice demonstrate that cells forming HO belong to the Prx lineage. Burn/tenotomy performed in lineage-specific Hif1α knockout mice (Prx-Cre/Hif1α(fl:fl)) resulted in substantially decreased HO, and again lack of de novo soft-tissue HO. Genetic loss of Hif1α in mesenchymal cells marked by Prx-cre prevents the formation of the mesenchymal condensations as shown by routine histology and immunostaining for Sox9 and PDGFRα. Pharmacologic inhibition of Hif1α had a similar effect on mesenchymal condensation development. Our findings indicate that Hif1α represents a promising target to prevent and treat pathologic extraskeletal bone.
[Mh] Termos MeSH primário: Subunidade alfa do Fator 1 Induzível por Hipóxia/antagonistas & inibidores
Ossificação Heterotópica/genética
Ossificação Heterotópica/prevenção & controle
Ferimentos e Lesões/complicações
[Mh] Termos MeSH secundário: Receptores de Ativinas Tipo I/metabolismo
Tecido Adiposo/efeitos dos fármacos
Tecido Adiposo/metabolismo
Animais
Queimaduras/complicações
Queimaduras/genética
Condrogênese/efeitos dos fármacos
Condrogênese/genética
Modelos Animais de Doenças
Redes Reguladoras de Genes/efeitos dos fármacos
Seres Humanos
Subunidade alfa do Fator 1 Induzível por Hipóxia/genética
Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo
Integrases/metabolismo
Medições Luminescentes
Células Mesenquimais Estromais/efeitos dos fármacos
Camundongos Knockout
Modelos Biológicos
Compostos de Mostarda/farmacologia
Ossificação Heterotópica/diagnóstico por imagem
Ossificação Heterotópica/tratamento farmacológico
Fenilpropionatos/farmacologia
RNA Mensageiro/genética
RNA Mensageiro/metabolismo
Receptor alfa de Fator de Crescimento Derivado de Plaquetas/metabolismo
Fatores de Transcrição SOX9/metabolismo
Transdução de Sinais/efeitos dos fármacos
Sirolimo/farmacologia
Tendões/efeitos dos fármacos
Tendões/patologia
Tendões/cirurgia
Tenotomia
Regulação para Cima/efeitos dos fármacos
Cicatrização/efeitos dos fármacos
Ferimentos e Lesões/patologia
Microtomografia por Raio-X
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T; RESEARCH SUPPORT, U.S. GOV'T, NON-P.H.S.
[Nm] Nome de substância:
0 (2-amino-3-(4'-N,N-bis(2-chloroethyl)amino)phenylpropionic acid N-oxide); 0 (Hypoxia-Inducible Factor 1, alpha Subunit); 0 (Mustard Compounds); 0 (Phenylpropionates); 0 (RNA, Messenger); 0 (SOX9 Transcription Factor); EC 2.7.10.1 (Receptor, Platelet-Derived Growth Factor alpha); EC 2.7.11.30 (Activin Receptors, Type I); EC 2.7.7.- (Cre recombinase); EC 2.7.7.- (Integrases); W36ZG6FT64 (Sirolimus)
[Em] Mês de entrada:1606
[Cu] Atualização por classe:170220
[Lr] Data última revisão:
170220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160102
[St] Status:MEDLINE
[do] DOI:10.1073/pnas.1515397113


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[PMID]:26640316
[Au] Autor:Li YN; Hu JA; Wang HM
[Ad] Endereço:Department of Pathology, Stomatology Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310006, China.
[Ti] Título:Inhibition of HIF-1α Affects Autophagy Mediated Glycosylation in Oral Squamous Cell Carcinoma Cells.
[So] Source:Dis Markers;2015:239479, 2015.
[Is] ISSN:1875-8630
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Purpose. To validate the function of autophagy with the regulation of hypoxia inhibitor-induced glycosylation in oral squamous cell carcinoma cell. Methods. Human Tca8113 cell line was used to detect autophagy and glycosylation related protein expression by western blotting and immunofluorescence with HIF-1α inhibitor. Short interfering RNA (siRNA) transfection blocked human ATG12 and ATG1. Results. HIF-1α inhibitor PX-478 reduced the amount of LC3-II and LC3-I in Tca8113 cells. PX-478 decreased the expression of O-GlcNAc and OGT and increased OGA expression. The tendency of O-GlcNAc showed a similar pattern to OGT. PX-478 gradually decreased OGT expression in Tca8113 cells. Protein level of O-GlcNAc and OGT increased in ATG12 and ATG1 depletion. The expression of OGT decreased at first and then rose slowly with the treatment of Atg12 and Atg1 siRNA and PX-478 fluctuant. Autophagy affected the stability of OGT when HIF-1α signaling was blocked. Conclusions. Autophagy reduced by hypoxic stress inhibited. HIF-1α inhibitor decreased glycosylation. OGT became unstable in the absence of autophagy when HIF-1α signaling was blocked.
[Mh] Termos MeSH primário: Autofagia
Carcinoma de Células Escamosas/metabolismo
Subunidade alfa do Fator 1 Induzível por Hipóxia/antagonistas & inibidores
Neoplasias Bucais/metabolismo
Processamento de Proteína Pós-Traducional
[Mh] Termos MeSH secundário: Proteína 12 Relacionada à Autofagia
Proteína Homóloga à Proteína-1 Relacionada à Autofagia
Linhagem Celular Tumoral
Inibidores Enzimáticos/farmacologia
Glicosilação
Seres Humanos
Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo
Peptídeos e Proteínas de Sinalização Intracelular/genética
Peptídeos e Proteínas de Sinalização Intracelular/metabolismo
Proteínas Associadas aos Microtúbulos/genética
Proteínas Associadas aos Microtúbulos/metabolismo
Compostos de Mostarda/farmacologia
N-Acetilglucosaminiltransferases/metabolismo
Fenilpropionatos/farmacologia
Proteínas Serina-Treonina Quinases/genética
Proteínas Serina-Treonina Quinases/metabolismo
Proteínas Modificadoras Pequenas Relacionadas à Ubiquitina/genética
Proteínas Modificadoras Pequenas Relacionadas à Ubiquitina/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (2-amino-3-(4'-N,N-bis(2-chloroethyl)amino)phenylpropionic acid N-oxide); 0 (ATG12 protein, human); 0 (Autophagy-Related Protein 12); 0 (Enzyme Inhibitors); 0 (HIF1A protein, human); 0 (Hypoxia-Inducible Factor 1, alpha Subunit); 0 (Intracellular Signaling Peptides and Proteins); 0 (Microtubule-Associated Proteins); 0 (Mustard Compounds); 0 (Phenylpropionates); 0 (Small Ubiquitin-Related Modifier Proteins); 0 (light chain 3, human); EC 2.4.1.- (N-Acetylglucosaminyltransferases); EC 2.7.11.1 (Autophagy-Related Protein-1 Homolog); EC 2.7.11.1 (Protein-Serine-Threonine Kinases); EC 2.7.11.1 (ULK1 protein, human)
[Em] Mês de entrada:1609
[Cu] Atualização por classe:161126
[Lr] Data última revisão:
161126
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:151208
[St] Status:MEDLINE
[do] DOI:10.1155/2015/239479


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[PMID]:25550470
[Au] Autor:Flannigan KL; Agbor TA; Motta JP; Ferraz JG; Wang R; Buret AG; Wallace JL
[Ad] Endereço:*Department of Medicine, McMaster University, Hamilton, Ontario, Canada; Departments of Biological Sciences, Medicine, and Physiology & Pharmacology, University of Calgary, Calgary, Alberta, Canada; and Department of Biology, Lakehead University, Thunder Bay, Ontario, Canada.
[Ti] Título:Proresolution effects of hydrogen sulfide during colitis are mediated through hypoxia-inducible factor-1α.
[So] Source:FASEB J;29(4):1591-602, 2015 Apr.
[Is] ISSN:1530-6860
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:During a course of colitis, production of the gaseous mediator hydrogen sulfide (H2S) is markedly up-regulated at sites of mucosal damage and contributes significantly to healing and resolution of inflammation. The signaling mechanisms through which H2S promotes resolution of colitis are unknown. We hypothesized that the beneficial effects of H2S in experimental colitis are mediated via stabilization of hypoxia-inducible factor (HIF)-1α. The hapten dinitrobenzene sulfonic acid was used to induce colitis in rats and mice. This resulted in an elevated expression of the H2S-producing enzyme, cystathionine γ-lyase (CSE), and HIF-1α at sites of mucosal ulceration, and the expression of these 2 enzymes followed a similar pattern throughout the course of colitis. This represented a functionally important relationship because the loss of CSE-derived H2S production led to decreased HIF-1α stabilization and exacerbation of colitis. Furthermore, application of an H2S-releasing molecule, diallyl disulfide (DADS), stabilized colonic HIF-1α expression, up-regulated hypoxia-responsive genes, and reduced the severity of disease during peak inflammation. Importantly, the ability of DADS to promote the resolution of colitis was abolished when coadministered with an inhibitor of HIF-1α in vivo (PX-478). DADS was also able to maintain HIF-1α expression at a later point in colitis, when HIF-1α levels would have normally returned to control levels, and to enhance resolution. Finally, we found that HIF-1α stabilization inhibited colonic H2S production and may represent a negative feedback mechanism to prevent prolonged HIF-1α stabilization. Our findings demonstrate an important link between H2S and HIF-1α in the resolution of inflammation and injury during colitis and provide mechanistic insights into the therapeutic value of H2S donors.
[Mh] Termos MeSH primário: Colite/metabolismo
Sulfeto de Hidrogênio/metabolismo
Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo
[Mh] Termos MeSH secundário: Compostos Alílicos/farmacologia
Animais
Benzenossulfonatos/toxicidade
Colite/tratamento farmacológico
Colite/patologia
Cistationina gama-Liase/antagonistas & inibidores
Cistationina gama-Liase/metabolismo
Modelos Animais de Doenças
Dissulfetos/farmacologia
Expressão Gênica
Células HT29
Seres Humanos
Subunidade alfa do Fator 1 Induzível por Hipóxia/antagonistas & inibidores
Masculino
Camundongos
Camundongos Endogâmicos C57BL
Compostos de Mostarda/farmacologia
Fenilpropionatos/farmacologia
Estabilidade Proteica
Ratos
Ratos Wistar
Cicatrização/efeitos dos fármacos
Cicatrização/fisiologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (2-amino-3-(4'-N,N-bis(2-chloroethyl)amino)phenylpropionic acid N-oxide); 0 (Allyl Compounds); 0 (Benzenesulfonates); 0 (Disulfides); 0 (Hypoxia-Inducible Factor 1, alpha Subunit); 0 (Mustard Compounds); 0 (Phenylpropionates); 12379-41-8 (dinitrobenzenesulfonic acid); 5HI47O6OA7 (diallyl disulfide); EC 4.4.1.1 (Cystathionine gamma-Lyase); YY9FVM7NSN (Hydrogen Sulfide)
[Em] Mês de entrada:1506
[Cu] Atualização por classe:161125
[Lr] Data última revisão:
161125
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150101
[St] Status:MEDLINE
[do] DOI:10.1096/fj.14-266015


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[PMID]:25544770
[Au] Autor:Zhao T; Ren H; Jia L; Chen J; Xin W; Yan F; Li J; Wang X; Gao S; Qian D; Huang C; Hao J
[Ad] Endereço:Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Department of Pancreatic Cancer, Tianjin, China.
[Ti] Título:Inhibition of HIF-1α by PX-478 enhances the anti-tumor effect of gemcitabine by inducing immunogenic cell death in pancreatic ductal adenocarcinoma.
[So] Source:Oncotarget;6(4):2250-62, 2015 Feb 10.
[Is] ISSN:1949-2553
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Pancreatic ductal adenocarcinoma (PDAC) is the worst prognoses among all the malignancies. Now, gemcitabine (Gem) is the first line chemotherapeutic drug for advanced pancreatic cancer. However, Gem is usually ineffective to the PDAC because of high degree of drug resistance. Hypoxia and immune suppressive milieu are the best-described hallmarks of PDAC; therefore, we investigated the impact of hypoxia inducible factor-1 (HIF-1) inhibitor, PX-478, in combination with Gem on the induction of immunogenic cell death (ICD). We verified that combined treatment with Gem/PX-478 significantly enhanced the anti-tumor effect and increased proportion of tumor infiltrating T-lymphocytes in Panc02-bearing immune-competent but not in immune-deficient mice. Vaccination using Panc02 cell line treated with single agent or in combination showed significant anti-tumor effects. Pancreatic cell lines treated with Gem and PX-478 can induce an increase in eIF2α phosphorylation was correlated with down-regulation of HIF-1α and elicited exposure of CRT and release of HMGB1 and ATP. Only co-treated cells induced DC maturation/phagocytosis and IFN-γ secretion by cytotoxic T lymphocytes. Altogether, combined treatment with Gem/PX-478 showed significantly inhibition on tumor growth and anti-tumor immunization. We propose that inhibition HIF-1α elicits Gem-induced immune response and eliminates PDAC cells by inducing ICD.
[Mh] Termos MeSH primário: Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico
Carcinoma Ductal Pancreático/tratamento farmacológico
Desoxicitidina/análogos & derivados
Subunidade alfa do Fator 1 Induzível por Hipóxia/antagonistas & inibidores
Compostos de Mostarda/farmacologia
Neoplasias Pancreáticas/tratamento farmacológico
Fenilpropionatos/farmacologia
[Mh] Termos MeSH secundário: Trifosfato de Adenosina/metabolismo
Animais
Western Blotting
Carcinoma Ductal Pancreático/metabolismo
Carcinoma Ductal Pancreático/patologia
Morte Celular/efeitos dos fármacos
Morte Celular/imunologia
Linhagem Celular Tumoral
Proteínas de Ligação a DNA/metabolismo
Desoxicitidina/administração & dosagem
Desoxicitidina/farmacologia
Sinergismo Farmacológico
Proteína HMGB1/metabolismo
Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo
Imunização
Camundongos Endogâmicos C57BL
Camundongos Nus
Microscopia de Fluorescência
Compostos de Mostarda/administração & dosagem
Neoplasias Pancreáticas/metabolismo
Neoplasias Pancreáticas/patologia
Fenilpropionatos/administração & dosagem
Fosforilação/efeitos dos fármacos
Análise de Sobrevida
Linfócitos T/efeitos dos fármacos
Linfócitos T/imunologia
Linfócitos T/metabolismo
Fatores de Transcrição/metabolismo
Carga Tumoral/efeitos dos fármacos
Carga Tumoral/imunologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (2-amino-3-(4'-N,N-bis(2-chloroethyl)amino)phenylpropionic acid N-oxide); 0 (DNA-Binding Proteins); 0 (Elf2 protein, mouse); 0 (HMGB1 Protein); 0 (Hypoxia-Inducible Factor 1, alpha Subunit); 0 (Mustard Compounds); 0 (Phenylpropionates); 0 (Transcription Factors); 0W860991D6 (Deoxycytidine); 8L70Q75FXE (Adenosine Triphosphate); B76N6SBZ8R (gemcitabine)
[Em] Mês de entrada:1601
[Cu] Atualização por classe:161215
[Lr] Data última revisão:
161215
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:141230
[St] Status:MEDLINE


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[PMID]:25282653
[Au] Autor:Yadav AA; Wu X; Patel D; Yalowich JC; Hasinoff BB
[Ad] Endereço:Faculty of Pharmacy, Apotex Centre, University of Manitoba, 750 McDermot Ave, Winnipeg, Manitoba R3E 0T5, Canada.
[Ti] Título:Structure-based design, synthesis and biological testing of etoposide analog epipodophyllotoxin-N-mustard hybrid compounds designed to covalently bind to topoisomerase II and DNA.
[So] Source:Bioorg Med Chem;22(21):5935-49, 2014 Nov 01.
[Is] ISSN:1464-3391
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Drugs that target DNA topoisomerase II isoforms and alkylate DNA represent two mechanistically distinct and clinically important classes of anticancer drugs. Guided by molecular modeling and docking a series of etoposide analog epipodophyllotoxin-N-mustard hybrid compounds were designed, synthesized and biologically characterized. These hybrids were designed to alkylate nucleophilic protein residues on topoisomerase II and thus produce inactive covalent adducts and to also alkylate DNA. The most potent hybrid had a mean GI(50) in the NCI-60 cell screen 17-fold lower than etoposide. Using a variety of in vitro and cell-based assays all of the hybrids tested were shown to target topoisomerase II. A COMPARE analysis indicated that the hybrids had NCI 60-cell growth inhibition profiles matching both etoposide and the N-mustard compounds from which they were derived. These results supported the conclusion that the hybrids displayed characteristics that were consistent with having targeted both topoisomerase II and DNA.
[Mh] Termos MeSH primário: Antineoplásicos/química
Etoposídeo/análogos & derivados
Compostos de Mostarda/química
Neoplasias/tratamento farmacológico
Podofilotoxina/análogos & derivados
Inibidores da Topoisomerase II/química
[Mh] Termos MeSH secundário: Antineoplásicos/farmacologia
Linhagem Celular Tumoral
Proliferação Celular/efeitos dos fármacos
DNA/genética
Quebras de DNA de Cadeia Dupla/efeitos dos fármacos
DNA Topoisomerases Tipo II/metabolismo
Etoposídeo/farmacologia
Seres Humanos
Leucemia/tratamento farmacológico
Leucemia/enzimologia
Leucemia/genética
Leucemia/patologia
Simulação de Acoplamento Molecular
Compostos de Mostarda/farmacologia
Neoplasias/enzimologia
Neoplasias/genética
Neoplasias/patologia
Podofilotoxina/farmacologia
Inibidores da Topoisomerase II/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Mustard Compounds); 0 (Topoisomerase II Inhibitors); 6PLQ3CP4P3 (Etoposide); 9007-49-2 (DNA); EC 5.99.1.3 (DNA Topoisomerases, Type II); L36H50F353 (Podophyllotoxin)
[Em] Mês de entrada:1507
[Cu] Atualização por classe:161019
[Lr] Data última revisão:
161019
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:141006
[St] Status:MEDLINE



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