Base de dados : MEDLINE
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[PMID]:28752896
[Au] Autor:Chen C; Tang Q; Zhang Y; Dai M; Jiang Y; Wang H; Yu M; Jing W; Tian W
[Ad] Endereço:State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China.
[Ti] Título:Metabolic reprogramming by HIF-1 activation enhances survivability of human adipose-derived stem cells in ischaemic microenvironments.
[So] Source:Cell Prolif;50(5), 2017 Oct.
[Is] ISSN:1365-2184
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:OBJECTIVES: Poor cell survival severely limits the beneficial effect of adipose-derived stem cell (ADSC)-based therapy for disease treatment and tissue regeneration, which might be caused by the attenuated level of hypoxia-inducible factor-1 (HIF-1) in these cells after having been cultured in 21% ambient oxygen in vitro for weeks. In this study, we explored the role of pre-incubation in dimethyloxalylglycine (DMOG, HIF-1 activator) in the survivability of human ADSCs in a simulated ischaemic microenvironment in vitro and in vivo. The underlying mechanism and angiogenesis were also studied. MATERIALS AND METHODS: Survivability of ADSCs was determined in a simulated ischaemic model in vitro and a nude mouse model in vivo. Cell metabolism and angiogenesis were investigated by tube formation assay, flow cytometry, fluorescence staining and real-time polymerase chain reaction (RT-PCR) after DMOG treatment. RESULTS: The results of the experimental groups showed significant enhancement of ADSC survivability in a simulated ischaemic microenvironment in vitro and transplanted model in vivo. Study of the underlying mechanisms suggested that the improved cell survival was regulated by HIF-1-induced metabolic reprogramming including decreased reactive oxygen species, increased intracellular pH, enhanced glucose uptake and increased glycogen synthesis. Tube formation assay revealed higher angiogenic ability in the DMOG-treated group than that in control group. CONCLUSIONS: The promotion of HIF-1 level in ADSCs induced by DMOG preconditioning suggests a potential strategy for improving the outcome of cell therapy due to increased survival and angiogenic ability.
[Mh] Termos MeSH primário: Tecido Adiposo/citologia
Aminoácidos Dicarboxílicos/farmacologia
Sobrevivência Celular/efeitos dos fármacos
Subunidade alfa do Fator 1 Induzível por Hipóxia/agonistas
Neovascularização Fisiológica/efeitos dos fármacos
Transplante de Células-Tronco
Células-Tronco/efeitos dos fármacos
[Mh] Termos MeSH secundário: Animais
Células Cultivadas
Metabolismo Energético/efeitos dos fármacos
Feminino
Seres Humanos
Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo
Isquemia/tratamento farmacológico
Isquemia/metabolismo
Camundongos Nus
Células-Tronco/citologia
Células-Tronco/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Amino Acids, Dicarboxylic); 0 (Hypoxia-Inducible Factor 1, alpha Subunit); VVW38EB8YS (oxalylglycine)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170913
[Lr] Data última revisão:
170913
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170729
[St] Status:MEDLINE
[do] DOI:10.1111/cpr.12363


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[PMID]:28679592
[Au] Autor:Zhang W; Zhou X; Yao Q; Liu Y; Zhang H; Dong Z
[Ad] Endereço:Department of Nephrology, The Third Xiangya Hospital of Central South University, Changsha, China.
[Ti] Título:HIF-1-mediated production of exosomes during hypoxia is protective in renal tubular cells.
[So] Source:Am J Physiol Renal Physiol;313(4):F906-F913, 2017 Oct 01.
[Is] ISSN:1522-1466
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Exosomes are nano-sized vesicles produced and secreted by cells to mediate intercellular communication. The production and function of exosomes in kidney tissues and cells remain largely unclear. Hypoxia is a common pathophysiological condition in kidneys. This study was designed to characterize exosome production during hypoxia of rat renal proximal tubular cells (RPTCs), investigate the regulation by hypoxia-inducible factor-1 (HIF-1), and determine the effect of the exosomes on ATP-depletion-induced tubular cell injury. Hypoxia did not change the average sizes of exosomes secreted by RPTCs, but it significantly increased exosome production in a time-dependent manner. HIF-1 induction with dimethyloxalylglycine also promoted exosome secretion, whereas pharmacological and genetic suppression of HIF-1 abrogated the increase of exosome secretion under hypoxia. The exosomes from hypoxic RPTCs had inhibitory effects on apoptosis of RPTCs following ATP depletion. The protective effects were lost in the exosomes from HIF-1α knockdown cells. It is concluded that hypoxia stimulates exosome production and secretion in renal tubular cells. The exosomes from hypoxic cells are protective against renal tubular cell injury. HIF-1 mediates exosome production during hypoxia and contributes to the cytoprotective effect of the exosomes.
[Mh] Termos MeSH primário: Exossomos/secreção
Fator 1 Induzível por Hipóxia/fisiologia
Hipóxia/fisiopatologia
Túbulos Renais Proximais/secreção
[Mh] Termos MeSH secundário: Aminoácidos Dicarboxílicos
Animais
Linhagem Celular
Camundongos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Amino Acids, Dicarboxylic); 0 (Hypoxia-Inducible Factor 1); VVW38EB8YS (oxalylglycine)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171108
[Lr] Data última revisão:
171108
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170707
[St] Status:MEDLINE
[do] DOI:10.1152/ajprenal.00178.2017


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[PMID]:28331062
[Au] Autor:Thomas JL; Pham H; Li Y; Hall E; Perkins GA; Ali SS; Patel HH; Singh P
[Ad] Endereço:Department of Biomedical Engineering, School of Engineering, Mercer University, Macon, Georgia.
[Ti] Título:Hypoxia-inducible factor-1α activation improves renal oxygenation and mitochondrial function in early chronic kidney disease.
[So] Source:Am J Physiol Renal Physiol;313(2):F282-F290, 2017 Aug 01.
[Is] ISSN:1522-1466
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The pathophysiology of chronic kidney disease (CKD) is driven by alterations in surviving nephrons to sustain renal function with ongoing nephron loss. Oxygen supply-demand mismatch, due to hemodynamic adaptations, with resultant hypoxia, plays an important role in the pathophysiology in early CKD. We sought to investigate the underlying mechanisms of this mismatch. We utilized the subtotal nephrectomy (STN) model of CKD to investigate the alterations in renal oxygenation linked to sodium (Na) transport and mitochondrial function in the surviving nephrons. Oxygen delivery was significantly reduced in STN kidneys because of lower renal blood flow. Fractional oxygen extraction was significantly higher in STN. Tubular Na reabsorption was significantly lower per mole of oxygen consumed in STN. We hypothesized that decreased mitochondrial bioenergetic capacity may account for this and uncovered significant mitochondrial dysfunction in the early STN kidney: higher oxidative metabolism without an attendant increase in ATP levels, elevated superoxide levels, and alterations in mitochondrial morphology. We further investigated the effect of activation of hypoxia-inducible factor-1α (HIF-1α), a master regulator of cellular hypoxia response. We observed significant improvement in renal blood flow, glomerular filtration rate, and tubular Na reabsorption per mole of oxygen consumed with HIF-1α activation. Importantly, HIF-1α activation significantly lowered mitochondrial oxygen consumption and superoxide production and increased mitochondrial volume density. In conclusion, we report significant impairment of renal oxygenation and mitochondrial function at the early stages of CKD and demonstrate the beneficial role of HIF-1α activation on renal function and metabolism.
[Mh] Termos MeSH primário: Aminoácidos Dicarboxílicos/farmacologia
Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo
Rim/irrigação sanguínea
Rim/efeitos dos fármacos
Mitocôndrias/efeitos dos fármacos
Consumo de Oxigênio/efeitos dos fármacos
Oxigênio/sangue
Insuficiência Renal Crônica/tratamento farmacológico
[Mh] Termos MeSH secundário: Trifosfato de Adenosina/metabolismo
Animais
Hipóxia Celular
Modelos Animais de Doenças
Metabolismo Energético/efeitos dos fármacos
Taxa de Filtração Glomerular/efeitos dos fármacos
Rim/metabolismo
Rim/ultraestrutura
Masculino
Mitocôndrias/metabolismo
Mitocôndrias/ultraestrutura
Ratos Wistar
Circulação Renal/efeitos dos fármacos
Insuficiência Renal Crônica/metabolismo
Insuficiência Renal Crônica/patologia
Insuficiência Renal Crônica/fisiopatologia
Reabsorção Renal/efeitos dos fármacos
Transdução de Sinais/efeitos dos fármacos
Sódio/metabolismo
Superóxidos/metabolismo
Fatores de Tempo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Amino Acids, Dicarboxylic); 0 (Hif1a protein, rat); 0 (Hypoxia-Inducible Factor 1, alpha Subunit); 11062-77-4 (Superoxides); 8L70Q75FXE (Adenosine Triphosphate); 9NEZ333N27 (Sodium); S88TT14065 (Oxygen); VVW38EB8YS (oxalylglycine)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171003
[Lr] Data última revisão:
171003
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170324
[St] Status:MEDLINE
[do] DOI:10.1152/ajprenal.00579.2016


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[PMID]:28234841
[Au] Autor:Duscher D; Januszyk M; Maan ZN; Whittam AJ; Hu MS; Walmsley GG; Dong Y; Khong SM; Longaker MT; Gurtner GC
[Ad] Endereço:Stanford, Calif.; Linz, Austria; and Munich, Germany From the Hagey Laboratory, Division of Plastic Surgery, Department of Surgery, Stanford University School of Medicine; the Section of Plastic Surgery, Department of Surgery, Johannes Kepler University; and the Department of Plastic Surgery and Hand Surgery, Technical University Munich.
[Ti] Título:Comparison of the Hydroxylase Inhibitor Dimethyloxalylglycine and the Iron Chelator Deferoxamine in Diabetic and Aged Wound Healing.
[So] Source:Plast Reconstr Surg;139(3):695e-706e, 2017 Mar.
[Is] ISSN:1529-4242
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: A hallmark of diabetes mellitus is the breakdown of almost every reparative process in the human body, leading to critical impairments of wound healing. Stabilization and activity of the transcription factor hypoxia-inducible factor (HIF)-1α is impaired in diabetes, leading to deficits in new blood vessel formation in response to injury. In this article, the authors compare the effectiveness of two promising small-molecule therapeutics, the hydroxylase inhibitor dimethyloxalylglycine and the iron chelator deferoxamine, for attenuating diabetes-associated deficits in cutaneous wound healing by enhancing HIF-1α activation. METHODS: HIF-1α stabilization, phosphorylation, and transactivation were measured in murine fibroblasts cultured under normoxic or hypoxic and low-glucose or high-glucose conditions following treatment with deferoxamine or dimethyloxalylglycine. In addition, diabetic wound healing and neovascularization were evaluated in db/db mice treated with topical solutions of either deferoxamine or dimethyloxalylglycine, and the efficacy of these molecules was also compared in aged mice. RESULTS: The authors show that deferoxamine stabilizes HIF-1α expression and improves HIF-1α transactivity in hypoxic and hyperglycemic states in vitro, whereas the effects of dimethyloxalylglycine are significantly blunted under hyperglycemic hypoxic conditions. In vivo, both dimethyloxalylglycine and deferoxamine enhance wound healing and vascularity in aged mice, but only deferoxamine universally augmented wound healing and neovascularization in the setting of both advanced age and diabetes. CONCLUSION: This first direct comparison of deferoxamine and dimethyloxalylglycine in the treatment of impaired wound healing suggests significant therapeutic potential for topical deferoxamine treatment in ischemic and diabetic disease.
[Mh] Termos MeSH primário: Aminoácidos Dicarboxílicos/farmacologia
Desferroxamina/farmacologia
Quelantes de Ferro/farmacologia
Oxigenases de Função Mista/antagonistas & inibidores
Cicatrização/efeitos dos fármacos
[Mh] Termos MeSH secundário: Fatores Etários
Animais
Diabetes Mellitus/fisiopatologia
Hiperglicemia/fisiopatologia
Camundongos
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Amino Acids, Dicarboxylic); 0 (Iron Chelating Agents); EC 1.- (Mixed Function Oxygenases); J06Y7MXW4D (Deferoxamine); VVW38EB8YS (oxalylglycine)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170601
[Lr] Data última revisão:
170601
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170225
[St] Status:MEDLINE
[do] DOI:10.1097/PRS.0000000000003072


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[PMID]:27811062
[Au] Autor:Barnes EA; Chen CH; Sedan O; Cornfield DN
[Ad] Endereço:Department of Pediatrics, Center for Excellence in Pulmonary Biology, Stanford University School of Medicine, Stanford, California, USA.
[Ti] Título:Loss of smooth muscle cell hypoxia inducible factor-1α underlies increased vascular contractility in pulmonary hypertension.
[So] Source:FASEB J;31(2):650-662, 2017 Feb.
[Is] ISSN:1530-6860
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Pulmonary arterial hypertension (PAH) is an often fatal disease with limited treatment options. Whereas current data support the notion that, in pulmonary artery endothelial cells (PAECs), expression of transcription factor hypoxia inducible factor-1α (HIF-1α) is increased, the role of HIF-1α in pulmonary artery smooth muscle cells (PASMCs) remains controversial. This study investigates the hypothesis that, in PASMCs from patients with PAH, decreases in HIF-1α expression and activity underlie augmented pulmonary vascular contractility. PASMCs and tissues were isolated from nonhypertensive control patients and patients with PAH. Compared with controls, HIF-1α and Kv1.5 protein expression were decreased in PAH smooth muscle cells (primary culture). Myosin light chain (MLC) phosphorylation and MLC kinase (MLCK) activity-major determinants of vascular tone-were increased in patients with PAH. Cofactors involved in prolyl hydroxylase domain activity were increased in PAH smooth muscle cells. Functionally, PASMC contractility was inversely correlated with HIF-1α activity. In PASMCs derived from patients with PAH, HIF-1α expression is decreased, and MLCK activity, MLC phosphorylation, and cell contraction are increased. We conclude that compromised PASMC HIF-1α expression may contribute to the increased tone that characterizes pulmonary hypertension.-Barnes, E. A., Chen, C.-H., Sedan, O., Cornfield, D. N. Loss of smooth muscle cell hypoxia inducible factor-1α underlies increased vascular contractility in pulmonary hypertension.
[Mh] Termos MeSH primário: Hipertensão Pulmonar/metabolismo
Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo
Miócitos de Músculo Liso/metabolismo
Artéria Pulmonar/fisiologia
Vasoconstrição/fisiologia
[Mh] Termos MeSH secundário: Aminoácidos Dicarboxílicos/farmacologia
Dimetil Sulfóxido/farmacologia
Regulação da Expressão Gênica/efeitos dos fármacos
Regulação da Expressão Gênica/fisiologia
Seres Humanos
Subunidade alfa do Fator 1 Induzível por Hipóxia/genética
Prolil Hidroxilases/genética
Prolil Hidroxilases/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Amino Acids, Dicarboxylic); 0 (Hypoxia-Inducible Factor 1, alpha Subunit); EC 1.14.11.- (Prolyl Hydroxylases); VVW38EB8YS (oxalylglycine); YOW8V9698H (Dimethyl Sulfoxide)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170901
[Lr] Data última revisão:
170901
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161105
[St] Status:MEDLINE
[do] DOI:10.1096/fj.201600557R


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[PMID]:27789715
[Au] Autor:Yang H; Jenni S; Colovic M; Merkens H; Poleschuk C; Rodrigo I; Miao Q; Johnson BF; Rishel MJ; Sossi V; Webster JM; Bénard F; Schaffer P
[Ad] Endereço:Life Sciences, TRIUMF, Vancouver, Canada.
[Ti] Título:F-5-Fluoroaminosuberic Acid as a Potential Tracer to Gauge Oxidative Stress in Breast Cancer Models.
[So] Source:J Nucl Med;58(3):367-373, 2017 Mar.
[Is] ISSN:1535-5667
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The cystine transporter (system x ) is an antiporter of cystine and glutamate. It has relatively low basal expression in most tissues and becomes upregulated in cells under oxidative stress (OS) as one of the genes expressed in response to the antioxidant response element promoter. We have developed F-5-fluoroaminosuberic acid (FASu), a PET tracer that targets system x The goal of this study was to evaluate F-FASu as a specific gauge for system x activity in vivo and its potential for breast cancer imaging. F-FASu specificity toward system x was studied by cell inhibition assay, cellular uptake after OS induction with diethyl maleate, with and without anti-xCT small interfering RNA knockdown, in vitro uptake studies, and in vivo uptake in a system x -transduced xenograft model. In addition, radiotracer uptake was evaluated in 3 breast cancer models: MDA-MB-231, MCF-7, and ZR-75-1. Reactive oxygen species-inducing diethyl maleate increased glutathione levels and F-FASu uptake, whereas gene knockdown with anti-xCT small interfering RNA led to decreased tracer uptake. F-FASu uptake was robustly inhibited by system x inhibitors or substrates, whereas uptake was significantly higher in transduced cells and tumors expressing xCT than in wild-type HEK293T cells and tumors ( < 0.0001 for cells, = 0.0086 for tumors). F-FASu demonstrated tumor uptake in all 3 breast cancer cell lines studied. Among them, triple-negative breast cancer MDA-MB-231, which has the highest xCT messenger RNA level, had the highest tracer uptake ( = 0.0058 when compared with MCF-7; < 0.0001 when compared with ZR-75-1). F-FASu as a system x substrate is a specific PET tracer for functional monitoring of system x and OS imaging. By enabling noninvasive analysis of x responses in vivo, this biomarker may serve as a valuable target for the diagnosis and treatment monitoring of certain breast cancers.
[Mh] Termos MeSH primário: Sistema y+ de Transporte de Aminoácidos/metabolismo
Aminoácidos Dicarboxílicos/farmacocinética
Neoplasias da Mama/diagnóstico por imagem
Neoplasias da Mama/fisiopatologia
Estresse Oxidativo
Tomografia por Emissão de Pósitrons/métodos
[Mh] Termos MeSH secundário: Antioxidantes/metabolismo
Linhagem Celular Tumoral
Estudos de Viabilidade
Seres Humanos
Compostos Radiofarmacêuticos/farmacocinética
Reprodutibilidade dos Testes
Sensibilidade e Especificidade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (5-fluoroaminosuberic acid); 0 (Amino Acid Transport System y+); 0 (Amino Acids, Dicarboxylic); 0 (Antioxidants); 0 (Radiopharmaceuticals); 0 (SLC7A11 protein, human)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:170902
[Lr] Data última revisão:
170902
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161030
[St] Status:MEDLINE
[do] DOI:10.2967/jnumed.116.180661


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[PMID]:27899144
[Au] Autor:Hookham MB; Ali IH; O'Neill CL; Hackett E; Lambe MH; Schmidt T; Medina RJ; Chamney S; Rao B; McLoone E; Sweet D; Stitt AW; Brazil DP
[Ad] Endereço:Centre for Experimental Medicine, Queen's University Belfast, 97 Lisburn Road, Belfast, BT9 7BL, UK.
[Ti] Título:Hypoxia-induced responses by endothelial colony-forming cells are modulated by placental growth factor.
[So] Source:Stem Cell Res Ther;7(1):173, 2016 Nov 29.
[Is] ISSN:1757-6512
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Endothelial colony-forming cells (ECFCs), also termed late outgrowth endothelial cells, are a well-defined circulating endothelial progenitor cell type with an established role in vascular repair. ECFCs have clear potential for cell therapy to treat ischaemic disease, although the precise mechanism(s) underlying their response to hypoxia remains ill-defined. METHODS: In this study, we isolated ECFCs from umbilical cord blood and cultured them on collagen. We defined the response of ECFCs to 1% O exposure at acute and chronic time points. RESULTS: In response to low oxygen, changes in ECFC cell shape, proliferation, size and cytoskeleton phenotype were detected. An increase in the number of senescent ECFCs also occurred as a result of long-term culture in 1% O . Low oxygen exposure altered ECFC migration and tube formation in Matrigel®. Increases in angiogenic factors secreted from ECFCs exposed to hypoxia were also detected, in particular, after treatment with placental growth factor (PlGF). Exposure of cells to agents that stabilise hypoxia-inducible factors such as dimethyloxalylglycine (DMOG) also increased PlGF levels. Conditioned medium from both hypoxia-treated and DMOG-treated cells inhibited ECFC tube formation. This effect was reversed by the addition of PlGF neutralising antibody to the conditioned medium, confirming the direct role of PlGF in this effect. CONCLUSIONS: This study deepens our understanding of the response of ECFCs to hypoxia and also identifies a novel and important role for PlGF in regulating the vasculogenic potential of ECFCs.
[Mh] Termos MeSH primário: Células Endoteliais/metabolismo
Células Endoteliais/fisiologia
Hipóxia/metabolismo
Hipóxia/patologia
Fator de Crescimento Placentário/metabolismo
Hormônios Placentários/metabolismo
[Mh] Termos MeSH secundário: Aminoácidos Dicarboxílicos/metabolismo
Movimento Celular/fisiologia
Proliferação Celular/fisiologia
Células Cultivadas
Colágeno/metabolismo
Meios de Cultivo Condicionados/metabolismo
Combinação de Medicamentos
Células Progenitoras Endoteliais/metabolismo
Sangue Fetal/metabolismo
Sangue Fetal/fisiologia
Seres Humanos
Laminina/metabolismo
Neovascularização Fisiológica/fisiologia
Proteoglicanas/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Amino Acids, Dicarboxylic); 0 (Culture Media, Conditioned); 0 (Drug Combinations); 0 (Laminin); 0 (PGF protein, human); 0 (Placental Hormones); 0 (Proteoglycans); 119978-18-6 (matrigel); 144589-93-5 (Placenta Growth Factor); 9007-34-5 (Collagen); VVW38EB8YS (oxalylglycine)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171113
[Lr] Data última revisão:
171113
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161201
[St] Status:MEDLINE


  8 / 709 MEDLINE  
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[PMID]:27789456
[Au] Autor:Manresa MC; Tambuwala MM; Radhakrishnan P; Harnoss JM; Brown E; Cavadas MA; Keogh CE; Cheong A; Barrett KE; Cummins EP; Schneider M; Taylor CT
[Ad] Endereço:School of Medicine and Medical Science, UCD Conway Institute, University College Dublin, Dublin, Ireland.
[Ti] Título:Hydroxylase inhibition regulates inflammation-induced intestinal fibrosis through the suppression of ERK-mediated TGF-ß1 signaling. [corrected].
[So] Source:Am J Physiol Gastrointest Liver Physiol;311(6):G1076-G1090, 2016 12 01.
[Is] ISSN:1522-1547
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Fibrosis is a complication of chronic inflammatory disorders such as inflammatory bowel disease, a condition which has limited therapeutic options and often requires surgical intervention. Pharmacologic inhibition of oxygen-sensing prolyl hydroxylases, which confer oxygen sensitivity upon the hypoxia-inducible factor pathway, has recently been shown to have therapeutic potential in colitis, although the mechanisms involved remain unclear. Here, we investigated the impact of hydroxylase inhibition on inflammation-driven fibrosis in a murine colitis model. Mice exposed to dextran sodium sulfate, followed by a period of recovery, developed intestinal fibrosis characterized by alterations in the pattern of collagen deposition and infiltration of activated fibroblasts. Treatment with the hydroxylase inhibitor dimethyloxalylglycine ameliorated fibrosis. TGF-ß1 is a key regulator of fibrosis that acts through the activation of fibroblasts. Hydroxylase inhibition reduced TGF-ß1-induced expression of fibrotic markers in cultured fibroblasts, suggesting a direct role for hydroxylases in TGF-ß1 signaling. This was at least in part due to inhibition of noncanonical activation of extracellular signal-regulated kinase (ERK) signaling. In summary, pharmacologic hydroxylase inhibition ameliorates intestinal fibrosis through suppression of TGF-ß1-dependent ERK activation in fibroblasts. We hypothesize that in addition to previously reported immunosupressive effects, hydroxylase inhibitors independently suppress profibrotic pathways.
[Mh] Termos MeSH primário: Colágeno/metabolismo
MAP Quinases Reguladas por Sinal Extracelular/metabolismo
Intestinos/patologia
Oxigenases de Função Mista/metabolismo
Fator de Crescimento Transformador beta1/metabolismo
[Mh] Termos MeSH secundário: Aminoácidos Dicarboxílicos/farmacologia
Animais
Células Cultivadas
Inibidores Enzimáticos/farmacologia
Fibroblastos/efeitos dos fármacos
Fibroblastos/metabolismo
Fibrose
Seres Humanos
Intestinos/efeitos dos fármacos
Intestinos/metabolismo
Camundongos
Camundongos Endogâmicos C57BL
Oxigenases de Função Mista/antagonistas & inibidores
Transdução de Sinais
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Amino Acids, Dicarboxylic); 0 (Enzyme Inhibitors); 0 (Transforming Growth Factor beta1); 9007-34-5 (Collagen); EC 1.- (Mixed Function Oxygenases); EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases); VVW38EB8YS (oxalylglycine)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170707
[Lr] Data última revisão:
170707
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161030
[St] Status:MEDLINE
[do] DOI:10.1152/ajpgi.00229.2016


  9 / 709 MEDLINE  
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[PMID]:27693634
[Au] Autor:Wang Y; Zhao W; Gao Q; Fan L; Qin Y; Zhou H; Li M; Fang J
[Ad] Endereço:Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China; University of Chinese Academy of Sciences, China.
[Ti] Título:pVHL mediates K63-linked ubiquitination of IKKß, leading to IKKß inactivation.
[So] Source:Cancer Lett;383(1):1-8, 2016 12 01.
[Is] ISSN:1872-7980
[Cp] País de publicação:Ireland
[La] Idioma:eng
[Ab] Resumo:Nuclear factor (NF)-κB is a transcription factor that plays an important role in many biological functions. Regulation of NF-κB activity is complicated, and ubiquitination is essential for NF-κB activation. Hypoxia can activate NF-κB. However, the underlying mechanism remains unclear. pVHL is a tumour suppressor and functions as an adaptor of E3-ligase. In this study, we demonstrated that pVHL inhibits NF-κB by mediating K63-ubiquitination of IKKß, which is dependent on oxygen. We found that pVHL mediates K63-linked ubiquitination of IKKß, which is an upstream regulator of NF-κB. The pVHL-mediated K63-ubiquitination of IKKß prevents TAK1 binding, which leads to the inhibition of IKKß phosphorylation and NF-κB activation. pVHL-mediated K63-ubiquitination of IKKß is inhibited under hypoxia. DMOG, which is a specific inhibitor of prolyl hydroxylases, also suppresses K63-ubiquitination of IKKß. Prolyl hydroxylase (PHD) 1 enhances K63-ubiquitination of IKKß and inhibits IKKß phosphorylation. These results suggest a novel function for pVHL in mediating K63-linked ubiquitination of IKKß, which plays a role in the regulation of IKK/NF-κB signalling. The results also provide new insight into the mechanism of NF-κB activation through hypoxia.
[Mh] Termos MeSH primário: Quinase I-kappa B/metabolismo
Ubiquitinação
Proteína Supressora de Tumor Von Hippel-Lindau/metabolismo
[Mh] Termos MeSH secundário: Aminoácidos Dicarboxílicos/farmacologia
Hipóxia Celular
Inibidores Enzimáticos/farmacologia
Feminino
Células HEK293
Células HeLa
Seres Humanos
Prolina Dioxigenases do Fator Induzível por Hipóxia/antagonistas & inibidores
Prolina Dioxigenases do Fator Induzível por Hipóxia/metabolismo
Quinase I-kappa B/genética
Lisina
MAP Quinase Quinase Quinases/metabolismo
NF-kappa B/metabolismo
Oxigênio/metabolismo
Fosforilação
Ligação Proteica
Interferência de RNA
Transdução de Sinais
Transfecção
Ubiquitinação/efeitos dos fármacos
Proteína Supressora de Tumor Von Hippel-Lindau/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Amino Acids, Dicarboxylic); 0 (Enzyme Inhibitors); 0 (NF-kappa B); EC 1.14.11.29 (EGLN2 protein, human); EC 1.14.11.29 (Hypoxia-Inducible Factor-Proline Dioxygenases); EC 2.3.2.27 (Von Hippel-Lindau Tumor Suppressor Protein); EC 2.7.11.10 (I-kappa B Kinase); EC 2.7.11.10 (IKBKB protein, human); EC 2.7.11.25 (MAP Kinase Kinase Kinases); EC 2.7.11.25 (MAP kinase kinase kinase 7); EC 6.3.2.- (VHL protein, human); K3Z4F929H6 (Lysine); S88TT14065 (Oxygen); VVW38EB8YS (oxalylglycine)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:171029
[Lr] Data última revisão:
171029
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161004
[St] Status:MEDLINE


  10 / 709 MEDLINE  
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[PMID]:27606625
[Au] Autor:Zhang L; Jiang G; Zhao X; Gong Y
[Ad] Endereço:Department of rehabilitation medicine, the first people's hospital of Yunnan province, Kunming, China.
[Ti] Título:Dimethyloxalylglycine Promotes Bone Marrow Mesenchymal Stem Cell Osteogenesis via Rho/ROCK Signaling.
[So] Source:Cell Physiol Biochem;39(4):1391-403, 2016.
[Is] ISSN:1421-9778
[Cp] País de publicação:Switzerland
[La] Idioma:eng
[Ab] Resumo:BACKGROUND/AIMS: We investigated the role of dimethyloxalylglycine (DMOG) in bone marrow mesenchymal stem cell (BMSC) osteogenesis mediated by RhoA/ROCK. METHODS: BMSCs were cultured with and without DMOG and/or Y-27632 (ROCK1 inhibitor). Cell proliferation, alkaline phosphatase (ALP) levels, and calcium deposits were determined. The expression of Runx2, OSX, p-cofilin, RhoA, and GTP-bound RhoA was determined by real-time RT-PCR and Western blot. Rho-associated coiled-coil-containing protein kinase (ROCK) activity was determined by measuring the phosphorylation of myosin-binding subunit of myosin phosphatase using an ELISA kit. Actin morphology was observed by immunofluorescence. RESULTS: After 24 h, DMOG (0.5 mM) increased the expression of GTP-bound RhoA (+141%, P < 0.001) and enhanced ROCK activity (315%, P < 0.001). DMOG (0.5 mM) enhanced ALP levels after 3, 7, and 21 days of osteogenic induction (all P < 0.001) and strengthened calcium deposition (P < 0.001). In addition, compared with controls, DMOG (0.5 mM) increased the mRNA levels of osteogenesis genes RUNX2 and OSX (all P < 0.001). Furthermore, compared with controls, DMOG increased the expression of p-cofilin (+57%, P < 0.001), which resulted in rearrangement of actin filaments. All these effects were abolished, at least in part, by Y-27632. CONCLUSION: DMOG promotes BMSC osteogenic differentiation via activation of RhoA/ROCK, suggesting clues for future therapies using BMSCs.
[Mh] Termos MeSH primário: Aminoácidos Dicarboxílicos/farmacologia
Células Mesenquimais Estromais/efeitos dos fármacos
Osteogênese/efeitos dos fármacos
Proteínas rho de Ligação ao GTP/genética
Quinases Associadas a rho/genética
[Mh] Termos MeSH secundário: Adipócitos/citologia
Adipócitos/efeitos dos fármacos
Adipócitos/metabolismo
Amidas/farmacologia
Animais
Células da Medula Óssea/efeitos dos fármacos
Células da Medula Óssea/metabolismo
Cálcio/metabolismo
Diferenciação Celular/efeitos dos fármacos
Proliferação Celular/efeitos dos fármacos
Condrócitos/citologia
Condrócitos/efeitos dos fármacos
Condrócitos/metabolismo
Cofilina 1/genética
Cofilina 1/metabolismo
Subunidade alfa 1 de Fator de Ligação ao Core/genética
Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo
Regulação da Expressão Gênica
Masculino
Células Mesenquimais Estromais/metabolismo
Camundongos
Fosfatase de Miosina-de-Cadeia-Leve/genética
Fosfatase de Miosina-de-Cadeia-Leve/metabolismo
Osteoblastos/citologia
Osteoblastos/efeitos dos fármacos
Osteoblastos/metabolismo
Osteogênese/genética
Cultura Primária de Células
Piridinas/farmacologia
Transdução de Sinais
Fator de Transcrição Sp7
Fatores de Transcrição/genética
Fatores de Transcrição/metabolismo
Proteínas rho de Ligação ao GTP/metabolismo
Quinases Associadas a rho/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Amides); 0 (Amino Acids, Dicarboxylic); 0 (Cofilin 1); 0 (Core Binding Factor Alpha 1 Subunit); 0 (Pyridines); 0 (Runx2 protein, mouse); 0 (Sp7 Transcription Factor); 0 (Sp7 protein, mouse); 0 (Transcription Factors); 138381-45-0 (Y 27632); EC 2.7.11.1 (Rock1 protein, mouse); EC 2.7.11.1 (rho-Associated Kinases); EC 3.1.3.53 (Myosin-Light-Chain Phosphatase); EC 3.6.5.2 (RhoA protein, mouse); EC 3.6.5.2 (rho GTP-Binding Proteins); SY7Q814VUP (Calcium); VVW38EB8YS (oxalylglycine)
[Em] Mês de entrada:1701
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160909
[St] Status:MEDLINE
[do] DOI:10.1159/000447843



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