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1.
Free Radic Biol Med ; 84: 246-253, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25843658

RESUMO

Vitamin E (VE) deficiency results in pronounced muscle weakness and atrophy but the cell biological mechanism of the pathology is unknown. We previously showed that VE supplementation promotes membrane repair in cultured cells and that oxidants potently inhibit repair. Here we provide three independent lines of evidence that VE is required for skeletal muscle myocyte plasma membrane repair in vivo. We also show that when another lipid-directed antioxidant, glutathione peroxidase 4 (Gpx4), is genetically deleted in mouse embryonic fibroblasts, repair fails catastrophically, unless cells are supplemented with VE. We conclude that lipid-directed antioxidant activity provided by VE, and possibly also Gpx4, is an essential component of the membrane repair mechanism in skeletal muscle. This work explains why VE is essential to muscle health and identifies VE as a requisite component of the plasma membrane repair mechanism in vivo.


Assuntos
Antioxidantes/farmacologia , Membrana Celular/metabolismo , Músculo Esquelético/fisiologia , Vitamina E/farmacologia , Animais , Membrana Celular/efeitos dos fármacos , Células Cultivadas , Glutationa Peroxidase/metabolismo , Masculino , Camundongos , Fibras Musculares Esqueléticas/efeitos dos fármacos , Fibras Musculares Esqueléticas/fisiologia , Músculo Esquelético/citologia , Músculo Esquelético/efeitos dos fármacos , Fosfolipídeo Hidroperóxido Glutationa Peroxidase , Ratos Sprague-Dawley
2.
Exp Eye Res ; 93(4): 350-4, 2011 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-21354136

RESUMO

Retinal neovascularization (RNV) is a critical pathological event and a major cause of blindness. Vascular inflammation and oxidative stress have been shown to play a key role in the induction and progression of RNV. Trans-Chalcone-derived flavonoids have been previously shown to be negative modulators of oxidative stress and inflammatory responses as well as tumor angiogenesis. In this study, we characterized the effects of the flavonoid trans-Chalcone in preventing RNV in a model of ischemic retinopathy. Ischemic retinopathy was induced in neonatal mice subjected to oxygen-induced retinopathy. Trans-Chalcone was administered intra-peritoneum at the dose of 25 mg/kg/day. Vascular density was assessed by morphometric analysis of flat mounted retinas stained with Texas red-Isolectin B4. Western blotting analysis was conducted to determine protein levels of vascular endothelial growth factor (VEGF), inter-cellular adhesion molecule 1 (ICAM-1) and the transcriptional activators' signal transducer and activator of transcription 3 (STAT3) and nuclear factor kappa beta (NF-κB). Treatment with trans-Chalcone significantly inhibited RNV in the ischemic retina, as shown by decreased number of neovascular tufts. Trans-Chalcone also blocked ischemia-induced VEGF and ICAM-1 expression and this effect correlated with inhibition of activated STAT3 and NF-κB. Our results show that trans-Chalcone effectively prevents RNV in the murine retina thus suggesting that Chalcone-derived flavonoids may be beneficial in preventing pathological neovascularization in the ischemic retina.


Assuntos
Antioxidantes/farmacologia , Chalconas/farmacologia , Modelos Animais de Doenças , Traumatismo por Reperfusão/prevenção & controle , Neovascularização Retiniana/prevenção & controle , Vasos Retinianos/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/metabolismo , Animais , Animais Recém-Nascidos , Western Blotting , Injeções Intraperitoneais , Molécula 1 de Adesão Intercelular/metabolismo , Camundongos , NF-kappa B/metabolismo , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia , Neovascularização Retiniana/metabolismo , Neovascularização Retiniana/patologia , Vasos Retinianos/patologia , Fator de Transcrição STAT3/metabolismo
3.
Nucleic Acids Res ; 37(22): 7581-9, 2009 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-19843605

RESUMO

DNA mismatch repair corrects mispaired bases and small insertions/deletions in DNA. In eukaryotes, the mismatch repair complex MSH2-MSH6 binds to mispairs with only slightly higher affinity than to fully paired DNA in vitro. Recently, the high-mobility group box1 protein, (HMGB1), has been shown to stimulate the mismatch repair reaction in vitro. In yeast, the closest homologs of HMGB1 are NHP6A and NHP6B. These proteins have been shown to be required for genome stability maintenance and mutagenesis control. In this work, we show that MSH2-MSH6 and NHP6A modulate their binding to DNA in vitro. Binding of the yeast MSH2-MSH6 to homoduplex regions of DNA significantly stimulates the loading of NHP6A. Upon binding of NHP6A to DNA, MSH2-MSH6 is excluded from binding unless a mismatch is present. A DNA binding-impaired MSH2-MSH6F337A significantly reduced the loading of NHP6A to DNA, suggesting that MSH2-MSH6 binding is a requisite for NHP6A loading. MSH2-MSH6 and NHP6A form a stable complex, which is responsive to ATP on mismatched substrates. These results suggest that MSH2-MSH6 binding to homoduplex regions of DNA recruits NHP6A, which then prevents further binding of MSH2-MSH6 to these sites unless a mismatch is present.


Assuntos
Proteínas de Ligação a DNA/metabolismo , Proteínas HMGN/metabolismo , Proteína 2 Homóloga a MutS/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Adenosina Trifosfatases/metabolismo , Trifosfato de Adenosina/metabolismo , Pareamento Incorreto de Bases , DNA/metabolismo , Proteínas HMGN/isolamento & purificação , Ligação Proteica , Proteínas de Saccharomyces cerevisiae/isolamento & purificação
4.
Dig Dis Sci ; 54(7): 1460-4, 2009 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-19424798

RESUMO

Fat infiltration and inflammation cause liver injury and fibrosis and may progress to nonalcoholic steatohepatitis (NASH) and end-stage liver disease. Currently, there are no effective treatments for NASH. Zeaxanthin is a carotenoid which has been shown to be preferentially accumulated in the adipose tissue and liver. We hypothesized that treatment with zeaxanthin may decrease oxidative stress in the liver and, possibly, halt the inflammation and fibrosis associated with NASH. Here we tested zeaxanthin effects in preventing progression of liver injury in a model of NASH. Mongolian gerbils, fed a methionine-choline-deficient diet, were treated with different doses of zeaxanthin. We assessed histopathological changes by hematoxylin-eosin and Masson trichrome staining and determined oxidative stress by measuring lipid peroxidation. The obtained results show that zeaxanthin significantly prevented NASH progression by decreasing oxidative stress and liver fibrosis, thus suggesting a potential therapeutic application for this carotenoid in the management of NASH.


Assuntos
Hepatite/metabolismo , Cirrose Hepática/prevenção & controle , Fígado/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Xantofilas/farmacologia , Animais , Modelos Animais de Doenças , Progressão da Doença , Gerbillinae , Hepatite/patologia , Hepatite/prevenção & controle , Peroxidação de Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/patologia , Cirrose Hepática/metabolismo , Masculino , Zeaxantinas
5.
Invest Ophthalmol Vis Sci ; 50(10): 4934-40, 2009 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-19098312

RESUMO

PURPOSE: Retinal neovascularization (RNV) is a primary cause of blindness and involves the dysfunction of retinal capillaries. Recent studies have emphasized the beneficial effects of inhibitors of HMG-CoA reductase (statins) in preventing vascular dysfunction. In the present study, the authors characterized the therapeutic effects of statins on RNV. METHODS: Statin treatment (10 mg/kg/d fluvastatin) was tested in a mouse model of oxygen-induced retinopathy. Morphometric analysis was conducted to determine the extent of capillary growth. Pimonidazole hydrochloride was used to assess retinal ischemia. Western blot and immunohistochemical analyses were used to assess protein expression levels and immunolocalization. Lipid peroxidation and superoxide radical formation were determined to assess oxidative changes. RESULTS: Fluvastatin treatment significantly reduced the area of the capillary-free zone (P < 0.01), decreased the formation of neovascular tufts (P < 0.01), and ameliorated retinal ischemia. These morphologic and functional changes were associated with statin effects in preventing the upregulation of VEGF, HIF-1 alpha, phosphorylated STAT3, and vascular expression of the inflammatory mediator ICAM-1 (P < 0.01). Superoxide production and lipid peroxidation in the ischemic retina were also reduced by statin treatment (P < 0.01). CONCLUSIONS: These data suggest the beneficial effects of statin treatment in preventing retinal neovascularization. These beneficial effects appear to result from the anti-oxidant and anti-inflammatory properties of statins.


Assuntos
Modelos Animais de Doenças , Ácidos Graxos Monoinsaturados/uso terapêutico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Indóis/uso terapêutico , Neovascularização Retiniana/prevenção & controle , Retinopatia da Prematuridade/prevenção & controle , Animais , Western Blotting , Capilares , Fluvastatina , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Imuno-Histoquímica , Recém-Nascido , Molécula 1 de Adesão Intercelular/metabolismo , Peroxidação de Lipídeos , Camundongos , Nitroimidazóis/farmacologia , Oxigênio/toxicidade , Fosforilação , Neovascularização Retiniana/metabolismo , Neovascularização Retiniana/patologia , Vasos Retinianos/patologia , Retinopatia da Prematuridade/metabolismo , Retinopatia da Prematuridade/patologia , Fator de Transcrição STAT3/metabolismo , Superóxidos/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo
6.
Circ Res ; 102(1): 95-102, 2008 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-17967788

RESUMO

Increases in arginase activity have been reported in a variety of disease conditions characterized by vascular dysfunction. Arginase competes with NO synthase for their common substrate arginine, suggesting a cause and effect relationship. We tested this concept by experiments with streptozotocin diabetic rats and high glucose (HG)-treated bovine coronary endothelial cells (BCECs). Our studies showed that diabetes-induced impairment of vasorelaxation to acetylcholine was correlated with increases in reactive oxygen species and arginase activity and arginase I expression in aorta and liver. Treatment of diabetic rats with simvastatin (5 mg/kg per day, subcutaneously) or L-citrulline (50 mg/kg per day, orally) blunted these effects. Acute treatment of diabetic coronary arteries with arginase inhibitors also reversed the impaired vasodilation to acetylcholine. Treatment of BCECs with HG (25 mmol/L, 24 hours) also increased arginase activity. This effect was blocked by treatment with simvastatin (0.1 micromol/L), the Rho kinase inhibitor Y-27632 (10 micromol/L), or L-citrulline (1 mmol/L). Superoxide and active RhoA levels also were elevated in HG-treated BCECs. Furthermore, HG significantly diminished NO production in BCECs. Transfection of BCECs with arginase I small interfering RNA prevented the rise in arginase activity in HG-treated cells and normalized NO production, suggesting a role for arginase I in reduced NO production with HG. These results indicate that increased arginase activity in diabetes contributes to vascular endothelial dysfunction by decreasing L-arginine availability to NO synthase.


Assuntos
Arginase/metabolismo , Doença das Coronárias/enzimologia , Doença das Coronárias/etiologia , Complicações do Diabetes , Animais , Arginina/sangue , Arginina/metabolismo , Ligação Competitiva , Bovinos , Vasos Coronários/fisiopatologia , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/complicações , Endotélio Vascular/fisiopatologia , Óxido Nítrico Sintase Tipo III/metabolismo , Ratos
7.
Essays Biochem ; 39: 89-104, 2003.
Artigo em Inglês | MEDLINE | ID: mdl-14585076

RESUMO

Although cancer is a disease that will afflict one out of three people in the Western world, when considered at a cellular level, it is a rare clonal event. Long-lived organisms, such as humans, have evolved strategies to restrict the development of potentially malignant cells, and one such mechanism is the coupling of proliferative and apoptotic pathways. Multiple oncogenes have the ability to trigger apoptosis when expressed in an inappropriate fashion, and this is thought to restrict tumour formation by eliminating potentially malignant cells that have acquired a mutation stimulating proliferation. Hence for a tumour to arise, in addition to mutations that drive proliferation, mutations that prevent apoptosis are also a prerequisite.


Assuntos
Apoptose , Regulação da Expressão Gênica , Oncogenes/fisiologia , Animais , Divisão Celular , Proteínas de Ligação a DNA/metabolismo , Genes Supressores de Tumor , Genes myc/fisiologia , Genes p53/fisiologia , Humanos , Camundongos , Mitocôndrias/metabolismo , Modelos Biológicos , Mutação , Proteínas Nucleares/metabolismo , Transdução de Sinais , Ativação Transcricional , Proteína Tumoral p73 , Proteínas Supressoras de Tumor
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