RESUMEN
Previous evidence suggests that palmitoylcarnitine incubations trigger mitochondrial-mediated apoptosis in HT29 colorectal adenocarcinoma cells, yet nontransformed cells appear insensitive. The mechanism by which palmitoylcarnitine induces cancer cell death is unclear. The purpose of this investigation was to examine the relationship between mitochondrial kinetics and glutathione buffering in determining the effect of palmitoylcarnitine on cell survival. HT29 and HCT 116 colorectal adenocarcinoma cells, CCD 841 nontransformed colon cells, and MCF7 breast adenocarcinoma cells were exposed to 0 µM, 50 µM, and 100 µM palmitoylcarnitine for 24-48 h. HCT 116 and HT29 cells showed decreased cell survival following palmitoylcarnitine compared with CCD 841 cells. Palmitoylcarnitine stimulated H2O2 emission in HT29 and CCD 841 cells but increased it to a greater level in HT29 cells due largely to a higher basal H2O2 emission. This greater H2O2 emission was associated with lower glutathione buffering capacity and caspase-3 activation in HT29 cells. The glutathione-depleting agent buthionine sulfoximine sensitized CCD 841 cells and further sensitized HT29 cells to palmitoylcarnitine-induced decreases in cell survival. MCF7 cells did not produce H2O2 when exposed to palmitoylcarnitine and were able to maintain glutathione levels. Furthermore, HT29 cells demonstrated the lowest mitochondrial oxidative kinetics vs. CCD 841 and MCF7 cells. The results demonstrate that colorectal cancer is sensitive to palmitoylcarnitine due in part to an inability to prevent oxidative stress through glutathione-redox coupling, thereby rendering the cells sensitive to elevations in H2O2. These findings suggest that the relationship between inherent metabolic capacities and redox regulation is altered early in response to palmitoylcarnitine.
Asunto(s)
Antineoplásicos/farmacología , Butionina Sulfoximina/farmacología , Células Epiteliales/efectos de los fármacos , Glutatión/antagonistas & inhibidores , Peróxido de Hidrógeno/agonistas , Palmitoilcarnitina/farmacología , Apoptosis/efectos de los fármacos , Caspasa 3/genética , Caspasa 3/metabolismo , Relación Dosis-Respuesta a Droga , Células Epiteliales/metabolismo , Células Epiteliales/patología , Expresión Génica/efectos de los fármacos , Glutatión/metabolismo , Células HCT116 , Células HT29 , Humanos , Peróxido de Hidrógeno/metabolismo , Células MCF-7 , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Especificidad de Órganos , Oxidación-Reducción , Estrés Oxidativo , Cultivo Primario de CélulasRESUMEN
Plants suffer from combined stress of sulfur deficiency and cadmium toxicity in some agricultural lands. However, little is known about the reaction in plants, such as responses in antioxidant enzymes and non-protein thiol compounds, to such combined stress. Therefore, in this study, four treatments, S-sufficiency (TS-Cd), S-deficiency (T-S-Cd), Cd stress (TS+Cd) and combined stress of S-deficiency and Cd stress (T-S+Cd), were set up to investigate (1) the effects of sulfur deficiency or sulfur sufficiency on Cd toxicity to kidney bean cultivar seedlings and the related mechanisms, and (2) the responses of two kidney bean cultivars to combined stress of S-deficiency and Cd-tolerance. The results showed significant increases in hydrogen peroxide (H2O2) and malondialdehyde contents and significant increases in antioxidant enzyme (superoxide dismutase, catalase, peroxidase, and glutathione S-transferase) activities and non-protein thiol compounds (non-protein thiols, reduced glutathione, phytochelatins) synthesis in the plants in TS+Cd and T-S+Cd. On the tissue level, higher proportion of Cd was found to be immobilized/deposited in roots, while on the sub-cell level, higher proportion of Cd was located in cell walls and vacuole fractions with lower in cell organelles. Taken together, the results indicated that Cd detoxification was achieved by the two kidney bean cultivars through antioxidant enzyme activation, non-protein thiol compound synthesis and sub-cellular compartmentalization. In addition, the results indicated that sufficient S supply helped to relieve Cd toxicity, which is of special significance for remediation or utilization of Cd-contaminated soils as S is a plant essential nutrient.
Asunto(s)
Adaptación Fisiológica/genética , Cadmio/toxicidad , Regulación de la Expresión Génica/efectos de los fármacos , Phaseolus/efectos de los fármacos , Proteínas de Plantas/genética , Azufre/deficiencia , Catalasa/genética , Catalasa/metabolismo , Pared Celular/efectos de los fármacos , Pared Celular/metabolismo , Glutatión/metabolismo , Glutatión Peroxidasa/genética , Glutatión Peroxidasa/metabolismo , Glutatión Transferasa/genética , Glutatión Transferasa/metabolismo , Peróxido de Hidrógeno/agonistas , Peróxido de Hidrógeno/metabolismo , Estrés Oxidativo , Phaseolus/genética , Phaseolus/metabolismo , Fitoquelatinas/metabolismo , Células Vegetales/efectos de los fármacos , Células Vegetales/metabolismo , Hojas de la Planta/efectos de los fármacos , Hojas de la Planta/genética , Hojas de la Planta/metabolismo , Proteínas de Plantas/metabolismo , Raíces de Plantas/efectos de los fármacos , Raíces de Plantas/genética , Raíces de Plantas/metabolismo , Plantones/efectos de los fármacos , Plantones/genética , Plantones/metabolismo , Especificidad de la Especie , Estrés Fisiológico , Superóxido Dismutasa/genética , Superóxido Dismutasa/metabolismo , Vacuolas/efectos de los fármacos , Vacuolas/metabolismoRESUMEN
BACKGROUND: Accumulating evidence suggests that activated hepatocytes are involved in the deposition of the excess extracellular matrix during liver fibrosis via the epithelial to mesenchymal transition. Lipid accumulation in hepatocytes are implicated in the pathogenesis of chronic liver injury. CD36 is known to mediate long-chain fatty acid (LCFA) uptake and lipid metabolism. However, it is unclear whether LCFA directly promotes hepatocyte activation and the involved mechanisms have not been fully clarified. METHODS: Mice were fed with a high fat diet (HFD) and normal hepatocyte cells (Chang liver cells) were treated with palmitic acid (PA) in vivo and in vitro. Real-time polymerase chain reaction (RT-PCR) and western blotting were used to examine the gene and protein expression of molecules involved in hepatic fibrogenesis and hepatocyte activation. CD36 was knocked down by transfecting CD36 siRNA into hepatocyte cells. Hydrogen peroxide (H2O2) and reactive oxygen species (ROS) levels were detected using commercial kits. RESULTS: HFD induced a profibrogenic response and up-regulated CD36 expression in vivo. Analogously, PA increased lipid accumulation and induced human hepatocyte activation in vitro, which was also accompanied by increased CD36 expression. Interestingly, knockdown of CD36 resulted in a reduction of hepatocyte lipid deposition and decreased expression of Acta2 (34% decrease), Vimentin (29% decrease), Desmin (60% decrease), and TGF-ß signaling pathway related genes. In addition, HFD and PA increased the production of H2O2 in vivo (48% increase) and in vitro (385% increase), and the antioxidant, NAC, ameliorated PA-induced hepatocyte activation. Furthermore, silencing of CD36 in vitro markedly attenuated PA-induced oxidative stress (H2O2: 41% decrease; ROS: 39% decrease), and the anti-activation effects of CD36 knockdown could be abolished by pretreatment with H2O2. CONCLUSIONS: Our study demonstrated that LCFA facilitates hepatocyte activation by up-regulating oxidative stress through CD36, which could be an important mechanism in the development of hepatic fibrosis.
Asunto(s)
Antígenos CD36/genética , Dieta Alta en Grasa/efectos adversos , Cirrosis Hepática/genética , Enfermedad del Hígado Graso no Alcohólico/genética , Estrés Oxidativo/efectos de los fármacos , Ácido Palmítico/farmacología , Actinas/genética , Actinas/metabolismo , Animales , Antígenos CD36/antagonistas & inhibidores , Antígenos CD36/metabolismo , Línea Celular , Desmina/genética , Desmina/metabolismo , Regulación de la Expresión Génica , Hepatocitos/efectos de los fármacos , Hepatocitos/metabolismo , Hepatocitos/patología , Humanos , Peróxido de Hidrógeno/agonistas , Peróxido de Hidrógeno/metabolismo , Hígado/efectos de los fármacos , Hígado/metabolismo , Hígado/patología , Cirrosis Hepática/etiología , Cirrosis Hepática/metabolismo , Cirrosis Hepática/patología , Ratones , Enfermedad del Hígado Graso no Alcohólico/etiología , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Enfermedad del Hígado Graso no Alcohólico/patología , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismo , Transducción de Señal , Factor de Crecimiento Transformador beta/genética , Factor de Crecimiento Transformador beta/metabolismo , Vimentina/genética , Vimentina/metabolismoRESUMEN
Cynara scolymus L., popularly known as artichoke, is consumed as food and used as tea infusions for pharmacological purposes to treat liver dysfunctions and other conditions. Scientific data on the safety and protective effect of artichoke in human-derived liver cells is missing. This study investigated the genotoxic and modulatory effect of a liophilized extract suspended in water of C. scolymus L. leaves. Four extract concentrations (0.62, 1.25, 2.5 and 5.0 mg/mL) were evaluated using the comet assay on human hepatocyte cultures, HepG2 cells. Genotoxicity was assessed after two treatment periods, 1 and 24 h. Antigenotoxicity was evaluated against oxidative lesions induced by hydrogen peroxide in pre-, simultaneous and post-treatment protocols. Artichoke leaves aqueous extract induced genotoxic effects in HepG2 cells after 1- and 24-h treatments. In turn, extract concentrations of 0.62, 1.25 and 2.5 mg/mL, exhibited a protective effect in pretreatment, compared to hydrogen peroxide alone. However, in simultaneous and post-treatment protocols, only the lowest concentration reduced the frequency of DNA damage induced by hydrogen peroxide. In addition, in the simultaneous treatment protocol, the highest artichoke extract concentration increased hydrogen peroxide genotoxicity. It can be concluded that artichoke is genotoxic, in vitro, to HepG2 cells, but can also modulate hydrogen peroxide DNA damage.
Asunto(s)
Antioxidantes/efectos adversos , Cynara scolymus/química , Daño del ADN , Células Hep G2/metabolismo , Estrés Oxidativo , Extractos Vegetales/efectos adversos , Hojas de la Planta/química , Antioxidantes/aislamiento & purificación , Antioxidantes/metabolismo , Brasil , Línea Celular Tumoral , Ensayo Cometa , Cynara scolymus/crecimiento & desarrollo , Suplementos Dietéticos/efectos adversos , Liofilización , Células Hep G2/efectos de los fármacos , Hepatocitos , Humanos , Peróxido de Hidrógeno/agonistas , Peróxido de Hidrógeno/antagonistas & inhibidores , Peróxido de Hidrógeno/toxicidad , Pruebas de Mutagenicidad , Mutágenos/química , Mutágenos/toxicidad , Agricultura Orgánica , Oxidantes/agonistas , Oxidantes/antagonistas & inhibidores , Oxidantes/toxicidad , Extractos Vegetales/aislamiento & purificación , Extractos Vegetales/metabolismo , Hojas de la Planta/crecimiento & desarrollo , Sustancias Protectoras/efectos adversos , Sustancias Protectoras/aislamiento & purificación , Sustancias Protectoras/metabolismoRESUMEN
BACKGROUND: Magnesium oxide nanoparticles (MgO nanoparticles, with average size of 20 nm) have considerable potential as antimicrobial agents in food safety applications due to their structure, surface properties, and stability. The aim of this work was to investigate the antibacterial effects and mechanism of action of MgO nanoparticles against several important foodborne pathogens. RESULTS: Resazurin (a redox sensitive dye) microplate assay was used for measuring growth inhibition of bacteria treated with MgO nanoparticles. The minimal inhibitory concentrations of MgO nanoparticles to 10(4) colony-forming unit/ml (CFU/ml) of Campylobacter jejuni, Escherichia coli O157:H7, and Salmonella Enteritidis were determined to be 0.5, 1 and 1 mg/ml, respectively. To completely inactivate 10(8-9) CFU/ml bacterial cells in 4 h, a minimal concentration of 2 mg/ml MgO nanoparticles was required for C. jejuni whereas E. coli O157:H7 and Salmonella Enteritidis required at least 8 mg/ml nanoparticles. Scanning electron microscopy examination revealed clear morphological changes and membrane structural damage in the cells treated with MgO nanoparticles. A quantitative real-time PCR combined with ethidium monoazide pretreatment confirmed cell membrane permeability was increased after exposure to the nanoparticles. In a cell free assay, a low level (1.1 µM) of H2O2 was detected in the nanoparticle suspensions. Consistently, MgO nanoparticles greatly induced the gene expression of KatA, a sole catalase in C. jejuni for breaking down H2O2 to H2O and O2. CONCLUSIONS: MgO nanoparticles have strong antibacterial activity against three important foodborne pathogens. The interaction of nanoparticles with bacterial cells causes cell membrane leakage, induces oxidative stress, and ultimately leads to cell death.
Asunto(s)
Antibacterianos/farmacología , Campylobacter jejuni/efectos de los fármacos , Escherichia coli O157/efectos de los fármacos , Óxido de Magnesio/farmacología , Nanopartículas/química , Salmonella enteritidis/efectos de los fármacos , Antibacterianos/química , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Campylobacter jejuni/crecimiento & desarrollo , Campylobacter jejuni/ultraestructura , Catalasa/genética , Catalasa/metabolismo , Recuento de Colonia Microbiana , Escherichia coli O157/crecimiento & desarrollo , Escherichia coli O157/ultraestructura , Contaminación de Alimentos , Microbiología de Alimentos , Expresión Génica , Peróxido de Hidrógeno/agonistas , Peróxido de Hidrógeno/metabolismo , Óxido de Magnesio/química , Pruebas de Sensibilidad Microbiana , Oxazinas/química , Estrés Oxidativo , Salmonella enteritidis/crecimiento & desarrollo , Salmonella enteritidis/ultraestructura , Xantenos/químicaRESUMEN
BACKGROUND: Barley straw (Hordeum vulgare L.) is an attractive lignocellulosic material and one of the most abundant renewable resources for fuel ethanol production. Although it has high cellulose and hemicellulose contents, there are several challenges and limitations in the process of converting it to fuel ethanol. High ash, silica and lignin contents in barley straw make it an inferior feedstock for enzymatic hydrolysis. Therefore pretreatment of barley straw could play an important role in inducing structural and compositional changes that increase the efficiency of enzymatic hydrolysis and make the whole process economically viable. RESULTS: Saccharification was enhanced using various concentrations (0.0, 0.5, 1.0, 2.0 and 3.0% v/v) of a solution of sodium hypochlorite (NaClO) and hydrogen peroxide (H2O2) and various reaction times (15, 30 and 45 min) during pretreatment at 121 °C. The highest yield of glucose (447 mg g⻹) was achieved by pretreatment with 2.0% NaClO+H2O2 solution for 30 min, representing an increase of 65.99% compared with untreated barley straw (152 mg g⻹). During fermentation, the highest amount of ethanol (207 mg g⻹) was obtained under anaerobic plus 0.4 mmol L⻹ benzoic acid conditions, representing an increase of 57.49, 38.16 and 10.14% compared with untreated sample (88 mg g⻹), aerobic (128 mg g⻹) and anaerobic (186 mg g⻹) conditions respectively. CONCLUSION: The results suggest that pretreatment with 2.0% NaClO+H2O2 solution disrupted the recalcitrant structure of barley straw and enhanced the glucose yield and subsequent bioethanol production.
Asunto(s)
Biocombustibles/análisis , Pared Celular/efectos de los fármacos , Productos Agrícolas/efectos de los fármacos , Etanol/metabolismo , Hordeum/efectos de los fármacos , Componentes Aéreos de las Plantas/efectos de los fármacos , Ácido Benzoico/farmacología , Pared Celular/química , Pared Celular/ultraestructura , Productos Agrícolas/química , Productos Agrícolas/metabolismo , Productos Agrícolas/microbiología , Sinergismo Farmacológico , Etanol/análisis , Etanol/química , Fermentación , Glucosa/análisis , Glucosa/química , Glucosa/metabolismo , Hordeum/química , Hordeum/metabolismo , Hordeum/microbiología , Peróxido de Hidrógeno/agonistas , Peróxido de Hidrógeno/farmacología , Hidrólisis , Cinética , Lignina/análisis , Lignina/química , Lignina/metabolismo , Microscopía Electrónica de Rastreo , Oxidantes/agonistas , Oxidantes/farmacología , Componentes Aéreos de las Plantas/química , Componentes Aéreos de las Plantas/metabolismo , Componentes Aéreos de las Plantas/microbiología , República de Corea , Saccharomyces cerevisiae/crecimiento & desarrollo , Saccharomyces cerevisiae/metabolismo , Hipoclorito de Sodio/agonistas , Hipoclorito de Sodio/farmacología , Propiedades de SuperficieRESUMEN
BACKGROUND: Shark liver oil (SLOil) and fish oil (FOil), which are respectively rich in alkylglycerols (AKGs) and n-3 polyunsaturated fatty acids (PUFAs), are able to reduce the growth of some tumors and the burden of cachexia. It is known that FOil is able to reduce proliferation rate and increase apoptotic cells and lipid peroxidation of tumor cells efficiently. However, there are few reports revealing the influence of SLOil on these parameters. In the current study, effects of FOil chronic supplementation on tumor growth and cachexia were taken as reference to compare the results obtained with SLOil supplementation. Also, we evaluated if the association of SLOil and FOil was able to promote additive effects. METHODS: Weanling male Wistar rats were divided into 4 groups: fed regular chow (C), supplemented (1 g/kg body weight) with SLOil (CSLO), FOil (CFO) and both (CSLO + FO). After 8 weeks half of each group was inoculated with Walker 256 cells originating new groups (W, WSLO, WFO and WSLO + FO). Biochemical parameters of cachexia, tumor weight, hydroperoxide content, proliferation rate and percentage of apoptotic tumor cells were analysed. Fatty acids and AKG composition of tumor and oils were obtained by high performance liquid chromatography and gas chromatography - mass spectrometry, respectively. Statistical analysis was performed by unpaired t-test and one-way ANOVA followed by a post hoc Tukey test. RESULTS: Fourteen days after inoculation, SLOil was able to restore cachexia parameters to control levels, similarly to FOil. WSLO rats presented significantly lower tumor weight (40%), greater tumor cell apoptosis (~3-fold), decreased tumor cell proliferation (35%), and higher tumor content of lipid hydroperoxides (40%) than observed in W rats, but FOil showed more potent effects. Supplementation with SLOil + FOil did not promote additive effects. Additionally, chromatographic results suggested a potential incorporation competition between the n-3 fatty acids and the AKGs in the tumor cells' membranes. CONCLUSIONS: SLOil is another marine source of lipids with similar FOil anti-cachectic capacity. Furthermore, despite being less potent than FOil, SLOil presented significant in vivo antitumor effects. These results suggest that the chronic supplementation with SLOil may be adjuvant of the anti-cancer therapy.
Asunto(s)
Antineoplásicos/farmacología , Caquexia/dietoterapia , Carcinoma 256 de Walker/dietoterapia , Suplementos Dietéticos , Aceites de Pescado/farmacología , Hígado/química , Animales , Antineoplásicos/aislamiento & purificación , Apoptosis/efectos de los fármacos , Caquexia/complicaciones , Caquexia/metabolismo , Caquexia/patología , Carcinoma 256 de Walker/complicaciones , Carcinoma 256 de Walker/metabolismo , Carcinoma 256 de Walker/patología , Proliferación Celular/efectos de los fármacos , Cromatografía Líquida de Alta Presión , Ácidos Grasos/metabolismo , Aceites de Pescado/aislamiento & purificación , Cromatografía de Gases y Espectrometría de Masas , Peróxido de Hidrógeno/agonistas , Peróxido de Hidrógeno/metabolismo , Masculino , Ratas , Ratas Wistar , Tiburones/metabolismo , Carga Tumoral/efectos de los fármacos , DesteteRESUMEN
Today the noxiousness of blue light from natural and particularly artificial (fluorescent tubes, LED panels, visual displays) sources is actively discussed in the context of various ocular diseases. Many of them have an important neurologic component and are associated with ocular pain. This neuropathic signal is provided by nociceptive neurons from trigeminal ganglia. However, the phototoxicity of blue light on trigeminal neurons has not been explored so far. The aim of the present in vitro study was to investigate the cytotoxic impact of various wavebands of visible light (410-630â¯nm) on primary cell culture of mouse trigeminal neural and glial cells. Three-hour exposure to narrow wavebands of blue light centered at 410, 440 and 480â¯nm of average 1.1â¯mW/cm2 irradiance provoked cell death, altered cell morphology and induced oxidative stress and inflammation. These effects were not observed for other tested visible wavebands. We observed that neurons and glial cells processed the light signal in different manner, in terms of resulting superoxide and hydrogen peroxide generation, inflammatory biomarkers expression and phototoxic mitochondrial damage. We analyzed the pathways of photic signal reception, and we proposed that, in trigeminal cells, in addition to widely known mitochondria-mediated light absorption, light could be received by means of non-visual opsins, melanopsin (opn4) and neuropsin (opn5). We also investigated the mechanisms underlying the observed phototoxicity, further suggesting an important role of the endoplasmic reticulum in neuronal transmission of blue-light-toxic message. Taken together, our results give some insight into circuit of tangled pain and photosensitivity frequently observed in patients consulting for these ocular symptoms.
Asunto(s)
Muerte Celular/efectos de la radiación , Peróxido de Hidrógeno/agonistas , Luz/efectos adversos , Neuroglía/efectos de la radiación , Neuronas/efectos de la radiación , Superóxidos/agonistas , Animales , Relación Dosis-Respuesta en la Radiación , Retículo Endoplásmico/metabolismo , Retículo Endoplásmico/efectos de la radiación , Expresión Génica/efectos de la radiación , Peróxido de Hidrógeno/metabolismo , Fototransducción , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Ratones , Mitocondrias/metabolismo , Mitocondrias/efectos de la radiación , Neuroglía/metabolismo , Neuronas/metabolismo , Opsinas/genética , Opsinas/metabolismo , Estrés Oxidativo/efectos de la radiación , Cultivo Primario de Células , Opsinas de Bastones/genética , Opsinas de Bastones/metabolismo , Superóxidos/metabolismo , Ganglio del Trigémino/metabolismo , Ganglio del Trigémino/efectos de la radiaciónRESUMEN
Leishmania establishes a successful parasitism by evading both oxidative and non-oxidative killing pathways, and its drug resistance against the currently available therapeutics demands for a safe and cheap drug. Since the parasite synthesizes ergosterol instead of cholesterol, using the same biochemical pathway and enzymes, an inhibitor of HMG-CoA-Reductase, Lovastatin, has been tried for its anti-Leishmanial effect. Lovastatin, being an inhibitor of HMG-CoA-Reductase, inhibits infection by cholesterol depletion, while chromium chloride complexes, at their higher concentrations, are reported to exhibit cytotoxicity. In intracellular amastigotes, cytotoxicity has been checked by assessing various manifestation of cell death, viz. DNA fragmentation, AnnexinV-FITC binding and JC-1 fluorescence ratio. Release of hydrogen peroxide (HPO) and nitric oxide (NO) has been assessed in live cell. Lovastatin and CrCl3.6H2O in combination has appeared to be ineffective on promastigotes but has induced cytotoxic effect on the intracellular amastigotes through up-regulation of cellular signalling mechanisms. CrCl 3.6H2O stimulates generation of NO, leading to reduction of the number of intracellular amastigote, while Lovastatin shows HPO-mediated killing of the same, keeping the host cell unaffected. This novel therapeutic approach, involving two known safe compounds in suboptimal doses, may resolve human visceral Leishmaniasis.
Asunto(s)
Antiprotozoarios/farmacología , Apoptosis/efectos de los fármacos , Cloruros/farmacología , Compuestos de Cromo/farmacología , Hipolipemiantes/farmacología , Leishmania donovani/efectos de los fármacos , Lovastatina/farmacología , Colesterol/metabolismo , Técnicas de Cocultivo , Combinación de Medicamentos , Sinergismo Farmacológico , Humanos , Peróxido de Hidrógeno/agonistas , Peróxido de Hidrógeno/metabolismo , Leishmania donovani/crecimiento & desarrollo , Leishmania donovani/metabolismo , Leucocitos Mononucleares/efectos de los fármacos , Leucocitos Mononucleares/parasitología , Metabolismo de los Lípidos/efectos de los fármacos , Óxido Nítrico/agonistas , Óxido Nítrico/biosíntesis , Pruebas de Sensibilidad Parasitaria , Cultivo Primario de Células , Células THP-1RESUMEN
Aminoguanidine (AG), a diamine oxidase and a nitric oxide synthase inhibitor, was used in diabetes, thyroid follicular carcinoma, hepatocellular carcinoma, pancreatic cancer xenografts and in breast cancer research. The effects of AG on these pathologic conditions may be related to its regulatory effects on cell proliferation, angiogenesis, and expression of antioxidant enzymes. However, its role as pro and/or anti-oxidant affecting signaling and function in pancreatic tumor cell lines has not been studied. The current study tested the hypothesis that exposure of AR42J cells to aminoguanidine will induce pro-oxidant effects that may lead to increased proliferation and growth of these cells. METHODS: AR42J cells were grown in F-12 nutrient medium in 5% CO2 at 37°C to attain over 90% confluency before being treated with 20 uM hydrogen peroxide (H2O2) for 20 min and 100 uM AG for 30 min separately and in combination. Cell lysates collected from these experiments were measured for formation of lipid peroxides by malondialdehyde (MDA) assay and for activation of phospho-ERK 1/2 signal transduction by Western blotting. The activation of ERK signaling was further confirmed by immunohistochemical analysis. Effect of ERK1/2 on cell proliferation in response to AG and H2O2 was evaluated by MTT assay while the functional status of AR42J cells was determined by release of amylase following CCK-8 stimulation. RESULTS: MDA concentration in cells treated with AG was not different from untreated cells. However, treatment with H2O2 either alone or in combination with AG increased MDA significantly (p<0.05). AG treatment alone induced 3.5 fold activation of pERK-1/2, as compared to 2.5 fold increase with H2O2 alone (p<0.05) as compared to untreated control. The results of ERK activation were confirmed further by its co-localization employing FITC-conjugated ERK antibody. AG -induced maximal cell proliferation occurred at 48 hr. incubation (p<0.05); these values were not significantly different from that of H2O2 treated and control cells. Cell function (CCK-stimulated amylase release) was significantly enhanced by AG (p<0.05). CONCLUSION: These data suggest that in an in-vitro system, AG acts as a pro-oxidant on AR42J cell proliferation and possibly affects the resulting function.
Asunto(s)
Antioxidantes/farmacología , Guanidinas/farmacología , Peroxidación de Lípido/efectos de los fármacos , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Oxidantes/agonistas , Estrés Oxidativo/efectos de los fármacos , Neoplasias Pancreáticas/tratamiento farmacológico , Animales , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Sinergismo Farmacológico , Activación Enzimática/efectos de los fármacos , Peróxido de Hidrógeno/agonistas , Peróxido de Hidrógeno/farmacología , Malondialdehído/metabolismo , Proteína Quinasa 1 Activada por Mitógenos/química , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/química , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Proteínas de Neoplasias/agonistas , Proteínas de Neoplasias/metabolismo , Oxidantes/farmacología , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patología , Transporte de Proteínas/efectos de los fármacos , RatasRESUMEN
The use of self-medication, which includes dietary supplements and over-the-counter drugs, is still on the rise, while safety issues are not well addressed yet. This especially holds for combinations. For example, iron supplements and magnesium peroxide both produce adverse effects via the formation of reactive oxygen species (ROS). This prompted us to investigate the effect of the combination of three different iron supplements with magnesium peroxide on ROS formation. Hydroxyl radical formation by the three iron supplements either combined with magnesium peroxide or alone was determined by performing a deoxyribose assay. Free iron content of iron supplements was determined using ferrozine assay. To determine hydrogen peroxide formation by magnesium peroxide, a ferrous thiocyanate assay was performed. Finally, electron spin resonance spectroscopy (ESR) was performed to confirm the formation of hydroxyl radicals. Our results show that magnesium peroxide induces the formation of hydrogen peroxide. All three iron supplements induced the formation of the extremely reactive hydroxyl radical, although the amount of radicals formed by the different supplements differed. It was shown that combining iron supplements with magnesium peroxide increases radical formation. The formation of hydroxyl radicals after the combination was confirmed with ESR. All three iron supplements contained labile iron and induced the formation of hydroxyl radicals. Additionally, magnesium peroxide in water yields hydrogen peroxide, which is converted into hydroxyl radicals by iron. Hence, iron supplements and magnesium peroxide is a hazardous combination and exemplifies that more attention should be given to combinations of products used in self-medication.
Asunto(s)
Antiácidos/efectos adversos , Suplementos Dietéticos/efectos adversos , Interacciones Alimento-Droga , Hierro de la Dieta/efectos adversos , Compuestos de Magnesio/efectos adversos , Peróxidos/efectos adversos , Especies Reactivas de Oxígeno/química , Autocuidado/efectos adversos , Antiácidos/química , Desoxirribosa/química , Espectroscopía de Resonancia por Spin del Electrón , Compuestos Ferrosos/efectos adversos , Compuestos Ferrosos/química , Humanos , Peróxido de Hidrógeno/agonistas , Peróxido de Hidrógeno/análisis , Peróxido de Hidrógeno/química , Concentración de Iones de Hidrógeno , Radical Hidroxilo/agonistas , Radical Hidroxilo/análisis , Radical Hidroxilo/química , Lactatos/efectos adversos , Lactatos/química , Compuestos de Magnesio/química , Países Bajos , Medicamentos sin Prescripción/efectos adversos , Concentración Osmolar , Peróxidos/química , Especies Reactivas de Oxígeno/análisis , Automedicación/efectos adversosRESUMEN
In our previous study, we demonstrated that combined treatment with hydrogen (H2) and platinum nanocolloid (Pt-nc) exerted markedly antiproliferative effects on cancer cells compared with each treatment alone. However, because the related mechanisms remain unclear, we investigated carcinostatic mechanisms of the combined treatment with H2 + Pt-nc. Significant suppression of cell proliferation was confirmed at 52 h following combined treatment, and the similar effect was also observed by the 30- or 40-min transient treatment with H2 + Pt-nc. The transient treatments led to changes in cell size and morphology, loss of microvilli, and apoptosis-like cell death at 120 h after treatment. Moreover, transient combined treatment with H2 + Pt-nc induced cell-cycle arrest, as reflected by decreased proportions of G1-phase cells and accumulation of G2/M-phase cells. In contrast, intracellular peroxide levels were temporarily and significantly increased immediately after H2 + Pt-nc treatment but not after treatment with H2 or Pt-nc alone. Additionally, combined treatment-induced carcinostatic effects were significantly diminished in the presence of catalase, and marked hydrogen peroxide (H2O2) generation was confirmed after mixing Pt-nc into cell culture media containing a high concentration of H2. These changes are in agreement with the results that carcinostatic effects were induced after only 40 min of treatment with H2 + Pt-nc. Thus, transient and marked generation of H2O2 is responsible for the carcinostatic effects of combined treatment with H2 + Pt-nc.
Asunto(s)
Antineoplásicos/farmacología , Citostáticos/farmacología , Puntos de Control de la Fase G2 del Ciclo Celular/efectos de los fármacos , Peróxido de Hidrógeno/agonistas , Hidrógeno/farmacología , Platino (Metal)/farmacología , Animales , Apoptosis/efectos de los fármacos , Catalasa/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Coloides , División del ADN/efectos de los fármacos , Combinación de Medicamentos , Sinergismo Farmacológico , Peróxido de Hidrógeno/metabolismo , Linfocitos/citología , Linfocitos/efectos de los fármacos , Linfocitos/metabolismo , Ratones , NanoestructurasRESUMEN
Tyramine is naturally occurring in food and induces pressor responses. Low-tyramine diets are recommended for patients treated with MAO inhibitors to avoid the fatal hypertensive crisis sadly known as "cheese effect". Hence, tyramine intake is suspected to have toxicological consequences in humans, while its administration to type 1 diabetic rodents has been reported to improve glucose tolerance. We investigated in mice whether prolonged tyramine ingestion could alter glucose homeostasis, insulin sensitivity, adipose tissue physiology or cardiovascular functions. Tyramine was added at 0.04 or 0.14 % in the drinking water since this was estimated to increase by 10- to 40-fold the spontaneous tyramine intake of control mice fed a standard diet. Ten to 12 weeks of such tyramine supplementation did not influence body weight gain, adiposity or food consumption. Both doses (reaching approx. 300 and 1100 µmol tyramine/kg bw/day) decreased nonfasting blood glucose but did not modify glucose tolerance or fasting levels of glucose, insulin or circulating lipids. Blood pressure was not increased in tyramine-drinking mice, while only the higher tested dose moderately increased heart rate without change in its variability. Markers of cardiac tissue injury or oxidative stress remained unaltered, except an increased hydrogen peroxide production in heart preparations. In isolated adipocytes, tyramine inhibited lipolysis similarly in treated and control groups, as did insulin. The lack of serious adverse cardiovascular effects of prolonged tyramine supplementation in normoglycemic mice together with the somewhat insulin-like effects found on adipose cells should lead to reconsider favourably the risk/benefit ratio of the intake of this dietary amine.
Asunto(s)
Enfermedades Cardiovasculares/etiología , Dieta/efectos adversos , Intolerancia a la Glucosa/etiología , Tiramina/efectos adversos , Vasoconstrictores/efectos adversos , Adipocitos/citología , Adipocitos/metabolismo , Adipocitos/patología , Adiposidad , Animales , Biomarcadores/sangre , Glucemia/análisis , Enfermedades Cardiovasculares/sangre , Enfermedades Cardiovasculares/metabolismo , Enfermedades Cardiovasculares/patología , Células Cultivadas , Ingestión de Energía , Intolerancia a la Glucosa/sangre , Intolerancia a la Glucosa/metabolismo , Intolerancia a la Glucosa/patología , Peróxido de Hidrógeno/agonistas , Peróxido de Hidrógeno/metabolismo , Insulina/análisis , Lípidos/sangre , Masculino , Ratones Endogámicos C57BL , Miocardio/metabolismo , Estrés Oxidativo , Factores de Tiempo , Pruebas de Toxicidad Crónica , Tiramina/administración & dosificación , Vasoconstrictores/administración & dosificación , Aumento de PesoRESUMEN
The rate of superoxide anion radical, hydroxyl radical and hydrogen peroxide generation, the level of oxidative modification of mitochondrial proteins in the liver of rats with toxic hepatitis was investigated on the background of alimentary protein deficiency. We did not find significant increases of the intensity of free radical processes in liver mitochondria of rats maintained on the protein-deficient ration. The most significant intensification of free radical processes in liver mitochondria is observed under the conditions of toxic hepatitis, induced on the background of alimentary protein deprivation. Under these conditions the aggravation of all studied forms of reactive oxygen species generation was observed in liver mitochondria. The generation rates were increased as follows: O2 by 1.7 times, Ð2Ð2 by 1.5 times, â¢ÐÐ practically double on the background of accumulation of oxidized mitochondria-derived proteins. The established changes in thiol groups' redox status of respiratory chain proteins insoluble in 0.05 M sodium-phosphate buffer (pH 11.5), and changes of their carbonyl derivatives content may be considered as one of the regulatory factors of mitochondrial energy-generating function.
Asunto(s)
Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Peróxido de Hidrógeno/metabolismo , Radical Hidroxilo/metabolismo , Mitocondrias Hepáticas/metabolismo , Deficiencia de Proteína/metabolismo , Superóxidos/metabolismo , Acetaminofén/toxicidad , Animales , Animales no Consanguíneos , Enfermedad Hepática Inducida por Sustancias y Drogas/complicaciones , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Dieta con Restricción de Proteínas/efectos adversos , Peróxido de Hidrógeno/agonistas , Radical Hidroxilo/agonistas , Hígado/efectos de los fármacos , Hígado/metabolismo , Hígado/patología , Mitocondrias Hepáticas/efectos de los fármacos , Oxidación-Reducción , Estrés Oxidativo , Carbonilación Proteica , Deficiencia de Proteína/complicaciones , Deficiencia de Proteína/etiología , Deficiencia de Proteína/patología , Ratas , Superóxidos/agonistasRESUMEN
To improve the treatment of advanced prostate cancer, the development of effective and innovative antitumor agents is needed. Our previous work demonstrated that the ROS (reactive oxygen species) scavenger, MnTE-2-PyP, inhibited human prostate cancer growth and also inhibited prostate cancer migration and invasion. We showed that MnTE-2-PyP treatment altered the affinity of the histone acetyltransferase enzyme, p300, to bind to DNA. We speculate that this may be one mechanism by which MnTE-2-PyP inhibits prostate cancer progression. Specifically, MnTE-2-PyP decreased p300/HIF-1/CREB complex (p300/hypoxia-inducible factor-1/cAMP response element-binding protein) binding to a specific hypoxia-response element (HRE) motif within the plasminogen activator inhibitor-1 (PAI-1) gene promoter region, and consequently, repressed PAI-1 expression. However, it remains unclear how MnTE-2-PyP reduces p300 complex binding affinity to the promoter region of specific genes. In this study, we found that overexpression of Cu/ZnSOD (superoxide dismutase 1, SOD1) significantly suppressed PAI-1 gene expression and p300 complex binding to the promoter region of PAI-1 gene, just as was observed in cells treated with MnTE-2-PyP. Furthermore, catalase (CAT) overexpression rescued the inhibition of PAI-1 expression and p300 binding by MnTE-2-PyP. Taken together, the above findings suggest that hydrogen peroxide (H2O2) is likely the mediator through which MnTE-2-PyP inhibits the PAI-1 expression and p300 complex binding in PC3 cells. To confirm this, we measured the production of H2O2 following overexpression of SOD1 or catalase with MnTE-2-PyP treatment in the presence or absence of radiation. We found that MnTE-2-PyP increased the intracellular steady-state levels of H2O2 and increased nuclear H2O2 levels. As expected, catalase overexpression significantly decreased the levels of intracellular H2O2 induced by MnTE-2-PyP. We then determined if this increased H2O2 production could result in oxidized protein thiol groups. In the presence of MnTE-2-PyP, there was a significant increase in oxidized thiols in PC3 cell lysates and this was reversed with catalase overexpression. Specifically, we showed that p300 was oxidized after MnTE-2-PyP treatment, indicating that MnTE-2-PyP is creating a more oxidizing environment and this is altering the oxidation state of p300 thiol residues. Our data provide an in depth mechanism by which MnTE-2-PyP regulates gene transcription through induced H2O2 mediated oxidation of particular proteins, supporting an important role for MnTE-2-PyP as an effective and innovative antitumor agent to enhance treatment outcomes in prostate cancer radiotherapy.
Asunto(s)
Antineoplásicos/farmacología , Proliferación Celular/efectos de los fármacos , Células Epiteliales/efectos de los fármacos , Peróxido de Hidrógeno/agonistas , Metaloporfirinas/farmacología , Catalasa/genética , Catalasa/metabolismo , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/genética , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Células Epiteliales/metabolismo , Células Epiteliales/patología , Humanos , Peróxido de Hidrógeno/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Masculino , Oxidación-Reducción , Inhibidor 1 de Activador Plasminogénico/genética , Inhibidor 1 de Activador Plasminogénico/metabolismo , Regiones Promotoras Genéticas , Próstata/efectos de los fármacos , Próstata/metabolismo , Próstata/patología , Unión Proteica , Superóxido Dismutasa-1/genética , Superóxido Dismutasa-1/metabolismo , Factores de Transcripción p300-CBP/genética , Factores de Transcripción p300-CBP/metabolismoRESUMEN
Glioblastoma multiforme is the most malignant tumor of the brain and is challenging to treat due to its highly invasive nature and heterogeneity. Malignant brain tumor displays high metabolic activity which perturbs its redox environment and in turn translates to high oxidative stress. Thus, pushing the oxidative stress level to achieve the maximum tolerable threshold that induces cell death is a potential strategy for cancer therapy. Previously, we have shown that gap junction inhibitor, carbenoxolone (CBX), is capable of enhancing tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) -induced apoptosis in glioma cells. Since CBX is known to induce oxidative stress, we hypothesized that the addition of another potent mediator of oxidative stress, powerful SOD mimic MnTnBuOE-2-PyP(5+) (MnBuOE), could further enhance TRAIL-driven therapeutic efficacy in glioma cells. Our results showed that combining TRAIL + CBX with MnBuOE significantly enhances cell death of glioma cell lines and this enhancement could be further potentiated by CBX pretreatment. MnBuOE-driven cytotoxicity is due to its ability to take advantage of oxidative stress imposed by CBX + TRAIL system, and enhance it in the presence of endogenous reductants, ascorbate and thiol, thereby producing cytotoxic H2O2, and in turn inducing death of glioma cells but not normal astrocytes. Most importantly, combination treatment significantly reduces viability of TRAIL-resistant Asian patient-derived glioma cells, thus demonstrating the potential clinical use of our therapeutic system. It was reported that H2O2 is involved in membrane depolarization-based sensitization of cancer cells toward TRAIL. MnBuOE is entering Clinical Trials as a normal brain radioprotector in glioma patients at Duke University increasing Clinical relevance of our studies.
Asunto(s)
Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Materiales Biomiméticos/farmacología , Carbenoxolona/farmacología , Metaloporfirinas/farmacología , Ligando Inductor de Apoptosis Relacionado con TNF/farmacología , Ácido Ascórbico/agonistas , Ácido Ascórbico/biosíntesis , Astrocitos/citología , Astrocitos/efectos de los fármacos , Materiales Biomiméticos/síntesis química , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Línea Celular , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Combinación de Medicamentos , Resistencia a Antineoplásicos/efectos de los fármacos , Sinergismo Farmacológico , Uniones Comunicantes/efectos de los fármacos , Glioblastoma/tratamiento farmacológico , Glioblastoma/genética , Glioblastoma/metabolismo , Glioblastoma/patología , Humanos , Peróxido de Hidrógeno/agonistas , Peróxido de Hidrógeno/metabolismo , Metaloporfirinas/síntesis química , Especificidad de Órganos , Estrés Oxidativo , Cultivo Primario de Células , Compuestos de Sulfhidrilo/agonistas , Compuestos de Sulfhidrilo/metabolismo , Superóxido Dismutasa/químicaRESUMEN
Bisphenol A (BPA) is an important industrial raw material. Because of its widespread use and increasing release into environment, BPA has become a new environmental pollutant. Previous studies about BPA's effects in plants focus on a certain growth stage. However, the plant's response to pollutants varies at different growth stages. Therefore, in this work, BPA's effects in soybean roots at different growth stages were investigated by determining the reactive oxygen species levels, membrane lipid fatty acid composition, membrane lipid peroxidation, and antioxidant systems. The results showed that low-dose BPA exposure slightly caused membrane lipid peroxidation but didn't activate antioxidant systems at the seedling stage, and this exposure did not affect above process at other growth stages; high-dose BPA increased reactive oxygen species levels and then caused membrane lipid peroxidation at all growth stages although it activated antioxidant systems, and these effects were weaker with prolonging the growth stages. The recovery degree after withdrawal of BPA exposure was negatively related to BPA dose, but was positively related to growth stage. Taken together, the effects of BPA on antioxidant systems in soybean roots were associated with BPA exposure dose and soybean growth stage.
Asunto(s)
Antioxidantes/metabolismo , Compuestos de Bencidrilo/farmacología , Contaminantes Ambientales/farmacología , Glycine max/efectos de los fármacos , Fenoles/farmacología , Raíces de Plantas/efectos de los fármacos , Catalasa/metabolismo , Membrana Celular/química , Membrana Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ácidos Grasos/aislamiento & purificación , Flores/efectos de los fármacos , Flores/crecimiento & desarrollo , Flores/metabolismo , Peróxido de Hidrógeno/agonistas , Peróxido de Hidrógeno/metabolismo , Peroxidación de Lípido/efectos de los fármacos , Malondialdehído/agonistas , Malondialdehído/metabolismo , Peroxidasa/metabolismo , Células Vegetales/química , Células Vegetales/efectos de los fármacos , Raíces de Plantas/crecimiento & desarrollo , Raíces de Plantas/metabolismo , Plantones/efectos de los fármacos , Plantones/crecimiento & desarrollo , Plantones/metabolismo , Semillas/efectos de los fármacos , Semillas/crecimiento & desarrollo , Semillas/metabolismo , Glycine max/crecimiento & desarrollo , Glycine max/metabolismo , Superóxido Dismutasa/metabolismo , Superóxidos/agonistas , Superóxidos/metabolismoRESUMEN
We have investigated the termination of agonist-stimulated mitogen-activated protein (MAP) kinase activity in EAhy926 cells by MAP kinase phosphatase-2 (MKP-2). In cells expressing either wild-type (WT) or catalytically inactive (CI)-MKP-2, there was no significant differences in TNFalpha-stimulated JNK or p38 MAP kinase activity, however hydrogen peroxide (H2O2)-stimulated JNK activity was substantially reduced in WT-MKP-2 expressing clones and enhanced in cells expressing CI-MKP-2. Consistent with these findings, we observed substantial nuclear translocation of JNK occurred in response to H2O2 but not TNFalpha. Using a phosphospecific anti-JNK antibody, we found that TNFalpha-stimulated JNK activity was associated principally with the cytosol while in response to H2O2, JNK activity was found within the nucleus. These results show that the role of MKP-2 in terminating JNK activity is determined by the translocation of JNK to the nucleus, which is under agonist-specific regulation and not a universal cellular response to stimulation.
Asunto(s)
Núcleo Celular/enzimología , Endotelio/citología , Endotelio/metabolismo , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Proteínas Tirosina Fosfatasas/metabolismo , Anticuerpos Antiidiotipos/inmunología , Fosfatasas de Especificidad Dual , Humanos , Peróxido de Hidrógeno/agonistas , Peróxido de Hidrógeno/metabolismo , Proteínas Quinasas JNK Activadas por Mitógenos , Fosfatasas de la Proteína Quinasa Activada por Mitógenos , Proteínas Quinasas Activadas por Mitógenos/química , Fosforilación , Proteína Fosfatasa 2 , Transporte de Proteínas/fisiología , Especificidad por Sustrato , Factor de Necrosis Tumoral alfa/agonistas , Factor de Necrosis Tumoral alfa/metabolismo , Proteínas Quinasas p38 Activadas por MitógenosRESUMEN
6-Hydroxydopamine (6-OHDA) neurotoxicity has often been related to the generation of free radicals. Here we examined the effect of the presence of iron (Fe(2+) and Fe(3+)) and manganese and the mediation of ascorbate, L-cysteine (CySH), glutathione (GSH), and N-acetyl-CySH on hydroxyl radical (*OH) production during 6-OHDA autoxidation. In vitro, the presence of 800 nM iron increased (> 100%) the production of *OH by 5 microM 6-OHDA while Mn(2+) caused a significant reduction (72%). The presence of ascorbate (100 microM) induced a continuous generation of *OH while the presence of sulfhydryl reductants (100 microM) limited this production to the first minutes of the reaction. In general, the combined action of metal + antioxidant increased the *OH production, this effect being particularly significant (> 400%) with iron + ascorbate. In vivo, tyrosine hydroxylase immunohistochemistry revealed that intrastriatal injections of rats with 6-OHDA (30 nmol) + ascorbate (600 nmol), 6-OHDA + ascorbate + Fe(2+) (5 nmol), and 6-OHDA + ascorbate + Mn(2+) (5 nmol) caused large striatal lesions, which were markedly reduced (60%) by the substitution of ascorbate by CySH. Injections of Fe(2+) or Mn(2+) alone showed no significant difference to those of saline. These results clearly demonstrate the role of ascorbate as an essential element for the neurotoxicity of 6-OHDA, as well as the diminishing action of sulfhydryl reductants, and the negligible effect of iron and manganese on 6-OHDA neurotoxicity.
Asunto(s)
Antioxidantes/metabolismo , Radical Hidroxilo/metabolismo , Hierro/metabolismo , Manganeso/metabolismo , Oxidopamina/metabolismo , Oxidopamina/toxicidad , Acetilcisteína/metabolismo , Acetilcisteína/farmacología , Animales , Antioxidantes/farmacología , Ácido Ascórbico/metabolismo , Ácido Ascórbico/farmacología , Cuerpo Estriado/metabolismo , Cisteína/metabolismo , Cisteína/farmacología , Femenino , Glutatión/metabolismo , Glutatión/farmacología , Peróxido de Hidrógeno/agonistas , Peróxido de Hidrógeno/antagonistas & inhibidores , Peróxido de Hidrógeno/metabolismo , Radical Hidroxilo/agonistas , Radical Hidroxilo/antagonistas & inhibidores , Hierro/farmacología , Manganeso/farmacología , Oxidación-Reducción , Ratas , Ratas Sprague-DawleyRESUMEN
Cancer chemotherapy is associated with neutropenia and impaired neutrophil function. This study aimed to investigate whether supplementation with low dose fish oil (FO), providing n-3 polyunsaturated fatty acids, in cancer patients receiving chemotherapy after surgical tumor (mainly gastrointestinal) removal is able to improve the function of blood neutrophils. Patients (n = 38) receiving chemotherapy (5-fluorouracil and leucovorin) were randomized into two groups; one group (control) did not receive a supplement, while the other group (FO) received 2 g FO/day for 8 weeks; the FO provided 0.3 g eicosapentaenoic acid plus 0.4 g docosahexaenoic acid per day. Patients in the control group lost an average of 2.5 kg of weight over the 8 weeks of the study. The number of blood polymorphonuclear cells (PMNC), mainly neutrophils, and their functions (phagocytosis and hydrogen peroxide production) decreased in the control group (average decreases of approximately 30, 45 and 17%, respectively). FO prevented these decreases and actually increased body weight (average of 1.7 kg weight gain; p < 0.002 vs. control group), PMNC number (average 29% increase), phagocytosis (average 14% increase) and superoxide production (average 28% increase). FO may be useful in preventing chemotherapy-induced decline in neutrophil number and function.