RESUMEN
BACKGROUND: Mitochondrial nucleoside diphosphate kinase (NDPK-D, NME4, NM23-H4) is a multifunctional enzyme mainly localized in the intermembrane space, bound to the inner membrane. RESULTS: We constructed loss-of-function mutants of NDPK-D, lacking either NDP kinase activity or membrane interaction and expressed mutants or wild-type protein in cancer cells. In a complementary approach, we performed depletion of NDPK-D by RNA interference. Both loss-of-function mutations and NDPK-D depletion promoted epithelial-mesenchymal transition and increased migratory and invasive potential. Immunocompromised mice developed more metastases when injected with cells expressing mutant NDPK-D as compared to wild-type. This metastatic reprogramming is a consequence of mitochondrial alterations, including fragmentation and loss of mitochondria, a metabolic switch from respiration to glycolysis, increased ROS generation, and further metabolic changes in mitochondria, all of which can trigger pro-metastatic protein expression and signaling cascades. In human cancer, NME4 expression is negatively associated with markers of epithelial-mesenchymal transition and tumor aggressiveness and a good prognosis factor for beneficial clinical outcome. CONCLUSIONS: These data demonstrate NME4 as a novel metastasis suppressor gene, the first localizing to mitochondria, pointing to a role of mitochondria in metastatic dissemination.
Asunto(s)
Neoplasias , Nucleósido-Difosfato Quinasa , Animales , Membranas Intracelulares , Ratones , Mitocondrias , Nucleósido Difosfato Quinasas NM23/genética , Nucleósido Difosfato Quinasas NM23/metabolismo , Neoplasias/genética , Neoplasias/metabolismo , Nucleósido Difosfato Quinasa D/metabolismo , Nucleósido-Difosfato Quinasa/genética , Nucleósido-Difosfato Quinasa/metabolismoRESUMEN
Helianthemum nummularium is a European shrub growing at high altitude where it copes with a high level of stress. It was found to be overexpressed in ungulates diets compared to more abundant surrounding plants. These elements combined with the fact that H. nummularium from the Alps has never been investigated prompted us to study the phytochemical composition of its aerial parts. The analysis of the polar extract allowed for the isolation of eight compounds: p-hydroxybenzoic acid, tiliroside, kaempferol, astragalin, quercetin, plantainoside B, quercetin-3-O-glucoside, and quercetin-3-O-glucuronide. We investigated the effect of the polar extract and isolated compounds on nuclear factor erythroid 2-related factor 2 transcription factor, which regulates the expression of a wide variety of cytoprotective genes. We found that the ethanolic extract activates the expression of nuclear factor erythroid 2-related factor 2 in a dose-dependent manner, whereas the pure compounds were much less active. The activation of the nuclear factor erythroid 2-related factor 2 pathway by the plant extract could pave the way for studies to promote healthy aging through protection of cells against oxidative stress. Moreover, the isolated compounds could be investigated alone or in combination in the perspective of making the link between the ungulate's preference for this plant and possible use of it for self-medication.
Asunto(s)
Altitud , Cistaceae , Dieta , Fitoquímicos/farmacología , Extractos Vegetales/farmacologíaRESUMEN
BACKGROUND: Nutritional choices, which include the source of dietary fatty acids (FA), have an important significant impact on coronary artery disease (CAD). We aimed to determine on patients with CAD the relationships between Trans fatty acids (Trans FA) and different CAD associated parameters such as inflammatory and oxidative stress parameters in addition to Gensini score as a vascular severity index. METHODS: Fatty acid profiles were established by gas chromatography from 111 CAD patients compared to 120 age-matched control group. Lipid peroxidation biomarkers, oxidative stress, inflammatory parameters and Gensini score were studied. RESULTS: Our study showed a significant decrease of the antioxidant parameters levels such as erythrocyte glutathione peroxydase (GPx) and superoxide dismutase (SOD) activities, plasma antioxidant status (FRAP) and thiol (SH) groups in CAD patients. On the other hand, catalase activity, conjugated dienes and malondialdehyde were increased. Plasmatic and erythrocyte Trans FA were also increased in CAD patients compared to controls. Furthermore, divergent associations of these Trans FA accumulations were observed with low-density lipoprotein-cholesterol/ high-density lipoprotein-cholesterol (LDL-C/HDL-C) ratio, Apolipoprotein B (ApoB), lipid peroxidation parameters, high-sensitivity C Reactive Protein (hs-CRP), Interleukin 6 (IL-6), tumor necrosis factor alpha (TNF-α) and Gensini score. Especially, elaidic acid (C18:1 trans 9), trans C18:2 isomers and trans 11 eicosanoic acid are correlated with these parameters. Trans FA are also associated with oxidative stress, confirmed by a positive correlation between C20:1 trans 11 and GPx in erythrocytes. CONCLUSIONS: High level of Trans FA was highly associated with the induction of inflammation, oxidative stress and lipoperoxidation which appear to be based on the vascular severity and might be of interest to assess the stage and progression of atherosclerosis. The measurement of these Trans FA would be of great value for the screening of lipid metabolism disorders in CAD patients.
Asunto(s)
HDL-Colesterol/sangre , LDL-Colesterol/sangre , Enfermedad de la Arteria Coronaria/sangre , Ácidos Grasos trans/sangre , Adulto , Anciano , Antioxidantes/metabolismo , Biomarcadores/sangre , Enfermedad de la Arteria Coronaria/genética , Enfermedad de la Arteria Coronaria/patología , Femenino , Humanos , Peroxidación de Lípido/genética , Masculino , Malondialdehído/sangre , Persona de Mediana Edad , Ácido Oléico/sangre , Ácido Oléico/genética , Ácidos Oléicos , Estrés Oxidativo/genética , Índice de Severidad de la Enfermedad , Ácidos Grasos trans/genética , Triglicéridos/sangre , Triglicéridos/genéticaRESUMEN
Decline in skeletal muscle mass and function starts during adulthood. Among the causes, modifications of the mitochondrial function could be of major importance. Polyunsaturated fatty (ω-3) acids have been shown to play a role in intracellular functions. We hypothesize that docosahexaenoic acid (DHA) supplementation could improve muscle mitochondrial function that could contribute to limit the early consequences of aging on adult muscle. Twelve-month-old male Wistar rats were fed a low-polyunsaturated fat diet and were given DHA (DHA group) or placebo (control group) for 9 wk. Rats from the DHA group showed a higher endurance capacity (+56%, P < 0.05) compared with control animals. Permeabilized myofibers from soleus muscle showed higher O2 consumptions (P < 0.05) in the DHA group compared with the control group, with glutamate-malate as substrates, both in basal conditions (i.e., state 2) and under maximal conditions (i.e., state 3, using ADP), along with a higher apparent Km for ADP (P < 0.05). Calcium retention capacity of isolated mitochondria was lower in DHA group compared with the control group (P < 0.05). Phospho-AMPK/AMPK ratio and PPARδ mRNA content were higher in the DHA group compared with the control group (P < 0.05). Results showed that DHA enhanced endurance capacity in adult animals, a beneficial effect potentially resulting from improvement in mitochondrial function, as suggested by our results on permeabilized fibers. DHA supplementation could be of potential interest for the muscle function in adults and for fighting the decline in exercise tolerance with age that could imply energy-sensing pathway, as suggested by changes in phospho-AMPK/AMPK ratio.
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Membrana Celular/efectos de los fármacos , Suplementos Dietéticos , Ácidos Docosahexaenoicos/farmacología , Tolerancia al Ejercicio/efectos de los fármacos , Mitocondrias Musculares/efectos de los fármacos , Músculo Esquelético/efectos de los fármacos , Resistencia Física/efectos de los fármacos , ARN Mensajero/efectos de los fármacos , 3-Hidroxiacil-CoA Deshidrogenasas/efectos de los fármacos , 3-Hidroxiacil-CoA Deshidrogenasas/metabolismo , Animales , Western Blotting , Calcio/metabolismo , Calorimetría Indirecta , Membrana Celular/metabolismo , Colesterol/metabolismo , Citrato (si)-Sintasa/efectos de los fármacos , Citrato (si)-Sintasa/metabolismo , Transporte de Electrón/efectos de los fármacos , Peróxido de Hidrógeno/metabolismo , Masculino , Mitocondrias Musculares/metabolismo , Fibras Musculares Esqueléticas/efectos de los fármacos , Fibras Musculares Esqueléticas/metabolismo , Músculo Esquelético/metabolismo , Consumo de Oxígeno/efectos de los fármacos , Fosfolípidos/metabolismo , Condicionamiento Físico Animal , ARN Mensajero/metabolismo , Ratas , Ratas Wistar , Reacción en Cadena en Tiempo Real de la Polimerasa , Triglicéridos/metabolismoRESUMEN
This study was performed to determine the hepatotoxicity of di(2-ethylhexyl)phthalate (DEHP) in relation to selenium status. In 3-week-old Sprague-Dawley rats, selenium deficiency was induced by a ≤0.05 selenium mg/kg. A selenium supplementation group was given 1 mg selenium/kg diet for 5 weeks. Di(2-ethylhexyl)phthalate-treated groups received 1000 mg/kg dose by gavage during the last 10 days of the experiment. Histopathology, peroxisome proliferation, catalase (CAT) immunoreactivity and activity and apoptosis were assessed. Activities of antioxidant selenoenzymes [glutathione peroxidase 1 (GPx1), glutathione peroxidase 4 (GPx4), thioredoxin reductase (TrxR1)], superoxide dismutase (SOD), and glutathione S-transferase (GST); aminotransferase, total glutathione (tGSH), and lipid peroxidation (LP) levels were measured. Di(2-ethylhexyl)phthalate caused cellular disorganization while necrosis and inflammatory cell infiltration were observed in Se-deficient DEHP group (DEHP/SeD). Catalase activity and immunoreactivity were increased in all DEHP-treated groups. Glutathione peroxidase 1 and GPx4 activities decreased significantly in DEHP and DEHP/SeD groups, while GST activities decreased in all DEHP-exposed groups. Thioredoxin reductase activity increased in DEHP and DEHP/SeS, while total SOD activities increased in all DEHP-treated groups. Lipid peroxidation levels increased significantly in SeD (26%), DEHP (38%) and DEHP/SeD (71%) groups. Selenium supplementation partially ameliorated DEHP-induced hepatotoxicity; while in DEHP/SeD group, drastic changes in hepatic histopathology and oxidative stress parameters were observed.
Asunto(s)
Dietilhexil Ftalato/farmacología , Hígado/efectos de los fármacos , Hígado/metabolismo , Selenio/deficiencia , Selenio/metabolismo , Animales , Apoptosis/efectos de los fármacos , Catalasa/efectos de los fármacos , Catalasa/metabolismo , Peroxidación de Lípido/efectos de los fármacos , Hígado/patología , Masculino , Modelos Animales , Estrés Oxidativo/efectos de los fármacos , Peroxisomas/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Selenio/farmacologíaRESUMEN
The intake of a high-fat/high-fructose (HF/HFr) diet is described to be deleterious to cognitive performances, possibly via the induction of inflammatory factors. An excess of glucocorticoids is also known to exert negative effects on cerebral plasticity. In the present study, we assessed the effects of an unbalanced diet on circulating and central markers of inflammation and glucocorticoid activity, as well as their reversal by dietary cinnamon (CN) supplementation. A group of male Wistar rats were subjected to an immune challenge with acute lipopolysaccharide under a HF/HFr or a standard diet. Another group of Wistar rats were fed either a HF/HFr or a control diet for 12 weeks, with or without CN supplementation, and with or without restraint stress (Str) application before being killed. We evaluated the effects of such regimens on inflammation parameters in the periphery and brain and on the expression of actors of brain plasticity. To assess hypothalamic-pituitary-adrenocortical axis activity, we measured the plasma concentrations of corticosterone and the expression of central corticotrophin-releasing hormone, mineralocorticoid receptor, glucocorticoid receptor and 11ß-hydroxysteroid dehydrogenase. We found that the HF/HFr diet induced the expression of cytokines in the brain, but only after an immune challenge. Furthermore, we observed the negative effects of Str on the plasma concentrations of corticosterone and neuroplasticity markers in rats fed the control diet but not in those fed the HF/HFr diet. Additionally, we found that CN supplementation exerted beneficial effects under the control diet, but that its effects were blunted or even reversed under the HF/HFr diet. CN supplementation could be beneficial under a standard diet. [corrected].
Asunto(s)
Cinnamomum zeylanicum/química , Dieta Alta en Grasa/efectos adversos , Modelos Animales de Enfermedad , Fructosa/efectos adversos , Fitoterapia , Especias , Estrés Psicológico/prevención & control , Animales , Biomarcadores/sangre , Biomarcadores/metabolismo , Citocinas/sangre , Citocinas/metabolismo , Fructosa/uso terapéutico , Regulación de la Expresión Génica , Hipocampo/inmunología , Hipocampo/metabolismo , Sistema Hipotálamo-Hipofisario/inmunología , Sistema Hipotálamo-Hipofisario/metabolismo , Sistema Hipotálamo-Hipofisario/fisiopatología , Masculino , Proteínas del Tejido Nervioso/biosíntesis , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Plasticidad Neuronal , Neuronas/inmunología , Neuronas/metabolismo , Sistema Hipófiso-Suprarrenal/inmunología , Sistema Hipófiso-Suprarrenal/metabolismo , Sistema Hipófiso-Suprarrenal/fisiopatología , Corteza de la Planta/química , Distribución Aleatoria , Ratas , Ratas Wistar , Estrés Psicológico/inmunología , Estrés Psicológico/metabolismo , Estrés Psicológico/fisiopatologíaRESUMEN
Di(ethylhexyl)phthalate (DEHP), the most widely used plasticizer, was investigated to determine whether an oxidative stress process was one of the underlying mechanisms for its testicular toxicity potential. To evaluate the effects of selenium (Se), status on the toxicity of DEHP was further objective of this study, as Se is known to play a critical role in testis and in the modulation of intracellular redox equilibrium. Se deficiency was produced in 3-weeks-old Sprague-Dawley rats feeding them ≤0.05 mg Se /kg diet for 5 weeks, and Se-supplementation group was on 1 mg Se/kg diet. DEHP-treated groups received 1000 mg/kg dose by gavage during the last 10 days of the feeding period. Activities of antioxidant selenoenzymes [glutathione peroxidase 1 (GPx1), glutathione peroxidase 4 (GPx4), thioredoxin reductase (TrxR)], catalase (CAT), superoxide dismutase (SOD), and glutathione S-transferase (GST); concentrations of reduced glutathione (GSH), oxidized glutathione (GSSG), and thus the GSH/GSSG redox ratio; and thiobarbituric acid reactive substance (TBARS) levels were measured. DEHP was found to induce oxidative stress in rat testis, as evidenced by significant decrease in GSH/GSSG redox ratio (>10-fold) and marked increase in TBARS levels, and its effects were more pronounced in Se-deficient rats with â¼18.5-fold decrease in GSH/GSSG redox ratio and a significant decrease in GPx4 activity, whereas Se supplementation was protective by providing substantial elevation of redox ratio and reducing the lipid peroxidation. These findings emphasized the critical role of Se as an effective redox regulator and the importance of Se status in protecting testicular tissue from the oxidant stressor activity of DEHP.
Asunto(s)
Dietilhexil Ftalato/toxicidad , Estrés Oxidativo/efectos de los fármacos , Selenio/administración & dosificación , Selenio/deficiencia , Testículo/efectos de los fármacos , Animales , Antioxidantes/metabolismo , Suplementos Dietéticos , Peroxidación de Lípido/efectos de los fármacos , Masculino , Oxidantes/metabolismo , Oxidantes/farmacología , Oxidación-Reducción/efectos de los fármacos , Plastificantes/toxicidad , Distribución Aleatoria , Ratas , Ratas Sprague-Dawley , Selenio/metabolismo , Testículo/enzimología , Testículo/metabolismoRESUMEN
BACKGROUND: There has been accumulating evidence associating diabetes mellitus and cardiovascular dysfunctions. However, most of the studies are focused on the late stages of diabetes and on the function of large arteries. This study aimed at characterizing the effects of the early phase of diabetes mellitus on the cardiac and vascular function with focus on the intact coronary microvasculature and the oxidative stress involved. MATERIALS AND METHODS: Zucker diabetic fatty rats and their lean littermates fed with standard diet A04 (Safe) were studied at the 11th week of age. Biochemical parameters such as glucose, insulin and triglycerides levels as well as their oxidative stress status were measured. Their hearts were perfused ex vivo according to Langendorff and their cardiac activity and coronary microvascular reactivity were evaluated. RESULTS: Zucker fatty rats already exhibited a diabetic state at this age as demonstrated by the elevated levels of plasma glucose, insulin, glycated hemoglobin and triglycerides. The ex vivo perfusion of their hearts revealed a decreased cardiac mechanical function and coronary flow. This was accompanied by an increase in the overall oxidative stress of the organs. However, estimation of the active form of endothelial nitric oxide synthase and coronary reactivity indicated a preserved function of the coronary microvessels at this phase of the disease. Diabetes affected also the cardiac membrane phospholipid fatty acid composition by increasing the arachidonic acid and n-3 polyunsaturated fatty acids levels. CONCLUSIONS: The presence of diabetes, even at its beginning, significantly increased the overall oxidative stress of the organs resulting to decreased cardiac mechanical activity ex vivo. However, adaptations were adopted at this early phase of the disease regarding the preserved coronary microvascular reactivity and the associated cardiac phospholipid composition in order to provide a certain protection to the heart.
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Diabetes Mellitus Experimental/fisiopatología , Endotelio Vascular/fisiología , Corazón/fisiología , Microvasos/fisiología , Estrés Oxidativo/fisiología , Vasodilatación/fisiología , Animales , Circulación Coronaria/fisiología , Diabetes Mellitus Experimental/metabolismo , Masculino , Técnicas de Cultivo de Órganos , Ratas , Ratas Zucker , Factores de TiempoRESUMEN
This study was designed to examine the oxidative stress potential of di(2-ethylhexyl)phthalate (DEHP) on rat kidney and to evaluate possible protective effect of selenium (Se) status. Se deficiency (SeD) was produced in 3-week old Sprague-Dawley rats by feeding them ≤ 0.05 Se mg/kg diet for 5 weeks; Se supplementation group (SeS) was on 1 mg Se/kg diet. DEHP treated groups received 1000 mg/kg dose by gavage during the last 10 days of the feeding period. Activities of antioxidant selenoenzymes [glutathione peroxidase 1 (GPx1), glutathione peroxidase 4 (GPx4), thioredoxin reductase (TrxR)], catalase (CAT), superoxide dismutase (SOD), and glutathione S-transferase (GST); concentrations of total glutathione (GSH), thiols and thiobarbituric acid reactive substance (TBARS) levels were measured. DEHP treatment was found to induce oxidative stress in rat kidney, as evidenced by significant decreases in GPx1 (~20%) and SOD (~30%) activities and GSH levels (~20%), along with marked decrease in thiol content (~40%) and increase in TBARS (~30%) levels. The effects of DEHP was more pronounced in SeD rats, whereas Se supplementation was protective by providing substantial elevations of GPx1 and GPx4 activities and GSH levels. These findings emphasized the critical role of Se as an effective redox regulator and the importance of Se status in protecting renal tissue from the oxidant stressor activity of DEHP.
Asunto(s)
Dietilhexil Ftalato/toxicidad , Riñón/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Plastificantes/toxicidad , Selenio/farmacología , Animales , Antioxidantes/metabolismo , Glutatión Peroxidasa/metabolismo , Riñón/enzimología , Riñón/metabolismo , Tamaño de los Órganos/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Reductasa de Tiorredoxina-Disulfuro/metabolismoRESUMEN
The purpose of this study was to determine whether magnesium L-lactate is responsible for having a beneficial effect on the myocardium and the skeletal muscles and how this substrate acts at the molecular level. Twenty seven young male Wistar rats were supplied with a magnesium L-lactate (L) solution, a magnesium chloride (M) solution and/or water (W) as a vehicle for 10 weeks. The treated animals absorbed the L and M solutions as they wished since they also had free access to water. After 9 weeks of treatment, in vivo cardiac function was determined ultrasonically. The animals were sacrificed at the end of the tenth week of treatment and the heart was perfused according to the Langendorff method by using a technique allowing the determination of cardiomyocyte activity (same coronary flow in the two groups). Blood was collected and skeletal muscles of the hind legs were weighed. The myocardial expressions of the sodium/proton exchange 1 (NHE1) and sodium/calcium exchange 1 (NCX1), intracellular calcium accumulation, myocardial magnesium content, as well as systemic and tissue oxidative stress, were determined. Animals of the L group absorbed systematically a low dose of L-lactate (31.5 ± 4.3 µg/100 g of body weight/day) which was approximately four times higher than that ingested in the W group through the diet supplied. Ex vivo cardiomyocyte contractility and the mass of some skeletal muscles (tibialis anterior) were increased by the L treatment. Myocardial calcium was decreased, as was evidenced by an increase in total CaMKII expression, without any change in the ratio between phosphorylated CaMKII and total CaMKII. Cardiac magnesium tended to be elevated. Our results suggest that the increased intracellular magnesium concentration was related to L-lactate-induced cytosolic acidosis and to the activation of the NHE1/NCX1 axis. Interestingly, systemic oxidative stress was reduced by the L treatment whereas the lipid profile of the animals was unaltered. Taken together, these results suggest that a chronic low-dose L-lactate intake has a beneficial health effect on some skeletal muscles and the myocardium through the activation of the NHE1/NCX1 axis, a decrease in cellular calcium and an increase in cellular magnesium. The treatment can be beneficial for the health of young rodents in relation to chronic oxidative stress-related diseases.
Asunto(s)
Calcio , Magnesio , Animales , Calcio/metabolismo , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/metabolismo , Lactatos/metabolismo , Magnesio/metabolismo , Magnesio/farmacología , Masculino , Músculo Esquelético/metabolismo , Miocardio/metabolismo , Ratas , Ratas Wistar , Sodio/metabolismo , AguaRESUMEN
Nutritional habits can have a significant impact on cardiovascular health and disease. This may also apply to cardiotoxicity caused as a frequent side effect of chemotherapeutic drugs, such as doxorubicin (DXR). The aim of this work was to analyze if diet, in particular creatine (Cr) supplementation, can modulate cardiac biochemical (energy status, oxidative damage and antioxidant capacity, DNA integrity, cell signaling) and functional parameters at baseline and upon DXR treatment. Here, male Wistar rats were fed for 4 weeks with either standard rodent diet (NORMAL), soy-based diet (SOY), or Cr-supplemented soy-based diet (SOY + Cr). Hearts were either freeze-clamped in situ or following ex vivo Langendorff perfusion without or with 25 µM DXR and after recording cardiac function. The diets had distinct cardiac effects. Soy-based diet (SOY vs. NORMAL) did not alter cardiac performance but increased phosphorylation of acetyl-CoA carboxylase (ACC), indicating activation of rather pro-catabolic AMP-activated protein kinase (AMPK) signaling, consistent with increased ADP/ATP ratios and lower lipid peroxidation. Creatine addition to the soy-based diet (SOY + Cr vs. SOY) slightly increased left ventricular developed pressure (LVDP) and contractility dp/dt, as measured at baseline in perfused heart, and resulted in activation of the rather pro-anabolic protein kinases Akt and ERK. Challenging perfused heart with DXR, as analyzed across all nutritional regimens, deteriorated most cardiac functional parameters and also altered activation of the AMPK, ERK, and Akt signaling pathways. Despite partial reprogramming of cell signaling and metabolism in the rat heart, diet did not modify the functional response to supraclinical DXR concentrations in the used acute cardiotoxicity model. However, the long-term effect of these diets on cardiac sensitivity to chronic and clinically relevant DXR doses remains to be established.
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Creatina , Doxorrubicina , Animales , Creatina/farmacología , Dieta , Doxorrubicina/toxicidad , Masculino , Ratas , Ratas Wistar , Transducción de SeñalRESUMEN
An increased rate of bone turnover increases risk of osteoporotic fracture later in life. The concentration of 25-hydroxyvitamin D that contributes to an elevated rate of bone turnover in older adults is unclear. The objective of this study was to investigate the associations between 25-hydroxyvitamin D and biochemical markers of bone turnover in an older, pan-European cohort. 25-hydroxyvitamin D and serum markers of bone-formation (osteocalcin and bone-specific alkaline phosphatase) were assessed by ELISA, while urinary markers of bone-resorption (pyridinoline and deoxypyridinoline) were assessed by HPLC. Six percent, 36 %, and 64 % of subjects had 25-hydroxyvitamin D concentrations < 25, < 50, and < 80 nmol/L throughout the year, respectively. 25-hydroxyvitamin D was significantly and inversely correlated with serum bone-specific alkaline phosphatase (r = 0.119; p = 0.022) and urinary pyridinoline (r = 0.207; p < 0.0001) and deoxypyridinoline (r = 0.230; p < 0.0001). Stratification on the basis of tertiles [T] of 25-hydroxyvitamin D (< 47.6 [T(1)]; 47.6 - 85.8 [T2]; > 85.8 [T3] nmol/L), showed that urinary pyridinoline and deoxypyridinoline were significantly lower in subjects in the 2(nd) and 3(rd) compared to the 1(st) tertile (p < 0.015). Low vitamin D status (< 50 nmol/L) was associated with an increased rate of bone turnover in this older pan-European cohort.
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Envejecimiento/fisiología , Biomarcadores/análisis , Remodelación Ósea/fisiología , Vitamina D/análogos & derivados , Anciano , Fosfatasa Alcalina/sangre , Aminoácidos/orina , Estudios Transversales , Europa (Continente) , Femenino , Humanos , Masculino , Persona de Mediana Edad , Osteocalcina/sangre , Vitamina D/administración & dosificación , Vitamina D/sangre , Deficiencia de Vitamina D/complicacionesRESUMEN
AMP-activated protein kinase (AMPK) is a key regulator of energy homeostasis under conditions of energy stress. Though heart is one of the most energy requiring organs and depends on a perfect match of energy supply with high and fluctuating energy demand to maintain its contractile performance, the role of AMPK in this organ is still not entirely clear, in particular in a non-pathological setting. In this work, we characterized cardiomyocyte-specific, inducible AMPKα1 and α2 knockout mice (KO), where KO was induced at the age of 8 weeks, and assessed their phenotype under physiological conditions. In the heart of KO mice, both AMPKα isoforms were strongly reduced and thus deleted in a large part of cardiomyocytes already 2 weeks after tamoxifen administration, persisting during the entire study period. AMPK KO had no effect on heart function at baseline, but alterations were observed under increased workload induced by dobutamine stress, consistent with lower endurance exercise capacity observed in AMPK KO mice. AMPKα deletion also induced a decrease in basal metabolic rate (oxygen uptake, energy expenditure) together with a trend to lower locomotor activity of AMPK KO mice 12 months after tamoxifen administration. Loss of AMPK resulted in multiple alterations of cardiac mitochondria: reduced respiration with complex I substrates as measured in isolated mitochondria, reduced activity of complexes I and IV, and a shift in mitochondrial cristae morphology from lamellar to mixed lamellar-tubular. A strong tendency to diminished ATP and glycogen level was observed in older animals, 1 year after tamoxifen administration. Our study suggests important roles of cardiac AMPK at increased cardiac workload, potentially limiting exercise performance. This is at least partially due to impaired mitochondrial function and bioenergetics which degrades with age.
RESUMEN
It has been proven that dietary eicosapentaenoic acid (C20:5 n-3 or EPA) protects the heart against the deleterious effects of sepsis in female rats. We do not know if this is the case for male rodents. In this case, the efficiency of other n-3 polyunsaturated fatty acids (PUFAs) remains to be determined in both female and male rats. This study aimed at (i) determining whether dietary EPA is cardioprotective in septic male rats; (ii) evaluating the influence of dietary α-linolenic (C18:3 n-3 or ALA) on cardiac function during this pathology; and (iii) finding out the physiological and molecular mechanisms responsible for the observed effects. Sixty male rats were divided into three dietary groups. The animals were fed a diet deficient in n-3 PUFAs (DEF group), a diet enriched with ALA (ALA group) or a diet fortified with EPA (EPA group) for 6 weeks. Thereafter, each group was subdivided into 2 subgroups, one being subjected to cecal ligation and puncture (CLP) and the other undergoing a fictive surgery. Cardiac function was determined in vivo and ex vivo. Several parameters related to the inflammation process and oxidative stress were determined. Finally, the fatty acid compositions of circulating lipids and cardiac phospholipids were evaluated. The results of the ex vivo situation indicated that sepsis triggered cardiac damage in the DEF group. Conversely, the ex vivo data indicated that dietary ALA and EPA were cardioprotective by resolving the inflammation process and decreasing the oxidative stress. However, the measurements of the cardiac function in the in vivo situation modulated these conclusions. Indeed, in the in vivo situation, sepsis deteriorated cardiac mechanical activity in the ALA group. This was suspected to be due to a restricted coronary flow which was related to a lack of cyclooxygenase substrates in membrane phospholipids. Finally, only EPA proved to be beneficial in sepsis. Its action necessitates both resolution of inflammation and increased coronary perfusion. In that sense, dietary ALA, which does not allow the accumulation of vasodilator precursors in membrane lipids, cannot be protective during the pathology.
RESUMEN
BACKGROUND: Tea polyphenols, as both insulin potentiating factors and antioxidants, are postulated to act in preventing the metabolic syndrome, which is characterized by insulin resistance, dyslipidemia, and increased oxidative stress. OBJECTIVE AND METHODS: Using an animal model of insulin resistance, our objective was to determine the effects of a green tea extract on oxidative stress parameters and insulin sensitivity. Wistar rats, 10 per group, received a high-fructose diet (FD) for 6 weeks, or the same diet (FD) plus 1 or 2 g of green tea solids/kg diet. RESULTS: Signs of insulin resistance (hyperglycemia, hypertriglyceridemia, and hyperinsulinemia) developed in rats receiving the FD, but not in those of the control group. In contrast, animals receiving added tea solids exhibited decreases in glycemia, insulinemia, and triglyceridemia, consistent with an insulin-potentiating effect of tea. In parallel, oxidative stress was decreased by tea consumption with lower plasma lipid peroxidation, sulfhydryl (SH) group oxidation, and DNA oxidative damage. In summary, the addition of green tea extracts to the diet, inducing insulin resistance, led to protective effects of green tea against both oxidative stress and insulin resistance. CONCLUSIONS: These data suggest that green tea may be beneficial for people with decreased insulin sensitivity and increased oxidative stress, such as those with the metabolic syndrome or type 2 diabetes.
Asunto(s)
Flavonoides/farmacología , Resistencia a la Insulina/fisiología , Estrés Oxidativo/efectos de los fármacos , Fenoles/farmacología , Té/química , Animales , Glucemia/metabolismo , Ensayo Cometa , Daño del ADN/fisiología , Modelos Animales de Enfermedad , Flavonoides/aislamiento & purificación , Insulina/sangre , Malondialdehído/sangre , Estrés Oxidativo/fisiología , Fenoles/aislamiento & purificación , Polifenoles , Distribución Aleatoria , Ratas , Ratas Wistar , Compuestos de Sulfhidrilo/sangre , Triglicéridos/sangreRESUMEN
Chelation therapy is thought to not only remove contaminating metals but also to decrease free radical production. However, in standard ethylene diamine tetracetic acid (EDTA) chelation therapy, high doses of vitamin C with potential pro-oxidant effects are often added to the chelation solution. The authors demonstrated previously that the intravenous administration of the standard chelation cocktail, containing high amounts of vitamin C, resulted in an acute transitory pro-oxidant burst that should be avoided in the treatment of pathologies at risk of increased oxidative stress such as diabetes and cardiovascular disease. The current study was designed to determine the acute and chronic biochemical effects of chelation therapy on accepted clinical, antioxidant variables. An EDTA chelation cocktail not containing ascorbic acid was administered to six adult patients for five weeks (10 sessions of chelation therapy); antioxidant indicators were monitored. Immediately after the initial chelation session, in contrast with the data previously reported with the standard cocktail containing high doses of vitamin C, none of the oxidative stress markers were adversely modified. After five weeks, plasma peroxide levels, monitored by malondialdehyde, decreased by 20 percent, and DNA damage, monitored by formamidopyrimidine-DNA glycosylase (Fpg) sensitive sites, decreased by 22 percent. Remaining antioxidant-related variables did not change. In summary, this study demonstrates that multiple sessions of EDTA chelation therapy in combination with vitamins and minerals, but without added ascorbic acid, decreases oxidative stress. These results should be beneficial in the treatment of diseases associated with increased oxidative stress such as diabetes and cardiovascular diseases.
Asunto(s)
Quelantes/uso terapéutico , Daño del ADN , Ácido Edético/uso terapéutico , Peroxidación de Lípido , Estrés Oxidativo , Anciano , Ácido Ascórbico/uso terapéutico , Eritrocitos/enzimología , Femenino , Humanos , Masculino , Malondialdehído/sangre , Persona de Mediana Edad , Superóxido Dismutasa/sangreRESUMEN
Antioxidant activity of isorhamnetin 3-O neohesperidoside (I3ON), isolated from the leaves of Acacia salicina, was determined by the ability of this compound to inhibit lipid peroxidation and to protect against hydroxyl radical-induced DNA damage in pKS plasmid DNA and Escherichia coli cultures. Antigenotoxic activity was assessed by using the comet assay. The IC(50) value of the inhibitory activity toward lipid peroxidation by I3ON is 0.6 mM. This compound was also able to protect against hydroxyl radical-induced DNA damage in pKS plasmid DNA. Moreover, this compound induced an inhibitory activity toward H2O2-induced genotoxicity. The protective effect exhibited by this molecule was also determined by analysis of gene expression as a response to an oxidative stress, using a cDNA microarray. Transcription of several genes related to the antioxidant system (HMOX2 and TXNL) and to the DNA repair pathway (XPC, POLD1, POLD2, PCNA, DDIT3, APEX, and LIG4) were upregulated after incubation with I3ON. Taken together, these observations provide evidence that the I3ON, isolated from the leaves of A. salicina, is able to protect cells against oxidative stress.
Asunto(s)
Acacia/química , Antimutagênicos/farmacología , Antioxidantes/farmacología , Estrés Oxidativo/efectos de los fármacos , Línea Celular Tumoral , Ensayo Cometa , Daño del ADN , Reparación del ADN/efectos de los fármacos , Reparación del ADN/genética , Flavonoles/farmacología , Expresión Génica/efectos de los fármacos , Humanos , Peróxido de Hidrógeno/toxicidad , Radical Hidroxilo/toxicidad , Peroxidación de Lípido/efectos de los fármacos , Análisis de Secuencia por Matrices de Oligonucleótidos , Oxidantes/toxicidad , Estrés Oxidativo/genética , Hojas de la Planta/química , Plásmidos/efectos de los fármacos , Plásmidos/genética , Regulación hacia Arriba/efectos de los fármacosRESUMEN
OBJECTIVE: The aim of the study was to investigate whether zinc supplementation affects antioxidant status in European middle-aged and elderly people. DESIGN: Multicentre prospective intervention study, randomized, double-blind, placebo-control. SETTING: France (Clermont-Ferrand/Theix, and Grenoble), Italy (Rome), Northern Ireland (Coleraine). SUBJECTS: A total of 387 healthy middle-aged (55-70 yrs) and free-living older aged (70-85 yrs) subjects were randomly allocated to three groups: 0, 15 or 30 mg zinc gluconate/d in addition to usual dietary intake during 6 months. METHODS: Oxidative stress status was evaluated by measurement of protein oxidation (plasma thiol groups), lipid peroxidation (plasma thio-barbituric acid reactants, TBARS), whole blood glutathione levels, erythrocyte copper/zinc superoxide dismutase activity and plasma antioxidant status (ferric reducing antioxidant power assay), at baseline and after 3 and 6 months. RESULTS: Zinc supplementation did not alter oxidative stress markers and antioxidant defenses in elderly, after 3 or 6 months, except an increase in Cu/Zn superoxide dismutase activity. CONCLUSIONS: In apparently healthy free living elderly people, a single zinc supplementation had no effects on oxidative stress status.
Asunto(s)
Antioxidantes/farmacología , Suplementos Dietéticos , Estrés Oxidativo/efectos de los fármacos , Zinc/farmacología , Anciano , Anciano de 80 o más Años , Antioxidantes/metabolismo , Antioxidantes/uso terapéutico , Biomarcadores/metabolismo , Creatinina/orina , Método Doble Ciego , Humanos , Isoprostanos/orina , Peroxidación de Lípido/efectos de los fármacos , Persona de Mediana Edad , Superóxido Dismutasa/metabolismo , Zinc/metabolismo , Zinc/uso terapéuticoRESUMEN
The total oligomers flavonoids (TOF), chloroform, petroleum ether and aqueous extracts from Acacia salicina, were investigated for the antioxidative, cytotoxic, antimutagenic and antigenotoxic activities. The viability of K562 cells were affected by all extracts after 48 h exposure. Our results showed that A. salicina extracts have antigenotoxic and/or antimutagenic activities. TOF and chloroform extracts exhibit antioxidant properties, expressed by the capacity of these extracts to inhibit xanthine oxidase activity. To further explore the mechanism of action of A. salicina extracts, we characterized expression profiles of genes involved in antioxidant protection and DNA repair in the human lymphoblastic cell line K562 exposed to H2O2. Transcription of several genes related to the thioredoxin antioxidant system and to the DNA base-excision repair pathway was up-regulated after incubation with chloroform, TOF and petroleum ether extracts. Moreover genes involved in the nucleotide-excision repair pathway and genes coding for catalase and Mn-superoxide-dismutase, two important antioxidant enzymes, were induced after incubation with the chloroform extract. Taken together, these observations provide evidence that the chloroform and TOF extracts of A. salicina leaves contain bioactive compounds that are able to protect cells against the consequences of an oxidative stress.