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1.
J Physiol ; 592(6): 1341-52, 2014 Mar 15.
Article in English | MEDLINE | ID: mdl-24396061

ABSTRACT

Studies have shown increased incorporation of omega-3 fatty acids into whole skeletal muscle following supplementation, although little has been done to investigate the potential impact on the fatty acid composition of mitochondrial membranes and the functional consequences on mitochondrial bioenergetics. Therefore, we supplemented young healthy male subjects (n = 18) with fish oils [2 g eicosapentaenoic acid (EPA) and 1 g docosahexanoic acid (DHA) per day] for 12 weeks and skeletal muscle biopsies were taken prior to (Pre) and following (Post) supplementation for the analysis of mitochondrial membrane phospholipid composition and various assessments of mitochondrial bioenergetics. Total EPA and DHA content in mitochondrial membranes increased (P < 0.05) ∼450 and ∼320%, respectively, and displaced some omega-6 species in several phospholipid populations. Mitochondrial respiration, determined in permeabilized muscle fibres, demonstrated no change in maximal substrate-supported respiration, or in the sensitivity (apparent Km) and maximal capacity for pyruvate-supported respiration. In contrast, mitochondrial responses during ADP titrations demonstrated an enhanced ADP sensitivity (decreased apparent Km) that was independent of the creatine kinase shuttle. As the content of ANT1, ANT2, and subunits of the electron transport chain were unaltered by supplementation, these data suggest that prolonged omega-3 intake improves ADP kinetics in human skeletal muscle mitochondria through alterations in membrane structure and/or post-translational modification of ATP synthase and ANT isoforms. Omega-3 supplementation also increased the capacity for mitochondrial reactive oxygen species emission without altering the content of oxidative products, suggesting the absence of oxidative damage. The current data strongly emphasize a role for omega-3s in reorganizing the composition of mitochondrial membranes while promoting improvements in ADP sensitivity.


Subject(s)
Fatty Acids, Omega-3/administration & dosage , Quadriceps Muscle/metabolism , Adenine Nucleotide Translocator 1/metabolism , Adenine Nucleotide Translocator 2/metabolism , Adenosine Diphosphate/metabolism , Cell Respiration/physiology , Dietary Supplements , Docosahexaenoic Acids/administration & dosage , Docosahexaenoic Acids/pharmacokinetics , Eicosapentaenoic Acid/administration & dosage , Eicosapentaenoic Acid/pharmacokinetics , Energy Metabolism , Fatty Acids, Omega-3/pharmacokinetics , Humans , Hydrogen Peroxide/metabolism , Kinetics , Male , Mitochondria, Muscle/metabolism , Mitochondrial Membranes/metabolism , Oxidative Stress , Phospholipids/metabolism , Reactive Oxygen Species/metabolism , Young Adult
2.
Transplant Proc ; 45(7): 2741-5, 2013 Sep.
Article in English | MEDLINE | ID: mdl-24034037

ABSTRACT

BACKGROUND: Primary graft dysfunction (PGD) might occur after lung transplantation. In some severe cases, conventional therapies like ventilatory support, administration of inhaled nitric oxide (iNO), and intravenous prostacyclins are not sufficient to provide an adequate gas exchange. The aim of our study was to evaluate the use of a lung protective ventilation strategy associated with a low-flow venovenous CO2 removal treatment to reduce ventilator-associated injury in patients that develop severe PGD after lung transplantation. METHODS: From January 2009 to January 2011, 3 patients developed PGD within 24 hours after lung transplantation. In addition to conventional medical treatment, including hemodynamic support, iNO and prostaglandin E1 (PGE1), we initiated a ventilatory protective strategy associated with low-flow venovenous CO2 removal treatment (LFVVECCO2R). Hemodynamic and respiratory parameters were assessed at baseline as well as after 3, 12, 24, and 48 hours. RESULTS: No adverse events were registered. Despite decreased baseline elevated pulmonary positive pressures, application of a protective ventilation strategy with LFVVECCO2R reduced PaCO2 and pulmonary infiltrates as well as increased pH values and PaO2/FiO2 ratios. Every patient showed simultaneous improvement of clinical and hemodynamic conditions. They were weaned from mechanical ventilation and extubated after 24 hours after the use of the low-flow venovenous CO2 removal device. CONCLUSION: The use of LFVVECCO2R together with a protective lung ventilation strategy during the perioperative period of lung transplantation may be a valid clinical strategy for patients with PGD and severe respiratory acidosis occured despite adequate mechanical ventilation.


Subject(s)
Acidosis/etiology , Carbon Dioxide/isolation & purification , Lung Transplantation/adverse effects , Respiration, Artificial , Adult , Carbon Dioxide/blood , Female , Humans , Male , Middle Aged
3.
Diabetologia ; 55(10): 2759-2768, 2012 Oct.
Article in English | MEDLINE | ID: mdl-22782287

ABSTRACT

AIMS/HYPOTHESIS: High-fat, high-sucrose diet (HF)-induced reactive oxygen species (ROS) levels are implicated in skeletal muscle insulin resistance and mitochondrial dysfunction. Here we investigated whether mitochondrial ROS sequestering can circumvent HF-induced oxidative stress; we also determined the impact of any reduced oxidative stress on muscle insulin sensitivity and mitochondrial function. METHODS: The Skulachev ion (plastoquinonyl decyltriphenylphosphonium) (SkQ), a mitochondria-specific antioxidant, was used to target ROS production in C2C12 muscle cells as well as in HF-fed (16 weeks old) male C57Bl/6 mice, compared with mice on low-fat chow diet (LF) or HF alone. Oxidative stress was measured as protein carbonylation levels. Glucose tolerance tests, glucose uptake assays and insulin-stimulated signalling were determined to assess muscle insulin sensitivity. Mitochondrial function was determined by high-resolution respirometry. RESULTS: SkQ treatment reduced oxidative stress in muscle cells (-23% p < 0.05), but did not improve insulin sensitivity and glucose uptake under insulin-resistant conditions. In HF mice, oxidative stress was elevated (56% vs LF p < 0.05), an effect completely blunted by SkQ. However, HF and HF+SkQ mice displayed impaired glucose tolerance (AUC HF up 33%, p < 0.001; HF+SkQ up 22%; p < 0.01 vs LF) and disrupted skeletal muscle insulin signalling. ROS sequestering did not improve mitochondrial function. CONCLUSIONS/INTERPRETATION: SkQ treatment reduced muscle mitochondrial ROS production and prevented HF-induced oxidative stress. Nonetheless, whole-body glucose tolerance, insulin-stimulated glucose uptake, muscle insulin signalling and mitochondrial function were not improved. These results suggest that HF-induced oxidative stress is not a prerequisite for the development of muscle insulin resistance.


Subject(s)
Dietary Fats/pharmacology , Insulin Resistance/physiology , Mitochondria, Muscle/drug effects , Mitochondria, Muscle/metabolism , Muscle, Skeletal/metabolism , Plastoquinone/analogs & derivatives , Reactive Oxygen Species/metabolism , Animals , Free Radical Scavengers/pharmacology , Glucose/metabolism , In Vitro Techniques , Insulin/metabolism , Lipids/blood , Male , Mice , Mice, Inbred C57BL , Models, Animal , Muscle, Skeletal/drug effects , Oxidative Stress/drug effects , Oxidative Stress/physiology , Plastoquinone/pharmacology
4.
Endocrinology ; 147(6): 2690-5, 2006 Jun.
Article in English | MEDLINE | ID: mdl-16513824

ABSTRACT

IL-6-deficient (IL-6(-/-)) mice develop obesity at 6-7 months of age. To elucidate the mechanisms of this mature-onset obesity, global gene expression profiles of 3-month-old preobese IL-6(-/-) were compared with those of IL-6(+/+) mice using DNA arrays. Genes that were up-regulated in IL-6(-/-) mice included the factors transthyretin and properdin in white adipose tissue and adipsin in muscle. These factors have been shown to influence the formation of acylation-stimulating protein (ASP), a cleavage product of complement C3. ASP stimulates the synthesis of triacylglycerol in adipocytes, and ASP-deficient mice are resistant to diet-induced obesity. In line with the increases in transthyretin, properdin, and adipsin, ASP levels in serum were increased by 31-54% in IL-6(-/-) compared with IL-6(+/+) mice. Furthermore, IL-6 replacement treatment in IL-6(-/-) mice decreased ASP levels significantly by 25-60%. In conclusion, ASP levels are increased in preobese IL-6(-/-) mice. This increase may result in increased triacylglycerol formation and uptake in IL-6(-/-) adipocytes and thereby contribute to the development of obesity in IL-6(-/-) mice.


Subject(s)
Complement C3a/analysis , Interleukin-6/physiology , Adipocytes/pathology , Adipose Tissue/metabolism , Animals , Body Weight , Complement C3/metabolism , Complement C3a/metabolism , Fatty Acids, Nonesterified/blood , Female , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Oligonucleotide Array Sequence Analysis , Prealbumin/genetics , Properdin/genetics , Triglycerides/biosynthesis
5.
Radiol Med ; 90(3): 272-7, 1995 Sep.
Article in Italian | MEDLINE | ID: mdl-7501833

ABSTRACT

To date, Doppler US has been rarely used to diagnose chronic renal transplant rejection because of its low sensitivity. Nevertheless, all the results have been obtained from the analysis of flow-metric indices, mainly considering the diastolic phase of the Doppler waveform, e.g., the resistance index (RI) and the pulsatility index (PI). This study was aimed at investigating if Doppler diagnostic accuracy in renal transplant monitoring can be increased by studying the systolic phase, considering peak arterial systolic velocity (Vp), acceleration time (AT) and acceleration index (AI). Seventy-six renal transplant recipients were examined with color-Doppler and duplex Doppler US, which showed 47 well-functioning and 29 hypofunctioning kidneys. The diagnosis was confirmed with perfusion scintigraphy with 99mTc DTPA, biopsy and 6-month clinical-laboratory follow-up. The means of Vp, AI, AT and RI relative to the group of patients with normal renal function were compared with those in the group of patients with chronic rejection. Critical values were measured at the segmental arteries (Vp = 70 cm/s, AI = 7 m/s2, AT = 100 ms), at the interlobar arteries (Vp = 45 cm/s, AI = 4 m/s2, AT = 100 ms) and at the arcuate arteries (Vp = 35 cm/s, AI = 3 m/s2, AT = 100 ms). On the basis of these values, normal functioning transplants were differentiated from hypofunctioning ones. RIs were altered (> 0.75) in 8 of 17 chronic rejections and in 3 of 47 normal transplants, with 47.1% sensitivity and 93.6% specificity. The combination of RI with Vp and AI strongly increased both sensitivity (100%) and specificity (82.98%). Combined AI and RI exhibited 94.1% sensitivity and 89.3% specificity. In conclusion, the indices of the ascending systolic phase, in peripheral vascular samplings, are clearly more efficacious than RI alone and index combination exhibits the highest diagnostic accuracy.


Subject(s)
Graft Rejection/diagnostic imaging , Kidney Transplantation/diagnostic imaging , Adult , Aged , Chronic Disease , Creatinine/blood , Female , Follow-Up Studies , Graft Rejection/blood , Graft Rejection/physiopathology , Humans , Kidney Transplantation/physiology , Male , Middle Aged , Radionuclide Imaging , Renal Artery/diagnostic imaging , Renal Artery/physiopathology , Sensitivity and Specificity , Systole , Technetium Tc 99m Pentetate , Ultrasonography, Doppler, Color/instrumentation , Ultrasonography, Doppler, Color/methods , Ultrasonography, Doppler, Color/statistics & numerical data , Ultrasonography, Doppler, Duplex/instrumentation , Ultrasonography, Doppler, Duplex/methods , Ultrasonography, Doppler, Duplex/statistics & numerical data
7.
Mutat Res ; 206(3): 311-5, 1988 Nov.
Article in English | MEDLINE | ID: mdl-3200255

ABSTRACT

Soluble metal compounds (CdCl2, K2Cr2O7) significantly increase the frequency of micronucleated cells in Vicia faba root tips with a clear dose-effect relationship. The addition of NTA (nitrilotriacetic acid) does not enhance the induction of micronucleated cells. Conversely, insoluble metal compounds (CdCO3, PbCRO4) significantly enhance the frequency of micronucleated cells only in the presence of NTA. Since some genotoxic metals are diffused in the environment and are often sequestered as insoluble precipitates in water sediments and sludges, the introduction of NTA is likely to increase the risk of environmental pollution because of its ability to solubilize and make those metals reactive.


Subject(s)
Acetates/toxicity , Cadmium/toxicity , Chromium/toxicity , Micronucleus Tests/methods , Mutation/drug effects , Nitrilotriacetic Acid/toxicity , Chromosome Aberrations , Drug Synergism , Plants , Solubility
8.
J Toxicol Environ Health ; 24(2): 251-60, 1988.
Article in English | MEDLINE | ID: mdl-3385800

ABSTRACT

We used a soft agar assay on cultured Syrian hamster fibroblasts to determine the ability of nitrilotriacetic acid (NTA) and Cr(VI) compounds to induce malignant cell transformation. Induction of extended anchorage-independent growth was detected in BHK 21/c13 cells by scoring colonies of transformed cells visible to the naked eye 20-25 d after plating in growth medium containing agar. Survival was determined by plating cells in liquid medium without agar and by counting the number of macroscopic colonies after 7-10 d. Mitomycin C and 4-nitroquinoline 1-oxide were used as reference direct transforming agents, with clearly positive results. In our hands no increase of the spontaneous transformation rate of BHK cells was induced by NTA concentrations ranging from 2 X 10(-3) to 10(-2) M, although the survival index was significantly reduced above 4 X 10(-3) M NTA. Two Cr(VI) compounds, K2Cr2O7, which is highly soluble in water, and CaCrO4, which is partially soluble, were tested in the soft agar assay either in the absence or in the presence of NTA. When used alone, both compounds behaved as positive transforming agents. NTA increased 4 or 10 times the cytotoxicity and the transforming activity of CaCrO4 and K2Cr2O7, respectively. As the amounts of soluble Cr(VI) detectable in the K2Cr2O7 and CaCrO4 solutions were not increased in the presence of NTA, a synergistic interaction between NTA and soluble Cr(VI) is inferred.


Subject(s)
Acetates/toxicity , Calcium Compounds , Carcinogens , Cell Transformation, Neoplastic/chemically induced , Chromates/toxicity , Nitrilotriacetic Acid/toxicity , Potassium Compounds , Animals , Cell Survival/drug effects , Cricetinae , Drug Synergism , Fibroblasts/drug effects , In Vitro Techniques , Mesocricetus
9.
J Toxicol Environ Health ; 21(3): 387-94, 1987.
Article in English | MEDLINE | ID: mdl-3586067

ABSTRACT

The frequencies of sister chromatid exchanges (SCE) were significantly increased in cultured Chinese hamster cells by insoluble salts of Cr(VI) (PbCrO4) and Pb(II) (PbSO4). A further significant increase of this effect was produced when diluted suspensions of PbCrO4 (1-4 mg/l) and PbSO4 (10-40 mg/l) were preincubated with nitrilotriacetic acid (NTA) concentrations (0.25-1 mg/l) such as those that are possibly found in highly contaminated environmental situations. NTA enhanced the induction of SCE by PbCrO4 and PbSO4 even in the presence, in the preincubation solution and in the medium used to treat the cells, of Na+ and K+ concentrations largely exceeding (e.g., 10(2)-10(6) times) those of the genotoxic metals.


Subject(s)
Acetates , Chromium , Lead , Nitrilotriacetic Acid , Cations , Chelating Agents , Potassium , Sodium , Solubility
10.
Mutat Res ; 156(3): 219-28, 1985 Jun.
Article in English | MEDLINE | ID: mdl-3889637

ABSTRACT

The influence of nitrilotriacetic acid trisodium salt (NTA) on the mutagenic and clastogenic activity of several water-insoluble or poorly soluble chromium compounds was determined by means of the Salmonella/microsome assay (plate test on TA100 strain) and the sister-chromatid exchange (SCE) test in mammalian cell cultures (CHO line). NTA in itself did not induce gene mutations nor did it increase the frequency of SCE. Cr(VI) compounds (Pb, Ba, Zn, Sr and Ca chromates) and an industrial Cr(VI) pigment, chromium orange (containing PbCrO4 PbO), were inactive or scarcely active mutagens in the Salmonella/microsome test when dissolved in water, but they were increasingly mutagenic when solubilized by 0.5 N NaOH or NTA (10 or 100 mg/ml). Also, the mutagenic activity of Cr(VI), contaminating an industrial Cr(III) pigment (chromite), was slightly enhanced by NTA. Mutagenicity of chromates was correlated with the amounts of Cr(VI) solubilized by NTA or alkali, as determined by the colorimetric reaction with diphenylcarbazide and atomic absorption spectrophotometry, and was decreased by incubation with microsomes, due to reduction of Cr(VI) to the genetically inactive Cr(III) form. In the SCE assay, the insoluble or poorly soluble Ba, Zn, Sr and Ca chromates and the insoluble Cr(VI) pigments zinc yellow (containing ZnCrO4 Zn(OH2], chromium yellow and molybdenum orange (both containing PbCrO4) were directly clastogenic due to cellular endocytosis taking place in prolonged treatments, and NTA significantly increased their chromosome-damaging activity.


Subject(s)
Acetates/pharmacology , Chromium/toxicity , Mutation/drug effects , Nitrilotriacetic Acid/pharmacology , Sister Chromatid Exchange/drug effects , Animals , Cells, Cultured , Cricetinae , Drug Interactions , Female , Ovary , Salmonella typhimurium/drug effects , Solubility
11.
Environ Mutagen ; 7(2): 185-200, 1985.
Article in English | MEDLINE | ID: mdl-3882415

ABSTRACT

Nitrilotriacetic acid trisodium salt (NTA), which is a substitute for polyphosphates in household laundry detergents, and N-nitrosoiminodiacetic acid (NIDA), a derivative of NTA produced by metabolism of soil microorganisms, were tested for in vitro mutagenicity in bacteria and yeasts. No gene reversions in five strains of Salmonella typhimurium (TA 1535, TA1537, TA1538, TA98, and TA100), no forward gene mutations in Schizosaccharomyces pombe P1, and no mitotic gene conversions at two loci in Saccharomyces cerevisiae D4 were induced by NTA (up to 870 micrograms/plate or 40 micrograms/ml) and NIDA (up to 2,000 micrograms/plate or 1,000 micrograms/ml), independently of the presence of rat liver metabolic activation. The influence of NTA on the mutagenic and clastogenic activity of several chromium compounds was examined in the Salmonella/microsome assay and in the sister chromatid exchange (SCE) assay in mammalian cell cultures (Chinese hamster ovary [CHO] line). NTA does not affect the genetic inactivity of water-soluble Cr(III) (Cr2[SO4]3) and the direct mutagenicity of soluble Cr(VI) (Na2CrO4,K2Cr2O7) compounds. The very insoluble Cr(VI) compounds PbCrO4 and PbCrO4 X PbO are instead clearly mutagenic in the Salmonella/microsome assay (TA100 strain) only in the presence of NTA or NaOH. The mutagenicity of lead chromates is correlated with the amounts of Cr(VI) solubilized by NTA or alkali, as detected by the colorimetric reaction with diphenylcarbazide and atomic absorption spectrophotometry. In the SCE assay, the insoluble lead chromates are directly clastogenic owing to prolonged treatment conditions and cellular endocytosis. The chromosome-damaging activity of PbCrO4 is significantly increased by NTA but not by NaOH.


Subject(s)
Acetates/toxicity , Chromium/toxicity , Mutagens , Nitrilotriacetic Acid/toxicity , Animals , Cricetinae , Cricetulus , Drug Synergism , Mutagenicity Tests , Salmonella typhimurium/drug effects , Sister Chromatid Exchange/drug effects , Solubility
12.
Environ Mutagen ; 7(3): 381-90, 1985.
Article in English | MEDLINE | ID: mdl-4043022

ABSTRACT

The ability of nitrilotriacetic acid trisodium salt (NTA) to induce sister chromatid exchanges (SCE) and to influence the induction of SCE by heavy metal compounds was evaluated with mammalian cell cultures. In accordance with the generally negative results obtained by other investigators on the mutagenic effects of NTA, no increase of SCE frequency was observed in Chinese hamster cells (CHO line) or in primary cultures of mouse (BALB/c and BALB/Mo strains) lymphocytes, after treatment with NTA at subtoxic concentrations (2 X 10(-3) M and 10(-3) M, respectively). The induction of SCE by salts of heavy metals (Cd, Hg, Ni, Pb) was evaluated with CHO cells. Soluble (CdCl2, HgCl2, NiCl2, Pb [CH3COO]2) and insoluble (CdCO3, HgCl, NiCO3, PbSO4) compounds were tested, and, with the exception of Pb(CH3COO)2, all were found to increase the frequency of SCE. NTA apparently did not affect the ability of the soluble metal compounds to induce SCE, but it significantly increased the frequency of SCE induced by treatment with all the insoluble salts.


Subject(s)
Acetates/pharmacology , Metals/toxicity , Nitrilotriacetic Acid/pharmacology , Sister Chromatid Exchange/drug effects , Animals , Cell Line , Cricetinae , Cricetulus , Drug Synergism , Female , Lymphocytes/drug effects , Mice , Solubility
15.
Cancer Res ; 36(6): 2013-8, 1976 Jun.
Article in English | MEDLINE | ID: mdl-178440

ABSTRACT

Transfer RNA methylase (tRNA methylase) activity and capacity were monitored in whole-rat-liver preparations during the induction of hepatocellular carcinomas by an 8-week aflatoxin B1 dosing regimen that produced minimal toxic effects. Significant phases of elevated tRNA methylase capacity occurred at 6 to 9 weeks (20%) and 24 to 29 weeks (40%). No significant change in tRNA methylase activity was noted over the course of the 55-week experiment. Higher aflatoxin B1 doses, producing acute toxic liver damage, resulted in elevated tRNA methylase activity (50%) and capacity (30%) at least as early as 1 week after dosing. Experiments with individual nodular lesions excised from livers of rats continuously fed a diet containing 2 ppm aflatoxin B1 demonstrated similarly elevated tRNA methylase activities and capacities in hyperplastic (preneoplastic)nodules, with and without histological evidence of carcinoma.


Subject(s)
Carcinoma, Hepatocellular/enzymology , Liver Neoplasms/enzymology , tRNA Methyltransferases/metabolism , Aflatoxins , Animals , Carcinoma, Hepatocellular/chemically induced , Liver/enzymology , Liver/pathology , Liver Neoplasms/chemically induced , Male , Neoplasms, Experimental/chemically induced , Neoplasms, Experimental/enzymology , Precancerous Conditions/enzymology , Precancerous Conditions/pathology , Rats , tRNA Methyltransferases/analysis , tRNA Methyltransferases/isolation & purification
16.
Cancer Res ; 35(8): 1981-4, 1975 Aug.
Article in English | MEDLINE | ID: mdl-167941

ABSTRACT

Carcinogenic activity of several synthetic N-nitroso compounds was evaluated in C57BL/6J X C3HeB/FeJ F1 mice. Test substances, suspended in trioctanoin, were injected i.p. in three equal doses given on Days 1, 4, and 7 after birth and animals were held without further treatment for up to 85 weeks. Nitrosoephedrine at a total dose of 600 mg/kg induced metastasizing liver cell carcinomas in 28 of 30 animals. Nitrososarcosine (225 mg/kg) induced similar tumors in 8 of 14 animals. Nitrosofolic acid (375 mg/kg) induced lung adenocarcinomas in 4 of 28 mice. Creatinine-5-oxime (600 mg/kg) showed no evidence of carcinogenic activity. Diethylnitrosamine (12 mg/kg given in four doses), included as a positive control, caused metastasizing liver cell tumors in 23 of 25 animals.


Subject(s)
Carcinogens , Carcinoma/chemically induced , Liver Neoplasms/chemically induced , Lung Neoplasms/chemically induced , Nitroso Compounds , Adenoma, Bile Duct/chemically induced , Animals , Creatinine/analogs & derivatives , Ephedrine/analogs & derivatives , Folic Acid/analogs & derivatives , Hyperplasia/chemically induced , Lethal Dose 50 , Mice , Mice, Inbred C3H , Mice, Inbred C57BL , Neoplasms, Experimental/chemically induced , Neurofibroma/chemically induced , Nitro Compounds/toxicity , Precancerous Conditions/chemically induced , Sarcosine/analogs & derivatives
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