Biomedical subjects

A Favier

Publications and source records attributed to A Favier.

At least 19 recordsLinked to original sources

PubMed1999

The interactions of substituted pyrido[1,2-e]purines with oligonucleotides depend on the amphiphilic properties of their side chain.

Three pyrido[1,2-e]purines of increasing hydrophilicity have been synthesized to evaluate as anticancer agents. These drugs interact quite differently with a synthetic oligodeoxynucleotide d(CGATCG)2. [1] is very hydrophobic due to a phenyl residue in its side chain. It only shows limited interactions with the minihelix without any evidence of intercalation. [2] and [3], on the other hand, have one ([2]) or two ([3]) hydroxyl groups in their acyl chain and present rather amphiphilic properties. The result is a similar intercalation of these derivatives between C and G base pairs as revealed by intermolecular nOe, 1H and 31P chemical shift variations. Models for the intercalation of [2] are proposed using energy minimizations and molecular dynamics (MD) calculations subject to restraints from nOe connectivities. Simulations and experiments indicate weak stability and thus fast exchange of [2] in its intercalation site.

Animals↗

PubMed1999

Gas chromatographic-mass spectrometric determination of total homocysteine in human plasma by stable isotope dilution: method and clinical applications.

The detection and quantitation of slight increases of plasma homocysteine levels is of growing interest. This has prompted us to develop a highly sensitive and accurate capillary gas chromatography-mass spectrometry (GC-MS) method. The method proved to be highly sensitive (DL=0.17 micromol/l) with between- and within-run precision less than 6% and 7%, respectively. Reference values of plasma total homocysteine have been determined for men (n=39) and women (n=36), showing a significant difference (P=0.003) between gender. Preliminary results in cerebrovascular accidents and in venous thrombosis are presented.

Adult↗

PubMed1999

The human immunodeficiency virus-1 Tat protein increases cell proliferation, alters sensitivity to zinc chelator-induced apoptosis, and changes Sp1 DNA binding in HeLa cells.

The HIV-1 transcriptional regulatory protein Tat is a pleiotropic factor that represses expression of the human Mn-superoxide dismutase. Tat increases oxidative stress, as shown by decreased glutathione and NADPH levels. These redox changes enhance proliferation and apoptosis and alter the activity of zinc thiolate-containing proteins such as Sp1. Cells stably producing the Tat protein have an increased proliferation rate, which can be inhibited by pretreatment with the antioxidant mercaptopropionylglycine. Conversely, cells exposed to low concentrations of the oxidant paraquat are stimulated to divide. Intermediate and higher paraquat levels result in increased apoptosis or necrosis, respectively, suggesting that the physiological end point depends on the dose of oxidant used. Furthermore, treatment with the zinc chelator (N,N,N', N'-tetrakis(2-pyridylmethyl)ethylenediamine (TPEN) sensitizes HeLa-tat cells to apoptosis. In these cells, binding of the zinc-containing factor Sp1 to its DNA sequence is higher than in parental cells. Normal DNA binding is partially restored by pretreatment with a compound that mimics superoxide dismutase activity. Interestingly, Sp1-DNA interactions decrease more rapidly in the HeLa-tat cells after TPEN treatment. HeLa cell extracts incubated in the presence of purified Tat protein have increased Sp1 binding, consistent with the results observed in Tat-transfected cells. These results suggest that the Tat protein, via direct or indirect mechanisms, increases proliferation, sensitizes cells to apoptosis, and changes the conformation of Sp1, affecting its ability to bind to its cognate DNA sequence and to retain its zinc.

Apoptosis↗

PubMed1999

Impairment of cultured cell proliferation and metallothionein expression by metal chelator NNN'N'-tetrakis-(2-pyridylmethyl)ethylene diamine.

Metallothioneins (MT) are a family of intracellular, cysteine-rich, zinc-binding proteins. Their expression is constitutive but can also be induced at the transcriptional level by various stimuli. In this study, we exposed HaCaT human keratinocytes to excess zinc (ZnCl2) or to zinc deprivation by the diffusible chelator NNN'N'-tetrakis(2-pyridylmethyl)ethylene diamine (TPEN), and to ultraviolet B (UVB) irradiation. We examined both cell proliferation and MT expression. Cell proliferation was maximally stimulated by 100 microM Zn2+ supply and was markedly inhibited by zinc deprivation or UVB irradiation. Zinc and UVB irradiation both increased MTI and/or MTII as detected by immunocytochemistry and enhanced the baseline level of MT-IIA mRNA, whereas TPEN treatment inhibited MT basal expression. Zinc partially prevented the concentration-dependent, UVB-induced decrease in cell proliferation. On the other hand, TPEN partially prevented the UVB-induced increase in MTIIA mRNA. These results suggest that zinc is involved in defense mechanisms of skin keratinocytes and in their stress-induced response.

Blotting, Northern↗

PubMed1999

Zinc protects against ultraviolet A1-induced DNA damage and apoptosis in cultured human fibroblasts.

Ultraviolet A1 (UVA1) radiation generates reactive oxygen species and the oxidative stress is known as a mediator of DNA damage and of apoptosis. We exposed cultured human cutaneous fibroblasts to UVA1 radiation (wavelengths in the 340-450-nm range with emission peak at 365 nm) and, using the alkaline unwinding method, we showed an immediate significant increase of DNA strand breaks in exposed cells. Apoptosis was determined by detecting cytoplasmic nucleosomes (enzyme-linked immunosorbent assay method) at different time points in fibroblasts exposed to different irradiation doses. In our conditions, UVA1 radiation induced an early (8 h) and a delayed (18 h) apoptosis. Delayed apoptosis increased in a UVA dose-dependent manner. Zinc is an important metal for DNA protection and has been shown to have inhibitory effects on apoptosis. The addition of zinc (6.5 mg/L) as zinc chloride to the culture medium significantly decreased immediate DNA strand breaks in human skin fibroblasts. Moreover, zinc chloride significantly decreased UVA1-induced early and delayed apoptosis. Thus, these data show for the first time in normal cutaneous cultured cells that UVA1 radiation induces apoptosis. This apoptosis is biphasic and appears higher 18 h after the stress. Zinc supplementation can prevent both immediate DNA strand breakage and early and delayed apoptosis, suggesting that this metal could be of interest for skin cell protection against UVA1 irradiation.

Apoptosis↗

PubMed1999

Plasma vitamin A, E, and beta-carotene levels in adult post-partum Algerian women.

Vitamins A and E are essential for foetal growth, reproduction, and lactation. In this article we report the results of a study, lead in three Eastern Algeria cities, that involved 786 post-partum women and 250 control. Plasma levels of vitamins A, E, beta-carotene, and some nutritional indexes were measured in both groups. In control women, plasma retinol and beta-carotene levels were significantly lower in Algeria than in France (retinol: 1.4 +/- 0.42 vs. 1.78 +/- 0.53 mumol/l; beta-carotene: 0.35 +/- 0.261 vs. 0.94 +/- 0.611). These differences could be the consequence of different beta-carotene and retinol intakes. In Algeria, comparisons between post-partum women and controls, showed that plasma vitamin A and beta-carotene levels were significantly lower in post-partum than in control women. This fact, and the lower level of retinol in control women, raises the question of supplementation for pregnant women in Algeria, at least for those with the lowest standard of living whose protein and zinc levels are also very low after delivery. Plasma vitamin E levels and vitamin E/total lipid ratios were not different in Algeria and in France. Vitamin E concentration was higher during pregnancy, but the vitamin E/total lipid ratio was significantly lower, which shows a relative deficiency at the end of pregnancy. Comparisons of plasma vitamin E levels, at delivery, in primiparous and in multiparous women reveal a better tocopherol status in multiparous women. This difference could reflect an adaptive response to oxidative stress in multiparous women.

Adolescent↗

PubMed1999

Effects of 8-oxo-7,8-dihydro-2'-deoxyguanosine on the binding of the transcription factor Sp1 to its cognate target DNA sequence (GC box).

Emphasis was placed in this work on the assessment of the role of guanine bases in the interaction of transcription factor SP1 with its cognate DNA sequence. For this purpose, each guanine residue of the 5'-GGGGCG-GGG-3' (GC box) target DNA sequence was substituted in turn by 8-oxo-7,8-dihydro-2'-deoxyguanosine. The latter oxidized nucleotide which is likely to be present in mammalian DNA and exhibit mutogenic features is expected to be involved in age-related diseases and cancer. The effect of the incorporation of 8-oxodGuo into DNA on the binding of transcription factor Sp1 was studied using electrophoretic mobility shift assays with nuclear extracts from HeLa cells. When guanines at position G '2, G '3, G '4, G '5 and G'6 were replaced with 8-oxodGuo, binding of Sp1 was only 28%, 30%, 7%, 5% and 21%, respectively, to that of the non-substituted oligonucleotide. The binding is less affected when guanines at position G'1, G'7, G'8 and G'9 were substituted by 8-oxodGuo. Results show up the importance of the core of the GC box and the stronger contribution of the second and the third zinc finger to the binding with DNA. All together, this suggests that incorporation of 8-oxodGuo may alter the expression of the gene regulated by Sp1 and affect the response of the cell.

8-Hydroxy-2'-Deoxyguanosine↗

PubMed1999

An insulin sensitizer improves the free radical defense system potential and insulin sensitivity in high fructose-fed rats.

Recently there has been growing interest in the effects of antioxidants on insulin activity. In the present study, we investigated the effect of metformin on free radical activity and insulin sensitivity in high fructose-fed rats, a diet that leads to insulin resistance. The animals were divided into four groups (n = 16 per group; experiment duration = 6 weeks): the control (C) group received a standard diet; the control metformin (CM) group was fed a control diet and received metformin (200 mg x kg(-1) x day(-1) in water); the fructose control (FT) group was fed a diet in which fructose composed 56.8% of the total carbohydrates; and the fructose metformin (FM) group received high-fructose diet and metformin (200 mg x kg(-1) x day(-1) in water). The glucose clamp technique was used to determine insulin sensitivity in eight animals per group. Metabolic and oxidative stress parameters were measured in the remaining rats. In the FT rats, insulin resistance, lower red cell CuZn superoxide dismutase activity and lower blood reduced glutathione were observed. Metformin treatment improved both the insulin activity and the antioxidant defense system. In the CM group, metformin had no effect on metabolic parameters, but improved red cell antioxidant enzyme activities and the blood GSH level, which suggests that it has an antioxidant activity independent of its effect on insulin activity.

Animals↗

PubMed1998

Age-dependent changes in myocardial susceptibility to zero flow ischemia and reperfusion in isolated perfused rat hearts: relation to antioxidant status.

Ageing is associated with an increase in myocardial susceptibility to ischemia and a decrease in post-ischemic recovery of function. In the present study, we have examined the effects of ageing on (i) myocardial ischemic contracture, (ii) the reperfusion syndrome and lipid peroxidation upon reperfusion, and (iii) the activity of enzymes involved in reactive oxygen species elimination. Hearts from male Wistar rats aged 4 (adults), 16 (old) or 24 months (senescent) were subjected to 20-min zero flow ischemia and 30-min reperfusion ex vivo. Cardiac activity of superoxide dismutase, catalase, and glutathione peroxidase, as well as cardiac content of thiobarbituric acid reactants were assessed in frozen heart samples. The effects of ageing on ischemic contracture of the sarcomeres were assessed on electromicrographs of tissues taken at the end of ischemia. In our experimental conditions, ischemic contracture of the sarcomeres increased progressively during ageing. In contrast, the severity of the reperfusion syndrome increased between 4 and 16 months of age, and then decreased up to 24 months of age. We propose that the peak of susceptibility of the myocardium to reperfusion observed during moderate ageing might be related to a decrease in the ability of cardiomyocytes to dismutate hydrogen peroxide as suggested by the observed decrease in catalase activity. Finally, the better resistance to the reperfusion syndrome exhibited by senescent rats compared to old rats might be due to a natural selection of a subpopulation of rats which is particularly resistant to oxidative stress.

Aging↗

PubMed1998

Metal chelator NNNNN-tetrakis-(2-pyridymethyl)ethylene diamine inhibits the induction of heat shock protein 70 synthesis by heat in cultured keratinocytes.

Heat shock protein (HSP) synthesis results from various types of injury, including heat shock (HS) and some oxidants. The intracellular signals leading to HSP synthesis are not yet fully elucidated. We have studied the influence of NNN'N'-tetrakis(2-pyridylmethyl)ethylene diamine (TPEN), a metal chelator known to induce cellular zinc and copper deprivation, on resistance to heat and on hsp70 synthesis in HaCaT keratinocytes. TPEN was shown to sensitize HaCaT cells to heat shock. The effect of TPEN was neutralized by equimolar Zn2+. By the use of sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis and Western blotting characterization of hsp70, it was shown that cultured HaCaT cells constitutively express the inducible form of hsp70. The application of TPEN alone slightly increases the level of hsp70 but inhibits its induction by HS. This inhibitory effect is related to metal deprivation, because it is eliminated when Cu2+ or Zn2+ ions are supplied together with TPEN. These results suggest that these metals are involved in the expression by keratinocytes of a stress protein which has a protective action against environmental stress.

Cell Survival↗

PubMed1998

A primary prevention trial using nutritional doses of antioxidant vitamins and minerals in cardiovascular diseases and cancers in a general population: the SU.VI.MAX study--design, methods, and participant characteristics. SUpplementation en VItamines et Minéraux AntioXydants.

The SUpplementation en VItamines et Minéraux AntioXydants (SU.VI.MAX) Study is a randomized, double-blind, placebo-controlled, primary-prevention trial designed to test the efficacy of daily supplementation with antioxidant vitamins (vitamin C, 120 mg; vitamin E, 30 mg; and beta-carotene, 6 mg) and minerals (selenium, 100 microg; and zinc, 20 mg) at nutrition-level doses (one to three times the daily recommended dietary allowances) in reducing several major health problems in industrialized countries, especially the main causes of premature death, cancers and cardiovascular diseases. The present report describes the design, implementation, and baseline characteristics of participants in this 8-year cohort study, which started in 1994 in France; 12,735 eligible subjects (women aged 35-60, and men aged 45-60) were included in 1994 and will be followed for 8 years. Participants undergo a yearly visit consisting, every other year, of either biological sampling or clinical examination. They also regularly provide information on health events and dietary intake by filling out computerized questionnaires using the Minitel Telematic Network. Data on baseline characteristics of the participants suggest that the present sample is close to the national population in terms of geographic density, socioeconomic status, and the distribution of various major risk factors for the diseases under study. The choice of the study population should allow the results of this trial to apply to adult populations of both sexes in France and other industrialized countries.

Adult↗

PubMed1998

Trace elements and cardioprotection: increasing endogenous glutathione peroxidase activity by oral selenium supplementation in rats limits reperfusion-induced arrhythmias.

Oxyradicals have been implicated as a possible cause of reperfusion-arrhythmias (RA). However, the use of diverse exogenous oxyradical scavengers designed to reduce RA has given contradictory results. The aim of the present study was to determine whether enhancing the activity of the main endogenous enzyme involved in peroxide elimination in cardiac cells, namely glutathione peroxidase, may limit RA in isolated heart preparations by increasing their antioxidant status. For this purpose, a group of 15 male Wistar rats received a selenium enriched diet for ten weeks (1.5 mg Se/kg diet). Control animals (n = 15) received a standard diet containing 0.05 mg Se/kg diet. The incidence of early ventricular arrhythmias was investigated during the reperfusion period following 10 min regional ischemia induced ex-vivo by left coronary artery ligation. Our results show that selenium-supplementation significantly increased the global selenium status of the animals. In the isolated heart preparations, the selenium supplementation induced a significant reduction of the severity of RA as assessed by the arrhythmia score and the limitation of the incidence of both ventricular tachycardia (control: 91% vs selenium: 36%, p < 0.05) and irreversible ventricular fibrillation (control: 45% vs selenium: 0%, p < 0.05). These effects were associated with a significant increase in cardiac mitochondrial and cytosolic glutathione peroxidase activities in both the left and the right ventricles. These results illustrate the potential protective effect of selenium against ischemia-reperfusion injury and suggest that peroxides might play a key role in the genesis of some aspects of the reperfusion syndrome.

Administration, Oral↗

PubMed1998

Determining factors in the iron status of adult women in the SU.VI.MAX study. SUpplementation en VItamines et Minéraux AntioXydants.

The iron status of a national sample of adults living in France and participating in the SU.VI.MAX cohort, was assessed using serum ferritin and hemoglobin concentrations. Complete data were obtained for 6648 women 35-60 y old and for 3283 men 45-60 y old. Assessment of iron dietary intakes was realized on a subsample of 3111 women and 2337 men who reported six 24 h dietary records during a one-year period; 22.7% of menstruating women and 5.3% of post-menopausal women presented a total depletion of iron stores (serum ferritin < 15 microg/l). Iron-deficient anemias were found in, respectively, 4.4% and less than 1% of these women. Three-quarters of the anemias were related to iron deficiency in menstruating women. In men, iron depletion and iron deficiency anemia were very rare. Post-menopausal women had much higher serum ferritin levels than menstruating women. In menstruating women, those using intrauterine devices had significantly lower serum ferritin levels than those without contraception, and much lower than those using oral contraception. The frequency of iron depletion reached 28.1% in women using intrauterine devices, but only 13.6% in those using oral contraceptives. The mean iron intake was 16.7 +/- 5.7 mg/d in men and 12.3 +/- 3.4 mg/d in women. Heme iron represented respectively, 11.1 and 10.4% of iron intake. Ninety-three percent of menstruating women had dietary iron intakes lower than recommended dietary allowances (RDA); 52.6% consumed less than two thirds of these RDA. In post-menopausal women and men, respectively 27.7% and 3.6% had dietary intakes lower than RDA. Serum ferritin was positively correlated with meat, fish and total iron intake, and negatively correlated with dietary products consumption, calcium and fiber intake.

Adult↗

PubMed1998

Effects of supplementation with a combination of antioxidant vitamins and trace elements, at nutritional doses, on biochemical indicators and markers of the antioxidant system in adult subjects.

OBJECTIVE: To test the impact of supplementation with nutritional doses of antioxidant nutrients on biochemical indicators of vitamin and trace element levels. DESIGN: A randomized double-blind trial was performed comparing two groups receiving daily either a combination of vitamins (beta-carotene, 6 mg; vitamin C, 120 mg; and vitamin E, 30 mg) and trace elements (zinc, 20 mg; and selenium, 100 micrograms); or a placebo. SUBJECTS: 401 subjects (166 males aged 45 to 60 years and 235 females aged to 35 to 60 years). MEASURE OF OUTCOME: Biological markers of vitamin and trace element status and free radical parameters were measured initially, 3 months, and 6 months after supplemention. RESULTS: Mean serum concentrations of alpha-tocopherol, vitamin C, beta-carotene, zinc and selenium increased significantly after 3 months of supplementation in the group receiving multivitamins associated with minerals. At baseline, 18.2% of the men and 5.1% of the women had low concentrations of serum vitamin C (< 20 mumol/l): 2.4% of the men and 17% of the women presented low concentrations of serum retinol (< 1.4 mumol/l): 18.7% of men and 10% of women had serum beta-carotene < 0.30 mumol/l. None of the study subjects had serum alpha-tocopherol concentrations below the limit cut-off point (< 9.3 mumol/l). Low serum zinc concentrations (< 10.7 mumol/l) were found in 15.1% of men and 23.8% of women. Low serum selenium concentrations (< 0.75 mumol/l) were found in 6% of men and 6.4% of women. A significant increase in plasma and red cell GPx activity was observed in groups receiving supplementation. No modifications were observed after 6 months of supplementation for malondyaldehyde. CONCLUSION: This study demonstrates the efficacy of an intake of antioxidant vitamins and trace elements, given at nutritional doses, on biochemical indicators of vitamin and trace elements status.

Adult↗

PubMed1998

Urine 8-oxo-7,8-dihydro-2-deoxyguanosine vs. 5-(hydroxymethyl) uracil as DNA oxidation marker in adriamycin-treated patients.

We measured the base 5-(hydroxymethyl) uracil (HMUra) and the nucleoside 8-oxo-7,8-dehydro-2'-deoxyguanosine (8-oxo-dGuo) in urine of adriamycin-treated cancer patients. Adriamycin has been shown to generate oxygen free radicals by various mechanisms. HMUra and 8-oxo-dGuo are two known lesions of DNA, produced by oxygen free reaction on thymine and 2'-deoxyguanosine, respectively. HMUra was measured by GC-MS/isotopic dilution and 8-oxo-dGuo by HPLC/EC, both after prepurification by semipreparative HPLC. Here we report the results of a study involving 20 cancer patients treated with flash doses of ADR. We found that urine HMUra is significantly increased (HMUra (nmol/24h): 80.8 8.44 vs. 98.7+/-6.87; p < 0.01) 24h after administration of the drug, while 8-oxo-dGuo did not show any significant variation. Urine HMUra seems to be a suitable short-term marker of DNA alterations by oxygen free radicals.

8-Hydroxy-2'-Deoxyguanosine↗

PubMed1998

Background and rationale behind the SU.VI.MAX Study, a prevention trial using nutritional doses of a combination of antioxidant vitamins and minerals to reduce cardiovascular diseases and cancers. SUpplementation en VItamines et Minéraux AntioXydants Study.

The "SUpplementation en VItamines et MinérauxAntioXydants" (SU.VI.MAX) study is a randomized double-blind, placebo-controlled, primary prevention trial designed to test the efficacy of daily supplementation with antioxidant vitamins (vitamin C, 120 mg; vitamin E, 30 mg; and beta-carotene, 6 mg) and minerals (selenium, 100 micrograms; and zinc, 20 mg), at nutritional doses (one to three times the daily recommended dietary allowances), in reducing the frequency of major health problems in industrialized countries, and especially the main causes of premature death (cancers and cardiovascular diseases). The study involves 12,735 eligible subjects (women aged 35 to 60 years; men aged 45 to 60 years) included in 1994 in France. They will be followed up for 8 years. The objectives and the specific design of this intervention study are linked to its public health aim. The targeted population is the general population (not simply high-risk subjects) and the antioxidant agents tested are being administered at a level which is not pharmacologic and which may be attained by dietary intake of natural sources of these micronutrients and/or enriched foods. The amounts we are testing in the SU.VI.MAX study are those which, in observational studies have been associated with the lowest risk of diseases. This report presents the rationale and discusses the justification of the design, doses and combination of antioxidant micronutrients chosen in the SU.VI.MAX study.

Adult↗

PubMed1997

Presence of zinc and calcium permeant channels in the inner membrane of the nuclear envelope.

The nuclear envelope possesses specific ion channels that regulate the ionic traffic between the cytoplasm or the perinuclear space and the nucleoplasm. Using the patch-clamp technique to isolated rat nuclei exhibiting only the inner membrane of the nuclear envelope, we report the existence of calcium and zinc permeant channels. These channels displayed similar characteristics (conductance : 8 and 11 pS respectively, open time constant (3.5 ms and 3.7 ms) and close time constant (5.1 ms and 4.8 ms)) and were insensitive to different types of calcium channels blockers and to calcium concentration in the bathing solution. The exact role of these channels remains to define, but they may contribute to the regulation of intranuclear Ca++ or Zn++ dependent processes as important as cell proliferation or programmed cell death. Moreover, this work demonstrates that our nuclei preparation provides a way to study the inner membrane of the nuclear envelope.

Animals↗

PubMed1997

Selenium and antioxidant vitamin and lipidoperoxidation levels in preaging French population. EVA Study Group. Edude de vieillissement artériel.

Selenium (Se) and antioxidant vitamins might play an important role in the etiology of free radical-related diseases and aging. In the Edude de vieillissement artériel (EVA) study, we have determined the plasma thiobarbituric acid reacting substances (TBARS) as an indicator of free radical-induced lipid peroxidation, plasma selenium and carotenoids, and erythrocyte vitamin E levels in 1389 subjects aged 59-71 years. We also looked for an association between these parameters and cardiovascular risk factors in early elderly. The results show that plasma TBARS were significantly increased in elderly in comparison with values reported in younger adults. However, plasma Se and carotenoids as well as erythrocyte vitamin E in elderly people are close to those reported in adult people. If plasma Se showed no difference between men and women, the three other parameters were significantly higher in women than in men. With regard with cardiovascular risk factors, plasma TBARS were highly positively correlated with total and low-density lipoprotein (LDL) cholesterol in men and women. Plasma carotenoids were also positively correlated with plasma total cholesterol and LDL cholesterol in both sexes. Finally, plasma TBARS were highly correlated with smoking and alcohol consumption. In conclusion, this part of the EVA study shows that some cardiovascular risk factors, like smoking and cholesterol level, are associated with high free radical-induced TBARS levels in the preaging population, although plasma Se and carotenoids as well as erythrocyte vitamin E levels in elderly people were close to those reported in adult younger people.

Aged↗