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Biomedical subjects

G Siest

Publications and source records attributed to G Siest.

At least 19 recordsLinked to original sources
PubMed2005

Pharmacogenomics education: International Society of Pharmacogenomics recommendations for medical, pharmaceutical, and health schools deans of education.

Pharmacogenomics would be instrumental for the realization of personalized medicine in coming decades. Efforts are evident to clarify the potential bioethical, societal, and legal implications of key pharmacogenomics-based technologies projected to be soon introduced into the core practice of medicine. In sharp contrast, a lack of sufficient attention to educational aspects of pharmacogenomics, both for professionals and for society at large, is evident. In order to contribute to this discussion, a 'Pharmacogenomics Education Forum' was held on October 2, 2004 during the 3rd Annual Meeting of the International Society of Pharmacogenomics (ISP) at Santorini, Greece. The participants, members of the ISP Pharmacogenomics Education Forum, after deliberate discussions, proposed a document of 'Background Statement' and 'Recommendations and Call for Action' addressed to Deans of Education at Medical, Pharmaceutical, and Health Schools globally. This document has been considered by the education committee of the International Society of Pharmacogenomics and the result is presented here. We hope that this call would be listened to, and soon followed by beneficial action, ultimately leading to enhanced implementation of personalized medicine into core medical education and practice.

Curriculum↗
PubMed2005

Association of CYP2A6*1B genetic variant with the amount of smoking in French adults from the Stanislas cohort.

This study was designed in order to investigate the influence of the genetic polymorphism of CYP2A6 on the amount of smoking. In all, 463 French adults included in the Stanislas cohort were studied and underwent two examinations at 5 years distance (t0 and t(+5) years). Information on their smoking habits was collected. They were genotyped by RFLP for the CYP2A6*1A, CYP2A6*1B and CYP2A6*4 alleles. CYP2A6*1B and CYP2A6*4 allele frequencies were 32 and 4%, respectively. The subjects carrying the CYP2A6*1B allele oxidize nicotine to cotinine faster than subjects with the CYP2A6*1A allele. The number of cigarettes smoked per day was significantly higher in the CYP2A6*1B/*1B group as compared to the CYP2A6*1A/*1A group (P = 0.01 at t0; P = 0.001 t(+5) years), with a larger increase in their daily cigarettes consumption over the 5-year period (P = 0.006). No significant difference in the smoking status was observed according to the CYP2A6 genotype. These data suggest that the CYP2A6*1B is associated with the number of cigarettes smoked per day.

Adult↗
PubMed2004

Pharmacogenomics and drug response in cardiovascular disorders.

There are a total of 17 families of drugs that are used for treating the heterogeneous group of cardiovascular diseases. We propose a comprehensive pharmacogenomic approach in the field of cardiovascular therapy that considers the five following sources of variability: the genetics of pharmacokinetics, the genetics of pharmacodynamics (drug targets), genetics linked to a defined pathology and its corresponding drug therapies, the genetics of physiologic regulation, and environmental-genetic interactions. Examples of the genetics of pharmacokinetics are presented for phase I (cytochromes P450) and phase II (conjugating enzymes) drug-metabolizing enzymes and for phase III drug transporters. The example used to explain the genetics of pharmacodynamics is glycoprotein IIIa and the response to antiplatelet effects of aspirin. Genetics linked to a defined pathology and its corresponding drug therapies is exemplified by ADRB1, ACE, CETP and APOE and drug response in metabolic syndrome. The examples of cytochrome P450s, APOE and ADRB2 in relation to ethnicity, age and gender are presented to describe genetics of physiologic regulation. Finally, environmental-genetic interactions are exemplified by CYP7A1 and the effects of diet on plasma lipid levels, and by APOE and the effects of smoking in cardiovascular disease. We illustrate this five-tiered approach using examples of cardiovascular drugs in relation to genetic polymorphism.

Animals↗
PubMed2003

Apolipoprotein E (apoE) uptake and distribution in mammalian cell lines is dependent upon source of apoE and can be monitored in living cells.

As part of investigations of the cellular uptake of apolipoprotein E (apoE) relevant to Alzheimer's disease we have found that different preparations of apoE are handled differently by cells expressing the LDL-receptor. Comparing recombinant, cellular and native apoE, complexed with different preparations of lipid we find that only cellular and native apoE enter a vesicular compartment. Some, but not all of these apoE containing vesicles are lysosomes. In order to further examine the intracellular fate of apoE we demonstrate that apoE-Enhanced green fluorescent protein chimeric protein can be taken up from medium by recipient cells and tracked within these cells for extended periods.

Animals↗
PubMed2003

Astroglial CYP1B1 up-regulation in inflammatory/oxidative toxic conditions: IL-1beta effect and protection by N-acetylcysteine.

The present work aims to determine the relevance of an astrocytoma cell line U373 MG, for assessing the role of some astroglial cytochrome P450 in neurotoxicity and neuroprotection. CYP1B1, CYP2C8, CYP2C9, CYP2D6, CYP2J2, CYP2E1 and CYP4A11 mRNA were detected by reverse transcriptase-polymerase chain reaction in control U373 MG cell cultures. Among them we focused on CYP1B1 expression. After 48 h treatment with a range of concentrations of interleukin-1beta (1, 5, 10 ng/ml) used to simulate stress conditions, CYP1B1 mRNA expression was enhanced in a dose-dependent way. This increased expression was followed 24 h later by an increase in protein level, determined by Western-blot. N-acetylcysteine (NAC) partially inhibited this effect both on the mRNA and protein levels. As CYP1B1 activates procarcinogenic compounds to reactive metabolites, an increase in this P450 isoform will participate to toxic consequences of an inflammatory/oxidative stress. NAC will prevent this deleterious effect.

Acetylcysteine↗
PubMed2002

Family resemblance in breakfast energy intake: the Stanislas Family Study.

BACKGROUND: There seems to be a consensus that family influences on dietary habits are important. However, no data relative to breakfast have been published yet. OBJECTIVE: To investigate whether and how breakfast energy intake aggregates within French families. DESIGN: A total of 398 families of the Stanislas Family Study who filled in a 3 day food consumption diary were selected. Absolute and relative breakfast energy intakes (BEI in kcal/day and RBEI in percentage of daily intake, respectively) were both studied. RESULTS: By using a variance component analysis, no genetic influence was shown in family aggregation of both BEI and RBEI. Intra-generation common environmental contribution to total phenotypic variance of BEI and RBEI was higher than inter-generation; both were increased with frequency of sharing breakfast. Furthermore frequency of sharing breakfast contributed to increase family resemblance in breakfast energy intake, particularly in offspring for BEI and RBEI, and in spouses for RBEI. Smoking habits, alcohol consumption, BMI or physical activity were related to family resemblance, but after adjustment on each factor degrees of resemblance were almost unchanged. CONCLUSION: General findings of this study were that family aggregation in breakfast absolute and relative energy intakes was significant within Stanislas families. Family resemblance depended on inter- and intra-generation components and was modified by the number of shared breakfasts. Our study confirmed that familial habits act on family resemblance in both absolute and relative breakfast energy intakes, so that family should be a favorite unit for health and diet promotion programs. SPONSORSHIP: Kellogg's PA, France.

Adolescent↗
PubMed2002

Molecular pharmacophore determination of lipid lowering drugs with the receptor mapping method.

Hypolipidemic pharmacophoric moieties of statins, fibrates, ACAT inhibitors and beta-sitosterol analog series were identified by computational modeling, and compared with the computed structure of new potential glycyrrhetinic acid derivatives lipid-lowering drugs. Their electronic and geometric domains, similar to those of fibrates, suggest a fibrate -like mechanism matching biochemical data.

Computational Biology↗
PubMed2001

Control of apolipoprotein E secretion in the human hepatoma cell line KYN-2.

Even though it is known that apolipoprotein E (apoE) is deeply involved in major age-related disorders such as atherosclerosis or Alzheimer's disease (AD), the control of cell-specific apoE expression is still poorly understood. We compared the apoE secretion as previously described in astrocytic cell17 to hepatic cell apoE secretion. We used the human hepatoma cell line KYN-2 to better delineate the characteristics of apoE secretion and to validate it with respect to the classical human hepatoma cell line HepG2. Interleukin-1beta (IL-1beta) and interferon-gamma (IFN-gamma) significantly inhibited, while IL-2, IL-6 and tumour necrosis factor-alpha (TNF-alpha) were inactive on apoE secretion by KYN-2 as well as HepG2 cells. Cholesterol and 25-OH cholesterol had no effect, while forskolin exerted a significant inhibitory effect, on apoE secretion in KYN-2 cells. Our results suggest that the KYN-2 cell line represents an appropriate cell model, and in any case an alternative model to the HepG2 cell line, to study the control of apoE secretion. The response of KYN-2 cells to both cytokines and cholesterol differs from that found in astrocytoma cells, suggesting that blood variations of apoE concentrations in AD may not reflect the dysregulations taking place in the brain.

Adenylyl Cyclases↗
PubMed2001

Protein-lipid interactions in reconstituted high density lipoproteins: apolipoprotein and cholesterol influence.

Two fluorescent probes-cis- and trans-parinaric acids were used to study the dimensions, lipid dynamics and apolipoprotein location in the reconstituted discoidal high density lipoproteins (rHDL). The rHDL particles made from apolipoprotein A-I (apoA-I), dipalmitoylphosphatidylcholine (DPPC), with or without cholesterol (Chol) were compared with the analogous particles with two other apolipoproteins-apoE and apoA-II. The data obtained for apoA-I-containing rHDL were as follows: (1) the inclusion of 8 mol.% of cholesterol did not significantly change the particle dimensions (13+/-1 nm) or the mean distance between apoA-I and the disc axis; (2) the phospholipid domains-boundary lipid region in the close vicinity to apoA-I molecule and the remaining part of the bilayer-existed at temperatures both lower and above DPPC transition temperature T(t); (3) at T<T(t) Chol molecules preferentially accumulated in the central area with a radius of 2.8 nm that conserved partially after DPPC phase transition; (4) inhomogeneous cholesterol distribution was assumed to exist within these domains. A hydrophobic matching concept was used to compare protein-lipid interactions in rHDL particles. For complexes with all three apolipoproteins studied, at T<T(t) the probe mobility in the lipid phase of rHDL was significantly higher compared to pure DPPC bilayer. After temperature-induced transition, mobility increased significantly still being lower in rHDL. The comparative study of lipid dynamics in apoA-I-, apoE- and apoA-II-containing complexes revealed the presence of boundary lipid in all three complexes without cholesterol. The degree of cholesterol exclusion from the boundary lipid region seems to increase in the order A-I<E<A-II for Chol-containing complexes, the exclusion being an inherent property of the particular apolipoprotein molecule.

1,2-Dipalmitoylphosphatidylcholine↗
PubMed2001

Apolipoproteins E and C-III in apo B- and non-apo B-containing lipoproteins in middle-aged women from the Stanislas cohort: effect of oral contraceptive use and common apolipoprotein E polymorphism.

Oral contraceptive (OC) use and common apo E polymorphism are well known to modify serum lipid and lipoprotein concentrations. The combined effect of OC use and apo E genotype on the concentration of apo E or apo C-III in apo B- (apo E-LpB or apo C-III-LpB) or in non-apo B-containing lipoparticles (apo E-Lp-non-B or apo C-III-Lp-non-B) are unknown. Our study comprised 613 women, aged 30-45 years, genotyped for common apo E polymorphism and who differed in their combined low-dose OC consumption. The concentrations of apo C-III, apo C-III-LpB and apo C-III-Lp-non-B were significantly higher in OC users than in non-users by 13, 23 and 8% respectively, without significant interaction with the apo E genotype. The concentrations of apo E and apo E-Lp-non-B were significantly lower (differences being -14% and -31% respectively) in OC users than in controls whereas the apo E-LpB concentration was significantly higher (+19%), resulting in a redistribution of apo E from Lp-non-B towards LpB. Total apo E and apo E-Lp-non-B concentrations were higher in subjects carrying the epsilon2 allele and lower in those with the epsilon4 allele when compared to epsilon3/epsilon3 subjects (P < 0.001). The opposite held for the apo E- LpB concentration (P < 0.05). The main finding is the significant interaction between apo E genotype and OC use (P < 0.01) on apo E-Lp-non-B concentration, the epsilon4 carriers showing the smallest differences between OC users and non-users in comparison with the epsilon2 or epsilon3/epsilon3 carriers. These results suggest that the common apo E polymorphism can modulate the OC use effect.

Adult↗
PubMed2001

Control of apolipoprotein E secretion by 25-hydroxycholesterol and proinflammatory cytokines in the human astrocytoma cell line CCF-STTG1.

During the last few years the increased presence of proinflammatory cytokines and oxidation products in Alzheimer's disease (AD) has been largely described. Oxysterols, formed by hydroxylation of cholesterol, occur naturally in the brain and are increased in the serum of AD patients. Of these oxysterols, 25-hydroxycholesterol is the most potent regulator of gene transcription. It stimulates the synthesis of apolipoprotein E (apo E) in macrophages. Apo E plays a major role in the brain as a phospholipid and cholesterol carrier molecule in compensatory synaptogenesis. Cytokines might also be able to modulate apo E expression. Accordingly, this study examined the control of apo E secretion by several proinflammatory cytokines and oxysterols in the human astrocytoma cell line CCF-STTG1. A time-dependent stimulation of apo E secretion by 25-hydroxycholesterol was observed. Among several cytokines tested, only tumor necrosis factor (TNF)-alpha inhibited apo E secretion in basal conditions in CCF-STTG1 human astrocytoma cells. In the presence of 25-hydroxycholesterol, TNF-alpha reduced apo E secretion by 80%, while interleukins (IL) IL-1beta, IL-6, and IL-2 had no significant effects. In Alzheimer's disease, the increase in the concentrations of cytokines and the concomitant decrease of cholesterol concentration in the brain could contribute jointly to reduce apo E concentration, and in doing so accelerate neurodegeneration. Surprisingly, oxysterols would be able to limit this phenomenon.

Alzheimer Disease↗
PubMed2001

APOC3, CETP, fibrinogen, and MTHFR are genetic determinants of carotid intima-media thickness in healthy men (the Stanislas cohort).

The purpose of this study was to examine the relationship between carotid intima-media thickness (CIMT) inter-individual variability and 16 polymorphisms of 11 genes associated with cardiovascular risk factors (genes among lipid and homocysteine metabolisms, blood viscosity, platelet aggregation, leukocyte adhesion and renin-angiotensin system). CIMT was measured by high resolution B-mode ultrasonography in an healthy population of 77 men and 84 women, aged 35-54 years and selected from a French Cohort: the Stanislas Cohort. The polymorphisms studied were genotyped by a multilocus approach. Statistical analyses were carried out by ANOVA, after adjustment of CIMT for age, body mass index, and smoking, and by multiple regression analyses. No association was found with APOB Thr71Ile, APOC3 -482C/T, -455T/C, GpIIIa P1A, AT1R 1166A/C, AGT Met235Thr, CBS Ile278Thr, SELE 98G/T, and SELE Ser128Arg, polymorphisms neither in men nor in women. Although, in women we did not find any association for APOC3 3206T/G, 3175C/G, 1100C/T, CETP Ile405Val, MTHFR 677C/T and fibrinogen -455G/A polymorphisms; in men these polymorphisms were associated with CIMT variability (p< or =0.01; p< or =0.05). The most interesting finding was that altogether these genes in men were able to explain a considerable part, 20.6%, of CIMT variability. Therefore, our study gives a new opportunity to understand CIMT variability.

Adult↗
PubMed2001

Serum myeloperoxidase concentration in a healthy population: biological variations, familial resemblance and new genetic polymorphisms.

Myeloperoxidase (MPO) has been involved in the pathogenesis of several diseases through excessive production of reactive oxygen species (ROS) as well as through its genetic polymorphism. The aims of this study were to identify the factors affecting MPO serum concentration, to study the familial resemblance of MPO levels and to investigate the association between newly described MPO polymorphisms as well as the G-463A one and MPO levels in a healthy population. MPO serum concentrations were measured by an enzymatic immuno-assay (EIA) in 82 healthy families of the STANISLAS Cohort and MPO genotype, determination was performed using PCR-restriction fragment length polymorphism or allele specific oligonucleotide assay. MPO concentrations were significantly higher in parents than in offspring. The factors affecting MPO levels were age, the number of white cells, smoking in fathers and oral contraceptive intake in mothers. They explain from 12.4% up to 35.9% of MPO variability in men and women, respectively. Family correlations of MPO concentrations were of similar magnitude. The -129A allele of a newly described G-129A substitution was significantly associated with decreased MPO levels, whereas the -463A allele was suggested to be associated with increased levels of lipid variables. In this study, we identified factors affecting MPO serum concentrations and showed that molecular variations of the gene have only a weak influence on MPO variability. In contrast, the association between the G-463A polymorphism and lipid levels would suggest a possible implication of MPO in the risk of cardiovascular diseases. These results have to be confirmed and further investigations will be conducted in that way.

Adolescent↗