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Research Interests: Immunohistochemistry, Humans, cathepsin D, Mutation, Female, and 15 moreMale, American, Surfactant, Pedigree, Newborn Infant, SURFACTANT PROTEIN A, Western blot, Protein Expression, Pulmonary Surfactant, Case Control Studies, Bronchoalveolar lavage, Mutation analysis, Respiratory distress syndrome, Direct sequence, and Medical and Health Sciences
Research Interests: Mitochondria, Adolescent, Neurodegenerative Diseases, Biological Sciences, Brain, and 15 moreHumans, Child, Mutation, Female, Male, Iron, Molecular cloning, Adult, Amino Acid Sequence, Case Control Studies, Cohort Studies, Mitochondrial Proteins, Molecular Sequence Data, Child preschool, and Medical and Health Sciences
High-density lipoproteins (HDLs) are strongly related to risk of atherosclerotic cardiovascular disease. Low levels of HDL cholesterol are a major cardiovascular risk factor, and overexpression of the major HDL protein, apolipoprotein... more
High-density lipoproteins (HDLs) are strongly related to risk of atherosclerotic cardiovascular disease. Low levels of HDL cholesterol are a major cardiovascular risk factor, and overexpression of the major HDL protein, apolipoprotein (apo) A-I, markedly inhibits progression and even induces regression of atherosclerosis in animal models. Clinical data regarding the effect of increasing HDL cholesterol on vascular events are limited. HDL remains an important potential target for therapeutic intervention. A variety of gene products are involved in the regulation of HDL metabolism. Yet, the mechanisms by which HDL inhibits atherosclerosis are not yet fully understood. There remains much to be learned about HDL metabolism and its relation to atherosclerosis and other cardiovascular risk factors.
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The effects of fluvastatin, a new fully synthetic inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, on growth and cell-cycle kinetics of porcine and human vascular smooth muscle cells (SMC) were studied by growth... more
The effects of fluvastatin, a new fully synthetic inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, on growth and cell-cycle kinetics of porcine and human vascular smooth muscle cells (SMC) were studied by growth curves and flow cytometric determination of cellcycle distribution. Growth curves were obtained from counting after 2, 4, 7, 9, 11, and 14 days of incubation in Dulbecco's
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Objective: To test that a positive family history and ApoE e4 genotype are prevalent among dementia patients with onset before 70 years of age compared with healthy spousal controls. Methods: A total of 210 patients with dementia and 82... more
Objective: To test that a positive family history and ApoE e4 genotype are prevalent among dementia patients with onset before 70 years of age compared with healthy spousal controls. Methods: A total of 210 patients with dementia and 82 spousal control participants. Neuropsychiatric examination, Consortium to establish a registry on Alzheimer’s disease test battery, Clock-drawing Test, and ApoE genotyping were performed in patients and controls. Results: Of the 131 patients with Alzheimer dementia, 25 were homozygous for Apo e4. Among dementia patients with a positive family history (n = 83), homozygosity for the Apo e4 genotype was found in 19 (22.9%). A positive family history was highest among Apo e4 homozygous Alzheimer dementia patients (72.0%) and lowest among the cognitively normal spousal controls (9.3%). Conclusions: In our sample of patients with Alzheimer dementia, approximately 3 of 4 (72.0%) were homozygous for the genotype Apo e4 when they had a positive family history.
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This study explores the neurofunctional correlates of the recognition of famous faces in patients with amnestic mild cognitive impairment (aMCI) and healthy controls depending on the genetic risk factor, Apolipoprotein E (ApoE) ε4. An... more
This study explores the neurofunctional correlates of the recognition of famous faces in patients with amnestic mild cognitive impairment (aMCI) and healthy controls depending on the genetic risk factor, Apolipoprotein E (ApoE) ε4. An event-related functional magnetic resonance imaging experiment was conducted while participants discriminated between famous and nonfamous faces. We compared the results of 32 healthy controls [17 ApoE ε4 carriers (E4+); 15 noncarriers (E4-)] with those of 30 patients with aMCI (16 E4+; 14 E4-). Despite comparable task performance, patients with aMCI, E4+ showed significantly less activation in a large cortical network including the left parahippocampal gyrus than patients with aMCI E4-. Furthermore, in the aMCI group, we found significantly reduced activation in the left parahippocampal gyrus and posterior cingulate cortex compared with the control group. Our results show that critical regions of the brain show functional decline associated with major risk factors, such as ApoE ε4 allele and neuropsychological signs of aMCI for the development of Alzheimer disease. Importantly, the ApoE genotype seems to influence cortical activation in patients with aMCI and to a lesser degree in healthy controls as well, who are without any cognitive symptoms.
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Research Interests: Genetics, Adolescent, Genetics of complex disease, Humans, Diabetes mellitus, and 15 moreChronic Disease, Female, Male, Cell Signalling, Enzyme, Aged, Genotype, Adult, Gene Function, European Continental Ancestry Group, Genetic Analysis, Metabolic pathway, General Population, Cell Membrane, and Genetic control
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Research Interests:
Gram-negative bacterial infection, namely Chlamydia pneumoniae has been recently discussed as a risk factor for myocardial infarction. The lipopolysaccharide-binding protein (LBP) and the bactericidal/permeability-increasing protein (BPI)... more
Gram-negative bacterial infection, namely Chlamydia pneumoniae has been recently discussed as a risk factor for myocardial infarction. The lipopolysaccharide-binding protein (LBP) and the bactericidal/permeability-increasing protein (BPI) play a role in the processes leading to recognition and neutralisation of the Chlamydia pneumoniae and their endotoxins lipopolysaccharides (LPS). LPS interact with plasma LBP, and LBP-LPS complex activates monocytes/macrophages, which can influence the atherosclerotic process. BPI is cytotoxic for Gram-negative bacteria and BPI-LPS complexes do not activate monocytes. We have analysed the polymorphisms in the LBP gene (Gly98-->Cys; Pro436-->Leu) and BPI gene (Lys216-->Glu; PstI polymorphism in intron-5; G545-->C) in 313 patients after myocardial infarction (MI) and in 302 control individuals. Genotype frequencies in the LBP gene and BPI gene did not differ between MI patients and control individuals. Our findings suggest that LBP and BPI polymorphisms do not influence the risk of MI.
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Research Interests: Biological Sciences, Humans, Plasma, Physical sciences, Tandem Mass Spectrometry, and 12 moreSphingolipids, High Pressure Liquid Chromatography, Liquid Chromatography, Lipoproteins, Very high throughput, Clinical Study, Reproducibility of Results, Method Validation, Blood cells, Lipoprotein a, Medical and Health Sciences, and Blood Donor
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The association of elevated lipoprotein (a) (Lp(a)) with an increased risk for coronary events is clearly established. This increased risk may in part be due to the activation of monocytes as major cells involved in atherogenesis. High... more
The association of elevated lipoprotein (a) (Lp(a)) with an increased risk for coronary events is clearly established. This increased risk may in part be due to the activation of monocytes as major cells involved in atherogenesis. High concentrations of plasma Lp(a) were shown to influence the gene expression of human blood monocytes and in the present study we demonstrate a reduced abundance of the lysosomal acid lipase (LAL) mRNA in monocytes of patients with coronary disease and selective Lp(a) hyperlipidemia. This is also supported by in vitro studies where purified Lp(a) but not low-density lipoprotein (LDL) was shown to downregulate mRNA levels of the LAL in control monocytes. A correlation of Lp(a) serum levels and the proinflammatory cytokine IL-6 was recently also described. Therefore, we investigated whether Lp(a) is capable to enhance the release of this acute phase cytokine from human blood monocytes. Purified Lp(a) led to an increased secretion of IL-6, but not TNF-alpha arguing against a general activation of these cells. The association of reduced LAL activity with the premature development of coronary artery disease has been demonstrated in patients with hypercholesterolemia, and in the present study we show for the first time that LAL expression is suppressed in monocytes from patients with Lp(a) hyperlipidemia and by purified Lp(a). In addition, increased levels of IL-6 also predict future cardiovascular events and IL-6 secretion was also induced by purified Lp(a).
Research Interests: Medical Microbiology, Gene expression, Biological Sciences, Humans, Physical sciences, and 15 moreCoronary heart disease, Monocytes, Tumor necrosis factor-alpha, In Vitro Studies, Coronary Artery Disease, Lysosomes, Lipase, Predictive value of tests, Lipoprotein a, Biochemistry and cell biology, Interleukin, Down-Regulation, acute phase, Cardiovascular Events, and Hyperlipidemias
Research Interests: Genetics, Obesity, Lipids, Mice, Cholesterol, and 5 moreAnimals, Male, Triglycerides, Molecular sciences, and Body Weight
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BackgroundWhile involvement of ABCB1 is well known in drug transport, its metabolite transport role is not so well understood. Like other ABC transporters, ABCB1 might be implicated in cholesterol homeostasis and ABCB1 polymorphisms which... more
BackgroundWhile involvement of ABCB1 is well known in drug transport, its metabolite transport role is not so well understood. Like other ABC transporters, ABCB1 might be implicated in cholesterol homeostasis and ABCB1 polymorphisms which are responsible for drug resistance might affect lipid homeostasis. Our objective was thus to investigate the implication of ABCB1 polymorphisms and haplotypes in the genetic variability
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Research Interests: Information Systems, Genetics, Genomics, Gene expression, Metabolic Bone Disease, and 21 moreHumans, Female, Male, Polymerase Chain Reaction, DNA sequence design, Alternative splicing, Pedigree, Enzyme, Enzyme activity, Amino Acid Profile, Alternative Splicing, Amino Acid Sequence, Base Sequence, Autosomal Recessive, Structure activity Relationship, Lysosomes, Recombinant Proteins, Lipase, Full Length Movies, Nucleotides, and DNA sequence(Humans, Female, Male, Polymerase Chain Reaction, DNA sequence design, Alternative splicing, Pedigree, Enzyme, Enzyme activity, Amino Acid Profile, Alternative Splicing, Amino Acid Sequence, Base Sequence, Autosomal Recessive, Structure activity Relationship, Lysosomes, Recombinant Proteins, Lipase, Full Length Movies, Nucleotides, and DNA sequence)
(Humans, Female, Male, Polymerase Chain Reaction, DNA sequence design, Alternative splicing, Pedigree, Enzyme, Enzyme activity, Amino Acid Profile, Alternative Splicing, Amino Acid Sequence, Base Sequence, Autosomal Recessive, Structure activity Relationship, Lysosomes, Recombinant Proteins, Lipase, Full Length Movies, Nucleotides, and DNA sequence)
Phospholipids (PLs) possess the unique ability to contribute to synovial joint lubrication. The aim of our study was to determine for the first time the effect of dexamethasone and some adrenergic and cholinergic agonists on the... more
Phospholipids (PLs) possess the unique ability to contribute to synovial joint lubrication. The aim of our study was to determine for the first time the effect of dexamethasone and some adrenergic and cholinergic agonists on the biosynthesis and release of PLs from human fibroblast-like synoviocytes (FLS). Osteoarthritic human knee FLS were treated with dexamethasone, terbutaline, epinephrine, carbachol, and pilocarpine, or the glucocorticoid receptor antagonist RU 486. Simultaneously PL biosynthesis was determined through the incorporation of stable isotope-labeled precursors into PLs. Radioactive isotope-labeled precursors were used to radiolabel PLs for the subsequent quantification of their release into nutrient media. Lipids were extracted and quantified using electrospray ionization tandem mass spectrometry or liquid scintillation counting. Dexamethasone significantly decreased the biosynthesis of phosphatidylcholine, phosphatidylethanolamine (PE), PE-based plasmalogen, and sp...
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Amiodarone (AD) is a highly efficient antiarrhythmic drug with potentially serious side effects. Severe pulmonary toxicity is reported in patients receiving AD even at low doses and may cause interstitial pneumonia as well as lung... more
Amiodarone (AD) is a highly efficient antiarrhythmic drug with potentially serious side effects. Severe pulmonary toxicity is reported in patients receiving AD even at low doses and may cause interstitial pneumonia as well as lung fibrosis. Apoptosis of alveolar epithelial type II cells (AECII) has been suggested to play an important role in this disease. In the current study, we aimed to establish a murine model of AD-induced lung fibrosis and analyze surfactant homeostasis, lysosomal, and endoplasmic reticulum (ER) stress in this model. AD/vehicle was instilled intratracheally into C57BL/6 mice, which were sacrificed on days 7, 14, 21, and 28. Extent of lung fibrosis development was assessed by trichrome staining and hydroxyproline measurement. Cytotoxicity was assessed by lactate dehydrogenase assay. Phospholipids (PLs) were analyzed by mass spectrometry. Surfactant proteins (SP) and markers for apoptosis, lysosomal, and ER stress were studied by Western blotting and immunohistoc...
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Research Interests: Endocrinology, Chemistry, Medicine, Humans, Internal Medicine, and 15 moreMale, Biochemical, Body Mass Index, Aged, Middle Aged, Adiponectin, Adult, Monocytes, Molecular weight, Low molecular weight, Control Group, Biochemistry and cell biology, Interleukin, High Molecular Weight, and Medical biochemistry and metabolomics
Research Interests: Chemistry, Medicine, Biological Sciences, Humans, Metformin, and 11 morePhysical sciences, Tandem Mass Spectrometry, Sodium Dodecyl Sulfate-Polyacrylamide Gel Electrophoresis, Apolipoprotein B, Liquid Chromatography / Electrospray Ionization Mass Spectrometry, Hepatocytes, Oral Hypoglycemic Agents, Type 2 Diabetes Mellitus, Culture Media, Electrospray Ionization, and Medical and Health Sciences(Physical sciences, Tandem Mass Spectrometry, Sodium Dodecyl Sulfate-Polyacrylamide Gel Electrophoresis, Apolipoprotein B, Liquid Chromatography / Electrospray Ionization Mass Spectrometry, Hepatocytes, Oral Hypoglycemic Agents, Type 2 Diabetes Mellitus, Culture Media, Electrospray Ionization, and Medical and Health Sciences)
(Physical sciences, Tandem Mass Spectrometry, Sodium Dodecyl Sulfate-Polyacrylamide Gel Electrophoresis, Apolipoprotein B, Liquid Chromatography / Electrospray Ionization Mass Spectrometry, Hepatocytes, Oral Hypoglycemic Agents, Type 2 Diabetes Mellitus, Culture Media, Electrospray Ionization, and Medical and Health Sciences)
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Research Interests: Genetics, Biology, Atherosclerosis, Cardiovascular disease, Medicine, and 15 moreHumans, Female, Male, Clinical Sciences, Aged, Middle Aged, Adult, Elsevier, Membrane Protein, Molecular Diagnosis, Binding Site, Case Control Studies, DNA mutational analysis, Cardiovascular medicine and haematology, and Blood Donor
Research Interests: Polymorphism, France, Quantitative analysis, Humans, Haplotypes, and 13 morePharmacogenetics, Polymerase Chain Reaction, P-glycoprotein, Frequency, Genotype, Fundamental, Transporter, Quantitative Analysis, Genetic Variability, Haplotype, alleles, Gene frequency, and Pharmacology and pharmaceutical sciences
Research Interests: Polymorphism, France, Quantitative analysis, Humans, Haplotypes, and 13 morePharmacogenetics, Polymerase Chain Reaction, P-glycoprotein, Frequency, Genotype, Fundamental, Transporter, Quantitative Analysis, Genetic Variability, Haplotype, alleles, Gene frequency, and Pharmacology and pharmaceutical sciences
Research Interests: Polymorphism, France, Quantitative analysis, Humans, Haplotypes, and 13 morePharmacogenetics, Polymerase Chain Reaction, P-glycoprotein, Frequency, Genotype, Fundamental, Transporter, Quantitative Analysis, Genetic Variability, Haplotype, alleles, Gene frequency, and Pharmacology and pharmaceutical sciences
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High density lipoproteins (HDL) mediate reverse cholesterol transport as well as the clearance of oxidation products or inflammatory mediators, thereby contributing to tissue integrity. The decrease in HDL in inflammation has been... more
High density lipoproteins (HDL) mediate reverse cholesterol transport as well as the clearance of oxidation products or inflammatory mediators, thereby contributing to tissue integrity. The decrease in HDL in inflammation has been attributed to decreased lecithin:cholesterol acyltransferase activity, whereas the role of phospholipid transfer protein (PLTP) and cholesteryl ester transfer protein has not been analyzed in detail. We have studied the activities of HDL-modifying proteins and the heterogeneity of HDL in healthy control subjects and three groups of postsurgery patients: no bacterial infection (group 1), bacterial focus and systemic inflammatory response (group 2), and severe sepsis (group 3). For all patients, a decrease in total HDL could be demonstrated, with a loss of mainly large, apolipoprotein A-I (apoA-I) HDL particles, an almost total loss of apoC-I, and an increase in apoE HDL (200-500 kDa), which did not contain significant amounts of apoA-I, apoA-II, or apoC-I. ...
Research Interests: Chemistry, Membrane Proteins, Medicine, Lipids, Humans, and 15 moreFemale, Male, Sepsis, Aged, Middle Aged, Adult, Group, High Density Lipoprotein, Lipid, Bacterial Infection, Biochemistry and cell biology, Inflammatory response, reverse cholesterol transport, High density, and Medical biochemistry and metabolomics
Extracellular vesicles (EV) are secreted by most cells and are present in every body fluid. They can be seen as major players in the regulation and communication of cells. They are adressed as therapeutic and diagnostic tool for many... more
Extracellular vesicles (EV) are secreted by most cells and are present in every body fluid. They can be seen as major players in the regulation and communication of cells. They are adressed as therapeutic and diagnostic tool for many disorders including neurodegenerative diseases. Distinct subpopulations of platelet derived EVs have been shown to contain high concentrations of Alzheimer’s disease(AD)-associated proteins e. g. APP, APOE, lipids and miRNAs and thus might contribute actively to the progression of the disease.
Research Interests: Biology()
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The molecular cloning and identification of mutations in ATP-binding cassette transporters in hereditary diseases have greatly expanded our knowledge of the normal physiology of intracellular lipid transport processes. In addition to the... more
The molecular cloning and identification of mutations in ATP-binding cassette transporters in hereditary diseases have greatly expanded our knowledge of the normal physiology of intracellular lipid transport processes. In addition to the well-known ATP-binding cassette transporter A1 (ABCA1) molecule, ABC transporters belonging to the ABCG (White) subfamily (ABCG1, ABCG5, and ABCG8) have been shown to be critically involved in the regulation of lipid-trafficking mechanisms in macrophages, hepatocytes, and intestinal mucosa cells. ABCG1, the product of a sterol-induced gene, participates in cholesterol and phospholipid efflux. The ABCG5 and ABCG8 transporters, defective in beta-sitosterolemia, are also now considered interesting targets in the control and influence of total body sterol homeostasis. In this review, advances referring to the regulation and function of ABCG half-size transporters are summarized and discussed. In addition, new implications for the transcriptional control...
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Recent developments in lipid mass spectrometry enable extensive lipid class and species analysis in metabolic disorders such as diabesity and metabolic syndrome. The minor plasma lipid class sphingosylphosphorylcholine (SPC) was... more
Recent developments in lipid mass spectrometry enable extensive lipid class and species analysis in metabolic disorders such as diabesity and metabolic syndrome. The minor plasma lipid class sphingosylphosphorylcholine (SPC) was identified as a ligand for lipid sensitive G-protein coupled receptors playing a key role in cell growth, differentiation, motility, calcium signaling, tissue remodeling, vascular diseases and cancer. However, information about its role in diabesity patients is sparse. In this study, we analyzed plasma lipid species in patients at risk for diabesity and the metabolic syndrome and compared them with healthy controls. Our data show that SPC is significantly increased in plasma samples from metabolic syndrome patients but not in plasma from patients at risk for diabesity. Detailed SPC species analysis showed that the observed increase is due to a significant increase in all detected SPC subspecies. Moreover, a strong positive correlation is observed between tot...
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The molecular cloning and identification of mutations in ATP-binding cassette transporters in hereditary diseases have greatly expanded our knowledge of the normal physiology of intracellular lipid transport processes. In addition to the... more
The molecular cloning and identification of mutations in ATP-binding cassette transporters in hereditary diseases have greatly expanded our knowledge of the normal physiology of intracellular lipid transport processes. In addition to the well-known ATP-binding cassette transporter A1 (ABCA1) molecule, ABC transporters belonging to the ABCG (White) subfamily (ABCG1, ABCG5, and ABCG8) have been shown to be critically involved in the regulation of lipid-trafficking mechanisms in macrophages, hepatocytes, and intestinal mucosa cells. ABCG1, the product of a sterol-induced gene, participates in cholesterol and phospholipid efflux. The ABCG5 and ABCG8 transporters, defective in �-sitosterolemia, are also now considered interesting targets in the control and influence of total body sterol homeostasis. In this review, advances referring to the regulation and function of ABCG half-size transporters are summarized and discussed. In addition, new implications for the transcriptional control, a...
Adrenocortical carcinoma (ACC) is a rare malignancy that harbors a dismal prognosis in advanced stages. Mitotane is approved as an orphan drug for treatment of ACC and counteracts tumor growth and steroid hormone production. Despite... more
Adrenocortical carcinoma (ACC) is a rare malignancy that harbors a dismal prognosis in advanced stages. Mitotane is approved as an orphan drug for treatment of ACC and counteracts tumor growth and steroid hormone production. Despite serious adverse effects, mitotane has been clinically used for decades. Elucidation of its unknown molecular mechanism of action seems essential to develop better ACC therapies. Here, we set out to identify the molecular target of mitotane and altered downstream mechanisms by combining expression genomics and mass spectrometry technology in the NCI-H295 ACC model cell line. Pathway analyses of expression genomics data demonstrated activation of endoplasmic reticulum (ER) stress and profound alteration of lipid-related genes caused by mitotane treatment. ER stress marker CHOP was strongly induced and the two upstream ER stress signalling events XBP1-mRNA splicing and eukaryotic initiation factor 2 A (eIF2α) phosphorylation were activated by mitotane in NC...
Research Interests: Endocrinology, Immunohistochemistry, Endoplasmic Reticulum Stress, Apoptosis, Transcriptome, and 12 moreBiological Sciences, Lipids, Humans, HeLa cells, Gas Chromatography/mass Spectrometry, Cell Survival, Adrenocortical Carcinoma, Mitotane, Immunoblotting, reverse transcriptase polymerase chain reaction, Disease Free Survival, and Medical and Health Sciences
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Multiple biologically active components of human milk support infant growth, health and development. Milk provides a wide spectrum of mammary epithelial cell-derived extracellular vesicles (MEVs) for the infant. Although the whole... more
Multiple biologically active components of human milk support infant growth, health and development. Milk provides a wide spectrum of mammary epithelial cell-derived extracellular vesicles (MEVs) for the infant. Although the whole spectrum of MEVs appears to be of functional importance for the growing infant, the majority of recent studies report on the MEV subfraction of milk exosomes (MEX) and their miRNA cargo, which are in the focus of this review. MEX and the dominant miRNA-148a play a key role in intestinal maturation, barrier function and suppression of nuclear factor-κB (NF-κB) signaling and may thus be helpful for the prevention and treatment of necrotizing enterocolitis. MEX and their miRNAs reach the systemic circulation and may impact epigenetic programming of various organs including the liver, thymus, brain, pancreatic islets, beige, brown and white adipose tissue as well as bones. Translational evidence indicates that MEX and their miRNAs control the expression of glo...
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DNA mutation-induced activation of RAS-BRAF-MEK-ERK signaling associated with intermittent or chronic ultraviolet (UV) irradiation cannot exclusively explain the excessive increase of malignant melanoma (MM) incidence since the 1950s.... more
DNA mutation-induced activation of RAS-BRAF-MEK-ERK signaling associated with intermittent or chronic ultraviolet (UV) irradiation cannot exclusively explain the excessive increase of malignant melanoma (MM) incidence since the 1950s. Malignant conversion of a melanocyte to an MM cell and metastatic MM is associated with a steady increase in microRNA-21 (miR-21). At the epigenetic level, miR-21 inhibits key tumor suppressors of the RAS-BRAF signaling pathway enhancing proliferation and MM progression. Increased MM cell levels of miR-21 either result from endogenous upregulation of melanocytic miR-21 expression or by uptake of miR-21-enriched exogenous exosomes. Based on epidemiological data and translational evidence, this review provides deeper insights into environmentally and metabolically induced exosomal miR-21 trafficking beyond UV-irradiation in melanomagenesis and MM progression. Sources of miR-21-enriched exosomes include UV-irradiated keratinocytes, adipocyte-derived exoso...
Research Interests: Cancers()
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