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1.
Unique Role of Caffeine Compared to Other Methylxanthines (Theobromine, Theophylline, Pentoxifylline, Propentofylline) in Regulation of AD Relevant Genes in Neuroblastoma SH-SY5Y Wild Type Cells.
Janitschke, D, Lauer, AA, Bachmann, CM, Seyfried, M, Grimm, HS, Hartmann, T, Grimm, MOW
International journal of molecular sciences. 2020;(23)
Abstract
Methylxanthines are a group of substances derived from the purine base xanthine with a methyl group at the nitrogen on position 3 and different residues at the nitrogen on position 1 and 7. They are widely consumed in nutrition and used as pharmaceuticals. Here we investigate the transcriptional regulation of 83 genes linked to Alzheimer's disease in the presence of five methylxanthines, including the most prominent naturally occurring methylxanthines-caffeine, theophylline and theobromine-and the synthetic methylxanthines pentoxifylline and propentofylline. Methylxanthine-regulated genes were found in pathways involved in processes including oxidative stress, lipid homeostasis, signal transduction, transcriptional regulation, as well as pathways involved in neuronal function. Interestingly, multivariate analysis revealed different or inverse effects on gene regulation for caffeine compared to the other methylxanthines, which was further substantiated by multiple comparison analysis, pointing out a distinct role for caffeine in gene regulation. Our results not only underline the beneficial effects of methylxanthines in the regulation of genes in neuroblastoma wild-type cells linked to neurodegenerative diseases in general, but also demonstrate that individual methylxanthines like caffeine mediate unique or inverse expression patterns. This suggests that the replacement of single methylxanthines by others could result in unexpected effects, which could not be anticipated by the comparison to other substances in this substance class.
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2.
Comparative gene array analysis of progenitor cells from human paired deep neck and subcutaneous adipose tissue.
Tews, D, Schwar, V, Scheithauer, M, Weber, T, Fromme, T, Klingenspor, M, Barth, TF, Möller, P, Holzmann, K, Debatin, KM, et al
Molecular and cellular endocrinology. 2014;(1-2):41-50
Abstract
Brown and white adipocytes have been shown to derive from different progenitors. In this study we sought to clarify the molecular differences between human brown and white adipocyte progenitors cells. To this end, we performed comparative gene array analysis on progenitor cells isolated from paired biopsies of deep and subcutaneous neck adipose tissue from individuals (n = 6) undergoing neck surgery. Compared with subcutaneous neck progenitors, cells from the deep neck adipose tissue displayed marked differences in gene expression pattern, including 355 differentially regulated (>1.5 fold) genes. Analysis of highest regulated genes revealed that STMN2, MME, ODZ2, NRN1 and IL13RA2 genes were specifically expressed in white progenitor cells, whereas expression of LRRC17, CNTNAP3, CD34, RGS7BP and ADH1B marked brown progenitor cells. In conclusion, progenitors from deep neck and subcutaneous neck adipose tissue are characterized by a distinct molecular signature, giving rise to either brown or white adipocytes. The newly identified markers may provide potential pharmacological targets facilitating brown adipogenesis.
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3.
Assessment of OPG/RANK/RANKL gene expression levels in peripheral blood mononuclear cells (PBMC) after treatment with strontium ranelate and ibandronate in patients with postmenopausal osteoporosis.
Stuss, M, Rieske, P, Cegłowska, A, Stêpień-Kłos, W, Liberski, PP, Brzeziańska, E, Sewerynek, E
The Journal of clinical endocrinology and metabolism. 2013;(5):E1007-11
Abstract
CONTEXT Recent research results have confirmed the high significance of the OPG/RANK/RANKL system in the development of bone diseases. AIM: The aim of the reported study was to assess gene expression levels of the OPG/RANK/RANKL system in peripheral blood mononuclear cells (PBMCs) after strontium ranelate (SR) and ibandronate administered to patients with postmenopausal osteoporosis. PATIENTS AND METHODS A total of 89 postmenopausal women, aged 51 to 85 years, patients of the Outpatient Clinic of Osteoporosis of the Military Teaching Hospital in Lodz, were enrolled into the study. The patients were randomly assigned to different medical therapies: ibandronate and SR. Patients of the control group received only calcium and vitamin D₃ supplements. Patient visits were repeated after 3 and 6 months. Measurements of serum alkaline phosphatase concentrations and of RNA expression in PBMCs as well as of total serum calcium and phosphate levels and of their 24-hour urine excretion rates were carried out in material, collected at baseline and after 3 and 6 months of the therapy. Densitometry of the left hip and of the lumbar spine was done at the baseline visit and after 6 months. RESULTS The differences in gene expressions of RANKL and RANK were not significant during the study period and did not differ between the groups in a statistically significant manner. No OPG gene expression was observed in PBMCs of patients in any of the studied groups and at any time point. The tendency of correlation (P = .07) was observed between decreasing RANK gene expression and increasing bone mineral density in the patients treated with SR. CONCLUSIONS Both ibandronate and SR do not seem to cause any significant changes in gene expression levels of OPG/RANK/RANKL in PBMCs during the first 6 months of treatment.
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4.
A comparison of the acute effects of calcium and strontium ranelate on the serum marker of bone resorption.
Maresova, KB, Franek, T, Vondracek, T, Stepan, JJ
Clinical chemistry and laboratory medicine. 2011;(2):333-5
Abstract
BACKGROUND To investigate the mechanism by which strontium ranelate (SrR) inhibits the bone resorption, this study compared the effects of SrR and calcium on parathyroid hormone (PTH) and the biochemical marker of bone resorption (serum type 1 collagen cross-linked C-telopeptide, βCTX). METHODS In 10 healthy young subjects, after overnight fasting, 1000 mg of elemental calcium and 2000 mg of SrR containing 600 mg Sr²⁺ were administered consecutively with a 1 week washout period. During the control period no drug was given. Fasting blood samples were drawn at baseline and throughout the next 5-h period. RESULTS After the ingestion of either calcium or SrR, there was a significant increase in serum calcium and strontium concentrations, and a decrease in serum βCTX and intact PTH concentrations as compared to the baseline values (p<0.05). In the fasting subjects, no significant differences in the variable were found as compared to the baseline values. CONCLUSIONS The decrease in PTH and the marker of bone resorption observed after the SrR administration is comparable to the decrease observed after the calcium administration in young adults.
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5.
Rapamycin stimulates arginine influx through CAT2 transporters in human endothelial cells.
Visigalli, R, Barilli, A, Bussolati, O, Sala, R, Gazzola, GC, Parolari, A, Tremoli, E, Simon, A, Closs, EI, Dall'Asta, V
Biochimica et biophysica acta. 2007;(6):1479-87
Abstract
In endothelial cells Tumor Necrosis Factor-alpha (TNFalpha) stimulates arginine transport through the increased expression of SLC7A2/CAT2 transcripts. Here we show that also rapamycin, an inhibitor of mTOR kinase, stimulates system y(+)-mediated arginine uptake in human endothelial cells derived from either saphenous (HSVECs) or umbilical veins (HUVECs). When used together with TNFalpha, rapamycin produces an additive stimulation of arginine transport in both cell models. These effects are observed also upon incubation with AICAR, a stimulator of Adenosine-Monophosphate-dependent-Protein Kinase (AMPK) that produces a rapamycin-independent inhibition of the mTOR pathway. Rapamycin increases the V(max) of high affinity arginine transport and causes the appearance of a low affinity component that is particularly evident if the treatment is carried out in the presence of TNFalpha. RT-qPCR studies have demonstrated that these kinetic changes correspond to the induction of both the high affinity transporter CAT2B and the low affinity isoform CAT2A. Western blot and immunocytochemical analyses indicate that, consistently, the expression of CAT2 proteins is also stimulated under the same conditions. These changes are associated with an increase of the intracellular arginine concentration but with a decrease of NO production. Thus, our data suggest that mTOR activity is associated with the repression of CAT2 expression at mRNA and protein level.
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6.
Adipose tissue gene expression in obese subjects during low-fat and high-fat hypocaloric diets.
Viguerie, N, Vidal, H, Arner, P, Holst, C, Verdich, C, Avizou, S, Astrup, A, Saris, WH, Macdonald, IA, Klimcakova, E, et al
Diabetologia. 2005;(1):123-31
Abstract
AIMS/HYPOTHESIS Adaptation to energy restriction is associated with changes in gene expression in adipose tissue. However, it is unknown to what extent these changes are dependent on the energy restriction as such or on the macronutrient composition of the diet. METHODS We determined the levels of transcripts for 38 genes that are expressed in adipose tissue and encode transcription factors, enzymes, transporters and receptors known to play critical roles in the regulation of adipogenesis, mitochondrial respiration, and lipid and carbohydrate metabolism. Two groups of 25 obese subjects following 10-week hypocaloric diet programmes with either 20-25 or 40-45% of total energy derived from fat were investigated. Levels of mRNA were measured by performing real-time RT-PCR on subcutaneous fat samples obtained from the subjects before and after the diets. RESULTS The two groups of subjects lost 7 kg over the duration of the diets. Ten genes were regulated by energy restriction; however, none of the genes showed a significantly different response to the diets. Levels of peroxisome proliferator-activated receptor gamma co-activator 1alpha mRNA were increased, while the expression of the genes encoding leptin, osteonectin, phosphodiesterase 3B, hormone-sensitive lipase, receptor A for natriuretic peptide, fatty acid translocase, lipoprotein lipase, uncoupling protein 2 and peroxisome proliferator-activated receptor gamma was decreased. Clustering analysis revealed new potential coregulation of genes. For example, the expression of the genes encoding the adiponectin receptors may be regulated by liver X receptor alpha. CONCLUSIONS/INTERPRETATION In accordance with the comparable loss of fat mass produced by the two diets, this study shows that energy restriction and/or weight loss rather than the ratio of fat: carbohydrate in a low-energy diet is of importance in modifying the expression of genes in the human adipose tissue.
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7.
Regulation of metabolic genes in human skeletal muscle by short-term exercise and diet manipulation.
Arkinstall, MJ, Tunstall, RJ, Cameron-Smith, D, Hawley, JA
American journal of physiology. Endocrinology and metabolism. 2004;(1):E25-31
Abstract
Changes in dietary macronutrient intake alter muscle and blood substrate availability and are important for regulating gene expression. However, few studies have examined the effects of diet manipulation on gene expression in human skeletal muscle. The aim of this study was to quantify the extent to which altering substrate availability impacts on subsequent mRNA abundance of a subset of carbohydrate (CHO)- and fat-related genes. Seven subjects consumed either a low- (LOW; 0.7 g/kg body mass CHO) or high- (HIGH; 10 g/kg body mass CHO) CHO diet for 48 h after performing an exhaustive exercise bout to deplete muscle glycogen stores. After intervention, resting muscle and blood samples were taken. Muscle was analyzed for the gene abundances of GLUT4, glycogenin, pyruvate dehydrogenase kinase-4 (PDK-4), fatty acid translocase (FAT/CD36), carnitine palmitoyltransferase I (CPT I), hormone-sensitive lipase (HSL), beta-hydroxyacyl-CoA dehydrogenase (beta-HAD), and uncoupling binding protein-3 (UCP3), and blood samples for glucose, insulin, and free fatty acid (FFA) concentrations. Glycogen-depleting exercise and HIGH-CHO resulted in a 300% increase in muscle glycogen content (P < 0.001) relative to the LOW-CHO condition. FFA concentrations were twofold higher after LOW- vs. HIGH-CHO (P < 0.05). The exercise-diet manipulation exerted a significant effect on transcription of all carbohydrate-related genes, with an increase in GLUT4 and glycogenin mRNA abundance and a reduction in PDK-4 transcription after HIGH-CHO (all P < 0.05). FAT/CD36 (P < 0.05) and UCP3 (P < 0.01) gene transcriptions were increased following LOW-CHO. We conclude that 1) there was a rapid capacity for a short-term exercise and diet intervention to exert coordinated changes in the mRNA transcription of metabolic related genes, and 2) genes involved in glucose regulation are increased following a high-carbohydrate diet.
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8.
Analysing microarray data using modular regulation analysis.
Curtis, RK, Brand, MD
Bioinformatics (Oxford, England). 2004;(8):1272-84
Abstract
MOTIVATION Microarray experiments measure complex changes in the abundance of many mRNAs under different conditions. Current analysis methods cannot distinguish between direct and indirect effects on expression, or calculate the relative importance of mRNAs in effecting responses. RESULTS Application of modular regulation analysis to microarray data reveals and quantifies which mRNA changes are important for cellular responses. The mRNAs are clustered, and then we calculate how perturbations alter each cluster and how strongly those clusters affect an output response. The product of these values quantifies how an input changes a response through each cluster. Two published datasets are analysed. Two mRNA clusters transmit most of the response of yeast doubling time to galactose; one contains mainly galactose metabolic genes, and the other a regulatory gene. Analysis of the response of yeast relative fitness to 2-deoxy-D-glucose reveals that control is distributed between several mRNA clusters, but experimental error limits statistical significance.
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9.
Regression trees for regulatory element identification.
Phuong, TM, Lee, D, Lee, KH
Bioinformatics (Oxford, England). 2004;(5):750-7
Abstract
MOTIVATION The transcription of a gene is largely determined by short sequence motifs that serve as binding sites for transcription factors. Recent findings suggest direct relationships between the motifs and gene expression levels. In this work, we present a method for identifying regulatory motifs. Our method makes use of tree-based techniques for recovering the relationships between motifs and gene expression levels. RESULTS We treat regulatory motifs and gene expression levels as predictor variables and responses, respectively, and use a regression tree model to identify the structural relationships between them. The regression tree methodology is extended to handle responses from multiple experiments by modifying the split function. The significance of regulatory elements is determined by analyzing tree structures and using a variable importance measure. When applied to two data sets of the yeast Saccharomyces cerevisiae, the method successfully identifies most of the regulatory motifs that are known to control gene transcription under the given experimental conditions, and suggests several new putative motifs. Analysis of the tree structures also reconfirms several pairs of motifs that are known to regulate gene transcription in combination. AVAILABILITY http://if.kaist.ac.kr/~phuong/RegTree
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10.
Background rareness-based iterative multiple sequence alignment algorithm for regulatory element detection.
Narasimhan, C, LoCascio, P, Uberbacher, E
Bioinformatics (Oxford, England). 2003;(15):1952-63
Abstract
MOTIVATION Experimental methods capable of generating sets of co-regulated genes have become commonplace, however, recognizing the regulatory motifs responsible for this regulation remains difficult. As a result, computational detection of transcription factor binding sites in such data sets has been an active area of research. Most approaches have utilized either Gibbs sampling or greedy strategies to identify such elements in sets of sequences. These existing methods have varying degrees of success depending on the strength and length of the signals and the number of available sequences. We present a new deterministic iterative algorithm for regulatory element detection based on a Markov chain background. As in other methods, sequences in the entire genome and the training set are taken into account in order to discriminate against commonly occurring signals and produce patterns, which are significant in the training set. RESULTS The results of the algorithm compare favorably with existing tools on previously known and newly compiled data sets. The iteration based search appears rather rigorous, not only finding the binding sites, but also showing how the binding site stands out from genomic background. The approach used to score the results is critical and a discussion of various scoring schemes and options is also presented. Benchmarking of several methods shows that while most tools are good at detecting strong signals, Gibbs sampling algorithms give inconsistent results when the regulatory element signal becomes weak. A Markov chain based background model alleviates the drawbacks of MAP (maximum a posteriori log likelihood) scores. AVAILABILITY Available on request from the authors. SUPPLEMENTARY INFORMATION Data and the results presented in this paper are available on the web at http://compbio.ornl.gov/mira/index.html