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At least 487 records · Page 27Linked to original sources
PubMed2006

Redefining heart failure: the utility of genomics.

In this era of genomics, new technologies and the information that they generate have a wide range of potential applications to heart failure. Though there has not been widespread practical use of genomic information in everyday practice, there are many examples of how this information is beginning to transform the way we look at disease states in terms of diagnosis, prognosis, and treatment. The experience of oncology and other fields helps inform the heart failure field of not only the use of this information in investigating diagnosis, prognosis, and treatment response, but the reciprocal nature of this information. This information can be clinically useful (for instance, predicting treatment response) as well as further drive laboratory investigation (teasing out the biological pathways in non-responders to treatment can be a focus of new drug discovery); this is the essence of translational medicine. We believe that this is a good time to review where new technologies and information they generate can be placed into our classic understanding of heart failure: that is how we might redefine cardiomyopathy given our new information. Here we will review genomic evidence to date and how it can and may be considered in the evaluation and management of cardiomyopathies.

Cardiac Output, Low↗
PubMed2005

The genetics of generalized vitiligo and associated autoimmune diseases.

Generalized vitiligo is an acquired disorder in which patches of depigmented skin, overlying hair, and oral mucosa result from progressive autoimmune loss of melanocytes from the involved areas. Although vitiligo is perhaps the most common pigmentary disorder, insufficiently clear clinical definition of the disorder and lack of a good laboratory animal model have inhibited progress in understanding its pathobiology, its environmental triggers, and in developing specific and effective therapeutic approaches. Vitiligo results from a complex interaction of environmental, genetic, and immunologic factors, which ultimately contribute to melanocyte destruction, resulting in the characteristic depigmented lesions. In the past few years, studies of the genetic epidemiology of generalized vitiligo have led to the recognition that vitiligo is part of a broader, genetically-determined, autoimmune/autoinflammatory diathesis. Attempts to identify genes involved in vitiligo susceptibility have involved both allelic association studies of candidate genes and genome-wide linkage analyses to discover new genes, and these studies have begun to shed light on the mechanisms of vitiligo pathogenesis. It is anticipated that the discovery of biological pathways of vitiligo pathogenesis will provide novel therapeutic and prophylactic targets for future approaches to the treatment and prevention of vitiligo and its associated autoimmune diseases.

Autoimmune Diseases↗
PubMed2004

Structural delineation of the calcineurin-NFAT interaction and its parallels to PP1 targeting interactions.

Calcineurin is a phosphoprotein phosphatase that channels intracellular Ca signals into multiple biological pathways. Calcineurin is known to interact directly with its substrate nuclear factor of activated T cells (NFAT or NFATc), with other substrates, and with several targeting and scaffold proteins including AKAP79 and Cabin1/cain. The calcineurin-NFAT interaction depends on recognition of a PxIxIT sequence motif present in NFAT-family proteins and in certain other calcineurin-interacting proteins. Here, we define the structural basis for the interaction of calcineurin with NFAT and with other proteins possessing the PxIxIT motif. The calcineurin-PxIxIT contact has a direct parallel in the contact of protein phosphatase 1 with its regulatory proteins, suggesting that the evolution of these related phosphatases involved local remodelling of an ancestral docking site.

Amino Acid Sequence↗
PubMed2005

Design and validation of a neutral protein scaffold for the presentation of peptide aptamers.

Peptide aptamers are peptides constrained and presented by a scaffold protein that are used to study protein function in cells. They are able to disrupt protein-protein interactions and to constitute recognition modules that allow the creation of a molecular toolkit for the intracellular analysis of protein function. The success of peptide aptamer technology is critically dependent on the performance of the scaffold. Here, we describe a rational approach to the design of a new peptide aptamer scaffold. We outline the qualities that an ideal scaffold would need to possess to be broadly useful for in vitro and in vivo studies and apply these criteria to the design of a new scaffold, called STM. Starting from the small, stable intracellular protease inhibitor stefin A, we have engineered a biologically neutral scaffold that retains the stable conformation of the parent protein. We show that STM is able to present peptides that bind to targets of interest, both in the context of known interactors and in library screens. Molecular tools based on our scaffold are likely to be used in a wide range of studies of biological pathways, and in the validation of drug targets.

Active Transport, Cell Nucleus↗
PubMed2005

Structural basis of ARNT PAS-B dimerization: use of a common beta-sheet interface for hetero- and homodimerization.

The aryl hydrocarbon receptor nuclear translocator (ARNT) is a promiscuous bHLH-PAS (Per-ARNT-Sim) protein that forms heterodimeric transcriptional regulator complexes with several other bHLH-PAS subunits to control a variety of biological pathways, some of which are centrally involved in disease initiation and/or progression. One of these is the hypoxia response pathway, which allows eukaryotic cells to respond to low oxygen tension via the formation of a heterodimeric complex between ARNT and another bHLH-PAS protein, the hypoxia-inducible factor alpha (HIF-alpha). We have previously shown that the C-terminal PAS domains of an HIF-alpha isoform (HIF-2alpha) and ARNT interact in vitro, and that mutations in the solvent-exposed beta-sheet surface of the HIF-2alpha domain not only disrupt this interaction, but also greatly attenuate the hypoxia response in living cells. Here, we have solved the solution structure of the corresponding PAS domain of ARNT and show that it utilizes a very similar interface for the interaction with the HIF-2alpha PAS domain. We also show that this domain self-associates in a concentration-dependent manner, and that the interface used in this homodimeric complex is very similar to that used in the formation of heterodimer. In addition, using experimentally derived NMR restraints, we used the program HADDOCK to calculate a low-resolution model of the complex formed in solution by these two PAS domains, and confirm the validity of this model using site-directed spin labeling to obtain long-range distance information in solution. With this information, we propose a model for the mode of multi-PAS domain interaction in bHLH-PAS transcriptional activation complexes.

Aryl Hydrocarbon Receptor Nuclear Translocator↗
PubMed2004

Association of common T cell activation gene polymorphisms with multiple sclerosis in Australian patients.

Susceptibility to multiple sclerosis (MS) may be influenced by the interaction of several genes within a biological pathway. T cell activation and costimulation may be potentially important in MS pathogenesis. We have therefore investigated associations between MS and polymorphisms in the CD152 (CTLA-4), CD28, CD80 and CD86 genes in Australian patients. We found no significant MS association with CTLA-4 exon 1 +49 alleles, and meta-analysis showed no significant association across nine comparable datasets (OR=1.04, p=0.54), nor with primary progressive MS across seven datasets (OR=1.19, p=0.21). Haplotype analysis showed a trend towards a decrease of the CTLA-4-1722C, -1577G, +49G haplotype in +49 G positive MS patients compared with controls (p=0.06). Screening of CD28, CD80 and CD86 genes identified novel polymorphisms in the putative promoter regions of CD28 (-372 G/A) and CD86 (exon 2 -359 deletionAAG). There was a significant increase of the CD28 -372 G allele frequency in MS patients vs. controls (p=0.045) and a trend towards a significant interaction between this allele and the CTLA-4 +49 G allele (OR=4.00, p=0.058). Our results suggest that the CTLA-4 +49 alone is not associated with overall susceptibility to MS, but may be important in clinical subsets of patients and/or may interact epistatically with other gene polymorphisms.

Antigens, CD↗
PubMed2006

Bisphosphonates are associated with increased risk for jaw surgery in medical claims data: is it osteonecrosis?

PURPOSE: Bisphosphonates (BPs) have recently been associated with increased risk of osteonecrosis of the jaw. Using a large automated insurance database, we searched the medical claims for common procedure codes (CPT codes) denoting major surgery to the mandible or the maxilla. The primary aim of this pilot study was to alert readers to clinically relevant but preliminary information regarding the risk of jaw surgery among patients who received BPs, as compared with patients who did not. METHODS: The study utilized 2001-2004 claims data from a large nationwide medical insurer. Medical claims from 255,757 cancer patients with breast, lung, or prostate malignancies, or multiple myeloma were analyzed for CPT codes 21015, 21025, 21026, 21034, 21040, 21045, 21046, and 21047. RESULTS: We identified 224 cases of jaw surgery; of those, 39 cases were found among 26,288 BP users and 185 cases were found among 229,469 never-users. The odds ratio of jaw surgery for intravenous BP users was 4.24 (P<.05). Breast cancer patients experienced a 6-fold increase in risk as compared with nonusers. A trend of increased risk was noted for those on orally administered BPs, but the association was not significant. CONCLUSION: A significant association was noted between the administration of IV BPs and oral surgery in cancer patients. More studies are needed to understand the role of BPs in bone biology and necrosis along with the associated biologic pathways.

Administration, Oral↗
PubMed2026

Proteome Unravels Mechanism Differences in Embryogenesis Between Honey Bee Drone and Worker (Apis mellifera L.).

The physiological and social behaviors differ widely between honeybee workers and drones. All the organ rudiments of adult bees are formed during the embryonic stage. The initial molecular bases at the proteomic level for both embryonic developments have been identified, but a comprehensive understanding of the significant events involved in embryonic establishment remains elusive. To elucidate the molecular regulatory mechanisms underlying tissue differentiation during the embryogenesis of drones and workers, we implemented a state-of-the-art approach that combines in-hive inspection and targeted sampling (at nine embryogenesis stages) with high-throughput proteomics technology to investigate the developmental differences. In-hive inspection of hatching timing revealed an average developmental gap of approximately 3.6 h between the two embryos. Furthermore, proteomic analyses indicate that drone and worker embryos adopt distinct developmental strategies. Notably, proteins involved in fatty acid metabolism and key biological pathways related to organ formation-such as the Hedgehog and Wnt signaling pathways-are activated earlier in drones, suggesting that tissue development begins sooner in drone embryos than in workers. Additionally, the upregulation of cytoskeletal proteins and antioxidants in drone embryos likely supports their larger cell size and higher metabolic stress, reflecting distinct molecular characteristics of male development. Ribosomal proteins essential for biosynthetic support remain consistently expressed throughout the late stages in male embryos, indicating that drone embryogenesis lasts longer than that of workers. This work provides novel insights into the molecular foundations of honeybee embryogenesis and lays both theoretical and practical groundwork for future research into the mechanisms driving embryonic development.

Animals↗
PubMed2006

Environmental discontinuity hypothesis: Buffer dysfunctions as a source of human disease.

Adaptive physiologic buffers enable organisms to respond to environmental variation with appropriate plasticity. Modern humans have substantially remodeled their environment such that many interactions with the environment have become relatively discontinuous functions compared to the past. Examples include sunlight, temperature, and altitude. We propose that environmental discontinuity represents a Darwinian maladaptation and may promote disease by inducing buffer dysfunctions. Skin pigmentation is an adaptive, dynamic buffer that normalizes sunlight exposure to balance the potential harm of damaging rays with the importance of sunlight in driving systemic biologic functions such as melatonin and vitamin D. Due to lifestyle characteristics such as indoor-outdoor living, well-intended sun-avoidance campaigns, and inhomogeneous use of apparel and sunblock techniques, modern humans increasingly experience sunlight variation as a discontinuous function. The resulting skin pigmentation buffer dysfunction may promote diseases associated with over- or under-exposure to sunlight, the most striking example being melanoma. In addition to promoting discontinuity of sunlight exposure, sun-avoidance campaigns may undermine sun-dependent biologic pathways such as melatonin and vitamin D that appear to protect against cancer. These issues may partly explain the rise in melanoma rates despite the implementation of sun-avoidance campaigns. Also discussed is the potential role that discontinuous temperature variation associated with modern lifestyles plays in diseases such as viral infection, heart failure, and acute coronary syndromes. Acute discontinuous changes in pressure and oxygen levels related to air travel may contribute to autonomic dysfunction, venous thromboembolism, and viral infections. Therapeutic implications are discussed.

Adaptation, Physiological↗
PubMed2004

Genetic variation in fatty acid-binding protein-4 and peroxisome proliferator-activated receptor gamma interactively influence insulin sensitivity and body composition in males.

Obesity and type 2 diabetes are closely related, multifactorial metabolic conditions characterized by alterations in energy metabolism and glucose homeostasis, respectively. Peroxisome proliferator-activated receptor gamma (PPARgamma) is a ligand-dependent transcription factor that regulates genes involved in lipid and glucose homeostasis, including the adipocyte-specific fatty acid-binding protein (FABP4). In turn, FABP4 binds fatty acids and transports them to the nucleus where the FABP4/fatty acid complex activates PPARgamma in a positive feedback loop. In this study, we tested the hypothesis that the polymorphisms, FABP4-376 and PPARgamma Pro12Ala, interactively influence insulin sensitivity and body composition in nondiabetic, Hispanic and non-Hispanic white males (n = 314) participating in the San Luis Valley Diabetes Study (SLVDS). Although the individual sites were not statistically significantly associated with any of the outcomes, we found statistically significant interaction terms in 2-way analysis of covariance (ANCOVA) models for homeostasis model assessment of insulin resistance (HOMA-IR) (P =.014) and lean mass (P =.019). While the PPARgamma Pro12Ala site was the only statistically significant predictor of fat mass in the 2-way model (P =.012), the FABP4 and PPARgamma main effect terms individually became stronger when considered in one model compared with the analysis of each polymorphism separately. These findings provide evidence that FABP4 and PPARgamma work together to influence a biologic pathway affecting insulin sensitivity and body composition, illustrating the importance of investigating the joint effect of genes in determining susceptibility for complex disease.

Adult↗
PubMed2004

Profiling of genes associated with transcriptional responses in mouse hippocampus after transient forebrain ischemia using high-density oligonucleotide DNA array.

Several cascades of changes in gene expression have been shown to be involved in the neuronal injury after transient cerebral ischemia; however, little is known about the profile of genes showing alteration of expression in a mouse model of transient forebrain ischemia. We analyzed the gene expression profile in the mouse hippocampus during 24 h of reperfusion, after 20 min of transient forebrain ischemia, using a high-density oligonucleotide DNA array. Using statistical filtration (Welch's ANOVA and Welch's t-test), we identified 25 genes with a more than 3.0-fold higher or lower level of expression on average, with statistical significance set at p<0.05, in at least one ischemia-reperfusion group than in the sham group. Using unsupervised clustering methods (hierarchical clustering and k-means clustering algorithms), we identified four types of gene expression pattern that may be associated with the response of cell populations in the hippocampus to an ischemic insult in this mouse model. Functional classification of the 25 genes demonstrated alterations of expression of several kinds of biological pathways, regulating transcription (Bhlhb2, Jun, c-fos, Egr1, Egr2, Fosb, Junb, Ifrd1, Neurod6), the cell cycle (c-fos, Fosb, Jun, Junb, Dusp1), stress response (Dusp1, Dnajb1, Dnaja4), chaperone activity (Dnajb1, Dnaja4) and cell death (Ptgs2, Gadd45g, Tdag51), in the mouse hippocampus by 24 h of reperfusion. Using hierarchical clustering analysis, we also found that the same 25 genes clearly discriminated between the sham group and the ischemia-reperfusion groups. The alteration of expression of 25 genes identified in this study suggests the involvement of these genes in the transcriptional response of cell populations in the mouse hippocampus after transient forebrain ischemia.

Analysis of Variance↗
PubMed2006

The circadian gene per1 plays an important role in cell growth and DNA damage control in human cancer cells.

The Per1 gene is a core clock factor that plays an essential role in generating circadian rhythms. Recent data reveal that major biological pathways, including those critical to cell division, are under circadian control. We report here that Per1 provides an important link between the circadian system and the cell cycle system. Overexpression of Per1 sensitized human cancer cells to DNA damage-induced apoptosis; in contrast, inhibition of Per1 in similarly treated cells blunted apoptosis. The apoptotic phenotype was associated with altered expression of key cell cycle regulators. In addition, Per1 interacted with the checkpoint proteins ATM and Chk2. Ectopic expression of Per1 in human cancer cell lines led to significant growth reduction. Finally, Per1 levels were reduced in human cancer patient samples. Our results highlight the importance of circadian regulation to fundamental cellular functions and support the hypothesis that disruption of core clock genes may lead to cancer development.

Apoptosis↗
PubMed2005

Comparison of the expression profiles induced by genotoxic and nongenotoxic carcinogens in rat liver.

Application of recently developed gene expression techniques using microarrays in toxicological studies (toxicogenomics) facilitate the interpretation of a toxic compound's mode of action and may also allow the prediction of selected toxic effects based on gene expression changes. In order to test this hypothesis, we investigated whether carcinogens at doses known to induce liver tumors in the 2-year rat bioassay deregulate characteristic sets of genes in a short term in vivo study and whether these deregulated genes represent defined biological pathways. Male Wistar rats were dosed with the four nongenotoxic hepatocarcinogens methapyrilene (MPy, 60 mg/kg/day), diethylstilbestrol (DES, 10 mg/kg/day), Wy-14643 (Wy, 60 mg/kg/day), and piperonylbutoxide (PBO, 1200 mg/kg/day). After 1, 3, 7, and 14 days, the livers were taken for histopathological evaluation and for analysis of the gene expression profiles on Affymetrix RG_U34A arrays. The expression profile of the four nongenotoxic carcinogens were compared to the profiles of the four genotoxic carcinogens 2-nitrofluorene (2-NF), dimethylnitrosamine (DMN), 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), and aflatoxin B1 (AB1) from a similar study reported previously. By using statistical and clustering tools characteristically deregulated genes were extracted and functionally classified. Distinct cellular pathways were affected by the nongenotoxic carcinogens compared to the genotoxic carcinogens which at least partly correlated with the two-stage model of carcinogenesis. Characteristic to genotoxic carcinogens were a DNA damage response and the activation of proliferative and survival signaling. Nongenotoxic carcinogens showed responses to oxidative DNA or protein damage, as well as cell cycle progression and signs of regeneration. Many of the gene alterations found with the nongenotoxic carcinogens imply compound-specific mechanisms. Although neither a single gene nor a single pathway will be sufficient to discriminate the two classes of carcinogens, it became evident that combinations of pathway-associated gene expression profiles may be used to predict a genotoxic or nongenotoxic carcinogenic potential of a compound in short-term studies.

Animals↗
PubMed2005

Effects of chlorpromazine with and without UV irradiation on gene expression of HepG2 cells.

Damage to DNA can trigger a variety of stress-related signals that alter the expression of genes associated with numerous biological pathways. In this study, we have used a cDNA microarray representing 1089 genes related to DNA damage and repair, cell cycle, transcription, metabolism and other toxicologically important cell functions to identify genes regulated in response to DNA damage in HepG2 cells induced by UV-activated chlorpromazine (CPZ). CPZ itself is not genotoxic but, upon UV irradiation with a non-genotoxic dose in the UVA range, it produces reactive free radical intermediates with DNA damaging properties. Genotoxicity in HepG2 cells was assessed concomitantly to gene expression profiling using the Comet assay. Kinetic studies were performed at a non-cytotoxic but clearly photogenotoxic concentration of CPZ (1.25 microg/ml) to characterize gene expression profiles at four different time points (3, 7, 15, 23 h) post short-term treatment. The results obtained from repeated experiments display a time-dependent expression pattern of up-regulated and repressed genes with distinct peaks in the number of differentially expressed genes at the 7 and 23 h time points. Most of the genes with altered expression belonged to the functional categories of cell cycle regulation and cell proliferation. A comparison with published expression profiles established in response to other genotoxic compounds showed low levels of concordance, which is most likely caused by the fact that extremely different testing conditions were used.

Animals↗
PubMed2005

L-Carnitine protects mammalian cells from chromosome aberrations but not from inhibition of cell proliferation induced by hydrogen peroxide.

L-carnitine is a small essential molecule indispensable in fatty acid metabolism and required in several biological pathways regulating cellular homeostasis. Despite considerable progress in understanding of L-carnitine biosynthesis and metabolism, very few data are reported concerning the protective role of L-carnitine from oxidative stress-induced DNA damage that is known to be a factor in cell transformation and tumourigenesis. In order to detect the capability of L-carnitine to protect mammalian cells from oxidative stress-induced chromosomal effects, we analysed chromosome aberrations in mitotic CHO cells, which represent an appropriate cytogenetic model to study compounds that enhance cell protection against externally induced DNA damage. We chose H2O2 as an inducer of oxidative stress. Our results demonstrate for the first time a marked and reproducible reduction of H2O2-induced chromosome damage involving an L-carnitine-mediated capacity to buffer intracellular formation of reactive oxygen species (ROS). Furthermore, by studying the mitotic index and cell cycle progression, we also demonstrated that this protective effect is highly specific, since L-carnitine itself was not able to prevent the inhibition of cell growth caused by H2O2.

Animals↗
PubMed2005

RNA interference: from gene silencing to gene-specific therapeutics.

In the past 4 years, RNA interference (RNAi) has become widely used as an experimental tool to analyse the function of mammalian genes, both in vitro and in vivo. By harnessing an evolutionary conserved endogenous biological pathway, first identified in plants and lower organisms, double-stranded RNA (dsRNA) reagents are used to bind to and promote the degradation of target RNAs, resulting in knockdown of the expression of specific genes. RNAi can be induced in mammalian cells by the introduction of synthetic double-stranded small interfering RNAs (siRNAs) 21-23 base pairs (bp) in length or by plasmid and viral vector systems that express double-stranded short hairpin RNAs (shRNAs) that are subsequently processed to siRNAs by the cellular machinery. RNAi has been widely used in mammalian cells to define the functional roles of individual genes, particularly in disease. In addition, siRNA and shRNA libraries have been developed to allow the systematic analysis of genes required for disease processes such as cancer using high throughput RNAi screens. RNAi has been used for the knockdown of gene expression in experimental animals, with the development of shRNA systems that allow tissue-specific and inducible knockdown of genes promising to provide a quicker and cheaper way to generate transgenic animals than conventional approaches. Finally, because of the ability of RNAi to silence disease-associated genes in tissue culture and animal models, the development of RNAi-based reagents for clinical applications is gathering pace, as technological enhancements that improve siRNA stability and delivery in vivo, while minimising off-target and nonspecific effects, are developed.

Animals↗
PubMed2005

Stereoselective synthesis of monomeric flavonoids.

Polyphenolic compounds have recently attracted considerable interest in the field of nutrition, health and medicine. This is the result of the growing body of evidence suggesting that these compounds may act as potent antioxidants and/or modulate key biological pathways in vivo in mammals. Studies aimed at comprehending the intricate principles that govern the chemistry of these important natural products have thus accelerated over the past decade. Prominent amongst these is the ability to synthesize monomeric prototypes with and without 13C- and radio-labeling. Endeavors exploiting the stereoselective syntheses of representative classes of flavonoid monomers are reviewed here.

Flavonoids↗
PubMed2026

Mapping the Immune cell-specific gene regulatory network in bipolar disorder: A framework from scTWMR to exploratory drug-target annotation.

BACKGROUND: Although the involvement of the immune system in the genetic susceptibility of bipolar disorder (BD) is widely acknowledged, the causal relationship between gene expression in specific immune cell subtypes and BD requires systematic elucidation. METHODS: We implemented an analytical framework integrating single-cell transcriptome-wide Mendelian randomization (scTWMR) with colocalization analysis. This approach utilized cis-expression quantitative trait loci (cis-eQTLs) derived from 14 distinct immune cell types as instrumental variables to interrogate BD genome-wide association study (GWAS) summary statistics (comprising 41,917 cases and 371,549 controls). Subsequent investigations encompassed functional enrichment analysis, protein-protein interaction (PPI) network construction, phenome-wide association study (PheWAS), and performed an exploratory drug-target annotation. RESULTS: Our analysis identified 33 gene-immune cell associations. Colocalization analysis provided robust evidence (PPH4 > 90%) for shared causal variants implicating the MAD1L1, APOM, and NFKBIL1 loci. Significantly enriched biological pathways included cell cycle regulation, circadian rhythm entrainment, and neuroinflammation. The PPI network revealed a core regulatory module centered on histone-encoding and immune-related genes. Exploratory drug-target annotation nominated compounds for further investigation for compounds targeting APOM, TMEM258, and NFKBIL1. CONCLUSION: This study systematically delineates a genetically supported regulatory network of immune cell-specific gene expression in BD, predominantly implicating CD8&#x207a; effector T cells, plasma cells, and B cells. The findings corroborate established pathological pathways while uncovering novel cell type-specific therapeutic targets, thereby providing a genetic framework for prioritizing candidate targets for future investigation.

Bipolar disorder↗