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At least 973 records · Page 54Linked to original sources
PubMed2001

Bioinformatic identification of potential autocrine signaling loops in cancers from gene expression profiles.

Many biological signaling pathways involve autocrine ligand-receptor loops; misregulation of these signaling loops can contribute to cancer phenotypes. Here we present an algorithm for detecting such loops from gene expression profiles. Our method is based on the hypothesis that for some autocrine pathways, the ligand and receptor are regulated by coupled mechanisms at the level of transcription, and thus ligand-receptor pairs comprising such a loop should have correlated mRNA expression. Using our database of experimentally known ligand-receptor signaling partners, we found examples of ligand-receptor pairs with significantly correlated expression in five cancer-based gene expression datasets. The correlated ligand-receptor pairs we identified are consistent with known autocrine signaling events in cancer cells. In addition, our algorithm predicts new autocrine signaling loops that can be verified experimentally. Chemokines were commonly members of these potential autocrine pathways. Our analysis also revealed ligand-receptor pairs with expression patterns that may indicate cellular mechanisms for preventing autocrine signaling.

Algorithms↗
PubMed2004

Insulin receptor substrate-1/SHP-2 interaction, a phenotype-dependent switching machinery of insulin-like growth factor-I signaling in vascular smooth muscle cells.

Insulin-like growth factor-I (IGF-I) plays a role in mutually exclusive processes such as proliferation and differentiation in a variety of cell types. IGF-I is a potent mitogen and motogen for dedifferentiated vascular smooth muscle cells (VSMCs) in vivo and in vitro. However, in differentiated VSMCs, IGF-I is only required for maintaining the differentiated phenotype. Here we investigated the VSMC phenotype-dependent signaling and biological processes triggered by IGF-I. In differentiated VSMCs, IGF-I activated a protein-tyrosine phosphatase, SHP-2, recruited by insulin receptor substrate-1 (IRS-1). The activated SHP-2 then dephosphorylated IRS-1 Tyr(P)-895, resulting in blockade of the pathways from IRS-1/Grb2/Sos to the ERK and p38 MAPK. Conversely, such negative regulation was silent in dedifferentiated VSMCs, where IGF-I activated both MAPKs via IRS-1/Grb2/Sos interaction-linked Ras activation, leading to proliferation and migration. Thus, our present results demonstrate that the IRS-1/SHP-2 interaction acts as a switch controlling VSMC phenotype-dependent IGF-I-induced signaling pathways and biological processes, and this mechanism is likely to be applicable to other cells.

Animals↗
PubMed1999

[The role of leukotrienes in inflammation and leukotriene inhibitors].

Over recent years it has become widely accepted that asthma is a chronic persistent inflammatory condition regulated by a variety of inflammatory cells and mediators such as leukotrienes. It has been shown that there are increased levels of cysteinyl leukotrienes in biological fluids from patient with chronic asthma and in acute bronchospasm experimentally induced by allergen or other stimuli. The evidence suggests that blocking the formation or action of cysteinyl leukotrienes may be benefit in the treatment of chronic inflammatory diseases. In this article the leukotriene pathway, the biological role of these lipid mediators and their antagonists are widely characterised. There are three groups of leukotriene inhibitors: 5-lipooxygenase inhibitors, FLAP (activating protein) inhibitors and Cys-Lt1 receptor antagonists. On Polish market two representative drugs are currently: montelukast and zafirlukast, both leukotriene receptor antagonists. They bind competitively and selectively to Cys-Lt1 receptors blocking the pro-inflammatory effects of the cysteinyl leukotrienes. They offer protection against cold, dry air or exercise-induced bronchoconstriction significantly greater than placebo. These agents produce a modest improvement in lung function, symptom control and reduce the need for short acting inhaled beta2-agonist therapy. Some guidelines suggest that they may be considered as an alternative treatment to low dose inhaled corticosteroid therapy and cromones therapy of mild persistent asthma. It seems likely that aspirin-sensitive asthmatic patients may be benefited by LTD4-antagonists. These drugs have the great advantage of efficacy by oral administration and they do not appear any class-specific side effects. Also some basic information about zileuton--5-lipooxygenase inhibitor are given. Due to its induction of hepatic enzyme activity zileuton is not available in Poland, but it is important agent in evaluation of the leukotriene inhibitors in some models of inflammation. The introduction of leukotriene antagonists is undoubtedly an important breakthrough in asthma therapy.

Acetates↗
PubMed2004

Genome-wide expression profiling; a panel of mouse tissues discloses novel biological functions of liver X receptors in adrenals.

The liver X receptors alpha and beta (LXRalpha and LXRbeta ) are members of the nuclear receptor superfamily of proteins which are highly expressed in metabolically active tissues. They regulate gene expression of critical genes involved in cholesterol catabolism and transport, lipid and triglyceride biosynthesis and carbohydrate metabolism in response to distinct oxysterols and intermediates in the cholesterol metabolic pathway. The biological roles of the LXRs in tissues other than liver, intestine and adipose tissue are poorly elucidated. In this study we used global gene-expression profiling analysis to detect differences in expression patterns in several tissues from mice fed an LXR agonist or vehicle. Our results show that LXR plays an important role in the kidney, lung, adrenals, brain, testis and heart where several putative LXR target genes were found. The effects of the LXRs were further analysed in adrenals where treatment with an LXR agonist induced expression of adrenocorticotrophic hormone receptor, suppressed expression of uncoupling protein (UCP)-1 and UCP-3 as well as several glycolytic enzymes and led to increased serum corticosterone levels. These results indicate novel biological roles of the LXR including regulation of energy metabolism, glycolysis and steroidogenesis in the adrenals via alteration of expression profiles of putative target genes.

Adrenal Glands↗
PubMed2005

Microbial degradation of selected odorous substances.

A biological odor treatment system has several advantages compared to conventional physical and chemical treatment technologies: (1) it is highly efficient in the treatment of waste gases characterized by high flow rates and low concentrations of contaminants; (2) the biodegradable pollutants are completely destroyed; and (3) it has low cost [Devinny, J.S., Deshusses, M.A., Webster, T.S., 1999. Biofiltration for Air Pollution Control. Lewis Publisher, New York, USA; Kennes, C., Veiga, M.C., 2001. Bioreactors for waste gas treatment. Kluwer Academic Publishers, London]. Because microorganisms play the major role in the successful biological odor treatment system, the understanding of microbial degradation of the key odorants is very important. This article describes the occurrence and the characteristics of selected key odorous compounds such as sulphides, amines, and pyrazine compounds. The article reviews available information in the literature and our experimental results of microbial degradation of the selected compounds. This is the first article that presents the isolation and characterization of bacterial strains that can utilize dimethyl trisulfide (DMTS), triethylamine (TEA) or different pyrazines, as a sole carbon and energy source. The biological degradation pathways of some of these compounds are postulated. Moreover, the influence of the presence of other odorous compounds in the culture medium on the degradation of the target odorous compounds by the isolated bacteria is presented. The information presented in the paper can be used to develop new systems for biological odor treatment.

Air Pollution↗
PubMed2005

Novel target genes of the Wnt pathway and statistical insights into Wnt target promoter regulation.

The Wnt pathway controls biological processes via the regulation of target gene expression. The expression of direct Wnt target genes, e.g. cyclin D1 and MYC, is activated by the transcription factor TCF, which binds to specific sequence motifs in the promoter. Indirect target genes are regulated via transcription regulators, which are targets of the Wnt pathway. As an example, MYC regulates the MYC interacting zinc finger protein-1 (MIZ-1), which is able to inhibit the expression of the indirect target p21WAF1. We intended to identify new Wnt target genes and to get a deeper insight into the regulatory mechanisms of Wnt target gene expression. For this we analyzed the differential expression pattern of Wnt-1 activated cells by microarray analysis. We identified 43 sequences including eight expressed sequence tags (ESTs), which showed increased transcript levels, and 104 sequences including 19 ESTs with decreased RNA levels. Northern blot and real-time quantitative PCR analysis of the differential expression levels of 15 genes confirmed the differential expression trends of eight candidate genes. When the Wnt pathway was regulated at the lower level of glycogen synthase kinase-3 beta (GSK-3 beta) or adenomatous polyposis coli (APC), we detected discrepant expression trends. We compared the number of binding sites of transcription factors in the genomic regions of all candidate target genes with the number of sites in control genes. We found that the genomic regions of the down-regulated genes include an increased number of putative MIZ-1 binding sites. Our study introduces several new Wnt target genes and provides indications that the specific gene expression pattern depends on the type of the activation trigger or the level of interference with the Wnt pathway. Furthermore, our data indicate that a high proportion of Wnt target genes are regulated by indirect mechanisms.

Animals↗
PubMed2006

Functional annotation and analysis of Korean patented biological sequences using bioinformatics.

A recent report of the Korean Intellectual Property Office (KIPO) showed that the number of biological sequence-based patents is rapidly increasing in Korea. We present biological features of Korean patented sequences though bioinformatic analysis. The analysis is divided into two steps. The first is an annotation step in which the patented sequences were annotated with the Reference Sequence (RefSeq) database. The second is an association step in which the patented sequences were linked to genes, diseases, pathway, and biological functions. We used Entrez Gene, Online Mendelian Inheritance in Man (OMIM), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Ontology (GO) databases. Through the association analysis, we found that nearly 2.6% of human genes were associated with Korean patenting, compared to 20% of human genes in the U.S. patent. The association between the biological functions and the patented sequences indicated that genes whose products act as hormones on defense responses in the extra-cellular environments were the most highly targeted for patenting. The analysis data are available at http://www.patome.net.

Base Sequence↗
PubMed2005

Deficiency in the gap junction protein connexin32 alters p27Kip1 tumor suppression and MAPK activation in a tissue-specific manner.

Connexin32 knockout mice (Cx32-KO) exhibit increased chemical- and radiation-induced liver and lung tumor formation with many lung tumors demonstrating decreased levels of the tumor suppressor p27KIP1. To determine if p27 deficiency alters Cx32-influenced tumorigenesis, we have generated a Cx32/p27 double-deficient mouse strain (DKO) and show here that exposure of these mice to X-ray radiation resulted in an increase or decrease in tumorigenesis depending on the tissue. Several tissues were highly sensitive to loss of p27 tumor suppressor function (intestine, adrenal, pituitary) resulting in an increased overall tumor burden in DKO mice compared to both wild-type (P<0.005) and Cx32-KO mice (P=0.066). However, additional deletion of p27 in a Cx32-KO background resulted in a statistically significant decrease in the liver tumor incidence suggesting that Cx32 and p27 pathways mechanistically interact. Immunohistochemical analysis revealed an increased percentage of Cx32-KO liver and lung tumors harboring active mitogen-activated protein kinase (Erk1, Erk2) pathways in contrast to lower percentages of activated wild-type (P<0.005) and DKO tumors (P=0.027). Increased MAPK activation in liver tumors did not correlate with Ha-ras codon-61 mutation status. This study demonstrates that tissues dependent on Cx32 tumor suppression, such as the liver and lung, exhibit altered tumorigenesis and tumor biology (MAPK pathway activation) related to p27 status.

Adenoma↗
PubMed2024

Bioinformatics analysis of ferroptosis in frozen shoulder.

OBJECTIVES: Frozen shoulder is a common shoulder disease that significantly affects the patient's life and work. Ferroptosis is a new type of programmed cell death, which is involved in many diseases. However, there have been no studies reporting the relationship between frozen shoulders and ferroptosis. This study identified potential molecular markers of ferroptosis in frozen shoulders to provide more effective strategies for the treatment of frozen shoulders. METHODS: GSE238053 was downloaded from the Gene Expression Omnibus (GEO) dataset and intersected with ferroptosis genes to obtain differentially expressed genes (DEGs). The signaling pathways and biological functions of DEGs were performed by WebGestalt and Metascape. The interactions related to these DEGs and the key genes between frozen shoulders and ferroptosis was performed by STRING and Cytoscape. A frozen shoulders rat model was used to validate our predicted genes, Western Blot and qRT-PCR was used to assess the expression levels of our genes of interest. RESULTS: A total of 34 DEGs between GSE238053 and Ferroptosis Database were obtained, most of which were involved in the HIF-1 signaling pathway and inflammatory response. A protein-protein interaction network was obtained by Cytoscape and the key genes (IL-6, HMOX1 and TLR4) were screened by MCODE. Our results of Western Blot showed that the protein expression level of TLR4 and HMOX1 were elevated, and the protein level of IL-6 decreased in frozen shoulders rat model. The mRNA level after frozen shoulders showed that IL-6 was upregulated, whereas TLR4 and HMOX1were downregulated. CONCLUSIONS: The results demonstrated that ferroptosis may affect the pathological process of frozen shoulders through these signaling pathways and genes. The identification of IL-6, HMOX1 and TLR4 genes can provide new therapeutic targets for frozen shoulders.

Ferroptosis↗
PubMed2005

Metabolic control through the PGC-1 family of transcription coactivators.

Many complex biological programs are controlled at the level of gene transcription by DNA binding transcription factors. Recent studies have revealed a novel mode of regulation by coactivator proteins, best illustrated by the PGC-1 family of coactivators. These factors are highly responsive to a variety of environmental cues, from temperature to nutritional status to physical activity, and they coordinately regulate metabolic pathways and biological processes in a tissue-specific manner. Notably, the PGC-1 coactivators play a critical role in the maintenance of glucose, lipid, and energy homeostasis and are likely involved in the pathogenic conditions such as obesity, diabetes, neurodegeneration, and cardiomyopathy. These actions also raise new opportunities for the development of novel therapeutics.

Animals↗
PubMed2006

Apoptolidin: induction of apoptosis by a natural product.

Apoptolidin is a natural product that selectively induces apoptosis in several cancer cell lines. Apoptosis, programmed cell death, is a biological key pathway for regulating homeostasis and morphogenesis. Apoptotic misregulations are connected with several diseases, in particular cancer. The extrinsic way to apoptosis leads through death ligands and death receptors to the activiation of the caspase cascade, which results in proteolytic degradation of the cell architecture. The intrinsic pathway transmits signals of internal cellular damage to the mitochondrion, which loses its structural integrity, and forms an apoptosome that initiates the caspase cascade. Compounds which regulate apoptosis are of high medical significance. Many natural products regulate apoptotic pathways, and apoptolidin is one of them. The known synthetic routes to apoptolidin are described and compared in this Review. Selected further natural products which regulate apoptosis are introduced briefly.

Animals↗
PubMed2003

Effect of DNA superhelicity and bound proteins on mechanistic aspects of the Hin-mediated and Fis-enhanced inversion.

Using a recently developed inhomogeneous, macroscopic model for long DNA bound to proteins, we examine topological and geometric aspects of DNA/protein structures and dynamics on various stages of the Hin inversion pathway. This biological reaction involves exchange of DNA in a synaptic complex that brings together several DNA sites bound to Hin dimers as well as Fis enhancers. Brownian dynamics simulations in the millisecond timescale allow us to follow and analyze the DNA/protein dynamics trajectories and to examine the effects of DNA superhelicity and protein binding on various reaction steps. Analysis of the generated kinetic pathways helps explain mechanistic aspects regarding the process by which two or three protein-bound DNA sites come to close spatial proximity and show that how topological selectivity (two trapped supercoils), enhancer binding, and properties of supercoiled DNA play critical roles in regulating the inversion reaction. Specifically, a critical amount of DNA superhelicity (e.g., |sigma| > 0.02) leads to an optimal interplay for the first reaction step-two-site juxtaposition-between large-scale random rearrangements of Hin-bound DNA and local slithering within branches of plectonemes. The three-site juxtaposition, the second step, is significantly accelerated by the presence of an enhancer protein that, due to severe local bending, also alters juxtaposition mechanisms, especially for superhelical density magnitude greater than around 0.04.

Binding Sites↗
PubMed2000

Multivariate measurement of gene expression relationships.

The operational activities of cells are based on an awareness of their current state, coupled to a programmed response to internal and external cues in a context-dependent manner. One key goal of functional genomics is to develop analytical methods for delineating the ways in which the individual actions of genes are integrated into our understanding of the increasingly complex systems of organelle, cell, organ, and organism. This paper describes a novel approach to assess the codetermination of gene transcriptional states based upon statistical evaluation of reliably informative subsets of data derived from large-scale simultaneous gene expression measurements with cDNA microarrays. The method finds associations between the expression patterns of individual genes by determining whether knowledge of the transcriptional levels of a small gene set can be used to predict the associated transcriptional state of another gene. To test this approach for identification of the relevant contextual elements of cellular response, we have modeled our approach using data from known gene response pathways including ionizing radiation and downstream targets of inactivating gene mutations. This approach strongly suggests that evaluation of the transcriptional status of a given gene(s) can be combined with data from global expression analyses to predict the expression level of another gene. With data sets of the size currently available, this approach should be useful in finding sets of genes that participate in particular biological processes. As larger data sets and more computing power become available, the method can be extended to validating and ultimately identifying biologic (transcriptional) pathways based upon large-scale gene expression analysis.

Cyclin-Dependent Kinase Inhibitor p21↗
PubMed1988

Arachidonic acid metabolites: basic concepts relevant to plastic surgery.

AA is the precursor of oxygenated metabolites called the eicosanoids, that are generated by the cyclooxygenase, lipoxygenase, or cytochrome P450 enzymatic pathways. The biologically active eicosanoids are labile, usually but not always, act near their site of synthesis, and are not stored in any tissue to any appreciable degree. In most tissues, there is a continuous low-level synthesis that is probably essential to normal function. Injury or surgical trauma can evoke a dramatic change in the quality and quantity of the metabolites. Pharmacologic manipulation of the pathways of AA metabolism, or alteration of the effects of AA metabolites, can significantly improve tissue perfusion in a variety of clinical situations. (See Figure 1 for a schematic summary of the pathways involved in arachidonic acid metabolites.

Animals↗
PubMed1996

Systematic mutational analysis of the death domain of the tumor necrosis factor receptor 1-associated protein TRADD.

Tumor necrosis factor receptor 1 (TNF-R1) mediates most of the biological properties of TNF including activation of the transcription factor NF-kappaB and programmed cell death. An approximately 80-amino acid region within the intracellular domain of the receptor, termed the death domain, is required for signaling NF-kappaB activation and cytotoxicity. A TNF-R1-associated protein TRADD has been discovered that interacts with the death domain of the receptor. Elevated expression of TRADD in cells triggers both NF-kappaB activation and programmed cell death pathways. The biological activities of TRADD have been mapped to a 111-amino acid region within the carboxyl-terminal half of the protein. This region shows sequence similarity to the death domain of TNF-R1 and can self-associate and bind to the TNF-R1 death domain. We have performed an alanine scanning mutagenesis of TRADD's death domain to explore the relationship among its various functional properties. Mutations affecting the different activities of TRADD do not map to discrete regions but rather are spread over the entire death domain, suggesting that the death domain is a multifunctional unit. A mutant that separates cell killing from NF-kappaB activation by the TRADD death domain has been identified indicating that these two signaling pathways diverge with TRADD. Additionally, one of the TRADD mutants that fails to activate NF-kappaB was found to act as dominant negative mutant capable of preventing induction of NF-kappaB by TNFalpha. Such observations provide evidence that TRADD performs an obligate role in TNF-induced NF-kappaB activation.

Alanine↗
PubMedDate not supplied

Data input module for Birth Defects Systems Manager.

The need for a computational bioinformatics infrastructure to manage the vast digital information from functional genomics and proteomics motivated us to develop Birth Defects Systems Manager (BDSM) as an open resource to facilitate analysis and discovery in developmental biology and developmental toxicity. This report describes the design, development and implementation of the data loading module of BDSM, referred to as LoadBDSM. It includes a shared data directory resource that can be granted various levels of security for different research groups or investigators to manage experimental datasets individually or in groups. LoadBDSM allows the upload of data and experiment details using controlled semantics for developmental exposure (toxicant, dosing scenario, intervention), biological sample (species, tissue, stage) and disease outcome (time, risk, phenotype). It adheres to existing controlled vocabulary plus rules of inference (ontologies) for experiment, data and metadata annotations. LoadBDSM extends the capabilities of BDSM to support the emergence of "embryo-formatics" defined here as the data, information and knowledge from genomic sciences applied to, or derived from, an embryological context. This includes, but is not limited to, delineating pathways and biological regulatory networks for specific chemicals or classes of developmental toxicants, developing novel biomarkers indicative of exposure and/or predictive of adverse effects, and integrating modern computing and information technology with data from molecular biology.

Abnormalities, Drug-Induced↗
PubMed2005

GPR4 plays a critical role in endothelial cell function and mediates the effects of sphingosylphosphorylcholine.

Angiogenesis is critical for many physiological and pathological processes. We show here that the lipid sphingosylphosphorylcholine (SPC) induces angiogenesis in vivo and GPR4 is required for the biological effects of SPC on endothelial cells (EC). In human umbilical vein EC, down-regulation of GPR4 specifically inhibits SPC-, but not sphingosine-1-phosphate-, or vascular endothelial growth factor (VEGF)-induced tube formation. Re-introduction of GPR4 fully restores the activity of SPC. In microvascular EC, GPR4 plays a pivotal role in cell survival, growth, migration, and tube formation through both SPC-dependent and -independent pathways. The biological effects resulting from SPC/GPR4 interactions involve the activation of both phosphatidylinositol-3 kinase and Akt. Moreover, the effects of SPC on EC require SPC induced trans-phosphorylation and activation of the VEGF receptor 2. These results identify SPC and its receptor, GPR4, as critical regulators of the angiogenic potential of EC.

Animals↗
PubMed2004

A multidrug resistance-associated protein involved in anthocyanin transport in Zea mays.

Anthocyanin biosynthesis is one of the most thoroughly studied enzymatic pathways in biology, but little is known about the molecular mechanisms of its final stage: the transport of the anthocyanin pigment into the vacuole. We have identified a multidrug resistance-associated protein (MRP), ZmMrp3, that is required for this transport process in maize (Zea mays). ZmMrp3 expression is controlled by the regulators of anthocyanin biosynthesis and mirrors the expression of other anthocyanin structural genes. Localization of ZmMRP3 in vivo shows its presence in the tonoplast, the site at which anthocyanin transport occurs. Mutants generated using antisense constructs have a distinct pigmentation phenotype in the adult plant that results from a mislocalization of the pigment as well as significant reduction in anthocyanin content, with no alteration in the anthocyanin species produced. Surprisingly, mutant plants did not show a phenotype in the aleurone. This appears to reflect the presence of a second, highly homologous gene, ZmMrp4, that is also coregulated with the anthocyanin pathway but is expressed exclusively in aleurone tissue. This description of a plant MRP with a role in the transport of a known endogenous substrate provides a new model system for examining the biological and biochemical mechanisms involved in the MRP-mediated transport of plant secondary metabolites.

Amino Acid Sequence↗