Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Biologic pathways”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 1,333 records · Page 74Linked to original sources
PubMed2026

Pathway-driven target prioritisation in drug discovery.

Genome-scale association studies and functional screens routinely implicate hundreds of candidate genes per disease, yet only a few will be clinically validated as drug targets. Choosing which to pursue is a central drug-discovery decision that depends on interpreting each candidate in its biological context. Curated pathway databases provide this context, while enrichment analysis applies it at scale, turning gene-level signals from genome-wide association, transcriptomic, proteomic and CRISPR studies into mechanistic hypotheses for prioritisation. This review examines how pathway-based methods inform target prioritisation, the databases and tools available for this purpose, and why pathway co-membership should be viewed as a starting point for validation rather than as evidence of causal involvement.

CRISPR↗
PubMed1998

Distinct adapter proteins mediate acid versus neutral sphingomyelinase activation through the p55 receptor for tumor necrosis factor.

Ceramide, generated by the enzymatic function of sphingomyelinases (SMases) has emerged as an important signaling pathway transducing diverse biological effects of various cytokine receptors. The 55-kDa receptor for tumor necrosis factor (TNF-R55) activates two types of SMases through distinct cytoplasmic domains. The death domain that is responsible for the initiation of the apoptotic pathway also signals for the activation of an acid SMase (A-SMase). The adapter protein TRADD binds to TNF-R55 in a ligand-dependent manner and serves as anchor for the subsequent recruitment of other proteins into the signaling complex that directly lead to cell death or nuclear factor-kappaB (NF-kappaB) induction. Notably, the two pro-apoptotic adapter proteins TRADD and FADD are also involved in the activation of A-SMase. In contrast, the NF-kappaB-inducing adapters TRAF2 and RIP do not signal for A-SMase. Thus, activation of A-SMase appears to belong to signals leading to TNF-induced cell death. A second signaling domain (NSD) is located upstream of the death domain and directly links the TNF-R55 to the activation of a neutral SMase (N-SMase). A novel adapter protein, FAN, has been identified that specifically binds to the NSD. FAN contains five WD repeats at its carboxy terminus, while it shows significant sequence homology with the mouse beige protein and its human homolog, the CHS protein, in the center portion of the protein. Overexpression of full-length FAN enhanced N-SMase activity in TNF-treated cells, whereas truncated mutants of FAN produced dominant negative effects. FAN, however, did not interfere with any of the TNF responses signaled for by the death domain. Taken together, our data suggest that distinct cytoplasmic domains of TNF-R55 initiate independent signaling pathways by binding different adapter proteins.

Adaptor Proteins, Signal Transducing↗
PubMed2005

Microarray annotation and biological information on function.

OBJECTIVES: Many methods for statistical analysis of gene expression studies by DNA microarrays produce lists of genes as output. To understand gene lists in terms of traditional biology, e.g. which pathways may be affected, it is necessary to get appropriate annotations for the probes on an array. METHODS: Problems arise with the different sources that have been used by manufacturers to design microarray probes, and their association to biological entities like genes, transcripts and proteins. Function annotation is of crucial importance, and systems like Gene Ontology can be used for this purpose. It arranges annotation terms in a hierarchical manner and thus makes annotations in a gene list amenable to automated analysis. RESULTS: Several methods for analyses of gene function are described. The hierarchical nature of systems like Gene Ontology particularly suggests using methods from graph theory. CONCLUSIONS: The main problem in annotating microarray probes and inferring affected functional modules is the incompleteness and degree of error in current biological databases. Initial approaches to make use of functional annotation exist, but have to be extended, in particular with respect to estimating the statistical significance of results.

Computational Biology↗
PubMed2006

Interaction of nitric oxide with tetrathiolato iron(II) complexes: relevance to the reaction pathways of iron nitrosyls in sulfur-rich biological coordination environments.

The mechanism of formation of dinitrosyl iron complexes (DNICs) coordinated by cysteine residues at iron-sulfur protein sites has received little attention in the chemical literature. As a logical first step toward elucidating this mechanism and characterizing new iron-nitrosyl intermediates, we investigated the interaction of NO (g) and NO+ with iron-sulfur complexes chosen to mimic sulfur-rich iron sites in biology. The reaction of NO (g) with [Fe(StBu)4]2- cleanly affords the mononitrosyl complex, [Fe(StBu)3(NO)]- (1), a previously unknown species evoked in this chemistry. Reaction of [Fe(StBu)4]2- with NO derivatives, such as NO+, yields the corresponding dinitrosyl S-bridged Roussin red ester [Fe2(mu-StBu)2(NO)4] (2). The nitrosyl complexes 1 and 2 can chemically convert to the DNIC, [Fe(StBu)2(NO)2]- (3). The results should aid in the spectroscopic identification and elucidation of reaction pathways for the nitrosylation of iron in biologically related sulfur-rich coordination environments.

Crystallography, X-Ray↗
PubMed2006

The expanding transcriptome: the genome as the 'Book of Sand'.

The central dogma of molecular biology inspired by classical work in prokaryotic organisms accounts for only part of the genetic agenda of complex eukaryotes. First, post-transcriptional events lead to the generation of multiple mRNAs, proteins and functions from a single primary transcript, revealing regulatory networks distinct in mechanism and biological function from those controlling RNA transcription. Second, a variety of populous families of small RNAs (small nuclear RNAs, small nucleolar RNAs, microRNAs, siRNAs and shRNAs) assemble on ribonucleoprotein complexes and regulate virtually all aspects of the gene expression pathway, with profound biological consequences. Third, high-throughput methods of genomic analysis reveal that RNAs other than non-protein-coding RNAs (ncRNAs) represent a major component of the transcriptome that may perform novel functions in gene regulation and beyond. Post-transcriptional regulation, small RNAs and ncRNAs provide an expanding picture of the transcriptome that enriches our views of what genes are, how they operate, evolve and are regulated.

Animals↗
PubMed2004

Tissue factor and tissue factor pathway inhibitor.

The classical 'cascade/waterfall' hypothesis formulated to explain in vitro coagulation organised the amplification processes into the intrinsic and extrinsic pathways. Recent molecular biology and clinical data indicate that tissue factor/factor-VII interaction is the primary cellular initiator of coagulation in vivo. The process of blood coagulation is divided into an initiation phase followed by a propagation phase. The discovery of tissue factor pathway inhibitor further supports the revised theory of coagulation. Tissue factor is also a signalling receptor. Recent evidence has shown that blood-borne tissue factor has an important procoagulant function in sepsis, atherosclerosis and cancer, and other functions beyond haemostasis such as immune function and metastases.

Animals↗
PubMed1997

Molecular mechanisms of angiotensin II in modulating cardiac function: intracardiac effects and signal transduction pathways.

Angiotensin II (Ang II), the effector peptide of the renin-angiotensin system (RAS), regulates volume and electrolyte homeostasis and is involved in cardiac and vascular cellular growth in humans and other species. This system, which has been conserved throughout evolution, plays an important role in cardiac and vascular pathology associated with hypertension, coronary heart disease, myocarditis and congestive heart failure. The traditional RAS is viewed as a system in which circulating Ang II is delivered to target organs and cells. However, in the past decade, a local RAS has been described in cardiac cells, providing evidence for autocrine and paracrine pathways by which biological actions of Ang II could be mediated. The critical actions of Ang II are mediated primarily through the AT1, G-protein (guanylyl nucleotide binding protein) coupled receptor. In addition to coupling to conventional G-protein signal transduction pathways, the AT1 receptor was recently shown to increase the tyrosine phosphorylation of several intracellular substrates, including the STAT (Signal Transducers and Activators of Transcription) family of novel transcription factors, in rat cardiac fibroblasts, myocytes and vascular smooth muscle cells, and AT1 receptor transfected CHO cells. It has been shown that Ang II stimulates the tyrosine phosphorylation and nuclear translocation of Stat1 (Stat 91) and Stat3 (Stat 92). Angiotensin II acting directly through the AT1 receptor, induces the formation of a complex of STAT proteins termed SIF (sis-inducing factor) which binds the DNA sequence, SIE (sis-inducing element) present in the promotor element of many genes. This provides evidence for a direct role of Ang II in mediating inflammatory and remodeling responses through the JAK-STAT pathway. Thus, it is likely that the JAK-STAT pathway has an important role in Ang II-mediated effects on gene transcription, cardiac and vascular cellular growth/development, and inflammatory responses.

Angiotensin II↗
PubMed2000

Genetic approaches to the study of uterine leiomyomata.

The use of a variety of genetic methods to dissect underlying molecular events in tumors continues to be a highly successful approach. Cytogenetic evaluations of uterine leiomyomata have revealed consistent rearrangements that have provided biological landmarks for positional cloning experiments. Genetic linkage analysis makes possible the identification of genes that might predispose women to develop myomas. New gene expression chip methods to study globally the transcripts present in uterine leiomyomata promise insight into molecular pathways in tumor biology.

Causality↗
PubMed2006

Regulation of Ci and Su(fu) nuclear import in Drosophila.

The Hedgehog (Hh) signal transduction pathway plays a central role in the development of invertebrates and vertebrates. While much is known about the pathway, the role of Suppressor of fused (Su(fu)), a component of the pathway's signaling complex has remained enigmatic. Previous studies have linked Su(fu) to the cytoplasmic sequestration of the zinc finger transcription factor, Cubitus interruptus (Ci), while other studies suggest a role in modulating target gene expression. In examining the cell biology of the pathway, we have found that like its vertebrate homologue, Drosophila Su(fu) enters the nucleus. Furthermore, we find that the nuclear import of Su(fu) occurs in concert with that of Ci in response to Hh signaling. Here, we examine the mechanism by which Su(fu) regulates Ci import by investigating the importance of the Ci nuclear localization signal (NLS) and the effect of adding an additional NLS. Finally, we demonstrate that Ci can bring Su(fu) with it to a multimerized Ci DNA binding site. These results provide a basis for understanding the dual roles played by Su(fu) in the regulation of Ci.

Active Transport, Cell Nucleus↗
PubMed2005

Phosphoproteomics in analyzing signaling pathways.

A surprisingly fewer than expected number of genes in the human genome suggests that sophistication of its biologic system is, in part, due to complex regulation of protein activities. The activities of most cellular proteins are regulated by post-translational modifications. One of the most important post-translational modifications is reversible protein phosphorylation, which decorates more than 30% of the proteome and regulates signal transduction pathways under normal conditions as well as in disorders such as diabetes, neurodegenerative diseases, autoimmune diseases and several forms of cancers. This review examines the recent developments in mass spectrometry-based methods for phosphoproteome analysis and its applications for the study of signal transduction pathways. The basic principles of non-mass spectrometry-based methods, such as chemical genetics and flow cytometry-based approaches, are also discussed as well as their specific advantages to signaling studies. Finally, signaling pathways are discussed in the light of large-scale protein interaction studies. The proteomic methods addressed in this review are emerging as some of the essential components in systems biology, which seeks to describe signaling networks through integration of diverse types of data and, in the future, to allow computational simulations of complex biologic pathways in health and disease.

Chromatography, Affinity↗
PubMed2004

Differentiation of H9c2 cardiomyoblasts: The role of adenylate cyclase system.

The adenylate cyclase (AC)/cAMP/cAMP-dependent protein kinase pathway controls many biological phenomena. The molecular mechanisms by which cAMP induces alternative commitment towards differentiation or proliferation are not still completely known. The differentiation of myoblast cell lines into myocytes/myotubes represents a well-established model of skeletal muscle differentiation. We analyzed the AC/cAMP pathway during terminal differentiation of H9c2 myoblasts. When cultured in low-serum containing medium, H9c2 myoblasts exit the cell cycle and differentiate into myocytes/myotubes. A key step of this process is the expression of myogenin, an essential transcription factor for the terminal differentiation into myocytes. During this phenomenon we observed a decrease in both cAMP levels and AC activity, which suggests a functional negative role of cAMP on the differentiation process of H9c2 cells. 8-Br-cAMP and other cAMP-elevating agents, such as forskolin, IBMX, and isoproterenol, negatively affected skeletal muscle differentiation of H9c2 myoblasts. Both AC activity down-regulation and intracellular cAMP reduction were accompanied by significant variations in the levels of membrane proteins belonging to the AC system (AC catalytic subunit, G(alphai-1), G(alphas)). The functional relationship between intracellular cAMP content and protein levels of AC system is discussed.

Adenylyl Cyclases↗
PubMed2001

Molecular biology of the plastidic phosphorylated serine biosynthetic pathway in Arabidopsis thaliana.

Serine biosynthesis in plants proceeds by two pathways; the glycolate pathway which is associated with photorespiration and the pathway from 3-phosphoglycerate which is presumed to take place in the plastids. The 3-phosphoglycerate pathway (phosphorylated pathway) involves three enzymes catalyzing three sequential reactions: 3-phosphoglycerate dehydrogenase (PGDH), 3-phosphoserine aminotransferase (PSAT) and 3-phosphoserine phosphatase (PSP). cDNA and genomic clones encoding these three enzymes from spinach and Arabidopsis thaliana were isolated by means of heterologous probe screening, homologous EST clones and genetic complementation in an Escherichia coli mutant. The identity of the isolated cDNAs was confirmed by functional complementation of serine auxotrophy in E. coli mutants and/or the detection of catalytic activity in the recombinant enzymes produced in E. coli. Northern blot analyses indicated the most preferential expression of these three genes in light-grown roots. In contrast, the mRNAs of two proteins involved in the glycolate pathway (H-protein of glycine decarboxylase multienzyme complex and serine hydroxymethyltransferase) accumulated to high levels in light-grown shoots. Environmental stresses, such as high salinity, flooding and low temperature, induced changes in mRNA levels of enzymes in the plastidic phosphorylated serine biosynthetic pathway but not in that of the glycolate pathway. These results indicate that the plastidic 3-phosphoglycerate pathway plays an important role in supplying serine in non-photosynthetic tissues in plants and under environmental stresses.

Arabidopsis↗
PubMed2003

Structural biology of enzymes of the thiamin biosynthesis pathway.

Thiamin pyrophosphate is an essential cofactor of carbohydrate and branched-chain amino acid metabolism. Although its mechanistic role is well studied, the biosynthesis of thiamin has only recently been understood. Thiamin biosynthesis in Escherichia coli and Bacillus subtilis show some similarities, but diverge at key steps of thiazole formation. The biosynthesis of thiamin in eukaryotes is at a very early stage of understanding. Structural and mechanistic studies on thiamin biosynthetic enzymes have played a key role in increasing our understanding of thiamin pyrophosphate biosynthesis and have revealed unexpected evolutionary ties.

Bacteria↗
PubMed1998

Biology and function of the reversible sulfation pathway catalysed by human sulfotransferases and sulfatases.

Sulfation and sulfate conjugate hydrolysis play an important role in metabolism, and are catalysed by members of the sulfotransferase and sulfatase enzyme super-families. In general, sulfation is a deactivating, detoxication pathway, but for some chemicals the sulfate conjugates are much more reactive than the parent compound. The range of compounds which are sulfated is enormous, yet we still understand relatively little of the function of this pathway. This review summarises current knowledge of the sulfation system and the enzymes involved, and illustrates how heterologous expression of sulfotransferases (SULTs) and sulfatases is aiding our appreciation of the properties of these important proteins. The role of sulfation in the bioactivation of procarcinogens and promutagens is discussed, and new data on the inhibition of the sulfotransferase(s) involved by common dietary components such as tea and coffee are presented. The genetic and environmental factors which are known to influence the activity and expression of human SULTs and sulfatases are also reviewed.

Amino Acid Sequence↗
PubMed2002

Nitric oxide production mediated by nitrate reductase in the green alga Chlamydomonas reinhardtii: an alternative NO production pathway in photosynthetic organisms.

Biological activity of nitric oxide (NO) production was investigated in the unicellular green alga Chlamydomonas reinhardtii. An NO specific electrode detected a rapid increase in signal when nitrite (NO(2)(-)) was added into a suspension of C. reinhardtii intact cells in the dark. The addition of KCN or the NO quencher bovine hemoglobin completely abolished the signal, verifying that the nitrite-dependent increase in signal is due to enzymatic NO production. L-arginine, the substrate for NO synthase, did not induce detectable NO production and the NOS inhibitor N(omega)-nitro-L-arginine showed no inhibitory effect on the nitrite-dependent production of NO. Illuminating cells showed a significant suppressive effect on NO production. When the photosynthetic electron transport inhibitor 3-(3,4-dichlorophenyl)-1,1-dimethylurea was present in the suspension, C. reinhardtii cells produced NO after the addition of nitrite even under illumination. Kinetic and microscopic observations, using the intracellular fluorescent NO probe 4,5-diaminofluorescein-2 diacetate, both demonstrated that NO was produced within the cells in response to the addition of nitrite. The Chlamydomonas mutant cc-2929, which lacks nitrate reductase (NR) activity, did not display any of the responses observed in the wild-type cells. The results presented here provide direct in vivo evidence to confirm that NR is involved in the nitrite-dependent NO production in the green alga.

Animals↗
PubMed2001

Metabolism of chiisanoside from Acanthopanax divaricatus var. albeofructus by human intestinal bacteria and its relation to some biological activities.

The metabolic pathway of chiisanoside isolated from leaves of Acanthopanax divaricatus var. albeofructus (Araliaceae) by human intestinal bacteria and by the protein fraction of leaves of this plant were investigated, and the cytotoxic and anti-rotaviral activities of chiisanoside and its metabolite, chiisanogenin, were assayed. Chiisanogenin was produced as a main metabolite, when chiisanoside were incubated for 15 h with human intestinal bacteria. This metabolic pathway proceeded more potently with the protein fraction than with human intestinal bacteria. The in vitro cytotoxicity of chiisanogenin was superior to that of chiisanoside. H+/K+ ATPase was more potently inhibited by chiisanogenin than by chiisanoside. However, the anti-rotaviral activity of chiisanoside was more potent than that of chiisanogenin.

Animals↗