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PubMed1987

Gold disposition in the rat: studies of its plasma half-life and its urinary, biliary and fecal elimination pathways.

The biologic half-life of gold, a subject of controversy for many years, was found to be much longer in the rat than that reported for other species in the bulk of the literature. The longer observed half-life supports recent findings in man and is more consistent with the monthly maintenance dosing normally used in patients with rheumatoid arthritis. Excretion studies revealed that, after administration of gold sodium thiomalate, gold was eliminated via urinary and fecal pathways by approximately a 2:1 ratio. The relative importance of these pathways was not altered after multiple dosing. Biliary and intestinal excretion studies were performed to identify the means by which gold is eliminated via the feces. Only a small percentage of the dose was recovered from the bile after 2 hr, and biliary excretion was shown to be dose dependent. Results suggest that passive diffusion may be responsible for plasma-to-bile transfer and stand in contrast to the results of similar studies on other metals. Administration of gold as gold chloride [Au(III)] instead of gold sodium thiomalate [Au(I)] did not alter the excretion into bile, nor did stimulation of metallothionein, a metal-binding protein in the liver and kidney, by Cd pretreatment. Intestinal excretion was shown to be an insignificant pathway of gold elimination. The results of these studies suggest that, at high doses, gold-binding sites on plasma proteins may be saturated, resulting in an increase in excretion into the urine and bile, as well as an increase in distribution to peripheral tissues where tissue binding results in an overall increase in half-life.

Animals↗
PubMed2005

The 5-lipoxygenase pathway in arterial wall biology and atherosclerosis.

Leukotrienes (LTs) are powerful inflammatory lipid mediators derived from the 5-lipoxygenase (5-LO) cascade of arachidonic acid. Recent clinical, population genetic, cell biological, and mouse studies indicate participation of the 5-LO pathway in atherogenesis and arterial wall remodeling. 5-LO is expressed by leukocytes including blood monocytes, tissue macrophages, dendritic cells, neutrophils, and mast cells. LTB4 and the cysteinyl LTs LTC4, LTD4, and LTE4, act through two BLT and two cysLT receptors that are differentially expressed on hematopoietic and arterial wall cells. The precise roles of LTs or the LT receptors in cardiovascular physiology remain largely to be explored. In this review, we will discuss what is currently known about the 5-LO atherosclerosis connection. We will attempt to propose strategies to further explore potential links between the 5-LO pathway and blood vessel physiology and disease progression.

Animals↗
PubMed1995

Degradation of iprodione by a soil Arthrobacter-like strain.

A bacterial strain able to transform iprodione was isolated from a fast iprodione-degrading soil by enrichment procedures. Transformation was detected through 3,5-dichloroaniline production as measured by a rapid colorimetric method. The strain, MA6, was tentatively identified as an Arthrobacter sp. When it was incubated with MA6 in a minimum mineral medium (pH 6.5), iprodione (8.8 mumol/liter) was transformed into two major metabolites that were identified by high-performance liquid chromatography analysis: 3,5-dichlorophenylcarboximide (metabolite 1) and (3,5-dichlorophenylurea) acetic acid (metabolite 2), which was produced after ring cleavage of the former product. These products were synthesized in the laboratory and compared with metabolites 1 and 2 which were formed during iprodione degradation. Small quantities of 3,5-dichloroaniline also appeared in the bacterial culture but did not substantially increase between the first and second days of incubation. In contrast, in the sterile control medium, iprodione was spontaneously transformed into hydantoic acid and an iprodione isomer. Chemical and biological transformations of iprodione seem to occur through two different pathways. One biological degradation pathway is proposed.

Aminoimidazole Carboxamide↗
PubMed2000

Kinetic analysis of the M1 RNA folding pathway.

The biological activity of large RNAs is dependent on the formation of complex folded structures that determine function. Typically the creation of such structures requires divalent magnesium and in many cases the folding process takes place over the course of several minutes. It has been proposed that the folding paths of large RNAs proceed through discrete intermediates but the nature of these intermediates is not known in most cases. Here, we describe our studies on the folding of the M1 RNA sub-unit of Escherichia coli RNase P. We performed kinetic footprinting studies of M1 RNA folding with the chemical footprinting reagent peroxynitrous acid to provide a detailed description of the folding pathway of RNase P RNA. Our results indicate that, in contrast to the Group I ribozyme, the M1 RNA folds into its catalytically active structure through the formation of two separately folded domains and that the folding of each proceeds through a discrete series of intermediates. Similar rates of folding were observed for regions believed to form the interface between the two domains. This observation is consistent with a kinetic trap which occurs by interaction of the domains during folding.

Binding Sites↗
PubMed2000

Rit, a non-lipid-modified Ras-related protein, transforms NIH3T3 cells without activating the ERK, JNK, p38 MAPK or PI3K/Akt pathways.

The biological functions of Rit (Ras-like protein in tissues) and Rin (Ras-like protein in neurons), members of a novel branch of Ras-related GTP-binding proteins that are approximately 50% identical to Ras, have not been characterized. Therefore, we assessed their activity in growth control, transformation and signaling. NIH cells stably expressing a constitutively activated mutant of Rit [Rit(79L)] (analogous to the oncogenic mutant H-Ras(61L)) demonstrated strong growth transformation, proliferating rapidly in low serum and forming colonies in soft agar and tumors in nude mice. Although Rit(79L) alone did not promote morphologically transformed foci, it cooperated with both Raf and Rho A to form Rac/Rho-like foci. Rin [Rin(78L)] cooperated only with Raf. Rit(79L) but not Rin(78L) stimulated transcription from luciferase reporter constructs regulated by SRF, NF-kappaB, Elk-1 and Jun. However, neither activated ERK, JNK or p38, or PI3-K/Akt kinases in immune complex kinase assays. Interestingly, although Rit lacks any known recognition signal for C-terminal lipidation, Rit-transformed cell growth and survival in low serum is dependent on a farnesylated protein, as treatment with farnesyltransferase inhibitors caused apoptosis. Rin cooperated with Raf in focus assays but did not otherwise function in these assays, perhaps due to a lack of appropriate effector pathways in NIH3T3 fibroblasts for this neural-specific Ras family member. In summary, although Rit shares most core effector domain residues with Ras, our results suggest that Rit uses novel effector pathways to regulate proliferation and transformation.

3T3 Cells↗
PubMed2003

Interaction of filamin A with the insulin receptor alters insulin-dependent activation of the mitogen-activated protein kinase pathway.

The biological actions of insulin are associated with a rapid reorganization of the actin cytoskeleton within cells in culture. Even though this event requires the participation of actin-binding proteins, the effect of filamin A (FLNa) on insulin-mediated signaling events is still unknown. We report here that human melanoma M2 cells lacking FLNa expression exhibited normal insulin receptor (IR) signaling, whereas FLNa-expressing A7 cells were unable to elicit insulin-dependent Shc tyrosine phosphorylation and p42/44 MAPK activation despite no significant defect in IR-stimulated phosphorylation of insulin receptor substrate-1 or activation of the phosphatidylinositol 3-kinase/AKT cascade. Insulin-dependent translocation of Shc, SOS1, and MAPK to lipid raft microdomains was markedly attenuated by FLNa expression. Coimmunoprecipitation experiments and in vitro binding assays demonstrated that FLNa binds constitutively to IR and that neither insulin nor depolymerization of actin by cytochalasin D affected this interaction. The colocalization of endogenous FLNa with IR was detected at the surface of HepG2 cells. Ectopic expression of a C-terminal fragment of FLNa (FLNaCT) in HepG2 cells blocked the endogenous IR-FLNa interaction and potentiated insulin-stimulated MAPK phosphorylation and transactivation of Elk-1 compared with vector-transfected cells. Expression of FLNaCT had no major effect on insulin-induced phosphorylation of the IR, insulin receptor substrate-1, or AKT, but it elicited changes in actin cytoskeletal structure and ruffle formation in HepG2 cells. Taken together, these results indicate that FLNa interacts constitutively with the IR to exert an inhibitory tone along the MAPK activation pathway.

Base Sequence↗
PubMed2005

A coherent framework for multiresolution analysis of biological networks with "memory": Ras pathway, cell cycle, and immune system.

Various biological processes exhibit characteristics that vary dramatically in response to different input conditions or changes in the history of the process itself. One of the examples studied here, the Ras-PKC-mitogen-activated protein kinase (MAPK) bistable pathway, follows two distinct dynamics (modes) depending on duration and strength of EGF stimulus. Similar examples are found in the behavior of the cell cycle and the immune system. A classification methodology, based on time-frequency analysis, was developed and tested on these systems to understand global behavior of biological processes. Contrary to most traditionally used statistical and spectral methods, our approach captures complex functional relations between parts of the systems in a simple way. The resulting algorithms are capable of analyzing and classifying sets of time-series data obtained from in vivo or in vitro experiments, or in silico simulation of biological processes. The method was found to be considerably stable under stochastic noise perturbation and, therefore, suitable for the analysis of real experimental data.

Algorithms↗
PubMed2000

Analysis of gene expression data with pathway scores.

We present a new approach for the evaluation of gene expression data. The basic idea is to generate biologically possible pathways and to score them with respect to gene expression measurements. We suggest sample scoring functions for different problem specifications. We assess the significance of the scores for the investigated pathways by comparison to a number of scores for random pathways. We show that simple scoring functions can assign statistically significant scores to biologically relevant pathways. This suggests that the combination of appropriate scoring functions with the systematic generation of pathways can be used in order to select the most interesting pathways based on gene expression measurements.

Animals↗
PubMed2006

Deviant effects in molecular reaction pathways.

In biological networks, any manifestations of behaviors substantially 'deviant' from the predictions of continuous-deterministic classical chemical kinetics (CCK) are typically ascribed to systems with complex dynamics and/or a small number of molecules. Here we show that in certain cases such restrictions are not obligatory for CCK to be largely incorrect. By systematically identifying properties that may cause significant divergences between CCK and the more accurate discrete-stochastic chemical master equation (CME) system descriptions, we comprehensively characterize potential CCK failure patterns in biological settings, including consequences of the assertion that CCK is closer to the 'mode' rather than the 'average' of stochastic reaction dynamics, as generally perceived. We demonstrate that mechanisms underlying such nonclassical effects can be very simple, are common in cellular networks and result in often unintuitive system behaviors. This highlights the importance of deviant effects in biotechnologically or biomedically relevant applications, and suggests some approaches to diagnosing them in situ.

Biotechnology↗
PubMed2000

Genetic dissection of c-myc apoptotic pathways.

All biological functions mediated by the c-myc oncoprotein require an intact transactivation domain (TAD). We compared TAD mutants for their ability to promote apoptosis of 32D myeloid cells in response to interleukin-3 (IL-3) deprivation and exposure to chemotherapeutic drugs, and to activate ornithine decarboxylase, an endogenous c-myc target. Different sub-regions of the TAD were required to mediate each function. cDNA microarrays were then used to identify multiple c-myc-regulated transcripts, some of which were also modulated by IL-3 or cytotoxic drugs, as well as by specific sub-regions of the TAD. Several of the c-myc-regulated transcripts had also been previously identified as targets for IFN-gamma. The functional consequences of their deregulation were manifested by a marked sensitivity of c-myc-overexpressing cells to IFN-gamma-mediated apoptosis. Our results establish that several well-characterized functions of c-myc are separable and correlate with the expression of a novel group of target genes, some of which also mediate the apoptotic action of IFN-gamma.

Animals↗
PubMed2003

Steroid hormone interactions with target cells: cross talk between membrane and nuclear pathways.

The biological effects of steroid hormones are mediated by receptors associated with the plasma membrane as well as located inside of target cells. This perspective focuses on recent advances in our understanding of the integration that occurs between membrane-associated rapid signaling events and various changes in gene transcription that modulate the function and phenotype of steroid-responsive cells. Three frequently studied members of the steroid hormone receptor superfamily, the estrogen receptors, the thyroid hormone receptors, and the vitamin D receptors, are included to illustrate the emerging concepts. Each of these hormones has been conclusively shown to function at multiple subcellular sites leading to a continuum of signals intimately linked by intracellular cross talk. Understanding the molecular mechanisms by which these steroid hormones and their receptors transduce cellular signals will allow us to create new pharmacologic therapies aimed at treatment of a variety of human diseases affecting the cardiovascular system, the reproductive system, the skeletal system, the nervous system, the mammary gland, and many others.

Animals↗
PubMed1999

CD30 overexpression enhances negative selection in the thymus and mediates programmed cell death via a Bcl-2-sensitive pathway.

The biological function of CD30 in the thymus has been only partially elucidated, although recent data indicate that it may be involved in negative selection. Because CD30 is expressed only by a small subpopulation of medullary thymocytes, we generated transgenic (Tg) mice overexpressing CD30 in T lymphocytes to further address its role in T cell development. CD30 Tg mice have normal thymic size with a normal number and subset distribution of thymocytes. In vitro, in the absence of CD30 ligation, thymocytes of CD30 Tg mice have normal survival and responses to apoptotic stimuli such as radiation, dexamethasone, and Fas. However, in contrast to controls, CD30 Tg thymocytes are induced to undergo programmed cell death (PCD) upon cross-linking of CD30, and the simultaneous engagement of TCR and CD30 results in a synergistic increase in thymic PCD. CD30-mediated PCD requires caspase 1 and caspase 3, is not associated with the activation of NF-kappaB or c-Jun, but is totally prevented by Bcl-2. Furthermore, CD30 overexpression enhances the deletion of CD4+/CD8+ thymocytes induced by staphylococcal enterotoxin B superantigen and specific peptide. These findings suggest that CD30 may act as a costimulatory molecule in thymic negative selection.

Amino Acid Sequence↗
PubMed2004

Mapping critical biological motifs and biosynthetic pathways of heparan sulfate.

Heparan sulfate (HS) interacts with numerous proteins at the cell surface and orchestrates myriad biological events. Unraveling the mechanisms of these events at the molecular level calls for the structural analysis of these negatively charged and highly heterogeneous biopolymers. However, HS is often available only in small quantities, and the task of structural analysis necessitates the use of ultra-sensitive methods, such as mass spectrometry. Sequence heterogeneity within HS chains required us to identify critical functional groups and their spacing to determine structure-function relationships for HS. We carried out structural analysis of HS isolated from wild type, 3-OST-1, 3-OST-3A, or 3-OST-5 sulfotransferase-transduced Chinese hamster ovary cells and also from various tissues. In the context of tissue-specific HS, the data allowed us to map the biosynthetic pathways responsible for the placement of critical groups. As a means of determining the distance between critical groups within a motif, we determined the spacing of the rare GlcNAc-GlcA disaccharide sequence in the completely desulfated re-N-sulfated porcine intestinal heparin. These disaccharides are biosynthetic regulatory markers for 3-OST-1 modification and the partial structure of the antithrombin III binding site. They occur only at the distance of hexasaccharide, octasaccharide, decasaccharide, or dodecasaccharide. Thus this approach allowed us to map both the biosynthetic pathways for generating critical functional groups and their spacing within HS. Our new strategy removes two obstacles to rapid progress in this field of research.

Animals↗
PubMed2006

The alternative NF-kappaB pathway from biochemistry to biology: pitfalls and promises for future drug development.

The past two decades have led to a tremendous work on the transcription factor NF-kappaB and its molecular mechanisms of activation. The nuclear translocation of NF-kappaB is controlled by two main pathways: the classical and the alternative NF-kappaB pathways. The classical NF-kappaB pathway activates the IKK complex that controls the inducible degradation of most IkappaB family members that are IkappaBalpha, IkappaBbeta, IkappaBvarepsilon and p105. The alternative NF-kappaB pathway induces p100 processing and p52 generation through the activation of at least two kinases, which are NIK and IKKalpha. Genetic studies have shown that IKKgamma is dispensable for the alternative pathway, which suggests the existence of an alternative IKKalpha-containing complex. It is noteworthy that activation of particular p52 heterodimers like p52/RelB requires solely the alternative pathway while activation of p52/p65 or p52/c-Rel involves a "hybrid pathway". Among others, LTbetaR, BAFF-R, CD40 and RANK have the ability to induce the alternative pathway. The latter plays some roles in biological functions controlled by these receptors, which are the development of secondary lymphoid organs, the proliferation, survival and maturation of B cell, and the osteoclastogenesis. Exacerbated activation of the alternative pathway is potentially associated to a wide range of disorders like rheumatoid arthritis, ulcerative colitis or B cell lymphomas. Therefore, inhibitors of the alternative pathway could be valuable tools for the treatment of inflammatory disorders and cancers.

Animals↗
PubMed1995

Plasminogen activation by human keratinocytes: molecular pathways and cell-biological consequences.

Keratinocytes are the major cellular constituent of stratified epithelia. Defects in these epithelia are re-epithelialized by keratinocytes migrating from the edge of the defect into the wound. The cells form a monolayer with subsequent differentiation into a multilayered epithelium. It is thought that plasminogen activation by migrating keratinocytes is an important event during re-epithelialization. In the present report we summarize the studies on plasminogen activation by human keratinocytes in vitro and in vivo. Under the aspect of pericellular proteolysis the discussion is focused on the molecular mechanisms of plasminogen activation at the keratinocyte surface and on the cell-biological consequences of pericellular plasmin formation. We describe a cell surface-associated pathway of plasminogen activation which crucially depends on cell surface receptors for (pro)-uPA and plasmin(ogen). uPA bound to its receptor converts cell-bound plasminogen into the active protease plasmin. Compared to plasminogen activation in solution, activation at the keratinocyte cell surface is accelerated by a factor of approx. 7-10, and the plasmin generated and bound at the cell surface is protected against its specific inhibitor alpha 2-antiplasmin. Plasmin thus provided in the pericellular space leads to detachment of cultured keratinocytes from the growth substratum. Plasmin interferes with the adhesion of keratinocytes to fibrin, but not with the adhesion to collagen type I. By demonstrating that keratinocytes of the epithelial outgrowth in healing skin wounds express uPA and the uPA-R and that plasmin(ogen) is colocalized with uPA and/or uPA-R, indirect evidence is provided that this pathway may be operative in vivo. In view of previous findings that plasminogen activation is also observed under certain pathologic conditions in the epidermis, we conclude that plasminogen activation by keratinocytes is rather related to tissue damage and subsequent repair mechanisms than to a specific pathologic situation.

Fibrinolysin↗
PubMed2006

A case study in pathway knowledgebase verification.

BACKGROUND: Biological databases and pathway knowledge-bases are proliferating rapidly. We are developing software tools for computer-aided hypothesis design and evaluation, and we would like our tools to take advantage of the information stored in these repositories. But before we can reliably use a pathway knowledge-base as a data source, we need to proofread it to ensure that it can fully support computer-aided information integration and inference. RESULTS: We design a series of logical tests to detect potential problems we might encounter using a particular knowledge-base, the Reactome database, with a particular computer-aided hypothesis evaluation tool, HyBrow. We develop an explicit formal language from the language implicit in the Reactome data format and specify a logic to evaluate models expressed using this language. We use the formalism of finite model theory in this work. We then use this logic to formulate tests for desirable properties (such as completeness, consistency, and well-formedness) for pathways stored in Reactome. We apply these tests to the publicly available Reactome releases (releases 10 through 14) and compare the results, which highlight Reactome's steady improvement in terms of decreasing inconsistencies. We also investigate and discuss Reactome's potential for supporting computer-aided inference tools. CONCLUSION: The case study described in this work demonstrates that it is possible to use our model theory based approach to identify problems one might encounter using a knowledge-base to support hypothesis evaluation tools. The methodology we use is general and is in no way restricted to the specific knowledge-base employed in this case study. Future application of this methodology will enable us to compare pathway resources with respect to the generic properties such resources will need to possess if they are to support automated reasoning.

Algorithms↗
PubMed2001

Structural biology of the alternative pathway convertase.

Complement convertases are bimolecular complexes expressing protease activity only against C3 and C5. Their action is necessary for production of the biological activities of the complement system. Formation of these complexes proceeds through sequential protein-protein interactions and proteolytic cleavages of high specificity. Recent structural, mutational and functional data on factors D and B have significantly enhanced our understanding of the assembly, action, and regulation of the alternative pathway convertase. These processes were shown to depend critically on conformational changes, only some of which are reversible. The need for such changes is dictated by the zymogen-like configurations of the active centers of these unique serine proteases. The structural determinants of some of these changes have been defined from structural and mutational analyses of the two enzymes. Transition of factor D from the zymogen-like to the catalytically active conformation is completely reversible, while the active conformation of the catalytic center of the Bb fragment of factor B is irreversibly attenuated to a great extent on dissociation of the convertase complex. Both mechanisms contribute to the regulation of the proteolytic activity of these enzymes. Additional studies are necessary for a complete description of the elegant mechanisms mediating these processes.

Animals↗
PubMed2026

Shared genetic architecture and therapeutic targets across paediatric immune-mediated diseases.

OBJECTIVES: Paediatric-onset immune-mediated inflammatory diseases (IMIDs), including juvenile idiopathic arthritis and related rheumatic diseases, remain genetically undercharacterised. We aimed to define shared and category-specific genetic architecture across paediatric IMIDs, compare signals with adult IMIDs, and identify therapeutic opportunities. METHODS: We analysed 24 paediatric IMIDs classified as autoimmune, polygenic-autoinflammatory, mixed-pattern, or allergic. Genome-wide association analyses included 18,086 cases and 131,019 controls of European ancestry. We estimated single nucleotide polymorphism (SNP)-based heritability, genetic correlations, and polygenic overlap; performed subset-based meta-analysis; and conducted functional annotation, gene prioritisation, pathway and protein network analyses, adult-IMID comparison, and drug-target prioritisation. RESULTS: SNP-based heritability ranged from 28.9% for allergic IMIDs to 61.9% for autoimmune IMIDs. Genetic correlation and polygenic modelling supported partial sharing across categories with category-specific components. Meta-analysis identified 39 genome-wide significant loci outside the Major Histocompatibility Complex (MHC) region, including 15 previously unreported loci; 19 loci were shared between categories. Gene-prioritisation and protein interaction analyses identified a core MHC-centred antigen-presentation network, with category-enriched modules involving complement, innate/barrier pathways, epithelial biology, and type 2 immunity. Enriched pathways included nuclear factor κB signalling, T helper 17 related pathways, Janus kinase-signal transducer and activator of transcription signalling, programmed cell death protein 1/programmed death‑ligand 1, cytotoxic T‑lymphocyte associated protein 4 regulation, and osteoclast differentiation, several of which are relevant to rheumatic diseases. Paediatric IMIDs shared broad polygenic architecture with adult IMIDs, whereas top-ranked genes converged strongly with adult rheumatic diseases. Priority Index analysis identified 178 high-scoring genes, including 43 approved or investigational IMID drug targets. CONCLUSIONS: Paediatric-onset IMIDs share core pathways with adult forms but exhibit distinct genetic architecture shaped by age-specific immune and neurodevelopmental biology. These findings provide a genomic framework for paediatric precision medicine, guiding classification, risk prediction, and therapeutic development.

Humans↗