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Results for “Candidate pathways”

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PubMed1998

Subtleties in control by metabolic channelling and enzyme organization.

Because of its importance to cell function, the free-energy metabolism of the living cell is subtly and homeostatically controlled. Metabolic control analysis enables a quantitative determination of what controls the relevant fluxes. However, the original metabolic control analysis was developed for idealized metabolic systems, which were assumed to lack enzyme-enzyme association and direct metabolite transfer between enzymes (channelling). We here review the recently developed molecular control analysis, which makes it possible to study non-ideal (channelled, organized) systems quantitatively in terms of what controls the fluxes, concentrations, and transit times. We show that in real, non-ideal pathways, the central control laws, such as the summation theorem for flux control, are richer than in ideal systems: the sum of the control of the enzymes participating in a non-ideal pathway may well exceed one (the number expected in the ideal pathways), but may also drop to values below one. Precise expressions indicate how total control is determined by non-ideal phenomena such as ternary complex formation (two enzymes, one metabolite), and enzyme sequestration. The bacterial phosphotransferase system (PTS), which catalyses the uptake and concomitant phosphorylation of glucose (and also regulates catabolite repression) is analyzed as an experimental example of a non-ideal pathway. Here, the phosphoryl group is channelled between enzymes, which could increase the sum of the enzyme control coefficients to two, whereas the formation of ternary complexes could decrease the sum of the enzyme control coefficients to below one. Experimental studies have recently confirmed this identification, as well as theoretically predicted values for the total control. Macromolecular crowding was shown to be a major candidate for the factor that modulates the non-ideal behaviour of the PTS pathway and the sum of the enzyme control coefficients.

Energy Metabolism↗

PubMed1991

Indication for invasive diagnostic studies and surgical therapy in cerebral ischemia, based on results of non-invasive transcranial Doppler sonography.

In order to better define patients who might benefit from cerebral revascularization surgery, transcranial Doppler sonography was used in more than 480 patients. Thus invasive diagnostic studies could be limited to probable surgical candidates. Transcranial Doppler sonography has proven to be reliable for the study of the degree of efficacy of intracranial collateral pathways in hemodynamic borderline situations. Over the last 4 years, the application of the algorithm presented in this paper resulted in a reduction of the number of candidates for surgical revascularization to 19.

Algorithms↗

PubMed2001

Complement components as uremic toxins and their potential role as mediators of microinflammation.

Cardiovascular disease is the major cause of death in end-stage renal disease (ESRD) patients. There is growing evidence that atherogenesis is an inflammatory rather than a purely degenerative process leading to a state of microinflammation. This raises the issue of whether treatment modalities of ESRD contribute to the microinflammatory state. One potential candidate in this context is the complement system. Here we consider three potential pathways linking complement activation to progression of atherosclerosis: (1) complement activation on artificial surfaces depends on their physicochemical characteristics, the effect of which is amplified because of the accumulation of complement factor D; (2) the exposure of ESRD patients to endotoxin creates a microinflammatory state, and this may amplify complement-induced damage; exposure to endotoxin may result from frequent infections because of the impairment of host-defense mechanisms or from transfer of bacterial contaminants across dialysis membranes into the blood stream; and (3) direct transduction of proinflammatory signals from blood-material interactions to the vascular system. We conclude that the complement system is an important candidate system in the genesis of microinflammation and accelerated atherogenesis in ESRD. We advance the hypothesis that the generation of proinflammatory signals, in which the complement system appears to be involved--both through systemic and local activation--plays a role in the development of late complications of uremia, including coronary heart disease. This hypothesis provides a rationale to maximize the biocompatibility of the dialysis procedure, that is, selection of nonactivating materials, use of ultrapure dialysis fluid, and--still theoretical--high-flux dialysis to remove factor D.

Acute-Phase Reaction↗

PubMed2004

Virus-induced gene silencing in Solanum species.

Virus-induced gene silencing (VIGS) has been used routinely in Nicotiana benthamiana to assess functions of candidate genes and as a way to discover new genes required for diverse pathways, especially disease resistance signalling. VIGS has recently been shown to work in Arabidopsis thaliana and in tomato. Here, we report that VIGS using the tobacco rattle virus (TRV) viral vector can be used in several Solanum species, although the choice of vector and experimental conditions vary depending on the species under study. We have successfully silenced the phytoene desaturase (PDS) gene in the diploid wild species Solanum bulbocastanum and S. okadae, in the cultivated tetraploid S. tuberosum and in the distant hexaploid relative S. nigrum (commonly known as deadly nightshade). To test whether the system could be utilised as a rapid way to assess gene function of candidate resistance (R) genes in potato and its wild relatives, we silenced R1 and Rx in S. tuberosum and RB in S. bulbocastanum. Silencing of R1, Rx and RB successfully attenuated R-gene-mediated disease resistance and resulted in susceptible phenotypes in detached leaf assays. Thus, the VIGS system is an effective method of rapidly assessing gene function in potato.

Gene Silencing↗

PubMed2004

Cutting edge: CD28-mediated transcriptional and posttranscriptional regulation of IL-2 expression are controlled through different signaling pathways.

Despite the clear functional importance of CD28 costimulation, the signaling pathways transduced through CD28 have remained controversial. PI3K was identified early as a candidate for CD28 signaling, but conflicting data during the past decade has left the role of PI3K unresolved. In this report, we have resolved this controversy. We show that mutation of the PI3K interaction site in the cytosolic tail of CD28 site disrupts the ability of CD28 to recruit protein kinase C-theta; to the central supramolecular activation cluster (c-SMAC) region of the immunological synapse, promote NF-kappaB nuclear translocation, and enhance IL-2 gene transcription. In contrast, mutation of the PI3K interaction site had no effect on the ability of CD28 to enhance IL-2 mRNA stability. These results suggest that two distinct pathways mediate CD28-induced up-regulation of IL-2 expression, a PI3K-dependent pathway that may function through the immunological synapse to enhance IL-2 transcription and a PI3K-independent pathway that induces IL-2 mRNA stability.

Active Transport, Cell Nucleus↗

PubMed2006

Proton transfer in bacterial nitric oxide reductase.

The NOR (nitric oxide reductase) from Paracoccus denitrificans catalyses the two-electron reduction of NO to N(2)O (2NO+2H(+)+2e(-)-->N(2)O+H(2)O). The NOR is a divergent member of the superfamily of haem-copper oxidases, oxygen-reducing enzymes which couple the reduction of oxygen with translocation of protons across the membrane. In contrast, reduction of NO catalysed by NOR is non-electrogenic which, since electrons are supplied from the periplasmic side of the membrane, implies that the protons needed for NO reduction are also taken from the periplasm. Thus NOR must contain a proton-transfer pathway leading from the periplasmic side of the membrane into the catalytic site. The proton pathway has not been identified, and the mechanism and timing of proton transfer during NO reduction is unknown. To address these questions, we have studied the reaction between NOR and the chemically less reactive oxidant O(2). When fully reduced NOR reacts with O(2), proton-coupled electron transfer occurs in a reaction that is rate-limited by internal proton transfer from a group with a pK(a) of 6.6. This group is presumably an amino acid residue close to the active site that acts as a proton donor also during NO reduction. The results are discussed in the framework of a structural model that identifies possible candidates for the proton donor as well as for the proton-transfer pathway.

Bacterial Proteins↗

PubMed2006

Identification of the last unknown genes in the fermentation pathway of lysine.

Although the proteins of the lysine fermentation pathway were biochemically characterized more than thirty years ago, the genes encoding the proteins that catalyze three steps of this pathway are still unknown. We combined gene context, similarity of enzymatic mechanisms, and molecular weight comparisons with known proteins to select candidate genes for these three orphan proteins. We used a wastewater metagenomic collection of sequences to find and characterize the missing genes of the lysine fermentation pathway. After recombinant protein production and purification following cloning in Escherichia coli, we demonstrated that these genes (named kdd, kce, and kal) encode a l-erythro-3,5-diaminohexanoate dehydrogenase, a 3-keto-5-aminohexanoate cleavage enzyme, and a 3-aminobutyryl-CoA ammonia lyase, respectively. Because all of the genes of the pathway are now identified, we used this breakthrough to detect lysine-fermenting bacteria in sequenced genomes. We identified twelve bacteria that possess these genes and thus are expected to ferment lysine, and their gene organization is discussed.

Amino Acid Oxidoreductases↗

PubMed1998

Roles of chemical mediators in the taste system.

Recent advances in neural mechanisms of taste are reviewed with special reference to neuroactive substances. In the first section, taste transduction mechanisms of basic tastes are explained in two groups, whether taste stimuli directly activate ion channels in the taste cell membrane or they bind to cell surface receptors coupled to intracellular signaling pathways. In the second section, putative transmitters and modulators from taste cells to afferent nerves are summarized. The candidates include acetylcholine, catecholamines, serotonin, amino acids and peptides. Studies favor serotonin as a possible neuromodulator in the taste bud. In the third section, the role of neuroactive substances in the central gustatory pathways is introduced. Excitatory and inhibitory amino acids (e.g., glutamate and GABA) and peptides (substance P and calcitonin gene-related peptide) are proved to play roles in transmission of taste information in both the brainstem relay and cortical gustatory area. In the fourth section, conditioned taste aversion is introduced as a model to study gustatory learning and memory. Pharmacobehavioral studies to examine the effects of glutamate receptor antagonists and protein kinase C inhibitors on the formation of conditioned taste aversion show that both glutamate and protein kinase C in the amygdala and cortical gustatory area play essential roles in taste aversion learning. Recent molecular and genetic approaches to disclose biological mechanisms of gustatory learning are also introduced. In the last section, behavioral and pharmacological approaches to elucidate palatability, taste pleasure, are described. Dopamine, benzodiazepine derivatives and opioid substances may play some roles in evaluation of palatability and motivation to ingest palatable edibles.

Animals↗

PubMed2006

Cell death pathways differ in several mouse models with motoneurone disease: analysis of pure motoneurone populations at a presymptomatic age.

To identify candidate genes that are responsible for motoneurone degeneration, we combined laser capture microdissection with microarray technology. We analysed gene expression in pure motoneurones from two mouse mutants that develop motoneurone degeneration, progressive motor neuronopathy and wobbler. At a presymptomatic age, there was a significant differential expression of a restricted number of genes (25 and 72 in progressive motor neuronopathy and wobbler respectively, of 22 600 transcripts screened). We compared these results to our previous analyses in the copper-zinc superoxide dismutase mutant mouse (SOD1(G93A)) in which we observed a de-regulation of 27 genes. Some of these genes were de-regulated uniquely in one mouse mutant and some have already been identified in cell death pathways implicated in amyotrophic lateral sclerosis and animal models of motoneurone degeneration (i.e. de-regulation of intermediate filaments, axonal transport, the ubiquitin-proteasome system and excitotoxicity). One gene, vimentin, was differentially up-regulated in all mouse mutants; this main candidate gene has been confirmed by in situ hybridization and immunohistochemistry to be expressed in motoneurones in all mouse mutants. Furthermore, vimentin expression correlated with the state of motoneurone degeneration. These results identify early molecular changes that may be involved in the pathogenesis of motoneurones leading to cell death and favour a complex multipathway induction of the disease; surprisingly, there was no important modification in cell death-associated genes. This is the first study to show a clear difference in the genes that are de-regulated at an early stage in three different mouse models of motoneurone disease.

Animals↗

PubMed2026

Lymphangiogenesis-related gene signature-based risk model for prognostic assessment of cervical cancer: immune-metabolic characterization and molecular subtype analysis.

BACKGROUND: Lymphangiogenesis promotes tumor dissemination and may shape the immune contexture of cervical cancer, yet lymphangiogenesis-related prognostic stratification and its immunometabolic implications remain insufficiently defined in cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC). METHODS: TCGA-CESC transcriptomes and clinical data were obtained from UCSC Xena and integrated with normal cervix tissues from the Genotype-Tissue Expression Project after batch correction. Prognostic LYMRGs were first identified from the differentially expressed set using univariable Cox proportional hazards analysis. Candidate genes were then reduced using an L1-regularized Cox model (Least Absolute Shrinkage and Selection Operator), and the remaining markers were entered into a multivariable Cox regression to obtain the final coefficients and compute an individualized risk score. The model's prognostic value was further assessed in an independent Gene Expression Omnibus dataset. In addition, expression patterns of the signature genes were leveraged for molecular subtyping of TCGA samples via non-negative matrix factorization (NMF). Immune infiltration and immunotherapy-associated characteristics were interrogated through a multi-algorithm strategy (single-sample gene set enrichment analysis, CIBERSORT, ESTIMATE, Tumor Immune Dysfunction and Exclusion (TIDE), and Immunophenoscore . Additional analyses included pathway enrichment (GSEA/GO/KEGG), drug sensitivity prediction (pRRophetic/CellMiner), and ceRNA network analysis. RESULTS: A six-gene LYMRG signature robustly stratified survival. High-risk patients had significantly worse overall survival in The Cancer Genome Atlas with AUCs of 0.819/0.801/0.801 at 1/3/5 years, and in GSE52903 (P = 0.001) with AUCs of 0.733/0.719/0.725. NMF identified two subtypes with distinct prognosis (P = 0.01) and divergent immune landscapes. Risk groups and subtypes exhibited consistent differences in immune infiltration, checkpoint expression, TIDE/IPS patterns, and pathway enrichment. Predicted chemosensitivity differed by risk group, and the ceRNA network suggested candidate upstream lncRNA regulators of the signature. CONCLUSION: A lymphangiogenesis-related six-gene model enables clinically meaningful prognostic stratification of CESC and links lymphangiogenesis programs to distinct tumor immune phenotypes and therapeutic vulnerabilities.

cancer↗

PubMed2005

Identification and characterization of regions of the rice genome associated with broad-spectrum, quantitative disease resistance.

Much research has been devoted to understanding the biology of plant-pathogen interactions. The extensive genetic analysis of disease resistance in rice, coupled with the sequenced genome and genomic resources, provides the opportunity to seek convergent evidence implicating specific chromosomal segments and genes in the control of resistance. Published data on quantitative and qualitative disease resistance in rice were synthesized to evaluate the distributions of and associations among resistance loci. Quantitative trait loci (QTL) for resistance to multiple diseases and qualitative resistance loci (R genes) were clustered in the rice genome. R genes and their analogs of the nucleotide binding site-leucine-rich repeat class and genes identified on the basis of differential representation in disease-related EST libraries were significantly associated with QTL. Chromosomal segments associated with broad-spectrum quantitative disease resistance (BS-QDR) were identified. These segments contained numerous positional candidate genes identified on the basis of a range of criteria, and groups of genes belonging to two defense-associated biochemical pathways were found to underlie one BS-QDR region. Genetic dissection of disease QTL confidence intervals is needed to reduce the number of positional candidate genes for further functional analysis. This study provides a framework for future investigations of disease resistance in rice and related crop species.

Blotting, Northern↗

PubMed1991

Integrated genetic databases in the study of neuropsychiatric diseases: inborn errors of cerebral metabolic pathways?

1. Genetic databases are an expanding and readily accessible repository of information on the mapping and sequencing of the human genome, and that of other model organisms. The integration and application of this information to neuropsychiatric disease is illustrated using neuroendocrine and neuropharmacologic data, computerized and other genetic databases. 2. This computer-assisted integrated approach to knowledge structures permits the rapid generation of hypotheses, the prompt identification of candidate gene loci, an explanation for genetic heterogeneity, and strategies for the use of potential linked markers. 3. Results using this integrated search strategy demonstrate that over 30 candidate loci for neuropsychiatric disease have currently been mapped in man (spread over 14 chromosomes in the human genome), and that at least 6 homologous loci have been mapped in mouse. 4. Using a metabolic pathway approach, it can be shown that the best current candidate gene locus for a subtype of schizophrenia located on chromosome 5q11-13 (HGML10 # SCZD1 and OMIM #181510) is in the serotonergic pathway, i.e. a receptor for 5-hydroxytryptamine (subtype 1A; HGML10 #HTR1A) which also maps in the same chromosomal region. 5. Parallels are suggested between inborn errors of metabolic pathways in the somatic endocrine system (using insulin-dependent diabetes mellitus as a paradigm) and the neurotransmitter and hormonal systems within the brain. 6. A subset of neuropsychiatric disorders may thus be viewed as inborn errors of cerebral metabolic pathways primarily affecting the biogenic amine pathways.

Animals↗

PubMed2006

The meningococcal vaccine candidate GNA1870 binds the complement regulatory protein factor H and enhances serum resistance.

Neisseria meningitidis binds factor H (fH), a key regulator of the alternative complement pathway. A approximately 29 kD fH-binding protein expressed in the meningococcal outer membrane was identified by mass spectrometry as GNA1870, a lipoprotein currently under evaluation as a broad-spectrum meningococcal vaccine candidate. GNA1870 was confirmed as the fH ligand on intact bacteria by 1) abrogation of fH binding upon deleting GNA1870, and 2) blocking fH binding by anti-GNA1870 mAbs. fH bound to whole bacteria and purified rGNA1870 representing each of the three variant GNA1870 families. We showed that the amount of fH binding correlated with the level of bacterial GNA1870 expression. High levels of variant 1 GNA1870 expression (either by allelic replacement of gna1870 or by plasmid-driven high-level expression) in strains that otherwise were low-level GNA1870 expressers (and bound low amounts of fH by flow cytometry) restored high levels of fH binding. Diminished fH binding to the GNA1870 deletion mutants was accompanied by enhanced C3 binding and increased killing of the mutants. Conversely, high levels of GNA1870 expression and fH binding enhanced serum resistance. Our findings support the hypothesis that inhibiting the binding of a complement down-regulator protein to the neisserial surface by specific Ab may enhance intrinsic bactericidal activity of the Ab, resulting in two distinct mechanisms of Ab-mediated vaccine efficacy. These data provide further support for inclusion of this molecule in a meningococcal vaccine. To reflect the critical function of this molecule, we suggest calling it fH-binding protein.

Adjuvants, Immunologic↗

PubMed2006

Entamoeba histolytica: computational identification of putative microRNA candidates.

MicroRNAs are an abundant class of approximately 20-24-nucleotide noncoding RNAs that control the expression of several genes at the post-transcriptional level, regulating several important biochemical pathways. MicroRNAs have been identified in many vertebrates including humans, and also in flies, nematodes, plants, and viruses. In the present work we have identified seventeen putative candidate microRNAs in the pathogenic parasite Entamoeba histolytica using a bioinformatic approach. Putative microRNA identification in E. histolytica may act as a starting reference for cloning and characterization of miRNAs in Entamoeba genome.

Animals↗

PubMed2005

Discovery of aberrant expression of R-RAS by cancer-linked DNA hypomethylation in gastric cancer using microarrays.

Although hypomethylation was the originally identified epigenetic change in cancer, it was overlooked for many years in preference to hypermethylation. Recently, gene activation by cancer-linked hypomethylation has been rediscovered. However, in gastric cancer, genome-wide screening of the activated genes has not been found. By using microarrays, we identified 1,383 gene candidates reactivated in at least one cell line of eight gastric cancer cell lines after treatment with 5-aza-2'deoxycytidine and trichostatin A. Of the 1,383 genes, 159 genes, including oncogenes ELK1, FRAT2, R-RAS, RHOB, and RHO6, were further selected as gene candidates that are silenced by DNA methylation in normal stomach mucosa but are activated by DNA demethylation in a subset of gastric cancers. Next, we showed that demethylation of specific CpG sites within the first intron of R-RAS causes activation in more than half of gastric cancers. Introduction of siRNA into R-RAS-expressing cells resulted in the disappearance of the adhered cells, suggesting that functional blocking of the R-RAS-signaling pathway has great potential for gastric cancer therapy. Our extensive gene list provides other candidates for this class of oncogene.

Azacitidine↗

PubMed2005

Contribution of acetaminophen-cysteine to acetaminophen nephrotoxicity in CD-1 mice: I. Enhancement of acetaminophen nephrotoxicity by acetaminophen-cysteine.

Acetaminophen (APAP) nephrotoxicity has been observed both in humans and research animals. Recent studies suggest a contributory role for glutathione (GSH)-derived conjugates of APAP in the development of nephrotoxicity. Inhibitors of either gamma-glutamyl transpeptidase (gamma-GT) or the probenecid-sensitive organic anion transporter ameliorate APAP-induced nephrotoxicity but not hepatotoxicity in mice and inhibition of gamma-GT similarly protected rats from APAP nephrotoxicity. Protection against APAP nephrotoxicity by disruption of these GSH conjugate transport and metabolism pathways suggests that GSH conjugates are involved. APAP-induced renal injury may involve the acetaminophen-glutathione (APAP-GSH) conjugate or a metabolite derived from APAP-GSH. Acetaminophen-cysteine (APAP-CYS) is a likely candidate for involvement in APAP nephrotoxicity because it is both a product of the gamma-GT pathway and a probable substrate for the organic anion transporter. The present experiments demonstrated that APAP-CYS treatment alone depleted renal but not hepatic glutathione (GSH) in a dose-responsive manner. This depletion of renal GSH may predispose the kidney to APAP nephrotoxicity by diminishing GSH-mediated detoxification mechanisms. Indeed, pretreatment of male CD-1 mice with APAP-CYS before challenge with a threshold toxic dose of APAP resulted in significant enhancement of APAP-induced nephrotoxicity. This was evidenced by histopathology and plasma blood urea nitrogen (BUN) levels at 24 h after APAP challenge. APAP alone was minimally nephrotoxic and APAP-CYS alone produced no detectable injury. By contrast, APAP-CYS pretreatment did not alter the liver injury induced by APAP challenge. These data are consistent with there being a selective, contributory role for APAP-GSH-derived metabolites in APAP-induced renal injury that may involve renal-selective GSH depletion.

Acetaminophen↗

PubMed2006

Links between biology, prognosis and prediction of response to chemotherapy in colorectal cancer.

Compared with the progress achieved in breast cancer, the use of prognostic and predictive parameters in colorectal cancer is lagging behind. One of the reasons is the limited information provided by 'classic' mutations as markers for response to therapy. To bridge this gap, prospective clinical trials need to be conducted to evaluate the usefulness of gene expression profiling and candidate markers, such as DNA repair proteins, onset of the methylator phenotype, neo-angiogenetic pathways related to inflammation, matrix metalloproteinases, tumor suppressors and cell signaling pathways (e.g. Akt). In parallel, the unrivalled sensitivity of molecular techniques may be applied to diagnostic parameters, such as cytokeratin 20 mRNA, for the detection of lymph node metastases. This article reviews the current knowledge on prognostic and predictive parameters in order to highlight the close link between tumor biology and tumor pharmacology. The increasing number of candidate markers together with recently introduced therapeutic options offer novel opportunities for a stepwise approach to the ambitious goal of individualized therapy in colorectal cancer.

Antineoplastic Agents↗

PubMed1997

More marked stimulation by lithium than insulin of the glycogenic pathway in rat skeletal muscle.

Lithium's impact on glucose metabolism was compared with that of insulin in isolated rat soleus muscle. Lithium chloride (20 mmol/l) induced a 4.8-fold more pronounced increment over basal glycogen synthase activity than insulin (10 nmol/l) (nmol UDP-glucose into glycogen in synthase activity assay.g-1.min-1: lithium, +22.1 +/- 1.8 vs. insulin, +4.6 +/- 3.9; P < 0.01). In parallel, lithium was less efficient than insulin in stimulating glucose transport (counts per minute 2-deoxy-D-[3H]glucose.mg-1.h-1: lithium, +211 +/- 19 vs. insulin, +311 +/- 57; P < 0.05) and lactate release (mumol.g-1.h-1: lithium, +1.0 +/- 0.5 vs. insulin, +3.9 +/- 0.5; P < 0.01), and similar increments were induced in glycogen synthesis (mumol glucose into glycogen.g-1.h-1: lithium, +3.32 +/- 0.43 vs. insulin, +3.46 +/- 0.47; not significant). Full additivity of glycogenic effects and divergent dependency on phosphatidylinositol 3-kinase activation provided further evidence for different mechanisms of action. In muscle from insulin-resistant obese Zucker rats (fa/fa), failure of lithium to reverse deficits in glucose metabolism suggested a primary deficit in muscle glucose uptake rather than glycogen synthesis. Hence lithium distinctly stimulates glycogen synthase activity in skeletal muscle and may therefore be regarded as a candidate for the treatment of disorders associated with primary deficits in the glycogenic pathway.

Androstadienes↗