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At least 703 records · Page 39Linked to original sources
PubMed1987

Neural specificity of acrylamide action upon enzymes associated with oxidative energy-producing pathways. I. Histochemical analysis of NADH-tetrazolium reductase activity.

The mechanism by which acrylamide (ACR) produces a distal neurofilamentous axonopathy has not been determined. Our investigations are focused upon the effects of this toxicant on energy transformations; more specifically, on enzymes of oxidative metabolism. The current study determines the effects of ACR on NADH-tetrazolium reductase (TR) activity (composite of primarily lipoamide and NADH dehydrogenases) in a variety of neural and non-neural tissues in order to test for a correlation between the neural specificity of enzyme inhibition with specific neurotoxicity. Quantitative histochemical assays demonstrate a significant inhibition of NADH-TR activity in ligated axons (-9.5%), Purkinje neurons (-17.3%) and dorsal root ganglion neurons (-17.8%) following a single ACR injection. Non-neural tissue enzymes were not significantly inhibited. A non-neurotoxic analogue, methylene-bis-ACR, had no effect upon these enzymes except in Purkinje neurons. The data supports, in general, the hypothesis that specific inhibition of neural NADH-TR activity by acrylamide is the primary site of action in producing the neuropathy. The neural specificity is attributed to lower levels of glutathione in neural tissues rather than specific inhibition of neural isoenzymes of NADH-TR.

Acrylamide↗
PubMed1983

Study of inhibitory effect of amygdaloid stimulation on auditory response of medial geniculate body (MGB) and analysis of transmissive pathway of the said effect.

Experiments performed on 103 rabbits immobilized with Flaxedil, and the recording of the electrical discharges of single MGB neuron caused by clicks, burst or sustained tone showed marked inhibition of the reaction of 47 out of 75 (62.7%) MGB units responding to sound stimuli, when the amygdaloid complex was stimulated. The latent period of such an inhibitory effect was 5-12 msec and its duration about 2-13 msec. Evoked responses with the latency of 1-2 msec for the stimulation of medial, central and lateral nuclei of amygdala could be recorded from the temporal and parietal cortex. The largest response was recorded from Woolsey's AI area of the temporal cortex. Stimulation of the Woolsey's AI auditory area could also result in a distinct inhibition of the spontaneous as well as the evoked discharges of MGB neurons in response to sound stimulation. Moreover, application of 1% procaine to the surface of auditory cortex could block the inhibitory effect of the amygdala on the MGB neurons. Based on the facts mentioned above, the authors have reason to believe that the inhibitory effect of the amygdaloid complex on the activity of MGB units might be transmitted via the amygdala-auditory cortex-MGB circuit. The biological significance of such an suppressive effect has been discussed.

Acoustic Stimulation↗
PubMed1995

RAW264 macrophages stably transfected with an HIV-1 LTR reporter gene provide a sensitive bioassay for analysis of signalling pathways in macrophages stimulated with lipopolysaccharide, TNF-alpha or taxol.

Bacterial lipopolysaccharide (LPS) modulates expression of a variety of genes in macrophages, and additionally activates viral promoters including the HIV-1 LTR. The HIV-1 LTR driving the luciferase reporter gene was stably transfected into the murine macrophage cell line, RAW264. In stably transfected cells, luciferase activity was LPS-dependent. As little as 0.01 ng/ml LPS was sufficient to increase luciferase activity over basal levels with maximal stimulation resulting in a 10- to 20-fold response. The cells also responded to human and murine tumour necrosis factor (TNF alpha). Endogenous TNF alpha was not involved in LPS responses, since pretreatment with alpha-TNF alpha antibody did not affect activation. Induction of HIV-1 LTR activity by LPS occurred independently of phorbol myristate acetate (PMA) sensitive protein kinase C (PKC), since depletion of PKC by prolonged exposure to PMA blocked TNF alpha and PMA responses but was not able to abolish LPS action on these cells. Taxol (5-20 micrograms/ml), a chemotherapeutic agent which mimics LPS action on macrophages, was also able to increase expression of the reporter gene driven by the HIV-1 LTR. However, lower doses of taxol that were not sufficient to trans-activate the LTR or to induce TNF alpha expression were cytotoxic to RAW264 cells suggesting that the cytotoxic and LPS-like activities of taxol were not linked. This cell line provides a convenient method for detecting LPS-like activity and is a useful tool for examining LPS and TNF alpha signalling pathways.

Animals↗
PubMed1994

A functional anatomical analysis of central pathways subserving the effects of interleukin-1 on stress-related neuroendocrine neurons.

Systemic administration of the cytokine interleukin-1 (IL-1) results in increased secretion of ACTH and corticosterone in rats. The available evidence suggests that the acute effects of IL-1 are exerted ultimately at the level of the hypothalamus to increase corticotropin-releasing factor (CRF) secretion into the hypophyseal portal circulation, and hence the central drive on the pituitary-adrenal system. However, the route(s) and mechanism(s) by which circulating IL-1 gains access to central mechanisms governing pituitary-adrenal output remain poorly understood. In this study, we show that intravenous injection of IL-1 beta provokes time- and dose-dependent increases in the expression of the immediate-early gene c-fos, in identified CRF and oxytocin-producing cells of the paraventricular nucleus of the hypothalamus (PVH). Several cell groups known to be involved in central visceromotor regulation also displayed comparable time- and dose-related activation to systemic IL-1, including the bed nucleus of the stria terminalis, the central nucleus of the amygdala, the lateral parabrachial nucleus, and cell groups of the dorsomedial and ventrolateral medulla. Activation of circumventricular organs, which have been hypothesized to serve as central monitors of circulating IL-1, required doses roughly an order of magnitude above those required to activate CRF neurons in the PVH. Combined immunohistochemical and retrograde tracing experiments revealed many IL-1-responsive cells in the nucleus of the solitary tract and the ventrolateral medulla to be catecholaminergic and to project to the region of the PVH. Discrete and unilateral interruption of ascending catecholaminergic projections from the medulla attenuated IL-1-stimulated increases in Fos immunoreactivity and CRF mRNA in the PVH on the ipsilateral side. Disruption of descending projections from circumventricular structures associated with the lamina terminalis did not affect IL-1-mediated Fos induction in the PVH. We conclude that medullary catecholaminergic projections to the PVH play either a mediating or a permissive role in the IL-1-induced activation of the central limb of the hypothalamo-pituitary-adrenal axis.

Animals↗
PubMed1993

Cell-permeable non-hydrolyzable cAMP derivatives as tools for analysis of signaling pathways controlling gene regulation in Dictyostelium.

A novel class of cAMP derivatives were tested for binding to surface cAMP receptors (CAR), protein kinase A (PKA), and cAMP-phosphodiesterase (PDE) and for induction of three classes of cAMP regulated genes in Dictyostelium discoideum. These derivatives carry sulfur substitutions for either the axial (Sp) or equatorial (Rp) exocyclic oxygen atoms, while further modifications were introduced to provide specificity for binding to either CAR or PKA, and/or to increase lipophilicity and render the derivatives membrane-permeable. All derivatives bind weakly to PDE and are almost not degraded during incubation with Dictyostelium cells. One cAMP derivative, 6-thioethyl-purineriboside 3',5'-monophosphorothioate, Sp-isomer (Sp-6SEtcPuMPS), fulfills the criteria for selective activation of PKA in vivo. The compound enters Dictyostelium cells and reaches an intracellular concentration of 1 microM, sufficient to activate PKA, at an extracellular concentration of 30 microM, which is insufficient to activate CAR. Expression of cAMP-regulated prespore and prestalk genes and the aggregative PDE gene are effectively induced by CAR agonists and very poorly by PKA agonists. Even Sp-6SEtcPuMPS is ineffective to induce gene expression. These data not only indicate that surface cAMP receptors are the first targets for cAMP-induced gene expression, but argue against direct induction of expression of these genes by cAMP-induced PKA activation.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1995

Flux analysis of microbial metabolic pathways using a visual programming environment.

This paper describes the use of a visual programming environment (LabVIEW) for the flux analysis of metabolic pathways. Representations of metabolic pathways are constructed in software from individual reaction elements (icons) which are linked together to indicate potential flux routes. Off-line bioprocess data are then used to supply the inputs and outputs to the metabolic pathway and the pathway fluxes are calculated. The metabolic system can be modelled at different levels of complexity and new pathways can be inserted into existing models. To illustrate this, flux analyses are performed on three Escherichia coli mutants with metabolic pathway deletions and insertions. The first analysis looks at organic acid production and the second at the effect of the presence in E. coli of an engineered pathway for toluene degradation.

Acetates↗
PubMed2006

Analysis of aromatic catabolic pathways in Pseudomonas putida KT 2440 using a combined proteomic approach: 2-DE/MS and cleavable isotope-coded affinity tag analysis.

Proteomic analysis of Pseudomonas putida KT2440 cultured in monocyclic aromatic compounds was performed using 2-DE/MS and cleavable isotope-coded affinity tag (ICAT) to determine whether proteins involved in aromatic compound degradation pathways were altered as predicted by genomic analysis (Jiménez et al., Environ Microbiol. 2002, 4, 824-841). Eighty unique proteins were identified by 2-DE/MS or MS/MS analysis from P. putida KT2440 cultured in the presence of six different organic compounds. Benzoate dioxygenase (BenA, BenD) and catechol 1,2-dioxygenase (CatA) were induced by benzoate. Protocatechuate 3,4-dixoygenase (PcaGH) was induced by p-hydroxybenzoate and vanilline. beta-Ketoadipyl CoA thiolase (PcaF) and 3-oxoadipate enol-lactone hydrolase (PcaD) were induced by benzoate, p-hydroxybenzoate and vanilline, suggesting that benzoate, p-hydroxybenzoate and vanilline were degraded by different dioxygenases and then converged in the same beta-ketoadipate degradation pathway. An additional 110 proteins, including 19 proteins from 2-DE analysis, were identified by cleavable ICAT analysis for benzoate-induced proteomes, which complemented the 2-DE results. Phenylethylamine exposure induced beta-ketoacyl CoA thiolase (PhaD) and ring-opening enzyme (PhaL), both enzymes of the phenylacetate (pha) biodegradation pathway. Phenylalanine induced 4-hydroxyphenyl-pyruvate dioxygenase (Hpd) and homogentisate 1,2-dioxygenase (HmgA), key enzymes in the homogentisate degradation pathway. Alkyl hydroperoxide reductase (AphC) was induced under all aromatic compounds conditions. These results suggest that proteome analysis complements and supports predictive information obtained by genomic sequence analysis.

Affinity Labels↗
PubMed2024

Assessment of Gene Set Enrichment Analysis using curated RNA-seq-based benchmarks.

Pathway enrichment analysis is a ubiquitous computational biology method to interpret a list of genes (typically derived from the association of large-scale omics data with phenotypes of interest) in terms of higher-level, predefined gene sets that share biological function, chromosomal location, or other common features. Among many tools developed so far, Gene Set Enrichment Analysis (GSEA) stands out as one of the pioneering and most widely used methods. Although originally developed for microarray data, GSEA is nowadays extensively utilized for RNA-seq data analysis. Here, we quantitatively assessed the performance of a variety of GSEA modalities and provide guidance in the practical use of GSEA in RNA-seq experiments. We leveraged harmonized RNA-seq datasets available from The Cancer Genome Atlas (TCGA) in combination with large, curated pathway collections from the Molecular Signatures Database to obtain cancer-type-specific target pathway lists across multiple cancer types. We carried out a detailed analysis of GSEA performance using both gene-set and phenotype permutations combined with four different choices for the Kolmogorov-Smirnov enrichment statistic. Based on our benchmarks, we conclude that the classic/unweighted gene-set permutation approach offered comparable or better sensitivity-vs-specificity tradeoffs across cancer types compared with other, more complex and computationally intensive permutation methods. Finally, we analyzed other large cohorts for thyroid cancer and hepatocellular carcinoma. We utilized a new consensus metric, the Enrichment Evidence Score (EES), which showed a remarkable agreement between pathways identified in TCGA and those from other sources, despite differences in cancer etiology. This finding suggests an EES-based strategy to identify a core set of pathways that may be complemented by an expanded set of pathways for downstream exploratory analysis. This work fills the existing gap in current guidelines and benchmarks for the use of GSEA with RNA-seq data and provides a framework to enable detailed benchmarking of other RNA-seq-based pathway analysis tools.

Humans↗
PubMed2002

Genomic analysis of the aromatic catabolic pathways from Pseudomonas putida KT2440.

Analysis of the catabolic potential of Pseudomonas putida KT2440 against a wide range of natural aromatic compounds and sequence comparisons with the entire genome of this microorganism predicted the existence of at least four main pathways for the catabolism of central aromatic intermediates, that is, the protocatechuate (pca genes) and catechol (cat genes) branches of the beta-ketoadipate pathway, the homogentisate pathway (hmg/fah/mai genes) and the phenylacetate pathway (pha genes). Two additional gene clusters that might be involved in the catabolism of N-heterocyclic aromatic compounds (nic cluster) and in a central meta-cleavage pathway (pcm genes) were also identified. Furthermore, the genes encoding the peripheral pathways for the catabolism of p-hydroxybenzoate (pob), benzoate (ben), quinate (qui), phenylpropenoid compounds (fcs, ech, vdh, cal, van, acd and acs), phenylalanine and tyrosine (phh, hpd) and n-phenylalkanoic acids (fad) were mapped in the chromosome of P. putida KT2440. Although a repetitive extragenic palindromic (REP) element is usually associated with the gene clusters, a supraoperonic clustering of catabolic genes that channel different aromatic compounds into a common central pathway (catabolic island) was not observed in P. putida KT2440. The global view on the mineralization of aromatic compounds by P. putida KT2440 will facilitate the rational manipulation of this strain for improving biodegradation/biotransformation processes, and reveals this bacterium as a useful model system for studying biochemical, genetic, evolutionary and ecological aspects of the catabolism of aromatic compounds.

Adipates↗
PubMed1998

Increasing the flux in metabolic pathways: A metabolic control analysis perspective

The problems of engineering increased flux in metabolic pathways are analyzed in terms of the understanding provided by metabolic control analysis. Over-expression of a single enzyme is unlikely to be effective unless it is known to have a high flux control coefficient, which can be used as an approximate predictive tool. This is likely to rule out enzymes subject to feedback inhibition, because it transfers control downstream from the inhibited enzyme to the enzymes utilizing the feedback metabolite. Although abolishing feedback inhibition can restore flux control to an enzyme, it is also likely to cause large increases in the concentrations of metabolic intermediates. Simultaneous and coordinated over-expression of most of the enzymes in a pathway can, in principle, produce substantial flux increases without changes in metabolite levels, though technically it may be difficult to achieve. It is, however, closer to the method used by cells to change flux levels, where coordinated changes in the level of activity of pathway enzymes are the norm. Another option is to increase the demand for the pathway product, perhaps by increasing its rate of excretion or removal. Copyright 1998 John Wiley & Sons, Inc.

Journal Article↗
PubMed1987

A quantitative analysis of the metabolic pathways of hepatic glucose synthesis in vivo with 13C-labeled substrates.

A quantitative analysis of the major metabolic pathways of hepatic glucose synthesis in fasted rats was conducted. [2-13C]Acetate was administered intraintestinally into awake fasted rats. 13C NMR and GC-MS analysis were used to quantitate the isotopic enrichments of glutamate, glutamine, lactate, alanine and the newly synthesized liver glucose. By measuring the ratio of carbon atoms in glutamate molecules derived from acetyl-CoA to carbon atoms in the glucose molecule derived from oxaloacetate and gluconeogenic substrates, such as lactate and alanine, the relative activities of the Krebs cycle and gluconeogenesis were quantified. Our results indicate that the percentage of glucose carbons originating by 'metabolic exchange' with the oxaloacetate pool, via the Krebs cycle, is less than 7%.

Acetates↗
PubMed2026

Comparative transcriptome analysis provides insights into dorso-ventral color pattern formation of Holothuria edulis.

Animal body color patterns are highly diverse and play critical roles in camouflage, intraspecific communication, and environmental adaptation. Holothuria edulis, an important echinoderm inhabiting tropical waters, exhibits a typical dorsoventral dichromatism. This unique body color difference represents a key phenotypic trait for its habitat adaptation; however, the core differential genes regulating this trait remain to be elucidated. In this study, comparative transcriptome sequencing was performed on the dorsal and ventral body wall tissues of H. edulis, leading to the identification of a number of differentially expressed genes (DEGs), followed by GO functional annotation and KEGG pathway enrichment analysis. GO enrichment analysis indicated that the DEGs were significantly enriched in functional categories such as extracellular region, peptidase inhibitor activity, and tetrapyrrole binding. KEGG pathway analysis further revealed significant enrichment of protein digestion and absorption, the TNF signaling pathway, and cholesterol metabolism. Notably, the pigmentation-related gene FMO2 was highly expressed in the dorsal body wall tissue, whereas cyp1a1, ZIC1, Slc7a11, WNT-1, and ADAMTS20 were highly expressed in the ventral body wall tissue. This study identified DEGs and enriched pathways associated with dorsoventral body color differences in H. edulis, providing new insights into the molecular regulatory mechanisms underlying body color pattern formation. From the perspective of aquaculture applications, body color is one of the important traits affecting the quality and market value of sea cucumber products. Elucidating the molecular mechanisms of body color variation can provide a scientific basis for molecular marker-assisted breeding of superior sea cucumber variety.

Animals↗
PubMed1997

Cytochrome c terminal oxidase pathways of Azotobacter vinelandii: analysis of cytochrome c4 and c5 mutants and up-regulation of cytochrome c-dependent pathways with N2 fixation.

The Azotobacter vinelandii cytochrome c5 gene (termed cycB) was cloned and sequenced. Mutants in this c-type cytochrome as well as cytochrome c4 mutants (mutations in cycA) and double mutants in both of the c-type respiratory pathways were characterized. Spectral and heme staining experiments on membranes from the mutants were consistent with the anticipated characteristics of all the gene-directed mutants. Membranes of the individual cytochrome c4 or c5 mutants had normal respiratory rates with physiological substrates but respiration significantly lower than the wild-type rate with ascorbate-N,N,N',N',-tetramethyl-p-phenylenediamine (TMPD) as a reductant. The growth rates of the individual cytochrome c4 or c5 mutants were not markedly different from that of the wild-type strain, but the cycA cycB double-mutant strain was noticeably growth retarded at and below 7.5% O2 on both N-containing and N-free media. The double-mutant strain was unable to grow on agar plates at O2 tensions of 2.5% or less on N-free medium. As the wild-type growth was unaffected by varying the O2 tension, the results indicate that the role of the cytochrome c-dependent pathways is to provide respiration at intermediate (5 to 10%) and low (below 5%) O2 tensions. The two c-type cytochrome genes are transcriptionally up-regulated with N2 fixation; N starvation caused 2.8-fold and 7- to 10-fold increases in the promoter activities of cycA and cycB, respectively, but these activities were affected little by the O2 level supplied to the cultures.

Amino Acid Sequence↗
PubMedDate not supplied

Genomic analyses of bacterial respiratory and cytochrome c assembly systems: Bordetella as a model for the system II cytochrome c biogenesis pathway.

An analysis of thirty-three genomes of selected bacteria for the presence of specific respiratory pathways and cytochrome c biogenesis systems has led to observations on respiration and biogenesis. A table summarizing these results is presented. The data suggested that Bordetella pertussis would be an excellent genetic model to study the System II cytochrome c biogenesis pathway. These observations are discussed and the results of genetic studies on System II biogenesis in B. pertussis are presented as a case for the power of comparative genomics. System II is present in organisms as diverse as Helicobacter, Neisseria, Porphyromonas, mycobacteria, cyanobacteria, and plants (chloroplasts), indicating this pathway's prominence and that horizontal transfer of system II (and/or System I) must have occurred on multiple occasions.

Bacteria↗
PubMed1985

Spontaneous termination of reciprocating tachycardia owing to interaction of dual atrioventricular nodal pathways in patients with an accessory pathway.

Retrospective analysis of the electrophysiologic recordings from 125 consecutive patients with reciprocating tachycardia involving an accessory atrioventricular (AV) pathway suggested, by the mode of spontaneous termination of reciprocating tachycardia, the coexistence of dual AV nodal pathways in 7 patients. Three different modes of spontaneous tachycardia termination were observed. In 2 patients with antidromic tachycardia, termination was a result of AV nodal reentry, preceded by a decrease in retrograde AV nodal conduction. In 3 other patients with antidromic tachycardia, termination occurred after a sudden switch from a slow to a fast AV nodal pathway, leading to conduction block in either the accessory pathway or the His-Purkinje system. In 2 patients with orthodromic tachycardia, termination was caused by a sudden change of anterograde conduction from a fast to a slow AV nodal pathway, eliciting an AV nodal echo beat. The interaction of dual AV nodal pathways within the reentry circuit incorporating the accessory pathway always inhibited sustained reciprocating tachycardia.

Adult↗