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PubMed1985

Molecular pathways in the transformation of model discoidal lipoprotein complexes induced by lecithin:cholesterol acyltransferase.

Incubation (24 h, 37 degrees C) of discoidal complexes of phosphatidylcholine and apolipoprotein A-I (molar ratio 95 +/- 10 egg yolk phosphatidylcholine-apolipoprotein A-I; 10.5 X 4.0 nm, long X short dimension; designated, class 3 complexes) with the ultracentrifugal d greater than 1.21 g/ml fraction transformed the discoidal complexes to a small product with apparent mean hydrated and nonhydrated diameter of 7.8 and 6.6 nm, respectively. Formation of the small product was associated with marked reduction in phosphatidylcholine-apolipoprotein AI molar ratio of the complexes (on average from 95:1 to 45:1). Phospholipase A2 activity of lecithin:cholesterol acyltransferase participated in the depletion process, as evidenced by production of unesterified fatty acids. In the presence of the d greater than 1.21 g/ml fraction or partially purified lecithin:cholesterol acyltransferase and a source of unesterified cholesterol, the small product could be transformed to a core-containing (cholesteryl ester) round product with a hydrated and nonhydrated diameter of 8.6 and 7.5 nm, respectively. By means of cross-linking with dimethylsuberimidate, the protein moiety of the small product was shown to contain primarily two apolipoprotein A-I molecules per particle, while the large product contained three apolipoprotein A-I molecules per particle. The increase in number of apolipoprotein A-I molecules per particle during transformation of the small to the large product appeared to result from fusion of the small particles during core build-up and release of excess apolipoprotein A-I from the fusion product. The results obtained with the model complexes were consistent for the most part with recent observations (Chen, C., Applegate, K., King, W.C., Glomset, J.A., Norum, K.R. and Gjone, E. (1984) J. Lipid Res. 25, 269-282) on the transformation, by lecithin:cholesterol acyltransferase, of the small spherical high-density lipoproteins of patients with familial lecithin:cholesterol acyltransferase deficiency.

Apolipoproteins A↗
PubMed1976

Regulation of rat adrenal dopamine beta-hydroxylase. II. Receptor interaction in the regulation of enzyme synthesis and degradation.

Rat adrenal gland dopamine beta-hydroxylase is under neuronal regulation from the splanchnic nerve and hormonal control via adrenal cortical glucocorticoids. The regulatory systems act in different ways; neuronal stimuli induce dopamine beta-hydroxylase synthesis while hormonal stimulation inhibits enzyme degradation. Despite these mechanistic differences, both systems require a normally innervated cholinergic receptor to exert their effect. The enzyme response to either neural stimulation or ACTH administration is blocked by splanchnic denervation. Glucocorticoid stimulation of dopamine beta-hydroxylase, however, can occur after adrenal denervation, suggesting that ACTH acts on a receptor which requires splanchnic innervation, but glucocorticoids act distal to the receptor. Similar results were obtained when the effect of these manipulations were studied on phenylethanolamine N-methyltransferase, another enzyme in the catecholamine biosynthetic pathway. A model attempting to unify these and earlier findings is presented, in which the splanchnic nerve is involved in regulating both adrenal cortical glucocorticoidogenesis (by allowing ACTH to act on glucocorticoid synthesis) and adrenal medullary catecholamine biosynthesis (by induction of enzyme synthesis.).

Adrenal Glands↗
PubMed1987

Subpopulations and functions of long C3-C5 propriospinal neurones.

Long C3-C5 propriospinal neurones (PNs) are classified in 3 types depending on their pyramidal and vestibular input. The first type of PNs received pyramidal excitation but lacked vestibular effects. The second type of PNs was excited from the medial vestibular nucleus but not from the pyramid. The third type of PNs was excited from the lateral vestibular nucleus either from second order neurones or from non-second order neurones. Monosynaptic excitatory postsynaptic potentials from neck afferents and/or oligosynaptic postsynaptic potentials from forelimb afferents were found in some of the PNs of the second and third type but not in those of the first type. Collision experiments revealed that cortico- and rubrospinal fibres to the long C3-C5 PNs terminate in the rostral spinal cord, presumably in the forelimb segments. Vestibular and reticular effects on the PNs are partly from fibres terminating in the rostral spinal cord and partly from fibres projecting to the lumbar cord. It is postulated that the different types of PNs contribute to the adjustment of hindlimb posture which is required during different movements of the forebody. It is suggested that the basic tonus is maintained mainly by the direct projection to the hindlimb segments from lateral vestibulospinal and reticulospinal neurones which excite antigravity muscles via lumbar interneurones and that the long C3-C5 PNs converge onto the same interneurones so that they act by modulation of the basic tonus.

Afferent Pathways↗
PubMed1996

Alcohol and coronary heart disease: consistent relationship and public health implications.

The relationship between alcohol consumption and coronary heart disease (CHD) in various epidemiologic study designs is consistent, showing protection at < or = 2 drinks per day, with an increase in risk of CHD in several studies at higher alcohol consumption levels. Studies of potential mediators of the effects of alcohol on CHD show beneficial effects on HDL cholesterol and some coagulation factors, but, at higher levels of consumption, adverse effects on blood pressure, arrhythmias, and the myocardium. Statistical modeling of pathways for alcohol's effect on coronary disease is consistent with a protective pathway via elevated HDL cholesterol and an adverse pathway through elevated blood pressure. Maximum benefit for CHD appears to be reached at only one drink daily. Given that alcohol is an intoxicating and potentially addictive substance with a high abuse potential, and given the high morbidity and mortality associated with heavier drinking, public health recommendations to consume alcohol are contraindicated.

Alcohol Drinking↗
PubMed1992

Simulation of ozone uptake distribution in the human airways by orthogonal collocation on finite elements.

Ozone transport in a rigid single-pathway anatomic model of the lung was analyzed by a stable convergent numerical algorithm, the method of orthogonal collocation on finite elements. The simulations predicted the dynamic behavior of gas phase concentration profiles for both ozone and an insoluble inert gas. An internal quasi-stationary diffusion front was observed during early inspiration for both gases. In addition, the absorptive distribution of ozone in lung airways was computed as a total dose as well as a tissue dose. The total dose of ozone decreased along the airway path from the mouth. However, the tissue dose of ozone increased along the conducting airways, reached a maximal dose in the terminal bronchioles, and decreased sharply in the respiratory airways.

Algorithms↗
PubMed1989

Transcription of early developmental isogenes in cardiac myocyte hypertrophy.

We have developed a cell culture system to study molecular mechanisms important in myocardial hypertrophy. alpha 1-Adrenergic receptor stimulation produces hypertrophy of neonatal rat cardiac myocytes. Myocyte hyperplasia is not induced by alpha 1 stimulation, although alpha 1-adrenergic receptor-mediated DNA synthesis and cell division have been observed in other types of cells. The myocyte hypertrophic response does not require contractile activity. Activation of the alpha 1 receptor also produces highly specific alterations in gene expression, as measured at the mRNA and protein levels. In particular, there is selective up-regulation of two contractile protein isogenes that are expressed in vivo during early development and in pressure-load hypertrophy, skeletal alpha-actin and beta-myosin heavy chain. Studies with an in vitro transcription assay indicate that stimulation of the alpha 1-adrenergic receptor leads to a distinctive temporal sequence of transcriptional activation. Transcription of the skeletal alpha-actin isogene is induced preferentially to that of cardiac alpha-actin. Thus, early developmental isogene induction in alpha 1-stimulated hypertrophy reflects a fundamental change in the transcriptional program of the cardiac myocyte nucleus. The goal now is to define an intracellular pathway connecting the alpha 1-adrenergic receptor in the plasma membrane to activation of RNA polymerase II on the skeletal alpha-actin gene in the cardiac myocyte nucleus. There is evidence that protein kinase C may be one component of this pathway. A model for alpha 1-mediated transcription is presented.

Animals↗
PubMed1994

The role of hydration and radiation quality in the induction of DNA damage--chemical aspects.

The mutagenic and lethal effects of ionising radiation are thought to result from chemical modifications induced within DNA. This DNA damage is significantly influenced by the chemical environment and the radiation quality (LET). Water closely associated with the DNA and its immediate environment is involved in the early chemical pathways which lead to the induction of DNA damage and is reflected in the cellular radiosensitivity. For instance, hydration of DNA influences hole migration leading to its localisation at guanine. Changes in the radiation quality are discussed in terms of the complexity of the radical clusters produced. It is inferred that at higher LET, the influence of the chemical environment (O2 etc) decreases with respect to DNA damage and cellular radiosensitivity. It is therefore important to include these effects of environment of the DNA upon the early chemical pathways in models of radiation action.

DNA↗
PubMed1994

Furin-mediated proprotein processing activity: involvement of negatively charged amino acid residues in the substrate binding region.

Furin, which is encoded by the recently discovered FUR gene, appears to be the first known mammalian member of the subtilisin family of serine proteases with cleavage selectivity for paired or multiple basic residues. A consensus cleavage sequence, Arg-X-Lys/Arg-Arg has been proposed. Most likely, furin is primarily involved in the processing of precursors of proteins that are secreted via the constitutive secretory pathway. Homology modelling of the catalytic domain of this protein suggested that negatively charged amino acid residues near or in the substrate binding region might contribute to the observed specificity for substrate segments with paired and multiple basic amino acid residues. To investigate this hypothesis, furin mutants were generated in which negatively charged residues, predicted to be located near or in the substrate binding pockets and involved in interactions with basic residues of the substrate, were replaced by neutral residues. Analysis of processing by these furin mutants of wild-type and cleavage mutants of pro-von Willebrand factor (pro-vWF) revealed that particular negatively charged residues are critical for specific cleavage activity.

Amino Acid Sequence↗
PubMed1996

Why and when channelling can decrease pool size at constant net flux in a simple dynamic channel.

Cornish-Bowden and Cárdenas (Cornish-Bowden, A. and Cárdenas M.L. (1993) Eur. J. Biochem. 213, 87-92) have suggested that simulation results peviously published by us (Mendes, P., Kell, D.B. and Westerhoff, H.V. (1992) Eur. J. Biochem. 204, 255-266) which had demonstrated that large reductions of intermediate pool sizes could be accompanied by increasing channel flux in a model metabolic pathway, were an artefact of changes in the pathway's overall flux of the order of 0.0075%, or of inappropriate alterations of enzyme activities. They also asserted to prove that the "channelling of an intermediate cannot affect its free concentration at constant net flux". We consider the co-response of the intermediate metabolite concentration ('pool') and the channel flux to changes in kinetic (or thermodynamic) parameters. Both by analytical proofs and by numerical examples we show that this co-response can be positive, negative or null, depending on the parameter change. In particular, we prove that there is always a number of ways of changing parameters such that the intermediate metabolite concentration decreases with increasing channel flux, whether the total flux varies or is constant. We also show that increased stability of the (dynamic) enzyme-intermediate-enzyme complex, as well as a single parameter change that similarly displays no cross-over effects, can lead to decreased intermediate metabolite concentration and increased channel flux at constant total flux. In general, a non-zero co-response of the intermediate metabolite concentration ('pool') and the channel flux to changes in kinetic (or other) parameters is the rule rather than the exception. More specifically: (i) The algebraic analysis ('general proof') given in Cornish-Bowden and Cárdenas (1993) contains the constraint that the elasticities of various steps to the modulation parameters which were used to vary the channel flux at constant net flux were unity. This is an unfortunate and unnecessary constraint which, when lifted, means that the concentration of the pool in the general case can indeed change at constant net flux. A 'simplified proof' given in Cornish-Bowden and Cárdenas (1993) also fails, due in addition to the consequent failure to include mass conservation relations for some of the enzymes. (ii) In the systems studied by Cornish-Bowden and Cárdenas (1993), flux is properly to be considered as a variable (since it varies during the transition to the steady state), and not a parameter, and as such cannot per se affect the magnitude of other variables in the steady state. (iii) By relaxing the constraint referred to in (i), above, and by making dual modulations (i.e., of more than one parameter at once) which are different from those carried out in Cornish-Bowden and Cárdenas (1993) we find many instances in which channelling (described by a parameter p) does significantly affect the concentration of the pool intermediate C at constant total flux. (iv) In the same pathways, but in which the flux is held constant by setting it via a zero-order flux-generating reaction, the addition of a channel is also able to significantly to modulate the size of the pool at constant total flux. Our results show that the effectiveness of channelling in decreasing a pool, even at constant flux, is very much a reality.

Animals↗
PubMed2006

Civilization as a biosystem examined by the comparative analysis of biosystems.

Darwinian evolutionary theory has played a central role in the life sciences. However, this principle is rarely applied to exceptional life-like systems such as human societies and the life-like chemical systems associated with the origin of life. For a description of the nature of these exceptional life-like biosystems, the development of alternative approaches is necessary. The existence of analogies among biosystems at different hierarchical levels has frequently been discussed. The present paper, however, focuses on the analogies of the structures and functions of different biosystems, based on the following perspectives. The roles of an individual biosystem and its building blocks in relation to the environment are evaluated from the standpoint of the hierarchies of organisms, whereby the principle of which hierarchy is regarded as an "individual" biosystem is proposed. In addition, the definition and characteristics of civilization are discussed on the basis of this principle. The analogies between cell-type systems, civilizations, ecosystems, and other biosystems are qualitatively evaluated. It is reasonable to regard all biosystems as possessing clear or ambiguous boundaries. Biosystems at higher levels than prokaryotes comprise both living and non-living building blocks, while prokaryotes comprise only non-living building blocks. The similarities concerning the interactions among the building blocks in relation to their environment are also discussed. Furthermore, the analogy between different biosystems concerning metabolism, self-reproduction, mutation, the relationship between genotype and phenotype (information and function), individuality, and stability are evaluated. The proposed analytical approach not only provides an insight into the characteristics of civilizations as biosystems, but also the characteristics of biosystems at different hierarchical levels.

Biological Evolution↗
PubMed2006

Switching mechanism for branched biochemical fluxes: graph-theoretical analysis.

A graph-theoretical method is applied to characterize the structure of a simplest switching mechanism of common biochemical importance. This mechanism is based on competition of two coupled substrate-binding pathways for a single substrate. No other regulatory interactions are shown to be needed for the switching phenomenon to be observed. It is shown that switch in branch effluxes is observed as bistability or reciprocal oscillations, depending on the value of steady influx. Frequency of reciprocal efflux oscillations in branches is regulated by steady influx. Therefore, the switching mechanism can function as the coding mechanism in the manner of "influx steady level-efflux frequency". The calculated kinetic equations for the switching mechanism demonstrate very steep transitions in the branch fluxes without using high non-linearity of these equations.

Enzymes↗
PubMed2006

Degradation characteristics and metabolic pathway of 17alpha-ethynylestradiol by Sphingobacterium sp. JCR5.

A 17alpha-ethynylestradiol (EE2)-degrading bacterium was isolated from the activated sludge of the wastewater treatment plant (WWTP) of an oral contraceptives producing factory in Beijing, China. On the basis of its morphology, biochemical properties and the 16S rDNA sequence analysis, this strain was identified as Sphingobacterium sp. JCR5. This strain grew on EE2 as sole source of carbon and energy, and metabolized up to 87% of the substrate added (30 mgl-1) within 10 d at 30 degrees C. In addition to EE2 the strain could be cultivated on steroidal estrogens like estrone (E1), 17beta-estradiol (E2), estriol (E3) and mestranol (MeEE2), the intermediates of contraceptive medicine processing and on some aromatic compounds. Mass spectrum analysis of the EE2 degradation showed that in the first step it is oxygenized to E1, 2-hydroxy-2,4-dienevaleric acid and 2-hydroxy-2,4-diene-1,6-dioic acid, which are the main catabolic intermediates. The former was analogous to the pathway of a previously reported testosterone-degrading bacterium Comamonas testosteroni TA441 and the latter is a metabolite with a different cleavage position of 3-hydroxy-4,5-9,10-disecoestrane-1(10),2-diene-5,9,17-trione-4-oic acid from the former.

Ethinyl Estradiol↗
PubMed2006

Essential genes on metabolic maps.

Within the past five years genome-scale gene essentiality data sets have been published for ten diverse bacterial species. These data are a rich source of information about cellular networks that we are only beginning to explore. The analysis of these data, very heterogeneous in nature, is a challenging task. Even the definition of 'essential genes' in various genome-scale studies varies from genes 'absolutely required for survival' to those 'strongly contributing to fitness' and robust competitive growth. A comparative analysis of gene essentiality across multiple organisms based on projection of experimentally observed essential genes to functional roles in a collection of metabolic pathways and subsystems is emerging as a powerful tool of systems biology.

Computational Biology↗
PubMed2006

Pathways of neurodegeneration and experimental models of basal ganglia disorders: downstream effects of mitochondrial inhibition.

The basal ganglia circuit plays a key role in the regulation of voluntary movements as well as in behavioural control and cognitive functions. The main pathogenic role of mitochondrial dysfunctions is now accepted in the neurodegenerative process and the mitochondria have been successfully used as subcellular targets to obtain relevant experimental models of basal ganglia neurodegenerative disorders. Mitochondrial toxins act through an inhibition of the respiratory chain complexes. These toxins, by uncoupling cellular respiration, shift the cell into a state of oxidative stress and trigger several bidirectional links with the excitotoxic process. Moreover, the in vitro inhibition of the respiratory chain complexes alters the electrophysiological properties of the neurons. The downstream effects triggered by mitochondrial complexes inhibition provide a model integrating genetic and environmental pathogenic factors to explain the selective neuronal vulnerability.

Animals↗
PubMed2006

The antioxidant N-acetyl-L-cysteine does not prevent hippocampal glutathione loss or mitochondrial dysfunction associated with status epilepticus.

Hippocampal reduced glutathione (GSH) levels diminish after status epilepticus (SE), which precedes damage to mitochondrial enzymes, which is associated with cell death. The rat perforant pathway stimulation model was used to assess whether intraperitoneal administration of the GSH precursor N-acetyl-L-cysteine (NAC) protected against these changes. NAC (300 mg/kg) treated animals exhibited the same GSH decrease post SE as vehicle treated. Furthermore, NAC treatment had no protective effects on mitochondrial dysfunction.

Acetylcysteine↗
PubMed2005

Identification of mouse retinal genes differentially regulated by dim and bright cyclic light rearing.

Bright cyclic light rearing protects BALB/c mice from light-induced photoreceptor apoptosis compared to dim cyclic light rearing. We used a microarray approach to search for putative neuroprotection genes that were up- or down-regulated under these environmental conditions. Retinal protection by bright cyclic rearing was determined by quantitative histology and DNA fragmentation analysis. Total RNA was isolated from 5-week-old mice raised in bright (400 lux) or dim (5 lux) cyclic light and prepared for analysis on microarrays produced using a 70-mer oligonucleotide library that represented 16,463 mouse genes. Genes of interest were identified using statistically robust bioinformatics analysis methods that were developed in-house. Changes in some genes were confirmed with quantitative real time PCR. We found that 952 genes were up- or down-regulated by bright cyclic light rearing compared to dim cyclic light rearing. One hundred and eighty-four of them, having >/=2-fold differences, were grouped into 13 categories, and selected for further consideration. Eleven up-regulated and two down-regulated genes were confirmed by semi-quantitative PCR. Five neuroprotection-associated genes were up-regulated by bright cyclic light rearing as confirmed by real-time PCR. The human orthologue chromosomal location of 22 differentially expressed genes map to known retinal degeneration loci. Using PathwayAssist software, we modeled the pathway networks of up- and down-regulated genes that are functionally related to the retina. We identified retinal genes that are differentially regulated by environmental light history. Those that directly affect cell processes such as survival, apoptosis, and transcription are likely play a pivotal role in the regulation of retinal neuroprotection against light-induced photoreceptor apoptosis.

Adaptation, Ocular↗