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Physiological Implications (physiological + implication)
Selected AbstractsIn vivo functions of the prolyl-4-hydroxylase domain oxygen sensors: direct route to the treatment of anaemia and the protection of ischaemic tissuesACTA PHYSIOLOGICA, Issue 4 2009D. M. Katschinski Abstract The prolyl-4-hydroxylase domain (PHD) 1,3 enzymes have been identified based on their ability to regulate the stability of hypoxia-inducible factor , subunits and thus to modify hypoxia-inducible gene expression. Transgenic mouse models provided insights into the isoform-specific functions of these oxygen sensors with physiological implications for angiogenesis, erythropoiesis/oxygen transport, cardiovascular function, metabolism and tissue homeostasis. This knowledge is important for the ongoing development of small molecule PHD inhibitors that are currently tested in preclinical and clinical trials for the treatment of anaemia and for cytoprotection. This review aims at summarizing the insights obtained from key mouse knock-out models as well as first experiences in the therapeutic application of PHD inhibitors. [source] Proteolytic cleavage of the voltage-gated Ca2+ channel ,2, subunit: structural and functional featuresEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 6 2007Arturo Andrade Abstract By mediating depolarization-induced Ca2+ influx, high-voltage-activated Ca2+ channels control a variety of cellular events. These heteromultimeric proteins are composed of an ion-conducting (,1) and three auxiliary (,2,, , and ,) subunits. The ,2, subunit enhances the trafficking of the channel complex to the cell surface and increases channel open probability. To exert these effects, ,2, must undergo important post-translational modifications, including a proteolytic cleavage that separates the extracellular ,2 from its transmembrane , domain. After this proteolysis both domains remain linked by disulfide bonds. In spite of its central role in determining the final conformation of the fully mature ,2,, almost nothing is known about the physiological implications of this structural modification. In the current report, by using site-directed mutagenesis, the proteolytic site of ,2, was mapped to amino acid residues Arg-941 and Val-946. Substitution of these residues renders the protein insensitive to proteolytic cleavage as evidenced by the lack of molecular weight shift upon treatment with a disulfide-reducing agent. Interestingly, these mutations significantly decreased whole-cell patch-clamp currents without affecting the voltage dependence or kinetics of the channels, suggesting a reduction in the number of channels targeted to the plasma membrane. [source] Role of differential changes in sympathetic nerve activity in the preparatory adjustments of cardiovascular functions during freezing behaviour in ratsEXPERIMENTAL PHYSIOLOGY, Issue 1 2010Kenju Miki Freezing behaviour is associated with a distinct pattern of changes in cardiovascular function, which has been considered as a preparatory reflex for ,fight or flight' behaviour. However, the detailed mechanisms underlying preparatory cardiovascular adjustments and their physiological implications have received less attention. We studied responses in renal and lumbar sympathetic nerve activity and cardiovascular function during freezing behaviour in conscious rats, which was induced by exposure to loud white noise. Freezing behaviour was associated with regionally specific alterations in sympathetic nerve activity, in that renal sympathetic nerve activity increased while lumbar sympathetic nerve activity did not change. Moreover, freezing behaviour was associated with differential shifts in baroreflex control of sympathetic outflows, which could help to explain the selective responses in renal and lumbar sympathetic nerve activity during freezing behaviour. These differential changes in sympathetic outflows would result in a visceral vasoconstriction without having any impact on the skeletal muscle vasculature. These cardiovascular adjustments during freezing behaviour may help to explain the immediate and massive increase in muscular blood flow that occurs at the onset of fight or flight behaviour. It is hypothesized that central command originating from the defence area could somehow modulate separate baroreflex pathways, causing differential changes in sympathetic nerve activity to generate the preparatory cardiovascular adjustments during the freezing behaviour. [source] Gene expression profiles of O3 -treated Arabidopsis plantsPLANT CELL & ENVIRONMENT, Issue 9 2006NICOLA TOSTI ABSTRACT To analyse cellular response to O3, the tolerant Arabidopsis thaliana genotype Col-0 was exposed to O3 fumigation (300 ppb) for 6 h and the modulation of gene expression during the treatment (3 h after the beginning of the treatment, T3 h) and the recovery phase (6 h from the end of the treatment, T12 h) assessed by gene chip microarray and real-time reverse transcriptase (RT)-PCR analyses. The Arabidopsis transcriptional profile is complex, as new genes (i.e. reticuline oxidase) and pathways, other than those already reported as O3 -responsive, appear to be involved in the O3 response. The steady-state transcript levels of several WRKY genes were increased in O3 -treated plants and the W-box was the cis -element over-represented in the promoter region of T3 h up-regulated genes. The fact that the W-box element was also over-represented in almost all T3 h-induced receptor-like kinases (RLKs) suggests a WRKY-mediated control of RLKs under O3 stress and a mechanicistic similarity with the pathogen-induced transcriptional responses. We investigated the molecular and physiological implications of our findings in relation to O3 -induced plant stress response. [source] Structural studies of human alkaline phosphatase in complex with strontium: Implication for its secondary effect in bonesPROTEIN SCIENCE, Issue 7 2006Paola Llinas Abstract Strontium is used in the treatment of osteoporosis as a ranelate compound, and in the treatment of painful scattered bone metastases as isotope. At very high doses and in certain conditions, it can lead to osteomalacia characterized by impairment of bone mineralization. The osteomalacia symptoms resemble those of hypophosphatasia, a rare inherited disorder associated with mutations in the gene encoding for tissue-nonspecific alkaline phosphatase (TNAP). Human alkaline phosphatases have four metal binding sites,two for zinc, one for magnesium, and one for calcium ion,that can be substituted by strontium. Here we present the crystal structure of strontium-substituted human placental alkaline phosphatase (PLAP), a related isozyme of TNAP, in which such replacement can have important physiological implications. The structure shows that strontium substitutes the calcium ion with concomitant modification of the metal coordination. The use of the flexible and polarizable force-field TCPEp (topological and classical polarization effects for proteins) predicts that calcium or strontium has similar interaction energies at the calcium-binding site of PLAP. Since calcium helps stabilize a large area that includes loops 210,228 and 250,297, its substitution by strontium could affect the stability of this region. Energy calculations suggest that only at high doses of strontium, comparable to those found for calcium, can strontium substitute for calcium. Since osteomalacia is observed after ingestion of high doses of strontium, alkaline phosphatase is likely to be one of the targets of strontium, and thus this enzyme might be involved in this disease. [source] Prenatal alcohol exposure alters phosphorylation and glycosylation of proteins in rat offspring liverPROTEINS: STRUCTURE, FUNCTION AND BIOINFORMATICS, Issue 3 2010Bourlaye Fofana Abstract To gain more insights into the translational and PTM that occur in rat offspring exposed to alcohol in utero, 2-D PAGE with total, phospho- and glycoprotein staining and MALDI-MS/MS and database searching were conducted. The results, based on fold-change expression, revealed a down-regulation of total protein expression by prenatal alcohol exposure in 7-day-old and 3-month-old rats. There was an up-regulation of protein phosphorylation but a down-regulation of glycosylation by prenatal alcohol exposure in both age groups. Of 31 protein spots examined per group, differentially expressed proteins were identified as ferritin light chain, aldo-keto reductase, tumor rejection antigen gp96, fructose-1,6-bisphosphatase, glycerol-3-phosphate dehydrogenase, malate dehydrogenase, and ,-actin. Increased phosphorylation was observed in proteins such as calmodulin, gluthatione S-transferase, glucose regulated protein 58, ,-enolase, eukaryotic translation elongation factor 1 ,-2, riboprotein large P2, agmatinase, ornithine carbamoyltransferase, quinolinate phosphoribosyltransferase, formimidoyltransferase cyclodeaminase, and actin. In addition, glycosylation of adenosine kinase, adenosylhomocysteine hydrolase, and 3-hydroxyanthranilate dioxygenase was reduced. Pathways affected by these protein alterations include cell signaling, cellular stress, protein synthesis, cytoskeleton, as well as glucose, aminoacid, adenosine and energy metabolism. The activity of the gluconeogenic enzyme fructose-1,6-bisphosphatase was elevated by prenatal alcohol. The observations may have important physiological implications. [source] Mechanisms of adenosine-induced cytotoxicity and their clinical and physiological implicationsBIOFACTORS, Issue 1-4 2006Sharmila P. Seetulsingh-Goorah Abstract Extracellular ATP (ATPo) and adenosine are cytotoxic to several cancer cell lines, suggesting their potential use for anticancer therapy. Adenosine causes cytotoxicity, either when added exogenously or when generated from ATPo hydrolysis, via mechanisms which are not mutually exclusive and which involve, adenosine receptor activation, pyrimidine starvation and/or increases in intracellular S-adenosylhomocysteine: S-adenosylmethionine ratio. Given that adenosine also appears to protect against cytotoxicity via mechanisms including immunity against damage by oxygen free radicals, an understanding of the contribution of adenosine to ATPo-induced cytotoxicity is thus crucial, when considering any potential therapeutic use for these compounds. However, such an understanding has been largely hindered by the fact that many studies have not focused enough on the possibility that both ATPo and adenosine may mediate cytotoxicity in the same system. Such studies can benefit from use a range of ATPo concentrations when assessing the contribution of adenosine to ATPo-induced cytotoxicity. Whilst future molecular and pharmacological studies are needed to establish the nature of the cytotoxic adenosine receptor, it is possible that more than just one adenosine receptor type is involved and that the cytotoxic receptor(s) type is more likely to have a low affinity for adenosine. Activation of the adenosine receptor(s) would thus lead to cytotoxicity only at relatively high adenosine concentrations, while lower adenosine concentrations mediate non-cytotoxic physiological effects. [source] | |||||||||||||