Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P01189 (beta-endorphin)
 21,003 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Sepsis and its sequelae (sepsis syndrome and septic shock) are increasingly common and are still potentially lethal diagnoses. Many mediators of the pathogenesis of sepsis have recently been described. These include tumor necrosis factor alpha (TNF alpha), interleukins, platelet activating factor, leukotrienes, thromboxane A2, and activators of the complement cascade. Neutrophil and platelet activation may also play a role. Other agents that may participate in the sepsis cascade include adhesion molecules, kinins, thrombin, myocardial depressant substance, beta-endorphin, and heat shock proteins. Endothelium-derived relaxing factor and endothelin-1 are released from the endothelium and seem to exert a regulatory effect, counterbalancing each other. A central mediator of sepsis does not seem to exist, although TNF alpha has been commonly proposed for this role. Animal studies are difficult to extrapolate to the clinical setting because of cross-species differences and variations in experimental design. Rather than being caused by any single pathogenic mechanism, it is more likely that sepsis is related to the state of activation of the target cell, the nearby presence of other mediators, and the ability of the target cell to release other mediators. Also important is the downregulation or negative feedback of these mediators or the generation of natural inflammation inhibitors, such as interleukin-4 and interleukin-8. Endothelial damage in sepsis probably results from persistent and repetitive inflammatory insults. Eventually, these insults produce sufficient damage that downregulation can no longer occur; this leads to a state of metabolic anarchy in which the body can no longer control its own inflammatory response.
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PMID:The pathogenesis of sepsis. 187 94

Calmodulin, a ubiquitous Ca2+-binding regulatory protein, is phosphorylated exclusively on tyrosine-99 in an insulin-dependent manner by wheat germ lectin-purified preparations of insulin receptors from rat adipocyte plasma membranes. Calmodulin is phosphorylated in the presence of polylysine, histone Hf2b, and protamine sulfate, but not in the absence of these cofactors or in the presence of other basic compounds known to interact with calmodulin, such as mellitin, myelin basic protein, chlorpromazine, trifluoperazine, substance P, glucagon, polyarginine, mastoparin, beta-endorphin, spermine, spermidine, and putrescine. The incorporation of 32P into calmodulin, expressed in terms of moles of phosphate per moles of calmodulin and assayed at calmodulin concentrations of 1.2 and 0.06 microM, is 0.023 + 0.002 and 0.046 + 0.006, respectively. This low stoichiometry is likely due to the relative impurity of the receptor preparation, as similar studies not shown here, using highly purified human insulin receptors, yield a stoichiometry of 1 mol phosphate/mol calmodulin. The time course of phosphorylation is characterized by a short initial lag phase of approximately 5 min, a rapid linear rate from approximately 5 to 40 min, with a steady state of 32P incorporation being approached at approximately 60 min. The K0.5 for ATP is 104 + 18 microM. Phosphorylated calmodulin is partially purified by HPLC on a C4 column using a trifluoroacetic acid/acetonitrile gradient solvent system. Phosphoamino acid analysis and limited thrombin digestion were used to determine that the site of insulin-induced phosphorylation of calmodulin is exclusively on tyrosine-99 regardless of the basic protein cofactor used. Phosphorylated calmodulin does not exhibit the characteristic Ca2+ shift normally observed with calmodulin in electrophoretic gels, an observation that is consistent with this modification affecting the biological activity of the molecule. Thus, the tyrosine phosphorylation of calmodulin represents a potentially important post-translational modification altering calmodulin's ability to regulate a variety of enzymes involved in growth, differentiation, and metabolic regulation.
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PMID:The in vitro phosphorylation of calmodulin by the insulin receptor tyrosine kinase. 341 47

A synthetic nonapeptide fragment of thrombin inhibits the cellular motility in culture of a human melanoma subclone that possesses a high metastatic potential in mice. Concomitant with the loss of ability to translocate in culture, these cells exhibit increases in the average length of actin cables and cellular surface area in contact with the substratum. The spreading activity is observed at a nonapeptide concentration of 1 nM within 1 hr of exposure at 37 degrees C. Pretreatment of cells with this nonapeptide does not block signal transduction through plasma membrane receptors for the following growth or differentiation factors: alpha-melanotropin (alpha-melanocyte-stimulating hormone), nerve growth factor, and transforming growth factor type beta. Results of the present study suggest an approach to cancer chemotherapy in which naturally occurring peptides from two functionally orthogonal classes may be used to perform two complementary functions: inhibition of metastasis and induction of differentiation.
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PMID:Identification of a synthetic nonapeptide sequence that inhibits motility in culture of a melanoma subclone that possesses a high metastatic potential. 348 May 26

Picogram amounts (50-150 pg/mg protein) of immunoreactive met-enkephalin material (met-enkephalin IR) were detected by radioimmunoassay in human, rat and rabbit platelets. Characterization of this material by thin-layer chromatography, gel filtration chromatography and high-pressure liquid chromatography indicated that it behaves identically with synthetic met-enkephalin. No high molecular weight met-enkephalin IR could be detected in the platelet extracts, even after trypsin hydrolysis, using two antisera which are able to recognize some of the putative met-enkephalin precursors present in the adrenal gland or striatum. In vitro, thrombin released platelet-met-enkephalin IR concomitantly with 5-hydroxytryptamine (5-HT), suggesting a common subcellular localization, i.e. the 5-HT storing organelles, for met-enkephalin IR and the amine. In vivo, platelet met-enkephalin IR in the Sprague-Dawley rat was affected neither by adrenalectomy nor by hypophysectomy. Thirteen-and 18-week-old spontaneous hypertensive rats (SHR) had lower platelet concentrations of met-enkephalin IR than age matched normotensive Wistar-Kyoto rats.
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PMID:Met-enkephalin immunoreactivity in blood platelets. 709 67

Proteolysis of short N alpha-protected peptide substrates bound to polyoxyethylene-polystyrene beads releases selectively free amino sites in the enzyme-accessible "surface" area. The substantial majority of functional sites in the "interior" of the polymeric support are not reached by the enzyme and remain uncleaved (protected). Subsequent synthesis with two classes of orthogonal protecting groups-N alpha-tert-butyloxycarbonyl (Boc) and N alpha-9-fluorenylmethyloxy-carbonyl (Fmoc)-allows generation of two structures on the same bead. The surface structure is available for receptor interactions, whereas the corresponding interior structure is used for coding. Coding structures are usually readily sequenceable peptides. This "shaving" methodology was illustrated by the preparation of a peptide-encoded model peptide combinatorial library containing 1.0 x 10(5) members at approximately 6-fold degeneracy. From this single library, good ligands were selected for three different receptors: anti-beta-endorphin anti-body, streptavidin, and thrombin, and the binding structures were deduced correctly by sequencing the coding peptides present on the same beads.
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PMID:Enzyme-mediated spatial segregation on individual polymeric support beads: application to generation and screening of encoded combinatorial libraries. 871 Aug 46

Adrenomedullin, a potent vasoactive peptide, is actively secreted from primary cultures of human oral and skin keratinocytes, but nothing is known of the regulation of its release. This study describes the effects of a range of substances on adrenomedullin production from cultures of oral and skin keratinocytes. We have established that keratinocytes do not store adrenomedullin but secrete it constitutively. Cytokines interleukin-1alpha and -1beta, tumor necrosis factor-alpha and -beta, and the bacterial product, lipopolysaccharide, significantly stimulate adrenomedullin secretion from oral but not skin keratinocytes. Both transforming growth factor-beta1 and interferon-gamma are potent suppressors of adrenomedullin secretion from both cell types, as are forskolin, di-butyryl cyclic adenosine monophosphate, and adrenocorticotropin. The peptides thrombin and endothelin-1 increase adrenomedullin production, particularly from skin keratinocytes. These findings indicate that there are differences in the regulation of adrenomedullin production between oral and skin keratinocytes and that oral keratinocytes are particularly responsive to the action of inflammatory cytokines. This raises the possibility that adrenomedullin may serve a different functions in oral mucosa and skin.
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PMID:Regulation of adrenomedullin secretion in cultured human skin and oral keratinocytes. 1151 15

Thrombin generation induced by recombinant factor VIIa (rFVIIa) in patients with haemophilia and/or inhibitors to factor VIII/IX could enhance generation of thrombin-activatable fibrinolysis inhibitor (TAFI), a recently described link between coagulation and fibrinolysis. TAFI is unstable and it is not easy to measure its active form in vivo. Overall haemostatic potential (OHP) is a novel method for haemostasis estimation, based on determination of the fibrin aggregation curve in which tiny amounts of thrombin are used for activation of clotting. We measured OHP in six patients with inhibitors to factor VIII before injection of rFVIIa and 10 and 120 min thereafter. Overall fibrinolytic potential (OFP) and clot lysis time (CLT) analysed by this method could be used for indirect estimation of TAFI generation. We found no change in pro-TAFI and total TAFI antigen before and after treatment with rFVIIa. OHP was almost undetectable before treatment but increased into the range of normal pooled plasma 10 and 120 min after rFVIIa treatment, as did CLT. However, after addition of potato tuber carboxypeptidase inhibitor, a specific inhibitor of TAFI, the shortening of CLT was lower than that in NPP. OFP was increased in patient plasma both 10 and 120 min after treatment compared with NPP. There was a strong positive correlation between pro-TAFI concentration and shortening of CLT after PTCI addition and a negative correlation between pro-TAFI concentration and OFP 10 min after rFVIIa injection. Thus, rFVIIa normalizes OHP and CLT 10 min after injection. While this improvement slightly decreases, but still exists after 2 hours, it suggests efficacy in bleeding prevention using a protocol based on rFVIIa administration every 2 hours.
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PMID:Overall haemostatic potential can be used for estimation of thrombin-activatable fibrinolysis inhibitor-dependent fibrinolysis in vivo and for possible follow-up of recombinant factor VIIa treatment in patients with inhibitors to factor VIII. 1241 Jun 47

15-mer ssDNA aptamers play a vital role in the inhibition of alpha-thrombin in the blood clotting mechanism. It is of high importance to explore the structural factors controlling the inhibitory nature of the aptamer. Here we investigated the structure-function relationship of the anti-thrombin aptamer, as well as its 'caged' variant (2-(2-nitrophenyl)-propyl group (NPP)) by molecular dynamics simulations. The stability of the unmodified aptamer at different temperatures is examined in 2ns all-atom simulations and compared to experiment. The change in structure when introducing the photo-labile caged compound is analyzed, and the regiospecificity of this modification explained on atomic level. Removal of the photo-labile group leads to the reformation of the active aptamer structure from its inactive state. The mechanism for this formation process is a concerted movement of the aptamer backbone and some highly important bases. The binding of the aptamer to thrombin with regard to the 'caged' group is studied in an explicit simulation with the aptamer-thrombin complex and the reason for the binding/unbinding nature of the aptamer shown.
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PMID:Structure-activity relationships of a caged thrombin binding DNA aptamer: insight gained from molecular dynamics simulation studies. 1928 37

Enzymes of the pyrophosphatase/phosphodiesterase family have multiple roles in extracellular nucleotide metabolism and in the regulation of nucleotide-based intercellular signaling. Snake venoms contain enzymes that hydrolyze nucleic acids and nucleotides, but their function is poorly understood. Here we describe for the first time the isolation and functional characterization of a soluble phosphodiesterase from Bothrops jararaca venom, which shows amino acid sequence similarity to mammalian nucleotide pyrophosphatase/phosphodiesterase 3 (NPP3), and inhibits ADP-induced platelet aggregation. The enzyme, named NPP-BJ, showed an apparent molecular mass of 228 kDa by size exclusion chromatography. NPP-BJ exhibited nuclease activity as well as pyrophosphatase and phosphatase activities, preferentially hydrolyzing nucleoside 5'-triphosphates over nucleoside 5'-diphosphates, but was not active upon nucleoside 5'-monophosphates. Depending on the substrate used, dithiothreitol and EDTA differently inhibited the catalytic activity of NPP-BJ. Platelet aggregation induced by ADP was also abrogated by NPP-BJ, whereas thrombin-induced platelet aggregation was only slightly attenuated. However, polyclonal antibodies raised against NPP-BJ could not abolish the lethal activity of B. jararaca venom. Altogether, these results show that NPP-BJ has a minor contribution to the lethal activity of this venom, but interferes with mechanisms of ADP-induced platelet aggregation.
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PMID:NPP-BJ, a nucleotide pyrophosphatase/phosphodiesterase from Bothrops jararaca snake venom, inhibits platelet aggregation. 1948 61