Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We studied the abundance, subcellular distribution of a non-receptor protein-tyrosine kinase p72syk (Taniguchi, T., Kobayashi, T., Kondo, J., Takahashi, K., Nakamura, H., Suzuki, J., Nagai, K., Yamada, T., Nakamura, S., and Yamamura, H. (1991) J. Biol. Chem. 266, 15790-15796) in porcine polymorphonuclear neutrophils and the activation upon the stimulation with concanavalin A. The abundance was about 0.1% of total proteins and mainly distributed in the particulate fraction. Upon concanavalin A stimulation, the activity of p72syk increased within 30 s, attained to the maximum level at 1 min, and then returned to the basal level within 6 min. This activation was observed in a dose-dependent manner and abrogated by simultaneous addition of methyl alpha-mannopyranoside. When both extra- and intracellular Ca2+ were depleted, the activation of p72syk was still persistent; in contrast, the deactivation process was completely abrogated even at 6 min after stimulation. The replenishment of Ca2+ in the presence of A23187 resulted in a similar deactivation pattern as seen in the Ca(2+)-rich condition. In addition, genistein and herbimycin A, potent protein-tyrosine-kinase inhibitors, were capable of reducing concanavalin A-evoked p72syk activation and Ca2+ mobilization as well as the aggregation and lysozyme release. Furthermore, A23187-induced Ca2+ accumulation in inhibitor-treated cells resulted in the restoration of those cellular responses. These lines of evidence suggest that p72syk is activated with concanavalin A in a Ca(2+)-independent manner, participating in a mechanism of Ca2+ recruitment, and negatively regulated by a feedback mechanism through Ca2+ in neutrophils.
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PMID:Activation of protein-tyrosine kinase p72syk with concanavalin A in polymorphonuclear neutrophils. 822 57

Site-specific attachment of metal chelators or cytotoxic agents to the carbohydrate region of monoclonal antibodies results in clinically useful immunoconjugates [Doerr et al. (1991) Ann Surg 214: 118, Wynant et al. (1991) Prostate 18: 229]. Since the capacity of monoclonal antibodies (mAb) to mediate tumor cell lysis via antibody-dependent cellular cytotoxicity (ADCC) or complement-dependent cytotoxicity (CDC) may accentuate the therapeutic effectiveness of immunoconjugates, we determined whether site-specific modification of mAb carbohydrates interfered with these functions. The chemical modifications examined consisted of periodate oxidation and subsequent conjugation to either a peptide linker/chelator (GYK-DTPA) or a cytotoxic drug (doxorubicin adipic dihydrazide). mAb-associated carbohydrates were also modified metabolically by incubating hybridoma cells in the presence of a glucosidase inhibitor deoxymannojirimycin to produce high-mannose antibody. All four forms (unaltered, oxidized, conjugated and high-mannose) of murine mAb OVB-3 mediated tumor cell lysis via CDC. Similarly, equivalent ADCC was observed with native and conjugated forms of mAb OVB-3 and EGFR.1. ADCC was achieved with different murine effector cells such as naive (NS), poly (I*C)- and lipopolysaccharide-stimulated (SS) spleen cells, or Corynebacterium-parvum-elicited peritoneal cells (PEC). All murine effector cell types mediated tumor cell lysis but differed in potency such that PEC > SS > NS. Excellent ADCC activity was also demonstrable by human peripheral blood mononuclear cells with OVB-3-GYK-DTPA and high-mannose OVB-3 mAb. ADCC activity was detectable in vivo: both native and conjugated OVB-3 inhibited growth of OVCAR-3 xenografts in nude mice primed with C. parvum. In conclusion, modification of mAb carbohydrates did not compromise their in vivo or in vitro biological functions. Therefore, combination therapy using immunomodulators to enhance the effector functions of site-specific immunoconjugates could be seriously contemplated.
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PMID:Modification of monoclonal antibody carbohydrates by oxidation, conjugation, or deoxymannojirimycin does not interfere with antibody effector functions. 829 15

When rat peritoneal nonadherent cells were treated with inflammatory lipid metabolites and cultured with adherent cells in 1% fetal calf serum (FCS) supplemented medium RPMI 1640 (FCS medium) for 3 hr, markedly enhanced phagocytic and superoxide generating capacities of macrophages were observed. Stepwise preparation of conditioned medium of lysophosphatidylcholine (lyso-Pc)-treated B cells and untreated T cells in FCS medium generated a potent macrophage activating factor whereas cultivation of lyso-Pc-treated B cells alone in a 1% adult rat serum supplemented medium efficiently generated the macrophage activating factor. Generation of macrophage activating factor requires a precursor protein, serum vitamin D3-binding protein (DBP), as well as participation of lymphocyte glycosidases. The lyso-Pc-inducible beta-galactosidase of B lymphocytes and the Neu-1 sialidase of T lymphocytes modified bovine DBP (bDBP) to yield the macrophage activating factor, a protein with N-acetylgalactosamine as the remaining sugar. In contrast, lyso-Pc-inducible beta-galactosidase of B cells alone modified rat DBP (rDBP) to yield the macrophage activating factor, a protein with N-acetylgalactosamine as the remaining sugar. Thus, we conclude that bDBP carries a trisaccharide composed of N-acetylgalactosamine, galactose, and sialic acid while rDBP carries a disaccharide composed of N-acetylgalactosamine and galactose.
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PMID:Vitamin D3-binding protein as a precursor for macrophage activating factor in the inflammation-primed macrophage activation cascade in rats. 866 Aug 14

We studied the outermost constituents of the cell envelopes, which are involved in the interaction between the bacilli and the host cells, of five pathogenic and non-pathogenic mycobacterial species for comparison with those we have previously characterized from M. tuberculosis. The extracellular materials (ECMs) were isolated by ethanol precipitation and compared to the surface-exposed materials (SXMs) extracted by mechanical means. The materials from both sources were composed almost exclusively of polysaccharides and proteins. Two groups of mycobacteria were clearly distinguishable. The first group comprised the pathogenic species M. kansasii which produced large amounts of ECM, the glycosyl composition of which was similar to that of the SXM. The second group comprised M. avium and the non-pathogenic strains of M. gastri, M. phlei and M. smegmatis which produced small amounts of ECK This latter group could be subdivided into those which produced carbohydrate-rich ECM (M. avium and M. gastri) and those forming protein-rich ECM (M. phlei and M. smegmatis), a classification that correlated with the difference in the growth rate of the two subgroups. The glycosyl composition of the ECM of a given species was qualitatively similar to that of the SXM, except for M. avium and M. phlei whose SXM were devoid of arabinose. In addition to glucose, mannose and arabinose, xylose was detected in the hydrolysis products of the ECM and SXM of M. smegmatis, the SXM of M. phlei and the ECM of some batches of M. avium. The polysaccharide constituents of the ECM and SXM of the different mycobacteria were purified by anion-exchange and gel-filtration chromatography; all were found to be neutral compounds devoid of acyl substituents. The extracellular polysaccharides consisted of high-molecular-mass glycogen-like glucans, arabinomannans and mannans, structurally similar to the corresponding substances previously characterized from the capsule of M. tuberculosis. The same types of polysaccharides were characterized from the SXM of all the strains, except M. avium and M. phlei which were devoid of arabinomannans. This study questions the unique and universal representation of the mycobacterial cell envelope and the existence of the so-called acidic polysaccharide-rich outer layer.
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PMID:Extracellular and surface-exposed polysaccharides of non-tuberculous mycobacteria. 870 91

When mouse peritoneal nonadherent (lymphocytes) cells were treated with lysophosphatidylcholine (lyso-Pc) and cultured with adherent cells (macrophages) in 1% fetal calf serum (FCS)- or adult mouse serum (AMS)-supplemented medium for 3 h, markedly enhanced phagocytic and superoxide-generating capacities of macrophages were observed. Stepwise cultivation of lyso-Pc-treated B cells and untreated T cells with an FCS-supplemented medium generated a macrophage-activating factor (MAF), whereas cultivation of lyso-Pc-treated B cells alone in AMS-supplemented medium was sufficient to generate the MAF. The accumulated evidence suggests that lyso-Pc-inducible beta-galactosidase of B lymphocytes and the Neu-1 sialidase of T lymphocytes modified the bovine serum vitamin D3-binding protein (DBP) to yield the MAF, a protein with N-acetylgalactosamine as the remaining sugar. In contrast, the lyso-Pc-inducible beta-galactosidase of B cells alone modified mouse DBP to yield the MAF. These observations led us to conclude that bovine DBP carries a trisaccharide composed of N-acetylgalactosamine, galactose, and sialic acid, whereas mouse DBP carries a disaccharide composed of N-acetylgalactosamine and galactose. Thus, macrophages of a T-cell-deficient nude (BALB/c nu/nu) mouse and a T-cell Neu-1 sialidase-deficient SM/J mouse were efficiently activated by administration of lyso-Pc.
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PMID:Role of vitamin D3-binding protein in activation of mouse macrophages. 875 64

Hypoxic accumulation of 2-[5,6-3H]fluoro-2-deoxy-D-glucose ([3H]FDG),L-[methyl-3H] methionine ([3H]MET), and L-[1-3H]leucine ([3H]LEU) was evaluated in two cell lines (UT-SCC-5 and UT-SCC-20) obtained from patients with squamous-cell carcinoma of the head and neck. Both cell lines were exposed to decreasing oxygen atmosphere (20%, 1.5%, or 0% O2) for 6 h, after which they were incubated for a further 1 h with tritiated FDG, MET, or LEU. An anoxic atmosphere resulted in a mean increase of [3H]FDG uptake of 120% and 46% over a baseline 20% oxygen atmosphere for UT-SCC-5 and UT-SCC-20A, respectively. Both total and acid-precipitable [3H]MET uptake remained unchanged at 0% versus baseline, whereas acid-precipitable [3H]LEU uptake decreased by 46% for UT-SCC-5 and by 34% for UT-SCC-20A at 0% O2. Our findings demonstrate that [3H]FDG accumulation is increased in hypoxic UT-SCC cell lines probably through activation of the metabolic steps associated with the glycolytic pathway. The decrease in acid-precipitable [3H]LEU uptake in hypoxia may indicate a decline in protein synthesis, whereas the unchanged [3H]MET uptake probably reflects the unaffected amino acid transport and slow incorporation of radiolabeled methyl group of MET in tumor proteins and nucleic acids. FDG and LEU, but probably not MET, warrant additional study as hypoxia-avid or hypoxia-reduced tracers for assessment of treatment effects designed to modify hypoxia.
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PMID:Influence of hypoxia on tracer accumulation in squamous-cell carcinoma: in vitro evaluation for PET imaging. 900 82

In the framework of a project aimed at the elucidation of the nature of the functional importance of the N-glycosylation of the alpha-subunit of the glycoprotein hormones human lutropin and human chorionic gonadotropin, the structural element alpha-Neu p5Ac-(2-->6)-beta-D-GalpNac-(1-->4)- beta-D-GlcpNAc-(1-->2)-alpha-D-Manp, which is part of the carbohydrate chains of human lutropin, has been prepared by chemical and chemo-enzymatic synthesis in the form of its propyl glycoside. Condensation of 4-O- acetyl-3,6-di-O-benzyl-2-deoxy-2-phthalimido-alpha/beta-D-glucopyranosyl trichloroacetimidate with allyl 3,4,6-tri-O-benzyl-alpha-D-mannopyranoside gave after deacetylation allyl (3,6-di-O-benzyl-2-deoxy-2-phthalimido-beta-D-glucopyranosyl) -(1-->2)-3,4,6-tri-O-benzyl-alpha-D-mannopyranoside. Ethyl 3-O-benzyl-2-deoxy-2-phthalimido-l-thio-beta-D-glucopyranoside was converted into the galacto-derivative ethyl 4,6-di-O-acetyl-3-O-benzyl-2-deoxy-2-phthalimido-1-thio-beta-D -galactopyranoside via an oxidation-reduction route, as well as via SN2-type substitution with acetate. The use of this galacto thioglycoside, after its conversion into the corresponding bromide, as GaIN donor for condensation with the mentioned disaccharide derivative yielded after deacetylation allyl (3-O-benzyl-2-deoxy-2-phthalimido-beta-D-galactopyranosyl)-(1-->4) -(3,6-di-O-benzyl-2-deoxy-2-phthalimido-beta-D-glucopyranosyl)-(1-->2) -3,4,6-tri-O-benzyl-alpha-D-mannopyranoside. Methylsulfenyl bromide-silver triflate promoted sialylation of this trisaccharide derivative with O-ethyl S-[methyl (5-acetamido-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-D -glycero-alpha-D-galacto-non-2-ulopyranosyl)onate] dithiocarbonate and subsequent deprotection resulted into the aimed tetrasaccharide structural element. Alternatively, this compound was prepared via a block synthesis, which, however, was not superior to the linear strategy. Finally, a stereose lective sialylation of synthetically prepared beta-D-GalpNAc-(1-->4)-beta-D-GlcpNAc-(1-->2)-alpha-D-Manp-(1-->O) CH2CH2CH3 with CMP-Neu5Ac and rat liver alpha-2,6-sialyltransferase was accomplished affording the same tetrasaccharide structural element.
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PMID:Chemical and chemo-enzymatic synthesis of the alpha-Neu p5Ac-(2-->6)- beta-D-GalpNAc-(1-->4)-beta-D-GlcpNAc-(1-->2)-alpha-D-Manp element that is part of N-linked carbohydrate chains of human lutropin. 920 38

We used [18F]-2-fluoro-2-deoxy-D-glucose (FDG) and PET to study regional cerebral glucose utilization in seven patients with fatal familial insomnia (FFI), an inherited prion disease with a mutation at codon 178 of the prion protein gene. Four patients were methionine/methionine homozygotes at codon 129 (symptom duration, 8.5 +/- 1 months) and three were methionine/valine (MET/VAL129) heterozygotes (symptom duration, 35 +/- 11 months). A severely reduced glucose utilization of the thalamus and a mild hypometabolism of the cingulate cortex were found in all FFI patients. In six subjects the brain hypometabolism also affected the basal and lateral frontal cortex, the caudate nucleus, and the middle and inferior temporal cortex. Comparison between homozygous or heterozygous patients at codon 129 showed that the hypometabolism was more widespread in the MET/VAL129 group, which had a significantly longer symptom duration at the time of [18F] FDG PET study. Comparison between neuropathologic and [18F] FDG PET findings in six patients showed that areas with neuronal loss were also hypometabolic. However, cerebral hypometabolism was more widespread than the histopathologic changes and significantly correlated with the presence of protease-resistant prion protein (PrPres). Our findings indicate that hypometabolism of the thalamus and cingulate cortex is the hallmark of FFI, while the involvement of other brain regions depends on the duration of symptoms and some unknown factors specific to each patient. The present data also support the notion that PrPres formation is the cause of neuronal dysfunction in prion diseases.
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PMID:Cerebral metabolism in fatal familial insomnia: relation to duration, neuropathology, and distribution of protease-resistant prion protein. 922 80

Extracts of human liver were found to contain activities which copurified and coeluted with the two major subtypes of mediators (type A and type P) isolated from insulin-stimulated rat liver. The putative type A mediator from human liver inhibited cAMP-dependent protein kinase from bovine heart, decreased phosphoenolypyruvate carboxykinase mRNA levels in rat hepatoma cells, and stimulated lipogenesis in rat adipocytes. The putative type P mediator stimulated bovine heart pyruvate dehydrogenase phosphatase. Both fractions were able to stimulate proliferation of EGFR T17 fibroblasts and the type A was able to support growth in organotypic cultures of chicken embryo cochleovestibular ganglia. Both activities were resistant to Pronase treatment and the presence of carbohydrates, phosphate, and free-amino groups were confirmed in the two fractions. These properties are consistent with the structure/ function characteristics of the type A and P inositolphosphoglycans (IPG) previously characterized from rat liver. Further, the ability of the human-derived mediators to interact with rat adipocytes and bovine-derived metabolic enzymes suggests similarity in structure between the mediators purified from different species. Galactose oxidase-susceptible membrane-associated glycosylphosphatidylinositols (GPI) have been proposed to be the precursors of IPG. GPI was purified from human liver membranes followed by treatment with galactose oxidase and reduction with NaB3H4. Serial t.l.c. revealed three radiolabeled bands which comigrated with the putative GPI precursors found in rat liver. These galactose-oxidase-reactive lipidic compounds, however, were only partially susceptible to hydrolysis with phosphatidylinositol-specific phospholipase C from Bacillus thuringiensis and were resistant to glycosylphosphatidylinositol-specific phospholipase C from Trypanosoma brucei. These data indicate that IPG molecules with insulin-like biological activities are present in human liver.
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PMID:Isolation and partial characterisation of insulin-mimetic inositol phosphoglycans from human liver. 925 87

This study compared specific phenotypic and potential virulence characteristics of Staphylococcus aureus isolates from invasive infections and nasal carriers. Three hundred and sixty isolates were studied; 154 from septicaemia (69 line associated, 85 non-line), 79 from continuous ambulatory peritoneal dialysis (CAPD) peritonitis, 64 from bone/joint infections and 64 from healthy nasal carriers. The isolates were tested for production of enterotoxins (SE) A, B, C or E, toxic shock syndrome toxin-1 (TSST-1) protein A, and also for lipolytic, proteolytic, fibrinolytic and haemolytic activities. In addition phage typing, crystal violet reaction, urease and galactose breakdown were studied. Seventy-one percent of isolates were enterotoxigenic. Production of SEA was significantly lower amongst the bone/joint isolates. Production of SEB, was lower among the control group compared with CAPD, bone/joint, and non-line septicaemia isolates. SEE production was higher among the bone/joint isolates compared with the CAPD and non-line septicaemias and production of TSST-1 was significantly higher among nasal isolates compared with isolates causing infection. Almost all of the isolates were lipolytic, with highest activity amongst nasal and bone/joint isolates. Fibrinolytic activity was similar in the five groups of isolates. Proteolytic activity ranged from 35 to 62% of isolates with the lowest frequency among septicaemia isolates. In all, 80-90% of isolates were haemolytic, although CAPD isolates were less likely to be haemolytic. Isolates from the control and CAPD group more frequently belonged to phage group I. TSST-1 does not appear to be an important requirement for invasive infections, but SEB may be. Proteolysis and intensity of lipolysis appear to be less important in septicaemia, and haemolysis may not be important in CAPD peritonitis.
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PMID:Comparative phenotypic characteristics of Staphylococcus aureus isolates from line and non-line associated septicaemia, CAPD peritonitis, bone/joint infections and healthy nasal carriers. 951 32


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