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Biomedical subjects

P J Roberts

Publications and source records attributed to P J Roberts.

At least 19 recordsLinked to original sources
PubMed1992

L-aspartate-beta-hydroxamate exhibits mixed agonist/antagonist activity at the glutamate metabotropic receptor in rat neonatal cerebrocortial slices.

L-aspartate-beta-hydroxamate, a glutamate uptake inhibitor, was investigated for activity at a glutamate metabotropic receptor (mGluR) in neonatal rat cerebral cortical slices. Stimulation of phosphatidylinositol hydrolysis by 100 microM (1S,3R)-ACPD was inhibited only very weakly, to a maximal extent of 28%, L-aspartate-beta-hydroxamate did however exhibit agonist activity (EC50 = 760 microM) and, although much less potent than (1S,3R)-ACPD (EC50 = 20 microM), its efficacy was approximately 70% of the latter. These results indicate that, at least in this preparation, offspartate-beta-hydroxamate is of little value as an antagonist at the mGluR receptor.

Animals↗
PubMed1992

Modulation of [3H]3-((+-)-2-carboxypiperazin-4-yl)propyl-1-phosphonic acid ([3H]CPP) binding by ligands acting at the glycine and the polyamine sites of the rat brain NMDA receptor complex.

The competitive N-methyl-D-aspartate (NMDA) receptor antagonist [3H]3-((+-)-2-carboxypiperazin-4-yl)propyl-1-phosphonic acid ([3H]CPP) interacts with two discrete binding sites, one of high- and the other of low-affinity, on rat forebrain synaptic plasma membranes. The high affinity site exhibited a Kd of 101.5 nM and a Bmax of 2.01 pmol/mg, while for the low affinity site the Kd was 4.11 microM with a Bmax of 19.7 pmol/mg. The glycine site antagonists 3-amino-1-hydroxy-2-pyrrolidone (HA-966), 1-aminocyclobutanecarboxylic acid (ACBC), the glycine site agonist 1-aminocyclopropanecarboxylic acid (ACC) and glycine itself (as well as the polyamines spermine and spermidine), enhanced [3H]CPP binding. When subjected to saturation analysis, this enhancement was found primarily to involve an increase in the affinity of the high affinity component of [3H]CPP binding. Neither of the parameters of the low affinity component of binding were affected. Although a similar enhancement was observed with the polyamines, the effects of these two classes of ligands were additive, consistent with their having actions at different recognition sites on the NMDA receptor complex.

Amino Acids↗
PubMed1992

Down-regulation of human protein kinase C alpha is associated with terminal neutrophil differentiation.

We have established an RNase protection method to quantify the expression of mRNA for the human protein kinase C (PK-C) isoforms alpha, beta 1, beta 2, and gamma. This was used to investigate whether each isoform is differentially expressed during the differentiation of hematopoietic cells. Myeloid and lymphoid cells express PK-C alpha, beta 1, and beta 2 mRNAs in various proportions. PK-C gamma mRNA was detected in human brain, but not in hematopoietic cells. PK-C alpha mRNA decreases as HL-60 cells mature to a neutrophil phenotype in response to retinoic acid, but its abundance does not change during monocytic differentiation in response to vitamin D3. PK-C alpha mRNA and protein were undetectable in peripheral blood neutrophils, but are present in monocytes. The mRNAs for PK-C beta 1 and beta 2 isoforms increase during HL-60 differentiation and are expressed in both neutrophils and monocytes. Therefore, the PK-C alpha isoform is specifically down-regulated during human neutrophil terminal differentiation. These data suggest that mature neutrophil functions do not require the PK-C alpha isoform.

Calcitriol↗
PubMed1992

Heterogeneity of NMDA receptors labelled with [3H]3-((+-)-2-carboxypiperazin-4-yl) propyl-1-phosphonic acid ([3H]CPP): receptor status in Alzheimer's disease brains.

The binding of [3H]3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid ([3H]CPP) was studied in rat and human brain synaptic membranes. Specific binding was saturable, reversible and inhibited by a range of compounds active at N-methyl-D-aspartate (NMDA) receptors such as 2-amino-5-phosphonopentanoate (AP5), 2-amino-7-phosphonoheptanoate (AP7), NMDA and cis-2,4-methanoglutamate. Binding was heterogeneous as evidenced by non-linear Scatchard plots and Hill coefficients for binding inhibitors significantly different from unity. LIGAND analysis of the binding data indicated the likely presence of two distinct binding components for CPP, one of high (Kd values approx. = 70 nM) and the other of low (Kd values approx. 5 microM) affinity. Possible alterations in the binding of [3H]CPP to either site were investigated in medial frontal and medial temporal cortex from Alzheimer's disease brains and compared with control tissues, carefully matched for age and postmortem delay. While there were considerable inter-individual variations in binding, no significant differences were detected either between brain regions in either Alzheimer or control subjects, or between Alzheimer's disease and control brains. These data suggest the presence of at least two components of [3H]CPP binding in both rat and human brain tissue. The integrity of neither of these components is altered in Alzheimer's disease, consistent with a lack of gross alterations of NMDA receptors in this disorder.

2-Amino-5-phosphonovalerate↗
PubMed1992

(S)-homoquisqualate: a potent agonist at the glutamate metabotropic receptor.

The synthetic quisqualate analogue, (S)-homoquisqualate was examined for activity at the glutamate metabotropic receptor, in relation to its ability to stimulate phosphoinositide hydrolysis in rat pup cerebro-cortical slices. The compound produced a robust increase in hydrolysis (EC50 = 50.2 +/- 1.6 microM), which, in common with responses to quisqualate and (1S,3R)-1-aminocyclopentane-1,3-dicarboxylate ((1S,3R)-ACPD), was antagonized uncompetitively by L-2-amino-3-phosphonopropionate (L-AP3). In contrast to quisqualate which exhibits low efficacy, (S)-homoquisqualate behaves as a full agonist at the metabotropic receptor.

Animals↗
PubMed1992

Tumour markers CA 19-9 and CA 50 in digestive tract malignancies.

CA 19-9 and CA 50 are tumour marker tests measuring the same carbohydrate structure, sialosyl-fucosyl-lactotetraose--that is, the sialylated Lewis blood group antigen. In addition, the C50 antibody reacts with sialosyl-lactotetraose, which may be expressed in small amounts in some carcinomas. In this study we compared these tests in sera from patients with benign and malignant digestive tract diseases. The sensitivity of the markers for different cancers was also compared at several specificity levels with patients with benign diseases as reference groups. Both markers showed a high sensitivity for pancreatic cancer (77% for CA 19-9; 69% for CA 50) and biliary cancer (88%). The figures in colorectal cancer were almost as high as those reported for CEA; 16-21% elevated values in Dukes A and B tumours and 44-47% in Dukes C and D tumours. The sensitivity for gastric cancer was 48% for both markers. CA 50 had a higher sensitivity for liver cancer (55%) than CA 19-9 (9%), but the proportion of elevated values in benign liver diseases was also higher (33% versus 15%, respectively). Overall, there was good correlation between the CA 19-9 and CA 50 levels, and the difference in sensitivity and specificity was marginal. In clinical practice the greatest value of CA 19-9 and CA 50 is in the diagnosis of pancreatic cancer.

Antigens, Tumor-Associated, Carbohydrate↗
PubMed1992

Persistent free-running circannual reproductive cycles during prolonged exposure to a constant 12L:12D photoperiod in laboratory woodchucks (Marmota monax).

Serum levels of gonadal steroid were assayed at approximately 3-month intervals in groups of 5 to 8 male or female woodchucks which were exposed to a natural photoperiod for 1 year as yearlings or 3 years as adults (Study 1), or a constant photoperiod of 12L:12D from birth for 4.5 years (Study 2). After 4.5 years of 12L:12D, food intake was measured in November and compared with that in natural photoperiod animals (Study 3). Other groups of 11 males and 3 females were housed in 12L:12D for 2.5 years after capture at 2 months of age, and gonadal structure and serum steroid levels in November were compared with those of animals at selected times in the normal annual cycle (Study 4). All animals were provided food and water ad libitum and were not induced to hibernate. In Study 1, normal circannual breeding season elevations in testosterone in males and in progesterone in females were detected in most animals maintained in natural photoperiod. In Study 2, similar cycles persisted for 4.5 years in animals exposed to 12L:12D. However, based on quarterly blood samples, obvious asynchrony relative to natural light animals appeared to develop after 2, 3, or 4 years, with apparent free-running intervals of about 10 to 11 months. In Study 3, mean daily food consumption in late autumn for woodchucks in the 12L:12D group was 72% greater than animals in the natural photoperiod. In Study 4, some woodchucks exposed to 12L:12D for only 2.5 years had prematurely increased spermatogenic activity, Leydig tissue development, and elevated serum testosterone levels in November. They were similar in November to those in natural photoperiod animals in March, and significantly greater than those in natural photoperiod animals in November when normal regression and repair of the testis was complete. Likewise, females in the 12L:12D group had luteinized follicles and elevated progesterone in November which were not noted in natural photoperiod animals and which were similar to those observed during the spring in unbred females under normal conditions. The results suggest that circannual cycles of metabolic and reproductive activity in woodchucks persist in the absence of normal changes in photoperiod, are entrained to seasonal changes in the natural photoperiod, and can recede to a periodicity of less than 12 months within 2.5 to 4 years of laboratory maintenance in 12L:12D.

Animals↗
PubMed1991

Differentiation-linked activation of the respiratory burst in a monocytic cell line (U937) via Fc gamma RII. A study of activation pathways and their regulation.

Activation of the respiratory burst in the monocytic cell line U937 by cross-linking human 40-kDa FcR for IgG (Fc gamma RII) with the IgG1 mAb, CIKM5, is dependent on the maturation state of the cell. Addition of anti-Fc gamma RII to undifferentiated cells does not activate the respiratory burst but differentiation with human rIFN-gamma (200 U/ml) for 13 to 15 days results in maximal stimulation by this agonist, with half-maximal responses in cells incubated for 10 to 12 days. During maturation the development of responsiveness to cross-linking Fc gamma RII occurs later than the development of responsiveness to the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (maximal responses at 7 to 9 days), or the chemotactic peptide FMLP (half-maximal responses at 7 to 9 days). The late development of maximal Fc gamma RII responses is not associated with either increased Fc gamma RII expression, enhanced calcium mobilization induced by anti-Fc gamma RII, changes in protein kinase C activity (PKC) or a switch in PKC isotype expression. Activation of the respiratory burst via Fc gamma RII may not be mediated by activation of PKC as the kinase inhibitors 1-(5-isoquinolinesulfonyl)-2-methylpiperazine dihydrochloride and N-[2-(methylamino)ethyl]-5-isoquinolinesulfonamide dihydrochloride inhibited the Fc gamma RII response by less than 20% at concentrations which inhibit the 12-O-tetradecanoylphorbol-13-acetate-induced respiratory burst by more than 80%. IFN-gamma U937 cells did not metabolize incorporated arachidonate into eicosanoids when stimulated with anti-Fc gamma RII, suggesting that eicosanoids do not mediate activation of the respiratory burst, and this was confirmed by the lack of inhibition by the specific 5'-lipoxygenase and glutathione S-transferase inhibitor, piriprost, and the cyclo-oxygenase inhibitor, indomethacin. In addition there was no significant release of radiolabeled arachidonate in response to anti-Fc gamma RII. The response to anti-Fc gamma RII is inhibited by pertussis toxin, suggesting that signal transduction is via a GTP-binding protein. Agents that elevate intracellular cAMP increased the magnitude of the cAMP transients stimulated by anti-Fc gamma RII and also inhibited the respiratory burst. FMLP responses showed a similar pattern of sensitivity to this range of inhibitors, suggesting that both Fc gamma RII and FMLP receptor share common regulatory mechanisms. However, the termination of the respiratory burst activated via Fc gamma RII and FMLP receptor is independently regulated, in that after FMLP-induced activation there is no subsequent inhibition of the Fc gamma RII-mediated response and vice versa.

Antigens, Differentiation↗
PubMed1978

The uptake and release of [3-H]-2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthlane (ADTN) by striatal nerve terminals.

A study has been made of the uptake and release of [G-3H]-2-amino 6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene (ADTN) by crude striatal synaptosomes of the rat. 2 Uptake was rapid, temperature-dependent and could be suppressed by a variety of metabolic inhibitors. 3 The Michaelis-Menten kinetincs indicated the presence of two distinct transport systems in the striatum which were of much higher capacity than those found in the cerebellum, which lacks dopaminergic innervation. 4 Uptake of [3-H]ADTN was strongly inhibited by dopamine and the two potent dopamine-uptake inhibitors, benztropine and nomifensine, but only weakly by imipramine and amphetamine (the latter in non-reserpine-treated animals). 5 Accumulated [3-H]ADTN could be released from striatal slices by elevated K+. A similar release was evoked upon the addition of the ionophore, A23187. 6 The most potent releaser of [3-H]ADTN was (+)-amphetamine. This effect occurred at concentrations inactive against ADTN uptake. The neuroleptic cis-flupenthixol produced an inhibition of the spontaneous release. 7 It is concluded that [3-H]ADTN is accumulated preferentially into areas of the rat brain rich in dopamine. The pharmacological specificity of the uptake suggests that it is a good substrate for the dopamine carrier. Following uptake, [3-H]-ADTN may be released by K+ and a calcium ioniphore, which raises the possibility that ADTN might act as a false transmitter.

Amphetamines↗