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At least 253 records · Page 14Linked to original sources
PubMed2001

Regulation of NMDA receptors by cyclin-dependent kinase-5.

Members of the N-methyl-d-aspartate (NMDA) class of glutamate receptors (NMDARs) are critical for development, synaptic transmission, learning and memory; they are targets of pathological disorders in the central nervous system. NMDARs are phosphorylated by both serine/threonine and tyrosine kinases. Here, we demonstrate that cyclin dependent kinase-5 (Cdk5) associates with and phosphorylates NR2A subunits at Ser-1232 in vitro and in intact cells. Moreover, we show that roscovitine, a selective Cdk5 inhibitor, blocks both long-term potentiation induction and NMDA-evoked currents in rat CA1 hippocampal neurons. These results suggest that Cdk5 plays a key role in synaptic transmission and plasticity through its up-regulation of NMDARs.

Animals↗
PubMed2001

N-methyl-D-aspartate receptors regulate a group of transiently expressed genes in the developing brain.

Mammalian brain development requires the transmission of electrical signals between neurons via the N-methyl-d-aspartate (NMDA) class of glutamate receptors. However, little is known about how NMDA receptors carry out this role. Here we report the first genes shown to be regulated by physiological levels of NMDA receptor function in developing neurons in vivo: NMDA receptor-regulated gene 1 (NARG1), NARG2, and NARG3. These genes share several striking regulatory features. All three are expressed at high levels in the neonatal brain in regions of neuronal proliferation and migration, are dramatically down-regulated during early postnatal development, and are down-regulated by NMDA receptor function. NARG2 and NARG3 appear to be novel, while NARG1 is the mammalian homologue of a yeast N-terminal acetyltransferase that regulates entry into the G(o) phase of the cell cycle. The results suggest that highly specific NMDA receptor-dependent regulation of gene expression plays an important role in the transition from proliferation of neuronal precursors to differentiation of neurons.

Acetyltransferases↗
PubMedDate not supplied

Global cerebral ischemia and reperfusion alters NMDA receptor binding in canine brain.

We employed a canine model to test whether binding to the N-methyl-D-aspartate (NMDA) class of glutamate receptor channels is altered by global cerebral ischemia and/or reperfusion. Ischemia was induced by 10-min cardiac arrest, followed by restoration of spontaneous circulation for periods of 0, 0.5, 2, 4, and 24 h. In vitro autoradiography was performed on frozen brain sections with three radioligands: [3H]glutamate (under conditions to label the NMDA site), [3H]glycine, and [3H]MK-801. Modest decreases in [3H]glutamate and [3H]MK-801 binding were seen in several regions of hippocampus, and parietal and temporal cortex at early times after reperfusion, with values returning toward control by 24 h. In the striatum, a different pattern was seen: [3H]glutamate and [3H]MK-801 binding increased 50-200% at 0.5-4 h after the start of reperfusion, returning toward control levels by 24 h. These increases correlate with findings of increased sensitivity to NMDA-stimulated release of dopamine from striatal tissue in the same model (Werling et al., 1993), and suggest that changes in tissue receptors may contribute to the selective vulnerability to ischemic damage during the first hours following reperfusion.

Animals↗
PubMed2004

Synthesis, biological evaluation, and structural studies on N1 and C5 substituted cycloalkyl analogues of the pyrazole class of CB1 and CB2 ligands.

A series of N1 and C5 substituted cycloalkyl and C5 4-methylphenyl analogues of the N-(piperidin-1-yl)-4-methyl-1H-pyrazole-3-carboxamide class of cannabinoid ligands were synthesized. The analogues were evaluated for CB1 and CB2 receptor binding affinities and receptor subtype selectivity. The effects of pyrazole substitution on ligand conformation and as such receptor affinities was not readily apparent; therefore, the geometries of the N1 and C5 substituents relative to the pyrazole ring were studied using high field NMR spectroscopy and systematic molecular mechanics geometry searches. An analysis of the relative ring geometries and functional group orientations provides new insight into the structural requirements of the CB1 and CB2 ligand binding pocket.

Animals↗
PubMed2003

Novel laccase redox mediators: spectral, electrochemical, and kinetic properties.

The screening of potential redox mediators for laccase was performed using homogeneous enzyme preparations from Coriolus hirsutus and Coriolus zonatus. It was discovered that derivatives of 1-phenyl-3-methyl-pyrazolones were efficient substrates for the laccases. The characterization of two representatives of the 1-phenyl-pyrazolone class, sodium 1-phenyl-3-methyl-4- methylamino-pyrazolone-5-N(4)-methanesulfonate and 1-(3'-sulfophenyl)-3- methylpyrazolone-5, in the reaction catalyzed by laccase was carried out using spectral, electrochemical, and enzyme kinetics methods. The kinetic parameters for the oxidation of the newly discovered substrates were comparable with those for 2,2'-azino-bis(3-ethylbenzthiazoline-6-sulfonate) (ABTS) oxidation by laccase. Electrochemical experiments demonstrated that oxidation of these compounds yielded two high-potential intermediates capable of oxidizing veratryl alcohol, which was used as a lignin model substrate, to the corresponding aldehyde and acid. 1-(3'-Sulfophenyl)-3- methylpyrazolone-5 was about 30-40% as effective in degrading veratryl alcohol compared to ABTS as judged from high-performance liquid chromatography kinetic studies. 1-Phenyl-3-methyl-pyrazolones may be of commercial interest for oxidoreductase-catalyzed biodegradation of organic compounds.

Basidiomycota↗
PubMed1986

Lack of class I H-2 antigens in cells transformed by radiation leukemia virus is associated with methylation and rearrangement of H-2 DNA.

Transformation of murine thymocytes by radiation leukemia virus is associated with reduced expression of the class I antigens encoded in the major histocompatibility complex (MHC) and increased methylation and altered restriction enzyme patterns of MHC DNA. These changes may play a role in host susceptibility to virus-induced leukemogenesis and accord with the notion that viral genomes play a regulatory function when they integrate adjacent to histocompatibility genes.

Animals↗
PubMed1977

Sensory transduction in Escherichia coli: two complementary pathways of information processing that involve methylated proteins.

The properties of two classes of behavioral mutants of Escherichia coli (called tsr and tar) are described. The mutations in these strains define two complementary pathways of information flow in bacterial chemotaxis: behavioral responses to one set of stimuli are defective in tsr mutants, while responses to a complementary set of stimuli are defective in tar mutants. A double mutant containing both genetic lesions is defective in responses to all stimuli tested. The behavioral defects are shown to correlate with alterations in the properties of a methylation reaction involved in chemotaxis. Two independent sets of methyl-accepting proteins are demonstrated in the wild type, each set functioning in one of the two pathways mentioned above. Methylation of one set of proteins is defective in tsr mutants, while methylation of the complementary set is defective in tar mutants. The double mutant shows no methylation of either set. The relationship between the genetic loci (tsr and tar) and the methyl-accepting proteins is discussed.

Bacterial Proteins↗
PubMed1996

beta-Cyano-L-alanine toxicity: evidence for the involvement of an excitotoxic mechanism.

The legume Vicia sativa (common vetch) harbors the neurotoxic nonprotein amino acid beta-cyano-L-alanine (BCLA) and its gamma-glutamyl derivative. BCLA elicits hyperexcitability, convulsions, and rigidity in chicks and rats after oral or intraperitoneal administration, but the mechanism of its action is unknown. The effect of different concentrations of BCLA (0.075-10.0 mM) has been investigated in an organotypic tissue culture system. BCLA concentrations of 0.075 and 0.60 mM had no effect, even up to 6 hr. No changes were observed in cultures treated with 1 mM BCLA for 4 hr. BCLA (2.0-10.0 mM) induces concentration-dependent changes in the explants. The explants display neurona vacuolation, chromatin, clumping, and dense shrunken cells, a pathological response generally seen with excitotoxin. MK-801 (35 microM), which blocks the open ion channel associated with the N-methyl-D-aspartate (NMDA) class of glutamate receptors, attenuates the neurotoxic property of BCLA, while the non-NMDA antagonist, 6-cyano-7-nitroquinoxaline-2,3-dione (10-20 microM), provides no significant protection. Treatment of isolated mouse brain mitochondria with up to 5 mM BCLA had no inhibitory effect on the activity of NADH dehydrogenase (complex I) or cytochrome or oxidase (complex IV), a cyanide-sensitive enzyme. These results suggest that the neurotoxicity of BCLA (or derivative) is mediated directly or indirectly through NMDA receptors.

6-Cyano-7-nitroquinoxaline-2,3-dione↗
PubMed2002

Characterisation of copia-like retrotransposons in oil palm ( Elaeis guineensis Jacq.).

The work aimed to isolate and characterise copia-like sequences from Elaeis guineensis. Thirty-two different RT (reverse transcriptase) sequences were isolated from a single oil palm genome using degenerate primers. Extreme sequence heterogeneity was observed. The DNA and protein sequences were assigned to three different classes (A, B, C) on the basis of bootstrapping. We estimated the copy number of the three different classes by using a dot-blot analysis. The comparative results suggest that class-B RT sequences occur at a higher copy number in Cocos nucifera than in Elaeis guineensis and E. oleifera. Class-C RT sequences, which comprise the bulk of isolated sequences, occur in much higher copy number in Elaeis guineensis than in Cocos nucifera, and E. oleifera. Class-A sequences, which have low copy number in Elaeis guineensis and Cocos nucifera, are not present in E. oleifera. Our preliminary results suggest that class-C sequences represent about 5% of the E. guineensis genome, class B, 1% and class A, 0.1%. The methylation status of genomic domains specified by the RT probes was analysed using two pairs of restriction enzymes, each pair having the same recognition sites but different methylation sensitivities ( MspI, HpaII and Sau3AI, MboI). Results from these experiments showed clearly that the genomic domains specified by the RT probes are methylated. These also suggest that a higher copy number appears to correlate to a higher degree of methylation. Our preliminary results suggest that copia-like retrotransposons, because of their ubiquity and diversity, have great potential as genetic markers for plant genome and biodiversity analysis in E. guineensis.

Journal Article↗
PubMed1988

NMDA receptor blockade prevents the increase in protein kinase C substrate (protein F1) phosphorylation produced by long-term potentiation.

Recent evidence has implicated activation of the N-methyl-D-aspartate (NMDA) class of glutamate receptor in the initiation of hippocampal long-term potentiation (LTP), an electrophysiological model of information storage in the brain. A separate line of evidence has suggested that activation of protein kinase C (PKC) and the consequent phosphorylation of its substrates is necessary for the maintenance of the LTP response. To determine if PKC activation is a consequence of NMDA receptor activation during LTP, we applied the NMDA receptor antagonist drug, DL-aminophosphonovalerate (APV) both immediately prior to and following high frequency stimulation, resulting in successful and unsuccessful blockade of LTP initiation, respectively. We then measured the phosphorylation of a PKC substrate (protein F1) in hippocampal tissue dissected from these animals. Only successful blockade of LTP initiation by prior application of APV was seen to block the LTP-associated increase in protein F1 phosphorylation measured in vitro (P less than 0.001 by ANOVA). This suggests that NMDA receptor-mediated initiation triggers maintenance processes that are, at least in part, mediated by protein F1 phosphorylation. These data provide the first evidence linking two mechanisms associated with LTP, NMDA receptor activation and PKC substrate phosphorylation.

2-Amino-5-phosphonovalerate↗
PubMed2005

Functional characterization and molecular modeling of methylcatechol 2,3-dioxygenase from o-xylene-degrading Rhodococcus sp. strain DK17.

Rhodococcus sp. strain DK17 is known to metabolize o-xylene and toluene through the intermediates 3,4-dimethylcatechol and 3- and 4-methylcatechol, respectively, which are further cleaved by a common catechol 2,3-dioxygenase. A putative gene encoding this enzyme (akbC) was amplified by PCR, cloned, and expressed in Escherichia coli. Assessment of the enzyme activity expressed in E. coli combined with sequence analysis of a mutant gene demonstrated that the akbC gene encodes the bona fide catechol 2,3-dioxygenase (AkbC) for metabolism of o-xylene and alkylbenzenes such as toluene and ethylbenzene. Analysis of the deduced amino acid sequence indicates that AkbC consists of a new catechol 2,3-dioxygenase class specific for methyl-substituted catechols. A computer-aided molecular modeling studies suggest that amino acid residues (particularly Phe177) in the beta10-beta11 loop play an essential role in characterizing the substrate specificity of AkbC.

Amino Acid Sequence↗
PubMed2003

A review of compounds exhibiting anti-orthopoxvirus activity in animal models.

Several animal models using mice (most frequently), rabbits, or monkeys have been used to identify compounds active against orthopoxvirus infections. The treatment of vaccinia virus infections has been well studied in models involving infection of scarified skin or eyes, or resulting from intravenous, intraperitoneal, intracerebral, or intranasal virus inoculation. Cowpox virus has been used in intranasal or aerosol infection studies to evaluate the treatment of lethal respiratory infections. Rabbitpox, monkeypox, and variola viruses have been employed to a lesser extent than the other viruses in chemotherapy experiments. A review of the literature over the past 50 years has identified a number of compounds effective in treating one or more of these infections, which include thiosemicarbazones, nucleoside and nucleotide analogs, interferon, interferon inducers, and other unrelated compounds. Substances that appear to have the greatest potential as anti-orthopoxvirus agents are the acyclic nucleotides, (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine (cidofovir, HPMPC) and 1-[((S)-2-hydroxy-2-oxo-1,4,2-dioxaphosphorinan-5-yl)methyl]cytosine (cyclic HPMPC), and the acyclic nucleoside analog, 2-amino-7-[(1,3-dihydroxy-2-propoxy)methyl]purine (S2242). Other classes of compounds that have not been sufficiently studied in lethal infection models and deserve further consideration are thiosemicarbazones related to methisazone, and analogs of adenosine-N(1)-oxide and 1-(benzyloxy)adenosine.

Animals↗
PubMed2002

Transcription factors and cancer: an overview.

Cancer represents the out-of-control proliferation of a particular cell type, which originates with an unwanted mutation, followed by an accumulation of defects in many classes of genes. The two well-known types of primary genes that govern cell division and are responsible for cancer include: protooncogenes (gain-of-function) that serve as accelerators to activate the cell cycle, and tumor suppressor genes (loss-of-function) that serve as brakes to slow the growth of cells. There are now 17 known signal transduction pathways, plus at least two stress-response pathways; all of these appear to be highly conserved in nematodes, flies and all vertebrates. Ultimately, transcription factors participate at the ends of all 19 pathways--by causing the up- or down-regulation of specific genes. All primary and modifier genes leading to cancer participate in one or another of these pathways. Innumerable exogenous and (autocrine and paracrine) endogenous signals bombard our cells each day and all are channeled through these 19 pathways, leading to the cell's response to these signals. Tumor progression represents a loss of normal cross-talk between cells, breakdown in communication between classes of genes, DNA methylation abnormalities, genetic instability, and hypermutability. Cancer is thus a multiplex phenotype: a crescendo of defects in hundreds if not thousands of genes, as a function of time, leading to an invasive and lethal disease.

Animals↗
PubMed2000

Design and synthesis of novel potent antinociceptive agents: methyl-imidazolyl N-acylhydrazone derivatives.

This paper describes recent results of design, synthesis and pharmacological evaluation of new N-heterocyclic functionalized N-acylhydrazone compounds, belonging to the 2-methyl-imidazolyl-3-acylhydrazone class (4a-e). These compounds were planned by applying the molecular simplification strategy to propose the structural modifications on the previously described functionalized imidazo [1,2-a]pyridine 3-acylhydrazone series (2), which presented an important analgesic profile. This new series (4) was synthesized in order to investigate the possible pharmacophoric contribution of the N-heteroaromatic ring and N-acylhydrazone moieties to the analgesic activity. Compounds 4a-b are the most potent antinociceptive agents from this series.

Acetic Acid↗
PubMedDate not supplied

Synthesis of N-[tris[2-[[N-(benzyloxy)amino]carbonyl]ethyl]methyl]succinamic acid, trisuccin. Hydroxamic acid derivatives as a new class of bifunctional chelating agents.

In an effort to generate bifunctional chelating agents (BCAs) with improved labeling, conjugation, and biodistribution properties, the synthesis of trisuccin is reported. This new hydroxamate BCA, after synthesis and characterization, was used for conjugation and radiolabeling of monoclonal antibodies with 99mTc. This new class of synthetic BCAs may be useful in the radioimmunodiagnosis and radioimmunotherapy of cancer.

Antibodies, Monoclonal↗
PubMed1990

Synthesis and bioactivity of a new class of rigid glutamate analogues. Modulators of the N-methyl-D-aspartate receptor.

A variety of derivatives of azetidine-2,4-dicarboxylic acid were synthesized and examined for their ability to stimulate 45Ca2+ uptake in cultures of cerebellar granule cells. Of the compounds tested, the cis-azetidine-2,4-dicarboxylic acid (10f) was found to be the most potent agent in potentiating glutamate, aspartate, or N-methyl-D-aspartate (NMDA) stimulated 45Ca2+ uptake at the NMDA receptor. The mechanism of action of 10f was further investigated in [3H]MK-801 binding assays and [3H]GABA release from cultured embryonic rat forebrain neurons. All of the results from the functional studies of azetidine 10f are consistent with a selectivity of action at the NMDA receptor. Moreover, azetidine 10f appears to exhibit a dual type of action, behaving as a glutamate-like agonist at higher concentrations and as a positive modulator at concentrations below 50 microM.

Animals↗
PubMed2004

Involvement of nitric oxide in adenosine release in the developing and adult mouse hippocampus.

The novel type of neurotransmitter/neuromodulator nitric oxide (NO) is linked to activation of the N-methyl-D-aspartate (NMDA) class of glutamate receptors and has been shown to modify transmitter release in the brain. The inhibitory neuromodulator adenosine has been thought to act as an endogenous neuroprotectant against cerebral ischemia and neuronal damage. The effects of NO-generating compounds on the release of preloaded [3H]adenosine from hippocampal slices from developing (7-day-old) and adult (3-month-old) mice were investigated, using a superfusion system, under normal conditions and in vitro ischemia. The release of adenosine was markedly potentiated at both ages by the NO-producing compounds S-nitroso-N-acetylpenicillamine, sodium nitroprusside, and hydroxylamine. The evoked releases were reduced by the NO synthase inhibitors nitroarginine and 7-nitroindazole at both ages. They were also reduced by the inhibitor of soluble guanylyl cyclase 1H-(1,2,4-oxadiazolo(4,3a)quinoxalin-1-one (ODQ) in adults, indicating that the NO/cGMP pathway is involved in this release. Release of adenosine was also evoked when the cGMP levels were increased by superfusing slices with the phosphodiesterase inhibitor zaprinast. The markedly enhanced adenosine release under ischemic conditions was further potentiated by the ionotropic glutamate receptor agonists and NO-generating compounds, whereas zaprinast and ODQ had no effect, rendering unlikely the involvement of cGMP in the ischemic release. Moreover, NO was able to provoke substantial release of adenosine in the presence of NMDA under both normal and ischemic conditions, which could significantly add to the neuroprotective potential of this neuromodulator in both adult and developing hippocampus.

Adenosine↗