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PubMed1985

Experimental methyl mercury neurotoxicity: locus of mercurial inhibition of brain protein synthesis in vivo and in vitro.

Brain cell-free protein synthesis is inhibited by methyl mercury chloride (MeHg) following in vivo or in vitro administration. In this report, we have identified the locus of mercurial inhibition of translation. Intraperitoneal injection of MeHg (40 nmol/g body wt) induced variable inhibition of amino acid incorporation into the post-mitochondrial supernatant (PMS) harvested from the brain of young (10-20-day-old) rats. No mercurial-induced disaggregation of brain polyribosomes nor change in the proportion of 80S monoribosomes was detected on sucrose density gradients. No difference in total RNA was found in the PMS. Initiation complex formation was stimulated by MeHg, as detected by radiolabelled methionine binding to 80S monoribosomes following continuous sucrose density gradient centrifugation. After micrococcal nuclease digestion of endogenous mRNA, both in vivo and in vitro MeHg inhibited polyuridylic acid-directed incorporation of [3H]phenylalanine. However, the in vivo inhibition was no longer observed when [3H]phenylalanyl-tRNAPhe replaced free [3H]phenylalanine in the incorporation assay. The formation of peptidyl[3H]puromycin revealed no difference from controls. There was significant mercurial inhibition of phenylalanyl-tRNA Phe synthetase activity in pH 5 enzyme fractions derived from brain PMS of MeHg-poisoned rats. These experiments revealed that the apparent MeHg inhibition of brain translation in vivo and in vitro is due primarily to perturbation in the aminoacylation of tRNA and is not associated with defective initiation, elongation, or ribosomal function.

Animals↗
PubMed2003

Muscarinic cholinergic and beta-adrenergic contribution to hindquarters vasodilation and cardiac responses to cocaine.

Cocaine produces a pressor response associated with an initial hindquarters vasoconstriction followed by a prolonged vasodilation in conscious rats. Propranolol pretreatment prevented the vasodilation and enhanced the pressor response, whereas atropine methylbromide pretreatment reduced the increase in systemic vascular resistance. We studied the role of selective muscarinic and beta-adrenoceptor antagonists on responses to cocaine in rats with an increase in systemic vascular resistance to cocaine (vascular responders). Arterial blood pressure and ascending aortic and distal descending aortic blood flow using pulsed Doppler flowmetry were measured. In conscious rats, cocaine (5 mg/kg i.v.) elicited consistent pressor responses but variable systemic and hindquarters vascular resistance responses that were directly correlated, suggesting that skeletal muscle resistance responses comprise an important component of systemic vascular resistance. ICI 118551 [(+/-)-1-[2,3-(dihydro-7-methyl-1H-inden-4-yl)oxy]-3-[(1-methylethyl)-amino]-2-butanol] (0.5 mg/kg i.v.) pretreatment prevented the hindquarters vasodilation, enhancing the increase in systemic vascular resistance and the pressor response while further depressing the cardiac output response, similar to the effects of propranolol. Atenolol (1 mg/kg) pretreatment attenuated the stroke volume and cardiac output responses while enhancing the increase in systemic vascular resistance without affecting the hindquarters responses. In contrast, M2 antagonist methoctramine (0.3 mg/kg) pretreatment had similar effects as atropine in reducing the decrease in cardiac output by reducing the increase in systemic vascular resistance, whereas the M1 antagonist pirenzipine (0.02 mg/kg) did not alter responses. Therefore, the cocaine-induced pressor response is ameliorated by beta2-adrenoceptor mediated skeletal muscle vasodilation, whereas the decrease in cardiac output and the increase in systemic vascular resistance are dependent on M2-cholinoceptor activation.

Adrenergic beta-Antagonists↗
PubMed1996

Vascular smooth muscle polyploidy and cardiac hypertrophy in genetic hypertension.

We studied the mechanisms responsible for vascular and cardiac hypertrophy in hypertension (pressure load and humoral and genetic factors) in two experimental approaches: (1) We carried out a cosegregation analysis to correlate cardiac and vascular hypertrophy with subphenotypes of blood pressure in an F2 generation of a cross between stroke-prone spontaneously hypertensive rats (SHRSP) and normotensive Wistar-Kyoto rats; (2) we treated 8-week-old SHRSP with perindopril, an angiotensin-converting enzyme inhibitor; losartan, an angiotensin type 1 receptor antagonist; or perindopril combined with a nitric oxide synthase inhibitor to investigate the relative contributions of blood pressure and angiotensin II to the pathogenesis of cardiac hypertrophy and vascular smooth muscle polyploidy. Vascular smooth muscle polyploidy was measured with flow cytometry DNA analysis. Cardiac hypertrophy was assessed by measuring the ratios of heart weight to body weight and left ventricle + septum weight to body weight. Blood pressure was measured with radiotelemetry in the F2 cosegregation experiment and with tail-cuff plethysmography in the pharmacological study. In the F2 rats, the best predictor of smooth muscle polyploidy by ANCOVA was systolic pressure (F=29.28, P < .0001). The ratio of left ventricle + septum weight to body weight had four major predictors: the male progenitor of the cross, sex, pulse pressure, and change in systolic pressure during salt (F=43.67, P < .0001; F=16.37, P < .0001; F=8.41, P=.0022; and F=12.39, P= .0003, respectively). The ratio of heart weight to body weight had similar predictors. In the pharmacological study, treatment with losartan alone, perindopril alone, or perindopril in combination with N(G)-nitro-L-arginine methyl ester prevented the development of smooth muscle polyploidy and cardiac hypertrophy. The prevention of cardiac hypertrophy was most marked in the SHRSP treated with perindopril plus N(G)-nitro-L-arginine methyl ester, despite blood pressure being higher in this group than in the two other treatment groups. We conclude that vascular and cardiac hypertrophy in this form of hypertension are regulated by different variables. However, suppression of the action of angiotensin II lessens hypertrophy of both types of muscle.

Angiotensin II↗
PubMed2004

Analysis of molecular pathways in neuroendocrine cancers of the gastroenteropancreatic system.

Neuroendocrine gastroenteropancreatic (GEP) tumors are rare and present with variable clinical syndromes. So far, there are no detailed studies concerning the molecular pathogenesis of sporadic GEP tumors. In our study, GEP tumors from 29 patients were assessed for microsatellite instability, aberrant promoter methylation, and LOH of various tumor suppressor genes. All tumors were microsatellite stable. One tumor showed LOH close to the APC locus, one tumor had an allelic loss near the hMLH1 gene, and one tumor showed hypermethylation of the hMLH1 promoter. Interestingly, none of the tumors was aberrantly methylated at the p16 promoter. However, 13 of 20 successfully amplified tumors (65%) were hypermethylated at the APC promoter. Of the hypermethylated tumors, none showed LOH of either the hMLH1 or the APC gene. The current study is the first report demonstrating that aberrant methylation of the APC promoter is strongly involved in the molecular tumorigenesis of neuroendocrine GEP tumors. MSI does not seem to be involved in the pathogenesis of these cancers. Further studies are required to investigate the role of hypermethylation in neuroendocrine GEP tumors and to further elucidate the role of the APC pathway in these tumors.

DNA Methylation↗
PubMed1982

Selected aminoacridines as fluorescent probes in cytochemistry in general and in the detection of cancer cells in particular.

Since cellular features can be visualized by proper staining of the biologic substrate, the interactions between the biologic dye and the substrate provide the parameters for automated cell recognition. A stock of 295 acridines and 19 derivatives of anthracene were tested as possible new compounds suitable as fluorescent probes in cytochemistry. Special attention was focused on marking fixed and unfixed cancer cells exfoliated from various organs. The results confirmed observations about the strong metachromatic properties of 3-aminoacridines and 9-aminoacridines. 9-amino-4-methyl-acridine showed an exceptionally high fluorescence of basophilic cellular structures. In addition to 4-aminoacridine, many quinacrine analogues, acridines lacking amino groups, 2-aminoacridine and some benzoacridines stained lipid droplets. A great variability in staining viable nuclei was found. 3-aminoacridine was superior as a Schiff's reagent, even in comparison to acriflavine. Not only aminoacridines but also pyrazol-anthracenes showed valuable properties as fluorochromes. Some further compounds (for instance, 9-aminoacridines) were accumulated in cytoplasmic vacuoles in a manner similar to that of the acridine orange. It is hoped that some of these compounds will prove useful in marking cancer cells.

Aminoacridines↗
PubMed1991

Characterisation of the glycine modulatory site of the N-methyl-D-aspartate receptor-ionophore complex in human brain.

[3H]Glycine binding and glycine modulation of [3H]MK-801 binding have been used to study the glycine allosteric site associated with the N-methyl-D-aspartate receptor complex in postmortem human brain. The effect of glycine on [3H]MK-801 binding appeared sensitive to duration of terminal coma, and possibly postmortem delay. Thirty percent of the binding occurred in a subfraction of brain tissue and did not show enhancement by glycine and glutamic acid. [3H]Glycine binding to a subfraction free from this component was studied and showed high specific binding. KD and Bmax values showed considerable intersubject variability which did not appear to be due to demographic features or to tissue content of amino acids with an affinity for this site. The pharmacological characteristics of binding in this subfraction and a correlation between Bmax values and the maximal enhancement of [3H]MK-801 binding by glycine are consistent with [3H]glycine binding occurring to an N-methyl-D-aspartate receptor complex associated site. Further support for this is provided by a significantly lower Bmax value for [3H]glycine binding in subjects with Alzheimer's disease and reduced glycine enhancement of [3H]MK-801 binding. However, the effect of perimortem factors makes it difficult to confidently attribute this solely to a disease-related change in the receptor. The possible role of the glycine allosteric site in the treatment of neuropsychiatric disorders is discussed.

Aged↗
PubMed1999

Nicotinic acetylcholine receptor agonist SIB-1508Y improves cognitive functioning in chronic low-dose MPTP-treated monkeys.

Monkeys that receive chronic low-dose 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine (MPTP) administration have difficulty performing numerous cognitive tasks. This study further examines the extent to which chronic low-dose MPTP exposure affects performance of a visual memory task [variable delayed response (VDR)] with both attentional and short-term memory components and assesses the effects of the novel neuronal nicotinic acetylcholine receptor agonist SIB-1508Y and levodopa on cognitive task performance. Before MPTP treatment, these monkeys displayed a delay-dependent decrement in performance on the VDR task and performed well on delayed matching-to-sample and visual pattern discrimination tasks. Chronic low-dose MPTP treatment caused a shift to a delay-independent pattern of responding on the VDR task, such that short-delay trials were performed as poorly as long-delay trials. There were also deficits in performing the delayed matching-to-sample task, whereas visual discrimination performance remained intact. SIB-1508Y normalized the pattern of response on the VDR task by significantly improving performance on short-delay trials and on the delayed matching-to-sample task. These effects lasted up to 24 to 48 h after SIB-1508Y administration. Neither levodopa nor nicotine significantly improved task performance. These results suggest that chronic low-dose MPTP exposure results in a cognitive disturbance that can be corrected by the nicotinic acetylcholine receptor agonist SIB-1508Y but not by levodopa. Thus, SIB-1508Y may be useful in the treatment of the cognitive deficits in Parkinson's disease.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed2002

Case-control study of dopamine transporter-1, monoamine oxidase-B, and catechol-O-methyl transferase polymorphisms in Parkinson's disease.

We investigated the association of Parkinson's disease (PD) with dopamine transporter-1 (DAT1), monoamine oxidase-B (MAO-B), and catechol-O-methyltransferase (COMT) gene polymorphisms. Overall, we observed no significant association of PD with the DAT1-3'-variable numbers of tandem repeats, the MAO-B-(GT)(n), and the COMT-Val108Met gene polymorphisms in a sample of 319 unrelated PD cases and 196 control subjects. Analyses stratified by sex, age at examination, family history of PD, and ethnic origin also yielded negative findings, with three exceptions. We found statistically significant associations of PD with MAO-B polymorphisms in older patients and with a COMT polymorphism in younger subjects and in women. These significant differences at the two-tailed alpha level of 0.05 and restricted to subgroup analyses may have a biological basis or may be chance findings.

Adult↗
PubMed1999

Insulin modulation of cloned mouse NMDA receptor currents in Xenopus oocytes.

Modulation of recombinant N-methyl-D-aspartate receptor (NMDAR) currents by insulin was studied using the Xenopus oocyte expression system. Insulin (0.8 microM, 10 min) regulated NMDAR currents in a subunit-specific manner. Currents from epsilon1/zeta1, epsilon2/zeta1, and epsilon4/zeta1 receptors were variably potentiated, whereas currents from epsilon3/zeta1 receptors were not. Protein tyrosine kinases (PTKs) and protein kinase C were found to be involved in insulin-mediated modulation in an NMDAR subtype-specific way. Pretreatment with a specific PTK inhibitor, lavendustin A, attenuated and blocked the insulin effect on epsilon2/zeta1 and epsilon4/zeta1, respectively. Preincubation with selective protein kinase C inhibitors, staurosporine or calphostin C, depressed the response of epsilon1/zeta1 and epsilon2/zeta1 receptors to insulin. Basal regulation of NMDAR currents by endogenous PTKs and protein tyrosine phosphatases (PTPs) was also investigated. Of the four receptor subtypes, only epsilon1/zeta1 receptor currents were affected by basal PTK inhibition via lavendustin A, whereas PTP inhibition by phenylarsine oxide or orthovanadate enhanced currents from epsilon1/zeta1 and epsilon2/zeta1 receptors. Surprisingly, a stimulatory PTP modulation was observed for epsilon4/zeta1. As NMDAR subunits are differentially expressed in the brain, the observed subtype-specific modulations of NMDAR currents by insulin, PTKs, and PTPs may provide important insights into certain NMDAR-dependent physiological and pathological processes.

Animals↗
PubMed2002

Predicting runoff-induced pesticide input in agricultural sub-catchment surface waters: linking catchment variables and contamination.

An urgent need exists for applicable methods to predict areas at risk of pesticide contamination within agricultural catchments. As such, an attempt was made to predict and validate contamination in nine separate sub-catchments of the Lourens River, South Africa, through use of a geographic information system (GIS)-based runoff model, which incorporates geographical catchment variables and physicochemical characteristics of applied pesticides. We compared the results of the prediction with measured contamination in water and suspended sediment samples collected during runoff conditions in tributaries discharging these sub-catchments. The most common insecticides applied and detected in the catchment over a 3-year sampling period were azinphos-methyl (AZP), chlorpyrifos (CPF) and endosulfan (END). AZP was predominantly found in water samples, while CPF and END were detected at higher levels in the suspended particle samples. We found positive (p < 0.002) correlations between the predicted average loss and the concentrations of the three insecticides both in water and suspended sediments (r between 0.87 and 0.94). Two sites in the sub-catchment were identified as posing the greatest risk to the Lourens River mainstream. It is assumed that lack of buffer strips, presence of erosion rills and high slopes are the main variables responsible for the high contamination at these sites. We conclude that this approach to predict runoff-related surface water contamination may serve as a powerful tool for risk assessment and management in South African orchard areas.

Agriculture↗
PubMed1994

Pyruvate dehydrogenase deficiency: molecular basis for intrafamilial heterogeneity.

Two half-brothers and their mother had symptomatic pyruvate dehydrogenase complex deficiency. The infants had severe congenital lactic acidosis, seizures, and apneic spells and died at the ages 3 and 4 months. The mother was less symptomatic with mental retardation, truncal ataxia, and dysarthria. The residual pyruvate dehydrogenase activities in cultured skin fibroblasts from the 2 infants and their mother were 7, 15, and 10% of control values. Immunoblot analysis showed negligible amounts of E1 alpha and E1 beta subunits of the complex. Northern blot analysis for the E1 alpha subunit showed normal results. In the 2 sons, complementary DNA sequence analysis revealed a cytosine to thymine mutation in exon 4, resulting in a change of arginine 127 to tryptophan in the E1 alpha subunit. Restriction enzyme analysis of the polymerase chain reaction product representing exon 4 of the E1 alpha gene revealed that the mother was a heterozygotes. Complementary DNA restriction analysis and methylation analysis of the X chromosome DXS255 loci revealed skewed activation of the mutant allele, consistent with the deficient pyruvate dehydrogenase activity in the mother's fibroblasts. The milder maternal phenotype is consistent with variable X-inactivation patterns in different organs of female heterozygotes.

Base Sequence↗
PubMed1995

Lateral domain formation in cholesterol/phospholipid monolayers as affected by the sterol side chain conformation.

The interaction of side-chain variable cholesterol analogues with dipalmitoylphosphatidylcholine (DPPC) or N-palmitoylsphingomyelin (N-PSPM) has been examined in monolayer membranes at the air/water interface. The sterols had either unbranched (n-series) or single methyl-branched (iso-series) side chains, with the length varying between 3 and 10 carbons (C3-C10). The efficacy of interaction between the sterols and the phospholipids was evaluated based on the ability of the sterols to form condensed sterol/phospholipid domains in the phospholipid monolayers. Domain formation was detected with monolayer fluorescence microscopy using NBD-cholesterol as the fluorescent probe. In general, a side chain length of at least 5 carbons was necessary for the unbranched sterols to form visible sterol/phospholipid domains in DPPC or N-PSPM mixed monolayers. With the iso-analogues, a side chain of at least 6 carbons was needed for sterol/phospholipid domains to form. The macroscopic domains were stable up to a certain surface pressure (ranging from 1 to 12 mN/m). At this onset phase transformation pressure, the domain line boundary dissipated, and the monolayer entered into an apparent one phase state (no clearly visible lateral domains). However, with some DPPC monolayers containing short chain sterols (n-C3, n-C4,n-C5, and i-C5), a new condensed phase appeared to form (at 20 mol%) when the monolayer was compressed beyond the phase transformation pressure. These precipitates formed at surface pressures between 6-8.3 mN/m, were clearly observable up to at least 30 mN/m. When the monolayers containing these four sterols were allowed to expand, the condensed precipitates dissolved at the same pressure at which they were formed during monolayer compression. No condensed precipitates were observed with these sterols in corresponding N-PSPM monolayers. Taken together, the results of this study emphasize the importance of the length and conformation of the cholesterol side chain in determining the efficacy of sterol/phospholipid interaction in model membranes. The major difference between DPPC and N-PSPM monolayers at different sterol compositions was mainly the lateral distribution and the size of the domains as well as the onset phase transformation pressure intervals.

1,2-Dipalmitoylphosphatidylcholine↗
PubMed1977

Effect of temperature and protonation upon the conformation of 2'-o-methyladenosine. Correlation of conformational parameters in purine nucleosides.

Proton magnetic resonance studies of 2'-o-methyladenosine in 2H2O have been carried out at variable temperature and p2H. The chemical shifts and H-H coupling constants are discussed in terms of the molecular conformation. Comparison of the data with those of adenosine reveals that 2'-O-methylation has little influence on the conformation. At neutral p2H where the adenine base is not protonated, the molecules favor a 2' endo, gauche-gauche conformation. Protonation of the base at the N(1) position leads to a decrease in the 2' endo, gauche-gauche bias. The data for 2'-O-methyladenosine and adenosine, as well as for several other purine derivatives, reveal the presence of a correlation between the sugar pucker and the C(5')-C(4') conformer distribution which is the inverse of the correlation previously reported for pyrimidine derivatives.

Adenosine↗
PubMed1999

High-performance liquid chromatography analysis of cholesterol linoleate hydroperoxide in oxidized low density lipoproteins: calibration by conjugated diene internal standard.

The cholesterol linoleate hydroperoxides formed in LDL after oxidant stress are measured by HPLC, with UV detection at 234 nm. Calibration is performed with a conjugated diene internal standard. This internal standard is synthesized by the transesterification of the methyl ester of conjugated diene linoleic acid with a long-chain alcohol, such as arachidyl alcohol (C20). Different long-chain alcohols can be used during the transesterification, to achieve internal standards with variable HPLC retention times. The method allows measurement of cholesterol linoleate hydroperoxide in LDL very early during attack with Cu2+ or other initiator, so that the kinetics of antioxidant loss and hydroperoxide formation can be concurrently monitored.

Cholesterol↗
PubMed2004

Sensitivity of aquatic plants to the herbicide metsulfuron-methyl.

The sensitivity of 12 aquatic plant species to the herbicide metsulfuron-methyl was tested in microcosm experiments under two growth conditions. As reference species, barley (Hordeum vulgare) and oil-seed rape (Brassica napus) were grown with their roots submerged in the microcosms. Two response variables were chosen: relative growth rate and specific leaf area (SLA). SLA was the most sensitive response variable, with 11 of the 12 aquatic species responding to the herbicide. EC(50) values varied 56-fold between species, with the commonly used aquatic test species Lemna minor being one of the most sensitive. Fast-growing species with a small exposed leaf area proved to be more sensitive to the herbicide than slow growing species with a large exposed leaf area, which was believed to be primarily due to variations in growth rates rather than to variations in exposed leaf area. The aquatic plants displayed high tolerance in growth to metsulfuron compared with the sensitive crop oil-seed rape. Hence, possible spray-drift events and leaching of the herbicide applied at agricultural rates are not considered to have a large impact on the growth of the aquatic flora tested.

Adaptation, Physiological↗
PubMed2003

Gene segment selection in V(D)J recombination: accessibility and beyond.

V(D)J recombination assembles genes encoding antigen receptors according to defined developmental programs in immature B and T lymphocytes. The 'accessibility hypothesis' was initially invoked to explain how a single recombinase complex could control the locus and allele specificity of V(D)J recombination. It has been since shown that recombination signal sequences themselves influence recombination efficiency and specificity in ways that had not been previously appreciated. Recent developments have increased our understanding of how the chromatin barrier to V(D)J recombination is regulated, and how chromatin control and the properties of the underlying recombination signal sequences may cooperate to create diverse, lineage-restricted and allelically excluded repertoires of antigen receptors.

Alleles↗