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At least 415 records · Page 23Linked to original sources
PubMed1976

Lupin alkaloids from teratogenic and nonteratogenic lupins. III. Identification of anagyrine as the probable teratogen by feeding trials.

Alkaloidal extracts from teratogenic lupins produced congenital deformities in calves typical of crooked calf disease when the extracts were administered to pregnant cows during the susceptible gestational period. These data and previous epidemiologic studies suggest that one of the four alkaloids in the preparation, anagyrine, is the responsible teratogen. Severity of the malformations was directly related to the level of anagyrine present in the preparations administered.

Abnormalities, Drug-Induced↗
PubMed1976

Lupin alkaloids from teratogenic and nonteratogenic lupins. IV. Concentration of total alkaloids, individual major alkaloids, and the teratogen anagyrine as a function of plant part and stage of growth and their relationship to crooked calf disease.

The concentrations of total alkaloids and individual major alkaloids including the teratogen anagyrine were measured in various plant parts of teratogenic lupins as the plants matured. All alkaloids including angyrine were high in concentration in above-ground parts early in growth and decreased as plants matured, except for an increase in mature, intact seeds. Seeds were highest, followed by early growth leaves and stems. Roots were lowest with mature leaves and stems only slightly higher. Pregnant cows have the greatest risk of giving birth to calves with crooked calf disease when the concentration of the teratogen anagyrine is highest and the cows are in the susceptible 40-75 day gestation period when ingesting the plant.

Abnormalities, Drug-Induced↗
PubMed1992

Mutagenicity of trinitrotoluene and its metabolites formed during composting.

TNT was mutagenic for Salmonella typhimurium without the need of a rat liver metabolic activation system (S9). The mutagenic potency of TNT decreased in proportion to the number of nitro groups that were reduced to the amino form. The presence of a nitro group on the 4 position of the diamino congener is necessary for mutagenicity. Among the active congeners, mutagenicity was generally greater for TA100 than TA98, except that for the 4-amino congener the reverse was true. In cases when S9 was included in the assay, there was always a decrease in the number of mutants induced as compared with those without S9. Tetryl behaved like TNT, except that it was approximately three times more potent. RDX and HMX were not mutagenic under the conditions of the assay. When TNT was composed, the major metabolites identified in organic extracts of compost samples were the 2-amino and 4-amino congeners. An acetonitrile extract of compost was tested and found to be more mutagenic for TA98 than TA100, much like the authentic 4-amino congener, but the amount of this congener in the extract did not account for the degree of mutagenicity.

Aniline Compounds↗
PubMed2006

Acute occupational poisoning by octogen: first case report.

BACKGROUND: Octogen (HMX) is a polynitramine explosive closely related to hexogen, a known occupational toxin in military munitions plants. No acute human poisoning with octogen has ever been reported. CASE REPORT: A 28-year-old man with no history of epilepsy was admitted to the Emergency Department for seizures that had developed during the night after a full working day when he manually sieved large amounts of dry octogen. On admission, the clinical examination was normal and all other examinations could not substantiate the development of essential or secondary epilepsy. Elevated octogen concentrations were measured in his plasma, which confirmed occupational exposure to the explosive. CONCLUSION: The rarity of acute human poisonings by octogen is due to the infrequent use of this explosive and, more importantly, its very low oral bioavailability. However, acute poisoning can occur, but should be easily avoided by implementing adequate preventive measures.

Acute Disease↗
PubMed2004

Mathematical modeling of RDX and HMX metabolism in poplar (Populus deltoides x Populus nigra, DN34) tissue culture.

Three mathematical models were developed based on a fate study as an approach to define transformation pathways of hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX) and octahydro-1,3,5,7-tetranitro-1,3,5,7-tetrazocine (HMX) within plant cells. [U-14C]RDX and [U-14C]HMX were added in Murashige and Skoog (MS) liquid media containing Populus deltoides x P. nigra (DN34) tissue cultures. Radioactivity of samples was analyzed using HPLC, a bio-oxidizer and liquid scintillation counter. Based on information collected, transformation pathways of nitramine compounds were fitted with the raw data obtained and using a modified "green liver" model. Ordinary differential equations were developed and simulations were performed with MicroMath Scientist version 2.0 (MicroMath Inc., St. Louis, MO, USA). The three models, with different sequential transformation processes, were tested in order to support the raw data (model I) and the assumptions of the modified "green liver" model (models II and III). The results showed a high correlation between the collected data and the simulated concentrations for all models. Thus, the simplest model developed (model I) is the best model description of these particular results. The results obtained suggest that the principle of parsimony should be applied. The "green liver"-based models also demonstrated a reliable approach for the investigation of degradation pathways of nitramines within plant cells.

Azocines↗
PubMed2001

Spinal nicotinic receptor activity in a genetic model of hypertension.

Intrathecal cytisine, a nicotinic receptor agonist, elicits greater dose-dependent increases in blood pressure, heart rate and nociceptive responses in SHR than normotensive rat strains. Similar to adult rats, cardiovascular and nociceptive responses were augmented in prehypertensive SHR than age-matched WKY. While hydralazine or captopril pretreatment significantly lowered blood pressure in both SHR and WKY rats, responses to i.t. cytisine were still greater in SHR. By contrast, i.t. cytisine elicited responses were not exaggerated in DOCA-salt hypertensive WKY rats. Pressor and irritation responses to i.t. cytisine can be divided into a transient, initial and persisting, late phases. Both are augmented in SHR. In F1 rats, only the late phase pressor and pain responses to i.t. cytisine are similar in magnitude to those observed in SHR suggesting a possible dominant trait in the SHR. Overall, our findings suggest that hyper-responsiveness in nociception and pressor activity to spinal cytisine in SHR may be pathogenetically associated, but not a consequence, of hypertension.

Alkaloids↗
PubMed2001

Functional properties of human nicotinic AChRs expressed by IMR-32 neuroblastoma cells resemble those of alpha3beta4 AChRs expressed in permanently transfected HEK cells.

We characterized the functional and molecular properties of nicotinic acetylcholine receptors (AChRs) expressed by IMR-32, a human neuroblastoma cell line, and compared them to human alpha3 AChRs expressed in stably transfected human embryonic kidney (HEK) cells. IMR-32 cells, like neurons of autonomic ganglia, have been shown to express alpha3, alpha5, alpha7, beta2, and beta4 AChR subunits. From these subunits, several types of alpha3 AChRs as well as homomeric alpha7 AChRs could be formed. However, as we show, the properties of functional AChRs in these cells overwhelmingly reflect alpha3beta4 AChRs. alpha7 AChR function was not detected, yet we estimate that there are 70% as many surface alpha7 AChRs in IMR-32 when compared with alpha3 AChRs. Agonist potencies (EC(50) values) followed the rank order of 1,1-dimethyl-4-phenylpiperazinium (DMPP; 16+/-1 microM) > nicotine (Nic; 48 +/- 7 microM) > or = cytisine (Cyt; 57 +/- 3 microM) = acetylcholine (ACh; 59 +/- 6 microM). All agonists exhibited efficacies of at least 80% relative to ACh. The currents showed strong inward rectification and desensitized at a rate of 3 s(-1) (300 microM ACh; -60 mV). Assays that used mAbs confirmed the predominance of alpha3- and beta4-containing AChRs in IMR-32 cells. Although 18% of total alpha3 AChRs contained beta2 subunits, no beta2 subunit was detected on the cell surface. Chronic Nic incubation increased the amount of total, but not surface alpha3beta2 AChRs in IMR-32 cells. Nic incubation and reduced culture temperature increased total and surface AChRs in alpha3beta2 transfected HEK cells. Characterization of various alpha3 AChRs expressed in HEK cell lines revealed that the functional properties of the alpha3beta4 cell line best matched those found for IMR-32 cells. The rank order of agonist potencies (EC(50) values) for this line was DMPP (14 +/- 1 microM) = Cyt (18 +/- 1 microM) > Nic (56 +/- 15 microM > ACh (79 +/- 8 microM). The efficacies of both Cyt and DMPP were approximately 80% when compared with ACh and the desensitization rate was 2 s(-1). These data show that even with the potential to express several human nicotinic AChR subtypes, the functional properties of AChRs expressed by IMR-32 are completely attributable to alpha3beta4 AChRs.

Acetylcholine↗
PubMed1998

Evaluation of AL-05712 and AL-05741 as thioltransferase mimics for the prevention and recovery of pre-cataractous changes in lens.

It has been previously shown that during the aging process, the human eye lens accumulates protein-glutathione mixed disulfides (PSSG) and that the reduced glutathione (GSH) level drops. These changes become even more pronounced during cataractogenesis. In this report, the ability of AL-05712 and AL-05741 to lower PSSG and elevate GSH in three separate model systems was evaluated. AL-05741 was able to decrease PSSG in the cell-free system by over 30% at a concentration of 0.1 mM. AL-05712, the ester form of AL-05741, decreased mixed disulfides by about 8% in the same system in the absence of any cellular esterases. Both compounds could partially inhibit the loss of GSH seen in the H2O2 control in cultured rat lenses and in addition, the accumulation of PSSG was substantially decreased. Human lenses incubated in AL-05712 showed a significant elevation of cortical GSH and a decrease in PSSG in three of four sets of cultured human lenses.

Animals↗
PubMedDate not supplied

Alcohol preference: association with reduced striatal nicotinic receptors.

This study was designed to determine whether inherent alcohol preference is associated with differential expression of central nicotinic receptors. [(3)H]Cytisine and [(125)I]alpha-bungarotoxin binding-site, ligands selective for alpha4beta2 and alpha7 nicotinic receptor subtypes, respectively, were determined in various brain regions of alcohol-preferring (P) and non-preferring (NP) rats. Only the striatum of P rats had a reduction in the number of binding sites for both ligands, compared to NP rats. The data suggest a link between striatal nicotinic receptors and alcohol preference.

Alkaloids↗
PubMed1991

The determination of nitroaromatics and nitramines in ground and drinking water by wide-bore capillary gas chromatography.

A method has been developed to determine the concentration of nitroaromatics and nitramines in drinking water at levels below those previously achieved by gas chromatography. The nitroaromatics and nitramines are extracted from water using toluene and isoamyl acetate, respectively. The extracts are analyzed via a gas chromatograph equipped with a DB-1301 widebore fused-silica capillary column and an electron capture detector. Method detection limits of 0.003 micrograms/L for 2,6-dinitrotoluene (2,6-DNT), 0.04 micrograms/L for 2,4-dinitrotoluene (2,4-DNT), 0.06 micrograms/L for 2,4,6-trinitrotoluene (TNT), 0.3 micrograms/L for cyclotrimethylenetrinitramine (RDX), and 6.0 micrograms/L for cyclotetramethylenetetranitramine (HMX) have been obtained using this method.

Azocines↗
PubMed2003

Attenuation of cell adhesion in lymphocytes is regulated by CYTIP, a protein which mediates signal complex sequestration.

An important theme in molecular cell biology is the regulation of protein recruitment to the plasma membrane. Fundamental biological processes such as proliferation, differentiation or leukocyte functions are initiated and controlled through the reversible binding of signaling proteins to phosphorylated membrane components. This is mediated by specialized interaction modules, such as SH2 and PH domains. Cytohesin-1 is an intracellular guanine nucleotide exchange factor, which regulates leukocyte adhesion. The activity of cytohesin-1 is controlled by phospho inositide-dependent membrane recruitment. An interacting protein was identified, the expression of which is upregulated by cytokines in hematopoietic cells. This molecule, CYTIP, is also recruited to the cell cortex by integrin signaling via its PDZ domain. However, stimulation of Jurkat cells with phorbol ester results in re-localization of CYTIP to the cytoplasm, and membrane detachment of cytohesin-1 strictly requires co-expression of CYTIP. Consequently, stimulated adhesion of Jurkat cells to intracellular adhesion molecule-1 is repressed by CYTIP. These findings outline a novel mechanism of signal chain abrogation through sequestration of a limiting component by specific protein-protein interactions.

Adenosine Triphosphate↗
PubMed1976

Epithelial lesions induced by N-nitrosoheptamethyleneimine in host and transplanted rat tracheas.

N-Nitrosoheptamethyleneimine (NHMI) was given by gastric intubation, at a dosage of 10 mg/kg body weight twice weekly for 5-20 weeks, to F344 rats bearing subcutaneous tracheal transplants. Groups of 5 rats were killed at 5, 10, 15, and 20 weeks, and 1 group was killed at week 33 of the experiment (13 weeks after the last NHMI dose). Sequential changes in host tracheas consisted of hyperplasia with complete loss of mucociliary epithelium, squamous metaplasia, intense mononuclear infiltration, reestablishment of mucocillary epithelium (during the course of NHMI administration) except for focal areas of hyperkeratotic squamous metaplasia or marked dystrophic changes, and finally, papillomas, polyps, and invasive squamous cell carcinomas. Lesions in tracheal transplants consisted mostly of atrophic and dystrophic changes, with only a few small foci of squamous metaplasia and no neoplastic changes.

Animals↗
PubMed1978

Carcinogenicity of subcutaneously injected N-nitrosoheptamethyleneimine in European hamsters.

Male and female European hamsters (45 of each sex) recieved sc injections once weekly for life of N-nitrosoheptamethyleneimine (NHMI) at one-fifth the median lethal dose (LD50) (females: 44 mg/kg body wt; males: 66 mg/kg body wt), one-tenth the LD50 (females: 22 mg/kg body wt; males: 33 mg/kg body wt), or one-twentieth the LD50 (females: 11 mg/kg body wt; males: 16.5 mg/kg body wt). Survival times for both males and females were dependent on the dose of NHMI. Pulmonary neoplasms were induced in almost all the treated animals. They were histologically diagnosed as adenocarcinomas, squamous cell carcinomas, and mixed cell carcinomas. In addition, nasal cavity tumors developed in all hamsters of all treatment groups; these were papillomas, squamous cell carcinomas, and a few adenocarcinomas. Only 1 tumor of the larynx and 1 tumor of the trachea were observed. Several papillomas and a few carcinomas were also detected in the forestomach. The results were discussed with reference to previous findings in rats and Syrian golden hamsters.

Adenocarcinoma↗
PubMed2000

Examination of the DNA substrate selectivity of DNA cytosine methyltransferases using mass tagging.

The biological significance of cytosine methylation is as yet incompletely understood, but substantial and growing evidence strongly suggests that perturbation of methylation patterns, resulting from the infidelity of DNA cytosine methyltransferase, is an important component of the development of human cancer. We have developed a novel in vitro assay that allows us to quantitatively determine the DNA substrate preferences of cytosine methylases. This approach, which we call mass tagging, involves the labeling of target cytosine residues in synthetic DNA duplexes with stable isotopes, such as (15)N. Methylation is then measured by the formation of 5-methylcytosine (5mC) by gas chromatography/mass spectrometry. The DNA substrate selectivity is determined from the mass spectrum of the product 5mC. With the non-symmetrical duplex DNA substrate examined in this study we find that the bacterial methyltransferase HPA:II (duplex DNA recognition sequence CCGG) methylates the one methylatable cytosine of each strand similarly. Introduction of an A-C mispair at the methylation site shifts methylation exclusively to the mispaired cytosine residue. In direct competition assays with HPA:II methylase we observe that the mispaired substrate is methylated more extensively than the fully complementary, normal substrate, although both have one HPA:II methylation site. Through the use of this approach we will be able to learn more about the mechanisms by which methylation patterns can become altered.

Alkaloids↗
PubMed1988

Effects of an opioid antagonist on pulsatile luteinizing hormone secretion in the ewe vary with changes in steroid negative feedback.

In ewes during the breeding season, estradiol (E) and progesterone (P) synergistically regulate pulsatile luteinizing hormone (LH) secretion. E primarily inhibits LH pulse amplitude and P inhibits LH pulse frequency. To determine if endogenous opioid peptides (EOP) mediate these negative feedback effects, we administered the long-acting opioid antagonist WIN 44,441-3 (WIN) to intact ewes during the luteal and follicular phases of the estrous cycle and to ovariectomized ewes treated with no steroids, E, P, or E plus P. Steroid levels were maintained at levels seen during the estrous cycle by Silastic implants placed shortly after surgery. WIN increased LH pulse frequency, but not amplitude, in luteal phase ewes. In contrast, during the follicular phase, LH pulse amplitude was increased by WIN and pulse frequency was unchanged. Neither LH pulse frequency nor pulse amplitude was affected by WIN in long-term ovariectomized ewes untreated with steroids. In contrast, WIN slightly increased LH pulse frequency in short-term ovariectomized ewes. WIN also increased LH pulse frequency in ovariectomized ewes treated with P or E plus P. WIN did not affect pulse frequency but did increase LH pulse amplitude in E-treated ewes. These results support the hypothesis that EOP participate in the negative feedback effects of E and P on pulsatile LH secretion during the breeding season and that the inhibitory effects of EOP may persist for some time after ovariectomy.

Animals↗
PubMed1985

Evidence for a dual mechanism in the anesthetic action of an opioid peptide.

Loss of righting reflex (LRR) produced by various concentrations of the leucine-enkephalin analog BW831c (TYR.D-ALA.GLY.PHE.D-LEU.NHEt.HCI) was determined in amphibia at 1 atm and 120 atm of helium. EC50 for LRR was 22.1 +/- 1.6 microM and 44 +/- 6.9 microM, respectively. The octanol/water partition coefficient (P) was 26 +/- 3.6, suggesting that this peptide is sufficiently lipid soluble for a classic Meyer-Overton type of anesthetic action. The ratio (EC50 at 120 atm)/(EC50 at 1 atm) for the peptide (2.0 +/- 0.31) was essentially the same as that for the long-chain alcohol, octanol (1.8 +/- 0.08), and similar to those reported for phenobarbital and the gaseous anesthetics. Thus, peptide-induced LRR was reversible by pressure. Peptide-induced LRR also was completely reversible by naloxone, whereas octanol-induced LRR was unaffected by up to 100 microM naloxone. These findings are consistent with a dual mechanism of anesthetic action for this peptide: one, an opiate receptor-specific mechanism, reversible with the specific opiate antagonist, naloxone; the other, a nonspecific mechanism, related to lipid solubility and reversible with the application of the physical agent, pressure.

1-Octanol↗