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At least 289 records · Page 16Linked to original sources
PubMed2004

17beta-estradiol attenuates glutamate-induced apoptosis and preserves electrophysiologic function in primary cortical neurons.

Glutamate toxicity causes neuronal death in neurodegenerative diseases; hence, there is a need for therapeutic agents rendering functional neuroprotection. We tested the effects of 17beta-estradiol (estrogen) in rat primary cortical neurons after glutamate exposure. Wright staining and ApopTag assays indicated that 0.5 microM glutamate for 24 hr caused apoptosis. Glutamate-induced apoptosis correlated with upregulation of calpain, a proapoptotic shift in the Bax:Bcl-2 ratio, and increased activation of caspase-3. Pretreatment with 10 nM estrogen prevented apoptosis, attenuated calpain upregulation, shifted the Bax:Bcl-2 ratio toward survival, and decreased caspase-3 activation. Single-cell voltage-clamp techniques were used to record whole-cell currents associated with Na+ channels, N-methyl-D-aspartate receptor channels, and kainate receptor channels. No significant differences were recorded in membrane capacitance at -70 mV in neurons treated with estrogen or estrogen plus glutamate, relative to controls. Notably, no changes in capacitance indicated that neurons treated with estrogen and glutamate did not experience apoptosis-associated cell shrinkage. No membrane potential could be recorded in the neurons treated with glutamate due to apoptosis. All recorded currents were similar in amplitude and activation/inactivation kinetics in control neurons and neurons treated with estrogen plus glutamate. Estrogen thus preserved both neuronal viability and function in this in vitro glutamate toxicity model.

Animals↗
PubMed1995

Flow cytometric detection of abnormal fetal erythropoiesis: application to 5-fluorouracil-induced anemia.

We sought to determine whether flow cytometric analysis of circulating fetal blood cells could be used to rapidly detect perturbations of fetal erythropoiesis. In addition, we wanted to determine whether this approach would allow sample collection by exsanguination instead of fetal cardiac puncture, a difficult technique used to prevent contamination of samples with maternal erythrocytes. To monitor fetal erythropoiesis from gestational day (GD) 14-20, we analyzed the cell size, RNA content, and percentage of circulating liver-derived reticulocytes relative to yolk-sac-derived erythroblasts. As a model toxicant, we chose 5-fluorouracil (5-FU), since we previously observed that maternal administration at 20-40 mg/kg on gestational day (GD) 14 produced fetal anemia on GD 16-17, as evidenced by dose-dependent decreases in the cell counts, hematocrit, and hemoglobin content of fetal blood obtained by cardiac puncture. We report herein that 48 hr after maternal 5-FU administration, both cardiac and peripheral blood samples exhibited a dose-dependent decrease in the relative percentage of reticulocytes, indicating a reduced rate of reticulocyte release from the fetal liver. Moreover, at 30 and 40 mg/kg, reticulocytes exhibited increased size and reduced RNA content on GD 16, but elevated RNA content (indicative of premature release) by GD 18. These data suggest that 5-FU inhibits both erythroid cell proliferation and RNA synthesis reversibly, resulting in an anemia that triggers compensatory release of immature reticulocytes.(ABSTRACT TRUNCATED AT 250 WORDS)

Anemia↗
PubMed1999

Combining life-history and toxicokinetic parameters to interpret differences in sensitivity to cadmium between populations of Polycelis tenuis (Platyhelminthes).

Five populations of the planarian Polycelis tenuis, collected from four locations in a metal contaminated stream and from one location in an unpolluted tributary stream, were compared for their sensitivity to cadmium by measuring survival, reproduction, and body size changes during 28 days of exposure via the water. Survival data and bioconcentration of cadmium measured at the end of the experiment enabled the use of a kinetic-based toxicity model, estimating the lethal body concentration, the uptake rate constant, the elimination rate constant, and the ultimate LC(50) as estimated toxicokinetic parameters. Accurate body size selection and a one-month acclimatization period to standardized laboratory conditions were applied to enhance the comparability between populations. An increased elimination rate constant and a greater ultimate LC(50) were estimated for one of the populations, located downstream from an ancient lead-zinc mine. The cadmium concentration causing an effect on reproduction varied considerably (a factor of 10) among populations but did not differ significantly between populations. For the number of reproducing individuals as a function of cadmium concentration, EC(50) and steepness of slope of the concentration/effect relationship tended to be correlated positively (P<0.10), indicating that selection in the field may have occurred. Cadmium was found to enhance shrinkage of P. tenuis under conditions of food limitation.

Animals↗
PubMed1983

Cytotoxic effects of adriamycin on mouse hypoglossal neurons following retrograde axonal transport from the tongue.

We reported recently that the fluorescent, cytostatic drug, adriamycin (Doxorubicin) may reach the hypoglossal neurons by retrograde axonal transport from the nerve terminals of the tongue. The present investigation was undertaken to ascertain whether morphological changes occur in the hypoglossal neurons due to retrograde transport of adriamycin. Neuronal degeneration was observed in the hypoglossal nucleus 14 days after i.m. injection of adriamycin into the tongue. Early neuronal changes, such as rarefaction of the nuclear chromatin and segregation and fragmentation of the nucleolar components, were succeeded by cytoplasmic vacuolation, disappearance of ribosomes and other degenerative features. These observations are important from a neurotoxicologic viewpoint since they demonstrate that retrograde axonal transport may provide a route for the entry of adriamycin into the nervous system. Thus far, adriamycin appears to be the only known substance which can be traced directly in the neurons and cause their degeneration. An experimental method of damaging the motor neurons of the CNS has been introduced. A new toxic model for the investigation of experimental motor neuron disease is therefore available by the use of adriamycin.

Animals↗
PubMed1991

Glutathione redox cycle is an important defense system of endothelial cells against chronic hyperoxia.

Exposure of cultured pulmonary artery endothelial cells to 95% O2 resulted in the following sequence of events: decrease in [3H]thymidine incorporation after 24 h; increase of intracellular glutathione (GSH) and loss of cellular protein after 48 h; increase of spontaneous and decrease of provoked prostacyclin formation as well as increased release of cellular LDH after 72 h. This oxygen toxicity model was used to study the following 2 questions. (1) What is the relative importance of the GSH redox cycle compared to catalase as antioxidative defense against hyperoxia? Endothelial cells were grown in selenium-depleted medium to inhibit glutathione peroxidase activity. Endothelial GSH biosynthesis was inhibited by buthionine sulfoximine. Catalase activity was reduced by aminotriazole. Endothelial cells with an impaired GSH redox cycle were easily killed by hyperoxia within 24 h, while inhibition of catalase did not enhance the susceptibility of endothelial cells to hyperoxia. (2) Can endothelial GSH content be increased by exogenous sulfhydryl reagents and does this result in an increase of endothelial cells' resistance to hyperoxia? Exogenous GSH, N-acetylcysteine, cysteine, and L-2-oxothiazolidine-4-carboxylate (L-2-oxo) increased intracellular GSH. All sulfhydryl reagents (with the exception of L-2-oxo) protected endothelial cells from hyperoxia. Concentrations of exogenous GSH and N-acetylcysteine that did not increase intracellular GSH reduced hyperoxia-induced endothelial cell injury. Thus the capacity of the GSH redox cycle rather than intracellular GSH levels or catalase determines endothelial cells' resistance to hyperoxia.

Animals↗
PubMed1998

Practical implementation of a modified continual reassessment method for dose-finding trials.

PURPOSE: We describe a practical, reliable, efficient dose-finding design for cytotoxic drugs applied in a multi-institutional setting. METHODS: The continual reassessment method (CRM) was modified for use in phase I trials conducted through the New Approaches to Brain Tumor Therapy (NABTT) Consortium. Our implementation of the CRM uses (1) a simple dose-toxicity model to guide data interpolation, (2) groups of three patients to minimize calculations and stabilize estimates, (3) investigators' clinical knowledge or opinion in the form of data to make the process easier to understand, and (4) a flexible computer program and interface to facilitate calculations. RESULTS: The modified CRM was used in two dose-finding trials of 9-aminocamptothecin in patients with newly diagnosed and recurrent glioblastoma who were taking anticonvulsant medication. The CRM located the maximum tolerated dose (MTD) efficiently in both trials. Compared to conventional designs, the CRM required slightly more than half the number of patients expected, did not greatly overshoot the MTD (i.e. no patients were treated at dangerously high doses), and did not underestimate the MTD. CONCLUSIONS: Our experience demonstrates the feasibility of implementing this design in multi-institutional trials and the possibility of performing dose-finding studies that require fewer patients than conventional methods.

Antineoplastic Agents↗
PubMed2006

Schistosomiasis--a century searching for chemotherapeutic drugs.

Schistosomiasis affects 200 million individuals in underdeveloped and developing regions and is a growing concern for travelers worldwide. There has been evidence of resistance to the praziquantel-based therapy and reports of acute-disease manifestation; therefore, other drugs affecting different stages of the schistosome parasites life cycle and alternative therapeutic regimens should be developed and become accessible. The present review results from a comprehensive search in the scientific literature for substances and compounds tested in the past centennial for schistosomiasis therapy. We gathered over 40 drugs providing information on therapeutic action in humans or animal model, toxicity, susceptible Schistosoma stages, species, etc. The drugs were grouped according to their known metabolic effects on the parasite, whether they are on membrane structure and function, carbohydrate metabolism, protein synthesis and function, or on nucleic acid metabolism. We discuss the current knowledge of drug-target interactions, their mechanism of action and possible therapy combinations. Furthermore, based in the literature and in our own experience with large-scale Schistosoma mansoni genome and transcriptome analyses, we put forward several recently described gene products that are promising target candidates for existing or new drugs.

Animals↗
PubMed2004

Estrogen as a multi-active neuroprotective agent in traumatic injuries.

In the past decade, research has demonstrated that estrogen's role in physiology and development is far more complicated than previously assumed. Among these discoveries, there has been an increased recognition of the impact estrogen has in neurodevelopment, central nervous system physiology, and neuropathophysiology. These observations have led many researchers to consider using estrogen pharmacotherapeutically, at physiologic or supraphysiologic doses, for a variety of injury and toxicity models. In this short review, the effects of estrogen as an anti-apoptotic agent, as an anti-oxidant, and as an anti-inflammatory agent are discussed. Finally, the possibility of using estrogen as a neuroprotectant in neurotrauma is addressed.

Animals↗
PubMed1984

Effect of proline analogs on oxygen toxicity-induced pulmonary fibrosis in the rat.

Proline analogs inhibit collagen biosynthesis and prevent accumulation of collagen in tissues. The antifibrotic effects of three proline analogs, cis-hydroxyproline, L-azetidine-2-carboxylic acid, and L-3,4-dehydroproline, were compared in a rat oxygen toxicity model. The specificity of these agents for collagen was examined by measuring their effects on noncollagen protein and elastin accumulation in the lung. Increased lung collagen was produced by exposing rats to 95% O2 for 60 hr followed by a 2-week recovery period. Animals were treated with the proline analogs for the 2-week period. Oxygen exposure in untreated animals increased lung collagen 26% above air-breathing controls, and this increase was prevented by all three analogs. Increased noncollagen protein was also prevented by these agents, suggesting they were not entirely specific for collagen. Elastin accumulation, however, was not inhibited by cis-hydroxyproline. It was concluded that proline analogs were antifibrotic, but affected the metabolism of noncollagen protein.

Animals↗
PubMed1988

"Crack smoke" is a respirable aerosol of cocaine base.

The smoking of cocaine base [corrected] ("crack") has emerged as a significant substance abuse problem. A detailed characterization of cocaine smoke is a prerequisite for studies of its pharmacokinetics, abuse potential and toxicity. Model pipes were used to generate cocaine smoke analogous to that inhaled by human "crack" abusers. Using procedures to minimize pyrolysis, cocaine base smoke was determined to be 93.5% cocaine particles with the remainder being cocaine vapor. The average particle size generated from all model pipes was 2.3 mu which is small enough to ensure deposition into the alveolar region of the human lung. Although this particle size is eminently respirable [corrected] by primates, a much smaller fraction will reach the alveolar region of rodents. Special generating procedures would therefore be required to expose rodents to meaningful doses of airborne cocaine that mimic the rapid absorption achieved by "crack" smokers.

Aerosols↗
PubMedDate not supplied

Short-term inhalation test for evaluating industrial hepatotoxicants in rats.

Liver damage was investigated in rat using serum enzyme activities measurements. Responses were recorded 24 h after whole body inhalation exposure to vapors of bromobenzene, carbon tetrachloride, chloroform, o-dichlorobenzene, 1,2-dichloroethane and dimethylformamide as model toxicants. First, rats were exposed during a single 4 h period to different concentrations of each solvent and the minimally active concentration was determined. Second, repeated exposures to chemicals at this concentration level (6 h daily, 2 or 4 days) were used in order to examine whether hepatotoxicity was enhanced. GLDH and SDH are more sensitive and more constant indices than GOT and GPT. It appears that a single exposure period induced more marked serum activities enhancement than repeated exposures.

Alanine Transaminase↗
PubMed1986

Concentration-related changes in blood and tissue parameters of hepatotoxicity and their interdependence in rats exposed to bromobenzene and 1,2-dichlorobenzene.

Liver damage resulting from 4 h exposure to bromobenzene (BB) (146-957 ppm) and 1,2-dichlorobenzene (DCB) (245-739 ppm) as model toxicants was evaluated in rats. The modifications considered were the increases in serum glutamate dehydrogenase (GLDH) and sorbitol dehydrogenase (SDH) activities and the decreases in centrolobular liver-cell glucose-6-phosphatase (G6-Pase) staining intensity. A linear inverse relationship was established between the logarithmic values of blood enzyme activities and liver G6-Pase staining intensity. In addition, the levels of exposure to each test chemical were found to be linearly related to liver G6-Pase staining intensity and to the logarithmic values of blood enzyme activities.

Animals↗
PubMedDate not supplied

Structure-toxicity relationship of monoketones: in vitro effects on beta-adrenergic receptor binding and Na(+)-K(+)-ATPase activity in mouse synaptosomes.

The structure-toxicity relationship of monoketones, a class of organic solvents widely used in industry, was investigated with respect to their in vitro effects on synaptosomal membrane proteins. The toxic parameters used were Na(+)-K(+)-adenosine triphosphatase (Na(+)-K(+)-ATPase), a well-known marker enzyme often used as a membrane toxicity model, and 3H-dihydroalprenolol (3H-DHA)-labeled beta-adrenergic receptor binding that has been shown to be vulnerable to solvent-induced changes in membrane fluidity. In vitro treatments with 12 kinds of monoketones (carbon chain length from 3-10) dose-dependently inhibited both 3H-DHA binding to mouse synaptosomes and Na(+)-K(+)-ATPase activity. The potency of inhibition (IC50) for both the two parameters was linearly related to n-octanol/water partition coefficient and synaptosome/buffer partition coefficient of the test compounds. Additions of monoketones did not significantly alter the number of 3H-DHA binding sites but markedly decreased their affinity. In each monoketone, the IC50 values for 3H-DHA binding and Na(+)-K(+)-ATPase activity were generally within the same range. The anisotropy of fluorescence probe 1,6-diphenyl-1,3,5-hexatriene-labeled synaptosomal membranes was dose-dependently decreased by the monoketones, implying increased membrane fluidity. These results indicate that increasing lipophilicity of monoketones results in increased solvent penetration of synaptic membrane preparations, leading to conformational changes in membrane structure and increased ability to inhibit both neuroreceptor binding and enzyme activity. The present data confirm the importance of the lipid micro-environment of membranes in maintaining the normal functions of membrane-bound proteins.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2005

Lysosomal enlargement in digestive cells of mussels exposed to cadmium, benzo[a]pyrene and their combination.

Digestive cell lysosomes in mussels are known to respond to individual organic chemicals and metals after experimental exposure under laboratory conditions but reports dealing with the response to mixtures of pollutants are scarce. The aim of the present investigation was to compare the lysosomal responses elicited by exposure to a model organic chemical compound (benzo(a)pyrene, B[a]P), a model toxic metal (Cd) and their combination (B[a]P+Cd) under controlled laboratory conditions. Dimethylsulfoxide (DMSO) was used as vehicle to dissolve organic chemicals into seawater. Control mussels were either kept untreated in clean seawater or treated with DMSO. Digestive glands were excised on Day 21. beta-Glucuronidase activity was demonstrated in 8 mum cryotome sections. Lysosomal volume, surface and numerical densities (Vv, Sv and Nv), and surface-to-volume ratio (S/V) were quantified by image analysis. Lysosomal enlargement was evident in digestive cells of mussels exposed to either Cd, B[a]P or B[a]P+Cd. Such enlargement was more marked after exposure to B[a]P+Cd than to B[a]P, but did not reach the levels recorded after Cd exposure. It seems therefore that the presence of B[a]P reduced to some extent the effects of Cd on digestive cell lysosomes in mussels.

Animals↗
PubMed2006

Electrochemical degradation of 4-chlorophenol at nickel-antimony doped tin oxide electrode.

The effectiveness of a novel nickel-antimony doped tin oxide electrode for electrochemical degradation of organic pollutants was investigated using 4-chlorophenol (4-CP) as a model toxic organic. The experimental results demonstrate that the optimal Ni content was at Ni:Sn=1:500 in atomic ratio in the precursor coating solution, whereas the Sb:Sn ratio was set at 8:500. Using the electrode prepared with the optimal Ni doping ratio for 4-CP degradation, the charge-based efficiencies were up to 89 microg C(-1) for 4-CP destruction and 15 microg C(-1) for TOC removal, which were considerably higher than the efficiencies observed for other electrodes. It is suggested that the enhancement of the electrode for electrochemical oxidation of organics could be attributed to the production of hydroxyl radicals in anodic water electrolysis.

Antimony↗
PubMed2006

Can we estimate the accuracy of ADME-Tox predictions?

There have recently been developments in the methods used to access the accuracy of the prediction and applicability domain of absorption, distribution, metabolism, excretion and toxicity models, and also in the methods used to predict the physicochemical properties of compounds in the early stages of drug development. The methods are classified into two main groups: those based on the analysis of similarity of molecules, and those based on the analysis of calculated properties. An analysis of octanol-water distribution coefficients is used to exemplify the consistency of estimated and calculated accuracy of the ALOGPS program (http://www.vcclab.org) to predict in-house and publicly available datasets.

Algorithms↗
PubMed2006

Lethality of essential oil constituents towards the human louse, Pediculus humanus, and its eggs.

Essential oils have been widely used in traditional medicine for the eradication of lice, including head lice, but due to the variability of their constitution the effects may not be reproducible. In an attempt to assess the contribution of their component monoterpenoids, a range of common individual compounds were tested in in vitro toxicity model against both human lice (Pediculus humanus, an accepted model of head lice lethality) and their eggs, at different concentrations. No detailed study into the relative potencies of their constituent terpenoids has so far been published. Adult lice were observed for lack of response to stimuli over 3 h and the LT(50) calculated, and the percentage of eggs failing to hatch was used to generate ovicidal activity data. A ranking was compiled for adult lice and partially for eggs, enabling structure-activity relationships to be assessed for lethality to both, and showed that, for activity in both life-cycle stages, different structural criteria were required. (+)-Terpinen-4-ol was the most effective compound against adult lice, followed by other mono-oxygenated monocyclic compounds, whereas nerolidol was particularly lethal to eggs, but ineffective against adult lice.

Animals↗
PubMed2006

Protective effect of Lygodium flexuosum (L.) Sw. extract against carbon tetrachloride-induced acute liver injury in rats.

The hepatoprotective potential of Lygodium flexuosum (L.) Sw. was evaluated in male Wistar rats against carbon tetrachloride-induced liver damage in preventive and curative models. Toxic control and n-hexane extract-treated rats received a single dose of CCl4 (150 microL/100g, 1:1 in corn oil). Pre-treated rats were given n-hexane extracts at 200 and 100 mg/kg dose 48, 24 and 2 h prior to CCl4 administration. In post-treatment groups, rats were treated with n-hexane extract at a dose of 200 and 100 mg/kg, 2, 24 and 48 h after CCl4 intoxication. Rats pre-treated with Lygodium flexuosum remarkably prevented the elevation of serum AST, ALT, LDH and liver lipid peroxides in CCl4-treated rats. Rats treated with the extract after the establishment of CCl4 induced liver injury showed significant (p < or = 0.05) protection of liver as evidenced from normal AST, ALT, LDH and MDA levels. Hepatic glutathione levels were significantly (p < or = 0.05) increased by the treatment with the extracts in both the experimental groups. Histopathological changes induced by CCl4 were also significantly (p < or = 0.05) reduced by the extract treatment in preventive and curative groups. Phytochemical studies revealed the presence of saponins, triterpenes, sterols and bitter principles in Lygodium flexuosumn-hexane extract which could be responsible for the possible hepatoprotective action.

Animals↗