Web-based course in neuroimmune pharmacology.

Web-based instruction of biomedical sciences courses has increased dramatically during the last decade, and this increase has been driven by the need to increase student access to educational programs and by the increasing demand for courses that are compatible with distance learning. Here, a blended learning curriculum in neuroimmune pharmacology is described that combines web-based learning modules with traditional face-to-face lectures. The course content is appropriate for graduate-level students and can be adapted to an entirely web-based course that can be deployed for distance learning.

Trichloroethylene risk assessment: a review and commentary.

Trichloroethylene (TCE) is a widespread environmental contaminant that is carcinogenic when given in high, chronic doses to certain strains of mice and rats. The capacity of TCE to cause cancer in humans is less clear. The current maximum contaminant level (MCL) of 5 ppb (microg/L) is based on an US Environment Protection Agency (USEPA) policy decision rather than the underlying science.

Application of cryopreserved human hepatocytes in trichloroethylene risk assessment: relative disposition of chloral hydrate to trichloroacetate and trichloroethanol.

Background: Trichloroethylene (TCE) is a suspected human carcinogen and a common groundwater contaminant. Chloral hydrate (CH) is the major metabolite of TCE formed in the liver by cytochrome P450 2E1. CH is metabolized to the hepatocarcinogen trichloroacetate (TCA) by aldehyde dehydrogenase (ALDH) and to the noncarcinogenic metabolite trichloroethanol (TCOH) by alcohol dehydrogenase (ADH).

S-adenosylmethionine but not glutathione protects against galactosamine-induced cytotoxicity in rat hepatocyte cultures.

A gradual but extensive depletion of hepatic GSH has long been known to accompany development of galactosamine-induced hepatotoxicity in rats, and some protection from liver injury has been observed after administration of sulfhydryl-donating compounds. Although these observations support a key role for GSH in the underlying mechanism, the impact of GSH depletion and repletion on the hepatotoxic response to galactosamine is unclear. To investigate the role of GSH in galactosamine-induced liver injury, we examined the effect of modulating GSH content on galactosamine toxicity in rat primary hepatocyte cultures.

Lipids versus proteins as major targets of pro-oxidant, direct-acting hemolytic agents.

Lipid peroxidation and the accompanying translocation of phosphatidylserine (PS) from the inner to the outer leaflet of the lipid bilayer have recently been identified as key components of a signaling pathway for phagocytosis of apoptotic cells by macrophages. Drug-induced hemolytic anemia has long been known to be caused by an accelerated uptake of damaged (but intact) erythrocytes by macrophages in the spleen, and this process has been associated with enhanced formation of reactive oxygen species (ROS). However, the role of lipid peroxidation in hemolytic injury has remained unclear, and the effect of hemolytic agents on the distribution of PS in the erythrocyte membrane is unknown.

Primaquine-induced hemolytic anemia: role of splenic macrophages in the fate of 5-hydroxyprimaquine-treated rat erythrocytes.

Primaquine-induced hemolytic anemia is known to result from premature sequestration of damaged (but intact) erythrocytes by the spleen. We have shown previously that a phenolic metabolite, 5-hydroxyprimaquine (5-HPQ), is a direct-acting hemolytic agent in rats, suggesting that 5-HPQ is a mediator of the hemolytic response to primaquine. To investigate the fate of erythrocytes in vivo after in vitro exposure to 5-HPQ, rat (51)Cr-labeled erythrocytes were incubated with hemolytic concentrations of 5-HPQ and then readministered intravenously to rats.

Primaquine-induced hemolytic anemia: role of membrane lipid peroxidation and cytoskeletal protein alterations in the hemotoxicity of 5-hydroxyprimaquine.

Primaquine-induced hemolytic anemia is a toxic side effect that is due to premature splenic sequestration of intact erythrocytes. Previous studies have suggested that a phenolic metabolite, 5-hydroxyprimaquine (5-HPQ), mediates primaquine hemotoxicity by generating reactive oxygen species (ROS) within erythrocytes that overwhelm antioxidant defenses. However, the nature of the oxidative stress is not understood, and the molecular targets, whether protein and/or lipid, are unknown.

Role of oxidant stress in lawsone-induced hemolytic anemia.

Lawsone (2-hydroxy-1,4-naphthoquinone) is the active ingredient of henna (Lawsonia alba), the crushed leaves of which are used as a cosmetic dye. Application of henna can induce a severe hemolytic anemia, and lawsone is thought to be the causative agent. Administration of lawsone to rats has been shown to induce a hemolytic response that is associated with oxidative damage to erythrocytes.

Primaquine-induced hemolytic anemia: susceptibility of normal versus glutathione-depleted rat erythrocytes to 5-hydroxyprimaquine.

Primaquine is an important antimalarial agent because of its activity against exoerythrocytic forms of Plasmodium spp. Methemoglobinemia and hemolytic anemia, however, are dose-limiting side effects of primaquine therapy. These hemotoxic effects are believed to be mediated by metabolites, although the identity of the toxic specie(s) and the mechanism underlying hemotoxicity have remained unclear.

Primaquine-induced hemolytic anemia: formation of free radicals in rat erythrocytes exposed to 6-methoxy-8-hydroxylaminoquinoline.

Primaquine is an important antimalarial drug that is often dose-limited in therapy by the onset of hemolytic anemia. We have shown recently that an N-hydroxy metabolite of primaquine, 6-methoxy-8-hydroxylaminoquinoline (MAQ-NOH), is a direct-acting hemolytic agent in rat red cells and that the hemolytic activity of this metabolite is associated with GSH oxidation and oxidative damage to both membrane lipids and skeletal proteins. To determine whether the formation of free radicals may be involved in this process, rat red cells (40% suspensions) were incubated with hemolytic concentrations of MAQ-NOH (150-750 microM) and examined by EPR spectroscopy using 2-ethoxycarbonyl-2-methyl-3,4-dihydro-2H-pyrrole-1-oxide (EMPO) as a spin trap.

Primaquine-induced hemolytic anemia: effect of 6-methoxy-8-hydroxylaminoquinoline on rat erythrocyte sulfhydryl status, membrane lipids, cytoskeletal proteins, and morphology.

Previous studies have shown that 6-methoxy-8-hydroxylaminoquinoline (MAQ-NOH), an N-hydroxy metabolite of the antimalarial drug, primaquine, is a direct-acting hemolytic agent in rats. To investigate the mechanism underlying this hemolytic activity, the effects of hemotoxic concentrations of MAQ-NOH on rat erythrocyte sulfhydryl status, membrane lipids, skeletal proteins, and morphology have been examined. Treatment of rat erythrocytes with a TC(50) concentration of MAQ-NOH (350 microM) caused only a modest and transient depletion of reduced glutathione (GSH) (~30%), which was matched by modest increases in the levels of glutathione disulfide and glutathione-protein mixed disulfides.