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Archives of Toxicology (v.81, #6)
Uranium induces oxidative stress in lung epithelial cells by Adaikkappan Periyakaruppan; Felix Kumar; Shubhashish Sarkar; Chidananda S. Sharma; Govindarajan T. Ramesh (pp. 389-395).
Uranium compounds are widely used in the nuclear fuel cycle, antitank weapons, tank armor, and also as a pigment to color ceramics and glass. Effective management of waste uranium compounds is necessary to prevent exposure to avoid adverse health effects on the population. Health risks associated with uranium exposure includes kidney disease and respiratory disorders. In addition, several published results have shown uranium or depleted uranium causes DNA damage, mutagenicity, cancer and neurological defects. In the current study, uranium toxicity was evaluated in rat lung epithelial cells. The study shows uranium induces significant oxidative stress in rat lung epithelial cells followed by concomitant decrease in the antioxidant potential of the cells. Treatment with uranium to rat lung epithelial cells also decreased cell proliferation after 72 h in culture. The decrease in cell proliferation was attributed to loss of total glutathione and superoxide dismutase in the presence of uranium. Thus the results indicate the ineffectiveness of antioxidant system’s response to the oxidative stress induced by uranium in the cells.
Keywords: Uranium; Glutathione; Reactive oxygen species; Superoxide dismutase; Cell proliferation; Lipid hydroperoxide
Attenuation of cadmium chloride induced cytotoxicity in murine hepatocytes by a protein isolated from the leaves of the herb Cajanus indicus L. by Mahua Sinha; Prasenjit Manna; Parames C. Sil (pp. 397-406).
Cadmium has been recognized as a strong environmental pollutant. Exposure to this heavy metal occurs through the intake of foodstuffs, drinking water and also via the inhalation of air. Present study was conducted to evaluate the protective effect of a 43 kDa protein, isolated from the leaves of the herb Cajanus indicus, against cadmium-induced cytotoxicity in hepatocytes. For this study, cadmium chloride (CdCl2) has been used as the source of cadmium. Treatment of hepatocytes with 800 μM CdCl2 for 3 h caused significant reduction in cell viability in association with the increased levels of glutamate pyruvate transaminase (GPT) and alkaline phosphatase (ALP) leakage. The activities of the antioxidant enzymes, superoxide dismutase, catalase (CAT), glutathione-S-transferase and glutathione reductase, and the levels of cellular metabolites, reduced glutathione (GSH) as well as total thiols have also been decreased under the same treatment. In addition, the toxin enhanced the levels of the lipid peroxidation end products and oxidized glutathione (GSSG). Incubation of hepatocytes with the protein at a dose of 0.1 mg/ml for 3 h prior to the toxin treatment (at a dose of 800 μM for 3 h) restored the activities of all the antioxidant enzymes, the levels of GSH, total thiols, cell viability and also attenuated the increased levels of GPT, ALP, lipid peroxidation and GSSG. In addition, the protein resisted CdCl2 induced alterations of all the parameters when applied in combination with CdCl2. Effects of a known antioxidant, vitamin E, and a non-relevant protein, bovine serum albumin against CdCl2 induced cytotoxicity have also been included in the study. Combining all, we would like to say that the protein possessed protective activity against CdCl2 induced cytotoxicity in mouse hepatocytes probably via its antioxidant property.
Keywords: Cadmium chloride; Cytotoxicity; Hepatocytes; Cajanus indicus ; 43 kDa protein; Cytoprotection
Exposure of C6 glioma cells to Pb(II) increases the phosphorylation of p38MAPK and JNK1/2 but not of ERK1/2 by Thaís Posser; Cláudia B. N. Mendes de Aguiar; Ricardo C. Garcez; Francesco M. Rossi; Camila S. Oliveira; Andréa G. Trentin; Vivaldo Moura Neto; Rodrigo B. Leal (pp. 407-414).
Pb(II) is a neurotoxic pollutant that produces permanent cognitive deficits in children. Pb(II) can modulate cell signaling pathways and cell viability in a variety of cell types. However, these actions are not well demonstrated on glial cells, which represent an important target for metals into the central nervous system. The present work was undertaken to determine the ability of Pb(II) in modulating the activity of mitogen activated protein kinases (MAPKs) in cultures of C6 rat glioma cells, a useful functional model for the study of astrocytes. Additionally, cell viability was analyzed by measurement of MTT reduction. Cells were exposed to lead acetate 0.1, 1, 10 μM for 24 and 48 h. MAPKs activation—in particular ERK1/2, p38MAPK and JNK1/2—were analyzed by western blotting. Results showed that 10 μM Pb(II) treatment for 24 h caused a discrete stimulation of p38MAPK phosphorylation. However, 1 and 10 μM Pb(II) treatment for 48 h provoked a significant stimulation in the phosphorylation state of p38MAPK and JNK1/2. The phosphorylation state of ERK1/2 was not modified by any Pb(II) treatment. Moreover, data indicate that at 48 h treatment even 1 μM Pb(II) can be cytotoxic, causing impairment on cell viability. Therefore, depending on a long incubation period, a significant concomitant activation of p38MAPK and JNK1/2 by Pb(II) took place in parallel with the impairment of C6 glioma cells viability.
Keywords: Lead acetate; Pb(II); Heavy metals; C6 glioma cells; MAPK; Cell viability
Direct reaction of oximes with crotylsarin, cyclosarin, or VX in vitro by G. Becker; A. Kawan; D. Gutzeit; F. Worek; L. Szinicz (pp. 415-420).
The direct reaction of seven pyridinium oximes with the organophosphorus compounds (OPCs) crotylsarin, cyclosarin, and VX was studied by spectrophotometry. This method allows to quantify different parameters: (a) the half-life times (t 1/2) of the oxime-OPC reactions on the basis of the changes in the absorption at the zwitterion (betaine) peak maximum, (b) the first- and second-order rate constants (k 1, k 2), and (c) the maximum reaction velocities (v max). The results of the study show that the reaction velocity of the nerve agents with any of the oximes investigated decreased in the order crotylsarin > cyclosarin > VX. The comparison of the reaction rates of the three therapeutically used oximes (2-PAM, obidoxime, HI 6) with the respective OPC gave the highest rate for crotylsarin and cyclosarin with obidoxime and to a similar degree with HI 6, while in the case of VX the most reactive oxime was HI 6. The reaction velocity of the nerve agents with the monopyridinium oxime 2-PAM was lower as compared to the bispyridinium oximes (obidoxime, HI 6). The results obtained with the two sarin analogues indicate that the direct reaction with 2-PAM, obidoxime, or HI 6 could be used for non-corrosive decontamination purposes, especially, if sensitive biological surfaces like skin, mucous membranes, or wounds are considered. However, in view of the concentrations of nerve agents and oximes, which could be expected during OPC poisoning in man, the maximum reaction velocities would not be high enough to contribute markedly to the detoxication of nerve agents in vivo.
Keywords: Oximes; Crotylsarin; Cyclosarin; VX; Direct reaction
Protective effects of magnolol against oxidized LDL-induced apoptosis in endothelial cells by Hsiu-Chung Ou; Fen-Pi Chou; Wayne Huey-Herng Sheu; Shih-Lan Hsu; Wen-Jane Lee (pp. 421-432).
Magnolol, a compound extracted from the Chinese medicinal herb Magnolia officinalis, has several biological effects. However, its protective effects against endothelial injury remain unclear. In this study, we examined whether magnolol prevents oxidized low density lipoprotein (oxLDL)-induced vascular endothelial apoptosis. Incubation of oxLDL with magnolol (2.5–20 μM) inhibited copper-induced oxidative modification via diene formation, thiobarbituric acid reactive substances (TBARS) assay and electrophoretic mobility assay. Apoptotic cell death as characterized by terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) stain. We measured the production of reactive oxygen species (ROS) by using the fluorescent probe 2′,7′-dichlorofluorescein acetoxymethyl ester (DCF-AM), and observed the activity of antioxidant enzymes. Furthermore, several apoptotic signaling pathways which showed NF-κB activation, increased cytosolic calcium, alteration of mitochondrial membrane potential, cytochrome c release and activation of caspase 3 were also investigated. We demonstrated that magnolol prevented the copper-induced oxidative modification of LDL. Magnolol attenuated the oxLDL-induced ROS generation and subsequent NF-κB activation. Furthermore, intracellular calcium accumulation and subsequent mitochondrial membrane potential collapse, cytochome c release and activation of caspase 3 caused by oxLDL were also inhibited by magnolol. Our results suggest that magnolol may have clinical implications in the prevention of atherosclerotic vascular disease through decreasing the oxLDL-induced ROS production.
Keywords: Endothelium; OxLDL; Magnolol; Apoptosis; Mitochondrial membrane potential; Calcium homeostasis
The pharmacological effects of ozone on isolated guinea pig tracheal preparations by C. J. Lotriet; D. W. Oliver; D. P. Venter (pp. 433-440).
Ozone is a potent oxidizing agent with a variety of potential uses, including its antimicrobial and deodorising properties. The recent increased use of ozone led to questions regarding its safety in humans. This study specifically focussed on the in vitro effect of ozone on isolated guinea pig tracheal tissue as well as its effect on the isolated trachea in the presence of various drugs with well-known effects, including methacholine and isoproterenol. The results found in this study identified two direct effects on the isolated trachea due to ozone exposure: (1) a definite contraction of the isolated trachea immediately after exposure to ozone, and (2) a clearly visible and significant hyper responsiveness of the isolated trachea to irritants, e.g. methacholine. Although ozone has a negative effect on the trachea, it was concluded that ozone has no adverse effect on muscarinic receptors. We found that ozone has a significant desensitizing effect on the pharmacological response of β sympathomimetics (isoproterenol), while isoproterenol itself has a relaxing effect on the ozone-induced contraction of the isolated trachea. Observations in this in vitro study further emphasised that ozone does have a negative effect on respiratory health. It is underlined that the inhalation of ozone should be avoided by workers who are often in contact with the gas, and especially by those with existing airway diseases. An apparent EC50 value of ozone on the trachea was established by two different methods as 5.71 and 9.78 × 10−3 M, respectively.
Keywords: Isolated trachea; Hyper responsiveness; Methacholine; Isoproterenol; Ozone concentration–response curve
Carbon black particles increase reactive oxygen species formation in rat alveolar macrophages in vitro by Berit Bjugan Aam; F. Fonnum (pp. 441-446).
Alveolar macrophages (AM) have an important role in clearing particles from the lungs. In response to different stimuli they can release reactive oxygen species (ROS) and inflammatory mediators and promote pulmonary inflammation. We exposed rat AM to carbon black (CB) particles (0.63–20 μg/ml) and measured the generation of ROS by using the fluorescent probe 2′,7′-dichlorofluorescein diacetate. Fluorescence was elevated in a concentration dependent manner in the AM exposed to CB. Follow-up experiments using a series of enzyme inhibitors indicate that the ERK MAP kinase pathway and the p38 MAP kinase pathway may be involved in the formation of ROS.
Keywords: Carbon black (CB) particles; Reactive oxygen species (ROS); Alveolar macrophages (AM); Intracellular signalling pathways
Effect of quinupristin/dalfopristin on 3T3 and Eahy926 cells in vitro in comparison to other antimicrobial agents with the potential to induce infusion phlebitis by Matthias Kruse; Bülent Kilic; Burkhard Flick; Ralf Stahlmann (pp. 447-452).
Infusion phlebitis is a common clinical problem that is observed with some antimicrobial agents, when being administered intravenously. In this study, cultured murine fibroblasts and immortalised human endothelial cells were exposed to three antibiotics at clinically relevant concentrations to assess their toxic potential in two established cytotoxicity assays. BALB/c 3T3 fibroblasts and Eahy926 endothelial cells were exposed to quinupristin/dalfopristin (QD), erythromycin and levofloxacin at increasing concentrations. For assessment of cytotoxicity the cells were incubated with neutral red (NR) or stained with crystal violet (CV). Measurements were done by photometry. At the concentration range tested QD and erythromycin showed a concentration-dependent cytotoxic effect in both cell cultures. In 3T3 cells the half-maximal effect concentration (EC50) was 20 mg/l for QD and 340 mg/l for erythromycin in the NR uptake test and 12 and 200 mg/l, respectively, in the CV assay. In Eahy926 cells the EC50 was 50 mg/l for QD and 880 mg/l for erythromycin in the NR uptake test and 40 and 750 mg/l, respectively, in the CV assay. No EC50 could be established in both cell types for levofloxacin. Eahy926 cells were less sensitive to cytotoxic stimuli than 3T3 fibroblasts. Cytotoxic effects in both cell cultures occurred in the following order: QD > erythromycin >> levofloxacin. This ranking correlates well with the frequency of local adverse effects observed with the infusion of these antibiotics in patients. Thus, these in vitro assays may serve as an estimate for the prediction of local tolerability of antibiotics when administered parenterally.
Keywords: Quinupristin; Dalfopristin; Erythromycin; Levofloxacin; Cytotoxicity; Infusion phlebitis; Fibroblasts; Endothelial cells
Comparative effects of selective and non-selective nitric oxide synthase inhibition in gentamicin-induced rat nephrotoxicity by R. Ghaznavi; M. Kadkhodaee (pp. 453-457).
Different nitric oxide synthase (NOS) isoforms are found in the kidney. Some studies provided evidences that increased endothelial NOS (eNOS) activity leads to restoration of renal function after injury, but activation of inducible NOS (iNOS) aggravates renal failure. In the present study, the beneficial effects of selective iNOS blockade in gentamicin (GM) induced nephrotoxicity have been investigated. Four groups of rats were studied. Untreated control rats received saline. In GM group, GM was injected (IV, 4 mg kg−1). In GM + L-NAME group rats received L-NAME (N-omega-l-arginine methyl ester, a non-selective NOS inhibitor) simultaneously with GM (IV, 30 mg kg−1). Additional doses of L-NAME were administered 2 and 4 h after GM (IP, 30 mg kg−1). In GM + L-NIL group rats were treated by N-imino-ethyl lysine (L-NIL, a selective iNOS inhibitor). First dose (IV, 3 mg kg−1) administrated simultaneously with GM. Next doses (IP, 3 mg kg−1) were administered 2 and 4 h after GM. In all groups, serum and urine creatinine levels were measured. Creatinine clearance was calculated and considered as an estimation of glomerular filtration rate (GFR). Urine N-acetyl-b-d-glucose aminidase (NAG) activities were also determined. After experiments, kidney sections were histologically studied. Selective iNOS inhibition by L-NIL prevented the GM-induced decrease in GFR and increase in creatinine levels, while complete non-selective NOS inhibition by L-NAME aggravated the GFR reduction, elevation of creatinine levels and enzyme release (P < 0.05). Histological studies showed that GM-treated kidneys had evidences of tubular damages and these damages were less evident by the administration of L-NIL. In conclusion, selective inhibition of iNOS may prevent GM-induced nephrotoxicity, whereas non-selective inhibition of NOS aggravates it.
Keywords: Nitric oxide; Gentamicin; Nephrotoxicity; L-NIL; L-NAME