Toxicology letters
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Epilepsy in children is associated with a broad spectrum of cognitive deficits, which is associated with hippocampal mossy fiber sprouting. The underlying molecular mechanisms involved in mossy fiber sprouting in hippocampus following developmental seizures are not completely known. We studied the timing of cognitive dysfunction following neonatal seizures and the relation of this cognitive impairment to zinc transporter 1 (ZnT-1), 3 (ZnT-3), calcium/calmodulin-dependent protein kinase II (CaMK II), plasticity-related gene 1 (PRG-1) expression in hippocampus. ⋯ RT-PCR densitometry analysis showed that the ratios of hippocampal ZnT-1 to beta-actin of SS and RS group were decreased significantly compared with that of control group. Meanwhile, CaMK II to beta-actin of RS group was markedly lower compared with those of SS and control groups. Our results suggest that the long-term adverse effects of recurrent neonatal seizures on cognition and mossy fiber sprouting may be associated with the down-regulated expression of ZnT-1 and CaMK II in hippocampus.
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Bromine is an industrial chemical that is irritating to the skin and causes cutaneous burns. An important factor in selecting or developing an effective treatment is to understand the underlying molecular mechanisms of tissue damage and wound healing. This study used a weanling swine burn model and microarray analysis to evaluate the effect of exposure length and sampling times on the transcriptional changes in response to cutaneous bromine injury. ⋯ Ingenuity Pathways Analysis (IPA) revealed six common biological functions among the top 10 functions of each experimental group, while canonical pathway analysis revealed 11 genes that were commonly shared among 24 significantly altered signaling pathways. Additionally, there were 11 signaling pathways in which there were no commonly shared transcripts. The present study is an initial assessment of the transcriptional responses to cutaneous bromine exposure identifying molecular networks and genes that could serve as targets for developing therapeutics for bromine-induced skin injury.
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Cytochrome P450s (CYP) play a pivotal role in the metabolism of drugs and xenobiotics, and have been intensively studied over many years. Much of the work carried out on the role of hepatic cytochrome P450s in drug metabolism and disposition has been done in vitro, and has yielded vital information on P450 regulation and function. However, additional factors such as route of administration, absorption, drug transporters, renal clearance and extra-hepatic P450s, make it difficult to extrapolate from in vitro data to in vivo pharmacokinetics. ⋯ We have developed a mouse line (HRN) in which cytochrome P450 oxidoreductase (POR), the unique electron donor to cytochrome P450s is deleted specifically in the liver, resulting in the loss of essentially all hepatic P450 function. The HRN mouse, although having disturbances in lipid and bile acid homeostasis develops and breeds normally. We have used the HRN mouse as a model to establish the role of hepatic versus extra-hepatic metabolism in drug metabolism and disposition, and also to investigate the relationship between drug toxicokinetics and therapeutic effect, initially with the chemotherapeutic prodrug cyclophosphamide (CPA).
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The aim of this study was to further investigate the mechanism of development of cardiac lesions occurring under treatment with milrinone in dogs, by using echocardiography for assessing the effects of this drug on cardiac function. Milrinone is a cAMP phosphodiesterase 3 inhibitor having positive inotropic and vasodilatory effects. We treated groups of three dogs with milrinone at a single dose of 0.5 or 1 mg/kg and recorded M-mode and Doppler parameters at different time points before and after treatment. ⋯ In particular, there was an increase in the Vmax of the A-wave of the tricuspid flow, suggesting an increase in contractility of the right atrium. This change, by increasing blood flow in atrial wall, may be involved in the induction of the lesions observed in the right atrium. In conclusion, Doppler and M-mode echocardiography are useful tools to assess haemodynamic changes occurring upon treatment with vasodilators or cardiac stimulants in order to further understand the mechanism of development of cardiac lesions produced by such compounds.
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Different members of tricyclic antidepressants (TCAs) were found to induce free radical and oxidative stress in vitro. Accordingly, in the present study we tried to explore the possible role of oxidative stress in TCAs-induced cardiotoxicity. Rats were given a single injection of clomipramine (45 mg/kg). ⋯ Addition of hydroxyl radical scavenger or iron chelator significantly counteracted the effect of clomipramine. In conclusion, the present study demonstrates that free radical generation and oxidative stress play a role in clomipramine-induced cardiotoxicity. In addition, clomipramine can induce hydroxyl radical in vitro.