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991.
Many adverse drug reactions are caused by the cytochrome P450 (CYP) dependent activation of drugs into reactive metabolites. In order to reduce attrition due to metabolism-mediated toxicity and to improve safety of drug candidates, we developed two in vitro cell-based assays by combining an activating system (human CYP3A4) with target cells (HepG2 cells): in the first method we incubated microsomes containing cDNA-expressed CYP3A4 together with HepG2 cells; in the second approach HepG2 cells were transiently transfected with CYP3A4. In both assay systems, CYP3A4 catalyzed metabolism was found to be comparable to the high levels reported in hepatocytes. Both assay systems were used to study ten CYP3A4 substrates known for their potential to form metabolites that exhibit higher toxicity than the parent compounds. Several endpoints of toxicity were evaluated, and the measurement of MTT reduction and intracellular ATP levels were selected to assess cell viability. Results demonstrated that both assay systems are capable to metabolize the test compounds leading to increased toxicity, compared to their respective control systems. The co-incubation with the CYP3A4 inhibitor ketoconazole confirmed that the formation of reactive metabolites was CYP3A4 dependent. To further validate the functionality of the two assay systems, they were also used as a "detoxification system" using selected compounds that can be metabolized by CYP3A4 to metabolites less toxic than their parent compounds. These results show that both assay systems can be used to screen for metabolic activation, or de-activation, which may be useful as a rapid and relatively inexpensive in vitro assay for the prediction of CYP3A4 metabolism-mediated toxicity. 相似文献
992.
993.
Pasini A D'Agati E Pitzianti M Casarelli L Curatolo P 《Acta paediatrica (Oslo, Norway : 1992)》2012,101(1):e15-e18
Aim: Evaluating whether motor skills could differentiate drug‐naive subjects with two neurodevelopmental disorders: Attention‐Deficit Hyperactivity Disorder (ADHD) and Asperger Syndrome (AS). Methods: Thirty‐six boys (12 with ADHD, 12 with AS and 12 with typical development) aged 8–12 were evaluated using the Physical and Neurological Examination for Subtle Signs. Three primary outcome variables were obtained as follows: (i) total speed of timed activities, (ii) total overflow and (iii) total dysrhythmia. Results: Children with AS performed more slowly than those with ADHD and healthy children independently of age and IQ. Total dysrhythmia differentiates ADHD and AS children from controls. Conclusion: Dysfunction of the fronto‐striatal–cerebellar networks related to motor control could be the physiopathological basis of the reported findings. 相似文献
994.
C Fava M Montagnana E Danese M Sjögren P Almgren G Engström B Hedblad GC Guidi P Minuz O Melander 《BMC medical genetics》2012,13(1):57
ABSTRACT: BACKGROUND: Renalase (gene name RNLS), a recently discovered enzyme with monoamine oxidase activity, is implicated in the degradation of catecholamines. Recent studies delineate a possible role of this enzyme in blood pressure (BP) maintenance and cardiac protection and two single nucleotide polymorphisms, RNLS rs2576178 A>G and rs2296545 C>G have been associated with hypertension. The latter SNP leads to a non synonymous Asp to Glu substitution deleting a flavin adenine dinucleotide (FAD) binding site with possible impaired functionality. We tested the hypothesis that these polymorphisms could affect BP levels, hypertension prevalence, and risk of incident cardiovascular events in middle-aged Swedes. METHODS: The polymorphisms were genotyped in 5696 participants of the population-based Cardiovascular Cohort of the "Malmo Diet and Cancer" (MDC-CC). The incidence of cardiovascular events (coronary events [n=408], strokes [n=330], heart failure [n=190] and atrial fibrillation/flutter [n=406]) was monitored for an average of approximately 15 years of follow-up. RESULTS: Both before and after adjustment for sex, age and BMI the polymorphisms did not show any effect on BP level and hypertension prevalence. Before and after adjustment for major cardiovascular risk factors, the hazard ratio for cardiac and cerebrovascular events was not significantly different in carriers of different genotypes. A significant interaction was found between the rs2296545 C>G and age with respect to BP/hypertension. CONCLUSIONS: Our data do not support a major role for these RNLS polymorphisms in determining BP level and incident events at population level. The positive interaction with age suggest that the effect of the rs2296545 C>G polymorphism, if any, could vary between different ages. 相似文献
995.
996.
997.
Baseri B Choi JJ Deffieux T Samiotaki G Tung YS Olumolade O Small SA Morrison B Konofagou EE 《Physics in medicine and biology》2012,57(7):N65-N81
The brain-derived neurotrophic factor (BDNF) has been shown to have broad neuroprotective effects in addition to its therapeutic role in neurodegenerative disease. In this study, the efficacy of delivering exogenous BDNF to the left hippocampus is demonstrated in wild-type mice (n = 7) through the noninvasively disrupted blood-brain barrier (BBB) using focused ultrasound (FUS). The BDNF bioactivity was found to be preserved following delivery as assessed quantitatively by immunohistochemical detection of the pTrkB receptor and activated pAkt, pMAPK, and pCREB in the hippocampal neurons. It was therefore shown for the first time that systemically administered neurotrophic factors can cross the noninvasively disrupted BBB and trigger neuronal downstream signaling effects in a highly localized region in the brain. This is the first time that the administered molecule is tracked through the BBB and localized in the neuron triggering molecular effects. Additional preliminary findings are shown in wild-type mice with two additional neurotrophic factors such as the glia-derived neurotrophic factor (n = 12) and neurturin (n = 2). This further demonstrates the impact of FUS for the early treatment of CNS diseases at the cellular and molecular level and strengthens its premise for FUS-assisted drug delivery and efficacy. 相似文献
998.
Chareza S Slavkovic Lukic D Liu Y Räthe AM Münk C Zabogli E Pistello M Löchelt M 《Virology》2012,424(2):138-146
Defined host-encoded feline APOBEC3 (feA3) cytidine deaminases efficiently restrict the replication and spread of exogenous retroviruses like Feline Immunodeficiency Virus (FIV) and Feline Foamy Virus (FFV) which developed different feA3 counter-acting strategies. Here we characterize the molecular interaction of FFV proteins with the diverse feA3 proteins. The FFV accessory protein Bet is the virus-encoded defense factor which is shown here to bind all feA3 proteins independent of whether they restrict FFV, a feature shared with FIV Vif that induces degradation of all feA3s including those that do not inactivate FIV. In contrast, only some feA3 proteins bind to FFV Gag, a pattern that in part reflects the restriction pattern detected. Additionally, one-domain feA3 proteins can homo- and hetero-dimerize in vitro, but a trans-dominant phenotype of any of the low-activity feA3 forms on FFV restriction by one of the highly-active feA3Z2 proteins was not detectable. 相似文献
999.
Sodium deficiency reliably produces a robust intake of saline in rats, which is associated with an increased preference for sodium solutions at hypertonic concentrations that would normally be avoided. The mechanisms underlying the shift to an increased preference for sodium in the deficient state are not well understood. The current experiments examined the role of opioids on changes of behavioral responses that are modified as a function of body sodium status by studying the intake of 0.3 M saline in a free access drinking test and by characterizing the changes in orofacial-related behaviors in response to intra-orally delivered 0.3 M NaCl. In intake tests, systemic treatment with morphine and naltrexone respectively, enhanced and attenuated intake of 0.3 M saline in sodium depleted rats. In taste reactivity tests systemic treatment with morphine significantly decreased negative responses to 0.3 M saline infusions in both sodium replete and sodium depleted rats. Systemically administered naltrexone significantly decreased positive hedonic responses to 0.3 M saline infusions only in sodium depleted rats. These results indicate that peripheral administration of opioid agonists and antagonists alter both hypertonic saline ingestion in a free access situation and taste reactivity responses to hypertonic saline under sodium replete and deplete conditions. The results indicate that endogenous opioids alter the processing of central information to affect hedonic mechanisms that influence behaviors related to sodium consumption and palatability. 相似文献
1000.