1,721,097 research outputs found
Acute cognitive effects of MRI related magnetic fields: the role of vestibular sensitivity.
No full textOBJECTIVES: Movement in the magnetic fields around MRI systems showed acute negative effects on concentration, memory, visuo-spatial orientation and postural body sway. A crucial role of the vestibular system has been hypothesised. We aimed to gain more insight whether subjects with a relatively (un)sensitive vestibular system performed differently on cognitive tasks when (moving) in a the static magnetic field of an MRI scanner.\n\nMETHOD: In a double blind randomised cross over experiment 36 healthy volunteers underwent several cognitive tasks in 4 experimental sessions. Two were exposure conditions near a 7 Tesla (T) MRI system with personal exposure of 1.0 T. In one of these conditions additional time-varying magnetic fields of 2.4 T/s were induced by making standardised head movements. Of the two sham conditions (0 T) one was with and the other without such head movements. Vestibular sensitivity of each subject was assessed by the rotary chair test, the caloric reflex test and self-reported sensitivity to motion sickness.\n\nRESULTS: Linear mixed models are currently in progress to test cognitive performance in a magnetic field for subjects with a low, normal and high sensitive vestibular organ. Preliminary results seem to suggest some differential cognitive effects of magnetic field exposure according to relative vestibular sensitivity. Further results will be presented at the conference.\n\nCONCLUSIONS: These findings are important to better understand a possible working mechanism evoking these cognitive effects. Moreover, these finding can form a basis for the design of relevant protective and precautionary control measures for employees working close to an MRI system
Spinosad is a potent inhibitor of canine P-glycoprotein
No full textInhibition of the drug transporter P-glycoprotein (P-gp) by the oral flea preventative spinosad has been suggested as the underlying cause of the drug-drug interaction with ivermectin. In this study, an in vitro model consisting of canine cells was validated to describe the inhibitory effect of drugs on canine P-gp. In this model, ivermectin, cyclosporin, verapamil, loperamide and ketoconazole inhibited P-gp function with IC50 values ranging from 0.1 to 3.7 μmol/L. Spinosad was a potent inhibitor of canine P-gp with an IC50 value of 0.27 μmol/L or 0.2 μg/mL. The risk of spinosad causing P-gp related drug-drug interactions in the dog could be predicted by the IC50 value, the oral dosage and plasma concentrations
Sensitizing potential of enzymatically cross-linked peanut proteins in a mouse model of peanut allergy.
No full textSCOPE: The cross-linking of proteins by enzymes to form high-molecular-weight protein, aggregates can be used to tailor the technological or physiological functionality of food products. Aggregation of dietary proteins by food processing may promote allergic sensitization, but the effects of enzymatic cross-linking of dietary proteins on the allergenic potential of food are not known. In this study, the bioavailability and the sensitizing or tolerizing potential of peanut proteins (PE) cross-linked with microbial tyrosinase from Trichoderma reesei and mushroom tyrosinase from Agaricus bisporus, were investigated. METHODS AND RESULTS: The impact of cross-linking of PE on the in vitro bioavailability of fluorescein isothiocyanate-labeled peanut proteins was tested in a Caco-2 cell monolayer and by competitive ELISA. The in vivo allergenicity or capacity to induce oral tolerance in mice were measured by serum levels of PE-specific antibodies and T cell cytokine production after exposure to PE and cross-linked PE. CONCLUSION: Enzymatic processing of peanut proteins by the two tyrosinases increased the bioavailability of major peanut allergen Ara h 2, but did not significantly change the allergenic or tolerizing properties of peanut. Enzymatic treatment of peanut proteins yielded cross-linked proteins with preserved molecular and immunological features of peanut allergens
Feline hepatic biotransformation and transport mechanisms
No full textHepatic biotransformation and drug transport mechanisms vary significantly between species. While these processes that determine largely the kinetic behavior of drugs have been studied abundantly in dogs, corresponding investigations in cats are hardly available, despite the increasing role of cats in veterinary practice, following the increasing popularity of cats in The Netherlands. Drug intolerance, toxic side effects or a lack of efficacy have been observed when treating feline patients with drugs licensed for other species. In this thesis, we designed a series of experimental in vitro approaches that address the major phases of hepatic drug metabolism and excretion. Main findings: Phase I - Cytochrome P450 (CYP) activities and substrate specificities differ between feline and canine liver microsomes, as expected. Also gender differences are observed. However, fluorometric assays intended for rapid analysis of CYP activity of patient-derived liver biopsies, was found to be non-realistic for a clinical routine as its sensitivity is too low and in turn the amount of liver tissue needed for quantitative results is too high to allow the application in clinical diagnostics. - Diazepam, a drug that is regularly associated with undesirable hepatic side effects in cats, is converted in feline hepatic microsomes mainly into temazepam, while in dog microsomes nordiazepam appears to be the principle metabolite. The lack of quantifiable formation of nordiazepam and oxazepam in feline liver microsomes suggests a feline CYP2B11 ortholog that significantly differs from the corresponding enzyme in dogs. Phase II - A deficient UDP-glucuronosyltransferase (UGT) 1A6 activity was confirmed in feline liver microsomes, and also functional UGT2B homologs are apparently absent in the feline liver. However a functional UGT1A1 and probably other UGT1A homologs in cats were identified, albeit with a lower capacity than dogs. - The overall very low glucuronidation capacity in cats and its small substrate-specificity remain of clinical importance in pharmacotherapy and clinical toxicology. Phase III - Structure and functional characteristics of the feline bile salt export pump (BSEP) was described for the first time and appeared to be very similar between cats, dogs and humans. - BSEP is essential for the transport of bile acids out of the hepatocyte, and inhibition of BSEP, as demonstrated for diazepam and its metabolites, seems to contribute to the observed hepatotoxicity in feline patients after repeated dosing. Everted membrane vesicles transfected with feline BSEP are a valuable screening tool to assess the transport capacity of feline BSEP . - Feline lymphoma cells express the efflux transporter P-glycoprotein (P-gp) at a high rate and hence constitute an easy accessible tool to study P-gp inhibition and drug-drug interactions at the level of P-gp transport. In conclusion, our investigations identified some major differences between hepatic drug metabolism between humans, dogs and cats, explaining various undesirable drug side effects that have been observed in cats and serving as a tool for pre-clinical drug safety assessment
Reply on 'Prerequisites for a reliable introduction of in vitro neurotoxicity testing within the REACH framework'
No full textInhibition of P-glycoprotein by psychotherapeutic drugs in a canine cell model
No full textDrug-drug interactions related to long-term therapies are of increasing concern. Psychotherapeutic drugs, licensed for the use in dogs for the management of separation anxiety and other behavioural disorders, are examples of drugs used in long-term therapies. In an in vitro system with canine P-glycoprotein (P-gp) expressing cell lines, three psychotherapeutic drugs with a different mode of action were tested for their ability to inhibit the canine multidrug transporter P-gp. At 10 μm, the selective serotonin reuptake inhibitor fluoxetine and the tricyclic antidepressant clomipramine inhibited P-gp for 41% and 59%, respectively. In contrast, selegeline did not inhibit the function of the canine P-gp
Galacto-oligosaccharides exert a protective effect against heat stress in a Caco-2 cell model
Get PDFThermal stress can evoke a stress response and enhance the synthesis of heat shock proteins, while gut barrier dysfunction is considered as an important adverse effect of thermal stress. Considering the previously described effects of galacto-oligosaccharides, nowadays mainly used in infant formulas, we hypothesized that galacto-oligosaccharides may protect the intestinal barrier against heat stress. Human epithelial colorectal adenocarcinoma cells were pre-treated with galacto-oligosaccharides prior to thermal stress exposure (40-42 degrees C) for 24 h. Pre-treatment of galacto-oligosaccharides prevented the heat stress-induced upregulation of heat shock proteins and reduced the heat-induced stress response as observed by a decrease in haem oxygenase-1. Galacto-oligosaccharides partly prevented the heat-induced effects on monolayer integrity as measured by transepithelial electrical resistance, paracellular permeability and E-cadherin expression. In addition to their prebiotic effect, galacto-oligosaccharides may have beneficial potency to protect the intestinal epithelial barrier against heat stress and may be an attractive dietary application for people who are at high risk of developing heat stress. (C) 2015 Elsevier Ltd. All rights reserved
Modulation of cell viability, oxidative stress, calcium homeostasis, and voltage- and ligand-gated ion channels as common mechanisms of action of (mixtures of) non-dioxin-like polychlorinated biphenyls and polybrominated diphenyl ethers
No full textNon-dioxin-like polychlorinated biphenyls (NDL-PCBs) and polybrominated diphenyl ethers (PBDEs) are environmental pollutants that exert neurodevelopmental and neurobehavioral effects in vivo in humans and animals. Acute in vitro neurotoxic effects include changes in cell viability, oxidative stress, and basal intracellular calcium levels. Though these acute cellular effects could partly explain the observed in vivo effects, other mechanisms, such as effects on calcium influx and neurotransmitter receptor function, likely contribute to the disturbance in neurotransmission. This concise review combines in vitro data on cell viability, oxidative stress and basal calcium levels with recent data that clearly demonstrate that (hydroxylated) PCBs and (hydroxylated) PBDEs can exert acute effects on voltage-gated Ca2+ channels as well as on excitatory and inhibitory neurotransmitter receptors in vitro. These novel mechanisms of action are shared by NDL-PCBs, OH-PBDEs, and some other persistent organic pollutants, such as tetrabromobisphenol-A, and could have profound effects on neurodevelopment, neurotransmission, and neurobehavior in vivo
Introduction to special issue: Neurotoxicity of brominated flame retardants and the quest for safer alternatives
Get PDFAssessment and characterisation of yeast-based products intended to mitigate ochratoxin exposure using in vitro and in vivo models
Get PDFThe aim of this paper was to evaluate the capacity of several yeast-based products, derived from baker's and brewer's yeasts, to sequester the mycotoxin ochratoxin A (OTA) and to decrease its rate of absorption and DNA adduct formation in vivo. The experimental protocol included in vitro binding studies using isotherm models, in vivo chicken experiments, in which the serum and tissue concentrations of OTA were analysed in the absence and presence of the test compounds, and the profile of OTA-derived metabolites and their associated DNA adducts were determined. Additionally in vitro cell culture studies (HK2 cells) were applied to assess further the effects for yeast cell product enriched with glutathione (GSH) or selenium. Results of the in vitro binding assay in a buffer system indicated the ability of the yeast-based products, as sequester of OTA, albeit at a different level. In the in vitro experiments in chickens, decreased serum and tissue concentrations of treated animals confirmed that yeast-based products are able to prevent the absorption of OTA. A comparison of the binding affinity in a standard in vitro binding assay with the results obtained in an in vivo chicken experiment, however, showed a poor correlation and resulted in a different ranking of the products. More importantly, we could show that yeast-based products actively modulate the biotransformation of OTA in vivo as well as in vitro in a cell culture model. This effect seems to be attributable to residual enzymatic activities in the yeast-based products. An enrichment of yeast cell wall products with GSH or selenium further modulated the profile of the generated OTA metabolites and the associated pattern of OTA-induced DNA adducts by increasing the conversion of OTA into less toxic metabolites such as OTA, OTB and 4-OH-OTA. A reduced absorption and DNA adduct formation was particularly observed with GSH-enriched yeast, whereas selenium-enriched yeasts could counteract the OTA-induced decrease in cell viability, but at the same time increased the OTA-DNA adducts formation. These findings indicate the need for an in-depth characterisation of yeast-based products used as mycotoxin-mitigating feed additives, in in vivo models with target animal species taking into account not only their ability to sequester toxins in the gastrointestinal tract but also their potential effects on the biotransformation of mycotoxins
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