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- Andersson, Patrik, et al.
(författare)
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Toxicity with LXR agonists – Problem solving activities for mechanistic understanding
- 2012
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Ingår i: Toxicology Letters. - Shannon : Elsevier. - 0378-4274 .- 1879-3169. ; 211:Suppl. (S), s. S39-S39
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Tidskriftsartikel (refereegranskat)abstract
- Several lines of evidence points toward the potential positive effects of LXR (Liver X Receptor) modulators for effective and safe therapy of cardiovascular diseases (CVDs). LXR is a dimeric nuclear hormone receptor that exists as a combination of RXR and one of two subtypes LXR alpha or beta, which act as cholesterol sensors. LXR alpha is highly expressed in the liver, intestine and adipose tissue while LXR beta is ubiquitously expressed. Activation of LXR up-regulates several genes involved in reverse cholesterol transport (RCT), including ABC transporters. This results in increased efflux of cholesterol from macrophages in atherosclerotic vascular lesions to the circulation and further on to other tissues to ultimately be excreted into the faeces. These effects together with systemic and local anti-inflammatory properties of LXR modulation are likely to contribute to decreased atherosclerosis. The positive effects of LXR activation on RCT and cholesterol balance must be obtained without negative lipid effects, since LXR also activates lipogenic genes. Other types of toxicity and approaches to better understand the mechanism(s) behind these will be presented. Copyright © 2012 Published by Elsevier Ireland Ltd.
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- Nilsson, Anna, et al.
(författare)
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Fine Mapping the Spatial Distribution and Concentration of Unlabeled Drugs within Tissue Micro-Compartments Using Imaging Mass Spectrometry
- 2010
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Ingår i: PloS one. - : Public Library of Science (PLoS). - 1932-6203. ; 5:7, s. e11411-
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Tidskriftsartikel (refereegranskat)abstract
- Readouts that define the physiological distributions of drugs in tissues are an unmet challenge and at best imprecise, but are needed in order to understand both the pharmacokinetic and pharmacodynamic properties associated with efficacy. Here we demonstrate that it is feasible to follow the in vivo transport of unlabeled drugs within specific organ and tissue compartments on a platform that applies MALDI imaging mass spectrometry to tissue sections characterized with high definition histology. We have tracked and quantified the distribution of an inhaled reference compound, tiotropium, within the lungs of dosed rats, using systematic point by point MS and MS/MS sampling at 200 mu m intervals. By comparing drug ion distribution patterns in adjacent tissue sections, we observed that within 15 min following exposure, tiotropium parent MS ions (mass-to-charge; m/z 392.1) and fragmented daughter MS/MS ions (m/z 170.1 and 152.1) were dispersed in a concentration gradient (80 fmol-5 pmol) away from the central airways into the lung parenchyma and pleura. These drug levels agreed well with amounts detected in lung compartments by chemical extraction. Moreover, the simultaneous global definition of molecular ion signatures localized within 2-D tissue space provides accurate assignment of ion identities within histological landmarks, providing context to dynamic biological processes occurring at sites of drug presence. Our results highlight an important emerging technology allowing specific high resolution identification of unlabeled drugs at sites of in vivo uptake and retention.
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- Végvári, Ákos, et al.
(författare)
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Essential tactics of tissue preparation and matrix nano-spotting for successful compound imaging mass spectrometry
- 2010
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Ingår i: Journal of Proteomics. - : Elsevier BV. - 1876-7737 .- 1874-3919. ; 73:6, s. 1270-1278
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Tidskriftsartikel (refereegranskat)abstract
- The ultimate goal of MALDI-Imaging Mass Spectrometry (MALDI-IMS) is to achieve spatial localization of analytes in tissue sections down to individual tissue compartments or even at the level of a few cells. With compound tissue imaging, it is possible to track the transportation of an unlabelled, inhaled reference compound within lung tissue, through the application of MALDI-IMS. The procedure for isolation and preparation of lung tissues is found to be crucial in order to preserve the anatomy and structure of the pulmonary compartments. To avoid delocalization of analytes within lung tissue compartments we have applied an in-house designed nano-spotter, based on a microdispenser mounted on an XY table, of which movement and spotting functionality were fully computer controlled. We demonstrate the usefulness of this platform in lung tissue sections isolated from rodent in vivo model, applied to compound tissue imaging as exemplified with the determination of the spatial distribution of (1 alpha,2 beta,4 beta,7 beta)-7-[(hydroxidi-2-thienylacetyl)oxy]-9,9-dimethyl-3-oxa-9-azoniatric yclo[3.3.1.0(2,4)]nonane, also known as tiotropium. We provide details on tissue preparation protocols and sample spotting technology for successful identification of drug in mouse lung tissue by using MALDI-Orbitrap instrumentation.
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