Document Detail


Strategy for dual-analyte luciferin imaging: in vivo bioluminescence detection of hydrogen peroxide and caspase activity in a murine model of acute inflammation.
MedLine Citation:
PMID:  23347279     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
In vivo molecular imaging holds promise for understanding the underlying mechanisms of health, injury, aging, and disease, as it can detect distinct biochemical processes such as enzymatic activity, reactive small-molecule fluxes, or post-translational modifications. Current imaging techniques often detect only a single biochemical process, but, within whole organisms, multiple types of biochemical events contribute to physiological and pathological phenotypes. In this report, we present a general strategy for dual-analyte detection in living animals that employs in situ formation of firefly luciferin from two complementary caged precursors that can be unmasked by different biochemical processes. To establish this approach, we have developed Peroxy Caged Luciferin-2 (PCL-2), a H(2)O(2)-responsive boronic acid probe that releases 6-hydroxy-2-cyanobenzothiazole (HCBT) upon reacting with this reactive oxygen species, as well as a peptide-based probe, z-Ile-Glu-ThrAsp-D-Cys (IETDC), which releases D-cysteine in the presence of active caspase 8. Once released, HCBT and D-cysteine form firefly luciferin in situ, giving rise to a bioluminescent signal if and only if both chemical triggers proceed. This system thus constitutes an AND-type molecular logic gate that reports on the simultaneous presence of H(2)O(2) and caspase 8 activity. Using these probes, chemoselective imaging of either H(2)O(2) or caspase 8 activity was performed in vitro and in vivo. Moreover, concomitant use of PCL-2 and IETDC in vivo establishes a concurrent increase in both H(2)O(2) and caspase 8 activity during acute inflammation in living mice. Taken together, this method offers a potentially powerful new chemical tool for studying simultaneous oxidative stress and inflammation processes in living animals during injury, aging, and disease, as well as a versatile approach for concurrent monitoring of multiple analytes using luciferin-based bioluminescence imaging technologies.
Authors:
Genevieve C Van de Bittner; Carolyn R Bertozzi; Christopher J Chang
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2013-01-25
Journal Detail:
Title:  Journal of the American Chemical Society     Volume:  135     ISSN:  1520-5126     ISO Abbreviation:  J. Am. Chem. Soc.     Publication Date:  2013 Feb 
Date Detail:
Created Date:  2013-02-06     Completed Date:  2013-08-01     Revised Date:  2014-02-13    
Medline Journal Info:
Nlm Unique ID:  7503056     Medline TA:  J Am Chem Soc     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1783-95     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Acute Disease
Animals
Benzothiazoles / analysis*,  metabolism
Caspase 8 / analysis*,  metabolism
Cell Line
Disease Models, Animal
Enzyme Activation
Hydrogen Peroxide / analysis*,  metabolism
Inflammation / enzymology,  metabolism*
Luminescence
Luminescent Measurements
Mice
Mice, Transgenic
Molecular Imaging*
Molecular Structure
Grant Support
ID/Acronym/Agency:
GM 058867/GM/NIGMS NIH HHS; GM 79465/GM/NIGMS NIH HHS; R01 GM079465/GM/NIGMS NIH HHS; R37 GM058867/GM/NIGMS NIH HHS; //Howard Hughes Medical Institute
Chemical
Reg. No./Substance:
0/Benzothiazoles; 0/D-luciferin; BBX060AN9V/Hydrogen Peroxide; EC 3.4.22.-/Caspase 8
Comments/Corrections

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