Demonstration of elevated levels of active cathepsin S in dextran sulfate sodium colitis using a new activatable probe
Background Proteases play a major role in inflammatory diseases of the gastrointestinal tract. Activatable probes are a major technological advance, enabling sensitive detection of active proteases in tissue samples. Our aim was to synthesize an activatable probe for cathepsin S and validate its use...
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| Veröffentlicht in: | Neurogastroenterology and motility 2015-11, Vol.27 (11), p.1675-1680 |
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| creator | Barlow, N. Nasser, Y. Zhao, P. Sharma, N. Guerrero‐Alba, R. Edgington‐Mitchell, L. E. Lieu, T. Veldhuis, N. A. Poole, D. P. Conner, J. W. Lindström, E. Craig, A. W. Graham, B. Vanner, S. J. Bunnett, N. W. |
| description | Background
Proteases play a major role in inflammatory diseases of the gastrointestinal tract. Activatable probes are a major technological advance, enabling sensitive detection of active proteases in tissue samples. Our aim was to synthesize an activatable probe for cathepsin S and validate its use in a mouse model of colitis.
Methods
We designed and synthesized a new fluorescent activatable probe, NB200, for the detection of active cathepsin S. Colitis was induced in C57BL/6 mice by the administration of 3% dextran sulfate sodium (DSS). Homogenized mouse colons, with or without the addition of the specific cathepsin S inhibitor MV026031, were incubated with NB200 in a fluorescent plate reader.
Key Results
NB200 selectively detected purified cathepsin S and not other common inflammatory proteases. Homogenates of colon from mice with DSS colitis induced a significant fluorescent increase when compared to control animals (control vs DSS: p |
| doi_str_mv | 10.1111/nmo.12656 |
| format | Article |
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Proteases play a major role in inflammatory diseases of the gastrointestinal tract. Activatable probes are a major technological advance, enabling sensitive detection of active proteases in tissue samples. Our aim was to synthesize an activatable probe for cathepsin S and validate its use in a mouse model of colitis.
Methods
We designed and synthesized a new fluorescent activatable probe, NB200, for the detection of active cathepsin S. Colitis was induced in C57BL/6 mice by the administration of 3% dextran sulfate sodium (DSS). Homogenized mouse colons, with or without the addition of the specific cathepsin S inhibitor MV026031, were incubated with NB200 in a fluorescent plate reader.
Key Results
NB200 selectively detected purified cathepsin S and not other common inflammatory proteases. Homogenates of colon from mice with DSS colitis induced a significant fluorescent increase when compared to control animals (control vs DSS: p < 0.05 at 200 min and p < 0.01 at 220–240 min), indicating cathepsin S activation. The cathepsin S inhibitor abolished this increase in fluorescence (DSS vs DSS + MV026031: p < 0.05 at 140 min, p < 0.01 at 180 min, p < 0.001 at 200–240 min), which confirms cathepsin S activation. Cathepsin S activity correlated with the disease activity index (Spearman r = 0.77, p = 0.017).
Conclusions & Inferences
Our investigation has demonstrated the utility of activatable probes for detecting protease activity in intestinal inflammation. Panels of such probes may allow ‘signature’ protease profiles to be established for a range of inflammatory diseases and disorders.
We have developed an activatable probe to measure cathepsin S activity in body fluids and tissue samples. This has allowed us to demonstrate elevated levels of cathepsin S in the commonly used dextran sulfate sodium model of colitis – a model of chronic bowel inflammation. This simple, novel, and selective tool will be valuable in future preclinical and clinical investigations of the gut.]]></description><identifier>ISSN: 1350-1925</identifier><identifier>EISSN: 1365-2982</identifier><identifier>DOI: 10.1111/nmo.12656</identifier><identifier>PMID: 26303377</identifier><language>eng</language><publisher>England: Wiley Subscription Services, Inc</publisher><subject>activatable probes ; Animals ; cathepsin S ; Cathepsins - analysis ; Colitis - chemically induced ; Colitis - enzymology ; Dextran Sulfate - toxicity ; Disease Models, Animal ; DSS colitis ; Fluorescent Dyes - chemical synthesis ; Fluorescent Dyes - pharmacology ; inflammation ; Mice ; Mice, Inbred C57BL ; proteases</subject><ispartof>Neurogastroenterology and motility, 2015-11, Vol.27 (11), p.1675-1680</ispartof><rights>2015 John Wiley & Sons Ltd</rights><rights>2015 John Wiley & Sons Ltd.</rights><rights>Copyright © 2015 John Wiley & Sons Ltd</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4486-74e2ba050012f9560812d3b757d88a162aa17c6df5b4d1775fe0524c91bfdd803</citedby><cites>FETCH-LOGICAL-c4486-74e2ba050012f9560812d3b757d88a162aa17c6df5b4d1775fe0524c91bfdd803</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1111%2Fnmo.12656$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1111%2Fnmo.12656$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,776,780,1411,1427,27901,27902,45550,45551,46384,46808</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26303377$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Barlow, N.</creatorcontrib><creatorcontrib>Nasser, Y.</creatorcontrib><creatorcontrib>Zhao, P.</creatorcontrib><creatorcontrib>Sharma, N.</creatorcontrib><creatorcontrib>Guerrero‐Alba, R.</creatorcontrib><creatorcontrib>Edgington‐Mitchell, L. E.</creatorcontrib><creatorcontrib>Lieu, T.</creatorcontrib><creatorcontrib>Veldhuis, N. A.</creatorcontrib><creatorcontrib>Poole, D. P.</creatorcontrib><creatorcontrib>Conner, J. W.</creatorcontrib><creatorcontrib>Lindström, E.</creatorcontrib><creatorcontrib>Craig, A. W.</creatorcontrib><creatorcontrib>Graham, B.</creatorcontrib><creatorcontrib>Vanner, S. J.</creatorcontrib><creatorcontrib>Bunnett, N. W.</creatorcontrib><title>Demonstration of elevated levels of active cathepsin S in dextran sulfate sodium colitis using a new activatable probe</title><title>Neurogastroenterology and motility</title><addtitle>Neurogastroenterol Motil</addtitle><description><![CDATA[Background
Proteases play a major role in inflammatory diseases of the gastrointestinal tract. Activatable probes are a major technological advance, enabling sensitive detection of active proteases in tissue samples. Our aim was to synthesize an activatable probe for cathepsin S and validate its use in a mouse model of colitis.
Methods
We designed and synthesized a new fluorescent activatable probe, NB200, for the detection of active cathepsin S. Colitis was induced in C57BL/6 mice by the administration of 3% dextran sulfate sodium (DSS). Homogenized mouse colons, with or without the addition of the specific cathepsin S inhibitor MV026031, were incubated with NB200 in a fluorescent plate reader.
Key Results
NB200 selectively detected purified cathepsin S and not other common inflammatory proteases. Homogenates of colon from mice with DSS colitis induced a significant fluorescent increase when compared to control animals (control vs DSS: p < 0.05 at 200 min and p < 0.01 at 220–240 min), indicating cathepsin S activation. The cathepsin S inhibitor abolished this increase in fluorescence (DSS vs DSS + MV026031: p < 0.05 at 140 min, p < 0.01 at 180 min, p < 0.001 at 200–240 min), which confirms cathepsin S activation. Cathepsin S activity correlated with the disease activity index (Spearman r = 0.77, p = 0.017).
Conclusions & Inferences
Our investigation has demonstrated the utility of activatable probes for detecting protease activity in intestinal inflammation. Panels of such probes may allow ‘signature’ protease profiles to be established for a range of inflammatory diseases and disorders.
We have developed an activatable probe to measure cathepsin S activity in body fluids and tissue samples. This has allowed us to demonstrate elevated levels of cathepsin S in the commonly used dextran sulfate sodium model of colitis – a model of chronic bowel inflammation. This simple, novel, and selective tool will be valuable in future preclinical and clinical investigations of the gut.]]></description><subject>activatable probes</subject><subject>Animals</subject><subject>cathepsin S</subject><subject>Cathepsins - analysis</subject><subject>Colitis - chemically induced</subject><subject>Colitis - enzymology</subject><subject>Dextran Sulfate - toxicity</subject><subject>Disease Models, Animal</subject><subject>DSS colitis</subject><subject>Fluorescent Dyes - chemical synthesis</subject><subject>Fluorescent Dyes - pharmacology</subject><subject>inflammation</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>proteases</subject><issn>1350-1925</issn><issn>1365-2982</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1kU9PwyAYh4nR6Jwe_AKGxIseqkALtEcz_yZTD-q5oeWtstAyS7u5by9b1YOJ74GXkOd9IPwQOqLknIa6aGp3TpngYguNaCx4xLKUba_3nEQ0Y3wP7Xs_I4QIlohdtMdETOJYyhFaXEHtGt-1qjOuwa7CYGGhOtA4dLB-faTKziwAl6p7h7k3DX7GYdHwGcYa7HtbhQHsnTZ9jUtnTWc87gP4hhVuYDkIVKcKC3jeugIO0E6lrIfD7z5GrzfXL5O7aPp0ez-5nEZlkqQikgmwQhFOCGVVxgVJKdNxIbnUaaqoYEpRWQpd8SLRVEpeAeEsKTNaVFqnJB6j08Ebbv3owXd5bXwJ1qoGXO9zKpnMsiQONUYnf9CZ69smvG5DxSJJ2Zo6G6iydd63UOXz1tSqXeWU5Osw8hBGvgkjsMffxr6oQf-SP78fgIsBWBoLq_9N-ePD06D8Aj6Dk8g</recordid><startdate>201511</startdate><enddate>201511</enddate><creator>Barlow, N.</creator><creator>Nasser, Y.</creator><creator>Zhao, P.</creator><creator>Sharma, N.</creator><creator>Guerrero‐Alba, R.</creator><creator>Edgington‐Mitchell, L. E.</creator><creator>Lieu, T.</creator><creator>Veldhuis, N. A.</creator><creator>Poole, D. P.</creator><creator>Conner, J. W.</creator><creator>Lindström, E.</creator><creator>Craig, A. W.</creator><creator>Graham, B.</creator><creator>Vanner, S. J.</creator><creator>Bunnett, N. W.</creator><general>Wiley Subscription Services, Inc</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7TK</scope><scope>K9.</scope><scope>7X8</scope></search><sort><creationdate>201511</creationdate><title>Demonstration of elevated levels of active cathepsin S in dextran sulfate sodium colitis using a new activatable probe</title><author>Barlow, N. ; Nasser, Y. ; Zhao, P. ; Sharma, N. ; Guerrero‐Alba, R. ; Edgington‐Mitchell, L. E. ; Lieu, T. ; Veldhuis, N. A. ; Poole, D. P. ; Conner, J. W. ; Lindström, E. ; Craig, A. W. ; Graham, B. ; Vanner, S. J. ; Bunnett, N. W.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4486-74e2ba050012f9560812d3b757d88a162aa17c6df5b4d1775fe0524c91bfdd803</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>activatable probes</topic><topic>Animals</topic><topic>cathepsin S</topic><topic>Cathepsins - analysis</topic><topic>Colitis - chemically induced</topic><topic>Colitis - enzymology</topic><topic>Dextran Sulfate - toxicity</topic><topic>Disease Models, Animal</topic><topic>DSS colitis</topic><topic>Fluorescent Dyes - chemical synthesis</topic><topic>Fluorescent Dyes - pharmacology</topic><topic>inflammation</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>proteases</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Barlow, N.</creatorcontrib><creatorcontrib>Nasser, Y.</creatorcontrib><creatorcontrib>Zhao, P.</creatorcontrib><creatorcontrib>Sharma, N.</creatorcontrib><creatorcontrib>Guerrero‐Alba, R.</creatorcontrib><creatorcontrib>Edgington‐Mitchell, L. E.</creatorcontrib><creatorcontrib>Lieu, T.</creatorcontrib><creatorcontrib>Veldhuis, N. A.</creatorcontrib><creatorcontrib>Poole, D. P.</creatorcontrib><creatorcontrib>Conner, J. W.</creatorcontrib><creatorcontrib>Lindström, E.</creatorcontrib><creatorcontrib>Craig, A. W.</creatorcontrib><creatorcontrib>Graham, B.</creatorcontrib><creatorcontrib>Vanner, S. J.</creatorcontrib><creatorcontrib>Bunnett, N. W.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Neurosciences Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>MEDLINE - Academic</collection><jtitle>Neurogastroenterology and motility</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Barlow, N.</au><au>Nasser, Y.</au><au>Zhao, P.</au><au>Sharma, N.</au><au>Guerrero‐Alba, R.</au><au>Edgington‐Mitchell, L. E.</au><au>Lieu, T.</au><au>Veldhuis, N. A.</au><au>Poole, D. P.</au><au>Conner, J. W.</au><au>Lindström, E.</au><au>Craig, A. W.</au><au>Graham, B.</au><au>Vanner, S. J.</au><au>Bunnett, N. W.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Demonstration of elevated levels of active cathepsin S in dextran sulfate sodium colitis using a new activatable probe</atitle><jtitle>Neurogastroenterology and motility</jtitle><addtitle>Neurogastroenterol Motil</addtitle><date>2015-11</date><risdate>2015</risdate><volume>27</volume><issue>11</issue><spage>1675</spage><epage>1680</epage><pages>1675-1680</pages><issn>1350-1925</issn><eissn>1365-2982</eissn><abstract><![CDATA[Background
Proteases play a major role in inflammatory diseases of the gastrointestinal tract. Activatable probes are a major technological advance, enabling sensitive detection of active proteases in tissue samples. Our aim was to synthesize an activatable probe for cathepsin S and validate its use in a mouse model of colitis.
Methods
We designed and synthesized a new fluorescent activatable probe, NB200, for the detection of active cathepsin S. Colitis was induced in C57BL/6 mice by the administration of 3% dextran sulfate sodium (DSS). Homogenized mouse colons, with or without the addition of the specific cathepsin S inhibitor MV026031, were incubated with NB200 in a fluorescent plate reader.
Key Results
NB200 selectively detected purified cathepsin S and not other common inflammatory proteases. Homogenates of colon from mice with DSS colitis induced a significant fluorescent increase when compared to control animals (control vs DSS: p < 0.05 at 200 min and p < 0.01 at 220–240 min), indicating cathepsin S activation. The cathepsin S inhibitor abolished this increase in fluorescence (DSS vs DSS + MV026031: p < 0.05 at 140 min, p < 0.01 at 180 min, p < 0.001 at 200–240 min), which confirms cathepsin S activation. Cathepsin S activity correlated with the disease activity index (Spearman r = 0.77, p = 0.017).
Conclusions & Inferences
Our investigation has demonstrated the utility of activatable probes for detecting protease activity in intestinal inflammation. Panels of such probes may allow ‘signature’ protease profiles to be established for a range of inflammatory diseases and disorders.
We have developed an activatable probe to measure cathepsin S activity in body fluids and tissue samples. This has allowed us to demonstrate elevated levels of cathepsin S in the commonly used dextran sulfate sodium model of colitis – a model of chronic bowel inflammation. This simple, novel, and selective tool will be valuable in future preclinical and clinical investigations of the gut.]]></abstract><cop>England</cop><pub>Wiley Subscription Services, Inc</pub><pmid>26303377</pmid><doi>10.1111/nmo.12656</doi><tpages>6</tpages></addata></record> |
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| source | MEDLINE; Wiley Online Library Journals Frontfile Complete; Wiley Online Library Free Content |
| subjects | activatable probes Animals cathepsin S Cathepsins - analysis Colitis - chemically induced Colitis - enzymology Dextran Sulfate - toxicity Disease Models, Animal DSS colitis Fluorescent Dyes - chemical synthesis Fluorescent Dyes - pharmacology inflammation Mice Mice, Inbred C57BL proteases |
| title | Demonstration of elevated levels of active cathepsin S in dextran sulfate sodium colitis using a new activatable probe |
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