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Here, we investigated if methylene blue can inhibit caspases via the oxidation of their active site cysteine. Methylene blue and derivatives, azure A and azure B competitively inhibited recombinant Caspase-6 (Casp6) and inhibited Casp6 activity in transfected human colon carcinoma cells and in serum-deprived primary human neuron cultures. Methylene blue also inhibited recombinant Casp1 and Casp3. Furthermore, methylene blue inhibited Casp3 activity in an acute mouse model of liver toxicity. Mass spectrometry confirmed methylene blue and azure B oxidation of the catalytic Cys163 cysteine of Casp6. Together, these results show a novel inhibitory mechanism of caspases via sulfenation of the active site cysteine. These results indicate that methylene blue or its derivatives could (1) have an additional effect against Alzheimer Disease by inhibiting brain caspase activity, (2) be used as a drug to prevent caspase activation in other conditions and (3) predispose chronically treated individuals to cancer via the inhibition of caspases.<\/jats:p>","DOI":"10.1038\/srep13730","type":"journal-article","created":{"date-parts":[[2015,9,24]],"date-time":"2015-09-24T08:55:13Z","timestamp":1443084913000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":34,"title":["Methylene Blue Inhibits Caspases by Oxidation of the Catalytic Cysteine"],"prefix":"10.1038","volume":"5","author":[{"given":"Prateep","family":"Pakavathkumar","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gyanesh","family":"Sharma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vikas","family":"Kaushal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"B\u00e9n\u00e9dicte","family":"Foveau","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea C.","family":"LeBlanc","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2015,9,24]]},"reference":[{"key":"BFsrep13730_CR1","doi-asserted-by":"publisher","first-page":"e2327","DOI":"10.1016\/j.neurobiolaging.2010.12.012","volume":"32","author":"RH Schirmer","year":"2011","unstructured":"Schirmer, R. 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