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Anthrapyrazolone analogues intercept inflammatory JNK signals to moderate endotoxin induced septic shock
Severe sepsis or septic shock is one of the rising causes for mortality worldwide representing nearly 10% of intensive care unit admissions. Susceptibility to sepsis is identified to be mediated by innate pattern recognition receptors and responsive signaling pathways of the host. The c-Jun N-termin...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4245532/ https://www.ncbi.nlm.nih.gov/pubmed/25428720 http://dx.doi.org/10.1038/srep07214 |
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author | Prasad, Karothu Durga Trinath, Jamma Biswas, Ansuman Sekar, Kanagaraj Balaji, Kithiganahalli N. Guru Row, Tayur N. |
author_facet | Prasad, Karothu Durga Trinath, Jamma Biswas, Ansuman Sekar, Kanagaraj Balaji, Kithiganahalli N. Guru Row, Tayur N. |
author_sort | Prasad, Karothu Durga |
collection | PubMed |
description | Severe sepsis or septic shock is one of the rising causes for mortality worldwide representing nearly 10% of intensive care unit admissions. Susceptibility to sepsis is identified to be mediated by innate pattern recognition receptors and responsive signaling pathways of the host. The c-Jun N-terminal Kinase (JNK)-mediated signaling events play critical role in bacterial infection triggered multi-organ failure, cardiac dysfunction and mortality. In the context of kinase specificities, an extensive library of anthrapyrazolone analogues has been investigated for the selective inhibition of c-JNK and thereby to gain control over the inflammation associated risks. In our comprehensive biochemical characterization, it is observed that alkyl and halogen substitution on the periphery of anthrapyrazolone increases the binding potency of the inhibitors specifically towards JNK. Further, it is demonstrated that hydrophobic and hydrophilic interactions generated by these small molecules effectively block endotoxin-induced inflammatory genes expression in in vitro and septic shock in vivo, in a mouse model, with remarkable efficacies. Altogether, the obtained results rationalize the significance of the diversity oriented synthesis of small molecules for selective inhibition of JNK and their potential in the treatment of severe sepsis. |
format | Online Article Text |
id | pubmed-4245532 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-42455322014-12-05 Anthrapyrazolone analogues intercept inflammatory JNK signals to moderate endotoxin induced septic shock Prasad, Karothu Durga Trinath, Jamma Biswas, Ansuman Sekar, Kanagaraj Balaji, Kithiganahalli N. Guru Row, Tayur N. Sci Rep Article Severe sepsis or septic shock is one of the rising causes for mortality worldwide representing nearly 10% of intensive care unit admissions. Susceptibility to sepsis is identified to be mediated by innate pattern recognition receptors and responsive signaling pathways of the host. The c-Jun N-terminal Kinase (JNK)-mediated signaling events play critical role in bacterial infection triggered multi-organ failure, cardiac dysfunction and mortality. In the context of kinase specificities, an extensive library of anthrapyrazolone analogues has been investigated for the selective inhibition of c-JNK and thereby to gain control over the inflammation associated risks. In our comprehensive biochemical characterization, it is observed that alkyl and halogen substitution on the periphery of anthrapyrazolone increases the binding potency of the inhibitors specifically towards JNK. Further, it is demonstrated that hydrophobic and hydrophilic interactions generated by these small molecules effectively block endotoxin-induced inflammatory genes expression in in vitro and septic shock in vivo, in a mouse model, with remarkable efficacies. Altogether, the obtained results rationalize the significance of the diversity oriented synthesis of small molecules for selective inhibition of JNK and their potential in the treatment of severe sepsis. Nature Publishing Group 2014-11-27 /pmc/articles/PMC4245532/ /pubmed/25428720 http://dx.doi.org/10.1038/srep07214 Text en Copyright © 2014, Macmillan Publishers Limited. All rights reserved http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder in order to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ |
spellingShingle | Article Prasad, Karothu Durga Trinath, Jamma Biswas, Ansuman Sekar, Kanagaraj Balaji, Kithiganahalli N. Guru Row, Tayur N. Anthrapyrazolone analogues intercept inflammatory JNK signals to moderate endotoxin induced septic shock |
title | Anthrapyrazolone analogues intercept inflammatory JNK signals to moderate endotoxin induced septic shock |
title_full | Anthrapyrazolone analogues intercept inflammatory JNK signals to moderate endotoxin induced septic shock |
title_fullStr | Anthrapyrazolone analogues intercept inflammatory JNK signals to moderate endotoxin induced septic shock |
title_full_unstemmed | Anthrapyrazolone analogues intercept inflammatory JNK signals to moderate endotoxin induced septic shock |
title_short | Anthrapyrazolone analogues intercept inflammatory JNK signals to moderate endotoxin induced septic shock |
title_sort | anthrapyrazolone analogues intercept inflammatory jnk signals to moderate endotoxin induced septic shock |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4245532/ https://www.ncbi.nlm.nih.gov/pubmed/25428720 http://dx.doi.org/10.1038/srep07214 |
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