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Celastrol augments sensitivity of NLRP3 to CP-456773 by modulating HSP-90 and inducing autophagy in dextran sodium sulphate-induced colitis in rats.

Authors
  • Saber, Sameh1
  • Abd El-Kader, Eman M2
  • Sharaf, Hossam3
  • El-Shamy, Rewan4
  • El-Saeed, Baraah4
  • Mostafa, Asmaa4
  • Ezzat, Dalia4
  • Shata, Ahmed5
  • 1 Department of Pharmacology, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa, Egypt. Electronic address: [email protected] , (Egypt)
  • 2 Department of Pharmacology, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa, Egypt. , (Egypt)
  • 3 Department of Clinical Pharmacy, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa, Egypt. , (Egypt)
  • 4 Department of Biochemistry, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa, Egypt. , (Egypt)
  • 5 Department of Clinical pharmacology, Faculty of Medicine, Mansoura University, Mansoura, Egypt; Department of Clinical Pharmacy, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa, Egypt. , (Egypt)
Type
Published Article
Journal
Toxicology and Applied Pharmacology
Publisher
Elsevier
Publication Date
Aug 01, 2020
Volume
400
Pages
115075–115075
Identifiers
DOI: 10.1016/j.taap.2020.115075
PMID: 32470352
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

NLRP3, one of the HSP-90 clients, has been defined as a critical component of IBD. In a rat model of DSS-induced colitis, we investigated the anti-inflammatory potential of the combined therapy with CP-456773 (CP), an NLRP3 inhibitor, and celastrol (CSR), an NF-κB inhibitor. Our results revealed that the CSR/CP combined therapy (CCCT) attenuated colon shortening, DAI and MDI in addition to improvement of the colonic histological picture. Moreover, the CCCT increased the antioxidant defense machinery of the colonic tissue and decreased MPO activity. Furthermore, the inflammation markers such as TNF-α and IL-6 were downregulated. These effects might be attributed to the inhibitory effect of CSR on the priming step of the NLRP3 inflammasome activation by interrupting NF-κB signalling and inhibition of HSP-90 (at the protein and mRNA levels) along with inhibitory effect of CP on the expression of the NLRP3. These latter effects resulted in decreased tissue expression and activity of the caspase-1 and repressing the subsequent release of the active forms of IL-1β and IL-18, hence, the pyroptosis process is restrained. Additionally, the CCCT resulted in inducing autophagy by AMPK/mTOR-dependent mechanisms leading to the accumulation of BECN1 protein and a significant decrease in the levels of p62 SQSTM1. The inhibitory effect on HSP-90 in conjunction with induction of autophagy suggest increased autophagic degradation of NLRP3. This novel approach provides a basis for the clinical application of this combination in IBD treatment and might also be promising for the pharmacological intervention of other NLRP3 inflammasome-dependent inflammatory conditions. Copyright © 2020 Elsevier Inc. All rights reserved.

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