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Anti-inflammatory activities of novel heat shock protein 90 isoform selective inhibitors in BV-2 microglial cells.
Smith, Amanda G; Kliebe, Valentin M; Mishra, Sanket; McCall, Ryan P; Irvine, Megan M; Blagg, Brian S J; Lei, Wei.
Afiliación
  • Smith AG; Department of Pharmaceutical and Administrative Sciences, Presbyterian College School of Pharmacy, Clinton, SC, United States.
  • Kliebe VM; Department of Biology, Presbyterian College, Clinton, SC, United States.
  • Mishra S; Department of Chemistry and Biochemistry, University of Notre Dame College of Science, Notre Dame, IN, United States.
  • McCall RP; Department of Pharmaceutical and Administrative Sciences, Presbyterian College School of Pharmacy, Clinton, SC, United States.
  • Irvine MM; Department of Pharmaceutical and Graduate Life Sciences, Manchester University Fort Wayne, Fort Wayne, IN, United States.
  • Blagg BSJ; Department of Chemistry and Biochemistry, University of Notre Dame College of Science, Notre Dame, IN, United States.
  • Lei W; Department of Pharmaceutical and Administrative Sciences, Presbyterian College School of Pharmacy, Clinton, SC, United States.
Front Mol Biosci ; 11: 1405339, 2024.
Article en En | MEDLINE | ID: mdl-38756532
ABSTRACT
Heat shock protein 90 (Hsp90) is a family of chaperone proteins that consists of four isoforms Hsp90α, Hsp90ß, glucose-regulated protein 94 (Grp94), and tumor necrosis factor type 1 receptor-associated protein (TRAP1). They are involved in modulating the folding, maturation, and activation of their client proteins to regulate numerous intracellular signaling pathways. Previous studies demonstrated that pan-Hsp90 inhibitors reduce inflammatory signaling pathways resulting in a reduction of inflammation and pain but show toxicities in cancer-related clinical trials. Further, the role of Hsp90 isoforms in inflammation remains poorly understood. This study aimed to determine anti-inflammatory activities of Hsp90 isoforms selective inhibitors on the lipopolysaccharide (LPS)-induced inflammation in BV-2 cells, a murine microglial cell line. The production of inflammatory mediators such as nitric oxide (NO), interleukin 1 beta (IL-1ß), and tumor necrosis factor-alpha (TNF-α) was measured. We also investigated the impact of Hsp90 isoform inhibitors on the activation of nuclear factor kappa B (NF-κB), nuclear factor erythroid 2-related factor 2 (Nrf2), and mitogen-activated protein kinases (MAPKs). We found that selective inhibitors of Hsp90ß reduced the LPS-induced production of NO, IL-1ß, and TNF-α via diminishing the activation of NF-κB and Extracellular signal-regulated kinases (ERK) MAPK. The Hsp90α, Grp94, TRAP1 inhibitors had limited effect on the production of inflammatory mediators. These findings suggest that Hsp90ß is the key player in LPS-induced neuroinflammation. Thereby providing a more selective drug target for development of medications involved in pain management that can potentially contribute to the reduction of adverse side effects associated with Hsp90 pan inhibitors.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Front Mol Biosci Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Suiza
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Front Mol Biosci Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Suiza