Abstract |
Dysfunction of the blood-brain barrier (BBB) endothelium increases infiltration of lymphocytes and innate immune cells in the brain, leading to the development of neurological disorders. Heat shock protein 90 (Hsp90) inhibitors are anti-inflammatory agents and P53 inducers, which reduce the production of reactive oxygen species (ROS) in a diverse variety of human tissues. In this study, we investigate the effects of those compounds in LPS-induced brain endothelial inflammation, by utilizing human cerebral microvascular endothelial cells (hCMEC/D3). Our results suggest that Hsp90 inhibitors suppress inflammation by inhibiting the LPS-induced signal transducer and activator of transcription 3 (STAT3); and P38 activation. Moreover, those compounds reduce the P53 suppressors murine double minute 2 (MDM2) and murine double minute 4 (MDM4). Immunoglobulin heavy chain binding protein/ glucose-regulated protein 78 (BiP/ Grp78)-a key element of endothelial barrier integrity-was also increased by Hsp90 inhibition. Hence, we conclude that application of Hsp90 inhibitors in diseases related to BBB dysfunction may deliver a novel therapeutic possibility in the affected population.
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Authors | Mohammad A Uddin, Mohammad S Akhter, Khadeja-Tul Kubra, Nektarios Barabutis |
Journal | BioFactors (Oxford, England)
(Biofactors)
Vol. 48
Issue 4
Pg. 926-933
(Jul 2022)
ISSN: 1872-8081 [Electronic] Netherlands |
PMID | 35266593
(Publication Type: Journal Article)
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Copyright | © 2022 International Union of Biochemistry and Molecular Biology. |
Chemical References |
- Cell Cycle Proteins
- HSP90 Heat-Shock Proteins
- Lipopolysaccharides
- MDM4 protein, human
- Proto-Oncogene Proteins
- Tumor Suppressor Protein p53
- Proto-Oncogene Proteins c-mdm2
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Topics |
- Animals
- Brain
(metabolism)
- Cell Cycle Proteins
(metabolism)
- Cells, Cultured
- Endothelial Cells
- Endothelium
(metabolism)
- HSP90 Heat-Shock Proteins
- Humans
- Inflammation
(metabolism)
- Lipopolysaccharides
(metabolism)
- Mice
- Proto-Oncogene Proteins
- Proto-Oncogene Proteins c-mdm2
(metabolism, pharmacology)
- Tumor Suppressor Protein p53
(metabolism)
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