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| Status |
Public on Oct 07, 2022 |
| Title |
Identification of Cytoprotective Small Molecule Inducers of Heme Oxygenase-1 |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Acute kidney injury (AKI) is a major public health concern with significant attributable morbidity and mortality with no current FDA approved treatments other than supportive care through dialysis. Several pre-clinical studies have suggested that heme-oxygenase-1 (HO-1), an enzyme that catalyzes the breakdown of heme, has promise as a potential therapeutic target for AKI. Clinical trials involving HO-1 products (biliverdin, carbon monoxide, and iron), however, have not progressed beyond the Phase 1/2 level. We have identified small molecule inducers of HO-1 that enable us to exploit the full therapeutic potential of HO-1, the combination of its products, and as-yet-undefined effects of the enzyme system. Through cell-based, high throughput screens for induction of HO-1 through the human HO-1 promoter/enhancer, we identified two novel small molecules and broxaldine, an FDA approved antiprotozoal, for further consideration as candidate compounds exhibiting Emax ≥ 70% of 5 µM hemin and EC50<10 µM. RNA sequencing identified shared binding motifs to NRF-2, a transcription factor known to regulate antioxidant genes, including HO-1. siRNA knockdown of NRF-2 confirmed the role of NRF-2 in induction of HO-1. In vitro, cytoprotective function of the candidates was assessed against cisplatin-induced cytotoxicity and apoptosis. In vivo, delivery of candidate compounds induced HO-1 expression in the kidneys of mice. This study serves as the basis for further development of small molecule HO-1 inducers as preventative or therapeutic interventions for a variety of pathologies, including AKI.
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| Overall design |
Bulk RNA sequencing of HEK293 cells treated with small molecules SRI-37618, SRI-40109, broxaldine, hemin, or DMSO (vehicle) for 4 or 8 hours. N=2 per timepoint and condition.
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| Contributor(s) |
Ghajar-Rahimi G, Traylor AM, Mathew B, Bostwick JR, Nebane-Ngwa NM, Zmijewska A, Esman S, Zhai L, Sambandam V, Cowell RM, Suto MJ, George JF, Augelli-Szafran CE, Agarwal A |
| Citation(s) |
36290611 |
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| Submission date |
Aug 12, 2022 |
| Last update date |
Nov 02, 2022 |
| Contact name |
Anupam Agarwal |
| E-mail(s) |
agarwal@uab.edu
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| Organization name |
University of Alabama at Birmingham
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| Street address |
703 19th St S
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| City |
Birmingham |
| State/province |
AL |
| ZIP/Postal code |
35294 |
| Country |
USA |
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| Platforms (1) |
| GPL18573 |
Illumina NextSeq 500 (Homo sapiens) |
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| Samples (22)
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| Relations |
| BioProject |
PRJNA869065 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE211130_RAW.tar |
5.0 Mb |
(http)(custom) |
TAR (of TXT) |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data provided as supplementary file |
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