Identification of Cytoprotective Small-Molecule Inducers of Heme-Oxygenase-1
Acute kidney injury (AKI) is a major public health concern with significant morbidity and mortality and no current treatments beyond supportive care and dialysis. Preclinical studies have suggested that heme-oxygenase-1 (HO-1), an enzyme that catalyzes the breakdown of heme, has promise as a potenti...
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MDPI AG,
2022-09-01T00:00:00Z.
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| 001 | doaj_25f0f94d8f124a2fac06bb9aa63b0b1c | ||
| 042 | |a dc | ||
| 100 | 1 | 0 | |a Gelare Ghajar-Rahimi |e author |
| 700 | 1 | 0 | |a Amie M. Traylor |e author |
| 700 | 1 | 0 | |a Bini Mathew |e author |
| 700 | 1 | 0 | |a James R. Bostwick |e author |
| 700 | 1 | 0 | |a N Miranda Nebane |e author |
| 700 | 1 | 0 | |a Anna A. Zmijewska |e author |
| 700 | 1 | 0 | |a Stephanie K. Esman |e author |
| 700 | 1 | 0 | |a Saakshi Thukral |e author |
| 700 | 1 | 0 | |a Ling Zhai |e author |
| 700 | 1 | 0 | |a Vijaya Sambandam |e author |
| 700 | 1 | 0 | |a Rita M. Cowell |e author |
| 700 | 1 | 0 | |a Mark J. Suto |e author |
| 700 | 1 | 0 | |a James F. George |e author |
| 700 | 1 | 0 | |a Corinne E. Augelli-Szafran |e author |
| 700 | 1 | 0 | |a Anupam Agarwal |e author |
| 245 | 0 | 0 | |a Identification of Cytoprotective Small-Molecule Inducers of Heme-Oxygenase-1 |
| 260 | |b MDPI AG, |c 2022-09-01T00:00:00Z. | ||
| 500 | |a 10.3390/antiox11101888 | ||
| 500 | |a 2076-3921 | ||
| 520 | |a Acute kidney injury (AKI) is a major public health concern with significant morbidity and mortality and no current treatments beyond supportive care and dialysis. Preclinical 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 ½ level. We 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 yet-undefined effects of the enzyme system. Through cell-based, high-throughput screens for induction of HO-1 driven by the human HO-1 promoter/enhancer, we identified two novel small molecules and broxaldine (an FDA-approved drug) for further consideration as candidate compounds exhibiting an E<sub>max</sub> ≥70% of 5 µM hemin and EC<sub>50</sub> <10 µM. RNA sequencing identified shared binding motifs to NRF2, a transcription factor known to regulate antioxidant genes, including <i>HMOX1</i>. In vitro, the cytoprotective function of the candidates was assessed against cisplatin-induced cytotoxicity and apoptosis. In vivo, delivery of a candidate compound 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. | ||
| 546 | |a EN | ||
| 690 | |a acute kidney injury | ||
| 690 | |a heme oxygenase | ||
| 690 | |a cisplatin nephrotoxicity | ||
| 690 | |a small-molecule drugs | ||
| 690 | |a high-throughput screen | ||
| 690 | |a Therapeutics. Pharmacology | ||
| 690 | |a RM1-950 | ||
| 655 | 7 | |a article |2 local | |
| 786 | 0 | |n Antioxidants, Vol 11, Iss 10, p 1888 (2022) | |
| 787 | 0 | |n https://www.mdpi.com/2076-3921/11/10/1888 | |
| 787 | 0 | |n https://doaj.org/toc/2076-3921 | |
| 856 | 4 | 1 | |u https://doaj.org/article/25f0f94d8f124a2fac06bb9aa63b0b1c |z Connect to this object online. |