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Repurposing Rosiglitazone for Beta-Thal/HbE Therapy in the Circumstances of Ubiquitin-Proteasome Dysregulation
44 Pages Posted: 5 Jul 2024
More...Abstract
β-thalassemia/Hb E (β-thal/HbE) is among the four critical thalassemia disorders, characterized by an accumulation of α-globin chains within erythroid precursor cells. This accumulation results in cellular damage from mechanical and oxidative stress, leading to ineffective erythropoiesis. The breakdown of precipitated alpha-globin within erythrocyte stem cells as a part of the cell defense strategy depends on ubiquitin-dependent proteolysis and ubiquitin-proteasome systems. Comparison of mRNA expression of orthochromatic erythroblasts between healthy donors and patients with β-thal/HbE reveals a set of significantly differentially expressed proteins involved in ubiquitin-proteasome alterations that work in concert with SP1, RUNX1, CDK2, MAPK, and ERKs to elicit the pathophysiologic phenomenon of ineffective erythropoiesis. Moreover, rosiglitazone, one of the top five predicted drugs predicted by the connectivity map between the drug and these altered proteins, is selected to validate this prediction. Rosiglitazone can increase cell differentiation and nucleation in both groups. The proteomics study reveals that it can increase hemoglobin subunit delta in the orthochromatic erythroblast of patients with β-thal/HbE, but not in healthy donors. This may lead to an increase in HbA2 and be used as an alternative therapeutic approach for β-hemoglobinopathies.
Funding: This research project is supported by Mahidol University (Research Cluster in Integrated and Multidisciplinary, grant no. MRC-IM 02/2565 to S.H.), Ramathibodi Foundation for Children Cancer project (to S.H.), and partially supported by the Fundamental Fund from Thailand Science Research and Innovation (FRB650007/0185) to S.H.
Declaration of Interest: All authors have no conflicts of interest to declare relevant to this article's content.
Ethical Approval: The study was approved by the Human Research Ethics Committee, Faculty of Medicine Ramathibodi Hospital, Mahidol University, based on the Declaration of Helsinki (protocol ID COA. MURA2021/976). All participants in this study signed the informed consent.
Keywords: drug re-proposition, ineffective erythropoiesis, proteasome, thalassemia, ubiquitination
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