Molecular insights on Eltrombopag: potential mitogen stimulants, angiogenesis, and therapeutic radioprotectant through TPO-R activation.
Rajasekaran SubbarayanDhasarathdev SrinivasanSalman Shadula OsmaniaDinesh Murugan GirijaShoeb IkhlasNityanand SrivastavRanjith BalakrishnanRupendra ShresthaAnkush ChauhanPublished in: Platelets (2024)
The purpose of this study is to investigate the molecular interactions and potential therapeutic uses of Eltrombopag (EPAG), a small molecule that activates the cMPL receptor. EPAG has been found to be effective in increasing platelet levels and alleviating thrombocytopenia. We utilized computational techniques to predict and confirm the complex formed by the ligand (EPAG) and the Thrombopoietin receptor (TPO-R) cMPL, elucidating the role of RAS, JAK-2, STAT-3, and other essential elements for downstream signaling. Molecular dynamics (MD) simulations were employed to evaluate the stability of the ligand across specific proteins, showing favorable characteristics. For the first time, we examined the presence of TPO-R in human umbilical cord mesenchymal stem cells (hUCMSC) and human gingival mesenchymal stem cells (hGMSC) proliferation. Furthermore, treatment with EPAG demonstrated angiogenesis and vasculature formation of endothelial lineage derived from both MSCs. It also indicated the activation of critical factors such as RUNX-1, GFI-1b, VEGF-A, MYB, GOF-1, and FLI-1. Additional experiments confirmed that EPAG could be an ideal molecule for protecting against UVB radiation damage, as gene expression (JAK-2, ERK-2, MCL-1, NFkB, and STAT-3) and protein CD90/cMPL analysis showed TPO-R activation in both hUCMSC and hGMSC. Overall, EPAG exhibits significant potential in treating radiation damage and mitigating the side effects of radiotherapy, warranting further clinical exploration.
Keyphrases
- mesenchymal stem cells
- endothelial cells
- umbilical cord
- molecular dynamics
- small molecule
- gene expression
- vascular endothelial growth factor
- density functional theory
- bone marrow
- cell proliferation
- transcription factor
- signaling pathway
- cell therapy
- early stage
- oxidative stress
- protein protein
- radiation induced
- induced pluripotent stem cells
- pluripotent stem cells
- immune response
- toll like receptor
- stem cells
- single molecule
- locally advanced
- radiation therapy
- risk assessment
- squamous cell carcinoma
- nuclear factor
- inflammatory response
- cell fate