Abstract：
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.
What is the context?● Chemotherapy, radiation treatment, or immunological disorders can cause a decrease in platelet count (thrombocytopenia) or decrease all blood cell types (pancytopenia) in the bone marrow. This can make it challenging to choose the appropriate cancer treatment plan.● Eltrombopag (EPAG) is an oral non-peptide thrombopoietin (TPO) mimetic that activates the cMPL receptor in the body. This activation leads to cell differentiation and proliferation, stimulating platelet production and reducing thrombocytopenia. The cMPL receptor is present in liver cells, megakaryocytes, and hematopoietic cells. However, its effects on stem cell proliferation and differentiation are not entirely understood.What is the new?● This study delves into the molecular interactions and therapeutic applications of EPAG, a small molecule that activates cMPL (TPO-R).● The study offers a comprehensive analysis of the ligand-receptor complex formation, including an examination of downstream signaling elements. Furthermore, molecular dynamics simulations demonstrate the stability of the ligand when interacting with targeted proteins.● The research investigates the presence of TPO-R on stem cell-derived endothelial cells, shedding insight into the ability of EPAG TPO-mimetic to promote angiogenesis and vasculature formation.● The study revealed that EPAG has the potential to protect against UVB-induced radiation damage and stimulate stem cell growth.What is the implications?The study emphasizes the potential of EPAG as a promising option for addressing radiation injury and minimizing the adverse effects of radiotherapy. It could revolutionize treatments not only for thrombocytopenia but also for enhancing the growth of stem cells. Furthermore, the research deepens our understanding of EPAG’s molecular mechanisms, providing valuable insights for developing future drugs and therapeutic approaches for cell therapy to treat radiation damage.
What is the context?● Chemotherapy, radiation treatment, or immunological disorders can cause a decrease in platelet count (thrombocytopenia) or decrease all blood cell types (pancytopenia) in the bone marrow. This can make it challenging to choose the appropriate cancer treatment plan.● Eltrombopag (EPAG) is an oral non-peptide thrombopoietin (TPO) mimetic that activates the cMPL receptor in the body. This activation leads to cell differentiation and proliferation, stimulating platelet production and reducing thrombocytopenia. The cMPL receptor is present in liver cells, megakaryocytes, and hematopoietic cells. However, its effects on stem cell proliferation and differentiation are not entirely understood.What is the new?● This study delves into the molecular interactions and therapeutic applications of EPAG, a small molecule that activates cMPL (TPO-R).● The study offers a comprehensive analysis of the ligand-receptor complex formation, including an examination of downstream signaling elements. Furthermore, molecular dynamics simulations demonstrate the stability of the ligand when interacting with targeted proteins.● The research investigates the presence of TPO-R on stem cell-derived endothelial cells, shedding insight into the ability of EPAG TPO-mimetic to promote angiogenesis and vasculature formation.● The study revealed that EPAG has the potential to protect against UVB-induced radiation damage and stimulate stem cell growth.What is the implications?The study emphasizes the potential of EPAG as a promising option for addressing radiation injury and minimizing the adverse effects of radiotherapy. It could revolutionize treatments not only for thrombocytopenia but also for enhancing the growth of stem cells. Furthermore, the research deepens our understanding of EPAG’s molecular mechanisms, providing valuable insights for developing future drugs and therapeutic approaches for cell therapy to treat radiation damage.
摘要：
这项研究的目的是研究Eltrombopag（EPAG）的分子相互作用和潜在的治疗用途，激活cMPL受体的小分子。已经发现EPAG在增加血小板水平和减轻血小板减少方面是有效的。我们利用计算技术来预测和确认由配体（EPAG）和血小板生成素受体（TPO-R）cMPL形成的复合物，阐明RAS的作用，JAK-2、STAT-3和下游信令的其他基本元素。分子动力学（MD）模拟用于评估配体在特定蛋白质中的稳定性，表现出有利的特征。第一次,我们检测了TPO-R在人脐带间充质干细胞（hUCMSC）和人牙龈间充质干细胞（hGMSC）增殖中的存在。此外，用EPAG治疗证实了血管生成和血管形成来源于两种MSC的内皮谱系。它还表明了关键因素的激活，如RUNX-1，GFI-1b，VEGF-A,MYB,GOF-1和FLI-1。其他实验证实，EPAG可能是防止UVB辐射损伤的理想分子，作为基因表达(JAK-2，ERK-2，MCL-1，NFkB，和STAT-3）和蛋白质CD90/cMPL分析显示hUCMSC和hGMSC中的TPO-R激活。总的来说,EPAG在治疗辐射损伤和减轻放疗副作用方面表现出巨大的潜力，值得进一步的临床探索。
背景是什么？●化疗，放射治疗,或免疫疾病可导致血小板计数减少（血小板减少症）或骨髓中所有血细胞类型减少（全血细胞减少症）。这可能使选择适当的癌症治疗计划具有挑战性。●Eltrombopag(EPAG)是一种口服非肽类血小板生成素(TPO)模拟物，可激活体内cMPL受体。这种激活导致细胞分化和增殖，刺激血小板生成和减少血小板减少症。cMPL受体存在于肝细胞中，巨核细胞,和造血细胞。然而,其对干细胞增殖和分化的影响尚不完全清楚。这项研究深入研究了EPAG的分子相互作用和治疗应用，激活cMPL(TPO-R)的小分子。●该研究提供了对配体-受体复合物形成的全面分析，包括下游信号元素的检查。此外，分子动力学模拟证明了配体与目标蛋白质相互作用时的稳定性。●该研究调查了TPO-R在干细胞来源的内皮细胞上的存在，了解EPAGTPO模拟物促进血管生成和脉管系统形成的能力。●研究表明，EPAG具有防止UVB诱导的辐射损伤和刺激干细胞生长的潜力。该研究强调了EPAG作为解决辐射损伤和最大限度地减少放疗副作用的有希望的选择的潜力。它不仅可以彻底改变血小板减少症的治疗方法，还可以促进干细胞的生长。此外，这项研究加深了我们对EPAG分子机制的理解，为开发未来的细胞疗法治疗辐射损伤的药物和治疗方法提供有价值的见解。
背景是什么？●化疗，放射治疗,或免疫疾病可导致血小板计数减少（血小板减少症）或骨髓中所有血细胞类型减少（全血细胞减少症）。这可能使选择适当的癌症治疗计划具有挑战性。●Eltrombopag(EPAG)是一种口服非肽类血小板生成素(TPO)模拟物，可激活体内cMPL受体。这种激活导致细胞分化和增殖，刺激血小板生成和减少血小板减少症。cMPL受体存在于肝细胞中，巨核细胞,和造血细胞。然而,其对干细胞增殖和分化的影响尚不完全清楚。这项研究深入研究了EPAG的分子相互作用和治疗应用，激活cMPL(TPO-R)的小分子。●该研究提供了对配体-受体复合物形成的全面分析，包括下游信号元素的检查。此外，分子动力学模拟证明了配体与目标蛋白质相互作用时的稳定性。●该研究调查了TPO-R在干细胞来源的内皮细胞上的存在，了解EPAGTPO模拟物促进血管生成和脉管系统形成的能力。●研究表明，EPAG具有防止UVB诱导的辐射损伤和刺激干细胞生长的潜力。该研究强调了EPAG作为解决辐射损伤和最大限度地减少放疗副作用的有希望的选择的潜力。它不仅可以彻底改变血小板减少症的治疗方法，还可以促进干细胞的生长。此外，这项研究加深了我们对EPAG分子机制的理解，为开发未来的细胞疗法治疗辐射损伤的药物和治疗方法提供有价值的见解。
