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• W4386880648 abstract "Abstract Background Radiation-induced thrombocytopenia (RIT) poses a significant risk to cancer patients undergoing radiotherapy, leading to hemorrhage and mortality. Unfortunately, effective treatment options for RIT are currently limited. Methods We assessed the effectiveness of Fructus Psoraleae, a popular traditional Chinese medicine (TCM) known for its hemostatic properties, in treating thrombocytopenia through the application of network pharmacology. Utilizing a naive Bayes algorithm, we built a drug screening model to determine the effective compounds present in Fructus Psoraleae. Giemsa staining and flow cytometry were employed to evaluate the effects of the potential active compound, Bavachinin A, on the differentiation of megakaryocytes (MK) in K562 and Meg-01 cells. Furthermore, we conducted experiments using RIT mice and c-MPL knock-out (c-MPL −/− ) mice to assess the therapeutic efficacy of Bavachinin A in mitigating thrombocytopenia. Additionally, Tg (cd41:eGFP) transgenic zebrafish were utilized to investigate the impact of Bavachinin A on thrombopoiesis. To elucidate the underlying molecular mechanisms of Bavachinin A against thrombocytopenia, we employed RNA-sequencing (RNA-seq), network pharmacology analysis, molecular docking simulations, molecular dynamics simulations, drug affinity responsive target stability assay (DARTS), and biolayer interferometry (BLI). Results Bavachinin A emerged as the most promising candidate from our investigations. In vitro experiments demonstrated the significant ability of Bavachinin A to induce MK differentiation. In vivo experiments revealed that Bavachinin A had the capacity to augment platelet levels and improve coagulation in RIT mice, facilitated megakaryopoiesis and platelet level in c-MPL −/− mice, and accelerated thrombopoiesis in zebrafish. Furthermore, RNA-seq analysis revealed that the core signaling pathway regulated by Bavachinin A was PI3K/Akt. Molecular docking simulation, molecular dynamics simulation, DARTS and BLI demonstrated that Bavachinin A directly bound to FLT3. Notably, blocking FLT3 or PI3K/Akt hindered Bavachinin A-induced MK differentiation, but repressing TPO/c-MPL signaling pathway had no significant effect. Conclusions Our findings suggest that Bavachinin A promotes MK differentiation and thrombopoiesis by binding directly to FLT3 and activating the PI3K/Akt signaling. Importantly, this effect is not contingent upon the conventional TPO/c-MPL signaling pathway. Our study highlights translational potential of Bavachinin A as a novel therapeutic agent for thrombocytopenia, and presents a novel strategy for drug discovery using multimodal and multiscale methods." @default.
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• W4386880648 date "2023-09-20" @default.
• W4386880648 modified "2023-09-27" @default.
• W4386880648 title "Discovery of a novel FLT3 agonist for the treatment of thrombocytopenia using AI-based virtual screening" @default.
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• W4386880648 doi "https://doi.org/10.21203/rs.3.rs-3352768/v1" @default.
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