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Article: Discovery of a novel megakaryopoiesis enhancer, ingenol, promoting thrombopoiesis through PI3K-Akt signaling independent of thrombopoietin
Title | Discovery of a novel megakaryopoiesis enhancer, ingenol, promoting thrombopoiesis through PI3K-Akt signaling independent of thrombopoietin |
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Authors | |
Keywords | Ingenol Ingenol (PubChem CID: 442042) Machine learning Megakaryocyte differentiation Platelets Thrombocytopenia |
Issue Date | 1-May-2022 |
Publisher | Bioinfo Publications |
Citation | Journal of Pharmacology Research, 2022, v. 177 How to Cite? |
Abstract | Thrombocytopenia, a most common complication of radiotherapy and chemotherapy, is an important cause of morbidity and mortality in cancer patients. However, there are still no approved agents for the treatment of radiation- and chemotherapy-induced thrombocytopenia (RIT and CIT, respectively). In this study, a drug screening model for predicting compounds with activity in promoting megakaryocyte (MK) differentiation and platelet production was established based on machine learning (ML), and a natural product ingenol was predicted as a potential active compound. Then, in vitro experiments showed that ingenol significantly promoted MK differentiation in K562 and HEL cells. Furthermore, a RIT mice model and c-MPL knock-out (c-MPL-/-) mice constructed by CRISPR/Cas9 technology were used to assess the therapeutic action of ingenol on thrombocytopenia. The results showed that ingenol accelerated megakaryopoiesis and thrombopoiesis both in RIT mice and c-MPL-/- mice. Next, RNA-sequencing (RNA-seq) was carried out to analyze the gene expression profile induced by ingenol during MK differentiation. Finally, through experimental verifications, we demonstrated that the activation of PI3K/Akt signaling pathway was involved in ingenol-induced MK differentiation. Blocking PI3K/Akt signaling pathway abolished the promotion of ingenol on MK differentiation. Nevertheless, inhibition of TPO/c-MPL signaling pathway could not suppress ingenol-induced MK differentiation. In conclusion, our study builds a drug screening model to discover active compounds against thrombocytopenia, reveals the critical roles of ingenol in promoting MK differentiation and platelet production, and provides a promising avenue for the treatment of RIT. |
Persistent Identifier | http://hdl.handle.net/10722/340794 |
ISSN |
DC Field | Value | Language |
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dc.contributor.author | Wang, L | - |
dc.contributor.author | Zhang, T | - |
dc.contributor.author | Liu, S | - |
dc.contributor.author | Mo, Q | - |
dc.contributor.author | Jiang, N | - |
dc.contributor.author | Chen, Q | - |
dc.contributor.author | Yang, J | - |
dc.contributor.author | Han, YW | - |
dc.contributor.author | Chen, JP | - |
dc.contributor.author | Huang, FH | - |
dc.contributor.author | Li, H | - |
dc.contributor.author | Zhou, J | - |
dc.contributor.author | Luo, JS | - |
dc.contributor.author | Wu, JM | - |
dc.date.accessioned | 2024-03-11T10:47:12Z | - |
dc.date.available | 2024-03-11T10:47:12Z | - |
dc.date.issued | 2022-05-01 | - |
dc.identifier.citation | Journal of Pharmacology Research, 2022, v. 177 | - |
dc.identifier.issn | 0976-7134 | - |
dc.identifier.uri | http://hdl.handle.net/10722/340794 | - |
dc.description.abstract | <p><a href="https://www.sciencedirect.com/topics/pharmacology-toxicology-and-pharmaceutical-science/thrombocytopenia" title="Learn more about Thrombocytopenia from ScienceDirect's AI-generated Topic Pages">Thrombocytopenia</a>, a most common complication of radiotherapy and chemotherapy, is an important cause of morbidity and mortality in cancer patients. However, there are still no approved agents for the treatment of radiation- and chemotherapy-induced thrombocytopenia (RIT and CIT, respectively). In this study, a drug screening model for predicting compounds with activity in promoting megakaryocyte (MK) differentiation and platelet production was established based on machine learning (ML), and a natural product <a href="https://www.sciencedirect.com/topics/pharmacology-toxicology-and-pharmaceutical-science/ingenol" title="Learn more about ingenol from ScienceDirect's AI-generated Topic Pages">ingenol</a> was predicted as a potential active compound. Then, in vitro experiments showed that <a href="https://www.sciencedirect.com/topics/pharmacology-toxicology-and-pharmaceutical-science/ingenol" title="Learn more about ingenol from ScienceDirect's AI-generated Topic Pages">ingenol</a> significantly promoted MK differentiation in K562 and HEL cells. Furthermore, a RIT mice model and c-MPL knock-out (c-MPL<sup>-/-</sup>) mice constructed by CRISPR/Cas9 technology were used to assess the therapeutic action of ingenol on thrombocytopenia. The results showed that ingenol accelerated megakaryopoiesis and thrombopoiesis both in RIT mice and c-MPL<sup>-/-</sup> mice. Next, RNA-sequencing (RNA-seq) was carried out to analyze the gene expression profile induced by ingenol during MK differentiation. Finally, through experimental verifications, we demonstrated that the activation of PI3K/Akt signaling pathway was involved in ingenol-induced MK differentiation. Blocking PI3K/Akt signaling pathway abolished the promotion of ingenol on MK differentiation. Nevertheless, inhibition of TPO/c-MPL signaling pathway could not suppress ingenol-induced MK differentiation. In conclusion, our study builds a drug screening model to discover active compounds against thrombocytopenia, reveals the critical roles of ingenol in promoting MK differentiation and platelet production, and provides a promising avenue for the treatment of RIT.</p> | - |
dc.language | eng | - |
dc.publisher | Bioinfo Publications | - |
dc.relation.ispartof | Journal of Pharmacology Research | - |
dc.rights | This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. | - |
dc.subject | Ingenol | - |
dc.subject | Ingenol (PubChem CID: 442042) | - |
dc.subject | Machine learning | - |
dc.subject | Megakaryocyte differentiation | - |
dc.subject | Platelets | - |
dc.subject | Thrombocytopenia | - |
dc.title | Discovery of a novel megakaryopoiesis enhancer, ingenol, promoting thrombopoiesis through PI3K-Akt signaling independent of thrombopoietin | - |
dc.type | Article | - |
dc.identifier.doi | 10.1016/j.phrs.2022.106096 | - |
dc.identifier.scopus | eid_2-s2.0-85123703692 | - |
dc.identifier.hkuros | 341362 | - |
dc.identifier.volume | 177 | - |
dc.identifier.eissn | 0976-7142 | - |
dc.identifier.issnl | 0976-7134 | - |