Targeting a thrombopoietin-independent strategy in the discovery of a novel inducer of megakaryocytopoiesis, DMAG, for the treatment of thrombocytopenia

Wang, Long; Li, Sha; Luo, Jiesi; Mo, Qi; Ran, Mei; Zhang, Ting; Li, Xiaoxuan; Zhou, Wenjun; Mei, Qibing; Chen, Jianping; Yang, Jing; Zeng, Jing; Huang, Feihong; Wu, Anguo; Zhang, Chunxiang; Wu, Jianming

doi:10.3324/haematol.2022.282209

Cited by 11 publications

(6 citation statements)

References 52 publications

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“…Furthermore, because of its advantages of in vivo complexity and in vitro high-throughput screening simplicity, zebrafish is a commonly recognized vertebrate model for research in many fields, including developmental biology, toxicology, and drug discovery ( Kong et al, 2020 ). Previous studies showed the construction and application of megakaryocyte production in Tg (itga2b: eGFP) zebrafish ( Wang et al, 2023 ). At the same time, VLZ significantly promoted the hematopoietic system of transgenic zebrafish and increased platelet-labeled fluorescence.…”

Section: Discussionmentioning

confidence: 99%

Activating SRC/MAPK signaling via 5-HT1A receptor contributes to the effect of vilazodone on improving thrombocytopenia

Zhou,

Ni,

Liao

et al. 2024

eLife

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Thrombocytopenia caused by long-term radiotherapy and chemotherapy exists in cancer treatment. Previous research demonstrates that 5-Hydroxtrayptamine (5-HT) and its receptors induces the formation of megakaryocytes (MKs) and platelets. However, the relationships between 5-HT1A receptor (5-HTR1A) and MKs is unclear so far. We screened and investigated the mechanism of vilazodone as a 5-HTR1A partial agonist in promoting MK differentiation and evaluated its therapeutic effect in thrombocytopenia. We employed a drug screening model based on machine learning (ML) to screen the megakaryocytopoiesis activity of VLZ. The effects of Vilazodone (VLZ) on megakaryocytopoiesis were verified in HEL and Meg-01 cells. Tg (itga2b: eGFP) zebrafish was performed to analyze the alterations in thrombopoiesis. Moreover, we established a thrombocytopenia mice model to investigate VLZ administration accelerates platelet recovery and function. We carried out network pharmacology, Western blotting and immunofluorescence to demonstrate the potential targets and pathway of VLZ. VLZ has been predicted to have a potential biological action. Meanwhile, VLZ administration promotes MK differentiation and thrombopoiesis in cells and zebrafish models. Progressive experiments showed that VLZ has a potential therapeutic effect on radiation-induced thrombocytopenia in vivo . The network pharmacology and associated mechanism study indicated that SRC and MAPK signaling are both involved in the processes of megakaryopoiesis facilitated by VLZ. Furthermore, the expression of 5-HTR1A during megakaryocyte differentiation is closely related to the activation of SRC and MAPK. Our findings demonstrated that the expression of 5-HTR1A on MK, VLZ could bind to the 5-HTR1A receptor and further regulate the SRC/MAPK signaling pathway to facilitate megakaryocyte differentiation and platelet production, which provides new insights into the alternative therapeutic options for thrombocytopenia.

show abstract

Section: Discussionmentioning

confidence: 99%

Activating SRC/MAPK signaling via 5-HT1A receptor contributes to the effect of vilazodone on improving thrombocytopenia

Zhou,

Ni,

Liao

et al. 2024

eLife

Self Cite

View full text Add to dashboard Cite

show abstract

“…Furthermore, because of its advantages of in vivo complexity and in vitro high-throughput screening simplicity, zebrafish is a commonly recognized vertebrate model for research in many fields, including developmental biology, toxicology, and drug discovery (Kong et al, 2020). Previous studies showed the construction and application of megakaryocyte production in Tg (itga2b: eGFP) zebrafish (Wang et al, 2022). At the same time, VLZ significantly promoted the hematopoietic system of transgenic zebrafish and increased platelet labeled fluorescence.…”

Section: Discussionmentioning

confidence: 99%

Activating SRC/MAPK signaling via 5-HT1A receptor contributes to the effect of vilazodone on improving thrombocytopenia

Zhou,

Ni,

Liao

et al. 2023

Preprint

Self Cite

View full text Add to dashboard Cite

Thrombocytopenia caused by long-term radiotherapy and chemotherapy exists in cancer treatment. Previous research demonstrates that 5-Hydroxtrayptamine (5-HT) and its receptors induces the formation of megakaryocytes (MKs) and platelets. However, the relationships between 5-HT1A receptor (5-HTR1A) and MKs is unclear so far. We screened and investigated the mechanism of vilazodone as a 5-HTR1A partial agonist in promoting MK differentiation and evaluated its therapeutic effect in thrombocytopenia. We employed a drug screening model based on machine learning (ML) to screen the megakaryocytopoiesis activity of VLZ. The effects of Vilazodone (VLZ) on megakaryocytopoiesis were verified in HEL and Meg-01 cells. Tg (itga2b: eGFP) zebrafish was performed to analyze the alterations in thrombopoiesis. Moreover, we established a thrombocytopenia mice model to investigate VLZ administration accelerates platelet recovery and function. We carried out network pharmacology, Western blotting and immunofluorescence to demonstrate the potential targets and pathway of VLZ. VLZ has been predicted to have a potential biological action. Meanwhile, VLZ administration promotes MK differentiation and thrombopoiesis in cells and zebrafish models. Progressive experiments showed that VLZ has a potential therapeutic effect on radiation-induced thrombocytopeniain vivo. The network pharmacology and associated mechanism study indicated that SRC and MAPK signaling are both involved in the processes of megakaryopoiesis facilitated by VLZ. Furthermore, the expression of 5-HTR1A during megakaryocyte differentiation is closely related to the activation of SRC and MAPK. Our findings demonstrated that the expression of 5-HTR1A on MK, VLZ could bind to the 5-HTR1A receptor and further regulate the SRC/MAPK signaling pathway to facilitate megakaryocyte differentiation and platelet production, which provides new insights into the alternative therapeutic options for thrombocytopenia.

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“…The virtual screening model was established as described in the previous study 25 . Specifically, as a virtual screening flowchart shown in Figure A.…”

Section: Methodsmentioning

confidence: 99%

Genistin: A Novel Estrogen Analogue Targeting ERβ to Alleviate Thrombocytopenia

Tang,

Liao,

Zhou

et al. 2024

Int. J. Biol. Sci.

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Thrombocytopenia, a prevalent hematologic challenge, correlates directly with the mortality of numerous ailments. Current therapeutic avenues for thrombocytopenia are not without limitations. Here, we identify genistin, an estrogen analogue, as a promising candidate for thrombocytopenia intervention, discovered through AI-driven compound library screening. While estrogen's involvement in diverse biological processes is recognized, its role in thrombopoiesis remains underexplored. Our findings elucidate genistin's ability to enhance megakaryocyte differentiation, thereby augmenting platelet formation and production. In vivo assessments further underscore genistin's remedial potential against radiation-induced thrombocytopenia. Mechanistically, genistin's efficacy is attributed to its direct interaction with estrogen receptor β (ERβ), with subsequent activation of both ERK1/2 and the Akt signaling pathways membrane ERβ. Collectively, our study positions genistin as a prospective therapeutic strategy for thrombocytopenia, shedding light on novel interplays between platelet production and ERβ.

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Targeting a thrombopoietin-independent strategy in the discovery of a novel inducer of megakaryocytopoiesis, DMAG, for the treatment of thrombocytopenia

Cited by 11 publications

References 52 publications

Activating SRC/MAPK signaling via 5-HT1A receptor contributes to the effect of vilazodone on improving thrombocytopenia

Activating SRC/MAPK signaling via 5-HT1A receptor contributes to the effect of vilazodone on improving thrombocytopenia

Activating SRC/MAPK signaling via 5-HT1A receptor contributes to the effect of vilazodone on improving thrombocytopenia

Genistin: A Novel Estrogen Analogue Targeting ERβ to Alleviate Thrombocytopenia

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