Discovery of a novel megakaryopoiesis enhancer, ingenol, promoting thrombopoiesis through PI3K-Akt signaling independent of thrombopoietin

Wang, Long; Zhang, Ting; Li, Sha; Mo, Qi; Jiang, Nan; Chen, Qi; Yang, Jing; Han, Yunwei; Chen, Jianping; Huang, Feihong; Li, Hua; Zhou, Jie; Luo, Jiesi; Wu, Jianming

doi:10.1016/j.phrs.2022.106096

Cited by 20 publications

(11 citation statements)

References 63 publications

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“…Activation of the MAPK pathway is necessary for the development and maturation of MK progenitors (MkPs), while AKT regulates the cell cycle of MkPs by downregulating the Forkhead box O (FOXO) TF family [ 56 ]. For example, ingenol has been validated to induce MK differentiation by activating PI3K/Akt signaling pathway [ 57 ]. Similarly, ERK1/2 and JNK (but not P38) MAPK pathways have been demonstrated to be involved in megakaryopoiesis [ 58 ].…”

Section: Discussionmentioning

confidence: 99%

Caulis Polygoni Multiflori Accelerates Megakaryopoiesis and Thrombopoiesis via Activating PI3K/Akt and MEK/ERK Signaling Pathways

et al. 2022

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Thrombocytopenia is one of the most common complications of cancer therapy. Until now, there are still no satisfactory medications to treat chemotherapy and radiation-induced thrombocytopenia (CIT and RIT, respectively). Caulis Polygoni Multiflori (CPM), one of the most commonly used Chinese herbs, has been well documented to nourish blood for tranquilizing the mind and treating anemia, suggesting its beneficial effect on hematopoiesis. However, it is unknown whether CPM can accelerate megakaryopoiesis and thrombopoiesis. Here, we employ a UHPLC Q–Exactive HF-X mass spectrometer (UHPLC QE HF-X MS) to identify 11 ingredients in CPM. Then, in vitro experiments showed that CPM significantly increased megakaryocyte (MK) differentiation and maturation but did not affect apoptosis and lactate dehydrogenase (LDH) release of K562 and Meg-01 cells. More importantly, animal experiments verified that CPM treatment markedly accelerated platelet recovery, megakaryopoiesis and thrombopoiesis in RIT mice without hepatic and renal toxicities in vivo. Finally, RNA-sequencing (RNA-seq) and western blot were used to determine that CPM increased the expression of proteins related to PI3K/Akt and MEK/ERK (MAPK) signaling pathways. On the contrary, blocking PI3K/Akt and MEK/ERK signaling pathways with their specific inhibitors suppressed MK differentiation induced by CPM. In conclusion, for the first time, our study demonstrates that CPM may be a promised thrombopoietic agent and provide an experimental basis for expanding clinical use.

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Section: Discussionmentioning

confidence: 99%

Caulis Polygoni Multiflori Accelerates Megakaryopoiesis and Thrombopoiesis via Activating PI3K/Akt and MEK/ERK Signaling Pathways

et al. 2022

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“…A ferric chloride (FeCl 3 )-induced model of carotid arterial thrombus was constructed as described previously. 17 , 18 Briefly, the mice were administered normal saline, TPO (3,000 U/kg), or DMAG (5 mg/kg) daily after irradiation for 10 days and then anesthetized by intraperitoneal injection of sodium pentobarbital (50 mg/kg). The common carotid arteries were exposed, and filter paper (3 × 1.0 mm) saturated with 10% (w/v) FeCl 3 was placed on top of the left carotid artery for 3 min to induce thrombosis.…”

Section: Methodsmentioning

confidence: 99%

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

Wang

Luo

et al. 2022

haematol

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Thrombocytopenia is a TPO-related life-threatening disorder with very limited treatment options. Typical thrombopoietic agents targeting TPO signaling encounter a huge challenge. Thus, it is urgent to discover a novel TPO-independent mechanism involving thrombopoiesis and its potential targeted medications. Here, we developed a drug screening model by the Multi-Grained Cascade Forest (gcForest) algorithm and identified that 3,8-Di-O-methylellagic acid 2-O-glucoside (DMAG) (10, 20 and 40 μM) promoted megakaryocyte differentiation in vitro. Subsequent investigations revealed that DMAG (40 μM) activated ERK1/2, HIF-1β and NF-E2. Inhibition of ERK1/2 blocked megakaryocyte differentiation and attenuated the upregulation of HIF-1β and NF-E2 induced by DMAG. Megakaryocyte differentiation induced by DMAG was inhibited via knockdown of NF-E2. In vivo studies showed that DMAG (5 mg/kg) accelerated platelet recovery and megakaryocyte differentiation in mice with thrombocytopenia. The platelet level of DMAG-treated group recovered to almost 72% and 96% of control group at day 10 and 14. The platelet counts in the DMAG-treated group exhibited almost 1.5 and 1.3 fold higher compared with the irradiation (IR) group at day 10 and 14. Moreover, DMAG (10, 25 and 50 μM) stimulated thrombopoiesis in zebrafish. DMAG (5 mg/kg) could also increase platelet levels in c-MPL knockout (c-MPL-/-) mice. In summary, we establish a drug screening model through gcForest and demonstrate DMAG promotes megakaryocyte differentiation via the ERK/HIF1/NF-E2 pathway, which is more importantly independent of the TPO/c-MPL classic pathway. The present study may provide new insights into drug discovery for thrombopoiesis, TPO-independent regulation of thrombopoiesis and a promising avenue for thrombocytopenia treatment.

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“… 102 Especially, using c-MPL knock-out mice or deleting THPO or c-MPL by their neutralizing antibodies in K562 cells could not suppress the thrombopoietic effect of ingenol, indicating that ingenol may be a THPO-independent thrombopoiesis-stimulating agent, which provides a potential medicine for thrombocytopenia treatment. 102 …”

Section: Thrombopoiesis Agents With Potential Value Of Clinical Usementioning

confidence: 97%

“…Specifically, it could stimulate differentiation of MK in K562 and HEL cells, and accelerated thrombopoiesis in RIT mice model, as an increasing platelet counts and MKs in BM and spleen was seen. 102 RNA-sequencing revealed that the thrombopoiesis-stimulating process of ingenol may foster through PI3K-Akt signaling. 102 Especially, using c-MPL knock-out mice or deleting THPO or c-MPL by their neutralizing antibodies in K562 cells could not suppress the thrombopoietic effect of ingenol, indicating that ingenol may be a THPO-independent thrombopoiesis-stimulating agent, which provides a potential medicine for thrombocytopenia treatment.…”

Section: Thrombopoiesis Agents With Potential Value Of Clinical Usementioning

confidence: 99%

Application and investigation of thrombopoiesis-stimulating agents in the treatment of thrombocytopenia

Huang

Zhang

et al. 2023

Therapeutic Advances in Hematology

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Platelets, derived from a certain subpopulation of megakaryocytes, are closely related to hemostasis, coagulation, metastasis, inflammation, and cancer progression. Thrombopoiesis is a dynamic process regulated by various signaling pathways in which thrombopoietin (THPO)–MPL is dominant. Thrombopoiesis-stimulating agents could promote platelet production, showing therapeutic effects in different kinds of thrombocytopenia. Some thrombopoiesis-stimulating agents are currently used in clinical practices to treat thrombocytopenia. The others are not in clinical investigations to deal with thrombocytopenia but have potential in thrombopoiesis. Their potential values in thrombocytopenia treatment should be highly regarded. Novel drug screening models and drug repurposing research have found many new agents and yielded promising outcomes in preclinical or clinical studies. This review will briefly introduce thrombopoiesis-stimulating agents currently or potentially valuable in thrombocytopenia treatment and summarize the possible mechanisms and therapeutic effects, which may enrich the pharmacological armamentarium for the medical treatment of thrombocytopenia.

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Discovery of a novel megakaryopoiesis enhancer, ingenol, promoting thrombopoiesis through PI3K-Akt signaling independent of thrombopoietin

Cited by 20 publications

References 63 publications

Caulis Polygoni Multiflori Accelerates Megakaryopoiesis and Thrombopoiesis via Activating PI3K/Akt and MEK/ERK Signaling Pathways

Caulis Polygoni Multiflori Accelerates Megakaryopoiesis and Thrombopoiesis via Activating PI3K/Akt and MEK/ERK Signaling Pathways

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

Application and investigation of thrombopoiesis-stimulating agents in the treatment of thrombocytopenia

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