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Targeting TLR2/Rac1/cdc42/JNK Pathway to Reveal That Ruxolitinib Promotes Thrombocytopoiesis

Background: Thrombocytopenia has long been considered an important complication of chemotherapy and radiotherapy, which severely limits the effectiveness of cancer treatment and the overall survival of patients. However, clinical treatment options are extremely limited so far. Ruxolitinib is a poten...

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Autores principales: Yang, Shuo, Tang, Xiaoqin, Wang, Long, Ni, Chengyang, Wu, Yuesong, Zhou, Ling, Zeng, Yueying, Zhao, Chunling, Wu, Anguo, Wang, Qiaozhi, Xu, Xiyan, Wang, Yiwei, Chen, Rong, Zhang, Xiao, Zou, Lile, Huang, Xinwu, Wu, Jianming
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9787584/
https://www.ncbi.nlm.nih.gov/pubmed/36555781
http://dx.doi.org/10.3390/ijms232416137
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author Yang, Shuo
Tang, Xiaoqin
Wang, Long
Ni, Chengyang
Wu, Yuesong
Zhou, Ling
Zeng, Yueying
Zhao, Chunling
Wu, Anguo
Wang, Qiaozhi
Xu, Xiyan
Wang, Yiwei
Chen, Rong
Zhang, Xiao
Zou, Lile
Huang, Xinwu
Wu, Jianming
author_facet Yang, Shuo
Tang, Xiaoqin
Wang, Long
Ni, Chengyang
Wu, Yuesong
Zhou, Ling
Zeng, Yueying
Zhao, Chunling
Wu, Anguo
Wang, Qiaozhi
Xu, Xiyan
Wang, Yiwei
Chen, Rong
Zhang, Xiao
Zou, Lile
Huang, Xinwu
Wu, Jianming
author_sort Yang, Shuo
collection PubMed
description Background: Thrombocytopenia has long been considered an important complication of chemotherapy and radiotherapy, which severely limits the effectiveness of cancer treatment and the overall survival of patients. However, clinical treatment options are extremely limited so far. Ruxolitinib is a potential candidate. Methods: The impact of ruxolitinib on the differentiation and maturation of K562 and Meg-01 cells megakaryocytes (MKs) was examined by flow cytometry, Giemsa and Phalloidin staining. A mouse model of radiation-injured thrombocytopenia (RIT) was employed to evaluate the action of ruxolitinib on thrombocytopoiesis. Network pharmacology, molecular docking, drug affinity responsive target stability assay (DARTS), RNA sequencing, protein blotting and immunofluorescence analysis were applied to explore the targets and mechanisms of action of ruxolitinib. Results: Ruxolitinib can stimulate MK differentiation and maturation in a dose-dependent manner and accelerates recovery of MKs and thrombocytopoiesis in RIT mice. Biological targeting analysis showed that ruxolitinib binds directly to Toll Like Receptor 2 (TLR2) to activate Rac1/cdc42/JNK, and this action was shown to be blocked by C29, a specific inhibitor of TLR2. Conclusions: Ruxolitinib was first identified to facilitate MK differentiation and thrombocytopoiesis, which may alleviate RIT. The potential mechanism of ruxolitinib was to promote MK differentiation via activating the Rac1/cdc42/JNK pathway through binding to TLR2.
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spelling pubmed-97875842022-12-24 Targeting TLR2/Rac1/cdc42/JNK Pathway to Reveal That Ruxolitinib Promotes Thrombocytopoiesis Yang, Shuo Tang, Xiaoqin Wang, Long Ni, Chengyang Wu, Yuesong Zhou, Ling Zeng, Yueying Zhao, Chunling Wu, Anguo Wang, Qiaozhi Xu, Xiyan Wang, Yiwei Chen, Rong Zhang, Xiao Zou, Lile Huang, Xinwu Wu, Jianming Int J Mol Sci Article Background: Thrombocytopenia has long been considered an important complication of chemotherapy and radiotherapy, which severely limits the effectiveness of cancer treatment and the overall survival of patients. However, clinical treatment options are extremely limited so far. Ruxolitinib is a potential candidate. Methods: The impact of ruxolitinib on the differentiation and maturation of K562 and Meg-01 cells megakaryocytes (MKs) was examined by flow cytometry, Giemsa and Phalloidin staining. A mouse model of radiation-injured thrombocytopenia (RIT) was employed to evaluate the action of ruxolitinib on thrombocytopoiesis. Network pharmacology, molecular docking, drug affinity responsive target stability assay (DARTS), RNA sequencing, protein blotting and immunofluorescence analysis were applied to explore the targets and mechanisms of action of ruxolitinib. Results: Ruxolitinib can stimulate MK differentiation and maturation in a dose-dependent manner and accelerates recovery of MKs and thrombocytopoiesis in RIT mice. Biological targeting analysis showed that ruxolitinib binds directly to Toll Like Receptor 2 (TLR2) to activate Rac1/cdc42/JNK, and this action was shown to be blocked by C29, a specific inhibitor of TLR2. Conclusions: Ruxolitinib was first identified to facilitate MK differentiation and thrombocytopoiesis, which may alleviate RIT. The potential mechanism of ruxolitinib was to promote MK differentiation via activating the Rac1/cdc42/JNK pathway through binding to TLR2. MDPI 2022-12-17 /pmc/articles/PMC9787584/ /pubmed/36555781 http://dx.doi.org/10.3390/ijms232416137 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Yang, Shuo
Tang, Xiaoqin
Wang, Long
Ni, Chengyang
Wu, Yuesong
Zhou, Ling
Zeng, Yueying
Zhao, Chunling
Wu, Anguo
Wang, Qiaozhi
Xu, Xiyan
Wang, Yiwei
Chen, Rong
Zhang, Xiao
Zou, Lile
Huang, Xinwu
Wu, Jianming
Targeting TLR2/Rac1/cdc42/JNK Pathway to Reveal That Ruxolitinib Promotes Thrombocytopoiesis
title Targeting TLR2/Rac1/cdc42/JNK Pathway to Reveal That Ruxolitinib Promotes Thrombocytopoiesis
title_full Targeting TLR2/Rac1/cdc42/JNK Pathway to Reveal That Ruxolitinib Promotes Thrombocytopoiesis
title_fullStr Targeting TLR2/Rac1/cdc42/JNK Pathway to Reveal That Ruxolitinib Promotes Thrombocytopoiesis
title_full_unstemmed Targeting TLR2/Rac1/cdc42/JNK Pathway to Reveal That Ruxolitinib Promotes Thrombocytopoiesis
title_short Targeting TLR2/Rac1/cdc42/JNK Pathway to Reveal That Ruxolitinib Promotes Thrombocytopoiesis
title_sort targeting tlr2/rac1/cdc42/jnk pathway to reveal that ruxolitinib promotes thrombocytopoiesis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9787584/
https://www.ncbi.nlm.nih.gov/pubmed/36555781
http://dx.doi.org/10.3390/ijms232416137
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