2. Academic Validation
  3. Asebogenin Suppresses Thrombus Formation via Inhibition of Syk Phosphorylation

Asebogenin Suppresses Thrombus Formation via Inhibition of Syk Phosphorylation

  • Br J Pharmacol. 2022 Sep 27. doi: 10.1111/bph.15964.
Li Li 1,  Xulin Xu 1,  Keyu Lv 1,  Guijuan Zheng 2,  Hao Wang 1,  Shuai Chen 1,  Lang Huang 2,  Yi Liu 3,  Yadong Zhang 3,  Zhaoming Tang 4,  Lili Zhang 1,  Jinyu Wang 5,  Jianlin Qiao 6,  Hongliang Li 7,  Xuanbin Wang 7,  Guangmin Yao 2,  Chao Fang 1 8
Affiliations

Affiliations

  • 1 Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
  • 2 Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
  • 3 DeepKinase Biotechnologies Ltd., Beijing, China.
  • 4 Department of Clinical Laboratory, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
  • 5 School of Stomatology, Tongji Medical Collage, Huazhong University of Science and Technology, and the Key Laboratory of Oral and Maxillofacial Development and Regeneration of Hubei Province, Wuhan, Hubei, China.
  • 6 Department of Hematology, the Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China.
  • 7 Laboratory of Chinese Herbal Pharmacology, Department of Pharmacy, Renmin Hospital; Biomedical Research Institute, School of Pharmaceutical Sciences and Hubei Key Laboratory of Wudang Local Chinese Medicine Research, Hubei University of Medicine, Shiyan, Hubei, China.
  • 8 The Key Laboratory for Drug Target Researches and Pharmacodynamic Evaluation of Hubei Province, Hubei, China.
PMID: 36166754 DOI: 10.1111/bph.15964
Abstract

Background and purpose: Thrombosis is a major cause of morbidity and mortality worldwide. Platelet activation by exposed collagen through Glycoprotein VI (GPVI) and formation of neutrophil extracellular traps (NETs) are critical pathogenic factors for arterial and venous thrombosis. Both events are regulated by spleen tyrosine kinase (Syk)-mediated signaling events. Asebogenin is a dihydrochalcone whose pharmacological effects remain largely unknown. This study aims to investigate the antithrombotic effects of asebogenin and the underlying molecular mechanisms.

Experimental approach: Platelet aggregation was assessed using an aggregometer. Platelet P-selectin exposure, Integrin activation, and calcium mobilization were determined by flowcytometry. NETs formation was assessed by SYTOX Green staining and immunohistochemistry. Quantitative phosphoproteomics, microscale thermophoresis, in vitro kinase assay and molecular docking combined with dynamics simulation were performed to characterize the targets of asebogenin. The in vivo effects of asebogenin on arterial thrombosis were investigated using the FeCl3 -induced and laser-induced injury models, whereas venous thrombosis were induced by stenosis of the inferior vena cava (IVC).

Key results: Asebogenin inhibited series of GPVI-induced platelet responses, and suppressed NETs formation induced by proinflammatory stimulus. Mechanistically, asebogenin directly interfered with the phosphorylation of Syk at Tyr525/526, which is important for its activation. Further, asebogenin suppressed arterial thrombosis demonstrated by decreased platelet accumulation and fibrin generation, and attenuated venous thrombosis determined by reduced neutrophil accumulation and NETs formation, without increasing the bleeding risks.

Conclusion and implications: Asebogenin exhibits potent antithrombotic effects by targeting Syk and is a potential lead compound for the development of efficient and safe antithrombotic agents.

Keywords

Asebogenin; neutrophil extracellular traps; platelet activation; spleen tyrosine kinase; thrombus formation.

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