title: A novel STAT3 inhibitor negatively modulates platelet activation and aggregation.
abstract: The signal transducer and activator of transcription 3 (STAT3) plays a critical role in platelet functions. This study sought to understand the effects of the STAT3 inhibitor SC99 on platelet activation and aggregation. Immunoblotting assays were applied to measure the effects of SC99 on the STAT3 signaling pathway. A ChronoLog aggregometer was used to evaluate platelet aggregation. A flow cytometer was used to evaluate P-selectin expression in the presence of SC99. AlamarBlue and Annexin-V staining were used to evaluate platelet viability and apoptosis, respectively. A fluorescence microscope was applied to analyze platelet spreading. SC99 inhibited the phosphorylation of JAK2 and STAT3 in human platelets but had no effects on the phosphorylation of AKT, p65 or Src, all of which are involved in platelet activation. Further studies revealed that SC99 inhibited human platelet aggregation induced by collagen and thrombin in a dose-dependent manner. SC99 inhibited thrombin-induced P-selectin expression and fibrinogen binding to single platelets. Moreover, SC99 inhibited platelet spreading on fibrinogen and clot retraction mediated by outside-in signaling. SC99 inhibited platelet aggregation in mice but it did not significantly prolong the bleeding time. Taken together, the present study revealed that SC99 inhibited platelet activation and aggregation as a STAT3 inhibitor. This agent can be developed as a promising treatment for thrombotic disorders.
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-psycho-diseases, Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, China.|Department of Neurology, the First Affiliated Hospital of Soochow University, Suzhou 215006, China.
authors.forename: Zhuan
authors.initials: Z
authors.lastname: Xu
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-psycho-diseases, Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, China.
authors.forename: Yu-Jia
authors.initials: YJ
authors.lastname: Xu
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-psycho-diseases, Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, China.|Department of Neurology, the First Affiliated Hospital of Soochow University, Suzhou 215006, China.
authors.forename: Ya-Nan
authors.initials: YN
authors.lastname: Hao
authors.affiliation: Cyrus Tang Hematology Center, Soochow University, Suzhou 215123, China.
authors.forename: Li-Jie
authors.initials: LJ
authors.lastname: Ren
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-psycho-diseases, Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, China.
authors.forename: Zu-Bin
authors.initials: ZB
authors.lastname: Zhang
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-psycho-diseases, Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Xu
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-psycho-diseases, Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, China.
authors.forename: Bi-Yin
authors.initials: BY
authors.lastname: Cao
authors.affiliation: Jiangsu Institute of Hematology, the First Affiliated Hospital of Soochow University, Suzhou 215006, China.
authors.forename: Ke-Sheng
authors.initials: KS
authors.lastname: Dai
authors.affiliation: Cyrus Tang Hematology Center, Soochow University, Suzhou 215123, China.
authors.forename: Li
authors.initials: L
authors.lastname: Zhu
authors.affiliation: Department of Neurology, the First Affiliated Hospital of Soochow University, Suzhou 215006, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Fang
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-psycho-diseases, Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, China.|Department of Neurology, the First Affiliated Hospital of Soochow University, Suzhou 215006, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Kong
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-psycho-diseases, Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, China.|Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Soochow University, Suzhou 215123, China.
authors.forename: Xin-Liang
authors.initials: XL
authors.lastname: Mao
mesh_terms: D000818:Animals; D001760:Bleeding Time; D003018:Clot Retraction / Q000187:drug effects; D006801:Humans; D006835:Hydrazones / Q000494:pharmacology* / Q000633:toxicity; D008810:Mice, Inbred C57BL; D015539:Platelet Activation / Q000187:drug effects*; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology* / Q000633:toxicity; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors*; D015398:Signal Transduction
chemical_list: D006835:Hydrazones; D010975:Platelet Aggregation Inhibitors; C000613255:SC99 compound; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse