Mechanisms of glabridin inhibition of integrin αIIbβ3 inside-out signals and NF-κB activation in human platelets

Wei-Chieh Huang; Thanasekaran Jayakumar; Joen-Rong Sheu; Chih-Wei Hsia; Chih-Hsuan Hsia; Ting-Lin Yen; Chao-Chien Chang

doi:10.1186/s13020-023-00779-9

Mechanisms of glabridin inhibition of integrin α_IIbβ₃ inside-out signals and NF-κB activation in human platelets

Chin Med. 2023 Jun 10;18(1):71. doi: 10.1186/s13020-023-00779-9.

Authors

Wei-Chieh Huang^#¹, Thanasekaran Jayakumar², Joen-Rong Sheu^#^{1

3}, Chih-Wei Hsia¹, Chih-Hsuan Hsia⁴, Ting-Lin Yen⁵, Chao-Chien Chang^{6

7

8

9}

Affiliations

¹ Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, 110, Taiwan.
² Department of Ecology and Environmental Sciences, Pondicherry University, Puducherry, 605014, India.
³ Department of Pharmacology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, 110, Taiwan.
⁴ Translational Medicine Center, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, 111, Taiwan.
⁵ Department of Medical Research, Cathay General Hospital, Taipei, 106, Taiwan.
⁶ Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, 110, Taiwan. cgh05761@cgh.org.tw.
⁷ Department of Cardiovascular Center, Cathay General Hospital, Taipei, 106, Taiwan. cgh05761@cgh.org.tw.
⁸ School of Medicine, College of Medicine, Fu Jen Catholic University, New Taipei City, 242, Taiwan. cgh05761@cgh.org.tw.
⁹ Department of Pharmacology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, 110, Taiwan. cgh05761@cgh.org.tw.

^# Contributed equally.

Abstract

Background: Platelets play a crucial role in cardiovascular diseases (CVDs) and are activated by endogenous agonists like collagen. These agonists initiate signal transduction through specific platelet receptors, resulting in platelet aggregation. Glabridin, a prenylated isoflavonoid found in licorice root, is known for its significance in metabolic abnormalities. Glabridin has been observed to inhibit collagen-induced platelet aggregation, but the precise mechanisms, specifically concerning NF-κB activation and integrin α_IIbβ₃ signaling, are not yet fully understood.

Methods: In this study, platelet suspensions were prepared from healthy human blood donors, and the aggregation ability was observed using a lumi-aggregometer. The inhibitory mechanisms of glabridin in human platelets were evaluated through immunoblotting and confocal microscopy. The anti-thrombotic effects of glabridin were assessed by histological analysis of lung sections in acute pulmonary thromboembolism and by examining fluorescein-induced platelet plug formation in mesenteric microvessels in mice.

Results: Glabridin inhibited integrin α_IIbβ₃ inside-out signals such as Lyn, Fyn, Syk, and integrin β₃ activation and NF-κB-mediated signal events, with similar potency to classical inhibitors BAY11-7082 and Ro106-9920. Glabridin and BAY11-7082 inhibited IKK, IκBα, and p65 phosphorylation and reversed IκBα degradation, while Ro106-9920 only reduced p65 phosphorylation and reversed IκBα degradation. BAY11-7082 reduced Lyn, Fyn, Syk, integrin β₃, phospholipase Cγ2 and protein kinase C activation. Glabridin reduced platelet plug formation in mesenteric microvessels and occluded vessels in thromboembolic lungs of mice.

Conclusion: Our study revealed a new pathway for activating integrin α_IIbβ₃ inside-out signals and NF-κB, which contributes to the antiplatelet aggregation effect of glabridin. Glabridin could be a valuable prophylactic or clinical treatment option for CVDs.

Keywords: Glabridin; Human platelets; NF-κB; Platelet plug formation; Thromboembolic lungs; αIIbβ3 inside-out.

Abstract

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