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Cucurbitacins Elicit Anti-Platelet Activity via Perturbation of the Cytoskeleton and Integrin Function

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Cucurbitacins Elicit Anti-Platelet Activity via Perturbation of the Cytoskeleton and Integrin Function. / Kriek, Neline; Nock, Sophie; Sage, Tanya et al.

In: Thrombosis and Haemostasis, Vol. 122, No. 7, 31.07.2022, p. 1115-1129.

Research output: Contribution to Journal/MagazineJournal articlepeer-review

Harvard

Kriek, N, Nock, S, Sage, T, Khalifa, B, Bye, A, Mitchell, JL, Thomson, S, McLaughlin, MG, Jones, S, Gibbins, JM & Unsworth, A 2022, 'Cucurbitacins Elicit Anti-Platelet Activity via Perturbation of the Cytoskeleton and Integrin Function', Thrombosis and Haemostasis, vol. 122, no. 7, pp. 1115-1129. https://doi.org/10.1055/a-1788-5322

APA

Kriek, N., Nock, S., Sage, T., Khalifa, B., Bye, A., Mitchell, J. L., Thomson, S., McLaughlin, M. G., Jones, S., Gibbins, J. M., & Unsworth, A. (2022). Cucurbitacins Elicit Anti-Platelet Activity via Perturbation of the Cytoskeleton and Integrin Function. Thrombosis and Haemostasis, 122(7), 1115-1129. https://doi.org/10.1055/a-1788-5322

Vancouver

Kriek N, Nock S, Sage T, Khalifa B, Bye A, Mitchell JL et al. Cucurbitacins Elicit Anti-Platelet Activity via Perturbation of the Cytoskeleton and Integrin Function. Thrombosis and Haemostasis. 2022 Jul 31;122(7):1115-1129. Epub 2022 Mar 4. doi: 10.1055/a-1788-5322

Author

Kriek, Neline ; Nock, Sophie ; Sage, Tanya et al. / Cucurbitacins Elicit Anti-Platelet Activity via Perturbation of the Cytoskeleton and Integrin Function. In: Thrombosis and Haemostasis. 2022 ; Vol. 122, No. 7. pp. 1115-1129.

Bibtex

@article{920d58132ec2485d9b72a6b734a5ebe2,
title = "Cucurbitacins Elicit Anti-Platelet Activity via Perturbation of the Cytoskeleton and Integrin Function",
abstract = "Cucurbitacins are dietary compounds that have been shown to elicit a range of anti-tumour, anti-inflammatory and anti-atherosclerotic activities. Originally identified as STAT inhibitors, a variety of mechanisms of action have since been described, including dysregulation of the actin cytoskeleton and disruption of integrin function. Integrin outside-in signalling and cytoskeletal rearrangements are critical for the propagation of stable thrombus formation and clot retraction following platelet adhesion at the site of vessel damage. The effects of cucurbitacins on platelet function and thrombus formation are unknown. We report for the first time anti-platelet and anti-thrombotic effects of cucurbitacins B, E and I in human platelets. Treatment of platelets with cucurbitacins resulted in attenuation of platelet aggregation, secretion and fibrinogen binding following stimulation by ADP, TRAP6, collagen and CRP-XL. Cucurbitacins were also found to potently inhibit other integrin- and cytoskeleton-mediated events, including adhesion, spreading and clot retraction. Further investigation of cytoskeletal dynamics found treatment with cucurbitacins altered cofilin phosphorylation, enhanced activation, and increased F actin polymerisation and microtubule assembly. Disruption to cytoskeletal dynamics has been previously shown to impair integrin activation, platelet spreading and clot retraction. Anti-platelet properties of cucurbitacins were found to extend to a disruption of stable thrombus formation, with an increase in thrombi instability and de-aggregation under flow. Our research identifies novel, anti-platelet and anti-thrombotic actions of cucurbitacins that appear to be linked to dysregulation of cytoskeletal dynamics and integrin function.",
keywords = "thrombosis, platelet, cytoskeleton, cucurbitacins, signalling",
author = "Neline Kriek and Sophie Nock and Tanya Sage and Badrija Khalifa and Alexander Bye and Mitchell, {Joanne L} and Steven Thomson and McLaughlin, {Mark G} and Sarah Jones and Gibbins, {Jonathan Martin} and Amanda Unsworth",
year = "2022",
month = jul,
day = "31",
doi = "10.1055/a-1788-5322",
language = "English",
volume = "122",
pages = "1115--1129",
journal = "Thrombosis and Haemostasis",
issn = "0340-6245",
publisher = "SCHATTAUER GMBH-VERLAG MEDIZIN NATURWISSENSCHAFTEN",
number = "7",

}

RIS

TY - JOUR

T1 - Cucurbitacins Elicit Anti-Platelet Activity via Perturbation of the Cytoskeleton and Integrin Function

AU - Kriek, Neline

AU - Nock, Sophie

AU - Sage, Tanya

AU - Khalifa, Badrija

AU - Bye, Alexander

AU - Mitchell, Joanne L

AU - Thomson, Steven

AU - McLaughlin, Mark G

AU - Jones, Sarah

AU - Gibbins, Jonathan Martin

AU - Unsworth, Amanda

PY - 2022/7/31

Y1 - 2022/7/31

N2 - Cucurbitacins are dietary compounds that have been shown to elicit a range of anti-tumour, anti-inflammatory and anti-atherosclerotic activities. Originally identified as STAT inhibitors, a variety of mechanisms of action have since been described, including dysregulation of the actin cytoskeleton and disruption of integrin function. Integrin outside-in signalling and cytoskeletal rearrangements are critical for the propagation of stable thrombus formation and clot retraction following platelet adhesion at the site of vessel damage. The effects of cucurbitacins on platelet function and thrombus formation are unknown. We report for the first time anti-platelet and anti-thrombotic effects of cucurbitacins B, E and I in human platelets. Treatment of platelets with cucurbitacins resulted in attenuation of platelet aggregation, secretion and fibrinogen binding following stimulation by ADP, TRAP6, collagen and CRP-XL. Cucurbitacins were also found to potently inhibit other integrin- and cytoskeleton-mediated events, including adhesion, spreading and clot retraction. Further investigation of cytoskeletal dynamics found treatment with cucurbitacins altered cofilin phosphorylation, enhanced activation, and increased F actin polymerisation and microtubule assembly. Disruption to cytoskeletal dynamics has been previously shown to impair integrin activation, platelet spreading and clot retraction. Anti-platelet properties of cucurbitacins were found to extend to a disruption of stable thrombus formation, with an increase in thrombi instability and de-aggregation under flow. Our research identifies novel, anti-platelet and anti-thrombotic actions of cucurbitacins that appear to be linked to dysregulation of cytoskeletal dynamics and integrin function.

AB - Cucurbitacins are dietary compounds that have been shown to elicit a range of anti-tumour, anti-inflammatory and anti-atherosclerotic activities. Originally identified as STAT inhibitors, a variety of mechanisms of action have since been described, including dysregulation of the actin cytoskeleton and disruption of integrin function. Integrin outside-in signalling and cytoskeletal rearrangements are critical for the propagation of stable thrombus formation and clot retraction following platelet adhesion at the site of vessel damage. The effects of cucurbitacins on platelet function and thrombus formation are unknown. We report for the first time anti-platelet and anti-thrombotic effects of cucurbitacins B, E and I in human platelets. Treatment of platelets with cucurbitacins resulted in attenuation of platelet aggregation, secretion and fibrinogen binding following stimulation by ADP, TRAP6, collagen and CRP-XL. Cucurbitacins were also found to potently inhibit other integrin- and cytoskeleton-mediated events, including adhesion, spreading and clot retraction. Further investigation of cytoskeletal dynamics found treatment with cucurbitacins altered cofilin phosphorylation, enhanced activation, and increased F actin polymerisation and microtubule assembly. Disruption to cytoskeletal dynamics has been previously shown to impair integrin activation, platelet spreading and clot retraction. Anti-platelet properties of cucurbitacins were found to extend to a disruption of stable thrombus formation, with an increase in thrombi instability and de-aggregation under flow. Our research identifies novel, anti-platelet and anti-thrombotic actions of cucurbitacins that appear to be linked to dysregulation of cytoskeletal dynamics and integrin function.

KW - thrombosis

KW - platelet

KW - cytoskeleton

KW - cucurbitacins

KW - signalling

U2 - 10.1055/a-1788-5322

DO - 10.1055/a-1788-5322

M3 - Journal article

C2 - 35253142

VL - 122

SP - 1115

EP - 1129

JO - Thrombosis and Haemostasis

JF - Thrombosis and Haemostasis

SN - 0340-6245

IS - 7

ER -