ChemBio seminar by Dr Xuyu Liu (Uni Sydney) - CH-635
Event details
| Date | 25.06.2024 |
| Hour | 09:15 › 10:15 |
| Speaker | Dr Xuyu Liu |
| Location | |
| Category | Conferences - Seminars |
| Event Language | English |
Title: Unveiling hidden functions of dietary electrophiles in platelets through integrated phenotypic and chemoproteomic approaches
Abstract:
A wide range of dietary phytochemicals has been shown to modulate the activities of kinases, ubiquitin-conjugating enzymes, and transcription factors, providing long-lasting impacts on immune responses, neural plasticity, and cardiovascular health.1 Many of these bioactive compounds possess electrophilic functionalities, enabling covalent attachment to the sulfhydryl side chains of cysteine residues within proteins.2 Such diet-induced covalent modifications have recently been linked to a reduced risk of acute ischemic stroke and atherosclerosis.3, 4 Despite these findings, the effects of protein post-dietary modifications on the functions and activities of platelets – crucial cellular elements in regulating hemostasis and thrombosis – remain largely unexplored.
In our recent investigation, we analyzed platelet phenotypes resulting from the irreversible binding of proteins by 23 dietary electrophiles.5 This analysis revealed distinct antiplatelet selectivity profiles for naturally occurring isothiocyanates and polyphenols, notably attenuating the platelets' response to the ADP agonist without affecting thrombin-mediated activation. By integrating a Click chemistry-based target enrichment strategy with a multiplexed Tandem Mass Tag (TMT) proteomic mapping approach, we identified protein disulfide isomerase isoform A6 (PDIA6) as the key target modified through covalent bonds with these dietary electrophiles. Importantly, using murine models of electrolytic injury-induced thrombosis and tail bleeding, we demonstrated that selective inhibition of PDIA6 is effective in thrombolytic therapy in vivo without an increased risk of bleeding. Our findings suggest a new avenue for developing antiplatelet agents based on the mechanism of diet-induced electrophilic modifications, potentially offering safer and more effective therapeutic options for the treatment of stroke and thrombosis.
References:
(1) Manju Singh, M.; Arvind, K. S.; Raosaheb, K. In Antioxidants, Viduranga, W. Ed.; IntechOpen, 2021.
(2) Long, M. J. C.; Liu, X.; Aye, Y. Current Opinion in Chemical Biology 2019, 51, 48-56.
(3) van Steenwijk, H. P.; Winter, E.; Knaven, E.; et al. Frontiers in Nutrition 2023, 10, Clinical Trial.
(4) Rudolph, T. K.; Rudolph, V.; Edreira, M. M.; et al. Arteriosclerosis, Thrombosis, and Vascular Biology 2010, 30, 938-945.
(5) Guan, I. A.; Liu, J. T.; Sawyer, R. C.; et al. ACS Central Science 2024, 10, 344-357.
Speaker's biography:
Dr Xuyu (Johnny) Liu completed his Bachelor and Master of Biomedical Science at Victoria University, Wellington, NZ in 2012. He then moved to Sydney and conducted his PhD research under the supervision of Professor Richard J Payne in the School of Chemistry at The University of Sydney and graduated in 2016. His PhD research entailed developing new methods for sulfopeptide synthesis and evaluating sulfopeptides’ biological activity. In his postdoctoral work, he worked at Cornell University and École Polytechnique Fédérale de Lausanne (EPFL) under the guidance of Prof Yimon Aye. His postdoctoral research focused on hijacking endogenous lipid electrophile-signalling pathways for precision medicine development. The contribution of this work to anticancer research was recognised by Cornell University, and he was nominated by the university for the Blavatnik Award in 2018.
Dr Liu was awarded the Sydney Cardiovascular Fellowship and joins HRI to start his independent research in developing new chemoproteomic platforms for identification of novel therapeutic targets for cardiovascular disease.
Lab website: https://www.hri.org.au/our-research/cardiovascular-protective-signalling-and-drug-discovery
Abstract:
A wide range of dietary phytochemicals has been shown to modulate the activities of kinases, ubiquitin-conjugating enzymes, and transcription factors, providing long-lasting impacts on immune responses, neural plasticity, and cardiovascular health.1 Many of these bioactive compounds possess electrophilic functionalities, enabling covalent attachment to the sulfhydryl side chains of cysteine residues within proteins.2 Such diet-induced covalent modifications have recently been linked to a reduced risk of acute ischemic stroke and atherosclerosis.3, 4 Despite these findings, the effects of protein post-dietary modifications on the functions and activities of platelets – crucial cellular elements in regulating hemostasis and thrombosis – remain largely unexplored.
In our recent investigation, we analyzed platelet phenotypes resulting from the irreversible binding of proteins by 23 dietary electrophiles.5 This analysis revealed distinct antiplatelet selectivity profiles for naturally occurring isothiocyanates and polyphenols, notably attenuating the platelets' response to the ADP agonist without affecting thrombin-mediated activation. By integrating a Click chemistry-based target enrichment strategy with a multiplexed Tandem Mass Tag (TMT) proteomic mapping approach, we identified protein disulfide isomerase isoform A6 (PDIA6) as the key target modified through covalent bonds with these dietary electrophiles. Importantly, using murine models of electrolytic injury-induced thrombosis and tail bleeding, we demonstrated that selective inhibition of PDIA6 is effective in thrombolytic therapy in vivo without an increased risk of bleeding. Our findings suggest a new avenue for developing antiplatelet agents based on the mechanism of diet-induced electrophilic modifications, potentially offering safer and more effective therapeutic options for the treatment of stroke and thrombosis.
References:
(1) Manju Singh, M.; Arvind, K. S.; Raosaheb, K. In Antioxidants, Viduranga, W. Ed.; IntechOpen, 2021.
(2) Long, M. J. C.; Liu, X.; Aye, Y. Current Opinion in Chemical Biology 2019, 51, 48-56.
(3) van Steenwijk, H. P.; Winter, E.; Knaven, E.; et al. Frontiers in Nutrition 2023, 10, Clinical Trial.
(4) Rudolph, T. K.; Rudolph, V.; Edreira, M. M.; et al. Arteriosclerosis, Thrombosis, and Vascular Biology 2010, 30, 938-945.
(5) Guan, I. A.; Liu, J. T.; Sawyer, R. C.; et al. ACS Central Science 2024, 10, 344-357.
Speaker's biography:
Dr Xuyu (Johnny) Liu completed his Bachelor and Master of Biomedical Science at Victoria University, Wellington, NZ in 2012. He then moved to Sydney and conducted his PhD research under the supervision of Professor Richard J Payne in the School of Chemistry at The University of Sydney and graduated in 2016. His PhD research entailed developing new methods for sulfopeptide synthesis and evaluating sulfopeptides’ biological activity. In his postdoctoral work, he worked at Cornell University and École Polytechnique Fédérale de Lausanne (EPFL) under the guidance of Prof Yimon Aye. His postdoctoral research focused on hijacking endogenous lipid electrophile-signalling pathways for precision medicine development. The contribution of this work to anticancer research was recognised by Cornell University, and he was nominated by the university for the Blavatnik Award in 2018.
Dr Liu was awarded the Sydney Cardiovascular Fellowship and joins HRI to start his independent research in developing new chemoproteomic platforms for identification of novel therapeutic targets for cardiovascular disease.
Lab website: https://www.hri.org.au/our-research/cardiovascular-protective-signalling-and-drug-discovery
Practical information
- Informed public
- Free