Full metadata record
| DC Field | Value | Language |
|---|---|---|
| dc.contributor | Department of Applied Biology and Chemical Technology | en_US |
| dc.contributor.advisor | Ko, Ben (ABCT) | en_US |
| dc.creator | Chan, Wing Cheung | - |
| dc.identifier.uri | https://theses.lib.polyu.edu.hk/handle/200/11646 | - |
| dc.language | English | en_US |
| dc.publisher | Hong Kong Polytechnic University | en_US |
| dc.rights | All rights reserved | en_US |
| dc.title | Elucidation of the molecular targets and cellular actions of tetrandrine – a novel autophagic inducing compound | en_US |
| dcterms.abstract | S. tetrandra is a traditional Chinese medicinal plant for pain relief and promote diuresis. Tetrandrine (Tet) is a major component isolated from the herb. It is bisbenzylisoquinoline alkaloid exhibits a variety of pharmacological activities and implicated in the treatment for cancer, viral infection and inflammation, etc. However, the cellular target(s) of Tet remains elusive. An alkynyl diazirine derivative of Tet (AD-Tet), which is a clickable photoaffinity probe, was synthesized for the identification of the molecular target(s) of Tet. Biochemical and cellular analysis confirmed that AD-Tet and Tet exhibit highly similar, if not identical, pharmacological activities, and they have similar molecular targets. AD-Tet is localized specifically to the lysosomes. Integral analysis from pulldown SILAC-MS and transcriptomics analysis further revealed that lysosomal integral membrane protein-2 (LIMP-2) is a genuine molecular target of Tet. Tet at low micromolar concentration (5 μM) inhibits LIMP-2, resulting in the accumulation of intralysosomal cholesterol, the activation of sterol regulatory-element binding protein (SREBP), the upregulation of genes responsible for cholesterol synthesis, and the disruption of cellular cholesterol metabolism. On the other hand, Tet at high micromolar (15 μM) concentration resulted in the activation of unfolded protein response and cell death, presumably due to non-specific inhibition of lysosomal proteins. Concordantly, mice fed with Tet developed hypercholesteremia associated with microvascular steatosis, whereas mice fed of Tet at a higher dose resulted in hepatotoxicity. These findings suggested that many of the observed pharmacological activities of Tet are associated with the disruption of lysosomal functions. This study has identified Tet as the first-in-class LIMP-2-targeting molecule. LIMP-2 is the known cellular receptor for the Enterovirus 71 (EV71), the causative agent for hand, foot and mouth disease in children that could lead to mortality. Therefore, our findings suggested that Tet can be further explored for the treatment of EV71 infection. Along this direction, structural modification of Tet to maximize its affinity towards LIMP-2 and minimize its toxicity will facilitate its development into a clinical the therapeutic. | en_US |
| dcterms.extent | 248 pages : color illustrations | en_US |
| dcterms.isPartOf | PolyU Electronic Theses | en_US |
| dcterms.issued | 2022 | en_US |
| dcterms.educationalLevel | Ph.D. | en_US |
| dcterms.educationalLevel | All Doctorate | en_US |
| dcterms.LCSH | Medicinal plants | en_US |
| dcterms.LCSH | Plant cytochemistry | en_US |
| dcterms.LCSH | Hong Kong Polytechnic University -- Dissertations | en_US |
| dcterms.accessRights | open access | en_US |
Copyright Undertaking
As a bona fide Library user, I declare that:
- I will abide by the rules and legal ordinances governing copyright regarding the use of the Database.
- I will use the Database for the purpose of my research or private study only and not for circulation or further reproduction or any other purpose.
- I agree to indemnify and hold the University harmless from and against any loss, damage, cost, liability or expenses arising from copyright infringement or unauthorized usage.
By downloading any item(s) listed above, you acknowledge that you have read and understood the copyright undertaking as stated above, and agree to be bound by all of its terms.
Please use this identifier to cite or link to this item:
https://theses.lib.polyu.edu.hk/handle/200/11646