ORCID Profile
0000-0002-6143-5185
Current Organisation
Nanyang Technological University
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Publisher: The Company of Biologists
Date: 2020
DOI: 10.1242/JCS.244111
Abstract: RAS oncogenes are frequently mutated in human cancers and among the three isoforms (KRAS, HRAS and NRAS), KRAS is the most frequently mutated oncogene. Here we demonstrate that a subset of flavaglines, a class of natural anti-tumour drugs and chemical ligands of prohibitins, inhibit RAS GTP loading and oncogene activation in cells at nanomolar concentrations. Treatment with rocaglamide, the first discovered flavagline, inhibited the nanoclustering of KRAS, but not HRAS and NRAS, at specific phospholipid enriched plasma membrane domains. We further demonstrate that plasma membrane-associated prohibitins directly interact with KRAS, phosphatidyl serine and phosphatidic acid, and these interactions are disrupted by rocaglamide but not by a structurally related flavagline FL1. Depletion of prohibitin-1 phenocopied rocaglamide-mediated effects on RAS activation and stability. We also demonstrate that flavaglines inhibit the oncogenic growth of KRAS-mutated cells and treatment with rocaglamide reduces NSCLC tumours in autochthonous KRAS-driven mouse models without severe side effects. Our data suggest that it will be promising to further develop flavagline derivatives as specific KRAS inhibitors for clinical applications.
Publisher: Springer Science and Business Media LLC
Date: 31-01-2023
Publisher: Springer Science and Business Media LLC
Date: 12-08-2022
Publisher: Springer Science and Business Media LLC
Date: 23-08-2021
DOI: 10.1038/S41596-021-00600-7
Abstract: Intracellular delivery of advanced therapeutics, including biologicals and supramolecular agents, is complex because of the natural biological barriers that have evolved to protect the cell. Efficient delivery of therapeutic nucleic acids, proteins, peptides and nanoparticles is crucial for clinical adoption of emerging technologies that can benefit disease treatment through gene and cell therapy. Nanoneedles are arrays of vertical high-aspect-ratio nanostructures that can precisely manipulate complex processes at the cell interface, enabling effective intracellular delivery. This emerging technology has already enabled the development of efficient and non-destructive routes for direct access to intracellular environments and delivery of cell-impermeant payloads. However, successful implementation of this technology requires knowledge of several scientific fields, making it complex to access and adopt by researchers who are not directly involved in developing nanoneedle platforms. This presents an obstacle to the widespread adoption of nanoneedle technologies for drug delivery. This tutorial aims to equip researchers with the knowledge required to develop a nanoinjection workflow. It discusses the selection of nanoneedle devices, approaches for cargo loading and strategies for interfacing to biological systems and summarises an array of bioassays that can be used to evaluate the efficacy of intracellular delivery.
Publisher: American Chemical Society (ACS)
Date: 23-05-2007
DOI: 10.1021/LA7006843
Abstract: Gold nanoparticles are one of the popular nanomaterials, widely used in biosensor applications as well as nanostructure construction. An essential attribute of these gold nanoparticles (Au-nps) is their stabilization against salt-induced aggregation. In this work, utilization of deoxyribonucleotides (dNTPs) as a tunable surface-stabilization agent for Au-nps was investigated. It was found that surfaces of Au-nps are covered by a layer of dNTPs after an adequate incubation with dNTPs solutions. Electrostatic repulsion among dNTP-coated Au-nps could prevent aggregation of Au-nps at a high salt concentration. The strength of dNTP-based protection can be manipulated by changing preparation protocols (e.g., incubation temperature, ionic strength, and ratio of Au-nps to dNTPs). Four different types of dNTPs exhibit different binding affinity to Au-nps and thus various stabilization efficiency in the order of dATP > dCTP > dGTP approximately dTTP. Moreover, this salt-induced aggregation can be reinitiated by the increase of solution temperature, which leads to a partial removal of the protective dNTP layer on Au-nps. The advantage of thermally tunable aggregation/dispersion of Au-nps mediated by dNTP adsorption offers a useful approach for the preparation of biomolecule (oligonucleotides and oligopeptides) modified nanoparticles in applications of bioassay and nanobiotechnology.
Publisher: Springer Science and Business Media LLC
Date: 03-12-2022
DOI: 10.1038/S41467-022-35034-6
Abstract: Piezo1 is a bona fide mechanosensitive ion channel ubiquitously expressed in mammalian cells. The distribution of Piezo1 within a cell is essential for various biological processes including cytokinesis, cell migration, and wound healing. However, the underlying principles that guide the subcellular distribution of Piezo1 remain largely unexplored. Here, we demonstrate that membrane curvature serves as a key regulator of the spatial distribution of Piezo1 in the plasma membrane of living cells. Piezo1 depletes from highly curved membrane protrusions such as filopodia and enriches to nanoscale membrane invaginations. Quantification of the curvature-dependent sorting of Piezo1 directly reveals the in situ nano-geometry of the Piezo1-membrane complex. Piezo1 density on filopodia increases upon activation, independent of calcium, suggesting flattening of the channel upon opening. Consequently, the expression of Piezo1 inhibits filopodia formation, an effect that diminishes with channel activation.
No related grants have been discovered for Wenting Zhao.