ORCID Profile
0000-0002-0020-2572
Current Organisation
Republic Polytechnic
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Publisher: Wiley
Date: 18-01-2013
DOI: 10.1111/TRA.12035
Abstract: Regulated GLUT4 trafficking is a key action of insulin. Quantitative stepwise analysis of this process provides a powerful tool for pinpointing regulatory nodes that contribute to insulin regulation and insulin resistance. We describe a novel GLUT4 construct and workflow for the streamlined dissection of GLUT4 trafficking from simple high throughput screens to high resolution analyses of in idual vesicles. We reveal single cell heterogeneity in insulin action highlighting the utility of this approach - each cell displayed a unique and highly reproducible insulin response, implying that each cell is hard-wired to produce a specific output in response to a given stimulus. These data highlight that the response of a cell population to insulin is underpinned by extensive heterogeneity at the single cell level. This heterogeneity is pre-programmed within each cell and is not the result of intracellular stochastic events.
Publisher: Springer Science and Business Media LLC
Date: 10-02-2017
DOI: 10.1038/EMM.2016.144
Publisher: Portland Press Ltd.
Date: 29-03-2011
DOI: 10.1042/BJ20110040
Abstract: Many human tumours exhibit activation of the PI3K (phosphoinositide 3-kinase)/Akt pathway, and inhibition of this pathway slows tumour growth. This led to the development of specific Akt inhibitors for in vivo use. However, activation of Akt is also necessary for processes including glucose metabolism. Therefore a potential complication of such anticancer drugs is insulin resistance and/or diabetes. In the process of characterizing the metabolic effects of early-phase Akt inhibitors, we discovered an off-target inhibitory effect on mammalian facilitative glucose transporters. In view of the crucial role of glucose transport for all mammalian cells, such an off-target effect would have major implications for further development of this family of compounds. In the present study, we have characterized a next-generation Akt inhibitor, MK-2206. MK-2206 is an orally active allosteric Akt inhibitor under development for treating solid tumours. We report that MK-2206 potently inhibits Thr308Akt and Ser473Akt phosphorylation in 3T3-L1 adipocytes (IC50 0.11 and 0.18 μM respectively) as well as downstream effects of insulin on GLUT4 (glucose transporter 4) translocation (IC50 0.47 μM) and glucose transport (IC50 0.14 μM). Notably, the potency of MK-2206 is approximately 1 log higher than previous inhibitors and its specificity is significantly improved with modest inhibitory effects on glucose transport in GLUT4-expressing adipocytes and GLUT1-rich human erythrocytes, independently of Akt. Nevertheless, MK-2206 clearly has potent effects on Akt2, the principal isoform involved in peripheral insulin action, in which case insulin resistance will probably be a major complication following in vivo administration. We conclude that MK-2206 provides an optimal tool for studying the effects of Akt in vitro.
Publisher: Informa UK Limited
Date: 12-2012
DOI: 10.1128/MCB.00761-12
Publisher: Elsevier BV
Date: 02-2012
Publisher: Elsevier BV
Date: 05-2015
Publisher: Elsevier BV
Date: 03-2008
DOI: 10.1016/J.FREERADBIOMED.2007.12.008
Abstract: A total of 286 H2O2-sensitive Saccharomyces cerevisiae deletion mutants were screened to identify genes involved in cellular adaptation to H2O2 stress. YAP1, SKN7, GAL11, RPE1, TKL1, IDP1, SLA1, and PET8 were important for adaptation to H2O2. The mutants were isible into two groups based on their responses to a brief acute dose of H2O2 and to chronic exposure to H2O2. Transcription factors Yap1p, Skn7p, and Gal11p were important for both acute and chronic responses to H2O2. Yap1p and Skn7p were acting in concert for adaptation, which indicates that upregulation of antioxidant functions rather than generation of NADPH or glutathione is important for adaptation. Deletion of GPX3 and YBP1 involved in sensing H2O2 and activating Yap1p affected adaptation but to a lesser extent than YAP1 deletion. NADPH generation was also required for adaptation. RPE1, TKL1, or IDP1 deletants affected in NADPH production were chronically sensitive to H2O2 but resistant to an acute dose, and other mutants affected in NADPH generation tested were similarly affected in adaptation. These mutants overproduced reduced glutathione (GSH) but maintained normal cellular redox homeostasis. This overproduction of GSH was not regulated at transcription of the gene encoding gamma-glutamylcysteine synthetase.
Publisher: American Society for Cell Biology (ASCB)
Date: 03-2009
Abstract: Genome-wide screening for sensitivity to chronic endoplasmic reticulum (ER) stress induced by dithiothreitol and tunicamycin (TM) identified mutants deleted for Cu, Zn superoxide dismutase (SOD) function (SOD1, CCS1) or affected in NADPH generation via the pentose phosphate pathway (TKL1, RPE1). TM-induced ER stress led to an increase in cellular superoxide accumulation and an increase in SOD1 expression and Sod1p activity. Prior adaptation of the hac1 mutant deficient in the unfolded protein response (UPR) to the superoxide-generating agent paraquat reduced cell death under ER stress. Overexpression of the ER oxidoreductase Ero1p known to generate hydrogen peroxide in vitro, did not lead to increased superoxide levels in cells subjected to ER stress. The mutants lacking SOD1, TKL1, or RPE1 exhibited decreased UPR induction under ER stress. Sensitivity of the sod1 mutant to ER stress and decreased UPR induction was partially rescued by overexpression of TKL1 encoding transketolase. These data indicate an important role for SOD and cellular NADP(H) in cell survival during ER stress, and it is proposed that accumulation of superoxide affects NADP(H) homeostasis, leading to reduced UPR induction during ER stress.
Publisher: Springer Science and Business Media LLC
Date: 16-07-2022
DOI: 10.1038/S41539-022-00133-Y
Abstract: Adult hippoc al neurogenesis in the developmental process of generating and integrating new neurons in the hippoc us during adulthood and is a unique form of structural plasticity with enormous potential to modulate neural circuit function and behaviour. Dysregulation of this process is strongly linked to stress-related neuropsychiatric conditions such as anxiety and depression, and efforts have focused on unravelling the contribution of adult-born neurons in regulating stress response and recovery. Chronic stress has been shown to impair this process, whereas treatment with clinical antidepressants was found to enhance the production of new neurons in the hippoc us. However, the precise role of adult hippoc al neurogenesis in mediating the behavioural response to chronic stress is not clear and whether these adult-born neurons buffer or increase susceptibility to stress-induced mood-related maladaptation remains one of the controversial issues. In this review, we appraise evidence probing the causal role of adult hippoc al neurogenesis in the regulation of emotional behaviour in rodents. We find that the relationship between adult-born hippoc al neurons and stress-related mood disorders is not linear, and that simple subtraction or addition of these neurons alone is not sufficient to lead to anxiety/depression or have antidepressant-like effects. We propose that future studies examining how stress affects unique properties of adult-born neurons, such as the excitability and the pattern of connectivity during their critical period of maturation will provide a deeper understanding of the mechanisms by which these neurons contribute to functional outcomes in stress-related mood disorders.
Publisher: Oxford University Press (OUP)
Date: 24-10-2014
DOI: 10.1093/BIOINFORMATICS/BTT616
Abstract: Motivation: With the advancement of high-throughput techniques, large-scale profiling of biological systems with multiple experimental perturbations is becoming more prevalent. Pathway analysis incorporates prior biological knowledge to analyze genes roteins in groups in a biological context. However, the hypotheses under investigation are often confined to a 1D space (i.e. up, down, either or mixed regulation). Here, we develop direction pathway analysis (DPA), which can be applied to test hypothesis in a high-dimensional space for identifying pathways that display distinct responses across multiple perturbations. Results: Our DPA approach allows for the identification of pathways that display distinct responses across multiple perturbations. To demonstrate the utility and effectiveness, we evaluated DPA under various simulated scenarios and applied it to study insulin action in adipocytes. A major action of insulin in adipocytes is to regulate the movement of proteins from the interior to the cell surface membrane. Quantitative mass spectrometry-based proteomics was used to study this process on a large-scale. The combined dataset comprises four separate treatments. By applying DPA, we identified that several insulin responsive pathways in the plasma membrane trafficking are only partially dependent on the insulin-regulated kinase Akt. We subsequently validated our findings through targeted analysis of key proteins from these pathways using immunoblotting and live cell microscopy. Our results demonstrate that DPA can be applied to dissect pathway networks testing erse hypotheses and integrating multiple experimental perturbations. Availability and implementation: The R package ‘directPA’ is distributed from CRAN under GNU General Public License (GPL)-3 and can be downloaded from: eb ackages/directPA/index.html Contact: jean.yang@sydney.edu.au Supplementary Information: Supplementary data are available at Bioinformatics online.
Publisher: Elsevier BV
Date: 02-2010
Publisher: Portland Press Ltd.
Date: 08-2019
DOI: 10.1042/BSR20191601
Abstract: Cryopreservation has facilitated advancement of biological research by allowing the storage of cells over prolonged periods of time. While cryopreservation at extremely low temperatures would render cells metabolically inactive, cells suffer insults during the freezing and thawing process. Among such insults, the generation of supra-physiological levels of reactive oxygen species (ROS) could impair cellular functions and survival. Antioxidants are potential additives that were reported to partially or completely reverse freeze-thaw stress-associated impairments. This review aims to discuss the potential sources of cryopreservation-induced ROS and the effectiveness of antioxidant administration when used in idually or in combination.
Publisher: Elsevier BV
Date: 07-2008
DOI: 10.1016/J.BBAMCR.2008.01.023
Abstract: Apoptosis is associated in many cases with the generation of reactive oxygen species (ROS) in cells across a wide range of organisms including lower eukaryotes such as the yeast Saccharomyces cerevisiae. Currently there are many unresolved questions concerning the relationship between apoptosis and the generation of ROS. These include which ROS are involved in apoptosis, what mechanisms and targets are important and whether apoptosis is triggered by ROS damage or ROS are generated as a consequence or part of the cellular disruption that occurs during cell death. Here we review the nature of the ROS involved, the damage they cause to cells, summarise the responses of S. cerevisiae to ROS and discuss those aspects in which ROS affect cell integrity that may be relevant to the apoptotic process.
Publisher: Springer Science and Business Media LLC
Date: 13-06-2015
Publisher: Portland Press Ltd.
Date: 25-10-2010
DOI: 10.1042/BJ20100750
Abstract: The protein kinase Akt is involved in various cellular processes, including cell proliferation, growth and metabolism. Hyperactivation of Akt is commonly observed in human tumours and so this pathway has been the focus of targeted drug discovery. However, Akt also plays an essential role in other physiological processes, such as the insulin-regulated transport of glucose into muscle and fat cells. This process, which is essential for whole-body glucose homoeostasis in mammals, is thought to be mediated via Akt-dependent movement of GLUT4 glucose transporters to the plasma membrane. In the present study, we have investigated the metabolic side effects of non-ATP-competitive allosteric Akt inhibitors. In 3T3-L1 adipocytes, these inhibitors caused a decrease in the Akt signalling pathway concomitant with reduced glucose uptake. Surprisingly, a similar reduction in GLUT4 translocation to the plasma membrane was not observed. Further investigation revealed that the inhibitory effects of these compounds on glucose uptake in 3T3-L1 adipocytes were independent of the Akt signalling pathway. The inhibitors also inhibited glucose transport into other cell types, including human erythrocytes and T-47D breast cancer cells, suggesting that these effects are not specific to GLUT4. We conclude that these drugs may, at least in part, inhibit tumorigenesis through inhibition of tumour cell glucose transport.
Publisher: Elsevier BV
Date: 02-2011
Publisher: Elsevier BV
Date: 12-2016
Publisher: Elsevier BV
Date: 12-2010
DOI: 10.1016/J.FREERADBIOMED.2010.09.023
Abstract: Glutathione (GSH) is a key redox buffer and protectant. Growth (approx. one or two isions) of cells lacking γ-glutamylcysteine synthetase (gsh1) in the absence of GSH led to irreversible respiratory incompetency in all cells, and after five isions 75% of cells completely lacked mitochondrial DNA (mtDNA). The level of GSH required to allow continuous growth was distinct from that required to prevent loss of mtDNA. GSH limitation led to a change in the transcript levels of 190 genes, including 30 genes regulated by the Aft1p and/or Aft2p transcription factors, which regulate the cellular response to changes in iron availability. Disruption of AFT1 but not AFT2 in gsh1 cells afforded a protective effect on maintenance of respiratory competency, as did overexpression of GRX3 or GRX4 (encoding monothiol glutaredoxins that act as negative regulators of Aft1p). Importantly, an iron-independent mechanism (~30%) was also observed to mediate GSH-dependent mtDNA loss. Analysis of the redox environment in the cytosol, mitochondrial matrix, and intermembrane space (IMS) found that the cytosol was most severely and rapidly affected by GSH depletion. GSH may also modulate the redox environment of the IMS. The implications of altered GSH homeostasis for maintenance of mtDNA, compartmental redox, and the pathophysiology of certain diseases are discussed.
Publisher: Elsevier BV
Date: 04-2018
No related grants have been discovered for Shi-Xiong Tan.