Thi Ngoc Quy Tran
Email Address
quy.tran@nus.edu.sg
Organizational Units
YONG LOO LIN SCH OF MEDICINE
faculty
PHARMACOLOGY
dept
8 results
Publication Search Results
Now showing 1 - 8 of 8
Publication Multifunctional Antibacterial Nanonets Attenuate Inflammatory Responses through Selective Trapping of Endotoxins and Pro-Inflammatory Cytokines(WILEY, 2023-04-25) Tram, Nhan Dai Thien; Tran, Quy Thi Ngoc; Xu, Jian; Su, Jeannie Ching Ting; Liao, Wupeng; Wong, Wai Shiu Fred; Ee, Pui Lai Rachel; Prof Wai-Shiu Fred Wong; PHARMACOLOGY; PHARMACYExtracellular lipopolysaccharide (LPS) released from bacteria cells can enter the bloodstream and cause septic complications with excessive host inflammatory responses. Target-specific strategies to inactivate inflammation mediators have largely failed to improve the prognosis of septic patients in clinical trials. By utilizing their high density of positive charges, de novo designed peptide nanonets are shown to selectively entrap the negatively charged LPS and pro-inflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6). This in turn enables the nanonets to suppress LPS-induced cytokine production by murine macrophage cell line and rescue the antimicrobial activity of the last-resort antibiotic, colistin, from LPS binding. Using an acute lung injury model in mice, it is demonstrated that intratracheal administration of the fibrillating peptides is effective at lowering local release of TNF-α and IL-6. Together with previously shown ability to simultaneously trap and kill pathogenic bacteria, the peptide nanonets display remarkable potential as a holistic, multifunctional anti-infective, and anti-septic biomaterial.Publication Calcaratarin D, a labdane diterpenoid, attenuates mouse asthma via modulating alveolar macrophage function(WILEY, 2022-12-20) Liao, Wupeng; Foo, Hazel Yu Ci; Tran, Thi Ngoc Quy; Chai, Christina Li Lin; Wong, Wai Shiu Fred; Prof Wai-Shiu Fred Wong; PHARMACOLOGY; PHARMACYBackground and Purpose: Alveolar macrophages (AMs) contribute to airway inflammation and remodelling in allergic asthma. Calcaratarin D (CalD), a labdane diterpenoid from rhizomes of the medicinal plant Alpinia calcarata, has recently been shown to possess anti-inflammatory properties. The present study evaluated protective effects of CalD in a house dust mite (HDM)-induced asthma mouse model. Experimental Approach: The effects of CalD on AMs in contributing to anti-inflammatory effects in asthma were investigated through in vivo, ex vivo, and in vitro experiments. Key Results: CalD reduced total bronchoalveolar lavage fluid and differential cell count, serum IgE levels, mucus hypersecretion, and airway hyperresponsiveness in HDM-challenged mice. Additionally, CalD affected a wide array of pro-inflammatory cytokines and chemokines and oxidative damage markers in isolated lung tissues. CalD suppressed the HDM-induced increase in Arg1 (M2 macrophage marker) in AMs from lung tissue and reduced lung polyamine levels. CalD weakened antigen presentation capability of AMs by reducing CD80 expression, reduced AM-derived CCL17 and CCL22 levels, and lessened Th2 cytokines from CD4+ T-cells from asthma lung digest. CalD blocked the HDM-induced FoxO1/IRF4 pathway and restored impaired the Nrf2/HO-1 antioxidant pathway in lung tissues. CalD inhibited IL-4/IL-13-stimulated JAK1/STAT6 pathway, FoxO1 protein expression, and chemokine production in primary AMs. Structure–activity relationship study revealed the α,β-unsaturated γ-butyrolactone in CalD is capable of forming covalent bonds with cellular protein targets essential for its action. Conclusion and Implications: Our results demonstrate for the first time that CalD is a novel anti-inflammatory natural compound for allergic asthma that modulates AM function.Publication Discovery and development of labdane-oxindole hybrids as small-molecule inhibitors against chikungunya virus infection(ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER, 2022-02-15) Tran, Quy Thi Ngoc; Lee, Regina Ching Hua; Liu, Hon Jin; Ran, Danli; Low, Vincent Zhan Lin; To, Dong Quang; Chu, Justin Jang Hann; Chai, Christina Li Lin; PHARMACOLOGY; MICROBIOLOGY AND IMMUNOLOGY; PHARMACYChikungunya virus (CHIKV) infection, a febrile illness caused by a mosquito-transmitted alphavirus, has afflicted millions of people worldwide. There is currently no approved effective antiviral treatment for CHIKV infection. In this study, we report a new class of small-molecule CHIKV inhibitors, the oxindole-labdanes, that potently block the replication of CHIKV with good selectivity. Andrographolide, a previously reported inhibitor of CHIKV infection, was used as the lead compound for our initial structure-activity relationship (SAR) study. From a focused library of 72 andrographolide analogues, we identified the lead compound (E)-2 with improved antiviral activities. Further optimization of (E)-2 led to the discovery of the normal-labdane 7-chloro-oxindole (E)-42 as potent inhibitor against two low-passage CHIKV isolates from human patients with an EC50 of 1.55 μM against CHIKV-122508 and 0.14 μM against CHIKV-6708. Compound (E)-42 displayed minimal cytotoxic liability (CC50 > 100 μM), thus furnishing good selectivity relative to the host cells. Mechanistically, (E)-42 does not inactivate the viral particles but rather acts on the host cells to interfere with the viral replication, demonstrating both prophylactic and therapeutic effects. Our findings open a new avenue for the development of oxindole-labdane compounds as promising antiviral drugs against CHIKV infection.Publication From irreversible to reversible covalent inhibitors: Harnessing the andrographolide scaffold for anti-inflammatory action (vol 204, 112481, 2020)(ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER, 2021-01-01) Tran, Quy TN; Tan, WS Daniel; Wong, WS Fred; Chai, Christina LL; Prof Wai-Shiu Fred Wong; PHARMACOLOGY; PHARMACYThe authors regret an error in Figure 7 in the published article due to conversion problems from Mac to PC during the production of proofs. The μM appeared as αM. The corrected version is provided below. This correction does not change the conclusions of the article. [Figure presented] The authors would like to apologise for any inconvenience caused.Publication Polypharmacology of andrographolide: beyond one molecule one target(ROYAL SOC CHEMISTRY, 2021-04-01) Tran, Quy TN; Tan, WS Daniel; Wong, WS Fred; Chai, Christina LL; Prof Wai-Shiu Fred Wong; PHARMACOLOGY; PHARMACYCovering: 1951 to 2020 Andrographolide is one of the most widely studied plant secondary metabolites, known to display diverse pharmacological actions. Current literature has documented a sizeable list of pharmacological targets for andrographolide, suggesting its multi-targeting nature. Many of these targets are central to the pathophysiology of highly prevalent diseases such as cardiovascular diseases, neurodegenerative disorders, autoimmunity, and even cancer. Despite its well-documented therapeutic efficacy in various disease models, for years, the discrepancies between in vivo bioavailability and bioactivity of andrographolide and the debate surrounding its multi-targeting properties (polypharmacology or promiscuity?) have hindered the development of this versatile molecule into a potential therapeutic agent. Is andrographolide a valuable lead for therapeutic development or a potential invalid metabolic panacea (IMP)? This perspective article aims to discuss this by considering various contributing factors to the polypharmacology of andrographolide.Publication The identification of naturally occurring labdane diterpenoid calcaratarin D as a potential anti-inflammatory agent(ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER, 2019-07-15) Tran, Quy TN; Wong, WS Fred; Chai, Christina LL; Prof Wai-Shiu Fred Wong; PHARMACOLOGY; PHARMACYIn this study we report, for the first time, the synthesis of the natural product calcaratarin D via a stereo- and regio-selective aldol condensation with (S)-β-hydroxy-γ-butyrolactone as key steps. A concise synthetic route (under 10 steps) to a series of structurally related normal-labdane diterpenes was also developed and their anti-inflammatory activities were evaluated in an in vitro model of inflammation. The structure-activity relationships (SARs) pertaining to the labdane scaffold were elucidated and results suggest that an α-alkylidene-β-hydroxy-γ-butyrolactone system is necessary for potent activity in the labdanes. Our studies identified the natural product calcaratarin D (1) as a promising anti-inflammatory agent, which effectively modulates the production of pro-inflammatory mediators (e.g., TNF-α, IL-6, NO) at both transcriptional and translational levels. These inhibitory effects are likely to occur via the suppression of nuclear factor kappa B (NF-κB) activation by reducing the p65 nuclear translocation but not its phosphorylation or protein expression. Calcaratarin D exhibited significantly greater inhibition of NF-κB activation than andrographolide, a well-known NF-κB inhibitor from the labdane family, suggesting that a normal-configuration labdane ring or the absence of hydroxyl groups at C-3 and C-19 positions is favorable for potent NF-κB inhibition. We further investigated the effects of calcaratarin D on the upstream signalling pathways and found that the compound selectively suppressed the LPS-induced activation of PI3K/Akt pathway without affecting much of the MAPK (i.e., ERK, JNK, and p38) activation. These findings demonstrate that calcaratarin D exerts its anti-inflammatory effects via a selective Akt-NF-κB-mediated mechanism and potentially offers a new therapeutic strategy for the management of inflammatory diseases.Publication Labdane diterpenoids as potential anti-inflammatory agents(ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD, 2017-10-01) Tran, Quy TN; Wong, WS Fred; Chai, Christina LL; Prof Wai-Shiu Fred Wong; PHARMACOLOGYThe search for new anti-inflammatory agents is challenging due to the complexity of the inflammatory process and its role in host defense. Over the past few decades, a significant body of evidence has emerged, supporting the prominent role of labdane diterpenoids in therapeutic interventions of various inflammatory diseases. The anti-inflammatory activity of labdane diterpenoids has been attributed mainly to the inhibition of nuclear factor-κB (NF-κB) activity, the modulation of arachidonic acid (AA) metabolism and the reduction of nitric oxide (NO) production. This article provides extensive coverage of naturally occurring labdane diterpenes, discovered between 1981 and 2016, which have been verified as NF-κB, NO, or AA modulators. Herein, we also discuss the role of Michael acceptor, a common structural feature present in most of the active labdane diterpenes, and its association with NF-κB signaling inhibition. In the cases where a sufficient amount of data exists, structure-activity relationship (SAR) studies and clinical studies performed on the anti-inflammatory labdane diterpenoids are also discussed.Publication Angiotensin II type-2 receptor activation in alveolar macrophages mediates protection against cigarette smoke-induced chronic obstructive pulmonary disease(Elsevier BV, 2022-10-01) Mei, D; Liao, W; Gan, PXL; Tran, QTN; Chan, CCMY; Heng, CKM; Wong, WSF; Prof Wai-Shiu Fred Wong; PHARMACOLOGY; PHARMACYChronic obstructive pulmonary disease (COPD) is the third leading cause of death globally. Cumulative evidence has implicated renin-angiotensin system (RAS) in the pathogenesis of COPD. Alveolar macrophages (AMs) are the first line immune defense in the respiratory system and play a critical role in the lung homeostasis. This study aimed to investigate the role of AMs in contributing to the protective effects of angiotensin II type-2 receptor (AT2R) activation in cigarette smoke (CS)-induced COPD. The AM polarization, phagocytosis and metabolism, and the underlying biochemical mechanisms of compound 21 (C21), a selective and potent non-peptide small molecule AT2R agonist, were evaluated in a two-week CS-induced COPD mouse model. C21 restored AM phagocytosis ability, reversing CS-induced AM phagocytosis impairment. CS exposure polarized AMs towards M1 phenotype, whereas, C21 skewed the CS-exposed AMs towards M2 phenotype. C21 reprogrammed CS-exposed AM metabolism from a high glycolysis-driven process to support inflammation energy demand to a high mitochondrial respiration process to limit inflammation. Besides, C21 upregulated AT2R and Mas receptor levels in CS-exposed AMs, favoring the anti-inflammatory Ang II/AT2R axis and Ang 1–7/Mas axis in the RAS. C21 restored the normal levels of sirtuin 1 (SIRT1) and MAPK phosphatase 1 (MKP1) in CS-exposed AMs, leading to the reduction of phospho-p38, phospho-ERK and p65 subunit of NF-κB levels in CS-exposed AMs. We report here for the first time that AT2R agonist C21 acts by boosting the protective functions of AMs against CS-induced COPD, and our results support the development of AT2R agonist for the treatment of COPD.