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  1. Fulltext A Review of TENIS Syndrome in Hospital Pulau Pinang
    Khoo ACH, Fong LY, Hamzah F
    Indian J Nucl Med, 2018 11 6;33(4):284-289.
    PMID: 30386048 DOI: 10.4103/ijnm.IJNM_65_18
    Introduction: The treatment for differentiated thyroid cancers (DTCs) has always been radioactive iodine 131I therapy after definitive surgical management. Clinicians are faced with therapeutic challenges when dealing with patients having thyroglobulin-elevated negative iodine scintigraphy (TENIS) syndrome (elevated serum thyroglobulin [Tg] levels but negative whole-body scans [WBSs]).

    Objective: The aim of the study was to determine the prevalence of TENIS syndrome in our local setting and to evaluate the use of 18-fluoro-2-deoxyglucose (18F-FDG) positron emission tomography-computed tomography (PET-CT) in the management.

    Methodology: The data from DTC patients treated in the Department of Nuclear Medicine, Hospital Pulau Pinang from December 1, 2010, to November 30, 2016, with negative WBS and elevated Tg were reviewed. These patients should have undergone 18F-FDG PET-CT to be included in the study.

    Results: Only forty (10.4%) out of a total of 386 patients treated in Hospital Pulau Pinang during the study fulfilled the inclusion criteria. There were 28 women (70%) with median age of 59 years old. Thirty-four patients (85%) had papillary thyroid cancer (PTC) and six patients had follicular thyroid cancer. The use of 18F-FDG PET-CT revealed 23 patients (57.5%) with 18F-FDG avid metastases suggesting dedifferentiation of thyroid cancers. Based on this study, the probability of detecting FDG-avid disease is higher (P = 0.03) if 18F-FDG PET-CT was performed when Tg ≥15 ng/mL.

    Conclusion: TENIS syndrome constitutes a significant number of cases in our setting. Our data suggest a cutoff Tg ≥15 ng/mL for performing 18F-FDG PET-CT for these patients would be more beneficial than the currently American Thyroid Association recommended cutoff of 10 ng/mL.

  2. Cardiovascular Protective Effects of Centella asiatica and Its Triterpenes: A Review
    Razali NNM, Ng CT, Fong LY
    Planta Med, 2019 Nov;85(16):1203-1215.
    PMID: 31539918 DOI: 10.1055/a-1008-6138
    Centella asiatica, a triterpene-rich medicinal herb, is traditionally used to treat various types of diseases including neurological, dermatological, and metabolic diseases. A few articles have previously reviewed a broad range of pharmacological activities of C. asiatica, but none of these reviews focuses on the use of C. asiatica in cardiovascular diseases. This review aims to summarize recent findings on protective effects of C. asiatica and its active constituents (asiatic acid, asiaticoside, madecassic acid, and madecassoside) in cardiovascular diseases. In addition, their beneficial effects on conditions associated with cardiovascular diseases were also reviewed. Articles were retrieved from electronic databases such as PubMed and Google Scholar using keywords "Centella asiatica," "asiatic acid," "asiaticoside," "madecassic acid," and "madecassoside." The articles published between 2004 and 2018 that are related to the aforementioned topics were selected. A few clinical studies published beyond this period were also included. The results showed that C. asiatica and its active compounds possess potential therapeutic effects in cardiovascular diseases and cardiovascular disease-related conditions, as evidenced by numerous in silico, in vitro, in vivo, and clinical studies. C. asiatica and its triterpenes have been reported to exhibit cardioprotective, anti-atherosclerotic, antihypertensive, antihyperlipidemic, antidiabetic, antioxidant, and anti-inflammatory activities. In conclusion, more clinical and pharmacokinetic studies are needed to support the use of C. asiatica and its triterpenes as therapeutic agents for cardiovascular diseases. Besides, elucidation of the molecular pathways modulated by C. asiatica and its active constituents will help to understand the mechanisms underlying the cardioprotective action of C. asiatica.
  3. Interferon-gamma (IFN-γ): Reviewing its mechanisms and signaling pathways on the regulation of endothelial barrier function
    Ng CT, Fong LY, Abdullah MNH
    Cytokine, 2023 Jun;166:156208.
    PMID: 37088004 DOI: 10.1016/j.cyto.2023.156208
    Interferon-gamma (IFN-γ) is a pleiotropic cytokine that plays a critical role in mediating an array of immune responses including promotes antiviral activity, facilitates macrophage activation, controls Th1/Th2 balance, and regulates cellular apoptosis and proliferation. A few articles have previously reviewed the effects of IFN-γ in the regulation of barrier permeability, but none of these articles focuses on barrier function of endothelial cells. This review aims to discuss the regulatory mechanisms of IFN-γ on endothelial barrier function and its underlying signaling pathways. Articles were retrieved from electronic databases such as PubMed and Google Scholar using keywords "Interferon-gamma", "endothelial cells", "barrier function", and "signaling pathway". The articles published between 2000 and 2022 that are related to the aforementioned topics were selected. A few journals published beyond this period were also included due to limited information available. The results showed that IFN-γ modulates endothelial barrier function, mainly involves small GTPases, STAT1-dependent pathway, p38 MAPK and nitric oxide. In conclusion, more in depth cellular and molecular studies are needed to elucidate the pathways of IFN-γ in the regulation of endothelial barrier function.
  4. Barrier protective effect of asiatic acid in TNF-α-induced activation of human aortic endothelial cells
    Fong LY, Ng CT, Cheok ZL, Mohd Moklas MA, Hakim MN, Ahmad Z
    Phytomedicine, 2016 Feb 15;23(2):191-9.
    PMID: 26926181 DOI: 10.1016/j.phymed.2015.11.019
    Endothelial cell activation is characterized by increased endothelial permeability and increased expression of cell adhesion molecules (CAMs). This allows monocyte adherence and migration across the endothelium to occur and thereby initiates atherogenesis process. Asiatic acid is a major triterpene isolated from Centella asiatica (L.) Urban and has been shown to possess anti-oxidant, anti-hyperlipidemia and anti-inflammatory activities.
  5. Asiaticoside Inhibits TNF-α-Induced Endothelial Hyperpermeability of Human Aortic Endothelial Cells
    Fong LY, Ng CT, Zakaria ZA, Baharuldin MT, Arifah AK, Hakim MN, et al.
    Phytother Res, 2015 Oct;29(10):1501-8.
    PMID: 26171791 DOI: 10.1002/ptr.5404
    The increase in endothelial permeability often promotes edema formation in various pathological conditions. Tumor necrosis factor-alpha (TNF-α), a pro-atherogenic cytokine, impairs endothelial barrier function and causes endothelial dysfunction in early stage of atherosclerosis. Asiaticoside, one of the triterpenoids derived from Centella asiatica, is known to possess antiinflammatory activity. In order to examine the role of asiaticoside in preserving the endothelial barrier, we assessed its effects on endothelial hyperpermeability and disruption of actin filaments evoked by TNF-α in human aortic endothelial cells (HAEC). TNF-α caused an increase in endothelial permeability to fluorescein isothiocyanate (FITC)-dextran. Asiaticoside pretreatment significantly suppressed TNF-α-induced increased permeability. Asiaticoside also prevented TNF-α-induced actin redistribution by suppressing stress fiber formation. However, the increased F to G actin ratio stimulated by TNF-α was not changed by asiaticoside. Cytochalasin D, an actin depolymerizing agent, was used to correlate the anti-hyperpermeability effect of asiaticoside with actin cytoskeleton. Surprisingly, asiaticoside failed to prevent cytochalasin D-induced increased permeability. These results suggest that asiaticoside protects against the disruption of endothelial barrier and actin rearrangement triggered by TNF-α without a significant change in total actin pool. However, asiaticoside seems to work by other mechanisms to maintain the integrity of endothelial barrier rather than stabilizing the F-actin organization.
  6. Fulltext Malaysian Tualang Honey Inhibits Hydrogen Peroxide-Induced Endothelial Hyperpermeability
    Devasvaran K, Tan JJ, Ng CT, Fong LY, Yong YK
    Oxid Med Cell Longev, 2019;2019:1202676.
    PMID: 31531177 DOI: 10.1155/2019/1202676
    Malaysian Tualang honey (TH) is a known therapeutic honey extracted from the honeycombs of the Tualang tree (Koompassia excelsa) and has been reported for its antioxidant, anti-inflammatory, antiproliferative, and wound healing properties. However, the possible vascular protective effect of TH against oxidative stress remains unclear. In this study, the effects of TH on hydrogen peroxide- (H2O2-) elicited vascular hyperpermeability in human umbilical vein endothelial cells (HUVECs) and Balb/c mice were evaluated. Our data showed that TH concentrations ranging from 0.01% to 1.00% showed no cytotoxic effect to HUVECs. Induction with 0.5 mM H2O2 was found to increase HUVEC permeability, but the effect was significantly reversed attenuated by TH (p < 0.05), of which the permeability with the highest inhibition peaked at 0.1%. In Balb/c mice, TH (0.5 g/kg-1.5 g/kg) significantly (p < 0.05) reduced H2O2 (0.3%)-induced albumin-bound Evans blue leak, in a dose-dependent manner. Immunofluorescence staining confirmed that TH reduced actin stress fiber formation while increasing cortical actin formation and colocalization of caveolin-1 and β-catenin in HUVECs. Signaling studies showed that HUVECs pretreated with TH significantly (p < 0.05) decreased intracellular calcium release, while sustaining the level of cAMP when challenged with H2O2. These results suggested that TH could inhibit H2O2-induced vascular hyperpermeability in vitro and in vivo by suppression of adherence junction protein redistribution via calcium and cAMP, which could have a therapeutic potential for diseases related to the increase of both oxidant and vascular permeability.
  7. Fulltext The minimum amount of fluids needed to achieve the fastest time to reach permissible level for release in well-differentiated thyroid patients undergoing high-dose I-131 therapy
    Cheen Hoe AK, Fong LY, Halim FNA, Fatt QK, Hamzah F
    World J Nucl Med, 2018 7 24;17(3):182-187.
    PMID: 30034283 DOI: 10.4103/wjnm.WJNM_59_17
    Radioiodine (131I) therapy is the mainstay of treatment for patients who had undergone total thyroidectomy for well differentiated thyroid carcinoma. Increased fluid intake has always been encouraged to minimize the risk of non-target organ exposure to I-131radiation. This study aimed to determine the minimum amount of fluids needed for patients to have the fastest time to achieve permissible level for release after high dose I-131therapy.

    METHODOLOGY: All the patients who were treated with high dose I-131from 18th January 2016 till 31st December 2016 in Hospital Pulau Pinang, Malaysia were recruited. The data from 126 patients on thyroxine hormone withdrawal (THW) group and 18 patients on recombinant human thyroid stimulating hormone (rhTSH) group were analysed. There is no change in patient management in terms of preparation, dose or post therapy whole-body scan. Fluid intake of patients were monitored strictly and whole-body retention of I-131are measured using ionizing chamber meter immediately after ingestion of I-131then at 1 hour, 24 hours, 48 hours, 72 hours and 96 hours.

    RESULTS: The median time to achieve permissible release limit (50 μSV/hr at 1 meter) was 21.6 hours and 22.1 hours post-ingestion of I-131in the THW and rhTSH group respectively. The minimum amount of fluid needed to reach permissible release limit in the fastest time was 2,103 ml and 2,148ml for the THW and TSH respectively.

    CONCLUSION: Clinicians would be able to evidently advise their patient on the amount of fluid to consume and utilize their isolation wards faster to treat more patients.

  8. Nitric oxide participates in IFN-gamma-induced HUVECs hyperpermeability
    Ng CT, Fong LY, Low YY, Ban J, Hakim MN, Ahmad Z
    Physiol Res, 2016 12 13;65(6):1053-1058.
    PMID: 27539106
    The endothelial barrier function is tightly controlled by a broad range of signaling cascades including nitric oxide-cyclic guanosine monophosphate (NO-cGMP) pathway. It has been proposed that disturbances in NO and cGMP production could interfere with proper endothelial barrier function. In this study, we assessed the effect of interferon-gamma (IFN-gamma), a pro-inflammatory cytokine, on NO and cGMP levels and examined the mechanisms by which NO and cGMP regulate the IFN-gamma-mediated HUVECs hyperpermeability. The flux of fluorescein isothiocyanate-labeled dextran across cell monolayers was used to study the permeability of endothelial cells. Here, we found that IFN-gamma significantly attenuated basal NO concentration and the increased NO levels supplied by a NO donor, sodium nitroprusside (SNP). Besides, application of IFN-gamma also significantly attenuated both the basal cGMP concentration and the increased cGMP production donated by a cell permeable cGMP analogue, 8-bromo-cyclic GMP (8-Br-cGMP). In addition, exposure of the cell monolayer to IFN-gamma significantly increased HUVECs basal permeability. However, L-NAME pretreatment did not suppress IFN-gamma-induced HUVECs hyperpermeability. L-NAME pretreatment followed by SNP or SNP pretreatment partially reduced IFN-gamma-induced HUVECs hyperpermeability. Pretreatment with a guanylate cyclase inhibitor, 6-anilino-5,8-quinolinedione (LY83583), led to a further increase in IFN-gamma-induced HUVECs hyperpermeability. The findings suggest that the mechanism underlying IFN-gamma-induced increased HUVECs permeability is partly related to the inhibition of NO production.
  9. Interferon-γ induces biphasic changes in caldesmon localization as well as adherens junction organization and expression in HUVECs
    Ng CT, Fong LY, Yong YK, Hakim MN, Ahmad Z
    Cytokine, 2018 11;111:541-550.
    PMID: 29909980 DOI: 10.1016/j.cyto.2018.06.010
    Endothelial barrier dysfunction leads to increased endothelial permeability and is an early step in the development of vascular inflammatory diseases such as atherosclerosis. Interferon-γ (IFN-γ), a proinflammatory cytokine, is known to cause increased endothelial permeability. However, the mechanisms by which IFN-γ disrupts the endothelial barrier have not been clarified. This study aimed to investigate how IFN-γ impairs the endothelial barrier integrity by specifically examining the roles of caldesmon, adherens junctions (AJs) and p38 mitogen-activated protein (MAP) kinase in IFN-γ-induced endothelial barrier dysfunction. IFN-γ exhibited a biphasic effect on caldesmon localization and both the structural organization and protein expression of AJs. In the early phase (4-8 h), IFN-γ induced the formation of peripheral caldesmon bands and discontinuous AJs, while AJ protein expression was unchanged. Interestingly, IFN-γ also stimulated caldesmon phosphorylation, resulting in actin dissociation from caldesmon at 8 h. Conversely, changes seen in the late phase (16-24 h) included cytoplasmic caldesmon dispersal, AJ linearization and junctional area reduction, which were associated with reduced membrane, cytoskeletal and total AJ protein expression. In addition, IFN-γ enhanced myosin binding to caldesmon at 12 h and persisted up to 24 h. Furthermore, inhibition of p38 MAP kinase by SB203580 did not reverse either the early or late phase changes observed. These data suggest that IFN-γ may activate signaling molecules other than p38 MAP kinase. In conclusion, our findings enhance the current understanding of how IFN-γ disrupts endothelial barrier function and reveal potential therapeutic targets, such as caldesmon and AJs, for the treatment of IFN-γ-associated vascular inflammatory diseases.
  10. Interferon-Gamma Increases Endothelial Permeability by Causing Activation of p38 MAP Kinase and Actin Cytoskeleton Alteration
    Ng CT, Fong LY, Sulaiman MR, Moklas MA, Yong YK, Hakim MN, et al.
    J Interferon Cytokine Res, 2015 Jul;35(7):513-22.
    PMID: 25830506 DOI: 10.1089/jir.2014.0188
    Interferon-gamma (IFN-γ) is known to potentiate the progression of inflammatory diseases, such as inflammatory bowel disease and atherosclerosis. IFN-γ has been found to disrupt the barrier integrity of epithelial and endothelial cell both in vivo and in vitro. However, the mechanisms of IFN-γ underlying increased endothelial cell permeability have not been extensively elucidated. We reported that IFN-γ exhibits a biphasic nature in increasing endothelial permeability. The changes observed in the first phase (4-8 h) involve cell retraction and rounding in addition to condensed peripheral F-actin without a significant change in the F-/G-actin ratio. However, cell elongation, stress fiber formation, and an increased F-/G-actin ratio were noticed in the second phase (16-24 h). Consistent with our finding from the permeability assay, IFN-γ induced the formation of intercellular gaps in both phases. A delayed phase of increased permeability was observed at 12 h, which paralleled the onset of cell elongation, stress fiber formation, and increased F-/G-actin ratio. In addition, IFN-γ stimulated p38 mitogen-activated protein (MAP) kinase phosphorylation over a 24 h period. Inhibition of p38 MAP kinase by SB203580 prevented increases in paracellular permeability, actin rearrangement, and increases in the F-/G-actin ratio caused by IFN-γ. Our results suggest that p38 MAP kinase is activated in response to IFN-γ and causes actin rearrangement and altered cell morphology, which in turn mediates endothelial cell hyperpermeability. The F-/G-actin ratio might be involved in the regulation of actin distribution and cell morphology rather than the increased permeability induced by IFN-γ.
  11. Asiatic acid stabilizes cytoskeletal proteins and prevents TNF-α-induced disorganization of cell-cell junctions in human aortic endothelial cells
    Fong LY, Ng CT, Yong YK, Hakim MN, Ahmad Z
    Vascul Pharmacol, 2019 06;117:15-26.
    PMID: 30114509 DOI: 10.1016/j.vph.2018.08.005
    Endothelial hyperpermeability represents an initiating step in early atherosclerosis and it often occurs as a result of endothelial barrier dysfunction. Asiatic acid, a major triterpene isolated from Centella asiatica (L.) Urban, has previously been demonstrated to protect against tumor necrosis factor (TNF)-α-induced endothelial barrier dysfunction. The present study aimed to investigate the mechanisms underlying the barrier protective effect of asiatic acid in human aortic endothelial cells (HAECs). The localization of F-actin, diphosphorylated myosin light chain (diphospho-MLC), adherens junctions (AJs) and tight junctions (TJs) was studied using immunocytochemistry techniques and confocal microscopy. Their total protein expressions were examined using western blot analysis. The endothelial permeability was assessed using In Vitro Vascular Permeability Assay kits. In addition, intracellular redistribution of the junctional proteins was evaluated using subcellular fractionation kits. We show that asiatic acid stabilized F-actin and diphospho-MLC at the cell periphery and prevented their rearrangement stimulated by TNF-α. However, asiatic acid failed to attenuate cytochalasin D-induced increased permeability. Besides, asiatic acid abrogated TNF-α-induced structural reorganization of vascular endothelial (VE)-cadherin and β-catenin by preserving their reticulum structures at cell-cell contact areas. In addition, asiatic acid also inhibited TNF-α-induced redistribution of occludin and zona occludens (ZO)-1 in different subcellular fractions. In conclusion, the barrier-stabilizing effect of asiatic acid might be associated with preservation of AJs and prevention of TJ redistribution caused by TNF-α. This study provides evidence to support the potential use of asiatic acid in the prevention of early atherosclerosis, which is initiated by endothelial barrier dysfunction.
  12. Cryptotanshinone inhibits TNF-α-induced early atherogenic events in vitro
    Ahmad Z, Ng CT, Fong LY, Bakar NA, Hussain NH, Ang KP, et al.
    J Physiol Sci, 2016 May;66(3):213-20.
    PMID: 26732386 DOI: 10.1007/s12576-015-0410-7
    Endothelial dysfunction has been implicated in the pathogenesis of atherosclerosis. Salvia miltiorrhiza (danshen) is a traditional Chinese medicine that has been effectively used to treat cardiovascular disease. Cryptotanshinone (CTS), a major lipophilic compound isolated from S. miltiorrhiza, has been reported to possess cardioprotective effects. However, the anti-atherogenic effects of CTS, particularly on tumor necrosis factor-α (TNF-α)-induced endothelial cell activation, are still unclear. This study aimed to determine the effect of CTS on TNF-α-induced increased endothelial permeability, monocyte adhesion, soluble intercellular adhesion molecule 1 (sICAM-1), soluble vascular cell adhesion molecule 1 (sVCAM-1), monocyte chemoattractant protein 1 (MCP-1) and impaired nitric oxide production in human umbilical vein endothelial cells (HUVECs), all of which are early events occurring in atherogenesis. We showed that CTS significantly suppressed TNF-α-induced increased endothelial permeability, monocyte adhesion, sICAM-1, sVCAM-1 and MCP-1, and restored nitric oxide production. These observations suggest that CTS possesses anti-inflammatory properties and could be a promising treatment for the prevention of cytokine-induced early atherogenesis.
  13. Fulltext Water extract of Clinacanthus nutans leaves exhibits in vitro, ex vivo and in vivo anti-angiogenic activities in endothelial cell via suppression of cell proliferation
    Ng CT, Fong LY, Tan JJ, Rajab NF, Abas F, Shaari K, et al.
    BMC Complement Altern Med, 2018 Jul 06;18(1):210.
    PMID: 29980198 DOI: 10.1186/s12906-018-2270-1
    BACKGROUND: Clinacanthus nutans (Burm. f.) Lindau. has traditionally been using in South East Asia countries to manage cancer. However, scientific evidence is generally lacking to support this traditional claim. This study aims to investigate the in vitro, ex-vivo and in vivo effects of C. nutans extracts on angiogenesis.

    METHODS: C. nutans leaves was extracted with 50-100% ethanol or deionised water at 1% (w/v). Human umbilical veins endothelial cell (HUVEC) proliferation was examined using MTT assay. The in vitro anti-angiogenic effects of C. nutans were assessed using wound scratch, tube formation and transwell migration assays. The VEGF levels secreted by human oral squamous cell carcinoma (HSC-4) cell and HUVEC permeability were also measured. Besides, the rat aortic ring and chick embryo chorioallantoic membrane (CAM) assays, representing ex vivo and in vivo models, respectively, were performed.

    RESULTS: The MTT assay revealed that water extract of C. nutans leaves exhibited the highest activity, compared to the ethanol extracts. Therefore, the water extract was chosen for subsequent experiments. C. nutans leaf extract significantly suppressed endothelial cell proliferation and migration in both absence and presence of VEGF. However, the water extract failed to suppress HUVEC transmigration, differentiation and permeability. C. nutans water extract also did not suppress HSC-4 cell-induced VEGF production. Importantly, C. nutans water extract significantly abolished the sprouting of vessels in aortic rings as well as in chick embryo CAM.

    CONCLUSION: In conclusion, these findings reveal potential anti-angiogenic effects of C. nutans, providing new evidence for its potential application as an anti-angiogenic agent.

  14. Fulltext Cytoprotective Role of Omentin Against Oxidative Stress-Induced Vascular Endothelial Cells Injury
    Binti Kamaruddin NA, Fong LY, Tan JJ, Abdullah MNH, Singh Cheema M, Bin Yakop F, et al.
    Molecules, 2020 May 29;25(11).
    PMID: 32485974 DOI: 10.3390/molecules25112534
    Endothelial cell injury caused by reactive oxygen species (ROS) plays a critical role in the pathogenesis of cardiovascular diseases. Omentin, an adipocytokine that is abundantly expressed in visceral fat tissue, has been reported to possess anti-inflammatory and antidiabetic properties. However, endothelial protective effects of omentin against oxidative stress remain unclear. This study aimed to evaluate the protective effect of omentin against hydrogen peroxide (H2O2)-induced cell injury in human umbilical vein endothelial cells (HUVECs). Cytotoxicity and cytoprotective effects of omentin were evaluated using 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The apoptotic activity of HUVECs was detected using Annexin-V/PI and Hoechst 33258 staining methods. Antioxidant activity of omentin was evaluated by measuring both reactive oxygen species (ROS) levels and glutathione peroxidase (GPx) activity. No cytotoxicity effect was observed in HUVECs treated with omentin alone at concentrations of 150 to 450 ng/ml. MTT assay showed that omentin significantly prevented the cell death induced by H2O2 (p < 0.001). Hoechst staining and flow cytometry also revealed that omentin markedly prevented H2O2-induced apoptosis. Moreover, omentin not only significantly inhibited ROS production (p < 0.01) but also significantly (p < 0.01) increased GPx activity in HUVECs. In conclusion, our data suggest that omentin may protect HUVECs from injury induced by H2O2.
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