Displaying publications 1 - 20 of 32 in total

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  1. Fulltext Osteoarthritis and falls in the older person
    Ng CT, Tan MP
    Age Ageing, 2013 Sep;42(5):561-6.
    PMID: 23864423 DOI: 10.1093/ageing/aft070
    Osteoarthritis and falls are common conditions affecting older individuals which are associated with disability and escalating health expenditure. It has been widely assumed that osteoarthritis is an established risk factor for falls in older people. The relationship between osteoarthritis and falls has, quite surprisingly, not been adequately elucidated, and published reports have been conflicting. Our review of the existing literature has found limited evidence supporting the current assumption that the presence of osteoarthritis is associated with increased risk of falls with suggestions that osteoarthritis may actually be protective against falls related fractures. In addition, joint arthroplasty appears to increase the risk of falls in individuals with osteoarthritis.
  2. Fulltext Influence of hip and knee osteoarthritis on dynamic postural control parameters among older fallers
    Mat S, Ng CT, Tan MP
    J Rehabil Med, 2017 Mar 06;49(3):258-263.
    PMID: 28218341 DOI: 10.2340/16501977-2202
    OBJECTIVE: To compare the relationship between postural control and knee and hip osteoarthritis in older adults with and without a history of falls.
    METHODS: Fallers were those with ≥ 2 falls or 1 injurious fall over 12 months. Non-fallers were volunteers with no falls in the past year. Radiological evidence of osteoarthritis with no reported symptoms was considered "asymptomatic osteoarthritis", while "symptomatic osteoarthritis" was defined as radiographic osteoarthritis with pain or stiffness. Dynamic postural control was quantified with the limits of stability test measured on a balance platform (Neurocom® Balancemaster, California, USA). Parameters assessed were end-point excursion, maximal excursion, and directional control.
    RESULTS: A total of 102 older individuals, mean age 73 years (standard deviation 5.7) years were included. The association between falls and poor performance in maximal excursion and directional control was confounded by age and comorbidities. In the same linear equation model with falls, symptomatic osteoarthritis remained independently associated with poor end-point excursion (β-coefficient (95% confidence interval) -6.80 (-12.14 to -1.42)).
    CONCLUSION: Poor performance in dynamic postural control (maximal excursion and directional control) among fallers was not accounted for by hip/knee osteoarthritis, but was confounded by old age and comorbidities. Loss of postural control due to hip/knee osteoarthritis is not a risk factor for falls among community-dwelling older adults.
    Study site: Departments of Emergency Medicine, Primary Care and Geriatric Medicine, in a teaching hospital in Kuala Lumpur, Malaysia
  3. Monophasic synovial sarcoma of the pyriform fossa
    Ng CT, Wong EHC, Prepageran N
    BMJ Case Rep, 2020 Nov 30;13(11).
    PMID: 33257363 DOI: 10.1136/bcr-2020-236204
    Head and neck synovial sarcoma is rare. We report the case of a 71-year-old man who presented with progressive dysphagia, odynophagia, shortness of breath on exertion and hoarseness of voice. Nasendoscopy revealed a smooth, non-fungating, non-ulcerative mass arising from the left lateral pharyngeal wall. CT showed a well-defined, heterogenous enhancing lesion arising from the left pyriform fossa. Initial biopsy taken was inconclusive and patient underwent a transcervical complete excision of the tumour, where histopathological analysis confirmed the diagnosis of monophasic synovial sarcoma of the left pyriform fossa. This patient also received adjuvant radiotherapy postoperatively and remained disease free 1 year after completion of treatment.
  4. Fulltext Comparison of invasion by human microvascular endothelial cell lines in response to vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) in a threedimensional (3D) cell culture system
    Ng CT, Yip WK, Mohtarrudin N, Seow HF
    Malays J Pathol, 2015 Dec;37(3):219-25.
    PMID: 26712666 MyJurnal
    Immortalized human endothelial cells are widely used as in vitro models for debilitating conditions such as cancer, cardiovascular and ocular diseases. Human microvascular endothelial cell (HMEC-1) is immortalized via stable transfection with a gene encoding SV40 large antigen whilst telomerase-immortalized human microvascular endothelial (TIME) cells is immortalized by engineering the human telomerase catalytic protein (hTERT) into primary microvascular endothelial cells. Here, we established a three-dimensional (3D) spheroid invasion assay with HMEC-1 and TIME and compared the difference in their ability to invade through the collagen matrix in response to exogenous growth factors, namely vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF).
  5. Fulltext Physical therapies for improving balance and reducing falls risk in osteoarthritis of the knee: a systematic review
    Mat S, Tan MP, Kamaruzzaman SB, Ng CT
    Age Ageing, 2015 Jan;44(1):16-24.
    PMID: 25149678 DOI: 10.1093/ageing/afu112
    INTRODUCTION: osteoarthritis (OA) of knee has been reported as a risk factor for falls and reduced balance in the elderly. This systematic review evaluated the effectiveness of physical therapies in improving balance and reducing falls risk among patients with knee OA.
    METHODS: a computerised search was performed to identify relevant studies up to November 2013. Two investigators identified eligible studies and extracted data independently. The quality of the included studies was assessed by the PeDro score.
    RESULTS: a total of 15 randomised controlled trials involving 1482 patients were identified. The mean PeDro score was 7. The pooled standardised mean difference in balance outcome for strength training = 0.3346 (95% CI: 0.3207-0.60, P = 0.01 < 0.00001, P for heterogeneity = 0.85, I(2) = 0%). Tai Chi = 0.7597 (95% CI: 0.5130-1.2043, P<=0.0014, P for heterogeneity = 0.26, I(2) = 0%) and aerobic exercises = 0.6880 (95% CI: 0.5704-1.302, P < 0.00001, P for heterogeneity = 0.71, I(2) = 0%). While pooled results for falls risk outcomes in, strength training, Tai chi and aerobics also showed a significant reduction in reduced risk of falls significantly with pooled result 0.55 (95% CI: 0.41-0.68, P < 0.00001, P for heterogeneity = 0.39, I(2) = 6%).
    CONCLUSION: strength training, Tai Chi and aerobics exercises improved balance and falls risk in older individuals with knee OA, while water-based exercises and light treatment did not significantly improve balance outcomes. Strength training, Tai Chi and aerobics exercises can therefore be recommended as falls prevention strategies for individuals with OA. However, a large randomised controlled study using actual falls outcomes is recommended to determine the appropriate dosage and to measure the potential benefits in falls reduction.
    KEYWORDS: Tai Chi; elderly; exercises; falls; older people; osteoarthritis
  6. Myocardial infarction with normal coronaries: an unexpected finding in a 13-year-old girl with systemic lupus erythematosus
    Jasmin R, Ng CT, Sockalingam S, Yahya F, Cheah TE, Sadiq MA
    Lupus, 2013 Dec;22(14):1518-22.
    PMID: 24004952 DOI: 10.1177/0961203313503913
    We report a 13-year-old girl diagnosed with systemic lupus erythematosus (SLE) who presented with left-sided chest pain, with ECG changes and elevation troponins that were suggestive of an acute inferior wall myocardial infarction (MI). Her multi-slice computed tomography coronary angiogram and standard angiogram were normal. The cardiac magnetic resonance imaging revealed an area of infarcted myocardium that was in the right coronary artery territory. We believe her MI was most likely secondary to coronary vasospasm. MI is rare and coronary vasospasm is an uncommon cause of MI in children and adolescents with SLE.
  7. Open label randomized controlled trial assessing the efficacy of mycophenolate sodium against other conventional immunosuppressive agents in active systemic lupus erythematosus patients without renal involvement
    Yahya F, Jasmin R, Ng CT, Cheah TE, Sockalingam S
    Int J Rheum Dis, 2013 Dec;16(6):724-30.
    PMID: 24119227 DOI: 10.1111/1756-185X.12179
    Mycophenolate is an immunosuppressive agent which has been used in systemic lupus erythematosus (SLE) patients who have failed conventional therapy. However, the use of mycophenolate sodium in extra-renal SLE involvement has yet to be established. This study aimed to assess the efficacy of mycophenolate sodium in extra-renal SLE.
  8. Painless ascites and elevated CA125: initial presentation of lupus-associated protein-losing enteropathy
    Ong CS, Cheah TE, Jasmin R, Yahya F, Sockalingam S, Ng CT
    Lupus, 2013 Oct;22(11):1174-7.
    PMID: 23886639 DOI: 10.1177/0961203313498792
    Lupus associated protein loosing enteropathy (LUPLE) is a rare gastrointestinal manifestation of SLE. We presented a case of painless ascites from serve hypoalbuminaemia secondary to LUPLE. The patient responded to a course of intravenous cyclophosphamide. The remission was maintained by azathioprine and low dose prednisolone.
  9. Chronic intestinal pseudo-obstruction: a rare first manifestation of systemic lupus erythematosus
    Khairullah S, Jasmin R, Yahya F, Cheah TE, Ng CT, Sockalingam S
    Lupus, 2013 Aug;22(9):957-60.
    PMID: 23761180 DOI: 10.1177/0961203313492873
    Chronic intestinal pseudo-obstruction (CIPO) is a rare clinical syndrome of ineffective intestinal motility characterised by clinical and radiological evidence of intestinal obstruction with no identifiable mechanical lesion. CIPO can either be idiopathic or secondary to a systemic disease, like systemic lupus erythematosus (SLE). Fewer than 30 cases of CIPO secondary to SLE have been reported so far. Here we describe a case of SLE with the initial presentation of CIPO. In SLE-related CIPO, treatment includes a combination of high-dose intravenous corticosteroids, immunosuppressants and supportive care. With awareness of this condition, unnecessary surgical intervention and repeated invasive procedures could be avoided. Early initiation of treatment would avoid complications and bring about resolution of symptoms.
  10. 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.
  11. High-resolution oesophageal manometry and 24-hour impedance-pH study in systemic sclerosis patients: association with clinical features, symptoms and severity
    Raja J, Ng CT, Sujau I, Chin KF, Sockalingam S
    Clin Exp Rheumatol, 2016 Sep-Oct;34 Suppl 100(5):115-121.
    PMID: 26843456
    OBJECTIVES: To evaluate the associations between objectively measured gastroesophageal involvement using high-resolution manometry and 24- hour impedance-pH study, and clinical presentations in systemic sclerosis (SSc) patients.
    METHODS: This cross-sectional study was conducted in University of Malaya Medical Centre (UMMC) with 31 consecutive SSc patients recruited into this study. Clinical symptoms of gastroesophageal involvement, high-resolution impedance-manometry and 24-hour impedance-pH monitoring were assessed. Their associations with serological features and other organ involvement were evaluated.
    RESULTS: Twenty-five (80.6%) patients had gastroesophageal reflux disease (GORD) symptoms, mainly heartburn (45.1%), regurgitation (32.2%) and dysphagia (29%). Using manometry, oesophageal dysmotility was detected in 24 (88.9%) patients, while hypotensive lower oesophageal sphincter (LOS) was observed in 17 (63%) patients. 21 (84%) patients had GORD based on pH study. Hypotensive LOS was significantly associated with presence of digital ulcers. The main gastroesophageal symptoms were absent in majority of the SSc patients including in those with severe gastroesophageal manifestations demonstrating failed peristalsis >75%, hypotensive LOS, Demeester score >200 and acid reflux >200 per day. Demeester score >200 is associated with severity of GORD symptoms. Demeester score >200 was also associated with restrictive lung pattern (p=0.001). Significant association between GORD severity (daily number of acid reflux episodes >200) and pulmonary fibrosis was seen (p=0.030).
    CONCLUSIONS: The presence and severity of gastroesophageal symptoms may not accurately reflect the seriousness of oesophageal involvement. GORD severity is associated with presence of restrictive lung pattern and pulmonary fibrosis. Oesophageal manometry and 24-hour pH study should be considered more frequently in the assessment of SSc patients.
  12. 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.
  13. Increased tube formation and up-regulation of FGFR3 mRNA expression in microvascular endothelial cell by exosomes derived from SW480-7
    Ng CT, Yip WK, Mohtarrudin N, Jabar MF, Seow HF
    Malays J Pathol, 2023 Aug;45(2):195-204.
    PMID: 37658529
    INTRODUCTION: Extracellular vesicles (exosome-like vesicles) are small membrane vesicles ranging from 20-200nm in size that are released by various cells into the extracellular space. These extracellular vesicles play a major role in cell-to-cell communication and contain materials, such as proteins, mRNAs, microRNAs (miRNAs) and long non-coding RNAs (lncRNAs). The effect of exosomes derived from an invasive colon cancer cell line on angiogenesis is unclear. Hence, the aim of this study is to investigate the effect of exosomes derived from an invasive colon cancer cell line on angiogenesis of endothelial cells.

    MATERIALS AND METHODS: In the present study, the exosomes from the cell culture supernatants of an invasive colon cancer cell line SW480-7 were characterised. The effect on tube formation and expression of angiogenic genes in a microvascular endothelial cell, telomerase-immortalised microvascular endothelial cell (TIME) was examined after co-cultured with exosomes secreted from SW480-7.

    RESULTS: Zetasizer result showed average diameter of exosomes derived from SW480-7 was 246.2 nm and morphological analysis showed the size of majority of exosomes were less than 200 nm. Results showed that exosomes derived from SW480-7 increased tube formation and up-regulated FGFR3 mRNA expression in TIME.

    CONCLUSION: Our findings suggest that exosomes derived from SW480-7 increased tube formation and up-regulated expression of FGFR3 mRNA in TIME.

  14. Clinical and autoantibody profile in systemic sclerosis: baseline characteristics from a West Malaysian cohort
    Sujau I, Ng CT, Sthaneshwar P, Sockalingam S, Cheah TE, Yahya F, et al.
    Int J Rheum Dis, 2015 May;18(4):459-65.
    PMID: 24618222 DOI: 10.1111/1756-185X.12322
    AIM: To evaluate the clinical and antibody profile of systemic sclerosis (SSc) in a Malaysian cohort.
    METHODS: Consecutive patients with SSc in University Malaya Medical Centre from March to November 2012 were included in this study. In addition to clinical characterization, all subjects underwent autoantibody testing using Euroline immunoblot assay. The association between clinical features and autoantibody profile was evaluated.
    RESULTS: There were 31, predominantly Chinese (45.2%), subjects. Limited cutaneous disease was the most common subtype (71%). Raynaud's phenomenon was the most commonly observed feature (83.9%). Nine (29%) had esophageal dysmotility symptoms and 23 (74.2%), including all patients with diffuse SSc, had symptoms of gastro-esophageal reflux disease (GERD). Restrictive pattern on pulmonary function test and evidence of lung fibrosis were seen in more than 70% of patients. Echocardiographic evidence of pulmonary arterial hypertension was seen in 58.1%. Telangiectasia, calcinosis, digital ulcers, digital pulp loss or pitting were seen more commonly in the diffuse subtype. The two most prevalent autoantibodies were anti-Scl-70 and anti-Ro-52. The presence of anti-Scl-70 was significantly associated with restrictive lung disease (P = 0.05). Anti-Ro-52 was associated with control subjects with other autoimmune diseases (P = 0.043). The presence of anti-PM-Scl-75 was associated with overlap syndrome (P = 0.032). Patients with anticentromere antibodies were more likely to have vasculitic rash (P = 0.012).
    CONCLUSION: In Malaysia, SSc most commonly affects the Chinese. Limited cutaneous is more common than diffuse subtype. Features of CREST (calcinosis, Reynaud disease, esophageal dysmotility, sclerodactyly, telangiectasia) are more commonly observed in the diffuse cutaneous subgroup. Anti-Scl-70 and anti-Ro-52 antibodies are promising biomarkers for pulmonary involvement in SSc.
    KEYWORDS: Malaysia; autoantibodies; clinical profile; systemic sclerosis
  15. 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.
  16. 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.
  17. 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.
  18. 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.
  19. 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.
  20. 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.
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