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Fulltext The in vitro and in vivo anti-cancer activities of a standardized quassinoids composition from Eurycoma longifolia on LNCaP human prostate cancer cells

Tong KL, Chan KL, AbuBakar S, Low BS, Ma HQ, Wong PF

PLoS One, 2015;10(3):e0121752.
PMID: 25826409 DOI: 10.1371/journal.pone.0121752

Quassinoids are a group of diterpenoids found in plants from the Simaroubaceae family. They are also the major bioactive compounds found in Eurycoma longifolia which is commonly used as traditional medicine in South East Asia to treat various ailments including sexual dysfunction and infertility. These uses are attributed to its ability to improve testosterone level in men. Chronic consumption of E. longifolia extracts has been reported to increase testosterone level in men and animal model but its effect on prostate growth remains unknown. Therefore, the present study investigates the effects of a standardized total quassinoids composition (SQ40) containing 40% of the total quassinoids found in E. longifolia on LNCaP human prostate cancer cell line. SQ40 inhibited LNCaP cell growth at IC50 value of 5.97 μg/mL while the IC50 on RWPE-1 human prostate normal cells was 59.26 μg/mL. SQ40 also inhibited 5α-dihydrotestosterone-stimulated growth in LNCaP cells dose-dependently. The inhibitory effect of SQ40 in anchorage-independent growth of LNCaP cells was also demonstrated using soft agar assay. SQ40 suppressed LNCaP cell growth via G0/G1 phase arrest which was accompanied by the down-regulation of CDK4, CDK2, Cyclin D1 and Cyclin D3 and up-regulation of p21Waf1/Cip1 protein levels. SQ40 at higher concentrations or longer treatment duration can cause G2M growth arrest leading to apoptotic cell death as demonstrated by the detection of poly(ADP-ribose) polymerase cleavage in LNCaP cells. Moreover, SQ40 also inhibited androgen receptor translocation to nucleus which is important for the transactivation of its target gene, prostate-specific antigen (PSA) and resulted in a significant reduction of PSA secretion after the treatment. In addition, intraperitoneal injection of 5 and 10 mg/kg of SQ40 also significantly suppressed the LNCaP tumor growth on mouse xenograft model. Results from the present study suggest that the standardized total quassinoids composition from E. longifolia promotes anti-prostate cancer activities in LNCaP human prostate cancer cells.
Fulltext Senescent HUVECs-secreted exosomes trigger endothelial barrier dysfunction in young endothelial cells

Wong PF, Tong KL, Jamal J, Khor ES, Lai SL, Mustafa MR

EXCLI J, 2019;18:764-776.
PMID: 31611757 DOI: 10.17179/excli2019-1505

Accumulation of senescent endothelial cells can cause endothelium dysfunction which eventually leads to age-related vascular disorders. The senescent-associated secretory phenotype (SASP) cells secrete a plethora of soluble factors that negatively influence the surrounding tissue microenvironment. The present study sought to investigate the effects of exosomes, which are nano-sized extracellular vesicles known for intercellular communications secreted by SASP cells on young endothelial cells. Exosomes were isolated from the condition media of senescent human umbilical vein endothelial cells (HUVECs) and then confirmed by the detection of exosome specific CD63 and CD9 expressions, electron microscopy and acetylcholinesterase assay. The purified exosomes were used to treat young HUVECs. Exposure to exosomes repressed the expression of adherens junction proteins including vascular endothelial (VE)-cadherin and beta-catenin, decreased cell growth kinetics and impaired endothelial migration potential of young endothelial cells. These findings suggest that senescent HUVECs-secreted exosomes could disrupt barrier integrity that underpins endothelial barrier dysfunction in healthy young endothelial cells.
CircRNA-miRNA interactions in atherogenesis

Tong KL, Tan KE, Lim YY, Tien XY, Wong PF

Mol Cell Biochem, 2022 Dec;477(12):2703-2733.
PMID: 35604519 DOI: 10.1007/s11010-022-04455-8

Atherosclerosis is the major cause of coronary artery disease (CAD) which includes unstable angina, myocardial infarction, and heart failure. The onset of atherogenesis, a process of atherosclerotic lesion formation in the intima of arteries, is driven by lipid accumulation, a vicious cycle of reactive oxygen species (ROS)-induced oxidative stress and inflammatory reactions leading to endothelial cell (EC) dysfunction, vascular smooth muscle cell (VSMC) activation, and foam cell formation which further fuel plaque formation and destabilization. In recent years, there is a surge in the number of publications reporting the involvement of circular RNAs (circRNAs) in the pathogenesis of cardiovascular diseases, cancers, and metabolic syndromes. These studies have advanced our understanding on the biological functions of circRNAs. One of the most common mechanism of action of circRNAs reported is the sponging of microRNAs (miRNAs) by binding to the miRNAs response element (MRE), thereby indirectly increases the transcription of their target messenger RNAs (mRNAs). Individual networks of circRNA-miRNA-mRNA associated with atherogenesis have been extensively reported, however, there is a need to connect these findings for a complete overview. This review aims to provide an update on atherogenesis-related circRNAs and analyze the circRNA-miRNA-mRNA interactions in atherogenesis. The atherogenic mechanisms and clinical relevance of each atherogenesis-related circRNA were systematically discussed for better understanding of the knowledge gap in this area.
Fulltext Circulating MicroRNAs in Young Patients with Acute Coronary Syndrome

Tong KL, Mahmood Zuhdi AS, Wan Ahmad WA, Vanhoutte PM, de Magalhaes JP, Mustafa MR, et al.

Int J Mol Sci, 2018 May 15;19(5).
PMID: 29762500 DOI: 10.3390/ijms19051467

Circulating microRNAs (miRNAs) hold great potential as novel diagnostic markers for acute coronary syndrome (ACS). This study sought to identify plasma miRNAs that are differentially expressed in young ACS patients (mean age of 38.5 ± 4.3 years) and evaluate their diagnostic potentials. Small RNA sequencing (sRNA-seq) was used to profile plasma miRNAs. Discriminatory power of the miRNAs was determined using receiver operating characteristic (ROC) analysis. Thirteen up-regulated and 16 down-regulated miRNAs were identified in young ACS patients. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) validation showed miR-183-5p was significantly up-regulated (8-fold) in ACS patients with non-ST-segment elevated myocardial infarction (NSTEMI) whereas miR-134-5p, miR-15a-5p, and let-7i-5p were significantly down-regulated (5-fold, 7-fold and 3.5-fold, respectively) in patients with ST-segment elevated myocardial infarction (STEMI), compared to the healthy controls. MiR-183-5p had a high discriminatory power to differentiate NSTEMI patients from healthy controls (area under the curve (AUC) of ROC = 0.917). The discriminatory power for STEMI patients was highest with let-7i-5p (AUC = 0.833) followed by miR-134-5p and miR-15a-5p and this further improved (AUC = 0.935) with the three miRNAs combination. Plasma miR-183-5p, miR-134-5p, miR-15a-5p and let-7i-5p are deregulated in STEMI and NSTEMI and could be potentially used to discriminate the two ACS forms.
Deregulation of hsa-miR-20b expression in TNF-α-induced premature senescence of human pulmonary microvascular endothelial cells

Wong PF, Jamal J, Tong KL, Khor ES, Yeap CE, Jong HL, et al.

Microvasc Res, 2017 11;114:26-33.
PMID: 28595801 DOI: 10.1016/j.mvr.2017.06.002

miRNAs are important regulators of cellular senescence yet the extent of their involvement remains to be investigated. We sought to identify miRNAs that are involved in cytokine-induced premature senescence (CIPS) in endothelial cells. CIPS was established in young human pulmonary microvascular endothelial cells (HMVEC-Ls) following treatment with a sublethal dose (20ng/ml) of tumor necrosis factor alpha (TNF-α) for 15days. In parallel, HMVEC-Ls were grown and routinely passaged until the onset of replicative senescence (RS). Differential expression analysis following miRNA microarray profiling revealed an overlapped of eight deregulated miRNAs in both the miRNA profiles of RS and TNF-α-induced premature senescence cells. Amongst the deregulated miRNAs were members of the miR 17-92 cluster which are known regulators of angiogenesis. The role of hsa-miR-20b in TNF-α-induced premature senescence, a paralog member of the miR 17-92 cluster, was further investigated. Biotin-labeled hsa-miR-20b captured the enriched transcripts of retinoblastoma-like 1 (RBL1), indicating that RBL1 is a target of hsa-miR-20b. Knockdown of hsa-miR-20b attenuated premature senescence in the TNF-α-treated HMVEC-Ls as evidenced by increased cell proliferation, increased RBL1 mRNA expression level but decreased protein expression of p16INK4a, a cellular senescence marker. These findings provide an early insight into the role of hsa-miR-20b in endothelial senescence.
Fulltext Cholesterol goal achievement and lipid-lowering therapy in patients with stable or acute coronary heart disease in Singapore: results from the Dyslipidemia International Study II

Poh KK, Chin CT, Tong KL, Tan JKB, Lim JS, Yu W, et al.

Singapore Med J, 2019 Sep;60(9):454-462.
PMID: 30773600 DOI: 10.11622/smedj.2019021

INTRODUCTION: Dyslipidaemia is a major risk factor for coronary heart disease (CHD). There is a lack of data on the extent of lipid abnormalities and lipid-lowering therapy (LLT) in Singapore.
METHODS: The Dyslipidemia International Study (DYSIS) II was a multinational observational study of patients with stable CHD and hospitalised patients with an acute coronary syndrome (ACS). A full lipid profile and use of LLT were documented at baseline, and for the ACS cohort, at four months post-hospitalisation.
RESULTS: 325 patients were recruited from four sites in Singapore; 199 had stable CHD and 126 were hospitalised with an ACS. At baseline, 96.5% of the CHD cohort and 66.4% of the ACS cohort were being treated with LLT. In both cohorts, low-density lipoprotein cholesterol (LDL-C) levels were lower for the treated than the non-treated patients; accordingly, a higher proportion of patients met the LDL-C goal of < 70 mg/dL (CHD: 28.1% vs. 0%, p = 0.10; ACS: 20.2% vs. 0%, p < 0.01). By the four-month follow-up, a higher proportion of the ACS patients that were originally not treated with LLT had met the LDL-C goal (from 0% to 54.5%), correlating with the increased use of medication. However, there was negligible improvement in the patients who were treated prior to the ACS.
CONCLUSION: Dyslipidaemia is a significant concern in Singapore, with few patients with stable or acute CHD meeting the recommended European Society of Cardiology/European Atherosclerosis Society goal. LLT was widely used but not optimised, indicating considerable scope for improved management of these very-high-risk patients.
Differences in late cardiovascular mortality following acute myocardial infarction in three major Asian ethnic groups

de Carvalho LP, Gao F, Chen Q, Hartman M, Sim LL, Koh TH, et al.

Eur Heart J Acute Cardiovasc Care, 2014 Dec;3(4):354-62.
PMID: 24598820 DOI: 10.1177/2048872614527007

the purpose of this study was to investigate differences in long-term mortality following acute myocardial infarction (AMI) in patients from three major ethnicities of Asia.
Influence of Ethnicity, Age, and Time on Sex Disparities in Long-Term Cause-Specific Mortality After Acute Myocardial Infarction

Gao F, Lam CS, Yeo KK, Machin D, de Carvalho LP, Sim LL, et al.

J Am Heart Assoc, 2016 10 06;5(10).
PMID: 27792637

BACKGROUND: We examined the influence of sex, ethnicity, and time on competing cardiovascular and noncardiovascular causes of death following acute myocardial infarction in a multiethnic Asian cohort.
METHODS AND RESULTS: For 12 years, we followed a prospective nationwide cohort of 15 151 patients (aged 22-101 years, median age 63 years; 72.3% male; 66.7% Chinese, 19.8% Malay, 13.5% Indian) who were hospitalized for acute myocardial infarction between 2000 and 2005. There were 6463 deaths (4534 cardiovascular, 1929 noncardiovascular). Compared with men, women had a higher risk of cardiovascular death (age-adjusted hazard ratio [HR] 1.3, 95% CI 1.2-1.4) but a similar risk of noncardiovascular death (HR 0.9, 95% CI 0.8-1.0). Sex differences in cardiovascular death varied by ethnicity, age, and time. Compared with Chinese women, Malay women had the greatest increased hazard of cardiovascular death (HR 1.4, 95% CI 1.2-1.6) and a marked imbalance in death due to heart failure or cardiomyopathy (HR 3.4 [95% CI 1.9-6.0] versus HR 1.5 [95% CI 0.6-3.6] for Indian women). Compared with same-age Malay men, Malay women aged 22 to 49 years had a 2.5-fold (95% CI 1.6-3.8) increased hazard of cardiovascular death. Sex disparities in cardiovascular death tapered over time, least among Chinese patients and most among Indian patients; the HR comparing cardiovascular death of Indian women and men decreased from 1.9 (95% CI 1.5-2.4) at 30 days to 0.9 (95% CI 0.5-1.6) at 10 years.
CONCLUSION: Age, ethnicity, and time strongly influence the association between sex and specific cardiovascular causes of mortality, suggesting that health care policy to reduce sex disparities in acute myocardial infarction outcomes must consider the complex interplay of these 3 major modifying factors.
Increasing home-based dialysis therapies to tackle dialysis burden around the world: A position statement on dialysis economics from the 2nd Congress of the International Society for Hemodialysis

Li PK, Cheung WL, Lui SL, Blagg C, Cass A, Hooi LS, et al.

Hemodial Int, 2011 Jan;15(1):10-4.
PMID: 21231996 DOI: 10.1111/j.1542-4758.2010.00512.x
The effects of ethnicity on disease patterns in 472 Orientals with systemic lupus erythematosus

Thumboo J, Fong KY, Chng HH, Koh ET, Chia HP, Leong KH, et al.

J Rheumatol, 1998 Jul;25(7):1299-304.
PMID: 9676760

OBJECTIVE: To determine the effects of ethnicity on disease manifestations in Oriental patients with systemic lupus erythematosus (SLE) and to describe the risk of developing renal or central nervous system (CNS) involvement with time.
METHODS: A retrospective study of 472 patients with SLE seen at the only Rheumatology Unit in Singapore. The effect of ethnicity on selected disease manifestations at diagnosis was assessed after adjusting for demographic variables using multiple logistic regression. The probability of developing selected disease manifestations with time was determined using the Kaplan-Meier product limit method.
RESULTS: At diagnosis, Malays had a higher risk of renal or CNS involvement than Chinese (OR 2.26, 95% CI 1.21 to 4.21, and OR 3.07, 95% CI 1.01 to 9.34, respectively), and Indians a lower risk of malar rash and a higher risk of oral ulcers than Chinese (OR 0.30, 95% CI 0.13 to 0.68, and OR 2.90, 95% CI 1.45 to 7.34, respectively). The prevalence of renal or CNS involvement in the entire cohort increased with time, reaching 75.6% (95% CI 66.1% to 85.0%) and 16.7% (95% CI 11.7% to 21.6%), respectively, after 18 years of disease.
CONCLUSION: Ethnicity influenced disease manifestations at diagnosis in this cohort of Oriental patients with SLE. Renal or CNS involvement developed in previously unaffected patients up to 18 years after diagnosis, highlighting the need for continued vigilance in patients with lupus.