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Fulltext More than a drug target: Purinergic signalling as a source for diagnostic tools in epilepsy

Wong ZW, Engel T

Neuropharmacology, 2023 Jan 01;222:109303.
PMID: 36309046 DOI: 10.1016/j.neuropharm.2022.109303

Epilepsy is one of the most common and disabling chronic neurological diseases affecting people of all ages. Major challenges of epilepsy management include the persistently high percentage of drug-refractoriness among patients, the absence of disease-modifying treatments, and its diagnosis and prognosis. To date, long-term video-electroencephalogram (EEG) recordings remain the gold standard for an epilepsy diagnosis. However, this is very costly, has low throughput, and in some instances has very limited availability. Therefore, much effort is put into the search for non-invasive diagnostic tests. Purinergic signalling, via extracellularly released adenosine triphosphate (ATP), is gaining increasing traction as a therapeutic strategy for epilepsy treatment which is supported by evidence from both experimental models and patients. This includes in particular the ionotropic P2X7 receptor. Besides that, other components from the ATPergic signalling cascade such as the metabotropic P2Y receptors (e.g., P2Y1 receptor) and ATP-release channels (e.g., pannexin-1), have also been shown to contribute to seizures and epilepsy. In addition to the therapeutic potential of purinergic signalling, emerging evidence has also shown its potential as a diagnostic tool. Following seizures and epilepsy, the concentration of purines in the blood and the expression of different compounds of the purinergic signalling cascade are significantly altered. Herein, this review will provide a detailed discussion of recent findings on the diagnostic potential of purinergic signalling for epilepsy management and the prospect of translating it for clinical application. This article is part of the Special Issue on 'Purinergic Signaling: 50 years'.
An enzyme-free turn-on fluorescent strategy for nucleic acid detection based on hybridization chain reaction and transferable silver nanoclusters

Wong ZW, New SY

Mikrochim Acta, 2022 Dec 08;190(1):16.
PMID: 36480078 DOI: 10.1007/s00604-022-05591-0

A fluorescence biosensor has been developed based on hybridisation chain reaction (HCR) amplification coupled with silver nanoclusters (AgNCs) for nucleic acid detection. The fluorescence was activated via end-to-end transfer of dark AgNCs caged within a DNA template to another DNA sequence that could enhance their red fluorescence emission at 611 nm. Such cluster-transfer approach allows us to introduce fluorogenic AgNCs as external signal transducers, thereby enabling HCR to perform in a predictable manner. The resulted HCR-AgNC biosensor was able to detect target DNA with a detection limit of 3.35 fM, and distinguish the DNA target from single-base mismatch sequences. Moreover, the bright red fluorescence emission was detectable with the naked eye, with concentration of target DNA down to 1 pM. The biosensor also performed well in human serum samples with good recovery. Overall, our cluster-transfer approach provides a good alternative to construct HCR-AgNC assay with less risk of circuit leakage and produce AgNCs in a controllable manner.
Ratiometric Detection of microRNA Using Hybridization Chain Reaction and Fluorogenic Silver Nanoclusters

Wong ZW, Ng JF, New SY

Chem Asian J, 2021 Dec 13;16(24):4081-4086.
PMID: 34668337 DOI: 10.1002/asia.202101145

miRNA (miR)-155 is a potential biomarker for breast cancers. We aimed at developing a nanosensor for miR-155 detection by integrating hybridization chain reaction (HCR) and silver nanoclusters (AgNCs). HCR serves as an enzyme-free and isothermal amplification method, whereas AgNCs provide a built-in fluorogenic detection probe that could simplify the downstream analysis. The two components were integrated by adding a nucleation sequence of AgNCs to the hairpin of HCR. The working principle was based on the influence of microenvironment towards the hosted AgNCs, whereby unfolding of hairpin upon HCR has manipulated the distance between the hosted AgNCs and cytosine-rich toehold region of hairpin. As such, the dominant emission of AgNCs changed from red to yellow in the absence and presence of miR-155, enabling a ratiometric measurement of miR with high sensitivity. The limit of detection (LOD) of our HCR-AgNCs nanosensor is 1.13 fM in buffered solution. We have also tested the assay in diluted serum samples, with comparable LOD of 1.58 fM obtained. This shows the great promise of our HCR-AgNCs nanosensor for clinical application.
Molecular understanding of the protective role of natural products on isoproterenol-induced myocardial infarction: A review

Wong ZW, Thanikachalam PV, Ramamurthy S

Biomed Pharmacother, 2017 Oct;94:1145-1166.
PMID: 28826162 DOI: 10.1016/j.biopha.2017.08.009

Modern medicine has been used to treat myocardial infarction, a subset of cardiovascular diseases, and have been relatively effective but not without adverse effects. Consequently, this issue has stimulated interest in the use of natural products, which may be equally effective and better tolerated. Many studies have investigated the cardioprotective effect of natural products, such as plant-derived phytochemicals, against isoproterenol (ISO)-induced myocardial damage; these have produced promising results on the basis of their antioxidant, anti-atherosclerotic, anti-apoptotic and anti-inflammatory activities. This review briefly introduces the pathophysiology of myocardial infarction (MI) and then addresses the progress of natural product research towards its treatment. We highlight the promising applications and mechanisms of action of plant extracts, phytochemicals and polyherbal formulations towards the treatment of ISO-induced myocardial damage. Most of the products displayed elevated antioxidant levels with decreased oxidative stress and lipid peroxidation, along with restoration of ionic balance and lowered expression of myocardial injury markers, pro-inflammatory cytokines, and apoptotic parameters. Likewise, lipid profiles were positively altered and histopathological improvements could be seen from, for example, the better membrane integrity, decreased necrosis, edema, infarct size, and leukocyte infiltration. This review highlights promising results towards the amelioration of ISO-induced myocardial damage, which suggest the direction for future research on natural products that could be used to treat MI.
Ethnicity, obstructive sleep apnoea and ischaemic heart disease

Tan YK, Khoo KL, Low JA, Wong ZW, Theng CT, Ong TH, et al.

Ann Acad Med Singap, 1999 Mar;28(2):214-6.
PMID: 10497669

We studied the relationship between different ethnic groups, obstructive sleep apnoea (OSA) and ischaemic heart disease. Four hundred and thirty-two inpatients from the medical wards were interviewed. Limited overnight sleep studies were done in 129 of those who had habitual snoring, daytime sleepiness based on an Epworth sleepiness scale of 8 or more, or a large neck size of 40 cm or more. There were 315 Chinese (72.9%), 67 Malays (15.5%), 43 Indians (10%) and 3 from other races (1.4%). The prevalence of OSA was 19.7%, 30% and 12% among the Chinese, Malays and Indians, respectively. The prevalence ratio for OSA was 1.52 in Malays using Chinese patients as the baseline (P = 0.07). The median neck circumference was 37 cm in both racial groups. The median body mass index was 22.7 kg/m2 in Chinese compared to 23.6 kg/m2 in Malays. The median apnoea-hypopnoea index was 22.7, 19.0 and 26.9 events/hour among the Chinese, Malays and Indians, respectively. OSA was independently associated with the prevalence of IHD (adjusted prevalence ratio 1.68; 95% CI: 1.15, 2.46; P = 0.009). The prevalence of ischaemic heart disease (IHD) was 31%, 24% and 28% in Chinese, Malays and Indians, respectively. The prevalence ratio for IHD in Malays compared to Chinese was 0.77. After adjusting for OSA, there was an even greater reduction in the risk of IHD (adjusted prevalence ratio 0.70). This suggests that OSA is a confounder in the relationship between race and ischaemic heart disease.
Effects of palbociclib on oral squamous cell carcinoma and the role of PIK3CA in conferring resistance

Zainal NS, Lee BKB, Wong ZW, Chin IS, Yee PS, Gan CP, et al.

Cancer Biol Med, 2019 May;16(2):264-275.
PMID: 31516747 DOI: 10.20892/j.issn.2095-3941.2018.0257

Objective: Lack of effective therapies remains a problem in the treatment of oral squamous cell carcinoma (OSCC), especially in patients with advanced tumors. OSCC development is driven by multiple aberrancies within the cell cycle pathway, including amplification of cyclin D1 and loss of p16. Hence, cell cycle inhibitors of the CDK4/6-cyclin D axis are appealing targets for OSCC treatment. Here, we determined the potency of palbociclib and identified genetic features that are associated with the response of palbociclib in OSCC.
Methods: The effect of palbociclib was evaluated in a panel of well-characterized OSCC cell lines by cell proliferation assays and further confirmed by in vivo evaluation in xenograft models. PIK3CA-mutant isogenic cell lines were used to investigate the effect of PIK3CA mutation towards palbociclib response.
Results: We demonstrated that 80% of OSCC cell lines are sensitive to palbociclib at sub-micromolar concentrations. Consistently, palbociclib was effective in controlling tumor growth in mice. We identified that palbociclib-resistant cells harbored mutations in PIK3CA. Using isogenic cell lines, we showed that PIK3CA mutant cells are less responsive to palbociclib as compared to wild-type cells with concurrent upregulation of CDK2 and cyclin E1 protein levels. We further demonstrated that the combination of a PI3K/mTOR inhibitor (PF-04691502) and palbociclib completely controlled tumor growth in mice.
Conclusions: This study demonstrated the potency of palbociclib in OSCC models and provides a rationale for the inclusion of PIK3CA testing in the clinical evaluation of CDK4/6 inhibitors and suggests combination approaches for further clinical studies.
Current attempts to implement microRNA-based diagnostics and therapy in cardiovascular and metabolic disease: a promising future

Thanikachalam PV, Ramamurthy S, Wong ZW, Koo BJ, Wong JY, Abdullah MF, et al.

Drug Discov Today, 2018 Mar;23(3):460-480.
PMID: 29107764 DOI: 10.1016/j.drudis.2017.10.020

MicroRNAs (miRNAs) are small, noncoding RNAs regulating gene expression at the post-translational level. miRNA-based therapeutic agents are important because of the functionality of miRNAs in regulating lipid and glucose metabolism and their role in the pathogenesis of metabolic disorders such as diabetes and obesity, where dysregulation leads to disease; they are also important in angiogenesis. miRNAs additionally serve as biomarkers in the diagnosis, prognosis and risk assessment of disease and in monitoring the response to treatment. Here, we provide a brief overview of progress in miRNA-based therapeutics in the preclinical and clinical setting and highlight the novel outcomes and opportunities in the diagnosis and treatment of metabolic conditions. In addition, we present the role of miRNAs in stem cell therapy which could have great potential in regenerative medicine.