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Codonoboea (Gesneriaceae) in Terengganu, Peninsular Malaysia, including three new species

Kiew R, Lim CL

PhytoKeys, 2019;131:1-26.
PMID: 31537960 DOI: 10.3897/phytokeys.131.35944

Of the 92 Codonoboea species that occur in Peninsular Malaysia, 20 are recorded from the state of Terengganu, of which 9 are endemic to Terengganu including three new species, C. norakhirrudiniana Kiew, C. rheophytica Kiew and C. sallehuddiniana C.L.Lim, that are here described and illustrated. A key and checklist to all the Terengganu species are provided. The majority of species grow in lowland rain forest, amongst which C. densifolia and C. rheophytica are rheophytic. Only four grow in montane forest. The flora of Terengganu is still incompletely known, especially in the northern part of the state and in mountainous areas and so, with botanical exploration, more new species can be expected in this speciose genus.
Mortality impact of empirical antimicrobial therapy in ESBL- and AmpC-producing Enterobacteriaceae bacteremia in an Australian tertiary hospital

Lim CL, Spelman D

Infect Dis Health, 2019 08;24(3):124-133.
PMID: 30928569 DOI: 10.1016/j.idh.2019.02.001

BACKGROUND: Treatment of ESBL- and AmpC-producing Enterobacteriaceae bacteremia is often complicated by lack of appropriate antibiotics. We aimed to determine the predictors of mortality and impact of empirical antibiotics.
METHODS: A retrospective observational study was performed on consecutive adult cases of ESBL and AmpC bacteremia at the Alfred Hospital from 2014 through April 2018.
RESULTS: Among 110 patients with ESBL (88.2%) and AmpC (14.5%) bacteremia episodes, 96.4% had comorbidities such as hematological malignancy (30%). Approximately 45% were on immunosuppressive drugs, while 69% had recent antibiotic exposure. Over 84% of bacteremias were hospital acquired or healthcare associated. Urinary tract was the main source of infection (40%) with E. coli being the commonest organism (66.4%). The isolates were least resistant to gentamicin (21.8%), which was often appropriately used in empirical therapy. About 34% of patients presented with severe sepsis or shock. The 30-day mortality rate was 20% with no correlation with inappropriate empirical antibiotics (52%). There was no significant mortality difference between carbapenem use in empirical and definitive therapy. Respiratory source [OR 11.77, 95% CI 1.30-106.85; p = 0.03], severe sepsis or shock [OR 5.17, 95% CI 1.37-19.55; p = 0.02] and inappropriate definitive therapy [OR 27.93, 95%CI 3.69-211.35; p = 0.001] were independent predictors for mortality.
CONCLUSION: The choice and appropriateness of empirical therapy were not associated with mortality in ESBL and AmpC bacteremia. Prudent use of carbapenem is reasonable with gentamicin as alternative. Emphasis should be on prompt resuscitation in severe sepsis and early detection of ESBL and AmpC to facilitate appropriate switch to definitive therapy.
Nerve conduction velocities and distal latencies in normal Malaysian subjects

Lim CL, Loh TG

Med J Malaysia, 1978 Dec;33(2):137-42.
PMID: 755164
Fulltext Epithelial-mesenchymal plasticity-engaging stemness in an interplay of phenotypes

Chin VL, Lim CL

Stem Cell Investig, 2019;6:25.
PMID: 31559312 DOI: 10.21037/sci.2019.08.08

Cancer is a genetic disease which results in a functional imbalance between tumour-repressive and oncogenic signals. The WHO highlights the burden of this indomitable disease, listing it as the second leading cause of death globally. The major cause of cancer-related death is rarely the effect of the primary tumour itself, but rather, the devastating spread of cancer cells in metastases. Epithelial-mesenchymal plasticity (EMP)-termed as the ability of cells to maintain its plasticity and transit between epithelial-mesenchymal transition (EMT) and mesenchymal-epithelial transition (MET) states-plays a fundamental role in cancer metastasis. These cell transitions allow them migrate from the primary tumour and invade the secondary site. EMP is associated with migration, invasion, colonisation, self-renewal and drug resistance. This review briefly elucidates the mechanism of EMP and the association between cancer stem cells (CSCs) and circulating tumour cells (CTCs), biomarkers and signalling pathways involved in EMP as well as drug resistance and therapeutic targeting.
Breast cancer stem cells-from origins to targeted therapy

Sin WC, Lim CL

Stem Cell Investig, 2017;4:96.
PMID: 29270422 DOI: 10.21037/sci.2017.11.03

Breast cancer is marked as one of the leading causes of malignancy-related morbidities worldwide. In spite of aggressive interventions, the inevitability of relapse and metastasis severely impede survival rates. Mounting evidence highlight the insidious role of cancer stem cells (CSCs), a small but significant subpopulation of undifferentiated cells that drive tumour progression, spread and resistance to conventional therapy. The nature and significance of breast CSCs remains poorly understood, and even disputed by many researchers. This review discusses the origins, biomarkers, signalling pathways, regulatory mechanisms, and targeted therapy of breast CSCs.
Fulltext Dynamic heart rate measurements from video sequences

Yu YP, Raveendran P, Lim CL

Biomed Opt Express, 2015 Jul 1;6(7):2466-80.
PMID: 26203374 DOI: 10.1364/BOE.6.002466

This paper shows how dynamic heart rate measurements that are typically obtained from sensors mounted near to the heart can also be obtained from video sequences. In this study, two experiments are carried out where a video camera captures the facial images of the seven subjects. The first experiment involves the measurement of subjects' increasing heart rates (79 to 150 beats per minute (BPM)) while cycling whereas the second involves falling heart beats (153 to 88 BPM). In this study, independent component analysis (ICA) is combined with mutual information to ensure accuracy is not compromised in the use of short video duration. While both experiments are going on measures of heartbeat using the Polar heart rate monitor is also taken to compare with the findings of the proposed method. Overall experimental results show the proposed method can be used to measure dynamic heart rates where the root mean square error (RMSE) and the correlation coefficient are 1.88 BPM and 0.99 respectively.
DNA barcoding implicates 23 species and four orders as potential pollinators of Chinese knotweed (Persicaria chinensis) in Peninsular Malaysia

Wong MM, Lim CL, Wilson JJ

Bull. Entomol. Res., 2015 Aug;105(4):515-20.
PMID: 25913190 DOI: 10.1017/S0007485315000358

Chinese knotweed (Persicaria chinensis) is of ecological and economic importance as a high-risk invasive species and a traditional medicinal herb. However, the insects associated with P. chinensis pollination have received scant attention. As a widespread invasive plant we would expect P. chinensis to be associated with a diverse group of insect pollinators, but lack of taxonomic identification capacity is an impediment to confirm this expectation. In the present study we aimed to elucidate the insect pollinators of P. chinensis in peninsular Malaysia using DNA barcoding. Forty flower visitors, representing the range of morphological diversity observed, were captured at flowers at Ulu Kali, Pahang, Malaysia. Using Automated Barcode Gap Discovery, 17 morphospecies were assigned to 23 species representing at least ten families and four orders. Using the DNA barcode library (BOLD) 30% of the species could be assigned a species name, and 70% could be assigned a genus name. The insects visiting P. chinensis were broadly similar to those previously reported as visiting Persicaria japonica, including honey bees (Apis), droneflies (Eristalis), blowflies (Lucilia) and potter wasps (Eumedes), but also included thrips and ants.
Isolation, cultivation and immunostaining of single myofibers: An improved approach to study the behavior of satellite cells

Lim CL, Ling KH, Cheah PS

J Biol Methods, 2018;5(1):e87.
PMID: 31453240 DOI: 10.14440/jbm.2018.219

Satellite cells are myogenic cells responsible for muscle growth shortly after birth and muscle repair/regeneration during adulthood. Therapies based on satellite cells hold promise for treating muscular dysfunctions. Studying satellite cells is technically challenging owing to their low abundance, small size and anatomical dispersed location between the basal lamina and the sarcolemma of myofibers. In this article, we present three improved protocol strategies for studying the properties of satellite cells of the mouse during the different stages of muscle regeneration: (1) immunostaining of freshly isolated single myofibers to facilitate the study of quiescent satellite cells, (2) cultivation of single myofibers on Matrigel®-coated dish to study the myogenesis programs initiated by satellite cell activation, and (3) cultivation of single myofibers in floating conditions to analyze activated satellite cells or the doubling time of satellite cells in myofibers. In brief, when compared to previously published protocols, this article presented an improved protocol that requires shorter experimental time and less laborious approach for higher yield of intact single myofibers for downstream analyses.
Fulltext Dynamic heart rate estimation using principal component analysis

Yu YP, Raveendran P, Lim CL, Kwan BH

Biomed Opt Express, 2015 Nov 1;6(11):4610-8.
PMID: 26601022 DOI: 10.1364/BOE.6.004610

In this paper, facial images from various video sequences are used to obtain a heart rate reading. In this study, a video camera is used to capture the facial images of eight subjects whose heart rates vary dynamically, between 81 and 153 BPM. Principal component analysis (PCA) is used to recover the blood volume pulses (BVP) which can be used for the heart rate estimation. An important consideration for accuracy of the dynamic heart rate estimation is to determine the shortest video duration that realizes it. This video duration is chosen when the six principal components (PC) are least correlated amongst them. When this is achieved, the first PC is used to obtain the heart rate. The results obtained from the proposed method are compared to the readings obtained from the Polar heart rate monitor. Experimental results show the proposed method is able to estimate the dynamic heart rate readings using less computational requirements when compared to the existing method. The mean absolute error and the standard deviation of the absolute errors between experimental readings and actual readings are 2.18 BPM and 1.71 BPM respectively.
Fulltext Inhibitory effects of palm tocotrienol-rich fraction supplementation on bilirubin-metabolizing enzymes in hyperbilirubinemic adult rats

Kamisah Y, Lim JJ, Lim CL, Asmadi AY

PLoS One, 2014;9(2):e89248.
PMID: 24586630 DOI: 10.1371/journal.pone.0089248

Phenylhydrazine, a hemolytic agent, is widely used as a model of experimental hyperbilirubinemia. Palm tocotrienol-rich fraction (TRF) was shown to exert beneficial effects in hyperbilirubinemic rat neonates.
Treatment of Terasil Red R dye wastewater using H2O2/pyridine/Cu(II) system

Lim CL, Morad N, Teng TT, Ismail N

J Hazard Mater, 2009 Aug 30;168(1):383-9.
PMID: 19303709 DOI: 10.1016/j.jhazmat.2009.02.061

The H(2)O(2)/pyridine/Cu(II) advanced oxidation system was used to assess the efficiency of the treatment of a 1 g L(-1) Terasil Red R dye solution. This system was found to be capable in reducing the concentration of chemical oxygen demand (COD) of the dye solution up to 90%, and achieving 99% in decolorization at the optimal concentration of 5.5mM H(2)O(2), 38 mM pyridine and 1.68 mM Cu(II). The final concentration of COD was recorded at 117 mg L(-1) and color point at 320 PtCo. Full 2(4) factorial design and the response surface methodology using central composite design (CCD) were utilized in the screening and optimization of this study. Treatment efficiency was found to be pH independent. The amount of sludge generation was in the range of 100-175 mg L(-1) and the sludge produced at the optimal concentration was 170 mg L(-1).
Receptor-Interacting Protein Kinase 1 (RIPK1) as a Potential Therapeutic Target: An Overview of Its Possible Role in the Pathogenesis of Alzheimer's Disease

Chan HH, Koh RY, Lim CL, Leong CO

Curr Alzheimer Res, 2019;16(10):907-918.
PMID: 31642777 DOI: 10.2174/1567205016666191023102422

Alzheimer's Disease (AD) is an age-dependent neurodegenerative disorder, the most common type of dementia that is clinically characterized by the presence of beta-amyloid (Aβ) extracellularly and intraneuronal tau protein tangles that eventually leads to the onset of memory and cognition impairment, development of psychiatric symptoms and behavioral disorders that affect basic daily activities. Current treatment approved by the U.S Food and Drug Administration (FDA) for AD is mainly focused on the symptoms but not on the pathogenesis of the disease. Recently, receptor-interacting protein kinase 1 (RIPK1) has been identified as a key component in the pathogenesis of AD through necroptosis. Furthermore, genetic and pharmacological suppression of RIPK1 has been shown to revert the phenotype of AD and its mediating pathway is yet to be deciphered. This review is aimed to provide an overview of the pathogenesis and current treatment of AD with the involvement of autophagy as well as providing a novel insight into RIPK1 in reverting the progression of AD, probably through an autophagy machinery.
Roles of receptor-interacting protein kinase 1 in SH-SY5Y cells with beta amyloid-induced neurotoxicity

Chan HH, Leong CO, Lim CL, Koh RY

J Cell Mol Med, 2022 Feb 02.
PMID: 35106914 DOI: 10.1111/jcmm.17095

Alzheimer's disease (AD), the major cause of dementia, affects the elderly population worldwide. Previous studies have shown that depletion of receptor-interacting protein kinase 1 (RIPK1) expression reverted the AD phenotype in murine AD models. Necroptosis, executed by mixed lineage kinase domain-like (MLKL) protein and activated by RIPK1 and RIPK3, has been shown to be involved in AD. However, the role of RIPK1 in beta-amyloid (Aβ)-induced necroptosis is not yet fully understood. In this study, we explored the role of RIPK1 in the SH-SY5Y human neuroblastoma cells treated with Aβ 1-40 or Aβ 1-42. We showed that Aβ-induced neuronal cell death was independent of apoptosis and autophagy pathways. Further analyses depicted that activation of RIPK1/MLKL-dependant necroptosis pathway was observed in vitro. We demonstrated that inhibition of RIPK1 expression rescued the cells from Aβ-induced neuronal cell death and ectopic expression of RIPK1 was found to enhance the stability of the endogenous APP. In summary, our findings demonstrated that Aβ can potentially drive necroptosis in an RIPK1-MLKL-dependent manner, proposing that RIPK1 plays an important role in the pathogenesis of AD.
The Organisms and Factors Affecting Outcomes of External Ventricular Drainage Catheter-Related Ventriculitis: A Penang Experience

Sam JE, Lim CL, Sharda P, Wahab NA

Asian J Neurosurg, 2018 4 24;13(2):250-257.
PMID: 29682017 DOI: 10.4103/ajns.AJNS_150_16

Introduction: Ventriculostomy-related infection (VRI) from external ventricular drain (EVD) insertion is a common complication and carries a high mortality rate. Choice of empiric antibiotics depends on the institutions common causative organisms and their susceptibility. We determined risk factors for mortality in patients with VRI, the common organisms causing VRI, and the rate of EVD-related VRI at our institution.
Methods: Medical records and operative data of patients with cerebrospinal fluid positive cultures with an EVD inserted from 2012 to 2015 were traced. Forty-five patients with EVD-related VRI were included in the study.
Results: The overall rate of VRI was 6.3%, and the overall mortality rate due to VRI was 48.9%. Acinetobacter baumannii was the most common organism causing VRI (14 patients, 29.2%) with a mortality rate of 64.3%. Only 14.3% of A. baumannii are sensitive to meropenem and imipenem. We found that patients that had a decompressive craniectomy (DC) had a lower mortality rate (P = 0.042) and patients with a longer duration of the EVD being in place before the diagnosis of VRI had poor outcome (P = 0.040). Multivariate logistic regression was performed and we found that the use of steroid (P = 0.014), Pseudomonas aeruginosa infection (P = 0.010), multiple organism infection (P = 0.017), lower Glasgow Coma Scale (P = 0.043), and a longer duration the EVD was in place before the diagnosis of VRI (P = 0.008) were related with higher mortality.
Conclusion: VRI mortality rate is high with an alarming resistance pattern seen in Acinetobacter VRI. EVDs should be removed as soon as feasible, and DC may be offered to patients with severe ventriculitis or meningitis.
Unantimycin A, a new neoantimycin analog isolated from a microbial metabolite fraction library

Lim CL, Nogawa T, Okano A, Futamura Y, Kawatani M, Takahashi S, et al.

J Antibiot (Tokyo), 2016 06;69(6):456-8.
PMID: 26648115 DOI: 10.1038/ja.2015.124
Inhibition of transforming growth factor-β via the activin receptor-like kinase-5 inhibitor attenuates pulmonary fibrosis

Koh RY, Lim CL, Uhal BD, Abdullah M, Vidyadaran S, Ho CC, et al.

Mol Med Rep, 2015 May;11(5):3808-13.
PMID: 25585520 DOI: 10.3892/mmr.2015.3193

Idiopathic pulmonary fibrosis is a chronic pulmonary disease that is characterized by formation of scar tissue in lungs. Transforming growth factor-β (TGF-β) is considered an important cytokine in the pathogenesis of this disease. Hence, the antifibrotic effect of an inhibitor of the TGF-β type I receptor, namely, SB 431542, was investigated in our study. SB 431542 was used to treat TGF-β-treated IMR-90 cells; the expression of α-smooth muscle actin (α-SMA) was detected at the protein level by using an anti-α-SMA antibody, and at the gene level by reverse transcription-quantitative PCR. The effect of the inhibitor on cell proliferation was determined by a cell growth assay. The inhibitor was also administered into bleomycin-treated mice. Histopathological assessment and determination of total collagen levels were carried out to evaluate the severity of lung fibrosis in these mice. Our results demonstrated that treatment with SB 431542 inhibits TGF-β‑induced α-SMA expression in lung fibroblasts, at both the protein and the mRNA levels (P<0.05). However, the inhibitor did not significantly reduce lung fibroblast proliferation. In the bleomycin-induced pulmonary fibrosis mouse model, bleomycin treatment caused important morphological changes, accompanied by an increase in the collagen level of the lungs. Early treatment with SB 431542 prevented the manifestation of histopathological alterations, whereas delayed treatment significantly decreased the collagen level (P<0.05). These results suggest that inhibition of TGF-β signaling, via inhibition of the activin receptor-like kinase-5 (ALK-5) by SB 431542, may attenuate pulmonary fibrosis.
Anticancer Potential of Syzygium Species: a Review

Chua LK, Lim CL, Ling APK, Chye SM, Koh RY

Plant Foods Hum Nutr, 2019 Mar;74(1):18-27.
PMID: 30535971 DOI: 10.1007/s11130-018-0704-z

Cancer is a preventable and treatable disease, however, the incidence rates are on the rise. Classical treatment modalities for cancer include surgery, radiotherapy and chemotherapy. However, these are associated with detrimental side effects such as nausea and emesis. Therefore, researchers currently vest interest in complementary and alternative medicines for cancer treatment and prevention. Plants such as Syzygium sp. are a common basis of complementary medicines due to its abundance of bioactive phytochemicals. Numerous natural compounds derived from Syzygium sp., such as phenolics, oleanolic acids, and betulinic acids, and dimethyl cardamonins, were reported to have anticancer effects. Many possess the ability to inhibit cell proliferation and induce apoptosis. In this review, we discuss the vast potential Syzygium sp. harbours as a source of anticancer natural compounds due to its abundance, easy acceptability, affordability and safety for regular consumption.
Fulltext Effects of Amyloid Precursor Protein Overexpression on NF-κB, Rho-GTPase and Pro-Apoptosis Bcl-2 Pathways in Neuronal Cells

Chan HH, Leong YQ, Voon SM, Pan ML, Leong CO, Lim CL, et al.

Rep Biochem Mol Biol, 2021 Jan;9(4):417-425.
PMID: 33969135 DOI: 10.52547/rbmb.9.4.417

Background: Alzheimer's disease (AD) is a neurodegenerative disorder that causes cognitive dysfunction. Previous studies have suggested that amyloid plaques, mainly comprising of amyloid-beta peptides, play a pivotal role in AD pathophysiology. This study focuses on the evaluation of the effects of amyloid precursor protein (APP) overexpression on NF-κB, Rho-GTPase and Bcl-2 mediated pro-apoptotic pathways in neuronal cells.
Methods: A lentiviral transduction system was used to generate SH-SY5Y cells overexpressing APP. Immunoblotting was conducted to determine expression levels of NF-κB, Rho-GTPase, and Bcl-2 family proteins in the APP overexpressed cells.
Results: In the NF-κB signaling pathway, APP-overexpressing SH-SY5Y cells showed that there was a reduction of p-NF-κB (p< 0.05) and IKKα. Subsequently, there was upregulation of protein expression of NF-Κb, IKKβ and IκBα. On the other hand, protein expression of RhoC (p< 0.05) and Rac1/2/3 was upregulated as compared to the control group. Meanwhile, a decrease in RhoA, Cdc42 (p< 0.05) and p-Rac1/cdc42 protein levels was observed in the APP-overexpressed group. Lastly, in the pro-apoptotic pathway, the expression of Bcl-2, Bid, Bok and Puma (p< 0.05) was up regulated in the APP-overexpressed group. Downregulation of Bad and Bim expression was observed in the APP-overexpressed as compared to the control group, and Bax expression remained unchanged in the APP-overexpressed group.
Conclusion: APP overexpression regulated signaling in the NF-κB, Rho-GTPase and Bcl-2 family pathways in neuronal cells, suggesting that these are involved in promoting neuronal survival and modulating synaptic plasticity in AD. However, further studies are essential to elucidate the APP-mediated mechanism of action.
Opantimycin A, a new metabolite isolated from Streptomyces sp. RK88-1355

Nogawa T, Okano A, Lim CL, Futamura Y, Shimizu T, Takahashi S, et al.

J Antibiot (Tokyo), 2017 02;70(2):222-225.
PMID: 27599762 DOI: 10.1038/ja.2016.113
The Role of Monoamine Oxidase B Inhibitors in the Treatment of Parkinson's Disease - An Update

Chew ZX, Lim CL, Ng KY, Chye SM, Ling APK, Koh RY

CNS Neurol Disord Drug Targets, 2023;22(3):329-352.
PMID: 34970960 DOI: 10.2174/1871527321666211231100255

Parkinson's disease (PD) is a progressive neurodegenerative disease characterised by reduced dopamine levels in the substantial nigra. This may lead to typical motor features such as bradykinesia, resting tremors and rigid muscles, as well as non-motor symptoms such as neuropsychiatric symptoms, sleep disorders, autonomic dysfunction, and sensory disturbances. Inhibitors of monoamine oxidase B (MAO-B) are used to alleviate symptoms by reducing monoamine oxidase-catalysed degradation of dopamine; hence, preserving functional levels of dopamine. The very first MAO-B inhibitor used therapeutically was selegiline, followed by rasagiline, its indane derivative which has superior efficacy and selectivity. Both inhibitors can be used as monotherapy or in combination with other anti- Parkinson drugs. Safinamide, a reversible MAO-B inhibitor that utilises both dopaminergic and non-dopaminergic mechanisms, was recently approved by the European Medicines Agency (EMA) (2015) and U.S. FDA (2017) as an add-on therapy for patients with mid- or late-stage Parkinson's disease. Furthermore, MAO-B inhibitors were found to be associated with potential neuroprotective and disease modifying effects. However, evidence of their efficacy and role in PD models is scarce and warrants further investigation.

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