Browse publications by year: 2018

Anti-amoebic activity of acyclic and cyclic-samarium complexes on Acanthamoeba

Kusrini E, Hashim F, Gunawan C, Mann R, Azmi WNNWN, Amin NM

Parasitol Res, 2018 May;117(5):1409-1417.
PMID: 29532220 DOI: 10.1007/s00436-018-5814-x

This work investigated the anti-amoebic activity of two samarium (Sm) complexes, the acyclic complex [bis(picrato)(pentaethylene glycol)samarium(III)] picrate-referred to as [Sm(Pic)2(EO5)](Pic)-and the cyclic complex [bis(picrato)(18-crown-6)samarium(III)] picrate-referred to as [Sm(Pic)2(18C6)](Pic). Both Sm complexes caused morphological transformation of the protozoa Acanthamoeba from its native trophozoite form carrying a spine-like structure called acanthopodia, to round-shaped cells with loss of the acanthopodia structure, a trademark response to environmental stress. Further investigation, however, revealed that the two forms of the Sm complexes exerted unique cytotoxicity characteristics. Firstly, the IC50 of the acyclic complex (0.7 μg/mL) was ~ 10-fold lower than IC50 of the cyclic Sm complex (6.5 μg/mL). Secondly, treatment of the Acanthamoeba with the acyclic complex caused apoptosis of the treated cells, while the treatment with the cyclic complex caused necrosis evident by the leakage of the cell membrane. Both treatments induced DNA damage in Acanthamoeba. Finally, a molecular docking simulation revealed the potential capability of the acyclic complex to form hydrogen bonds with profilin-a membrane protein present in eukaryotes, including Acanthamoeba, that plays important roles in the formation and degradation of actin cytoskeleton. Not found for the cyclic complex, such potential interactions could be the underlying reason, at least in part, for the much higher cytotoxicity of the acyclic complex and also possibly, for the observed differences in the cytotoxicity traits. Nonetheless, with IC50 values of

MeSH terms: Acanthamoeba/drug effects*; Amebicides/pharmacology*; Animals; Cell Membrane/pathology*; DNA Damage/drug effects*; Samarium/pharmacology*; Samarium/chemistry*; Acanthamoeba Keratitis/drug therapy; Acanthamoeba Keratitis/parasitology; Apoptosis/drug effects*; Trophozoites/drug effects; Molecular Docking Simulation
A molecular dynamics approach to explore the structural characterization of cataract causing mutation R58H on human γD crystallin

Karunakaran R, Srikumar PS

Mol Cell Biochem, 2018 Dec;449(1-2):55-62.
PMID: 29532225 DOI: 10.1007/s11010-018-3342-8

The crystallins are a family of monomeric proteins present in the mammalian lens and mutations in these proteins cause various forms of cataracts. The aim of our current study is to emphasize the structural characterization of aggregation propensity of mutation R58H on γD crystallin using molecular dynamics (MD) approach. MD result revealed that difference in the sequence level display a wide variation in the backbone atomic position, and thus exhibits rigid conformational dynamics. Changes in the flexibility of residues favoured to increase the number of intra-molecular hydrogen bonds in mutant R58H. Moreover, notable changes in the hydrogen bonding interaction resulted to cause the misfolding of mutant R58H by introducing α-helix. Principal component analysis (PCA) result suggested that mutant R58H showed unusual conformational dynamics along the two principal components when compared to the wild-type (WT)-γD crystallin. In a nutshell, the increased surface hydrophobicity could be the cause of self-aggregation of mutant R58H leading to aculeiform cataract.

MeSH terms: Cataract*; Humans; Hydrogen Bonding; Amino Acid Substitution; Mutation, Missense*; gamma-Crystallins/genetics; gamma-Crystallins/metabolism; gamma-Crystallins/chemistry*; Molecular Dynamics Simulation*; Protein Domains
Efficacy and Safety of Autologous Cell-based Therapy in Patients with No-option Critical Limb Ischaemia: A Meta-Analysis

Wahid FSA, Ismail NA, Wan Jamaludin WF, Muhamad NA, Mohamad Idris MA, Lai NM

Curr Stem Cell Res Ther, 2018;13(4):265-283.
PMID: 29532760 DOI: 10.2174/1574888X13666180313141416

BACKGROUND: Revascularisation therapy is the current gold standard of care for critical limb ischemia (CLI), although a significant proportion of patients with CLI either are not fit for or do not respond well to this procedure. Recently, novel angiogenic therapies such as the use of autologous cellbased therapy (CBT) have been examined, but the results of individual trials were inconsistent.
OBJECTIVE: To pool all published studies that compared the safety and efficacy of autologous CBT derived from different sources and phenotypes with non cell-based therapy (NCT) in CLI patients.
METHODS: We searched Medline, Embase, Cochrane Library and ClinicalTrials.gov from 1974-2017. Sixteen randomised clinical trials (RCTs) involving 775 patients receiving the following interventions: mobilised peripheral blood stem cells(m-PBSC), bone marrow mononuclear cells(BM-MNC), bone marrow mesenchymal stem cells(BM-MSC), cultured BM-MNC(Ixmyelocel-T), cultured PB cells(VesCell) and CD34+ cells were included in the meta-analysis.
RESULTS: High-quality evidence (QoE) showed similar all-cause mortality rates between CBT and NCT. AR reduction by approximately 60% were observed in patients receiving CBT compared to NCT (moderate QoE). CBT patients experienced improvement in ulcer healing, ABI, TcO2, pain free walking capacity and collateral vessel formation (moderate QoE). Low-to-moderate QoE showed that compared to NCT, intramuscular BM-MNC and m-PBSC may reduce amputation rate, rest pain, and improve ulcer healing and ankle-brachial pressure index, while intramuscular BM-MSC appeared to improve rest pain, ulcer healing and pain-free walking distance but not AR. Efficacy of other types of CBT could not be confirmed due to limited data. Cell harvesting and implantation appeared safe and well-tolerated with similar rates of adverse-events between groups.
CONCLUSION: Implantation of autologous CBT may be an effective therapeutic strategy for no-option CLI patients. BM-MNC and m-PSBC appear more effective than NCT in improving AR and other limb perfusion parameters. BM-MSC may be beneficial in improving perfusion parameters but not AR, however, this observation needs to be confirmed in a larger population of patients. Generally, treatment using various sources and phenotypes of cell products appeared safe and well tolerated. Large-size RCTs with long follow-up are warranted to determine the superiority and durability of angiogenic potential of a particular CBT and the optimal treatment regimen for CLI.

MeSH terms: Bone Marrow Cells/cytology*; Humans; Ischemia/therapy*; Transplantation, Autologous*; Peripheral Vascular Diseases/therapy; Cell- and Tissue-Based Therapy*
Fulltext Leptospirosis Outbreak After the 2014 Major Flooding Event in Kelantan, Malaysia: A Spatial-Temporal Analysis

Mohd Radi MF, Hashim JH, Jaafar MH, Hod R, Ahmad N, Mohammed Nawi A, et al.

Am J Trop Med Hyg, 2018 05;98(5):1281-1295.
PMID: 29532771 DOI: 10.4269/ajtmh.16-0922

Severe floods increase the risk of leptospirosis outbreaks in endemic areas. This study determines the spatial-temporal distribution of leptospirosis in relation to environmental factors after a major flooding event in Kelantan, Malaysia. We conducted an observational ecological study involving incident leptospirosis cases, from the 3 months before, during, and three months after flood, in reference to the severe 2014 Kelantan flooding event. Geographical information system was used to determine the spatial distribution while climatic factors that influenced the cases were also analyzed. A total of 1,229 leptospirosis cases were notified within the three study periods where incidence doubled in the postflood period. Twelve of 66 subdistricts recorded incidence rates of over 100 per 100,000 population in the postflood period, in comparison with only four subdistricts in the preflooding period. Average nearest neighborhood analysis indicated that the cases were more clustered in the postflood period as compared with the preflood period, with observed mean distance of 1,139 meters and 1,666 meters, respectively (both at P < 0.01). Global Moran's I was higher in the postflood period (0.19; P < 0.01) as compared with the preflood period (0.06; P < 0.01). Geographic weighted regression showed that living close to water bodies increased the risk of contracting the disease. Postflooding hotspots were concentrated in areas where garbage cleanup occurred and the incidence was significantly associated with temperature, humidity, rainfall, and river levels. Postflooding leptospirosis outbreak was associated with several factors. Understanding the spatial distribution and associated factors of leptospirosis can help improve future disease outbreak management after the floods.

MeSH terms: Disease Outbreaks*; Humans; Leptospirosis/epidemiology*; Malaysia/epidemiology; Time Factors; Floods*
Synthesis, molecular docking study and in vitro thymidine phosphorylase inhibitory potential of oxadiazole derivatives

Ullah H, Rahim F, Taha M, Uddin I, Wadood A, Shah SAA, et al.

Bioorg Chem, 2018 08;78:58-67.
PMID: 29533215 DOI: 10.1016/j.bioorg.2018.02.020

We have synthesized oxadiazole derivatives (1-16), characterized by 1H NMR, 13C NMR and HREI-MS and screened for thymidine phosphorylase inhibitory potential. All derivatives display varied degree of thymidine phosphorylase inhibition in the range of 1.10 ± 0.05 to 49.60 ± 1.30 μM when compared with the standard inhibitor 7-Deazaxanthine having an IC50 value 38.68 ± 1.12 μM. Structure activity relationships (SAR) has been established for all compounds to explore the role of substitution and nature of functional group attached to the phenyl ring which applies imperious effect on thymidine phosphorylase activity. Molecular docking study was performed to understand the binding interaction of the most active derivatives with enzyme active site.

MeSH terms: Dose-Response Relationship, Drug; Enzyme Inhibitors/chemical synthesis; Enzyme Inhibitors/pharmacology*; Enzyme Inhibitors/chemistry; Humans; Oxadiazoles/chemical synthesis; Oxadiazoles/pharmacology*; Oxadiazoles/chemistry; Structure-Activity Relationship; Thymidine Phosphorylase/antagonists & inhibitors*; Thymidine Phosphorylase/metabolism; Molecular Structure; Molecular Docking Simulation*
Biofilm formation of filamentous fungi Coriolopsis sp. on simple muslin cloth to enhance removal of triphenylmethane dyes

Munck C, Thierry E, Gräßle S, Chen SH, Ting ASY

J Environ Manage, 2018 May 15;214:261-266.
PMID: 29533823 DOI: 10.1016/j.jenvman.2018.03.025

The isolate Coriolopsis sp. (1c3) was cultured on muslin cloth to induce formation of filamentous biofilm. The biofilm and the free-mycelium forms (control) were then used to treat two triphenylmethane dyes; Cotton Blue (CB) and Crystal Violet (CV). The biofilm comprised primarily of a compact mass of mycelium while sparse mycelium network was detected in free-mycelium forms. Results revealed significant decolourization activities by filamentous biofilm of 1c3 for CB (79.6%) and CV (85.1%), compared to free-mycelium forms (72.6 and 58.3%, for CB and CV, respectively). Biodegradation occurred in both biofilm and free-mycelium forms. FTIR spectra revealed that biofilm formation (stacking of mycelium), did not have severe implications to the number and types of functional groups available for dye biosorption. The findings here suggested that formation of biofilm in 1c3 was induced effectively on muslin cloth, leading to enhanced decolourization activities. This technology is simple, feasible and can be adopted and further improved to obtain biofilm to enhance their dye removal efficiency in aqueous solutions.

MeSH terms: Biodegradation, Environmental; Coloring Agents/isolation & purification*; Fungi*; Gentian Violet; Trityl Compounds/isolation & purification*; Biofilms*
2-Aryl benzimidazoles: Synthesis, In vitro α-amylase inhibitory activity, and molecular docking study

Adegboye AA, Khan KM, Salar U, Aboaba SA, Kanwal, Chigurupati S, et al.

Eur J Med Chem, 2018 Apr 25;150:248-260.
PMID: 29533872 DOI: 10.1016/j.ejmech.2018.03.011

Despite of many diverse biological activities exhibited by benzimidazole scaffold, it is rarely explored for the α-amylase inhibitory activity. For that purpose, 2-aryl benzimidazole derivatives 1-45 were synthesized and screened for in vitro α-amylase inhibitory activity. Structures of all synthetic compounds were deduced by various spectroscopic techniques. All compounds revealed inhibition potential with IC50 values of 1.48 ± 0.38-2.99 ± 0.14 μM, when compared to the standard acarbose (IC50 = 1.46 ± 0.26 μM). Limited SAR suggested that the variation in the inhibitory activities of the compounds are the result of different substitutions on aryl ring. In order to rationalize the binding interactions of most active compounds with the active site of α-amylase enzyme, in silico study was conducted.

MeSH terms: alpha-Amylases/antagonists & inhibitors*; alpha-Amylases/metabolism; Benzimidazoles/chemical synthesis; Benzimidazoles/pharmacology*; Benzimidazoles/chemistry; Dose-Response Relationship, Drug; Structure-Activity Relationship; Molecular Structure; Molecular Docking Simulation*; Glycoside Hydrolase Inhibitors/chemical synthesis; Glycoside Hydrolase Inhibitors/pharmacology*; Glycoside Hydrolase Inhibitors/chemistry
Fulltext The effects of self-efficacy enhancing program on foot self-care behaviour of older adults with diabetes: A randomised controlled trial in elderly care facility, Peninsular Malaysia

Ahmad Sharoni SK, Abdul Rahman H, Minhat HS, Shariff-Ghazali S, Azman Ong MH

PLoS One, 2018;13(3):e0192417.
PMID: 29534070 DOI: 10.1371/journal.pone.0192417

BACKGROUND: Self-care behaviour is essential in preventing diabetes foot problems. This study aimed to evaluate the effectiveness of health education programs based on the self-efficacy theory on foot self-care behaviour for older adults with diabetes.
METHODS: A randomised controlled trial was conducted for 12 weeks among older adults with diabetes in elderly care facility in Peninsular Malaysia. Six elderly care facility were randomly allocated by an independent person into two groups (intervention and control). The intervention group (three elderly care facility) received a health education program on foot self-care behaviour while the control group (three elderly care facility) received standard care. Participants were assessed at baseline, and at week-4 and week-12 follow-ups. The primary outcome was foot-self-care behaviour. Foot care self-efficacy (efficacy expectation), foot care outcome expectation, knowledge of foot care and quality of life were the secondary outcomes. Data were analysed with Mixed Design Analysis of Variance using the Statistical Package for the Social Sciences version 22.0.
RESULTS: 184 respondents were recruited but only 76 met the selection criteria and were included in the analysis. Foot self-care behaviour, foot care self-efficacy (efficacy expectation), foot care outcome expectation and knowledge of foot care improved in the intervention group compared to the control group (p < 0.05). However, some of these improvements did not significantly differ compared to the control group for QoL physical symptoms and QoL psychosocial functioning (p > 0.05).
CONCLUSION: The self-efficacy enhancing program improved foot self-care behaviour with respect to the delivered program. It is expected that in the future, the self-efficacy theory can be incorporated into diabetes education to enhance foot self-care behaviour for elderly with diabetes living in other institutional care facilities.
TRIAL REGISTRATION: Australian New Zealand Clinical Trial Registry ACTRN12616000210471.

MeSH terms: Aged; Diabetes Mellitus/therapy*; Female; Health Education/methods; Health Promotion/methods*; Humans; Malaysia; Male; Middle Aged; Quality of Life; Self Care/methods*; Program Evaluation; Outcome Assessment (Health Care); Diabetic Foot/prevention & control*; Self Efficacy*
De novo hotspot variants in CYFIP2 cause early-onset epileptic encephalopathy

Nakashima M, Kato M, Aoto K, Shiina M, Belal H, Mukaida S, et al.

Ann Neurol, 2018 04;83(4):794-806.
PMID: 29534297 DOI: 10.1002/ana.25208

OBJECTIVE: The cytoplasmic fragile X mental retardation 1 interacting proteins 2 (CYFIP2) is a component of the WASP-family verprolin-homologous protein (WAVE) regulatory complex, which is involved in actin dynamics. An obvious association of CYFIP2 variants with human neurological disorders has never been reported. Here, we identified de novo hotspot CYFIP2 variants in neurodevelopmental disorders and explore the possible involvement of the CYFIP2 mutants in the WAVE signaling pathway.
METHODS: We performed trio-based whole-exome sequencing (WES) in 210 families and case-only WES in 489 individuals with epileptic encephalopathies. The functional effect of CYFIP2 variants on WAVE signaling was evaluated by computational structural analysis and in vitro transfection experiments.
RESULTS: We identified three de novo CYFIP2 variants at the Arg87 residue in 4 unrelated individuals with early-onset epileptic encephalopathy. Structural analysis indicated that the Arg87 residue is buried at an interface between CYFIP2 and WAVE1, and the Arg87 variant may disrupt hydrogen bonding, leading to structural instability and aberrant activation of the WAVE regulatory complex. All mutant CYFIP2 showed comparatively weaker interactions to the VCA domain than wild-type CYFIP2. Immunofluorescence revealed that ectopic speckled accumulation of actin and CYFIP2 was significantly increased in cells transfected with mutant CYFIP2.
INTERPRETATION: Our findings suggest that de novo Arg87 variants in CYFIP2 have gain-of-function effects on the WAVE signaling pathway and are associated with severe neurological disorders. Ann Neurol 2018;83:794-806.

MeSH terms: Animals; Arginine/genetics*; Cell Line, Transformed; Child; Child, Preschool; Electroencephalography; Female; Humans; Infant; Magnetic Resonance Imaging; Male; Models, Molecular; Mutation/genetics*; Pedigree; Spasms, Infantile/genetics*; Transfection; Gene Expression Regulation, Developmental/genetics; Adaptor Proteins, Signal Transducing/genetics*; Adaptor Proteins, Signal Transducing/metabolism; Adaptor Proteins, Signal Transducing/chemistry; Green Fluorescent Proteins/genetics; Green Fluorescent Proteins/metabolism; Mice; HEK293 Cells
Prevention practices of vaginitis among Malaysian women and its associated factors

Wan Muda WM, Wong LP, Tay ST

J Obstet Gynaecol, 2018 Jul;38(5):708-715.
PMID: 29526143 DOI: 10.1080/01443615.2017.1405923

Information on vaginal-related issues among Malaysian women is very limited. This study aimed to explore factors associated with preventive practices of vaginitis among Malaysian women. A cross-sectional computer-assisted telephone interview survey of a representative sample of multi-racial Malaysian women aged 18-50 years old was conducted from January to April 2014. Women from 1446 households responded to the survey and nearly one-third (32.1%) reported to have experienced vaginitis. In multivariate analyses, respondents in the urban locality were more likely to practice vaginitis prevention (OR = 1.40, 95% CI = 1.06-1.84) compared with those in the rural areas. Respondents who perceived low susceptibility to vaginitis were less likely to practice vaginitis prevention (OR = 0.72, 95% CI = 0.57-0.91) compared with responders who highly perceive susceptibility. Respondents who had no formal education were less likely to practice vaginitis prevention (OR = 0.16, 95% CI = 0.05-0.48) compared with those with tertiary education. This study showed that comprehensive education and health programmes need to focus on women with a low educational level, living in rural areas and women with low perceived susceptibility to vaginitis. Impact statement What is already known on this subject? Little is known about vaginitis issues among women in Malaysia. This study provides information regarding vaginitis among Malaysian women by looking at the factors associated with prevention practices. What do the results of this study add? From our study, factors associated with prevention practices were found to be educational level, locality, and perceived susceptibility of vaginitis. Those who perform fewer vaginitis prevention practices were women with a low educational level and those who live in rural areas. From the Health Belief Model, women with a low perceived susceptibility of vaginitis were less likely to carry out vaginitis prevention practices. What are the implications of these findings for clinical practice and/or further research? The findings may provide additional insights for policy makers and healthcare providers to deliver effective approaches in order to improve prevention practices of vaginitis among women in multi-ethnic communities. This study has identified points of interest which need to be put in attention for women's health section which has been overlooked in Malaysia.

MeSH terms: Adolescent; Adult; Female; Humans; Health Knowledge, Attitudes, Practice*; Malaysia; Middle Aged; Vaginitis/prevention & control*; Young Adult
Pharmacometabolomics analysis of plasma to phenotype clopidogrel high on treatment platelets reactivity in coronary artery disease patients

Amin AM, Sheau Chin L, Teh CH, Mostafa H, Mohamed Noor DA, Abdul Kader MASK, et al.

Eur J Pharm Sci, 2018 May 30;117:351-361.
PMID: 29526765 DOI: 10.1016/j.ejps.2018.03.011

Dual antiplatelet therapy (DAPT) of clopidogrel and aspirin is crucial for coronary artery disease (CAD) patients undergoing percutaneous coronary intervention (PCI). However, some patients may endure clopidogrel high on treatment platelets reactivity (HTPR) which may cause thromboembolic events. Clopidogrel HTPR is multifactorial with some genetic and non-genetic factors contributing to it. We aimed to use nuclear magnetic resonance (1H NMR) pharmacometabolomics analysis of plasma to investigate this multifactorial and identify metabolic phenotypes and pathways associated with clopidogrel HTPR. Blood samples were collected from 71 CAD patients planned for interventional angiographic procedure (IAP) before the administration of clopidogrel 600 mg loading dose (LD) and 6 h after the LD. Platelets function testing was done 6 h post-LD using VerifyNow® P2Y12 assay. Pre-dose and post-dose plasma samples were analysed using 1H NMR. Multivariate statistical analysis was used to indicate the discriminating metabolites. Two metabotypes, each with 34 metabolites (pre-dose and post-dose) were associated with clopidogrel HTPR. Pathway analysis of these metabotypes revealed that aminoacyl-tRNA biosynthesis, nitrogen metabolism and glycine-serine-threonine metabolism are the most perturbed metabolic pathways associated with clopidogrel HTPR. Furthermore, the identified biomarkers indicated that clopidogrel HTPR is multifactorial where the metabolic phenotypes of insulin resistance, type two diabetes mellitus, obesity, gut-microbiota and heart failure are associated with it. Pharmacometabolomics analysis of plasma revealed new insights on the implicated metabolic pathways and the predisposing factors of clopidogrel HTPR.

MeSH terms: Aged; Blood Platelets/drug effects*; Blood Platelets/metabolism; Coronary Artery Disease/blood; Coronary Artery Disease/diagnosis; Coronary Artery Disease/therapy*; Drug Resistance*; Female; Genotype; Humans; Male; Middle Aged; Phenotype; Platelet Aggregation Inhibitors/adverse effects; Platelet Aggregation Inhibitors/blood; Platelet Aggregation Inhibitors/therapeutic use*; Platelet Function Tests; Predictive Value of Tests; Risk Factors; Ticlopidine/adverse effects; Ticlopidine/analogs & derivatives*; Ticlopidine/blood; Ticlopidine/therapeutic use; Time Factors; Biomarkers/blood; Treatment Outcome; Drug Monitoring/methods; Metabolomics/methods*; Cytochrome P-450 CYP2C19/genetics; Cytochrome P-450 CYP2C19/metabolism; Proton Magnetic Resonance Spectroscopy*; Pharmacogenomic Variants
Fulltext New Insights on Degumming and Bleaching Process Parameters on The Formation of 3-Monochloropropane-1,2-Diol Esters and Glycidyl Esters in Refined, Bleached, Deodorized Palm Oil

Sim BI, Muhamad H, Lai OM, Abas F, Yeoh CB, Nehdi IA, et al.

J Oleo Sci, 2018 Apr 01;67(4):397-406.
PMID: 29526878 DOI: 10.5650/jos.ess17210

This paper examines the interactions of degumming and bleaching processes as well as their influences on the formation of 3-monochloropropane-1,2-diol esters (3-MCPDE) and glycidyl esters in refined, bleached and deodorized palm oil by using D-optimal design. Water degumming effectively reduced the 3-MCPDE content up to 50%. Acid activated bleaching earth had a greater effect on 3-MCPDE reduction compared to natural bleaching earth and acid activated bleaching earth with neutral pH, indicating that performance and adsorption capacities of bleaching earth are the predominant factors in the removal of esters, rather than its acidity profile. The combination of high dosage phosphoric acid during degumming with the use of acid activated bleaching earth eliminated almost all glycidyl esters during refining. Besides, the effects of crude palm oil quality was assessed and it was found that the quality of crude palm oil determines the level of formation of 3-MCPDE and glycidyl esters in palm oil during the high temperature deodorization step of physical refining process. Poor quality crude palm oil has strong impact towards 3-MCPDE and glycidyl esters formation due to the intrinsic components present within. The findings are useful to palm oil refining industry in choosing raw materials as an input during the refining process.

MeSH terms: alpha-Chlorohydrin*; Esters*; Food Handling/methods*; Food-Processing Industry; Hot Temperature; Hydrogen-Ion Concentration; Phosphoric Acids; Food Quality
Fulltext Orthosiphon stamineus Leaf Extract Affects TNF-α and Seizures in a Zebrafish Model

Choo BKM, Kundap UP, Kumari Y, Hue SM, Othman I, Shaikh MF

Front Pharmacol, 2018;9:139.
PMID: 29527169 DOI: 10.3389/fphar.2018.00139

Epileptic seizures result from abnormal brain activity and can affect motor, autonomic and sensory function; as well as, memory, cognition, behavior, or emotional state. Effective anti-epileptic drugs (AEDs) are available but have tolerability issues due to their side effects. The Malaysian herbOrthosiphon stamineus, is a traditional epilepsy remedy and possesses anti-inflammatory, anti-oxidant and free-radical scavenging abilities, all of which are known to protect against seizures. This experiment thus aimed to explore if an ethanolic leaf extract ofO. stamineushas the potential to be a novel symptomatic treatment for epileptic seizures in a zebrafish model; and the effects of the extract on the expression levels of several genes in the zebrafish brain which are associated with seizures. The results of this study indicate thatO. stamineushas the potential to be a novel symptomatic treatment for epileptic seizures as it is pharmacologically active against seizures in a zebrafish model. The anti-convulsive effect of this extract is also comparable to that of diazepam at higher doses and can surpass diazepam in certain cases. Treatment with the extract also counteracts the upregulation of NF-κB, NPY and TNF-α as a result of a Pentylenetetrazol (PTZ) treated seizure. The anti-convulsive action for this extract could be at least partially due to its downregulation of TNF-α. Future work could include the discovery of the active anti-convulsive compound, as well as determine if the extract does not cause cognitive impairment in zebrafish.

MeSH terms: Animals; Antioxidants; Brain; Cognition; Convulsants; Diazepam; Epilepsy; Memory; Pentylenetetrazole; Seizures; Tumor Necrosis Factor-alpha; Zebrafish; Down-Regulation; Up-Regulation; NF-kappa B
Fulltext An 8-Year-Old Child with Delayed Diagnosis of Netherton Syndrome

Leung AKC, Barankin B, Leong KF

Case Rep Pediatr, 2018;2018:9434916.
PMID: 29527381 DOI: 10.1155/2018/9434916

We report an 8-year-old boy with Netherton syndrome who was misdiagnosed and treated as severe atopic dermatitis. The diagnosis of Netherton syndrome was not made until the child was 8 years of age. We discuss the pitfalls in the diagnosis and alert physicians to the proper and early diagnosis of this syndrome. The child was treated with a low dose (0.25 mg/kg) of oral acitretin and a topical moisturizer with marked improvement of his skin and pruritus in 2 months. At 6-month follow-up, the skin was almost clear of erythema and scaling, and the hair was longer and stronger. The dose of acitretin was reduced to 0.12 mg/kg for another 6 months and then discontinued.

MeSH terms: Child; Dermatitis, Atopic; Diagnostic Errors; Erythema; Follow-Up Studies; Hair; Humans; Male; Pruritus; Skin; Acitretin; Early Diagnosis; Netherton Syndrome
Fulltext Cellular prion protein and γ-synuclein overexpression in LS 174T colorectal cancer cell drives endothelial proliferation-to-differentiation switch

Ong SH, Goh KW, Chieng CK, Say YH

PeerJ, 2018;6:e4506.
PMID: 29527422 DOI: 10.7717/peerj.4506

Background: Tumor-induced angiogenesis is an imperative event in pledging new vasculature for tumor metastasis. Since overexpression of neuronal proteins gamma-synuclein (γ-Syn) and cellular prion protein (PrPC) is always detected in advanced stages of cancer diseases which involve metastasis, this study aimed to investigate whether γ-Syn or PrPCoverexpression in colorectal adenocarcinoma, LS 174T cells affects angiogenesis of endothelial cells, EA.hy 926 (EA).
Methods: EA cells were treated with conditioned media (CM) of LS 174T-γ-Syn or LS 174T-PrP, and their proliferation, invasion, migration, adhesion and ability to form angiogenic tubes were assessed using a range of biological assays. To investigate plausible background mechanisms in conferring the properties of EA cells above, nitrite oxide (NO) levels were measured and the expression of angiogenesis-related factors was assessed using a human angiogenesis antibody array.
Results: EA proliferation was significantly inhibited by LS 174T-PrP CM whereas its telomerase activity was reduced by CM of LS 174T-γ-Syn or LS 174T-PrP, as compared to EA incubated with LS 174T CM. Besides, LS 174T-γ-Syn CM or LS 174T-PrP CM inhibited EA invasion and migration in Boyden chamber assay. Furthermore, LS 174T-γ-Syn CM significantly inhibited EA migration in scratch wound assay. Gelatin zymography revealed reduced secretion of MMP-2 and MMP-9 by EA treated with LS 174T-γ-Syn CM or LS 174T-PrP CM. In addition, cell adhesion assay showed lesser LS 174T-γ-Syn or LS 174T-PrP cells adhered onto EA, as compared to LS 174T. In tube formation assay, LS 174T-γ-Syn CM or LS 174T-PrP CM induced EA tube formation. Increased NO secretion by EA treated with LS 174T-γ-Syn CM or LS 174T-PrP CM was also detected. Lastly, decreased expression of pro-angiogenic factors like CXCL16, IGFBP-2 and amphiregulin in LS 174T-γ-Syn CM or LS 174T-PrP CM was detected using the angiogenesis antibody array.
Discussion: These results suggest that overexpression of γ-Syn or PrPCcould possibly be involved in colorectal cancer-induced angiogenesis by inducing an endothelial proliferation-differentiation switch. NO could be the main factor in governing this switch, and modulation on the secretion patterns of angiogenesis-related proteins could be the strategy of colorectal cancer cells overexpressing γ-Syn or PrPCin ensuring this transition.

MeSH terms: Cell Adhesion; Colonic Neoplasms; Gelatin; Humans; Nitrites; Culture Media, Conditioned; Insulin-Like Growth Factor Binding Protein 2; Telomerase; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Endothelial Cells; Angiogenesis Inducing Agents; gamma-Synuclein; Amphiregulin; Prion Proteins
Fulltext Mechanistic insights into plasmonic photocatalysts in utilizing visible light

Leong KH, Aziz AA, Sim LC, Saravanan P, Jang M, Bahnemann D

Beilstein J Nanotechnol, 2018;9:628-648.
PMID: 29527438 DOI: 10.3762/bjnano.9.59

The utilisation of sunlight as an abundant and renewable resource has motivated the development of sustainable photocatalysts that can collectively harvest visible light. However, the bottleneck in utilising the low energy photons has led to the discovery of plasmonic photocatalysts. The presence of noble metal on the plasmonic photocatalyst enables the harvesting of visible light through the unique characteristic features of the noble metal nanomaterials. Moreover, the formation of interfaces between noble metal particles and semiconductor materials further results in the formation of a Schottky junction. Thereby, the plasmonic characteristics have opened up a new direction in promoting an alternative path that can be of value to the society through sustainable development derived through energy available for all for diverse applications. We have comprehensively prepared this review to specifically focus on fundamental insights into plasmonic photocatalysts, various synthesis routes, together with their strengths and weaknesses, and the interaction of the plasmonic photocatalyst with pollutants as well as the role of active radical generation and identification. The review ends with a pinnacle insight into future perspectives regarding realistic applications of plasmonic photocatalysts.
Fulltext Current progress of immunoinformatics approach harnessed for cellular- and antibody-dependent vaccine design

Kazi A, Chuah C, Majeed ABA, Leow CH, Lim BH, Leow CY

Pathog Glob Health, 2018 05;112(3):123-131.
PMID: 29528265 DOI: 10.1080/20477724.2018.1446773

Immunoinformatics plays a pivotal role in vaccine design, immunodiagnostic development, and antibody production. In the past, antibody design and vaccine development depended exclusively on immunological experiments which are relatively expensive and time-consuming. However, recent advances in the field of immunological bioinformatics have provided feasible tools which can be used to lessen the time and cost required for vaccine and antibody development. This approach allows the selection of immunogenic regions from the pathogen genomes. The ideal regions could be developed as potential vaccine candidates to trigger protective immune responses in the hosts. At present, epitope-based vaccines are attractive concepts which have been successfully trailed to develop vaccines which target rapidly mutating pathogens. In this article, we provide an overview of the current progress of immunoinformatics and their applications in the vaccine design, immune system modeling and therapeutics.

MeSH terms: Animals; Epitopes/genetics; Epitopes/immunology*; Humans; Immunity, Cellular*; Vaccines/genetics; Vaccines/immunology*; Vaccines/isolation & purification*; Computational Biology/methods*; Drug Discovery/methods*; Immunity, Humoral*
Assessment of toxic metals in water and sediment of Pasur River in Bangladesh

Ali MM, Ali ML, Islam MS, Rahman MZ

Water Sci Technol, 2018 Mar;77(5-6):1418-1430.
PMID: 29528329 DOI: 10.2166/wst.2018.016

This study was conducted to assess the levels of toxic metals like arsenic (As), chromium (Cr), cadmium (Cd), and lead (Pb) in water and sediments of the Pasur River in Bangladesh. The ranges of Cr, As, Cd, Pb in water were 25.76-77.39, 2.76-16.73, 0.42-2.98 and 12.69-42.67 μg/L and in sediments were 20.67-83.70, 3.15-19.97, 0.39-3.17 and 7.34-55.32 mg/kg. The level of studied metals in water samples exceeded the safe limits of drinking water, indicating that water from this river is not safe for drinking and cooking. Certain indices, including pollution load index (PLI) and contamination factor (Cif) were used to assess the ecological risk. The PLI indicated progressive deterioration of sediments by the studied metals. Potential ecological risks of metals in sediment indicated low to considerable risk. However, the Cif values of Cd ranged from 0.86 to 8.37 revealed that the examined sediments were strongly impacted by Cd. Considering the severity of potential ecological risk (PER) for single metal (Eir), the descending order of contaminants was Cd > Pb > As > Cr. According the results, some treatment scheme must formulate and implement by the researchers and related management organizations to save the Pasur River from metals contamination.

MeSH terms: Bangladesh; Environmental Monitoring*; Environmental Pollution; Water; Water Pollutants, Chemical/chemistry*; Risk Assessment; Geologic Sediments/chemistry*; Metals, Heavy/analysis; Rivers/chemistry*
Synthesis, molecular docking study and thymidine phosphorylase inhibitory activity of 3-formylcoumarin derivatives

Taha M, Adnan Ali Shah S, Afifi M, Imran S, Sultan S, Rahim F, et al.

Bioorg Chem, 2018 08;78:17-23.
PMID: 29525348 DOI: 10.1016/j.bioorg.2018.02.028

Thymidine phosphorylase (TP) over expression plays role in several pathological conditions, such as rheumatoid arthritis, chronic inflammatory diseases, psoriasis, and tumor angiogenesis. The inhibitor of this enzyme plays an important role in preventing the serious threat due to over expression of TP. In this regard, a series of seventeenanalogs of 3-formylcoumarin (1-17) were synthesized, characterized by 1HNMR and EI-MS and screened for thymidine phosphorylaseinhibitory activity. All analogs showed a variable degree of thymidine phosphorylase inhibition with IC50 values ranging between 0.90 ± 0.01 and 53.50 ± 1.20 μM when compared with the standard inhibitor 7-Deazaxanthine having IC50 value 38.68 ± 1.12 μM. Among the series, fifteenanalogs such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 15, 16 and 17 showed excellent inhibition which is many folds better than the standard 7-Deazaxanthine whiletwo analogs 13 and 14 showed good inhibition. The structure activity relationship (SAR) was mainly based upon by bring about difference of substituents on phenyl ring. Molecular docking study was carried out to understand the binding interaction of the most active analogs.

MeSH terms: Coumarins/chemical synthesis; Coumarins/pharmacology*; Coumarins/chemistry; Dose-Response Relationship, Drug; Enzyme Inhibitors/chemical synthesis; Enzyme Inhibitors/pharmacology*; Enzyme Inhibitors/chemistry; Humans; Structure-Activity Relationship; Thymidine Phosphorylase/antagonists & inhibitors*; Thymidine Phosphorylase/metabolism; Molecular Structure
Paraquat poisoning calls to the Malaysia National Poison Centre following its ban and subsequent restriction of the herbicide from 2004 to 2015

Leong YH, Ariff AM, Khan HRM, Rani NAA, Majid MIA

J Forensic Leg Med, 2018 May;56:16-20.
PMID: 29525581 DOI: 10.1016/j.jflm.2018.03.007

This study analyses the incidences and patterns of paraquat poisoning from calls received at the Malaysia National Poison Centre (NPC) since 2004 following the ban of the herbicide (2004-2006) and subsequent restriction up to year 2015. Related reported cases to the centre over twelve years (2004-2015) were retrieved and studied in respect to socio-demographic characteristics, mode and type of poisonings, exposure routes and location of incident. Ages of poisoned victims range from 10 months old to 98 years with males being intoxicated more frequently than females (ratio male to female = 2.7). The age group mainly involved in the poisoning was 20-39 years. The most common mode was intentional (62.8%) followed by unintentional (36.9%). Among the 1232 reported cases, suicidal poisoning was the highest (57.2%); accidental poisoning (30.8%) and occupational poisoning (3.3%). The findings showed an upward trend of suicidal poisoning over the years, clearly emphasizing the need for more stringent and effective enforcement to ensure the safe use of paraquat.

External Links