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Danshen (Salvia miltiorrhiza) water extract shows potential neuroprotective effects in Caenorhabditis elegans

Yuen CW, Murugaiyah V, Najimudin N, Azzam G

J Ethnopharmacol, 2021 Feb 10;266:113418.
PMID: 32991971 DOI: 10.1016/j.jep.2020.113418

ETHNOPHARMACOLOGICAL RELEVANCE: Danshen, is a traditional Chinese medicine obtained from the dried root and rhizome of Salvia miltiorrhiza Bunge. It is known to be used for neurological disorder including for Alzheimer's disease (AD). This study uncovers the effect of Danshen water extract on the Alzheimer's disease model of C.elegans.
MATERIAL AND METHODS: The composition of Danshen water extract was determined using (High Performance Liquid Chromatography (HPLC). Then Thioflavin T assay was used to determined if Danshen water extract could prevent the aggregation of amyloid-β peptide (Aβ). Alzheimer's disease C.elegans model was used to determine the effect of Danshen water extract. Finally, the reactive oxygen species (ROS) was determined using the 2,7-dichlorofuorescein diacetate method.
RESULTS: In this study, we found that standardized Danshen water extract that contains danshensu (1.26%), salvianolic acid A (0.35%) and salvianolic acid B (2.21%) are able to bind directly to Aβ and prevents it from aggregating. The IC50 for the inhibition of Aβ aggregation by Danshen water extract was 0.5 mg/ml. In the AD model of C.elegans, Danshen water extract managed to alleviates the paralysis phenotype. Furthermore, the administration of Danshen water extract displayed antioxidant properties toward the Aβ-induced oxidative stress.
CONCLUSIONS: AD is a widespread neurodegenerative disease attributed to the accumulation of extracellular plaques comprising Aβ. Danshen water extract could significantly reduce the progress of paralysis in the AD model of C. elegans, showing promising results with its antioxidant properties. It can be concluded that Danshen water extract could potentially serve as a therapeutic for AD.
Synthesis and discovery of highly functionalized mono- and bis-spiro-pyrrolidines as potent cholinesterase enzyme inhibitors

Kia Y, Osman H, Suresh Kumar R, Basiri A, Murugaiyah V

Bioorg Med Chem Lett, 2014 Apr 1;24(7):1815-9.
PMID: 24594354 DOI: 10.1016/j.bmcl.2014.02.019

Novel mono and bis spiropyrrolidine derivatives were synthesized via an efficient ionic liquid mediated, 1,3-dipolar cycloaddition methodology and evaluated in vitro for their AChE and BChE inhibitory activities in search for potent cholinesterase enzyme inhibitors. Most of the synthesized compounds displayed remarkable AChE inhibitory activities with IC50 values ranging from 1.68 to 21.85 μM, wherein compounds 8d and 8j were found to be most active inhibitors against AChE and BChE with IC50 values of 1.68 and 2.75 μM, respectively. Molecular modeling simulation on Torpedo californica AChE and human BChE receptors, showed good correlation between IC50 values and binding interaction template of the most active inhibitors docked into the active site of their relevant enzymes.
Acute and subchronic toxicity studies of methanol extract of Polygonum minus leaves in Sprague Dawley rats

Christapher PV, Parasuraman S, Asmawi MZ, Murugaiyah V

Regul Toxicol Pharmacol, 2017 Jun;86:33-41.
PMID: 28229903 DOI: 10.1016/j.yrtph.2017.02.005

Medicinal plant preparations may contain high levels of toxic chemical constituents to potentially cause serious harm to animals and/or humans. Thus, toxicity studies are important to assess the toxic effects of plant derived products. Polygonum minus is used traditionally for different ailments in Southeast Asia. This study was conducted to establish the acute and subchronic toxicity profile of the methanol extract of P. minus leaves. The acute toxicity study showed that the methanol extract of P. minus is safe even at the highest dose tested of 2000 mg/kg in female Sprague Dawley rats. There were no behavioural or physiological changes and gross pathological abnormalities observed. The subchronic toxicity study of methanol extract of P. minus at 250, 500, 1000 and 2000 mg/kg were conducted in both sexes of Sprague Dawley rats. There were no changes observed in the extract treated animal's body weight, food and water intake, motor coordination, behaviour and mental alertness. The values of haematological and biochemical parameters were not different between the treated and control animals. The relative organ weights of extract-treated animals did not differ with that of control animals. Based on the present findings, the methanol extract of P. minus leaves could be considered safe up to the dose of 2000 mg/kg.
The nootropic and anticholinesterase activities of Clitoria ternatea Linn. root extract: Potential treatment for cognitive decline

Damodaran T, Cheah PS, Murugaiyah V, Hassan Z

Neurochem Int, 2020 10;139:104785.
PMID: 32650028 DOI: 10.1016/j.neuint.2020.104785

BACKGROUND: Clitoria ternatea (CT) is an herbal plant that has been used as a memory booster in folk medicine. CT root extract has been proven to restore chronic cerebral hypoperfusion (CCH)-induced memory deficits in a rat model, but the underlying mechanisms and the toxicity profile following repeated exposure have yet to be explored.
THE AIM OF THE STUDY: To investigate the effects of the chronic (28 days) oral administration of CT root extract on CCH-induced cognitive impairment, neuronal damage and cholinergic deficit, and its toxicity profile in the CCH rat model.
MATERIALS AND METHODS: The permanent bilateral occlusion of common carotid arteries (PBOCCA) surgery method was employed to develop a CCH model in male Sprague Dawley (SD) rats. Then, these rats were given oral administration of CT root extract at doses of 100, 200, and 300 mg/kg, respectively for 28 days and subjected to behavioural tests. At the end of the experiment, the brain was harvested for histological analysis and cholinesterase activities. Then, blood samples were collected and organs such as liver, kidney, lung, heart, and spleen were procured for toxicity assessment.
RESULTS: Chronic treatment of CT root extract at doses of 200 and 300 mg/kg, restored memory impairments induced by CCH. CT root extract was also found to diminish CCH-induced neuronal damage in the CA1 region of the hippocampus. High dose (300 mg/kg) of the CT root extract was significantly inhibited the increased acetylcholinesterase (AChE) activity in the frontal cortex and hippocampus of the PBOCCA rats. In toxicity study, repeated doses of CT root extract were found to be safe in PBOCCA rats after 28 days of treatment.
CONCLUSIONS: Our findings provided scientific evidence supporting the therapeutic potential of CT root extract in the treatment of vascular dementia (VaD)-related cholinergic abnormalities and subsequent cognitive decline.
Addressing the standardisation of internal standards and preservative used in human bio fluids for NMR analysis: a method optimization

Abd Aziz F, Ibrahim B, Murugaiyah V, Sarriff A

Drug Metab Pers Ther, 2021 Mar 04;36(3):189-197.
PMID: 34412173 DOI: 10.1515/dmpt-2020-0154

OBJECTIVES: A database comprising multivariate data in developing a model from nuclear magnetic resonance (NMR) analysis using human bio fluids are necessary to have reproducibility and reliability of the data. To achieve reproducibility of the data, standardised experiments, including internal standard and preservative used should be attained, especially for samples such as human bio fluids to hinder the variation among samples. The aim of the study was to optimise in commonly used human bio fluids (serum and urine) for a suitable internal standard and preservative used in extended storage samples for NMR analysis.
METHODS: Serum and urine samples were collected from healthy human subjects. The experiment was divided into two parts, part one to evaluate 2,2,2,2-tetradeutero-4,4-dimethyl-4-silapentanoic acid (TSP) and 4,4-dimethyl-4-silapentane-1-ammonium trifluoroacetate (DSA) as the optimal internal standard for the serum and urine samples. The second part investigated the effects of preservatives in the serum and urine samples on extended storage.
RESULTS: Overall, TSP and DSA are suitable to be used as an internal standard in human urine samples. However, DSA is a superior internal standard in serum samples for NMR analysis. For the effect of preservative, the results indicated that human serum and urine samples could be stored without addition of preservative in -80 °C, as no changes in NMR fingerprinting have been observed during storage in the absence or presence of the preservative.
CONCLUSIONS: The findings suggest the use of DSA and TSP as an internal standard in serum and urine samples, respectively. Storage of serum and urine samples without any addition of preservative for an extended period has no effect on the metabolites changes. By having a standardised method, it will offer a considerable saving in both operator and spectrometer time and most importantly produce reproducible and reliable data.
Probing simple structural modification of α-mangostin on its cholinesterase inhibition and cytotoxicity

Khaw KY, Kumar P, Yusof SR, Ramanathan S, Murugaiyah V

Arch Pharm (Weinheim), 2020 Nov;353(11):e2000156.
PMID: 32716578 DOI: 10.1002/ardp.202000156

α-Mangostin has been reported to possess a broad range of pharmacological effects including potent cholinesterase inhibition, but the development of α-mangostin as a potential lead compound is impeded by its toxicity. The present study investigated the impact of simple structural modification of α-mangostin on its cholinesterase inhibitory activities and toxicity toward neuroblastoma and liver cancer cells. The dialkylated derivatives retained good acetylcholinesterase (AChE) inhibitory activities with IC50 values between 4.15 and 6.73 µM, but not butyrylcholinesterase (BChE) inhibitory activities, compared with α-mangostin, a dual inhibitor (IC50 : AChE, 2.48 µM; BChE, 5.87 µM). Dialkylation of α-mangostin produced AChE selective inhibitors that formed hydrophobic interactions at the active site of AChE. Interestingly, all four dialkylated derivatives of α-mangostin showed much lower cytotoxicity, being 6.4- to 9.0-fold and 3.8- to 5.5-fold less toxic than their parent compound on neuroblastoma and liver cancer cells, respectively. Likewise, their selectivity index was higher by 1.9- to 4.4-fold; in particular, A2 and A4 showed improved selectivity index compared with α-mangostin. Taken together, modification of the hydroxyl groups of α-mangostin at positions C-3 and C-6 greatly influenced its BChE inhibitory and cytotoxic but not its AChE inhibitory activities. These dialkylated derivatives are viable candidates for further structural modification and refinement, worthy in the search of new AChE inhibitors with higher safety margins.
Biomacromolecule immobilization: grafting of fish-scale collagen peptides onto aminolyzed P(3HB-co-4HB) scaffolds as a potential wound dressing

Vigneswari S, Murugaiyah V, Kaur G, Abdul Khalil HP, Amirul AA

Biomed Mater, 2016 10 06;11(5):055009.
PMID: 27710927

Polyhydroxyalkanoate (PHA) is a microbial polymer that has been at the forefront of many attempts at tissue engineering. However, the surface of poly(3-hydroxybutyrate-co-4-hydroxybutyrate) (P(3HB-co-4HB)) is hydrophobic with few recognition sites for cell attachment. Various concentrations of fish-scale collagen peptides (FSCPs) were incorporated into P(3HB-co-4HB) copolymer by aminolysis. Later, FSCPs were introduced onto the aminolyzed P(3HB-co-4HB) scaffolds. Introduction of the FSCP groups was verified using Fourier transform infrared spectroscopy and the ninhydrin method. The effect of the incorporation of FSCPs on hydrophilicity was investigated using the water contact angle. As the concentration of FSCPs increased, the water contact angle decreased. In vitro study demonstrated that P(3HB-co-4HB)/FSCP scaffolds provided better cell attachment and growth of L929 mouse fibroblast cells and better cell proliferation. In vivo study showed that P(3HB-co-4HB)/1.5 wt% FSCPs had a significant effect on wound contractions, with the highest percentage of wound closure (61%) in 7 d.
NMR-based plasma metabolomic discrimination for male fertility assessment of rats treated with Eurycoma longifolia extracts

Ebrahimi F, Ibrahim B, Teh CH, Murugaiyah V, Chan KL

Syst Biol Reprod Med, 2017 Jun;63(3):179-191.
PMID: 28306342 DOI: 10.1080/19396368.2017.1295332

Male infertility is one of the leading causes of infertility which affects many couples worldwide. Semen analysis is a routine examination of male fertility status which is usually performed on semen samples obtained through masturbation that may be inconvenient to patients. Eurycoma longifolia (Tongkat Ali, TA), native to Malaysia, has been traditionally used as a remedy to boost male fertility. In our recent studies in rats, upon the administration of high-quassinoid content extracts of TA including TA water (TAW), quassinoid-rich TA (TAQR) extracts, and a low-quassinoid content extract including quassinoid-poor TA (TAQP) extract, sperm count (SC) increased in TAW- and TAQR-treated rats when compared to the TAQP-treated and control groups. Consequently, the rats were divided into normal- (control and TAQP-treated) and high- (TAW- and TAQR-treated) SC groups [Ebrahimi et al. 2016]. Post-treatment rat plasma was collected. An optimized plasma sample preparation method was developed with respect to the internal standards sodium 3- (trimethylsilyl) propionate- 2,2,3,3- d4 (TSP) and deuterated 4-dimethyl-4-silapentane-1-ammonium trifluoroacetate (DSA). Carr-Purcell-Meibum-Gill (CPMG) experiments combined with orthogonal partial least squares discriminant analysis (OPLS-DA) was employed to evaluate plasma metabolomic changes in normal- and high-SC rats. The potential biomarkers associated with SC increase were investigated to assess fertility by capturing the metabolomic profile of plasma. DSA was selected as the optimized internal standard for plasma analysis due to its significantly smaller half-height line width (W h/2) compared to that of TSP. The validated OPLS-DA model clearly discriminated the CPMG profiles in regard to the SC level. Plasma profiles of the high-SC group contained higher levels of alanine, lactate, and histidine, while ethanol concentration was significantly higher in the normal-SC group. This approach might be a new alternative applicable to the fertility assessment in humans through the quantitative metabolomic analysis of plasma without requiring semen.
ABBREVIATIONS: TA: Tongkat Ali; LOD: limit of detection; LOQ: limit of quantification; HPLC-UV: high performance liquid chromatography-ultrviolet; PDA: photodiode array; NMR: nuclear magnetic resonance; FID: free induction decay; LC-MS: liquid chromatography-mass spectrometry; GC-MS: gas chromatography-mass spectrometry; HSQC: heteronuclear single quantum coherence; CPMG: Carr-Purcell-Meibum-Gill; VLDL: very low density lipoprotein; HDL: high density lipoprotein; EDTA: ethylenediaminetetraacetic acid; ANOVA: analysis of variance; AMIX: analysis of mixtures; SIMCA: soft independent modeling of class analogy; PCA: principal components analysis; OPLS-DA: orthogonal partial least-squares discriminant analysis; VIP: variable importance plot; AUROC: area under the receiver operating characteristic; TSP: sodium 3-(trimethylsilyl) propionate- 2,2,3,3- d4; DSA: deuterated 4-dimethyl-4-silapentane-1-ammonium trifluoroacetate; ESI: electrospray ionization; TCA: trichloroacetic acid; ACN: acetonitrile; dd H2O: distilled deionized water; FSH: follicle-stimulating hormone; LH: luteinizing hormone; OECD: Organisation for Economic Co-operation and Development.
Multi-analyte validation in heterogeneous solution by ELISA

Lakshmipriya T, Gopinath SCB, Hashim U, Murugaiyah V

Int J Biol Macromol, 2017 Dec;105(Pt 1):796-800.
PMID: 28732727 DOI: 10.1016/j.ijbiomac.2017.07.115

Enzyme Linked Immunosorbent Assay (ELISA) is a standard assay that has been used widely to validate the presence of analyte in the solution. With the advancement of ELISA, different strategies have shown and became a suitable immunoassay for a wide range of analytes. Herein, we attempted to provide additional evidence with ELISA, to show its suitability for multi-analyte detection. To demonstrate, three clinically relevant targets have been chosen, which include 16kDa protein from Mycobacterium tuberculosis, human blood clotting Factor IXa and a tumour marker Squamous Cell Carcinoma antigen. Indeed, we adapted the routine steps from the conventional ELISA to validate the occurrence of analytes both in homogeneous and heterogeneous solutions. With the homogeneous and heterogeneous solutions, we could attain the sensitivity of 2, 8 and 1nM for the targets 16kDa protein, FIXa and SSC antigen, respectively. Further, the specific multi-analyte validations were evidenced with the similar sensitivities in the presence of human serum. ELISA assay in this study has proven its applicability for the genuine multiple target validation in the heterogeneous solution, can be followed for other target validations.
Fulltext Freeze-Dried Lopinavir-Loaded Nanostructured Lipid Carriers for Enhanced Cellular Uptake and Bioavailability: Statistical Optimization, in Vitro and in Vivo Evaluations

Khan AA, Mudassir J, Akhtar S, Murugaiyah V, Darwis Y

Pharmaceutics, 2019 Feb 25;11(2).
PMID: 30823545 DOI: 10.3390/pharmaceutics11020097

Nanostructured lipid carriers (NLCs) loaded with lopinavir (LPV) were prepared by the high-shear homogenization method. The LPV-NLCs formulations were freeze-dried using trehalose as a cryoprotectant. In vitro release studies in simulated gastric fluid (pH 1.2) and simulated intestinal fluid (pH 6.8) showed a burst release. The optimized freeze-dried formulation (LPV-NLC-7-Tres) had a particle size (PS), polydispersity index (PdI), zeta potential (ZP) and % entrapment efficiency (%EE) of 286.8 ± 1.3 nm, 0.413 ± 0.017, -48.6 ± 0.89 mV and 88.31 ± 2.04%, respectively. The optimized formulation observed by transmission and scanning electron microscopes showed a spherical shape. Differential scanning calorimetry study revealed the absence of chemical interaction between the drug and lipids. In vitro cellular uptake study using Caco-2 cell line showed a higher LPV uptake from LPV-NLC-7-Tres formulation compared to the free LPV-suspension. The 6-month stability study showed a minimum rise of ~40 nm in PS, while no significant changes in PdI, ZP and drug content of the LPV-NLC-7-Tres formulation stored at 5 °C ± 3 °C. The bioavailability of LPV following oral administration of LPV-NLC-7-Tres in male Wistar rats was found 6.98-fold higher than the LPV-suspension. In conclusion, the nanostructure lipid carriers are potential carriers for improving the oral bioavailability of lopinavir.
Xanthone-enriched fraction of Garcinia mangostana and α-mangostin improve the spatial learning and memory of chronic cerebral hypoperfusion rats

Tiang N, Ahad MA, Murugaiyah V, Hassan Z

J Pharm Pharmacol, 2020 Nov;72(11):1629-1644.
PMID: 32743849 DOI: 10.1111/jphp.13345

OBJECTIVES: Xanthones isolated from the pericarp of Garcinia mangostana has been reported to exhibit neuroprotective effect.
METHODS: In this study, the effect of xanthone-enriched fraction of Garcinia mangostana (XEFGM) and α-mangostin (α-MG) were investigated on cognitive functions of the chronic cerebral hypoperfusion (CCH) rats.
KEY FINDINGS: HPLC analysis revealed that XEFGM contained 55.84% of α-MG. Acute oral administration of XEFGM (25, 50 and 100 mg/kg) and α-MG (25 and 50 mg/kg) before locomotor activity and Morris water maze (MWM) tests showed no significant difference between the groups for locomotor activity.
CONCLUSIONS: However, α-MG (50 mg/kg) and XEFGM (100 mg/kg) reversed the cognitive impairment induced by CCH in MWM test. α-MG (50 mg/kg) was further tested upon sub-acute 14-day treatment in CCH rats. Cognitive improvement was shown in MWM test but not in long-term potentiation (LTP). BDNF but not CaMKII was found to be down-regulated in CCH rats; however, both parameters were not affected by α-MG. In conclusion, α-MG ameliorated learning and memory deficits in both acute and sub-acute treatments in CCH rats by improving the spatial learning but not hippocampal LTP. Hence, α-MG may be a promising lead compound for CCH-associated neurodegenerative diseases, including vascular dementia and Alzheimer's disease.
1HNMR-Based Discriminatory Analysis of Eurycoma longifolia from Different Locations and Establishing a Profile for Primary Metabolites Identification and Quassinoids Quantification

Ebrahimi F, Ibrahim B, Teh CH, Murugaiyah V, Lam CK

Planta Med, 2017 Jan;83(1-02):172-182.
PMID: 27399233 DOI: 10.1055/s-0042-110857

Quassinoids, the major secondary metabolites of Eurycoma longifolia roots, improve male fertility. Hence, it is crucial to investigate their quantitative level in E. longifolia extracts. A profile was established to identify the primary metabolites and major quassinoids, and quantify quassinoids using external calibration curves. Furthermore, the metabolic discrimination of E. longifolia roots from different regions was investigated. The (1)H-NMR spectra of the quassinoids, eurycomanone, eurycomanol, 13,21-dihydroeurycomanone, and eurycomanol-2-O-β-D-glycopyranoside were obtained. The (1)H-NMR profiles of E. longifolia root aqueous extracts from Perak (n = 30) were obtained and used to identify primary metabolites and the quassinoids. Selangor, Kedah, Terengganu (n = 5 for each), and Perak samples were checked for metabolic discrimination. Hotelling's T(2) plot was used to check for outliers. Orthogonal partial least-squares discriminant analysis was run to reveal the discriminatory metabolites. Perak samples contained formic, succinic, methylsuccinic, fumaric, lactic, acetic and syringic acids as well as choline, alanine, phenylalanine, tyrosine, α-glucose, eurycomanone, eurycomanol, 13,21-dihydroeurycomanone, and eurycomanol-2-O-β-D-glycopyranoside. The extracts from other locations contained the same metabolites. The limit of quantification values were 1.96 (eurycomanone), 15.62 (eurycomanol), 3.91 (13,21-dihydroeurycomanone), and 31.25 (eurycomanol-2-O-β-D-glycopyranoside) ppm. The Hotelling's T(2) plot revealed no outlier. The orthogonal partial least-squares discriminant analysis model showed that choline, eurycomanol, eurycomanol-2-O-β-D-glycopyranoside, and lactic and succinic acid levels were different among regions. Terengganu and Perak samples contained higher amounts of eurycomanol and eurycomanol-2-O-β-D-glycopyranoside, respectively. The current approach efficiently detected E. longifolia root metabolites, quantified the quassinoids, and discriminated E. longifolia roots from different locations. These findings could be applicable to future research on E. longifolia where the higher content of quassinoids is required.
The effect of mitragynine on extracellular activity of brain dopamine and its metabolites

Yusoff NHM, Hassan Z, Murugaiyah V, Müller CP

Brain Res Bull, 2022 01;178:1-8.
PMID: 34774992 DOI: 10.1016/j.brainresbull.2021.11.002

Kratom, derived from the plant Mitragyna speciosa (M. speciosa) Korth is a traditional psychoactive preparation widely used in Southeast Asia and increasingly in the rest of the world. Use and abuse of Kratom preparations can be attributed to mitragynine (MIT), the main psychoactive compound isolated from its leaves. While MIT may have beneficial effects as a recreational drug, for pain management, and for opiate withdrawal, it may have an addiction potential at higher doses. However, its action in the reward system of the brain is currently unknown. This study investigated how mitragynine (10 mg/kg, i.p.) affects extracellular activity of dopamine (DA) and its metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the prefrontal cortex (PFC), nucleus accumbens (NAc) and caudate putamen (CPu) of the brain, compared to morphine (MOR; 10 mg/kg, i.p.) and methamphetamine (METH; 10 mg/kg, i.p.). Using in-vivo microdialysis in freely moving rats, we found a significant increase of extracellular DA after MOR and METH, but not after MIT in all three brain regions. MIT led to a significant increase of DOPAC and/or HVA in these brain regions while MOR and METH had only moderate effects. These findings suggest a strong and prolonged effect of MIT on DA synthesis/metabolism, but not on extracellular DA activity, which may limit the addiction risk of MIT, in contrast to MOR and METH.
Fulltext Development and Characterisation of a Topical Methyl Salicylate Patch: Effect of Solvents on Adhesion and Skin Permeation

Yeoh SC, Loh PL, Murugaiyah V, Goh CF

Pharmaceutics, 2022 Nov 17;14(11).
PMID: 36432686 DOI: 10.3390/pharmaceutics14112491

The advent of skin patch formulation design and technology has enabled the commercialisation of methyl salicylate (MS) as a topical patch. However, the most fundamental aspect of skin permeation is unknown at present. The study aims to investigate the effect of solvent choice on the skin permeation of MS in a neat solvent system and patch formulation with an emphasis on patch adhesion. MS in six selected solvents (propylene glycol (PG), Transcutol®, isopropyl myristate, Labrasol®, Plurol® oleique CC 497 and Maisine® CC) was characterised and in vitro permeation studies were also performed. An ATR-FTIR analysis on solvent-treated skin was conudcted. Patch formulation was prepared and characterised for adhesion, in vitro drug release and skin permeation studies. The highest MS permeation was found in neat PG over 24 h (~90 μg/cm2) due to its strong skin protein conformation effect. Transcutol® and isopropyl myristate showed better skin deposition and formulation retention, respectively. Nevertheless, PG enhanced the patch adhesion despite having a lower cumulative amount of MS permeated (~80 μg/cm2) as compared with Transcutol® and Maisine® (~110-150 μg/cm2). These two solvents, however, demonstrated better skin deposition and formulation retention but a lower patch adhesion. The unpredictable influence of the solvent on patch adhesion highlights the importance of the trade-off between patch adhesion and skin permeation during formulation design.
Fulltext Cholinesterase inhibitory activity and chemical constituents of Stenochlaena palustris fronds at two different stages of maturity

Chear NJ, Khaw KY, Murugaiyah V, Lai CS

J Food Drug Anal, 2016 04;24(2):358-366.
PMID: 28911590 DOI: 10.1016/j.jfda.2015.12.005

Stenochlaena palustris fronds are popular as a vegetable in Southeast Asia. The objectives of this study were to evaluate the anticholinesterase properties and phytochemical profiles of the young and mature fronds of this plant. Both types of fronds were found to have selective inhibitory effect against butyrylcholinesterase compared with acetylcholinesterase. However, different sets of compounds were responsible for their activity. In young fronds, an antibutyrylcholinesterase effect was observed in the hexane extract, which was comprised of a variety of aliphatic hydrocarbons, fatty acids, and phytosterols. In the mature fronds, inhibitory activity was observed in the methanol extract, which contained a series of kaempferol glycosides. Our results provided novel information concerning the ability of S. palustris to inhibit cholinesterase and its phytochemical profile. Further research to investigate the potential use of this plant against Alzheimer's disease is warranted, however, young and mature fronds should be distinguished due to their phytochemical differences.
Addressing the standardisation of internal standards and preservative used in human bio fluids for NMR analysis: a method optimization

Abd Aziz F, Ibrahim B, Murugaiyah V, Sarriff A

Drug Metab Pers Ther, 2021 Mar 04.
PMID: 33662189 DOI: 10.1515/dmdi-2020-0154

OBJECTIVES: A database comprising multivariate data in developing a model from nuclear magnetic resonance (NMR) analysis using human bio fluids are necessary to have reproducibility and reliability of the data. To achieve reproducibility of the data, standardised experiments, including internal standard and preservative used should be attained, especially for samples such as human bio fluids to hinder the variation among samples. The aim of the study was to optimise in commonly used human bio fluids (serum and urine) for a suitable internal standard and preservative used in extended storage samples for NMR analysis.
METHODS: Serum and urine samples were collected from healthy human subjects. The experiment was divided into two parts, part one to evaluate 2,2,2,2-tetradeutero-4,4-dimethyl-4-silapentanoic acid (TSP) and 4,4-dimethyl-4-silapentane-1-ammonium trifluoroacetate (DSA) as the optimal internal standard for the serum and urine samples. The second part investigated the effects of preservatives in the serum and urine samples on extended storage.
RESULTS: Overall, TSP and DSA are suitable to be used as an internal standard in human urine samples. However, DSA is a superior internal standard in serum samples for NMR analysis. For the effect of preservative, the results indicated that human serum and urine samples could be stored without addition of preservative in -80 °C, as no changes in NMR fingerprinting have been observed during storage in the absence or presence of the preservative.
CONCLUSIONS: The findings suggest the use of DSA and TSP as an internal standard in serum and urine samples, respectively. Storage of serum and urine samples without any addition of preservative for an extended period has no effect on the metabolites changes. By having a standardised method, it will offer a considerable saving in both operator and spectrometer time and most importantly produce reproducible and reliable data.
Ionic liquid mediated synthesis and molecular docking study of novel aromatic embedded Schiff bases as potent cholinesterase inhibitors

Abd Razik BM, Osman H, Basiri A, Salhin A, Kia Y, Ezzat MO, et al.

Bioorg Chem, 2014 Dec;57:162-168.
PMID: 25462993 DOI: 10.1016/j.bioorg.2014.10.005

Novel aromatic embedded Schiff bases have been synthesized in ionic liquid [bmim]Br and evaluated in vitro for their acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes inhibitory activities. Among the newly synthesized compounds, 5f, 5h and 7j displayed higher AChE enzyme inhibitory activities than standard drug, galanthamine, with IC50 values of 1.88, 2.05 and 2.03μM, respectively. Interestingly, all the compounds except for compound 5c displayed higher BChE inhibitories than standard with IC50 values ranging from 3.49 to 19.86μM. Molecular docking analysis for 5f and 7j possessing the most potent AChE and BChE inhibitory activities, disclosed their binding interaction templates to the active site of AChE and BChE enzymes, respectively.
Molecular docking studies and in vitro cholinesterase enzyme inhibitory activities of chemical constituents of Garcinia hombroniana

Jamila N, Yeong KK, Murugaiyah V, Atlas A, Khan I, Khan N, et al.

Nat Prod Res, 2015;29(1):86-90.
PMID: 25219673 DOI: 10.1080/14786419.2014.952228

Garcinia species are reported to possess antimicrobial, anti-inflammatory, anticancer, anti-HIV and anti-Alzheimer's activities. This study aimed to investigate the in vitro cholinesterase enzyme inhibitory activities of garcihombronane C (1), garcihombronane F (2), garcihombronane I (3), garcihombronane N (4), friedelin (5), clerosterol (6), spinasterol glucoside (7) and 3β-hydroxy lup-12,20(29)-diene (8) isolated from Garcinia hombroniana, and to perform molecular docking simulation to get insight into the binding interactions of the ligands and enzymes. The cholinesterase inhibitory activities were evaluated using acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes. In this study, compound 4 displayed the highest concentration-dependent inhibition of both AChE and BChE. Docking studies exhibited that compound 4 binds through hydrogen bonds to amino acid residues of AChE and BChE. The calculated docking and binding energies also supported the in vitro inhibitory profiles of IC50. In conclusion, garcihombronanes C, F, I and N (1-4) exhibited dual and moderate inhibitory activities against AChE and BChE.
Prenylated xanthones from mangosteen as promising cholinesterase inhibitors and their molecular docking studies

Khaw KY, Choi SB, Tan SC, Wahab HA, Chan KL, Murugaiyah V

Phytomedicine, 2014 Sep 25;21(11):1303-9.
PMID: 25172794 DOI: 10.1016/j.phymed.2014.06.017

Garcinia mangostana is a well-known tropical plant found mostly in South East Asia. The present study investigated acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activities of G. mangostana extract and its chemical constituents using Ellman's colorimetric method. Cholinesterase inhibitory-guided approach led to identification of six bioactive prenylated xanthones showing moderate to potent cholinesterases inhibition with IC50 values of lower than 20.5 μM. The most potent inhibitor of AChE was garcinone C while γ-mangostin was the most potent inhibitor of BChE with IC50 values of 1.24 and 1.78 μM, respectively. Among the xanthones, mangostanol, 3-isomangostin, garcinone C and α-mangostin are AChE selective inhibitors, 8-deoxygartanin is a BChE selective inhibitor while γ-mangostin is a dual inhibitor. Preliminary structure-activity relationship suggests the importance of the C-8 prenyl and C-7 hydroxy groups for good AChE and BChE inhibitory activities. The enzyme kinetic studies indicate that both α-mangostin and garcinone C are mixed-mode inhibitors, while γ-mangostin is a non-competitive inhibitor of AChE. In contrast, both γ-mangostin and garcinone C are uncompetitive inhibitors, while α-mangostin is a mixed-mode inhibitor of BChE. Molecular docking studies revealed that α-mangostin, γ-mangostin and garcinone C interacts differently with the five important regions of AChE and BChE. The nature of protein-ligand interactions is mainly hydrophobic and hydrogen bonding. These bioactive prenylated xanthones are worthy for further investigations.
Cholinesterase inhibitory activity versus aromatic core multiplicity: a facile green synthesis and molecular docking study of novel piperidone embedded thiazolopyrimidines

Basiri A, Murugaiyah V, Osman H, Kumar RS, Kia Y, Hooda A, et al.

Bioorg Med Chem, 2014 Jan 15;22(2):906-16.
PMID: 24369842 DOI: 10.1016/j.bmc.2013.11.020

Novel thiazolopyrimidine derivatives have been synthesized via microwave assisted, domino cascade methodology in ionic liquid and evaluated in vitro for their acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activities. Among the newly synthesized compounds 6d, 6a, 6e and 6b displayed higher AChE inhibitory activity than standard drug, galanthamine, with IC50 values of 0.53, 1.47, 1.62 and 2.05μM, respectively. Interestingly, all the compounds except for 6m-r and 6x displayed higher BChE inhibitory potentials than galanthamine with IC50 values ranging from 1.09 to 18.56μM. Molecular docking simulations for 6d possessing the most potent AChE and BChE inhibitory activities, disclosed its binding interactions at the active site gorge of AChE and BChE enzymes.

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