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Fulltext Complementary Analytical Platforms of NMR Spectroscopy and LCMS Analysis in the Metabolite Profiling of Isochrysis galbana

Bustamam MSA, Pantami HA, Azizan A, Shaari K, Min CC, Abas F, et al.

Mar Drugs, 2021 Mar 02;19(3).
PMID: 33801258 DOI: 10.3390/md19030139

This study was designed to profile the metabolites of Isochrysis galbana, an indigenous and less explored microalgae species. 1H Nuclear Magnetic Resonance (NMR) spectroscopy and Liquid Chromatography-Mass Spectrometry (LCMS) were used to establish the metabolite profiles of five different extracts of this microalga, which are hexane (Hex), ethyl acetate (EtOAc), absolute ethanol (EtOH), EtOH:water 1:1 (AqE), and 100% water (Aq). Partial least square discriminant analysis (PLS-DA) of the generated profiles revealed that EtOAc and Aq extracts contain a diverse range of metabolites as compared to the other extracts with a total of twenty-one metabolites, comprising carotenoids, polyunsaturated fatty acids, and amino acids, that were putatively identified from the NMR spectra. Meanwhile, thirty-two metabolites were successfully annotated from the LCMS/MS data, ten of which (palmitic acid, oleic acid, α-linolenic acid, arachidic acid, cholesterol, DHA, DPA, fucoxanthin, astaxanthin, and pheophytin) were similar to those present in the NMR profile. Another eleven glycerophospholipids were discovered using MS/MS-based molecular network (MN) platform. The results of this study, besides providing a better understanding of I.galbana's chemical make-up, will be of importance in exploring this species potential as a feed ingredient in the aquaculture industry.
In silico studies, nitric oxide, and cholinesterases inhibition activities of pyrazole and pyrazoline analogs of diarylpentanoids

Mohd Faudzi SM, Leong SW, Auwal FA, Abas F, Wai LK, Ahmad S, et al.

Arch Pharm (Weinheim), 2021 Jan;354(1):e2000161.
PMID: 32886410 DOI: 10.1002/ardp.202000161

A new series of pyrazole, phenylpyrazole, and pyrazoline analogs of diarylpentanoids (excluding compounds 3a, 4a, 5a, and 5b) was pan-assay interference compounds-filtered and synthesized via the reaction of diarylpentanoids with hydrazine monohydrate and phenylhydrazine. Each analog was evaluated for its anti-inflammatory ability via the suppression of nitric oxide (NO) on IFN-γ/LPS-activated RAW264.7 macrophage cells. The compounds were also investigated for their inhibitory capability toward acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), using a modification of Ellman's spectrophotometric method. The most potent NO inhibitor was found to be phenylpyrazole analog 4c, followed by 4e, when compared with curcumin. In contrast, pyrazole 3a and pyrazoline 5a were found to be the most selective and effective BChE inhibitors over AChE. The data collected from the single-crystal X-ray diffraction analysis of compound 5a were then applied in a docking simulation to determine the potential binding interactions that were responsible for the anti-BChE activity. The results obtained signify the potential of these pyrazole and pyrazoline scaffolds to be developed as therapeutic agents against inflammatory conditions and Alzheimer's disease.
Erratum to: Zebrafish phenotypic screen identifies novel Notch antagonists

Velaithan V, Okuda KS, Ng MF, Samat N, Leong SW, Faudzi SM, et al.

Invest New Drugs, 2017 04;35(2):250.
PMID: 28185040 DOI: 10.1007/s10637-017-0437-0
Zebrafish phenotypic screen identifies novel Notch antagonists

Velaithan V, Okuda KS, Ng MF, Samat N, Leong SW, Faudzi SM, et al.

Invest New Drugs, 2017 04;35(2):166-179.
PMID: 28058624 DOI: 10.1007/s10637-016-0423-y

Zebrafish represents a powerful in vivo model for phenotype-based drug discovery to identify clinically relevant small molecules. By utilizing this model, we evaluated natural product derived compounds that could potentially modulate Notch signaling that is important in both zebrafish embryogenesis and pathogenic in human cancers. A total of 234 compounds were screened using zebrafish embryos and 3 were identified to be conferring phenotypic alterations similar to embryos treated with known Notch inhibitors. Subsequent secondary screens using HEK293T cells overexpressing truncated Notch1 (HEK293TΔE) identified 2 compounds, EDD3 and 3H4MB, to be potential Notch antagonists. Both compounds reduced protein expression of NOTCH1, Notch intracellular domain (NICD) and hairy and enhancer of split-1 (HES1) in HEK293TΔE and downregulated Notch target genes. Importantly, EDD3 treatment of human oral cancer cell lines demonstrated reduction of Notch target proteins and genes. EDD3 also inhibited proliferation and induced G0/G1 cell cycle arrest of ORL-150 cells through inducing p27KIP1. Our data demonstrates the utility of the zebrafish phenotypic screen and identifying EDD3 as a promising Notch antagonist for further development as a novel therapeutic agent.
1 H-NMR metabolomics for evaluating the protective effect of Clinacanthus nutans (Burm. f) Lindau water extract against nitric oxide production in LPS-IFN-γ activated RAW 264.7 macrophages

Khoo LW, Kow ASF, Maulidiani M, Ang MY, Chew WY, Lee MT, et al.

Phytochem Anal, 2019 Jan;30(1):46-61.
PMID: 30183131 DOI: 10.1002/pca.2789

INTRODUCTION: Clinacanthus nutans, a small shrub that is native to Southeast Asia, is commonly used in traditional herbal medicine and as a food source. Its anti-inflammation properties is influenced by the metabolites composition, which can be determined by different binary extraction solvent ratio and extraction methods used during plant post-harvesting stage.
OBJECTIVE: Evaluate the relationship between the chemical composition of C. nutans and its anti-inflammatory properties using nuclear magnetic resonance (NMR) metabolomics approach.
METHODOLOGY: The anti-inflammatory effect of C. nutans air-dried leaves extracted using five different binary extraction solvent ratio and two extraction methods was determined based on their nitric oxide (NO) inhibition effect in lipopolysaccharide-interferon-gamma (LPS-IFN-γ) activated RAW 264.7 macrophages. The relationship between extract bioactivity and metabolite profiles and quantifications were established using 1 H-NMR metabolomics and liquid chromatography-tandem mass spectrometry (LC-MS/MS). The possible metabolite biosynthesis pathway was constructed to further strengthen the findings.
RESULTS: Water and sonication prepared air-dried leaves possessed the highest NO inhibition activity (IC50 = 190.43 ± 12.26 μg/mL, P
Novel 2-Benzoyl-6-(2,3-Dimethoxybenzylidene)-Cyclohexenol Confers Selectivity toward Human MLH1 Defective Cancer Cells through Synthetic Lethality

Song DSS, Leong SW, Ng KW, Abas F, Shaari K, Leong CO, et al.

SLAS Discov, 2019 06;24(5):548-562.
PMID: 30897027 DOI: 10.1177/2472555219831405

DNA mismatch repair (MMR) deficiency has been associated with a higher risk of developing colorectal, endometrial, and ovarian cancer, and confers resistance in conventional chemotherapy. In addition to the lack of treatment options that work efficaciously on these MMR-deficient cancer patients, there is a great need to discover new drug leads for this purpose. In this study, we screened through a library of commercial and semisynthetic natural compounds to identify potential synthetic lethal drugs that may selectively target MLH1 mutants using MLH1 isogenic colorectal cancer cell lines and various cancer cell lines with known MLH1 status. We identified a novel diarylpentanoid analogue, 2-benzoyl-6-(2,3-dimethoxybenzylidene)-cyclohexenol, coded as AS13, that demonstrated selective toxicity toward MLH1-deficient cancer cells. Subsequent analysis suggested AS13 induced elevated levels of oxidative stress, resulting in DNA damage where only the proficient MLH1 cells were able to be repaired and hence escaping cellular death. While AS13 is modest in potency and selectivity, this discovery has the potential to lead to further drug development that may offer better treatment options for cancer patients with MLH1 deficiency.
Fulltext Classification of Raw Stingless Bee Honeys by Bee Species Origins Using the NMR- and LC-MS-Based Metabolomics Approach

Razali MTA, Zainal ZA, Maulidiani M, Shaari K, Zamri Z, Mohd Idrus MZ, et al.

Molecules, 2018 Aug 28;23(9).
PMID: 30154302 DOI: 10.3390/molecules23092160

The official standard for quality control of honey is currently based on physicochemical properties. However, this method is time-consuming, cost intensive, and does not lead to information on the originality of honey. This study aims to classify raw stingless bee honeys by bee species origins as a potential classifier using the NMR-LCMS-based metabolomics approach. Raw stingless bee honeys were analysed and classified by bee species origins using proton nuclear magnetic resonance (¹H-NMR) spectroscopy and an ultra-high performance liquid chromatography-quadrupole time of flight mass spectrometry (UHPLC-QTOF MS) in combination with chemometrics tools. The honey samples were able to be classified into three different groups based on the bee species origins of Heterotrigona itama, Geniotrigona thoracica, and Tetrigona apicalis. d-Fructofuranose (H. itama honey), β-d-Glucose, d-Xylose, α-d-Glucose (G. thoracica honey), and l-Lactic acid, Acetic acid, l-Alanine (T. apicalis honey) ident d-Fructofuranose identified via ¹H-NMR data and the diagnostic ions of UHPLC-QTOF MS were characterized as the discriminant metabolites or putative chemical markers. It could be suggested that the quality of honey in terms of originality and purity can be rapidly determined using the classification technique by bee species origins via the ¹H-NMR- and UHPLC-QTOF MS-based metabolomics approach.
Fulltext Microplastics Pollution as an Invisible Potential Threat to Food Safety and Security, Policy Challenges and the Way Forward

Usman S, Abdull Razis AF, Shaari K, Amal MNA, Saad MZ, Mat Isa N, et al.

Int J Environ Res Public Health, 2020 Dec 21;17(24).
PMID: 33371479 DOI: 10.3390/ijerph17249591

Technological advances, coupled with increasing demands by consumers, have led to a drastic increase in plastic production. After serving their purposes, these plastics reach our water bodies as their destination and become ingested by aquatic organisms. This ubiquitous phenomenon has exposed humans to microplastics mostly through the consumption of sea food. This has led the World Health Organization (WHO) to make an urgent call for the assessment of environmental pollution due to microplastics and its effect on human health. This review summarizes studies between 1999 and 2020 in relation to microplastics in aquatic ecosystems and human food products, their potential toxic effects as elicited in animal studies, and policies on their use and disposal. There is a paucity of information on the toxicity mechanisms of microplastics in animal studies, and despite their documented presence in food products, no policy has been in place so far, to monitor and regulates microplastics in commercial foods meant for human consumption. Although there are policies and regulations with respect to plastics, these are only in a few countries and in most instances are not fully implemented due to socioeconomic reasons, so they do not address the problem across the entire life cycle of plastics from production to disposal. More animal research to elucidate pathways and early biomarkers of microplastic toxicity that can easily be detected in humans is needed. This is to create awareness and influence policies that will address this neglected threat to food safety and security.
Fulltext Embryonic mercury exposure in zebrafish: Alteration of metabolites and gene expression, related to visual and behavioral impairments

Abu Bakar N, Wan Ibrahim WN, Zulkiflli AR, Saleh Hodin NA, Kim TY, Ling YS, et al.

Ecotoxicol Environ Saf, 2023 May;256:114862.
PMID: 37004432 DOI: 10.1016/j.ecoenv.2023.114862

The widespread presence of mercury, a heavy metal found in the environment and used in numerous industries and domestic, raises concerns about its potential impact on human health. Nevertheless, the adverse effects of this environmental toxicant at low concentrations are often underestimated. There are emerging studies showing that accumulation of mercury in the eye may contribute to visual impairment and a comorbidity between autism spectrum disorders (ASD) trait and visual impairment. However, the underlying mechanism of visual impairment in humans and rodents is challenging. In response to this issue, zebrafish larvae with a cone-dominated retinal visual system were exposed to 100 nM mercury chloride (HgCl2), according to our previous study, followed by light-dark stimulation, a social assay, and color preference to examine the functionality of the visual system in relation to ASD-like behavior. Exposure of embryos to HgCl2 from gastrulation to hatching increased locomotor activity in the dark, reduced shoaling and exploratory behavior, and impaired color preference. Defects in microridges as the first barrier may serve as primary tools for HgCl2 toxicity affecting vision. Depletion of polyunsaturated fatty acids (PUFAs), linoleic acid, arachidonic acid (ARA), alpha-linoleic acid, docosahexaenoic acid (DHA), stearic acid, L-phenylalanine, isoleucine, L-lysine, and N-acetylputrescine, along with the increase of gamma-aminobutyric acid (GABA), sphingosine-1-phosphate, and citrulline assayed by liquid chromatography-mass spectrometry (LC-MS) suggest that these metabolites serve as biomarkers of retinal impairments that affect vision and behavior. Although suppression of adsl, shank3a, tsc1b, and nrxn1a gene expression was observed, among these tsc1b showed more positive correlation with ASD. Collectively, these results contribute new insights into the possible mechanism of mercury toxicity give rise to visual, cognitive, and social deficits in zebrafish.
Fulltext Preliminary insight on diarylpentanoids as potential antimalarials: In silico, in vitro pLDH and in vivo zebrafish toxicity assessment

Ramli AH, Swain P, Mohd Fahmi MSA, Abas F, Leong SW, Tejo BA, et al.

Heliyon, 2024 Mar 15;10(5):e27462.
PMID: 38495201 DOI: 10.1016/j.heliyon.2024.e27462

Malaria remains a major public health problem worldwide, including in Southeast Asia. Chemotherapeutic agents such as chloroquine (CQ) are effective, but problems with drug resistance and toxicity have necessitated a continuous search for new effective antimalarial agents. Here we report on a virtual screening of ∼300 diarylpentanoids and derivatives, in search of potential Plasmodium falciparum lactate dehydrogenase (PfLDH) inhibitors with acceptable drug-like properties. Several molecules with binding affinities comparable to CQ were chosen for in vitro validation of antimalarial efficacy. Among them, MS33A, MS33C and MS34C are the most promising against CQ-sensitive (3D7) with EC50 values of 1.6, 2.5 and 3.1 μM, respectively. Meanwhile, MS87 (EC50 of 1.85 μM) shown the most active against the CQ-resistant Gombak A strain, and MS33A and MS33C the most effective P. knowlesi inhibitors (EC50 of 3.6 and 5.1 μM, respectively). The in vitro cytotoxicity of selected diarylpentanoids (MS33A, MS33C, MS34C and MS87) was tested on Vero mammalian cells to evaluate parasite selectivity (SI), showing moderate to low cytotoxicity (CC50 > 82 μM). In addition, MS87 exhibited a high SI and the lowest resistance index (RI), suggesting that MS87 may exert effective parasite inhibition with low resistance potential in the CQ-resistant P. falciparum strain. Furthermore, the in vivo toxicity of the molecules on early embryonic development, the cardiovascular system, heart rate, motor activity and apoptosis were assessed in a zebrafish animal model. The overall results indicate the preliminary potential of diarylpentanoids, which need further investigation for their development as new antimalarial agents.
Anti-infective activities of 11 plants species used in traditional medicine in Malaysia

Nor Azman NS, Hossan MS, Nissapatorn V, Uthaipibull C, Prommana P, Jin KT, et al.

Exp Parasitol, 2018 Nov;194:67-78.
PMID: 30268422 DOI: 10.1016/j.exppara.2018.09.020

Treatment of drug resistant protozoa, bacteria, and viruses requires new drugs with alternative chemotypes. Such compounds could be found from Southeast Asian medicinal plants. The present study examines the cytotoxic, antileishmanial, and antiplasmodial effects of 11 ethnopharmacologically important plant species in Malaysia. Chloroform extracts were tested for their toxicity against MRC-5 cells and Leishmania donovani by MTT, and chloroquine-resistant Plasmodium falciparum K1 strain by Histidine-Rich Protein II ELISA assays. None of the extract tested was cytotoxic to MRC-5 cells. Extracts of Uvaria grandiflora, Chilocarpus costatus, Tabernaemontana peduncularis, and Leuconotis eugenifolius had good activities against L. donovani with IC50

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