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Metabolomics in Systems Biology

Baharum SN, Azizan KA

Adv Exp Med Biol, 2018 11 2;1102:51-68.
PMID: 30382568 DOI: 10.1007/978-3-319-98758-3_4

Over the last decade, metabolomics has continued to grow rapidly and is considered a dynamic technology in envisaging and elucidating complex phenotypes in systems biology area. The advantage of metabolomics compared to other omics technologies such as transcriptomics and proteomics is that these later omics only consider the intermediate steps in the central dogma pathway (mRNA and protein expression). Meanwhile, metabolomics reveals the downstream products of gene and expression of proteins. The most frequently used tools are nuclear magnetic resonance (NMR) spectroscopy and mass spectrometry (MS). Some of the common MS-based analyses are gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-mass spectrometry (LC-MS). These high-throughput instruments play an extremely crucial role in discovery metabolomics to generate data needed for further analysis. In this chapter, the concept of metabolomics in the context of systems biology is discussed and provides examples of its application in human disease studies, plant responses towards stress and abiotic resistance and also microbial metabolomics for biotechnology applications. Lastly, a few case studies of metabolomics analysis are also presented, for example, investigation of an aromatic herbal plant, Persicaria minor metabolome and microbial metabolomics for metabolic engineering applications.
Fulltext Metabolic profiling of Lactococcus lactis under different culture conditions

Azizan KA, Baharum SN, Mohd Noor N

Molecules, 2012 Jul 03;17(7):8022-36.
PMID: 22759915 DOI: 10.3390/molecules17078022

Gas chromatography mass spectrometry (GC-MS) and headspace gas chromatography mass spectrometry (HS/GC-MS) were used to study metabolites produced by Lactococcus lactis subsp. cremoris MG1363 grown at a temperature of 30 °C with and without agitation at 150 rpm, and at 37 °C without agitation. It was observed that L. lactis produced more organic acids under agitation. Primary alcohols, aldehydes, ketones and polyols were identified as the corresponding trimethylsilyl (TMS) derivatives, whereas amino acids and organic acids, including fatty acids, were detected through methyl chloroformate derivatization. HS analysis indicated that branched-chain methyl aldehydes, including 2-methylbutanal, 3-methylbutanal, and 2-methylpropanal are degdradation products of isoleucine, leucine or valine. Multivariate analysis (MVA) using partial least squares discriminant analysis (PLS-DA) revealed the major differences between treatments were due to changes of amino acids and fermentation products.
Fulltext Transcriptome of Aquilaria malaccensis containing agarwood formed naturally and induced artificially

Abdul Kadir FA, Azizan KA, Othman R

BMC Res Notes, 2021 Mar 25;14(1):117.
PMID: 33766087 DOI: 10.1186/s13104-021-05532-9

OBJECTIVES: Agarwood is the aromatic heartwood formed upon wounding of Aquilaria trees either naturally formed due to physical wound sustained from natural phenomena followed by microbial infection, or artificially induced using different inoculation methods. Different induction methods produce agarwoods with different aromas which have impacts on their commercial values. In lieu of elucidating the molecular mechanisms of agarwood formation under different treatment conditions, the transcriptome profiles of trunk tissues from healthy A. malaccensis tree, and naturally and artificially induced trees were obtained.
DATA DESCRIPTION: The transcriptome of trunk tissues from healthy A. malaccensis, and naturally and artificially induced trees were sequenced using Illumina HiSeq™ 4000 platform which resulted in a total of 38.4 Gb clean reads with Q30 rate of at least 91%. The transcriptome consists of 85,986 unigenes containing 1305 bases on average which were annotated against several databases. From this, 44,654 unigenes were mapped to 290 metabolic pathways in the Kyoto Encyclopedia of Genes and Genomes database. These transcriptome data represent considerable contribution towards Aquilaria transcriptome data and enhance current knowledge in comprehending the molecular mechanisms underlying agarwood formation in Aquilaria spp.
Fulltext Datasets of essential oils from naturally formed and synthetically induced Aquilaria malaccensis agarwoods

Abdul Kadir FA, Azizan KA, Othman R

Data Brief, 2020 Feb;28:104987.
PMID: 32226799 DOI: 10.1016/j.dib.2019.104987

Agarwood is the highly valuable fragrant resin of the wounded Aquilaria spp. trees widely used in fragrances, medicines and incenses. Among the Aquilaria spp., A. malaccensis is the primary producer and is mainly found in Indonesia and Malaysia. In normal condition, agarwood is naturally formed in Aquilaria trees as a defense mechanism upon physical damage or microbial infection on the trees, which is a slow process that occurs over several years. The high demand in agarwood has spurred the development of various artificial inoculation methods where agarwood formation is synthetically induced in a shorter period of time. However, the synthetic induction method produces agarwood with aromas different from the naturally formed agarwood. To understand the changes in the agarwoods produced from different induction conditions, metabolite profiling of agarwood essential oil from A. malaccensis has been performed. The essential oils of healthy undamaged tree trunks and, naturally formed and synthetically induced agarwoods were obtained using hydrodistillation (HS) method and analysed using gas chromatography mass spectrometer (GC-MS). These data will provide valuable resources for chemical components of agarwood produced by the species in the genus Aquilaria.
Fulltext Mass spectrometry data of metabolomics analysis of Nepenthes pitchers

Rosli MAF, Azizan KA, Baharum SN, Goh HH

Data Brief, 2017 Oct;14:295-297.
PMID: 28795107 DOI: 10.1016/j.dib.2017.07.068

Hybridisation plays a significant role in the evolution and diversification of plants. Hybridisation among Nepenthes species is extensive, either naturally or man-made. To investigate the effects of hybridisation on the chemical compositions, we carried out metabolomics study on pitcher tissue of Nepenthes ampullaria, Nepenthes rafflesiana and their hybrid, Nepenthes × hookeriana. Pitcher samples were harvested and extracted in methanol:chloroform:water via sonication-assisted extraction before analysed using LC-TOF-MS. MS data were analysed using XCMS online version 2.2.5. This is the first MS data report towards the profiling, identification and comprehensive comparison of metabolites present in Nepenthes species.
Fulltext 13C based proteinogenic amino acid (PAA) and metabolic flux ratio analysis of Lactococcus lactis reveals changes in pentose phosphate (PP) pathway in response to agitation and temperature related stresses

Azizan KA, Ressom HW, Mendoza ER, Baharum SN

PeerJ, 2017;5:e3451.
PMID: 28695065 DOI: 10.7717/peerj.3451

Lactococcus lactis subsp. cremoris MG1363 is an important starter culture for dairy fermentation. During industrial fermentations, L. lactis is constantly exposed to stresses that affect the growth and performance of the bacterium. Although the response of L. lactis to several stresses has been described, the adaptation mechanisms at the level of in vivo fluxes have seldom been described. To gain insights into cellular metabolism, 13C metabolic flux analysis and gas chromatography mass spectrometry (GC-MS) were used to measure the flux ratios of active pathways in the central metabolism of L. lactis when subjected to three conditions varying in temperature (30°C, 37°C) and agitation (with and without agitation at 150 rpm). Collectively, the concentrations of proteinogenic amino acids (PAAs) and free fatty acids (FAAs) were compared, and Pearson correlation analysis (r) was calculated to measure the pairwise relationship between PAAs. Branched chain and aromatic amino acids, threonine, serine, lysine and histidine were correlated strongly, suggesting changes in flux regulation in glycolysis, the pentose phosphate (PP) pathway, malic enzyme and anaplerotic reaction catalysed by pyruvate carboxylase (pycA). Flux ratio analysis revealed that glucose was mainly converted by glycolysis, highlighting the stability of L. lactis' central carbon metabolism despite different conditions. Higher flux ratios through oxaloacetate (OAA) from pyruvate (PYR) reaction in all conditions suggested the activation of pyruvate carboxylate (pycA) in L. lactis, in response to acid stress during exponential phase. Subsequently, more significant flux ratio differences were seen through the oxidative and non-oxidative pentose phosphate (PP) pathways, malic enzyme, and serine and C1 metabolism, suggesting NADPH requirements in response to environmental stimuli. These reactions could play an important role in optimization strategies for metabolic engineering in L. lactis. Overall, the integration of systematic analysis of amino acids and flux ratio analysis provides a systems-level understanding of how L. lactis regulates central metabolism under various conditions.
Fulltext ESI-LC-MS based-metabolomics data of mangosteen (Garcinia mangostana Linn.) fruit pericarp, aril and seed at different ripening stages

Mamat SF, Azizan KA, Baharum SN, Noor NM, Aizat WM

Data Brief, 2018 Apr;17:1074-1077.
PMID: 29876463 DOI: 10.1016/j.dib.2018.02.033

Fruit ripening is a complex phenomenon involving a series of biochemical, physiological and organoleptic changes. Ripening process in mangosteen (Garcinia mangostana Linn.) is unique of which the fruit will only ripen properly if harvested during its middle stage (emergence of purple/pink colour) but not earlier (green stage). The knowledge on the molecular mechanism and regulation behind this phenomenon is still limited. Hence, electrospray ionization liquid chromatography mass spectrometry (ESI-LC-MS) based metabolomics analysis was applied to determine the metabolome of mangosteen ripening. Specifically, mangosteen pericarp, aril and seed were collected at four different ripening stages (stage 0: green, stage 2: yellowish with pink patches, stage 4: brownish red and stage 6: dark purple) and subjected to metabolite profiling analysis. The data provided in this article have been deposited to the EMBL-EBI MetaboLights database (DOI: 10.1093/nar/gks1004. PubMed PMID: 23109552) with the identifier MTBLS595. The complete dataset can be accessed here https://www.ebi.ac.uk/metabolights/MTBLS595.
Fulltext Mass spectrometry dataset for LC-MS metabolomics analysis of Garcinia mangostana L. seed development

Mazlan O, Aizat WM, Baharum SN, Azizan KA, Noor NM

Data Brief, 2018 Dec;21:548-551.
PMID: 30370325 DOI: 10.1016/j.dib.2018.10.025

Garcinia mangostana L. (mangosteen) seed is recalcitrant, prone to low temperature and drying which limit its long-term storage. Therefore, it is imperative to understand the metabolic changes throughout its development, to shed some light into the recalcitrant nature of this seed. We performed metabolomics analysis on mangosteen seed at different stages of development; six, eight, ten, twelve and fourteen weeks after anthesis. Seed samples were subjected to methanol extraction prior analysis using liquid chromatography - mass spectrometry (LC-MS). The MS data acquired were analyzed using ProfileAnalysis (version 2.1). This data article refers to the article entitled "Metabolomics analysis of developing Garcinia mangostana seed reveals modulated levels of sugars, organic acids and phenylpropanoid compounds" (Mazlan et al., 2018) [1].
Fulltext Growth modulation and metabolic responses of Ganoderma boninense to salicylic acid stress

Ong CE, Ahmad R, Goh YK, Azizan KA, Baharum SN, Goh KJ

PLoS One, 2021;16(12):e0262029.
PMID: 34972183 DOI: 10.1371/journal.pone.0262029

Various phenolic compounds have been screened against Ganoderma boninense, the fungal pathogen causing basal stem rot in oil palms. In this study, we focused on the effects of salicylic acid (SA) on the growth of three G. boninense isolates with different levels of aggressiveness. In addition, study on untargeted metabolite profiling was conducted to investigate the metabolomic responses of G. boninense towards salicylic acid. The inhibitory effects of salicylic acid were both concentration- (P < 0.001) and isolate-dependent (P < 0.001). Also, growth-promoting effect was observed in one of the isolates at low concentrations of salicylic acid where it could have been utilized by G. boninense as a source of carbon and energy. Besides, adaptation towards salicylic acid treatment was evident in this study for all isolates, particularly at high concentrations. In other words, inhibitory effect of salicylic acid treatment on the fungal growth declined over time. In terms of metabolomics response to salicylic acid treatment, G. boninense produced several metabolites such as coumarin and azatyrosine, which suggests that salicylic acid modulates the developmental switch in G. boninense towards the defense mode for its survival. Furthermore, the liquid chromatography time-of-flight mass spectrometry (LC-TOF-MS) analysis showed that the growth of G. boninense on potato dextrose agar involved at least four metabolic pathways: amino acid metabolism, lipid pathway, tryptophan pathway and phenylalanine pathway. Overall, there were 17 metabolites that contributed to treatment separation, each with P<0.005. The release of several antimicrobial metabolites such as eudistomin I may enhance G. boninense's competitiveness against other microorganisms during colonisation. Our findings demonstrated the metabolic versatility of G. boninense towards changes in carbon sources and stress factors. G. boninense was shown to be capable of responding to salicylic acid treatment by switching its developmental stage.
Fulltext UPLC-TOF-MS/MS-Based Metabolomics Analysis Reveals Species-Specific Metabolite Compositions in Pitchers of Nepenthes ampullaria, Nepenthes rafflesiana, and Their Hybrid Nepenthes × hookeriana

Rosli MAF, Mediani A, Azizan KA, Baharum SN, Goh HH

Front Plant Sci, 2021;12:655004.
PMID: 33968110 DOI: 10.3389/fpls.2021.655004

Hybridization is key to the evolution and diversity of plants in nature. Nepenthaceae comprises a family of diverse tropical carnivorous pitcher plant species with extensive hybridization. However, there is no study to date on the metabolite expression of hybrids in this family. We performed a non-targeted metabolomics analysis of the pitchers of two Nepenthes species with different dietary habits, namely, the semi-detritivorous N. ampullaria and carnivorous N. rafflesiana with their hybrid (N. × hookeriana) for a comparative study. The whole-pitcher samples were extracted in methanol:chloroform:water (3:1:1) via sonication-assisted extraction and analyzed using ultra-performance liquid chromatography time-of-flight mass spectrometry (UPLC-TOF-MS) followed by data analysis to profile chemical compositions. A total of 1,441 metabolite features were profiled from the three species in which 43.3% of features in the hybrid samples were not found in either of its parents. The partial least squares discriminant analysis (PLS-DA) found 324 metabolite features with variable in projection (VIP) values greater than one in which 55 features were statistically significant. This showed that the hybrid is closer to N. rafflesiana, which is consistent to the previous study on gene and protein expressions. A total of 105 metabolites were putatively identified with manual searches using public metabolite databases. Phenols were detected to be the most abundant secondary metabolites due to a high flavonoid content, especially in N. rafflesiana. The most abundant feature 476.3s:449.102 was found to be the most significant VIP for distinguishing between the three species as a chemical marker. This is the first study comparing metabolites in the carnivory organs of different Nepenthes species with comprehensive profiling and putative identification. The differential metabolite compositions in the pitchers of different species might have ecological implications with the hybrid showing intermediate phenotype between the parents as well as manifesting unique metabolites. However, there is no clear evidence of metabolites related to the differences in dietary habits between the hybrid and the two parent species.
Fulltext Systematic Multi-Omics Integration (MOI) Approach in Plant Systems Biology

Jamil IN, Remali J, Azizan KA, Nor Muhammad NA, Arita M, Goh HH, et al.

Front Plant Sci, 2020;11:944.
PMID: 32754171 DOI: 10.3389/fpls.2020.00944

Across all facets of biology, the rapid progress in high-throughput data generation has enabled us to perform multi-omics systems biology research. Transcriptomics, proteomics, and metabolomics data can answer targeted biological questions regarding the expression of transcripts, proteins, and metabolites, independently, but a systematic multi-omics integration (MOI) can comprehensively assimilate, annotate, and model these large data sets. Previous MOI studies and reviews have detailed its usage and practicality on various organisms including human, animals, microbes, and plants. Plants are especially challenging due to large poorly annotated genomes, multi-organelles, and diverse secondary metabolites. Hence, constructive and methodological guidelines on how to perform MOI for plants are needed, particularly for researchers newly embarking on this topic. In this review, we thoroughly classify multi-omics studies on plants and verify workflows to ensure successful omics integration with accurate data representation. We also propose three levels of MOI, namely element-based (level 1), pathway-based (level 2), and mathematical-based integration (level 3). These MOI levels are described in relation to recent publications and tools, to highlight their practicality and function. The drawbacks and limitations of these MOI are also discussed for future improvement toward more amenable strategies in plant systems biology.
Omics approaches to unravel insecticide resistance mechanism in Bemisia tabaci (Gennadius) (Hemiptera: Aleyrodidae)

Rosli MAF, Syed Jaafar SN, Azizan KA, Yaakop S, Aizat WM

PeerJ, 2024;12:e17843.
PMID: 39247549 DOI: 10.7717/peerj.17843

Bemisia tabaci (Gennadius) whitefly (BtWf) is an invasive pest that has already spread worldwide and caused major crop losses. Numerous strategies have been implemented to control their infestation, including the use of insecticides. However, prolonged insecticide exposures have evolved BtWf to resist these chemicals. Such resistance mechanism is known to be regulated at the molecular level and systems biology omics approaches could shed some light on understanding this regulation wholistically. In this review, we discuss the use of various omics techniques (genomics, transcriptomics, proteomics, and metabolomics) to unravel the mechanism of insecticide resistance in BtWf. We summarize key genes, enzymes, and metabolic regulation that are associated with the resistance mechanism and review their impact on BtWf resistance. Evidently, key enzymes involved in the detoxification system such as cytochrome P450 (CYP), glutathione S-transferases (GST), carboxylesterases (COE), UDP-glucuronosyltransferases (UGT), and ATP binding cassette transporters (ABC) family played key roles in the resistance. These genes/proteins can then serve as the foundation for other targeted techniques, such as gene silencing techniques using RNA interference and CRISPR. In the future, such techniques will be useful to knock down detoxifying genes and crucial neutralizing enzymes involved in the resistance mechanism, which could lead to solutions for coping against BtWf infestation.
Fulltext Gut Microbiota Signature Among Asian Post-gestational Diabetes Women Linked to Macronutrient Intakes and Metabolic Phenotypes

Hasain Z, Raja Ali RA, Abdul Razak S, Azizan KA, El-Omar E, Razalli NH, et al.

Front Microbiol, 2021;12:680622.
PMID: 34248897 DOI: 10.3389/fmicb.2021.680622

Aberrant gut microbiota dysbiosis in women with a previous history of gestational diabetes mellitus (post-GDM) was comparable to that in adults with type 2 diabetes mellitus (T2DM). Nonetheless, potential relationships between diet, gut microbiota, and metabolic phenotypes in post-GDM women after delivery are yet to be discovered. In this research, we assessed the relationship of the macronutrient intakes, gut microbiota composition, and metabolic phenotypes (i.e., anthropometrics and glycemic control) in post-GDM women with and without postpartum glucose intolerance (GI). About 24 post-GDM women were included in this study, 14 women were grouped in the GI group and 10 women were grouped in the normal glucose tolerance (NGT) group according to oral glucose tolerance test. Macronutrient intake assessment using a 3-day dietary record, anthropometric measurements, biochemical analyses, and fecal sampling were done during 3-6 months postpartum. Gut microbiota profiling was determined using 16S rRNA genes sequencing targeting the V3-V4 regions. The relationships between macronutrient intakes, gut microbiota composition, and metabolic phenotypes were evaluated using Pearson's correlation coefficient and stepwise regression analyses. In this study, most post-GDM women had significantly poor dietary fiber adherence than the nutritional recommendations. Women from the GI group have significantly higher fasting blood glucose (FBG), HbA1c, and homeostasis model assessment-estimated insulin resistance (HOMA-IR) levels compared to the NGT group. The group also showed significant elevation of high-sensitivity C-reactive protein (hs-CRP) level when compared to the normal value. Specific gut microbial taxa derived from Proteobacteria and Bacteroidetes such as Parasutterella, Aquicella, Haliscomenobacter, and Prevotellaceae_NK3B31_group were significantly abundant in the GI group compared to the NGT group. Prevotellaceae_NK3B31_group was significantly associated with high FBG, HOMA-IR, and HbA1c levels. Low fiber and monounsaturated fatty acids intakes were associated with Lactobacillus. Meanwhile, Lactobacillus was associated with high body mass index, waist circumference, 2-h postprandial blood glucose, and hs-CRP levels. Our study suggested that macronutrient intake is an important predictor of gut microbiota dysbiosis and is associated with obesity, low-grade inflammation, and poor glycemic control in post-GDM women. Hence, dietary intake modification to remodel gut microbiota composition is a promising T2DM preventive strategy in post-GDM women.
Fulltext Metabolic Profile of Scytalidium parasiticum-Ganoderma boninense Co-Cultures Revealed the Alkaloids, Flavonoids and Fatty Acids that Contribute to Anti-Ganoderma Activity

Ahmad R, Lim CK, Marzuki NF, Goh YK, Azizan KA, Goh YK, et al.

Molecules, 2020 Dec 16;25(24).
PMID: 33339375 DOI: 10.3390/molecules25245965

In solving the issue of basal stem rot diseases caused by Ganoderma, an investigation of Scytalidium parasiticum as a biological control agent that suppresses Ganoderma infection has gained our interest, as it is more environmentally friendly. Recently, the fungal co-cultivation has emerged as a promising method to discover novel antimicrobial metabolites. In this study, an established technique of co-culturing Scytalidium parasiticum and Ganoderma boninense was applied to produce and induce metabolites that have antifungal activity against G. boninense. The crude extract from the co-culture media was applied to a High Performance Liquid Chromatography (HPLC) preparative column to isolate the bioactive compounds, which were tested against G. boninense. The fractions that showed inhibition against G. boninense were sent for a Liquid Chromatography-Time of Flight-Mass Spectrometry (LC-TOF-MS) analysis to further identify the compounds that were responsible for the microbicidal activity. Interestingly, we found that eudistomin I, naringenin 7-O-beta-D-glucoside and penipanoid A, which were present in different abundances in all the active fractions, except in the control, could be the antimicrobial metabolites. In addition, the abundance of fatty acids, such as oleic acid and stearamide in the active fraction, also enhanced the antimicrobial activity. This comprehensive metabolomics study could be used as the basis for isolating biocontrol compounds to be applied in oil palm fields to combat a Ganoderma infection.
Fulltext Metabolomics data of Mitragyna speciosa leaf using LC-ESI-TOF-MS

Veeramohan R, Azizan KA, Aizat WM, Goh HH, Mansor SM, Yusof NSM, et al.

Data Brief, 2018 Jun;18:1212-1216.
PMID: 29900296 DOI: 10.1016/j.dib.2018.04.001

Mitragyna speciosa is a psychoactive plant known as "ketum" in Malaysia and "kratom" in Thailand. This plant is distinctly known to produce two important alkaloids, namely mitragynine (MG) and 7-hydroxymitragynine (7-OH-MG) that can bind to opioid receptors [1]. MG was reported to exhibit antidepressant properties in animal studies [2]. These compounds were also proposed to have the potential to replace opioid analgesics with much lower risks of side effects [3]. To date, there are only over 40 metabolites identified in M. speciosa [4,5]. To obtain a more complete profile of secondary metabolites in ketum, we performed metabolomics study using mature leaves of the green M. speciosa variety. The leaf samples were extracted using methanol prior to liquid chromatography-electrospray ionization-time of flight-mass spectrometry (LC-ESI-TOF-MS) analysis. This data can be useful to for the identification of unknown metabolites that are associated with alkaloid biosynthesis pathway in M. speciosa.
Fulltext Bacterial Metabolomics: Sample Preparation Methods

Mohd Kamal K, Mahamad Maifiah MH, Abdul Rahim N, Hashim YZH, Abdullah Sani MS, Azizan KA

Biochem Res Int, 2022;2022:9186536.
PMID: 35465444 DOI: 10.1155/2022/9186536

Metabolomics is a comprehensive analysis of metabolites existing in biological systems. As one of the important "omics" tools, the approach has been widely employed in various fields in helping to better understand the complex cellular metabolic states and changes. Bacterial metabolomics has gained a significant interest as bacteria serve to provide a better subject or model at systems level. The approach in metabolomics is categorized into untargeted and targeted which serves different paradigms of interest. Nevertheless, the bottleneck in metabolomics has been the sample or metabolite preparation method. A custom-made method and design for a particular species or strain of bacteria might be necessary as most studies generally refer to other bacteria or even yeast and fungi that may lead to unreliable analysis. The paramount aspect of metabolomics design comprises sample harvesting, quenching, and metabolite extraction procedures. Depending on the type of samples and research objective, each step must be at optimal conditions which are significantly important in determining the final output. To date, there are no standardized nor single designated protocols that have been established for a specific bacteria strain for untargeted and targeted approaches. In this paper, the existing and current developments of sample preparation methods of bacterial metabolomics used in both approaches are reviewed. The review also highlights previous literature of optimized conditions used to propose the most ideal methods for metabolite preparation, particularly for bacterial cells. Advantages and limitations of methods are discussed for future improvement of bacterial metabolomics.
Fulltext Tocotrienol-Rich Fraction of Palm Oil Improves Behavioral Impairments and Regulates Metabolic Pathways in AβPP/PS1 Mice

Durani LW, Hamezah HS, Ibrahim NF, Yanagisawa D, Nasaruddin ML, Mori M, et al.

J Alzheimers Dis, 2018;64(1):249-267.
PMID: 29889072 DOI: 10.3233/JAD-170880

We have recently shown that the tocotrienol-rich fraction (TRF) of palm oil, a mixture of vitamin E analogs, improves amyloid pathology in vitro and in vivo. However, precise mechanisms remain unknown. In this study, we examined the effects of long-term (10 months) TRF treatment on behavioral impairments and brain metabolites in (15 months old) AβPP/PS1 double transgenic (Tg) Alzheimer's disease (AD) mice. The open field test, Morris water maze, and novel object recognition tasks revealed improved exploratory activity, spatial learning, and recognition memory, respectively, in TRF-treated Tg mice. Brain metabolite profiling of wild-type and Tg mice treated with and without TRF was performed using ultrahigh performance liquid chromatography (UHPLC) coupled to high-resolution accurate mass (HRAM)-orbitrap tandem mass spectrometry (MS/MS). Metabolic pathway analysis found perturbed metabolic pathways that linked to AD. TRF treatment partly ameliorated metabolic perturbations in Tg mouse hippocampus. The mechanism of this pre-emptive activity may occur via modulation of metabolic pathways dependent on Aβ interaction or independent of Aβ interaction.
Fulltext Comparative metabolomics analysis reveals alkaloid repertoires in young and mature Mitragyna speciosa (Korth.) Havil. Leaves

Veeramohan R, Zamani AI, Azizan KA, Goh HH, Aizat WM, Razak MFA, et al.

PLoS One, 2023;18(3):e0283147.
PMID: 36943850 DOI: 10.1371/journal.pone.0283147

The fresh leaves of Mitragyna speciosa (Korth.) Havil. have been traditionally consumed for centuries in Southeast Asia for its healing properties. Although the alkaloids of M. speciosa have been studied since the 1920s, comparative and systematic studies of metabolite composition based on different leaf maturity levels are still lacking. This study assessed the secondary metabolite composition in two different leaf stages (young and mature) of M. speciosa, using an untargeted liquid chromatography-electrospray ionisation-time-of-flight-mass spectrometry (LC-ESI-TOF-MS) metabolite profiling. The results revealed 86 putatively annotated metabolite features (RT:m/z value) comprising 63 alkaloids, 10 flavonoids, 6 terpenoids, 3 phenylpropanoids, and 1 of each carboxylic acid, glucoside, phenol, and phenolic aldehyde. The alkaloid features were further categorised into 14 subclasses, i.e., the most abundant class of secondary metabolites identified. As per previous reports, indole alkaloids are the most abundant alkaloid subclass in M. speciosa. The result of multivariate analysis (MVA) using principal component analysis (PCA) showed a clear separation of 92.8% between the young and mature leaf samples, indicating a high variance in metabolite levels between them. Akuammidine, alstonine, tryptamine, and yohimbine were tentatively identified among the many new alkaloids reported in this study, depicting the diverse biological activities of M. speciosa. Besides delving into the knowledge of metabolite distribution in different leaf stages, these findings have extended the current alkaloid repository of M. speciosa for a better understanding of its pharmaceutical potential.

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