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Fulltext Bioactive Constituents of Zanthoxylum rhetsa Bark and Its Cytotoxic Potential against B16-F10 Melanoma Cancer and Normal Human Dermal Fibroblast (HDF) Cell Lines

Santhanam RK, Ahmad S, Abas F, Safinar Ismail I, Rukayadi Y, Tayyab Akhtar M, et al.

Molecules, 2016 May 24;21(6).
PMID: 27231889 DOI: 10.3390/molecules21060652

Zanthoxylum rhetsa is an aromatic tree, known vernacularly as "Indian Prickly Ash". It has been predominantly used by Indian tribes for the treatment of many infirmities like diabetes, inflammation, rheumatism, toothache and diarrhea. In this study, we identified major volatile constituents present in different solvent fractions of Z. rhetsa bark using GC-MS analysis and isolated two tetrahydrofuran lignans (yangambin and kobusin), a berberine alkaloid (columbamine) and a triterpenoid (lupeol) from the bioactive chloroform fraction. The solvent fractions and purified compounds were tested for their cytotoxic potential against human dermal fibroblasts (HDF) and mouse melanoma (B16-F10) cells, using the MTT assay. All the solvent fractions and purified compounds were found to be non-cytotoxic to HDF cells. However, the chloroform fraction and kobusin exhibited cytotoxic effect against B16-F10 melanoma cells. The presence of bioactive lignans and alkaloids were suggested to be responsible for the cytotoxic property of Z. rhetsa bark against B16-F10 cells.
Fulltext Phytochemical Screening and Acute Oral Toxicity Study of Java Tea Leaf Extracts

Pariyani R, Ismail IS, Azam AA, Abas F, Shaari K, Sulaiman MR

Biomed Res Int, 2015;2015:742420.
PMID: 26819955 DOI: 10.1155/2015/742420

The term Java tea refers to the decoction of Orthosiphon stamineus (OS) Benth (Lamiaceae) leaves, which are widely consumed by the people in Europe and South East Asian countries. The OS leaves are known for their use in traditional medicinal systems as a prophylactic and curative agent for urinary stone, diabetes, and hypertension and also as a diuretic agent. The present study was aimed at evaluating its possible toxicity. Herein, the major phytochemical constituents of microwave dried OS leaf, which is the common drying process for tea sachets in the market, were also identified. The acute oral toxicity test of aqueous, 50% aqueous ethanolic, and ethanolic extracts of OS was performed at a dose of 5000 mg/Kg body weight of Sprague-Dawley rats. During the 14-day study, the animals were observed for any mortality, behavioral, motor-neuronal abnormalities, body weight, and feed-water consumption pattern. The hematological and serum biochemical parameters to assess the kidney and liver functions were carried out, along with the histological analysis of these organs. It was found that all microwave dried OS leaf extracts did not cause any toxic effects or mortality at the administered dose. No abnormality was noticed in all selected parameters in rats of both sexes as compared with their respective control groups. Thus, the possible oral lethal dose for microwave dried Java tea leaves is more than 5000 mg/Kg body weight.
Influence of Different Drying Treatments and Extraction Solvents on the Metabolite Profile and Nitric Oxide Inhibitory Activity of Ajwa Dates

Abdul-Hamid NA, Abas F, Ismail IS, Shaari K, Lajis NH

J Food Sci, 2015 Nov;80(11):H2603-11.
PMID: 26457883 DOI: 10.1111/1750-3841.13084

This study aimed to examine the variation in the metabolite profiles and nitric oxide (NO) inhibitory activity of Ajwa dates that were subjected to 2 drying treatments and different extraction solvents. (1)H NMR coupled with multivariate data analysis was employed. A Griess assay was used to determine the inhibition of the production of NO in RAW 264.7 cells treated with LPS and interferon-γ. The oven dried (OD) samples demonstrated the absence of asparagine and ascorbic acid as compared to the freeze dried (FD) dates. The principal component analysis showed distinct clusters between the OD and FD dates by the second principal component. In respect of extraction solvents, chloroform extracts can be distinguished by the absence of arginine, glycine and asparagine compared to the methanol and 50% methanol extracts. The chloroform extracts can be clearly distinguished from the methanol and 50% methanol extracts by first principal component. Meanwhile, the loading score plot of partial least squares analysis suggested that beta glucose, alpha glucose, choline, ascorbic acid and glycine were among the metabolites that were contributing to higher biological activity displayed by FD and methanol extracts of Ajwa. The results highlight an alternative method of metabolomics approach for determination of the metabolites that contribute to NO inhibitory activity.
Fulltext Metabolomics for characterization of gender differences in patients infected with dengue virus

Shahfiza N, Osman H, Hock TT, Shaari K, Abdel-Hamid AH

Asian Pac J Trop Med, 2015 Jun;8(6):451-6.
PMID: 26194829 DOI: 10.1016/j.apjtm.2015.05.012

OBJECTIVE: To determine the metabolic response associate with dengue infection based on human gender metabolic differences by means of (1)H NMR-spectrometry.
METHODS: The mid-stream urine collected from both male and female patients diagnosed with dengue fever at Penang General Hospital and fourty-three healthy individuals were analyzed with (1)H NMR spectroscopy, followed by chemometric multivariate analysis. NMR signals which highlighted in the OPLS-DA S-plot were further selected and identified using Human Metabolome Database, Chenomx Profiler.
RESULTS: The results pointed out that NMR urine profiling was able to capture human gender metabolic differences that are important for the distinction of classes of individuals of similar physiological conditions; infected with dengue. Distinct differences between dengue infected patients versus healthy individuals and subtle differences in male versus female infected with dengue were found to be related to the metabolism of amino acid and tricarboxylic acid intermediates cycle.
CONCLUSIONS: The (1)H NMR metabolomic investigation combined with appropriate algorithms and pattern recognition procedures, gave an evidence for the existence of distinct metabolic differentiation of individuals, according to their gender, modulates with the infection risk.
Nuclear magnetic resonance spectroscopy and liquid chromatography-mass spectrometry metabolomics studies on non-organic soybeans versus organic soybeans (Glycine max), and their fermentation by Rhizopus oligosporus

Chong SG, Ismail IS, Ahmad Azam A, Tan SJ, Shaari K, Tan JK

J Sci Food Agric, 2023 Apr;103(6):3146-3156.
PMID: 36426592 DOI: 10.1002/jsfa.12355

BACKGROUND: Soybeans (Glycine max) are high in proteins and isoflavones, which offer many health benefits. It has been suggested that the fermentation process enhances the nutrients in the soybeans. Organic foods are perceived as better than non-organic foods in terms of health benefits, yet little is known about the difference in the phytochemical content that distinguishes the quality of organic soybeans from non-organic soybeans. This study investigated the chemical profiles of non-organic (G, T, U, UB) and organic (C, COF, A, R, B, Z) soybeans (G. max [L.] Merr.) and their metabolite changes after fermentation with Rhizopus oligosporus.
RESULTS: A clear separation was only observed between non-organic G and organic Z, which were then selected for further investigation in the fermentation of soybeans (GF and ZF). All four groups (G, Z, GF, ZF) were analyzed using nuclear magnetic resonance (NMR) spectroscopy along with liquid chromatography-tandem mass spectrometry (LC-MS/MS). In this way a total of 41 and 47 metabolites were identified respectively, with 12 in common. A clear variation (|log1.5 FC| > 2 and P
Fulltext Polystyrene microplastics induce gut microbiome and metabolome changes in Javanese medaka fish (Oryzias javanicus Bleeker, 1854)

Usman S, Razis AFA, Shaari K, Azmai MNA, Saad MZ, Isa NM, et al.

Toxicol Rep, 2022;9:1369-1379.
PMID: 36518379 DOI: 10.1016/j.toxrep.2022.05.001

Microplastics (MPs) have become emerging pollutants of public health concern, due to their impact on aqua-terrestrial ecosystems and integration into the food web, with evidence of human exposure and unrevealed health implications. There is a paucity of information regarding the effects of MPs exposure on the gut system using metagenomic and metabolomic approaches. In this study, Javanese medaka fish was exposed to 5 µm beads of polystyrene microplastics (PS-MPs) suspensions, at concentrations of 100 μg/L (MP-LOW), 500 μg/L (MP-MED), and 1000 μg/L (MP-HIGH), for a duration of 21 days, and evaluated for gut microbiome and metabolome responses. The results revealed a significant reduction (p < 0.05) in richness and diversity of the gut microbiome in the MP-HIGH group, and identification of 7 bacterial genera as differential features by the Linear discriminant analysis Effect Size (LEfSe). The gut metabolic profile revealed upregulation of 9 metabolites related to energy metabolism, via tricarboxylic acid cycle (TCA), creatine pathway, and urea cycle, as determined by the pathway analysis. Furthermore, positive correlation was found between the genus Aeromonas and glucose, lactate, and creatine metabolites. The study revealed that PS-MPs exposure resulted in altered bacterial microbiome and metabolic disorder related to energy metabolism. It further provided additional data on gut bacterial genera and metabolites associated with MPs toxicity in aquatic organism, which will inevitably enable its future health risks assessment in animals and possibly humans.
Immunomodulatory effects of Isochrysis galbana incorporated diet on Oreochromis sp. (red hybrid tilapia) via Sera-1H NMR metabolomics study

Ahamad Bustamam MS, Pantami HA, Shaari K, Min CC, Mediani A, Ismail IS

Fish Shellfish Immunol, 2023 Jan;132:108455.
PMID: 36464078 DOI: 10.1016/j.fsi.2022.108455

Tilapia is one of the most common fish species that is intensively produced all over the world. However, significant measures at improving aquaculture health must be taken since disease outbreaks are often encountered in the rapidly developing aquaculture industry. Therefore, the objective of the study was designed to evaluate the metabolite changes in tilapia' sera through 1H NMR metabolomics in identifying the potential biomarkers responsible for immunomodulatory effect by the indigenous species of Malaysian microalgae Isochrysis galbana (IG). The results showed that IG-incorporated diet mainly at 5.0% has improved the immune response of innate immunity as observed in serum bactericidal activity (SBA) and serum lysozyme activity (SLA). The orthogonal partial least squares (OPLS) analysis indicated 5 important metabolites significantly upregulated namely as ethanol, lipoprotein, lipid, α-glucose and unsaturated fatty acid (UFA) in the 5.0% IG-incorporated diet compared to control. In conclusion, this study had successfully determined IG in improving aquaculture health through its potential use as an immune modulator. This work also demonstrated the effective use of metabolomics approach in the development of alternative nutritious diet from microalgae species to boost fish health in fulfilling the aquaculture's long-term goals.
Phenolic content of Terminalia catappa L. leaf and toxicity evaluation on red hybrid tilapia (Oreochromis sp.)

Yakubu Y, Ahmad MT, Chong CM, Ismail IS, Shaari K

J Fish Biol, 2023 Feb;102(2):358-372.
PMID: 36333916 DOI: 10.1111/jfb.15266

Despite the use of Terminalia catappa (TC) leaf by traditional fish farmers around the world to improve the health status of cultured fish, there is a paucity of information on comprehensive metabolite profile and the maximum safe dose of the plant. This study aims at profiling the methanol leaf extract of T. catappa, quantifying total phenolic content (TPC) as well as the total flavonoid content (TFC) and evaluating its acute toxicity on blood, plasma biochemical parameters and histopathology of some vital organs in red hybrid tilapia (Oreochromis sp.). The experimental fish were acclimatised for 2 weeks and divided into six groups. Group (1) served as a control group and was administered 0.2 ml,g-1 of phosphate buffer saline (PBS). Groups 2-6 were orally administered T. catappa leaf extracts (0.2 ml.50 g-1 ) in the following sequence; 31.25, 62.5, 125, 250 and 500 mg.kg-1 body weight. The metabolites identified in T. catappa using liquid chromatography-tandem mass electrospray ionisation spectrometry (LC-ESI-MS/MS) revealed the presence of organic acids, hydrolysable tannins, phenolic acids and flavonoids. Phenolic quantification revealed reasonable quantity of phenolic compounds (217.48 μg GAEmg-1 for TPC and 91.90 μg. QCEmg-1 for TFC). Furthermore, there was no significant difference in all the tested doses in terms of blood parameters and plasma biochemical analysis except for the packed cell volume (PCV) at 500 mg.kg-1 when compared to the control. Significant histopathological changes were observed in groups administered with the extract at 125, 250 and 500 mg.kg-1 doses. To a very large extent it is therefore safe to administer the extract at 31.25 and 62.5 mg.kg-1 in tilapia.
Fulltext Antagonism of nonaflatoxigenic Aspergillus flavus isolated from peanuts against aflatoxigenic A. flavus growth and aflatoxin B1 production in vitro

Rahman MAH, Selamat J, Samsudin NIP, Shaari K, Mahror N, John JM

Food Sci Nutr, 2022 Nov;10(11):3993-4002.
PMID: 36348788 DOI: 10.1002/fsn3.2995

Aspergillus section Flavi constitutes several species of opportunistic fungi, notable among them are A. flavus and A. parasiticus, capable of surviving harsh conditions and colonizing a wide range of agricultural products pre- and postharvest. Physical and chemical control methods are widely applied in order to mitigate the invasion of A. flavus in crops. However, physical control is not suitable for large scale and chemical control often leads to environmental pollution, whereas biological control offers a safer, environmentally friendly, and economical alternative. The present study aimed to investigate the antagonism of several non-aflatoxigenic A. flavus strains against the aflatoxigenic ones in vitro (semisynthetic peanut growth medium; MPA) in terms of colony growth rate and AFB1 inhibition. Different peanut concentrations were used to obtain the optimum peanut concentration in the formulated growth medium. A dual culture assay was performed to assess the antagonism of nonaflatoxigenic strains against the aflatoxigenic ones. Results revealed that 9% MPA exhibited the highest growth and AFB1 inhibition by nonaflatoxigenic strains. It was also found that different nonaflatoxigenic strains exhibited different antagonism against the aflatoxigenic ones which ranged from 11.09 ± 0.65% to 14.06 ± 0.14% for growth inhibition, and 53.97 ± 2.46% to 72.64 ± 4.54% for AFB1 inhibition. This variability could be due to the difference in antagonistic metabolites produced by different nonaflatoxigenic strains assessed in the present study. Metabolomics study to ascertain the specific metabolites that conferred the growth and aflatoxin inhibition is ongoing.
Biomarker triterpenoids of Centella asiatica as potential antidepressant agents: Combining in vivo and in silico studies

Mando Z, Mando H, Afzan A, Shaari K, Hassan Z, Mohamad Taib MNA, et al.

Behav Brain Res, 2024 May 28;466:114976.
PMID: 38599249 DOI: 10.1016/j.bbr.2024.114976

Although there are various treatments available for depression, some patients may experience resistance to treatment or encounter adverse effects. Centella asiatica (C. asiatica) is an ancient medicinal herb used in Ayurvedic medicine for its rejuvenating, neuroprotective and psychoactive properties. This study aims to explore the antidepressant-like effects of the major constituents found in C. asiatica, i.e., asiatic acid, asiaticoside, madecassic acid, and madecassoside at three doses (1.25, 2.5, and 5 mg/kg, i.p), on the behavioural and cortisol level of unpredictable chronic stress (UCS) zebrafish model. Based on the findings from the behavioural study, the cortisol levels in the zebrafish body after treatment with the two most effective compounds were measured using enzyme-linked immunosorbent assay (ELISA). Furthermore, a molecular docking study was conducted to predict the inhibitory impact of the triterpenoid compounds on serotonin reuptake. The in vivo results indicate that madecassoside (1.25, 2.5, and 5 mg/kg), asiaticoside and asiatic acid (5 mg/kg) activated locomotor behaviour. Madecassoside at all tested doses and asiaticoside at 2.5 and 5 mg/kg significantly decreased cortisol levels compared to the stressed group, indicating the potential regulation effect of madecassoside and asiaticoside on the hypothalamic-pituitary-adrenal axis overactivity. This study highlights the potential benefits of madecassoside and asiaticoside in alleviating depressive symptoms through their positive effects on behaviour and the hypothalamic-pituitary-adrenal (HPA)- axis in a chronic unpredictable stress zebrafish model. Furthermore, the in silico study provided additional evidence to support these findings. These promising results suggest that C. asiatica may be a valuable and cost-effective therapeutic option for depression, and further research should be conducted to explore its potential benefits.
Fulltext A comparative study on antioxidant properties, total phenolics, total flavonoid contents, and cytotoxic properties of marine green microalgae and diatoms

Ferdous UT, Nurdin A, Ismail S, Shaari K, Norhana Balia Yusof Z

J Genet Eng Biotechnol, 2025 Mar;23(1):100456.
PMID: 40074430 DOI: 10.1016/j.jgeb.2024.100456

Despite having valuable and novel metabolites, the marine microalgae species are still not thoroughly investigated for their pharmaceutical and nutraceutical importance. Therefore, this study was focused on investigating the crude extracts of marine green microalgae species, Tetraselmis sp., Nannochloropsis sp., and diatoms Chaetoceros sp., and Thalassiosira sp., isolated from the Malaysian coastal region in terms of their antioxidant activity, total phenolics, total flavonoid contents and cytotoxicity against human breast cancer cells, MCF-7. Among twenty-eight crude extracts, Tetraselmis ethanol and ethyl acetate extract showed the highest amount of total phenolic (19.87 mg GAE/g), and total flavonoid content (38.58 mg QE/g of extract), respectively. From the antioxidant assays, methanol and ethyl acetate extract of Tetraselmis sp. exhibited significantly higher (p
Plasma and urine metabolite profiling reveals the protective effect of Clinacanthus nutans in an ovalbumin-induced anaphylaxis model: 1H-NMR metabolomics approach

Khoo LW, Audrey Kow SF, Maulidiani M, Lee MT, Tan CP, Shaari K, et al.

J Pharm Biomed Anal, 2018 Sep 05;158:438-450.
PMID: 29957507 DOI: 10.1016/j.jpba.2018.06.038

The present study sought to identify the key biomarkers and pathways involved in the induction of allergic sensitization to ovalbumin and to elucidate the potential anti-anaphylaxis property of Clinacanthus nutans (Burm. f.) Lindau water leaf extract, a Southeast Asia herb in an in vivo ovalbumin-induced active systemic anaphylaxis model evaluated by 1H-NMR metabolomics. The results revealed that carbohydrate metabolism (glucose, myo-inositol, galactarate) and lipid metabolism (glycerol, choline, sn-glycero-3-phosphocholine) are the key requisites for the induction of anaphylaxis reaction. Sensitized rats treated with 2000 mg/kg bw C. nutans extract before ovalbumin challenge showed a positive correlation with the normal group and was negatively related to the induced group. Further 1H-NMR analysis in complement with Kyoto Encyclopedia of Genes and Genomes (KEGG) reveals the protective effect of C. nutans extract against ovalbumin-induced anaphylaxis through the down-regulation of lipid metabolism (choline, sn-glycero-3-phosphocholine), carbohydrate and signal transduction system (glucose, myo-inositol, galactarate) and up-regulation of citrate cycle intermediates (citrate, 2-oxoglutarate, succinate), propanoate metabolism (1,2-propanediol), amino acid metabolism (betaine, N,N-dimethylglycine, methylguanidine, valine) and nucleotide metabolism (malonate, allantoin). In summary, this study reports for the first time, C. nutans water extract is a potential anti-anaphylactic agent and 1H-NMR metabolomics is a great alternative analytical tool to explicate the mechanism of action of anaphylaxis.
Fulltext Water extract of Clinacanthus nutans leaves exhibits in vitro, ex vivo and in vivo anti-angiogenic activities in endothelial cell via suppression of cell proliferation

Ng CT, Fong LY, Tan JJ, Rajab NF, Abas F, Shaari K, et al.

BMC Complement Altern Med, 2018 Jul 06;18(1):210.
PMID: 29980198 DOI: 10.1186/s12906-018-2270-1

BACKGROUND: Clinacanthus nutans (Burm. f.) Lindau. has traditionally been using in South East Asia countries to manage cancer. However, scientific evidence is generally lacking to support this traditional claim. This study aims to investigate the in vitro, ex-vivo and in vivo effects of C. nutans extracts on angiogenesis.
METHODS: C. nutans leaves was extracted with 50-100% ethanol or deionised water at 1% (w/v). Human umbilical veins endothelial cell (HUVEC) proliferation was examined using MTT assay. The in vitro anti-angiogenic effects of C. nutans were assessed using wound scratch, tube formation and transwell migration assays. The VEGF levels secreted by human oral squamous cell carcinoma (HSC-4) cell and HUVEC permeability were also measured. Besides, the rat aortic ring and chick embryo chorioallantoic membrane (CAM) assays, representing ex vivo and in vivo models, respectively, were performed.
RESULTS: The MTT assay revealed that water extract of C. nutans leaves exhibited the highest activity, compared to the ethanol extracts. Therefore, the water extract was chosen for subsequent experiments. C. nutans leaf extract significantly suppressed endothelial cell proliferation and migration in both absence and presence of VEGF. However, the water extract failed to suppress HUVEC transmigration, differentiation and permeability. C. nutans water extract also did not suppress HSC-4 cell-induced VEGF production. Importantly, C. nutans water extract significantly abolished the sprouting of vessels in aortic rings as well as in chick embryo CAM.
CONCLUSION: In conclusion, these findings reveal potential anti-angiogenic effects of C. nutans, providing new evidence for its potential application as an anti-angiogenic agent.
Metabolomic analysis and biochemical changes in the urine and serum of streptozotocin-induced normal- and obese-diabetic rats

Mediani A, Abas F, Maulidiani M, Abu Bakar Sajak A, Khatib A, Tan CP, et al.

J Physiol Biochem, 2018 May 15.
PMID: 29766441 DOI: 10.1007/s13105-018-0631-3

Diabetes mellitus (DM) is a chronic disease that can affect metabolism of glucose and other metabolites. In this study, the normal- and obese-diabetic rats were compared to understand the diabetes disorders of type 1 and 2 diabetes mellitus. This was done by evaluating their urine metabolites using proton nuclear magnetic resonance (1H NMR)-based metabolomics and comparing with controls at different time points, considering the induction periods of obesity and diabetes. The biochemical parameters of the serum were also investigated. The obese-diabetic model was developed by feeding the rats a high-fat diet and inducing diabetic conditions with a low dose of streptozotocin (STZ) (25 mg/kg bw). However, the normal rats were induced by a high dose of STZ (55 mg/kg bw). A partial least squares discriminant analysis (PLS-DA) model showed the biomarkers of both DM types compared to control. The synthesis and degradation of ketone bodies, tricarboxylic (TCA) cycles, and amino acid pathways were the ones most involved in the variation with the highest impact. The diabetic groups also exhibited a noticeable increase in the plasma glucose level and lipid profile disorders compared to the control. There was also an increase in the plasma cholesterol and low-density lipoprotein (LDL) levels and a decline in the high-density lipoprotein (HDL) of diabetic rats. The normal-diabetic rats exhibited the highest effect of all parameters compared to the obese-diabetic rats in the advancement of the DM period. This finding can build a platform to understand the metabolic and biochemical complications of both types of DM and can generate ideas for finding targeted drugs.
Fulltext Hematological, Biochemical, Histopathological and ¹H-NMR Metabolomics Application in Acute Toxicity Evaluation of Clinacanthus nutans Water Leaf Extract

Khoo LW, Foong Kow AS, Maulidiani M, Lee MT, Tan CP, Shaari K, et al.

Molecules, 2018 Aug 29;23(9).
PMID: 30158427 DOI: 10.3390/molecules23092172

The present study aims for the first time to provide the in vivo acute toxicological profile of the highest dose of Clinacanthus nutans (Burm. f.) Lindau water leaf extract according to the Organization for economic co-operation and development (OECD) 423 guidelines through conventional toxicity and advanced proton nuclear magnetic resonance (¹H-NMR) serum and urinary metabolomics evaluation methods. A single dose of 5000 mg/kg bw of C. nutans water extract was administered to Sprague Dawley rats, and they were observed for 14 days. Conventional toxicity evaluation methods (physical observation, body and organ weight, food and water consumption, hematology, biochemical testing and histopathological analysis) suggested no abnormal toxicity signs. Serum ¹H-NMR metabolome revealed no significant metabolic difference between untreated and treated groups. Urinary ¹H-NMR analysis, on the other hand, revealed alteration in carbohydrate metabolism, energy metabolism and amino acid metabolism in extract-treated rats after 2 h of extract administration, but the metabolic expression collected after 24 h and at Day 5, Day 10 and Day 15 indicated that the extract-treated rats did not accumulate any toxicity biomarkers. Importantly, the outcomes further suggest that single oral administration of up to 5000 mg/kg bw of C. nutans water leaf extract is safe for consumption.
Fulltext Identification of α-glucosidase inhibitors from Clinacanthus nutans leaf extract using liquid chromatography-mass spectrometry-based metabolomics and protein-ligand interaction with molecular docking

Murugesu S, Ibrahim Z, Ahmed QU, Uzir BF, Nik Yusoff NI, Perumal V, et al.

J Pharm Anal, 2019 Apr;9(2):91-99.
PMID: 31011465 DOI: 10.1016/j.jpha.2018.11.001

The present study used in vitro and in silico techniques, as well as the metabolomics approach to characterise α-glucosidase inhibitors from different fractions of Clinacanthus nutans. C. nutans is a medicinal plant belonging to the Acanthaceae family, and is traditionally used to treat diabetes in Malaysia. n-Hexane, n-hexane: ethyl acetate (1:1, v/v), ethyl acetate, ethyl acetate: methanol (1:1, v/v), and methanol fractions were obtained via partitioning of the 80% methanolic crude extract. The in vitro α-glucosidase inhibitory activity was analyzed using all the fractions collected, followed by profiling of the metabolites using liquid chromatography combined with mass spectrometry. The partial least square (PLS) statistical model was developed using the SIMCA P+14.0 software and the following four inhibitors were obtained: (1) 4,6,8-Megastigmatrien-3-one; (2) N-Isobutyl-2-nonen-6,8-diynamide; (3) 1',2'-bis(acetyloxy)-3',4'-didehydro-2'-hydro-β, ψ-carotene; and (4) 22-acetate-3-hydroxy-21-(6-methyl-2,4-octadienoate)-olean-12-en-28-oic acid. The in silico study performed via molecular docking with the crystal structure of yeast isomaltase (PDB code: 3A4A) involved a hydrogen bond and some hydrophobic interactions between the inhibitors and protein. The residues that interacted include ASN259, HID295, LYS156, ARG335, and GLY209 with a hydrogen bond, while TRP15, TYR158, VAL232, HIE280, ALA292, PRO312, LEU313, VAL313, PHE314, ARG315, TYR316, VAL319, and TRP343 with other forms of bonding.
Fulltext Mast cell stabilizing effect of a geranyl acetophenone in dengue virus infection using in vitro model of DENV3-induced RBL-2H3 cells

Tan JW, Wan Zahidi NF, Kow ASF, Soo KM, Shaari K, Israf DA, et al.

Biosci Rep, 2019 06 28;39(6).
PMID: 31110077 DOI: 10.1042/BSR20181273

Mast cells (MCs), a type of immune effector cell, have recently become recognized for their ability to cause vascular leakage during dengue virus (DENV) infection. Although MC stabilizers have been reported to attenuate DENV induced infection in animal studies, there are limited in vitro studies on the use of MC stabilizers against DENV induced MC degranulation. 2,4,6-trihydroxy-3-geranyl acetophenone (tHGA) has been reported to be a potential MC stabilizer by inhibiting IgE-mediated MC activation in both cellular and animal models. The present study aims to establish an in vitro model of DENV3-induced RBL-2H3 cells using ketotifen fumarate as a control drug, as well as to determine the effect of tHGA on the release of MC mediators upon DENV infection. Our results demonstrated that the optimal multiplicities of infection (MOI) were 0.4 × 10-2 and 0.8 × 10-2 focus forming units (FFU)/cell. Ketotifen fumarate was proven to attenuate DENV3-induced RBL-2H3 cells degranulation in this in vitro model. In contrast, tHGA was unable to attenuate the release of both β-hexosaminidase and tumor necrosis factor (TNF)-α. Nonetheless, our study has successfully established an in vitro model of DENV3-induced RBL-2H3 cells, which might be useful for the screening of potential MC stabilizers for anti-dengue therapies.
Meliternatin: a feeding deterrent and larvicidal polyoxygenated flavone from Melicope subunifoliolata

Hung Ho S, Wang J, Sim KY, Ee GC, Imiyabir Z, Yap KF, et al.

Phytochemistry, 2003 Apr;62(7):1121-4.
PMID: 12591266

We screened more than 60 Malaysian plants against two species of insects and found that Melicope subunifoliolata (Stapf) T.G. Hartley (Rutaceae) showed strong feeding deterrent activity against Sitophilus zeamais Motsch. (Curculionidae) and very good larvicidal activity against Aedes aegypti L. (Diptera). One anti-insect compound, meliternatin (3,5-dimethoxy-3',4',6,7-bismethylendioxyflavone) (6) and six other minor polyoxygenated flavones were isolated from M. subunifoliolata.
Neuroprotective effects of glucomoringin-isothiocyanate against H2O2-Induced cytotoxicity in neuroblastoma (SH-SY5Y) cells

Jaafaru MS, Nordin N, Rosli R, Shaari K, Bako HY, Saad N, et al.

Neurotoxicology, 2019 12;75:89-104.
PMID: 31521693 DOI: 10.1016/j.neuro.2019.09.008

Neurodegenerative diseases (NDDs) are pathological conditions characterised by progressive damage of neuronal cells leading to eventual loss of structure and function of the cells. Due to implication of multi-systemic complexities of signalling pathways in NDDs, the causes and preventive mechanisms are not clearly delineated. The study was designed to investigate the potential signalling pathways involved in neuroprotective activities of purely isolated glucomoringin isothiocyanate (GMG-ITC) against H2O2-induced cytotoxicity in neuroblastoma (SH-SY5Y) cells. GMG-ITC was isolated from Moringa oleifera seeds, and confirmed with NMR and LC-MS based methods. Gene expression analysis of phase II detoxifying markers revealed significant increase in the expression of all the genes involved, due to GMG-ITC pre-treatment. GMG-ITC also caused significant decreased in the expression of NF-kB, BACE1, APP and increased the expressions of IkB and MAPT tau genes in the differentiated cells as confirmed by multiplex genetic system analysis. The effect was reflected on the expressed proteins in the differentiated cells, where GMG-ITC caused increased in expression level of Nrf2, SOD-1, NQO1, p52 and c-Rel of nuclear factor erythroid factor 2 (Nrf2) and nuclear factor kappa-B (NF-kB) pathways respectively. The findings revealed the potential of GMG-ITC to abrogate oxidative stress-induced neurodegeneration through Nrf2 and NF-kB signalling pathways.
Fulltext N-Ethyl-n-Nitrosourea Induced Leukaemia in a Mouse Model through Upregulation of Vascular Endothelial Growth Factor and Evading Apoptosis

Aliyu A, Shaari MR, Ahmad Sayuti NS, Reduan MFH, Sithambaram S, Noordin MM, et al.

Cancers (Basel), 2020 Mar 13;12(3).
PMID: 32183192 DOI: 10.3390/cancers12030678

Chemical carcinogens are commonly used to investigate the biology and prognoses of various cancers. This study investigated the mechanism of leukaemogenic effects of n-ethyl-n-nitrosourea (ENU) in a mouse model. A total of 14 3-week-old male Institute of Cancer Research (ICR)-mice were used for the study. The mice were divided into groups A and B with seven mice each. Group A served as the control while group B received intraperitoneal (IP) injections of 80 mg/kg ENU twice with a one-week interval and were monitored monthly for 3 months for the development of leukaemia via blood smear examination. The mice were sacrificed humanely using a CO2 chamber. Blood, spleen, lymph nodes, liver, kidney and lung samples were collected for blood smear examination and histopathological evaluation. The expression of angiogenic protein (VEGF), and pro and anti-apoptotic proteins (BCL2 and BAX), was detected and quantified using Western blot technique. Leukaemia was confirmed by the presence of numerous blast cells in the peripheral blood smear in group B. Similarly, the VEGF and BCL2 proteins were significantly (p < 0.05) upregulated in group B compared to A. It is concluded that IP administration of 80 mg/kg ENU induced leukaemia in ICR-mice 12 weeks post administration through upregulation of angiogenic and anti-apoptotic proteins: VEGF and BCL2.

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