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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.
Relationship Between Metabolites Composition and Biological Activities of Phyllanthus niruri Extracts Prepared by Different Drying Methods and Solvents Extraction

Mediani A, Abas F, Khatib A, Tan CP, Ismail IS, Shaari K, et al.

Plant Foods Hum Nutr, 2015 Jun;70(2):184-92.
PMID: 25800644 DOI: 10.1007/s11130-015-0478-5

The study investigated the changes in the metabolite, antioxidant and α-glucosidase inhibitory activities of Phyllanthus niruri after three drying treatments: air, freeze and oven dryings. Water extracts and extracts obtained using different solvent ratios of ethanol and methanol (50, 70, 80 and 100%) were compared. The relationships among the antioxidant, α-glucosidase inhibitory activity and metabolite levels of the extracts were evaluated using partial least-square analysis (PLS). The solvent selectivity was assessed based on the phytochemical constituents present in the extract and their concentrations quantitatively analyzed using high performance liquid chromatography. The freeze-dried P. niruri samples that were extracted with the mixture of ethanol or methanol with low ratio of water showed higher biological activity values compared with the other extracts. The PLS results for the ethanolic with different ratio and water extracts demonstrated that phenolic acids (chlorogenic acid and ellagic acid) and flavonoids were highly linked to strong α-glucosidase inhibitory and antioxidant activities.
Fulltext The anti-neuroinflammatory effects of Clinacanthus nutans leaf extract on metabolism elucidated through 1H NMR in correlation with cytokines microarray

Ahmad Azam A, Ismail IS, Kumari Y, Shaikh MF, Abas F, Shaari K

PLoS One, 2020;15(9):e0238503.
PMID: 32925968 DOI: 10.1371/journal.pone.0238503

Clinacanthus nutans (CN) (Acanthaceae) is well-known for its anti-inflammatory properties among Asian communities; however, there are currently no data specifically focused on the anti-inflammatory effects of CN on the brain tissue. Neuroinflammation is a common consequence of toxin intrusion to any part of the central nervous system (CNS). As an innate immune response, the CNS may react through both protective and/or toxic actions due to the activation of neuron cells producing pro- and/or anti-inflammatory cytokines in the brain. The unresolved activation of the inflammatory cytokines' response is associated with the pathogenesis of neurological disorders. The present study aimed to decipher the metabolic mechanism on the effects of 14 days oral treatment with CN aqueous extract in induced-lipopolysaccharides (LPS) rats through 1H NMR spectroscopic biomarker profiling of the brain tissue and the related cytokines. Based on the principal component analysis (PCA) of the nuclear magnetic resonance (NMR) spectral data, twenty-one metabolites in the brain tissue were profiled as biomarkers for the LPS (10 μL)-induced neuroinflammation following intracerebroventricular injection. Among the twenty-one biomarkers in the neuroinflammed rats, CN treatment of 1000 and 500 mg/kg BW successfully altered lactate, pyruvate, phosphorylcholine, glutamine, and α-ketoglutarate when compared to the negative control. Likewise, statistical isolinear multiple component analysis (SIMCA) showed that treatments by CN and the positive control drug, dextromethorphan (DXM, 5 mg/kg BW), have anti-neuroinflammatory potential. A moderate correlation, in the orthogonal partial least squares (OPLS) regression model, was found between the spectral metabolite profile and the cytokine levels. The current study revealed the existence of high levels of pro-inflammatory cytokines, namely IL-1α, IL-1β, and TNF-α in LPS-induced rats. Both CN dose treatments lowered IL-1β significantly better than DXM Interestingly, DXM and CN treatments both exhibited the upregulation of the anti-inflammatory cytokines IL-2 and 4. However, DXM has an advantage over CN in that the former also increased the expression of IL-10 of anti-inflammatory cytokines. In this study, a metabolomics approach was successfully applied to discover the mechanistic role of CN in controlling the neuroinflammatory conditions through the modulation of complex metabolite interactions in the rat brain.
Fulltext Metabolite profiling of Andrographis paniculata (Burm. f.) Nees. young and mature leaves at different harvest ages using 1H NMR-based metabolomics approach

Tajidin NE, Shaari K, Maulidiani M, Salleh NS, Ketaren BR, Mohamad M

Sci Rep, 2019 11 14;9(1):16766.
PMID: 31727911 DOI: 10.1038/s41598-019-52905-z

Andrographis paniculata (Burm. F.) Nees. is considered as the herb of the future due to its precious chemical compounds, andrographolide (ANDRO), neoandrographolide (NAG) and 14-deoxyandrographolide (DAG). This study aims to profile the metabolites in young and mature leaf at six different harvest ages using 1HNMR-based metabolomics combined with multivariate data analysis. Principal component analysis (PCA) indicated noticeable and clear discrimination between young and mature leaves. A comparison of the leaves stage indicated that young leaves were separated from mature leaves due to its larger quantity of ANDRO, NAG, DAG, glucose and sucrose. These similar metabolites are also responsible for the PCA separation into five clusters representing the harvest age at 14, 16, 18, 20, 22 weeks of leaves extract. Loading plots revealed that most of the ANDRO and NAG signals were present when the plant reached at the pre-flowering stage or 18 weeks after sowing (WAS). As a conclusion, A. paniculata young leaves at pre-flowering harvest age were found to be richer in ANDRO, NAG and DAG compared to mature leaves while glucose and choline increased with harvest age. Therefore, young leaves of A. paniculata should be harvested at 18 WAS in order to produce superior quality plant extracts for further applications by the herbal, nutraceutical and pharmaceutical industries.
Fulltext Prospective role of mitochondrial apoptotic pathway in mediating GMG-ITC to reduce cytotoxicity in H2O2-induced oxidative stress in differentiated SH-SY5Y cells

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

Biomed Pharmacother, 2019 Nov;119:109445.
PMID: 31541852 DOI: 10.1016/j.biopha.2019.109445

The antioxidant and neuroprotective activity of Glucomoringin isothiocyanate (GMG-ITC) have been reported in in vivo and in vitro models of neurodegenerative diseases. However, its neuroprotective role via mitochondrial-dependent pathway in a noxious environment remains unknown. The main objective of the present study was to unveil the mitochondrial apoptotic genes' profile and prospectively link with neuroprotective activity of GMG-ITC through its ROS scavenging. The results showed that pre-treatment of differentiated SH-SY5Y cells with 1.25 μg/mL purified isolated GMG-ITC, significantly reduced reactive oxygen species (ROS) production level, compared to H2O2 control group, as evidenced by flow cytometry-based evaluation of ROS generation. Presence of GMG-ITC prior to development of oxidative stress condition, downregulated the expression of cyt-c, p53, Apaf-1, Bax, CASP3, CASP8 and CASP9 genes with concurrent upregulation of Bcl-2 gene in mitochondrial apoptotic signalling pathway. Protein Multiplex revealed significant decreased in cyt-c, p53, Apaf-1, Bax, CASP8 and CASP9 due to GMG-ITC pre-treatment in oxidative stress condition. The present findings speculated that pre-treatment with GMG-ITC may alleviate oxidative stress condition in neuronal cells by reducing ROS production level and protect the cells against apoptosis via neurodegenerative disease potential pathways.
Fulltext Microwave synthesis, crystal structure, antioxidant, and antimicrobial study of new 6-heptyl-5,6-dihydrobenzo[4,5]imidazo[1,2-c]quinazoline compound

Hasan HA, Abdulmalek E, Rahman MBA, Shaari KB, Yamin BM, Chan KW

Chem Cent J, 2018 Dec 20;12(1):145.
PMID: 30570683 DOI: 10.1186/s13065-018-0509-z

BACKGROUND: Although the development of antibiotic and antioxidant manufacturing, the problem of bacterial resistance and food and/or cosmetics oxidation still needs more efforts to design new derivatives which can help to minimize these troubles. Benzimidazo[1,2-c]quinazolines are nitrogen-rich heterocyclic compounds that possess many pharmaceutical properties such as antimicrobial, anticonvulsant, immunoenhancer, and anticancer.
RESULTS: A comparative study between two methods, (microwave-assisted and conventional heating approaches), was performed to synthesise a new quinazoline derivative from 2-(2-aminophenyl)-1H-benzimidazole and octanal to produce 6-heptyl-5,6-dihydrobenzo[4,5]imidazo[1,2-c]quinazoline (OCT). The compound was characterised using FTIR, 1H and 13C NMR, DIMS, as well as X-ray crystallography. The most significant peak in the 13C NMR spectrum is C-7 at 65.5 ppm which confirms the cyclisation process. Crystal structure analysis revealed that the molecule grows in the monoclinic crystal system P21/n space group and stabilised by an intermolecular hydrogen bond between the N1-H1A…N3 atoms. The crystal packing analysis showed that the molecule adopts zig-zag one dimensional chains. Fluorescence study of OCT revealed that it produces blue light when expose to UV-light and its' quantum yield equal to 26%. Antioxidant activity, which included DPPH· and ABTS·+ assays was also performed and statistical analysis was achieved via a paired T-test using Minitab 16 software with P
Cytotoxic xanthones from Garcinia penangiana Pierre

Jabit ML, Khalid R, Abas F, Shaari K, Hui LS, Stanslas J, et al.

Z Naturforsch C J Biosci, 2008 2 16;62(11-12):786-92.
PMID: 18274278

Two new xanthones, characterized as 4-(1,1-dimethylprop-2-enyl)-1,3,5,8-tetrahydroxyxanthone (1) and penangianaxanthone (2), with three known xanthones, cudratricusxanthone H (3), macluraxanthone C (4) and gerontoxanthone C (5), as well as friedelin and stigmasterol were isolated from the leaves of Garcinia penangiana. Their structures were elucidated by analysis of spectroscopic data and comparison of the NMR data with the literature ones. Significant cytotoxicity against DU-145, MCF-7 and NCI-H460 cancer cell lines was demonstrated by compounds 1-5, with IC50 values ranging from 3.5 to 72.8 microM.
Biological evaluation of curcumin and related diarylheptanoids

Abas F, Hui LS, Ahmad S, Stanslas J, Israf DA, Shaari K, et al.

Z Naturforsch C J Biosci, 2006 12 2;61(9-10):625-31.
PMID: 17137104

Nine derivatives of three natural diarylheptanoids, curcumin, demethoxycurcumin and bisdemethoxycurcumin, were prepared. Their antioxidant, free radical scavenging, nitric oxide (NO) inhibitory and cytotoxic activities were evaluated and compared with those of the respective natural compounds. Curcumin (1), demethoxycurcumin (2), demethyldemethoxy-curcumin (C3), diacetyldemethoxycurcumin (AC2) and triacetyldemethylcurcumin (AC5) exhibited higher antioxidant activity than quercetin while products from demethylation of 1 and 2 exhibited higher free radical scavenging activity. Compounds AC2 and AC5 were found to be most active in inhibiting breast cancer cells (MCF-7) proliferation with IC50 values of 6.7 and 3.6 microM, respectively. The activity of AC2 is almost doubled and of AC5 almost tripled as compared to curcumin. Their selectivity towards different cell lines is also more noticeable. Compounds AC2 and AC5 also showed increased activity against a human prostate cancer cell line (DU-145) and non-small lung cancer cell line (NCI-H460) with IC50 values of 20.4, 16.3 and 18.3, 10.7 microM, respectively.
Fulltext Pharmacokinetics and Metabolism of Liposome-Encapsulated 2,4,6-Trihydroxygeranylacetophenone in Rats Using High-Resolution Orbitrap Liquid Chromatography Mass Spectrometry

Alkhateeb Y, Jarrar QB, Abas F, Rukayadi Y, Tham CL, Hay YK, et al.

Molecules, 2020 Jul 06;25(13).
PMID: 32640512 DOI: 10.3390/molecules25133069

2,4,6-trihydroxy-3-geranylacetophenone (tHGA) is a bioactive compound that shows excellent anti-inflammatory properties. However, its pharmacokinetics and metabolism have yet to be evaluated. In this study, a sensitive LC-HRMS method was developed and validated to quantify tHGA in rat plasma. The method showed good linearity (0.5-80 ng/mL). The accuracy and precision were within 10%. Pharmacokinetic investigations were performed on three groups of six rats. The first two groups were given oral administrations of unformulated and liposome-encapsulated tHGA, respectively, while the third group received intraperitoneal administration of liposome-encapsulated tHGA. The maximum concentration (Cmax), the time required to reach Cmax (tmax), elimination half-life (t1/2) and area under curve (AUC0-24) values for intraperitoneal administration were 54.6 ng/mL, 1.5 h, 6.7 h, and 193.9 ng/mL·h, respectively. For the oral administration of unformulated and formulated tHGA, Cmax values were 5.4 and 14.5 ng/mL, tmax values were 0.25 h for both, t1/2 values were 6.9 and 6.6 h, and AUC0-24 values were 17.6 and 40.7 ng/mL·h, respectively. The liposomal formulation improved the relative oral bioavailability of tHGA from 9.1% to 21.0% which was a 2.3-fold increment. Further, a total of 12 metabolites were detected and structurally characterized. The metabolites were mainly products of oxidation and glucuronide conjugation.
LAT is essential for the mast cell stabilising effect of tHGA in IgE-mediated mast cell activation

Tan JW, Israf DA, Md Hashim NF, Cheah YK, Harith HH, Shaari K, et al.

Biochem Pharmacol, 2017 Nov 15;144:132-148.
PMID: 28813645 DOI: 10.1016/j.bcp.2017.08.010

Mast cells play a central role in the pathogenesis of allergic reaction. Activation of mast cells by antigens is strictly dependent on the influx of extracellular calcium that involves a complex interaction between signalling molecules located within the cells. We have previously reported that tHGA, an active compound originally isolated from a local shrub known as Melicope ptelefolia, prevented IgE-mediated mast cell activation and passive systemic anaphylaxis by suppressing the release of interleukin-4 (IL-4) and tumour necrosis factor (TNF)-α from activated rat basophilic leukaemia (RBL)-2H3 cells. However, the mechanism of action (MOA) as well as the molecular target underlying the mast cell stabilising effect of tHGA has not been previously investigated. In this study, DNP-IgE-sensitised RBL-2H3 cells were pre-treated with tHGA before challenged with DNP-BSA. To dissect the MOA of tHGA in IgE-mediated mast cell activation, the effect of tHGA on the transcription of IL-4 and TNF-α mRNA was determined using Real Time-Polymerase Chain Reaction (qPCR) followed by Calcium Influx Assay to confirm the involvement of calcium in the activation of mast cells. The protein lysates were analysed by using Western Blot to determine the effect of tHGA on various important signalling molecules in the LAT-PLCγ-MAPK and PI3K-NFκB pathways. In order to identify the molecular target of tHGA in IgE-mediated mast cell activation, the LAT and LAT2 genes in RBL-2H3 cells were knocked-down by using RNA interference to establish a LAT/LAT2 competition model. The results showed that tHGA inhibited the transcription of IL-4 and TNF-α as a result of the suppression of calcium influx in activated RBL-2H3 cells. The results from Western Blot revealed that tHGA primarily inhibited the LAT-PLCγ-MAPK pathway with partial inhibition on the PI3K-p65 pathway without affecting Syk. The results from RNAi further demonstrated that tHGA failed to inhibit the release of mediators associated with mast cell degranulation under the LAT/LAT2 competition model in the absence of LAT. Collectively, this study concluded that the molecular target of tHGA could be LAT and may provide a basis for the development of a mast cell stabiliser which targets LAT.
Cytotoxic constituent of Melicope latifolia (DC.) T. G. Hartley

Lim PC, Ali Z, Khan IA, Khan SI, Kassim NK, Awang K, et al.

Nat Prod Res, 2021 Feb 12.
PMID: 33576269 DOI: 10.1080/14786419.2021.1885031

An undescribed conjugated sesquiterpene, amelicarin (1), together with nine known compounds (2-10) were isolated for the first time from Melicope latifolia. Their structures were elucidated by extensive NMR spectroscopic and mass spectrometric methods. The conjugated sesquiterpene possesses a unique 6/6/9/4-ring fused tetracyclic skeleton. The proposed biosynthesis pathway of 1 consist of three reactions steps: (1) polyketide formation, (2) cyclisation and (3) addition to form the conjugated sesquiterpenoid as final metabolite. Out of the ten isolated metabolites, amelicarin (1) showed activity against 4 cancerous cell lines namely SK-MEL skin cancer, KB oral cancer, BT-549 breast cancer, and SK-OV-3 ovarian cancer with IC50 values between 15 and 25 µg/mL.
Fulltext Multi-Platform Metabolomics Analyses Revealed the Complexity of Serum Metabolites in LPS-Induced Neuroinflammed Rats Treated with Clinacanthus nutans Aqueous Extract

Ahmad Azam A, Ismail IS, Shaikh MF, Abas F, Shaari K

Front Pharmacol, 2021;12:629561.
PMID: 34177565 DOI: 10.3389/fphar.2021.629561

The use of metabolomics as a comprehensive tool in the analysis of metabolic profiles in disease progression and therapeutic intervention is rapidly advancing. Yet, a single analytical platform could not be applied to cover the entire spectrum of a biological sample's metabolome. In the present paper, multi-platform metabolomics approaches were explored to determine the diverse rat sera metabolites extracted from intracerebroventricular lipopolysaccharides (LPS)-induced neuroinflammed rats treated with oral therapeutic interventions of positive drug (dextromethorphan, 5 mg/kg BW); with Clinacanthus nutans (CN) aqueous extract (CNE, 500 mg/kg BW); and with phosphate buffer saline (PBS) as the control group for 14 days. Analyzed by nuclear magnetic resonance (NMR) and liquid chromatography-mass spectrometry (LC-MS) techniques, this study depicted the potential of metabolites associated with neuroinflammation and verified by MetDisease. The key observations in the perturbed metabolic pathways that showed ameliorative effects were linked to the class of amino acid and peptide metabolism involving valine, leucine, and isoleucine biosynthesis; phenylalanine, tyrosine, and tryptophan biosynthesis; and phenylalanine metabolism. Lipid metabolism of arachidonic acid metabolism, glycerophospholipid metabolism, terpenoid backbone biosynthesis, and glycosphingolipid metabolism were also affected. Current findings suggested that the putative biomarkers, especially lysophosphatidic acid (LPA) and 5-diphosphomevalonic acid from glycerophospholipid and squalene/terpenoid and cholesterol biosynthesis, respectively, showed the ameliorative effects of the drug and CN treatments by controlling cell differentiation and proliferation. Our study proved that the complex and dynamic sera profiling affected during the CN treatment was greatly influenced by the analytical platform selection as integration between the two data yielded a more holistic summary of the metabolite pattern changes. Hence, an evidence-based herb, such as CN, can be used for novel diagnostic tools in the quest for ethnopharmacological studies.
Pharmacological Properties of 2,4,6-Trihydroxy-3-Geranyl Acetophenone and the Underlying Signaling Pathways: Progress and Prospects

Chan YH, Liew KY, Tan JW, Shaari K, Israf DA, Tham CL

Front Pharmacol, 2021;12:736339.
PMID: 34531753 DOI: 10.3389/fphar.2021.736339

2,4,6-Trihydroxy-3-geranyl acetophenone (tHGA) is a bioactive phloroglucinol compound found in Melicope pteleifolia (Champ. ex Benth.) T.G.Hartley, a medicinal plant vernacularly known as "tenggek burung". A variety of phytochemicals have been isolated from different parts of the plant including leaves, stems, and roots by using several extraction methods. Specifically, tHGA, a drug-like compound containing phloroglucinol structural core with acyl and geranyl group, has been identified in the methanolic extract of the young leaves. Due to its high nutritional and medicinal values, tHGA has been extensively studied by using various experimental models. These studies have successfully discovered various interesting pharmacological activities of tHGA such as anti-inflammatory, endothelial and epithelial barrier protective, anti-asthmatic, anti-allergic, and anti-cancer. More in-depth investigations later found that these activities were attributable to the modulatory actions exerted by tHGA on specific molecular targets. Despite these findings, the association between the mechanisms and signaling pathways underlying each pharmacological activity remains largely unknown. Also, little is known about the medicinal potentials of tHGA as a drug lead in the current pharmaceutical industry. Therefore, this mini review aims to summarize and relate the pharmacological activities of tHGA in terms of their respective mechanisms of action and signaling pathways in order to present a perspective into the overall modulatory actions exerted by tHGA. Besides that, this mini review will also pinpoint the unexplored potentials of this compound and provide some valuable insights into the potential applications of tHGA which may serve as a guide for the development of modern medication in the future.
Fulltext Clitorienolactones and Isoflavonoids of Clitorea ternatea Roots Alleviate Stress-Like Symptoms in a Reserpine-Induced Zebrafish Model

Ngadni MA, Akhtar MT, Ismail IS, Norazhar AI, Lee SY, Maulidiani M, et al.

Molecules, 2021 Jul 07;26(14).
PMID: 34299411 DOI: 10.3390/molecules26144137

Clitorea ternatea has been used in Ayurvedic medicine as a brain stimulant to treat mental illnesses and mental functional disorders. In this study, the metabolite profiles of crude C. ternatea root extract (CTRE), ethyl acetate (EA), and 50% aqueous methanol (50% MeOH) fractions were investigated using ultrahigh-performance liquid chromatography-diode array detector-tandem mass spectrometry (UHPLC-DAD-MS/MS), while their effect on the stress-like behavior of zebrafish, pharmacologically induced with reserpine, was investigated. A total of 32 compounds were putatively identified, among which, a series of norneolignans, clitorienolactones, and various flavonoids (flavone, flavonol, isoflavone, and isoflavanone) was found to comprise the major constituents, particularly in the EA and 50% MeOH fractions. The clitorienolactones, presently unique to the species, were present in both the free and glycosylated forms in the roots. Both the EA and 50% MeOH fractions displayed moderate effects on the stress-induced zebrafish model, significantly decreasing freezing duration and elevating the total distance travelled and average velocity, 72 h post-treatment. The results of the present study provide further evidence that the basis for the use of C. ternatea roots in traditional medicine to alleviate brain-related conditions, such as stress and depression, is attributable to the presence of clitorienolactones and the isoflavonoidal constituents.
Acetylcholinesterase and α-glucosidase inhibitory compounds from Callicarpa maingayi

Ado MA, Maulidiani M, Ismail IS, Ghazali HM, Shaari K, Abas F

Nat Prod Res, 2021 Sep;35(17):2992-2996.
PMID: 31631709 DOI: 10.1080/14786419.2019.1679138

Phytochemical investigation on the soluble fractions of n-hexane and dichloromethane of methanolic leaves extract of the Callicarpa maingayi K. & G. led to the isolation of three triterpenoids [euscaphic acid (1), arjunic acid (2), and ursolic acid (3)] together with two flavones [apigenin (4) and acacetin (5)], two phytosterols [stigmasterol 3-O-β-glycopyranoside (6) and sitosterol 3-O-β-glycopyranoside (7)], and a fatty acid [n-hexacosanoic acid (8)]. Six (6) compounds (1, 2, 3, 4, 5, and 8) are reported for the first time from this species. Their structures were elucidated and identified by extensive NMR techniques, GC-MS and comparison with the previously reported literature. Compound 3 was found to displayed good inhibition against acetylcholinesterase with an IC50 value of 21.5 ± 0.022 μM, while 1 and 2 exhibited pronounced α-glucosidase inhibitory activity with IC50 values of 22.4 ± 0.016 μM and 24.9 ± 0.012 μM, respectively.
Barrier protective effects of 2,4,6-trihydroxy-3-geranyl acetophenone on lipopolysaccharides-stimulated inflammatory responses in human umbilical vein endothelial cells

Chong YJ, Musa NF, Ng CH, Shaari K, Israf DA, Tham CL

J Ethnopharmacol, 2016 Nov 04;192:248-255.
PMID: 27404229 DOI: 10.1016/j.jep.2016.07.032

PHARMOCOLOGICAL RELEVANCE: 2,4,6-trihydroxy-3-geranyl acetophenone (tHGA), is a phloroglucinol compound found naturally in Melicope ptelefolia. Melicope ptelefolia has been used traditionally for centuries as natural remedy for wound infections and inflammatory diseases.
AIM OF THE STUDY: Endothelial barrier dysfunction is a pathological hallmark of many diseases and can be caused by lipopolysaccharides (LPS) stimulation. Therefore, this study aims to investigate the possible barrier protective effects of tHGA upon LPS-stimulated inflammatory responses in human umbilical vein endothelial cells (HUVECs).
MATERIALS AND METHODS: HUVECs were pretreated with tHGA prior to LPS stimulation, where inflammatory parameters including permeability, monocyte adhesion and migration, and release of pro-inflammatory mediators were examined. Additionally, the effect of tHGA on F-actin rearrangement and adhesion protein expression of LPS-stimulated HUVECs was evaluated.
RESULTS: It was found that pretreatment with tHGA inhibited monocyte adhesion and transendothelial migration, reduced endothelial hyperpermeability and secretion of prostaglandin E2 (PGE2). Additionally, tHGA inhibited cytoskeletal rearrangement and adhesion protein expression on LPS-stimulated HUVECs.
CONCLUSION: As the regulation of endothelial barrier dysfunction can be one of the therapeutic strategies to improve the outcome of inflammation, tHGA may be able to preserve vascular barrier integrity of endothelial cells following LPS-stimulated dysfunction, thereby endorsing its potential usefulness in vascular inflammatory diseases.
Fulltext Anti-Diabetic Activity and Metabolic Changes Induced by Andrographis paniculata Plant Extract in Obese Diabetic Rats

Akhtar MT, Bin Mohd Sarib MS, Ismail IS, Abas F, Ismail A, Lajis NH, et al.

Molecules, 2016 Aug 09;21(8).
PMID: 27517894 DOI: 10.3390/molecules21081026

Andrographis paniculata is an annual herb and widely cultivated in Southeast Asian countries for its medicinal use. In recent investigations, A. paniculata was found to be effective against Type 1 diabetes mellitus (Type 1 DM). Here, we used a non-genetic out-bred Sprague-Dawley rat model to test the antidiabetic activity of A. paniculata against Type 2 diabetes mellitus (Type 2 DM). Proton Nuclear Magnetic Resonance (¹H-NMR) spectroscopy in combination with multivariate data analyses was used to evaluate the A. paniculata and metformin induced metabolic effects on the obese and obese-diabetic (obdb) rat models. Compared to the normal rats, high levels of creatinine, lactate, and allantoin were found in the urine of obese rats, whereas, obese-diabetic rats were marked by high glucose, choline and taurine levels, and low lactate, formate, creatinine, citrate, 2-oxoglutarate, succinate, dimethylamine, acetoacetate, acetate, allantoin and hippurate levels. Treatment of A. paniculata leaf water extract was found to be quite effective in restoring the disturbed metabolic profile of obdb rats back towards normal conditions. Thisstudy shows the anti-diabetic potential of A. paniculata plant extract and strengthens the idea of using this plant against the diabetes. Further classical genetic methods and state of the art molecular techniques could provide insights into the molecular mechanisms involved in the pathogenesis of diabetes mellitus and anti-diabetic effects of A. paniculata water extract.
Biochemical studies of Piper betle L Leaf Extract on Obese Treated Animal using 1H-NMR-Based Metabolomic Approach of Blood Serum Samples

Abdul Ghani ZD, Husin JM, Rashid AH, Shaari K, Chik Z

J Ethnopharmacol, 2016 Oct 7.
PMID: 27725236 DOI: 10.1016/j.jep.2016.10.022

Piper Betle L. (PB) belongs to the Piperaceae family. The presence of a fairly large quantity of diastase in the betel leaf is deemed to play an important role in starch digestion and calls for the study of weight loss activities and metabolite profile from PB leaf extracts using metabolomics approach to be performed. PB dried leaves were extracted with 70% ethanol and the extracts were subjected to five groups of rats fed with high fat (HF) and standard diet (SD). They were then fed with the extracts in two doses and compared with a negative control group given water only according to the study protocol. The body weights and food intakes were monitored every week. At the end of the study, blood serum of the experimental animal was analysed to determine the biochemical and metabolite changes. PB treated group demonstrated inhibition of body weight gain without showing an effect on the food intake. In serum bioassay, the PB treated group (HF/PB (100mg/kg and 500mg/kg) showed an increased in glucose and cholesterol levels compared to the Standard Diet (SD/WTR) group, a decrease in LDL level and increase in HDL level when compared with High Fat Diet (HF/WTR) group. For metabolite analysis, two separation models were made to determine the metabolite changes via group activities. The best separation of PCA serum in Model 1 and 2 was achieved in principle component 1 and principle component 2. SUS-Plot model showed that HF group was characterized by high-level of glucose, glycine and alanine. Increase in the β-hydroxybutyrate level similar with SD group animals was evident in the HF/PB(500mg/kg) group. This finding suggested that the administration of 500mg/kg PB extracts leads to increase in oxidation process in the body thus maintaining the body weight and without giving an effect on the appetite even though HF was continuously consumed by the animals until the end of the studies and also a reduction in food intake, thus maintaining their body weight although they were continuously consumed HF.
Fulltext Isothiocyanate from Moringa oleifera seeds mitigates hydrogen peroxide-induced cytotoxicity and preserved morphological features of human neuronal cells

Jaafaru MS, Nordin N, Shaari K, Rosli R, Abdull Razis AF

PLoS One, 2018;13(5):e0196403.
PMID: 29723199 DOI: 10.1371/journal.pone.0196403

Reactive oxygen species are well known for induction of oxidative stress conditions through oxidation of vital biomarkers leading to cellular death via apoptosis and other process, thereby causing devastative effects on the host organs. This effect is believed to be linked with pathological alterations seen in several neurodegenerative disease conditions. Many phytochemical compounds proved to have robust antioxidant activities that deterred cells against cytotoxic stress environment, thus protect apoptotic cell death. In view of that we studied the potential of glucomoringin-isothiocyanate (GMG-ITC) or moringin to mitigate the process that lead to neurodegeneration in various ways. Neuroprotective effect of GMG-ITC was performed on retinoic acid (RA) induced differentiated neuroblastoma cells (SHSY5Y) via cell viability assay, flow cytometry analysis and fluorescence microscopy by means of acridine orange and propidium iodide double staining, to evaluate the anti-apoptotic activity and morphology conservation ability of the compound. Additionally, neurite surface integrity and ultrastructural analysis were carried out by means of scanning and transmission electron microscopy to assess the orientation of surface and internal features of the treated neuronal cells. GMG-ITC pre-treated neuron cells showed significant resistance to H2O2-induced apoptotic cell death, revealing high level of protection by the compound. Increase of intracellular oxidative stress induced by H2O2 was mitigated by GMG-ITC. Thus, pre-treatment with the compound conferred significant protection to cytoskeleton and cytoplasmic inclusion coupled with conservation of surface morphological features and general integrity of neuronal cells. Therefore, the collective findings in the presence study indicated the potentials of GMG-ITC to protect the integrity of neuron cells against induced oxidative-stress related cytotoxic processes, the hallmark of neurodegenerative diseases.
Fulltext The Protective Effects of a Synthetic Geranyl Acetophenone in a Cellular Model of TNF-α-Induced Pulmonary Epithelial Barrier Dysfunction

Sim TY, Harith HH, Tham CL, Md Hashim NF, Shaari K, Sulaiman MR, et al.

Molecules, 2018 Jun 05;23(6).
PMID: 29874809 DOI: 10.3390/molecules23061355

Alveolar epithelial barrier dysfunction contributes to lung edema and can lead to acute lung injury (ALI). The features include increased epithelial permeability, upregulation of inflammatory mediators and downregulation of junctional complex molecules; these changes are often induced by inflammation. tHGA is an acetophenone analogue with therapeutic potential in asthma. Its therapeutic potential in ALI is presently unknown. Herein, the effects of tHGA on epithelial barrier dysfunction were determined in TNF-α-induced human alveolar epithelial cells. The anti-inflammatory properties of tHGA were assessed by monocyte adhesion assay and analysis of MCP-1 and ICAM-1 expression. The epithelial barrier function was assessed by paracellular permeability and transepithelial electrical resistance (TEER) assays, and analysis of junctional complex molecules expression. To elucidate the mechanism of action, the effects of tHGA on the NF-κB and MAPK pathways were determined. Gene and protein expression were analyzed by RT-PCR and Western blotting or ELISA, respectively. tHGA suppressed leukocyte adhesion to TNF-α-induced epithelium and reduced MCP-1 and ICAM-1 gene expression and secretion. tHGA also increased TEER readings, reduced epithelial permeability and enhanced expression of junctional complex molecules (zona occludens-1, occludin and E-cadherin) in TNF-α-induced cells. Correspondingly, the NF-κB, ERK and p38 MAPK pathways were also inhibited by tHGA. These findings suggest that tHGA is able to preserve alveolar epithelial barrier function in response to acute inflammation, via its anti-inflammatory activity and stabilization of epithelial barrier integrity, mediated by NF-κB, ERK and p38 MAPK signaling.

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