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Genetic polymorphisms and drug interactions leading to clopidogrel resistance: why the Asian population requires special attention

Hasan MS, Basri HB, Hin LP, Stanslas J

Int J Neurosci, 2013 Mar;123(3):143-54.
PMID: 23110469 DOI: 10.3109/00207454.2012.744308

Ischemic heart disease and stroke are the two leading causes of death worldwide. Antiplatelet therapy plays the most significant role in the management of these cardiovascular and cerebrovascular occlusive events to prevent recurrent ischemic attack. Clopidogrel, an antiplatelet drug, is widely prescribed either alone or in combination with aspirin as dual antiplatelet therapy for the prevention of vascular occlusive events. The antiplatelet response to clopidogrel varies widely. Hyporesponders and nonresponders are likely to have adverse cardiovascular events during follow-up. Some drugs, such as proton pump inhibitors (omeprazole), calcium channel blockers, selective serotonin reuptake inhibitors (nefazadone), coumarin derivatives (phenprocoumon), benzodiazepines, sulfonylurea, erythromycin, and itraconazole, decrease the antiplatelet effect of clopidogrel when administered concomitantly. Decreased response to clopidogrel is common among Asians due to genetic polymorphisms associated with clopidogrel resistance, and it is nearly 70% in some of the Asian communities. It is necessary to study Asian populations, because there are a large number of Asians throughout the world due to increased migration. Current guidelines do not make genetic testing or platelet response testing mandatory prior to clopidogrel prescription. Therefore, it is important for clinicians treating Asian patients to keep in mind the interindividual variability in response to clopidogrel when prescribing the drug.
Efficiency of different Agrobacterium rhizogenes strains on hairy roots induction in Solanum mammosum

Ooi CT, Syahida A, Stanslas J, Maziah M

World J Microbiol Biotechnol, 2013 Mar;29(3):421-30.
PMID: 23090845 DOI: 10.1007/s11274-012-1194-z

This article presents the abilities and efficiencies of five different strains of Agrobacterium rhizogenes (strain ATCC 31798, ATCC 43057, AR12, A4 and A13) to induce hairy roots on Solanum mammosum through genetic transformation. There is significant difference in the transformation efficiency (average number of days of hairy root induction) and transformation frequency for all strains of A. rhizogenes (P < 0.05). Both A. rhizogenes strain AR12 and A13 were able to induce hairy root at 6 days of co-cultivation, which were the fastest among those tested. However, the transformation frequencies of all five strains were below 30 %, with A. rhizogenes strain A4 and A13 showing the highest, which were 21.41 ± 10.60 % and 21.43 ± 8.13 % respectively. Subsequently, the cultures for five different hairy root lines generated by five different strains of bacteria were established. However, different hairy root lines showed different growth index under the same culture condition, with the hairy root lines induced by A. rhizogenes strain ATCC 31798 exhibited largest increase in fresh biomass at 45 days of culture under 16 h light/8 h dark photoperiod in half-strength MS medium. The slowest growing hairy root line, which was previously induced by A. rhizogenes strain A13, when cultured in optimized half-strength MS medium containing 1.5 times the standard amount of ammonium nitrate and potassium nitrate and 5 % (w/v) sucrose, had exhibited improvement in growth index, that is, the fresh biomass was almost double as compared to its initial growth in unmodified half-strength MS medium.
A young lady with thalamic stroke mimicking acute Miller Fisher syndrome

Hasan S, Stanslas J, Hin LP, Basri HB

Neurosciences (Riyadh), 2012 Oct;17(4):380-1.
PMID: 23022907
Association of insertion/deletion polymorphism of alpha-adrenoceptor gene in essential hypertension with or without type 2 diabetes mellitus in Malaysian subjects

Vasudevan R, Ismail P, Stanslas J, Shamsudin N, Ali AB

Int J Biol Sci, 2008;4(6):362-7.
PMID: 18953403

An insertion/deletion (I/D) polymorphism of Alpha2B-Adrenoceptor (ADRA2B) gene located on chromosome 2 has been studied extensively in related to cardiovascular diseases. The main aim of the present study was to examine the potential association of D allele frequency of I/D polymorphism of ADRA2B gene in Malaysian essential hypertensive subjects with or without type 2 diabetes mellitus (T2DM). This study includes 70 hypertensive subjects without T2DM, 65 hypertensive subjects with T2DM and 75 healthy volunteers as control subjects. Genotyping of I/D polymorphism was performed by conventional PCR method. There was significant difference found in age, body mass index, systolic/diastolic blood pressure and high density lipoprotein cholesterol level between the case and control subjects. DD genotypic frequency of I/D polymorphism was significantly higher in hypertensive subjects (42.84% vs. 29.33%; P-=0.029) and in hypertensive with T2DM subjects (46.15% vs. 29.33%; P=0.046) than control group. D allele frequency was higher in hypertensive group (67.41%) than control subjects (52.67%). However, no significant difference was found between the three genotypes of I/D polymorphism of ADRA2B gene and the clinical characteristics of the subjects. The result obtained in this study show D allele of ADRA2B gene was associated with essential hypertension with or without T2DM in Malaysian subjects.
Naturally occurring labdane diterpene and benzofuran from Globba pendula

Maulidiani, Shaari K, Paetz C, Stanslas J, Abas F, Lajis NH

Nat Prod Commun, 2009 Aug;4(8):1031-6.
PMID: 19768978

Phytochemical investigation on Globba pendula resulted in the isolation of a new naturally occurring 16-oxo-(8)17-12-labdadien-15,11-olide 1 and benzofuran-2-carboxaldehyde 2. Other known compounds including isoandrographolide, indirubin, vanillin, vanillic acid, 2(3H)-benzoxazolone, as well as beta-sitosteryl-beta-D-glucopyranoside, beta-sitosterol, and 7alpha-hydroxysitosterol were also isolated. The structures were established based on spectroscopic data and comparison with the literature. Furthermore, the compound isoandrographolide has demonstrated strong cytotoxic properties towards a panel of cancer cell lines (MCF-7, PC-3, and H-460) with the IC50 values of 7.9, 8.7, and 9.0 microM, respectively.
Fulltext Encephalitis followed by optic neuritis: a case report and review of literature

Hasan S, B Basri H, P Hin L, Stanslas J

Pak J Med Sci, 2013 May;29(3):859-62.
PMID: 24353644

Encephalitis has been included in the causes of optic neuritis, but post encephalitic optic neuritis has been rarely reported. Majority of the cases of optic neuritis are either idiopathic or associated with multiple sclerosis, especially in western countries. This is very important in the Asian population where the incidence and prevalence of multiple sclerosis is not as high as in the Western countries. Although post infectious optic neuritis is more common in children, it can also be found in adults and is usually seen one to three weeks after a symptomatic infective prodrome. Here, we present a case of a 48 year-old-male who developed optic neuritis following viral encephalitis. His first presentation was with severe headache of two weeks duration. Viral encephalitis was diagnosed and treated. The patient presented again three weeks later with right eye pain and other features typical of optic neuritis. Corticosteroid therapy facilitated prompt recovery. Optic neuritis is an uncommon manifestation of encephalitis. It is important that both doctors and patients remain aware of post infectious cause of optic neuritis, which would enable a timely diagnosis and treatment of this reversible cause of vision loss.
Pharmacological modulation of oncogenic Ras by natural products and their derivatives: Renewed hope in the discovery of novel anti-Ras drugs

Quah SY, Tan MS, Teh YH, Stanslas J

Pharmacol Ther, 2016 06;162:35-57.
PMID: 27016467 DOI: 10.1016/j.pharmthera.2016.03.010

Oncogenic rat sarcoma (Ras) is linked to the most fatal cancers such as those of the pancreas, colon, and lung. Decades of research to discover an efficacious drug that can block oncogenic Ras signaling have yielded disappointing results; thus, Ras was considered "undruggable" until recently. Inhibitors that directly target Ras by binding to previously undiscovered pockets have been recently identified. Some of these molecules are either isolated from natural products or derived from natural compounds. In this review, we described the potential of these compounds and other inhibitors of Ras signaling in drugging Ras. We highlighted the modes of action of these compounds in suppressing signaling pathways activated by oncogenic Ras, such as mitogen-activated protein kinase (MAPK) signaling and the phosphoinositide-3-kinase (PI3K) pathways. The anti-Ras strategy of these compounds can be categorized into four main types: inhibition of Ras-effector interaction, interference of Ras membrane association, prevention of Ras-guanosine triphosphate (GTP) formation, and downregulation of Ras proteins. Another promising strategy that must be validated experimentally is enhancement of the intrinsic Ras-guanosine triphosphatase (GTPase) activity by small chemical entities. Among the inhibitors of Ras signaling that were reported thus far, salirasib and TLN-4601 have been tested for their clinical efficacy. Although both compounds passed phase I trials, they failed in their respective phase II trials. Therefore, new compounds of natural origin with relevant clinical activity against Ras-driven malignancies are urgently needed. Apart from salirasib and TLN-4601, some other compounds with a proven inhibitory effect on Ras signaling include derivatives of salirasib, sulindac, polyamine, andrographolide, lipstatin, levoglucosenone, rasfonin, and quercetin.
Fulltext Cytotoxic Properties and Complete Nuclear Magnetic Resonance Assignment of Isolated Xanthones from the Root of Garcinia cowa Roxb

Wahyuni FS, Shaari K, Stanslas J, Lajis NH, Hamidi D

Pharmacogn Mag, 2016 Jan;12(Suppl 1):S52-6.
PMID: 27041859 DOI: 10.4103/0973-1296.176115

To isolate compounds from the roots of Garcinia cowa and to evaluated their cytotoxic activity against breast (MCF-7), prostate (DU-145), and lung (H-460) cell lines.
Fulltext Effect of aflatoxin B1 exposure on the progression of depressive-like behavior in rats

Subramaniam S, Sabran MR, Stanslas J, Kirby BP

Front Nutr, 2022;9:1032810.
PMID: 36466381 DOI: 10.3389/fnut.2022.1032810

While it is well documented that aflatoxin B1 (AFB1); one of the most toxic food contaminants is linked to the development of depression. However, the mechanism on how it affects the gut and brain health leading to depressive-like behavior remains unclear. This study was conducted to determine the effect of AFB1 on the progression of depressive-like behavior. Thirty-two (n = 32) male Sprague Dawley rats were randomly allocated into four groups: control, low-dose (5 μg AFB1/kg), high-dose (25 μg AFB1/kg) and positive control group; exposed on chronic unpredictable mild stress (CUMS). After 4 weeks of exposure, sucrose preference test (SPT) and force swim test (FST) were used to measure behavioral despair. Fecal samples were selectively cultured to profile the bacteria. Body weight and relative organs weights were compared among groups. AFB1 and CUMS caused reduction in body weight and food intake as well as increased relative weight of adrenal glands, liver, and brain. Rats in AFB1 and CUMS groups had suppressed sucrose preference and prolonged immobility time in FST, wherein this could indicate anhedonia. Besides, fecal count of Lactobacillus spp. was significantly low following AFB1 exposure, with increasing count of Bifidobacterium spp, in comparison to the control. Indeed, further biochemical analysis and metagenomic approach are warranted to explore the underlying mechanisms on the role of gut microbiota dysbiosis and dysregulation of gut-brain axis due to AFB1 neurotoxicity on the progression of depressive-like behavior.
Exploring green solvent systems and enhanced solubility of xanthone in triglyceride-based tricaprin-tricaprylin mixtures with thermodynamic insights

Liu H, Stanslas J, Ren J, Suleiman NB, Chong GH

BMC Chem, 2024 Dec 04;18(1):239.
PMID: 39633458 DOI: 10.1186/s13065-024-01329-6

This study explores the use of green solvent systems by investigating the solubility and thermodynamic properties of xanthone (1) in triglyceride-based tricaprin (2) and tricaprylin (3) mixtures, aiming to replace traditional organic solvents. The solubility profile exhibited a concave trend, and the highest solubility was observed at a solute-free fraction (x2) of 0.36. The solubility exponentially increased with increasing temperature in the range from 30 °C to 75 °C. The solubility data were effectively correlated using the local composition-regular solution theory (LC-RST) model and achieved an ARDln value of 4.8 × 10-3. The model indicated strong interactions between tricaprin and tricaprylin, followed by interactions between tricaprylin and xanthone and between tricaprin and xanthone. The dissolution process of xanthone was primarily enthalpy driven. Based on the structural analysis, xanthone maintained its molecular structure after dissolution in tricaprin and tricaprylin; however, changes in crystallinity levels were observed. These findings provide insights into the use of triglycerides as solvents to improve the solubility and bioaccessibility of hydrophobic compounds such as xanthone.
Fulltext Effects of Different Types of Statins on Lipid Profile: A Perspective on Asians

Meor Anuar Shuhaili MFR, Samsudin IN, Stanslas J, Hasan S, Thambiah SC

Int J Endocrinol Metab, 2017 Apr;15(2):e43319.
PMID: 28848611 DOI: 10.5812/ijem.43319

CONTEXT: The present review aimed at reviewing the effects of different statins on lipid profile, particularly in Asians.
EVIDENCE ACQUISITION: PubMed searches were conducted using the keywords 'statin, effect, and lipid profile' from database inception through March 2016. In this review, 718 articles were retrieved from the primary search. After reviewing the titles, abstracts, and full texts, we found that 59 studies met our inclusion criteria. These also included subsequent reference searches of retrieved articles.
RESULTS: CURVES study compared the effect on lipid profile between atorvastatin and other statins. This study demonstrated that low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), and triglycerides (TG) were reduced more with atorvastatin compared to simvastatin, pravastatin, lovastatin, and fluvastatin. However, simvastatin provided a greater elevation of high-density lipoprotein cholesterol (HDL-C) compared to atorvastatin. The STELLAR trial was based on dose-to-dose comparisons between atorvastatin and rosuvastatin efficacy in reducing LDL-C. Te present study also revealed that as the doses of rosuvastatin, simvastatin, and pravastatin increased, HDL-C also increased, with rosuvastatin having the greatest effect. However, HDL-C levels decreased as the dose of atorvastatin increased. The DISCOVERY study involving the Asian population revealed that the percentage of patients achieving the European goals for LDL-C and TC at 12 weeks was higher in rosuvastatin group compared to atorvastatin group.
CONCLUSIONS: The effects of statins on lipid profile are dose dependent. Most studies showed that rosuvastatin has the best effect on lipid profile. Prescribing lower doses of statins in Asians seems necessary.
Oestrogenic activity of mimosine on MCF-7 breast cancer cell line through the ERα-mediated pathway

Huq AM, Wai LK, Rullah K, Mohd Aluwi MFF, Stanslas J, Jamal JA

Chem Biol Drug Des, 2019 03;93(3):222-231.
PMID: 30251480 DOI: 10.1111/cbdd.13404

Hormone replacement therapy has been a conventional treatment for postmenopausal symptoms in women. However, it has potential risks of breast and endometrial cancers. The aim of this study was to evaluate the oestrogenicity of a plant-based compound, mimosine, in MCF-7 cells by in silico model. Cell viability and proliferation, ERα-SRC1 coactivator activity and expression of specific ERα-dependent marker TFF1 and PGR genes were evaluated. Binding modes of 17β-oestradiol and mimosine at the ERα ligand binding domain were compared using docking and molecular dynamics simulation experiments followed by binding interaction free energy calculation with molecular mechanics/Poisson-Boltzmann surface area. Mimosine showed increased cellular viability (64,450 cells/ml) at 0.1 μM with significant cell proliferation (120.5%) compared to 17β-oestradiol (135.2%). ER antagonist tamoxifen significantly reduced proliferative activity mediated by mimosine (49.9%). Mimosine at 1 μM showed the highest ERα binding activity through increased SRC1 recruitment at 186.9%. It expressed TFF1 (11.1-fold at 0.1 μM) and PGR (13.9-fold at 0.01 μM) genes. ERα-mimosine binding energy was -49.9 kJ/mol, and it interacted with Thr347, Gly521 and His524 of ERα-LBD. The results suggested that mimosine has oestrogenic activity.
A standardised Andrographis paniculata Burm. Nees aqueous extract prevents Lipopolysaccharide-induced cognitive deficits through suppression of inflammatory cytokines and oxidative stress mediators

Sani D, Khatab NIO, Kirby BP, Yong A, Hasan S, Basri H, et al.

J Adv Res, 2019 Mar;16:87-97.
PMID: 30899592 DOI: 10.1016/j.jare.2018.11.005

Substantial evidence has shown that most cases of memory impairment are associated with increased neuroinflammation and oxidative stress. In this study, the potential of a standardised Andrographis paniculata aqueous extract (APAE) to reverse neuroinflammation and cognitive impairment induced by lipopolysaccharide (LPS) was examined in vivo. Rats were treated with APAE (50, 100, 200, and 400 mg·kg-1, p.o.) for 7 consecutive days prior to LPS (1 mg·kg-1, i.p.)-induced neuroinflammation and cognitive impairment. Spatial learning and memory were evaluated using the Morris water maze (MWM) test, while neuroinflammation and oxidative stress were assessed through the measurement of specific mediators, namely, tumour necrosis factor-α (TNF-α), interleukin-6 (IL-6), IL-1β, superoxide dismutase (SOD), catalase (CAT), antioxidant glutathione (GSH), reactive oxygen species (ROS), and thiobarbituric acid reactive substance (TBARS). Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) were also evaluated. LPS caused significant memory deficits in the 2-day MWM protocol, whereas pretreatment with standardised APAE dose-dependently improved performance in the MWM test. APAE treatment also blocked the LPS-induced hippocampal increase in the concentration and expression of proinflammatory cytokines (TNF-α, IL-1β, and IL-6) and production of ROS and TBARS and enhanced the activities of AChE and BChE. Furthermore, APAE enhanced the decrease in the levels and expression of hippocampal antioxidant enzymes (SOD and CAT) following LPS-induced neuroinflammation and cognitive deficit. The findings from these studies suggested that standardised APAE improved memory and had potent neuroprotective effects against LPS-induced neurotoxicity.
Advances and challenges in developing andrographolide and its analogues as cancer therapeutic agents

Soo HL, Quah SY, Sulaiman I, Sagineedu SR, Lim JCW, Stanslas J

Drug Discov Today, 2019 09;24(9):1890-1898.
PMID: 31154065 DOI: 10.1016/j.drudis.2019.05.017

Andrographolide (AGP), a naturally occurring bioactive compound, has been investigated as a lead compound in cancer drug development. Its multidimensional therapeutic effects have raised interest among medicinal chemists, which has led to extensive structural modification of the compound, resulting in analogues with improved pharmacological and pharmaceutical properties. Nevertheless, the analogues with the improved properties need to be rigorously studied to identify drug-like lead compounds. We scrutinised articles published from 2012 to 2018, to objectively provide opinions on the mechanisms of action of AGP and its analogues, as well as their potential as viable anticancer drugs. Preclinical and clinical data, along with the extensive medicinal chemistry efforts, indicate the compounds are potential anticancer agents with specific value in treating recalcitrant cancers such as pancreatic and lung cancers.
Fulltext Proximate Analysis and Safety Profile of Farmed Edible Bird's Nest in Malaysia and Its Effect on Cancer Cells

Tan SN, Sani D, Lim CW, Ideris A, Stanslas J, Lim CTS

Evid Based Complement Alternat Med, 2020;2020:8068797.
PMID: 32051689 DOI: 10.1155/2020/8068797

Edible bird's nest (EBN) which is solidified swiftlet's saliva contains high nutritional value. It is widely consumed in countries like Malaysia, Indonesia, and Thailand. However, previous proximate analysis of Malaysia EBN was not representative of all the regions in Malaysia. In recent years, safety issues such as high nitrate and nitrite contents, presence of heavy metal, adulteration, fungal infection, and cancer cell stimulation were associated with EBN. Hence, this study aimed to determine the proximate analysis, safety profile during normal weather and hazy periods, and its effect on cancer cells stimulation in Malaysia-farmed EBN. Seven raw cleaned EBN samples were sourced from 6 different regions in Malaysia. Proximate analysis and safety profile were performed using official AOCA methods and Malaysian Standard. High protein (53.03-56.37%) and carbohydrate content (27.97-31.68%) with an acceptable level of moisture (10.8-14.04%) and ash (2.22-3.38%) were reported. A good safety profile was obtained with low nitrite and nitrate levels, with undetectable heavy metals and no significant growth of pathogenic microorganism except mould. Epidermal growth factor was detected but below the quantification level with the chicken EGF ELISA kit. The microculture tetrazolium (MTT) assay was performed for growth stimulation assessment comparing human EGF and EBN. There was no significant cell growth observed in cancer cells after EBN treatment. In conclusion, EBN Malaysia has a good nutritional profile, free of heavy metals, and an acceptable level of nitrate, nitrite, and microorganism profile except for mould contents. Furthermore, the in vitro study indicated that EBN was not associated with cancer cell growth.
Serotonergic receptor gene polymorphism and response to selective serotonin reuptake inhibitors in ethnic Malay patients with first episode of major depressive disorder

Badamasi IM, Lye MS, Ibrahim N, Abdul Razaq NA, Ling KH, Stanslas J

Pharmacogenomics J, 2021 Aug;21(4):498-509.
PMID: 33731884 DOI: 10.1038/s41397-021-00228-6

The polymorphisms of the 5HTR1A and 5HTR2A receptor genes (rs6295C/G and rs6311G/A) have been evaluated for association with SSRI treatment outcome in various populations with different results. The present study was carried out to determine the association between genotypes of HTR1A-rs6295 and HTR2A-rs6311 with SSRI treatment outcome among the ethnic Malay patients diagnosed with first-episode major depressive disorder (MDD). The patients were recruited from four tertiary hospitals in the Klang Valley region of Malaysia. Predefined efficacy phenotypes based on 25% (partial early response) and 50% (clinical efficacy response) reduction in Montgomery Asberg Depression Rating Scale-self Rated score (MADRS-S) were adopted for assessment of treatment efficacy in this study. Self-reporting for adverse effects (AE) was documented using the Patient Rated Inventory of Side Effect (PRISE) after treatment with SSRI for up to 6 weeks. Adjusted binary logistic regression between genotypes of the polymorphism obtained using sequencing technique with the treatment outcome phenotypes was performed. The 142 patients recruited were made up of 96 females (67.6%) and 46 males (32.4%). Clinical efficacy and Partial early response phenotypes were not significantly associated with genotypes of HTR1A and HTR2A polymorphism. The GG genotype of HTR2A polymorphism has decreased odds for dizziness (CNS) and increased odds for poor concentration. The GA genotype increases the odd for excessive sweating, diarrhoea, constipation and blurred vision. The CC genotype of HTR1A-rs6295 decreases the odd for nausea/vomiting and increases the odd for anxiety. Thus, some genotypes of HTR1A and HTR2A polymorphism were associated with SSRI treatment outcomes in ethnic Malay MDD patients.
Synthesis of small molecules targeting paclitaxel-induced MyD88 expression in triple-negative breast cancer cell lines

Poh Yen K, Stanslas J, Zhang T, Li H, Wang X, Kok Meng C, et al.

Bioorg Med Chem, 2021 11 01;49:116442.
PMID: 34600241 DOI: 10.1016/j.bmc.2021.116442

Acquired paclitaxel (PTX) chemoresistance in triple-negative breast cancer (TNBC) can be inferred from the overexpression of toll-like receptor 4 (TLR4) and myeloid differentiation primary response 88 (MyD88) proteins and the activation of the TLR4/MyD88 cascading signalling pathway. Finding a new inhibitor that can attenuate the activation of this pathway is a novel strategy for reducing PTX chemoresistance. In this study, a series of small molecule compounds were synthesised and tested in combination with PTX against TNBC cells. The trimethoxy-substituted compound significantly decreased MyD88 overexpression and improved PTX activity in MDA-MB-231TLR4+ cells but not in HCCTLR4- cells. On the contrary, the trifluoromethyl-substituted compound with PTX synergistically improved the growth inhibition in both TNBC subtypes. The fluorescence titrations indicated that both compounds could bind with MD2 with good and comparable binding affinities. This was further supported by docking analysis, in which both compounds fit perfectly well and form some critical binding interactions with MD2, an essential lipid-binding accessory to TLR4 involved in activating the TLR-4/MyD88-dependent pathway.
Fulltext A Preliminary Nuclear Magnetic Resonance Metabolomics Study Identifies Metabolites that Could Serve as Diagnostic Markers of Major Depressive Disorder

Badamasi IM, Maulidiani M, Lye MS, Ibrahim N, Shaari K, Stanslas J

Curr Neuropharmacol, 2022;20(5):965-982.
PMID: 34126904 DOI: 10.2174/1570159X19666210611095320

BACKGROUND: The evaluation of metabolites that are directly involved in the physiological process, few steps short of phenotypical manifestation, remains vital for unravelling the biological moieties involved in the development of the (MDD) and in predicting its treatment outcome.
METHODOLOGY: Eight (8) urine and serum samples each obtained from consenting healthy controls (HC), twenty-five (25) urine and serum samples each from first episode treatment naïve MDD (TNMDD) patients, and twenty (22) urine and serum samples each s from treatment naïve MDD patients 2 weeks after SSRI treatment (TWMDD) were analysed for metabolites using proton nuclear magnetic resonance (1HNMR) spectroscopy. The evaluation of patients' samples was carried out using Partial Least Squares Discriminant Analysis (PLS-DA) and Orthogonal Partial Least Square- Discriminant Analysis (OPLSDA) models.
RESULTS: In the serum, decreased levels of lactate, glucose, glutamine, creatinine, acetate, valine, alanine, and fatty acid and an increased level of acetone and choline in TNMDD or TWMDD irrespective of whether an OPLSDA or PLSDA evaluation was used were identified. A test for statistical validations of these models was successful.
CONCLUSION: Only some changes in serum metabolite levels between HC and TNMDD identified in this study have potential values in the diagnosis of MDD. These changes included decreased levels of lactate, glutamine, creatinine, valine, alanine, and fatty acid, as well as an increased level of acetone and choline in TNMDD. The diagnostic value of these changes in metabolites was maintained in samples from TWMDD patients, thus reaffirming the diagnostic nature of these metabolites for MDD.
Andrographolide and its analogues: versatile bioactive molecules for combating inflammation and cancer

Lim JC, Chan TK, Ng DS, Sagineedu SR, Stanslas J, Wong WS

Clin Exp Pharmacol Physiol, 2012 Mar;39(3):300-10.
PMID: 22017767 DOI: 10.1111/j.1440-1681.2011.05633.x

1. Andrographis paniculata (Burm. f) Nees, commonly known as 'king of bitters', is a herbaceous plant belonging to the Family Acanthaceae. It has been widely used for centuries in Asian countries like China, India, Thailand and Malaysia for the treatment of sore throat, flu and upper respiratory tract infections. 2. Andrographolide, 14-deoxy-11,12-didehydroandrographolide and neoandrographolide are examples of the major labdane diterpenoids isolated from A. paniculata. These bioactive molecules have exhibited varying degrees of anti-inflammatory and anticancer activities in both in vitro and in vivo experimental models of inflammation and cancer. 3. Extensive libraries of andrographolide analogues have been synthesised mainly by modifying the α,β-unsaturated γ-butyrolactone moiety, the two double bonds Δ(8,(17)) and Δ(12,(13)) and the three hydroxyls at C-3 (secondary), C-14 (allylic) and C-19 (primary). Many of these synthetic analogues exhibit superior anticancer activity over the naturally occurring andrographolides. 4. Andrographolide and its derivatives have been shown to have anti-inflammatory effects in experimental models of asthma, stroke and arthritis, as well as in patients with upper respiratory tract infections. Andrographolide reduces the production of cytokines, chemokines, adhesion molecules, nitric oxide and lipid mediators, probably via inhibition of the nuclear factor (NF)-κB signalling pathway. 5. The anticancer mechanisms for andrographolide include inhibition of Janus tyrosine kinases-signal transducers and activators of transcription, phosphatidylinositol 3-kinase and NF-κB signalling pathways, suppression of heat shock protein 90, cyclins and cyclin-dependent kinases, metalloproteinases and growth factors, and the induction of tumour suppressor proteins p53 and p21, leading to inhibition of cancer cell proliferation, survival, metastasis and angiogenesis. 6. Andrographolide drug discovery is a promising strategy for the development of a novel class of anti-inflammatory and anticancer drugs.
SRJ23, a new semisynthetic andrographolide derivative: in vitro growth inhibition and mechanisms of cell cycle arrest and apoptosis in prostate cancer cells

Wong HC, Wong CC, Sagineedu SR, Loke SC, Lajis NH, Stanslas J

Cell Biol Toxicol, 2014 Oct;30(5):269-88.
PMID: 25070834 DOI: 10.1007/s10565-014-9282-5

3,19-(3-Chloro-4-fluorobenzylidene)andrographolide (SRJ23), a new semisynthetic derivative of andrographolide (AGP), exhibited selectivity against prostate cancer cells in the US National Cancer Institute (NCI) in vitro anti-cancer screen. Herein, we report the in vitro growth inhibition and mechanisms of cell cycle arrest and apoptosis induced by SRJ23.

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