Publications by authors named "Sue Mian Then"

15 Publications

  • Page 1 of 1

Cis-9, Trans-11 Conjugated Linoleic Acid Reduces Phosphoenolpyruvate Carboxykinase Expression and Hepatic Glucose Production in HepG2 Cells.

Lipids 2019 06 24;54(6-7):369-379. Epub 2019 May 24.

TIFAC CORE in Herbal Drugs, Department of Pharmacognosy, JSS College of Pharmacy (Ooty), JSS Academy of Higher Education & Research, Rocklands, Udhagamandalam, 643001, Tamil Nadu, India.

Dysregulated hepatic gluconeogenesis is a hallmark of insulin resistance and type 2 diabetes mellitus (T2DM). Although existing drugs have been proven to improve gluconeogenesis, achieving this objective with functional food is of interest, especially using conjugated linoleic acid (CLA) found in dairy products. Both cis-9, trans-11 (c9,t11) and trans-10, cis-12 (t10,c12) isomers of CLA were tested in human (HepG2) and rat (H4IIE) hepatocytes for their potential effects on gluconeogenesis. The hepatocytes exposed for 24 h with 20 μM of c9,t11-CLA had attenuated the gluconeogenesis in both HepG2 and H4IIE by 62.5% and 80.1%, respectively. In contrast, t10,c12-CLA had no effect. Of note, in HepG2 cells, the exposure of c9,t11-CLA decreased the transcription of gluconeogenic enzymes, cytosolic phosphoenolpyruvate carboxykinase (PCK1) by 87.7%, and glucose-6-phosphatase catalytic subunit (G6PC) by 38.0%, while t10,c12-CLA increased the expression of G6PC, suggesting the isomer-specific effects of CLA on hepatic glucose production. In HepG2, the peroxisome proliferator-activated receptor (PPAR) agonist, rosiglitazone, reduced the glucose production by 72.9%. However, co-administration of c9,t11-CLA and rosiglitazone neither exacerbated nor attenuated the efficacy of rosiglitazone to inhibit glucose production; meanwhile, t10,c12-CLA abrogated the efficacy of rosiglitazone. Paradoxically, PPARγ antagonist GW 9662 also led to 70.2% reduction of glucose production and near undetectable PCK1 expression by abrogating CLA actions. Together, while the precise mechanisms by which CLA isomers modulate hepatic gluconeogenesis directly or via PPAR warrant further investigation, our findings establish that c9,t11-CLA suppresses gluconeogenesis by decreasing PEPCK on hepatocytes.
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http://dx.doi.org/10.1002/lipd.12154DOI Listing
June 2019

Data on the water soluble sclerotial extract affecting intracellular calcium level in rat dorsal root ganglion cells.

Data Brief 2018 Jun 14;18:1322-1326. Epub 2018 Apr 14.

Faculty of Science, University of Nottingham Malaysia Campus, 43500 Semenyih, Malaysia.

The data in this article contain supporting evidence for the research manuscript entitled "Bronchodilator effects of extract on rat isolated airways is linked to the blockage of calcium entry" by Lee et al. (2018) [1]. The data were obtained by calcium imaging technique with fluorescent calcium indicator dyes, Fura 2-AM, to visualize calcium ion movement in the rat dorsal ganglion (DRG) cells. The effects of cold water extract (CWE) on intracellular calcium levels in the DRG cells were presented.
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http://dx.doi.org/10.1016/j.dib.2018.04.033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5997891PMC
June 2018

Bronchodilator effects of Lignosus rhinocerotis extract on rat isolated airways is linked to the blockage of calcium entry.

Phytomedicine 2018 Mar 13;42:172-179. Epub 2018 Mar 13.

Department of Biomedical Sciences, University of Nottingham Malaysia Campus, Semenyih 43500, Malaysia. Electronic address:

Background: Lignosus rhinocerotis (Cooke) Ryvarden is a popular medicinal mushroom used for centuries in Southeast Asia to treat asthma and chronic cough. The present study aimed to investigate the effect of this mushroom on airways patency.

Materials And Methods: The composition of L. rhinocerotis TM02 cultivar was analyzed. Organ bath experiment was employed to study the bronchodilator effect of Lignosus rhinocerotis cold water extract (CWE) on rat isolated airways. Trachea and bronchus were removed from male Sprague-Dawley rats, cut into rings of 2 mm, pre-contracted with carbachol before adding CWE into the bath in increasing concentrations. To investigate the influence of incubation time, tissues were exposed to intervals of 5, 15 and 30 min between CWE concentrations after pre-contraction with carbachol in subsequent protocol. Next, tissues were pre-incubated with CWE before the addition of different contractile agents, carbachol and 5-hydroxytrptamine (5-HT). The bronchodilator effect of CWE was compared with salmeterol and ipratropium. In order to uncover the mechanism of action of CWE, the role of beta-adrenoceptor, potassium and calcium channels was investigated.

Results: Composition analysis of TM02 cultivar revealed the presence of β-glucans and derivatives of adenosine. The extract fully relaxed the trachea at 3.75 mg/ml (p < 0.0001) and bronchus at 2.5 mg/ml (p < 0.0001). It was observed that lower concentrations of CWE were able to fully relax both trachea and bronchus but at a longer incubation interval between concentrations. CWE pre-incubation significantly reduced the maximum responses of carbachol-induced contractions (in both trachea, p = 0.0012 and bronchus, p = 0.001), and 5-HT-induced contractions (in trachea, p = 0.0048 and bronchus, p = 0.0014). Ipratropium has demonstrated a significant relaxation effect in both trachea (p = 0.0004) and bronchus (p = 0.0031), whereas salmeterol has only affected the bronchus (p = 0.0104). The involvement of β-adrenoceptor and potassium channel in CWE-mediated airway relaxation is ruled out, but the bronchodilator effect was unequivocally affected by influx of calcium.

Conclusions: The bronchodilator effect of L. rhinocerotis on airways is mediated by calcium signalling pathway downstream of G-coupled protein receptors. The airway relaxation effect is both concentration- and incubation time-dependent. Our findings provide unequivocal evidence to support its traditional use to relieve asthma and cough.
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http://dx.doi.org/10.1016/j.phymed.2018.03.025DOI Listing
March 2018

Effects of simulated microgravity on gene expression and biological phenotypes of a single generation Caenorhabditis elegans cultured on 2 different media.

Life Sci Space Res (Amst) 2017 Nov 24;15:11-17. Epub 2017 Jun 24.

UKM Medical Molecular Biology Institute, Universiti Kebangsaan Malaysia, Malaysia. Electronic address:

Studies of multigenerational Caenorhabditis elegans exposed to long-term spaceflight have revealed expression changes of genes involved in longevity, DNA repair, and locomotion. However, results from spaceflight experiments are difficult to reproduce as space missions are costly and opportunities are rather limited for researchers. In addition, multigenerational cultures of C. elegans used in previous studies contribute to mixture of gene expression profiles from both larvae and adult worms, which were recently reported to be different. Usage of different culture media during microgravity simulation experiments might also give rise to differences in the gene expression and biological phenotypes of the worms. In this study, we investigated the effects of simulated microgravity on the gene expression and biological phenotype profiles of a single generation of C. elegans worms cultured on 2 different culture media. A desktop Random Positioning Machine (RPM) was used to simulate microgravity on the worms for approximately 52 to 54 h. Gene expression profile was analysed using the Affymetrix GeneChip® C. elegans 1.0 ST Array. Only one gene (R01H2.2) was found to be downregulated in nematode growth medium (NGM)-cultured worms exposed to simulated microgravity. On the other hand, eight genes were differentially expressed for C. elegans Maintenance Medium (CeMM)-cultured worms in microgravity; six were upregulated, while two were downregulated. Five of the upregulated genes (C07E3.15, C34H3.21, C32D5.16, F35H8.9 and C34F11.17) encode non-coding RNAs. In terms of biological phenotype, we observed that microgravity-simulated worms experienced minimal changes in terms of lifespan, locomotion and reproductive capabilities in comparison with the ground controls. Taking it all together, simulated microgravity on a single generation of C. elegans did not confer major changes to their gene expression and biological phenotype. Nevertheless, exposure of the worms to microgravity lead to higher expression of non-coding RNA genes, which may play an epigenetic role in the worms during longer terms of microgravity exposure.
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http://dx.doi.org/10.1016/j.lssr.2017.06.002DOI Listing
November 2017

Mitochondrial DNA Mutations in Grade II and III Glioma Cell Lines Are Associated with Significant Mitochondrial Dysfunction and Higher Oxidative Stress.

Front Physiol 2017 21;8:231. Epub 2017 Apr 21.

UKM Medical Molecular Biology Institute, Universiti Kebangsaan MalaysiaKuala Lumpur, Malaysia.

The role of mitochondria in tumorigenesis has regained much attention as it could dysregulate cellular energetics, oxidative stress and apoptosis. However, the role of mitochondria in different grade gliomasis still unknown. This study aimed to identify mitochondrial DNA (mtDNA) sequence variations that could possibly affect the mitochondrial functions and also the oxidative stress status. Three different grades of human glioma cell lines and a normal human astrocyte cell line were cultured and tested for oxidative stress biomarkers. Relative oxidative stress level, mitochondria activity, and mitochondrial mass were determined by live cell imaging with confocal laser scanning microscope using CM-HDCFDA, MitoTracker Green, and MitoTracker Orange stains. The entire mitochondrial genome was sequenced using the AffymetrixGeneChip Human Mitochondrial Resequencing Array 2.0. The mitochondrial sequence variations were subjected to phylogenetic haplogroup assessment and pathogenicity of the mutations were predicted using pMUT and PolyPhen2. The Grade II astrocytoma cells showed increased oxidative stress wherea high level of 8-OHdG and oxidative stress indicator were observed. Simultaneously, Grade II and III glioma cells showed relatively poor mitochondria functions and increased number of mutations in the coding region of the mtDNA which could be due to high levels of oxidative stress in these cells. These non-synonymous mtDNA sequence variations were predicted to be pathogenic and could possibly lead to protein dysfunction, leading to oxidative phosphorylation (OXPHOS) impairment, mitochondria dysfunction and could create a vicious cycle of oxidative stress. The Grade IV cells had no missense mutation but preserved intact mitochondria and excellent antioxidant defense mechanisms thus ensuring better survival. In conclusion, Grade II and III glioma cells demonstrated coding region mtDNA mutations, leading to mitochondrial dysfunction and higher oxidative stress.
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http://dx.doi.org/10.3389/fphys.2017.00231DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5399085PMC
April 2017

Gamma-tocotrienol acts as a BH3 mimetic to induce apoptosis in neuroblastoma SH-SY5Y cells.

J Nutr Biochem 2016 05 9;31:28-37. Epub 2016 Feb 9.

UKM Medical Molecular Biology Institute (UMBI), Universiti Kebangsaan Malaysia Medical Center, 56000, Cheras, Kuala Lumpur, Malaysia; Department of Biochemistry, Faculty of Medicine, Universiti Kebangsaan Malaysia Medical Center, 56000, Cheras, Kuala Lumpur, Malaysia. Electronic address:

Bcl-2 family proteins are crucial regulators of apoptosis. Both pro- and antiapoptotic members exist, and overexpression of the latter facilitates evasion of apoptosis in many cancer types. Bcl-2 homology domain 3 (BH3) mimetics are small molecule inhibitors of antiapoptotic Bcl-2 family members, and these inhibitors are promising anticancer agents. In this study, we report that gamma-tocotrienol (γT3), an isomer of vitamin E, can inhibit Bcl-2 to induce apoptosis. We demonstrate that γT3 induces cell death in human neuroblastoma SH-SY5Y cells by depolarising the mitochondrial membrane potential, enabling release of cytochrome c to the cytosol and increasing the activities of caspases-9 and -3. Treatment of cells with inhibitors of Bax or caspase-9 attenuated the cell death induced by γT3. Simulated docking analysis suggested that γT3 binds at the hydrophobic groove of Bcl-2, while a binding assay showed that γT3 competed with a fluorescent probe to bind at the hydrophobic groove. Our data suggest that γT3 mimics the action of BH3-only protein by binding to the hydrophobic groove of Bcl-2 and inducing apoptosis via the intrinsic pathway in a Bax- and caspase-9-dependent manner.
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http://dx.doi.org/10.1016/j.jnutbio.2015.12.019DOI Listing
May 2016

Vitamin E, γ-tocotrienol, Protects Against Buthionine Sulfoximine-Induced Cell Death by Scavenging Free Radicals in SH-SY5Y Neuroblastoma Cells.

Nutr Cancer 2016 23;68(3):507-17. Epub 2016 Mar 23.

a UKM Medical Molecular Biology Institute, Universiti Kebangsaan Malaysia Medical Center , Kuala Lumpur , Malaysia.

The induction of reactive oxygen species (ROS) to selectively kill cancer cells is an important feature of radiotherapy and various chemotherapies. Depletion of glutathione can induce apoptosis in cancer cells or sensitize them to anticancer treatments intended to modulate ROS levels. In contrast, antioxidants protect cancer cells from oxidative stress-induced cell death by scavenging ROS. The role of exogenous antioxidants in cancer cells under oxidative insults remains controversial and unclear. This study aimed to identify protective pathways modulated by γ-tocotrienol (γT3), an isomer of vitamin E, in human neuroblastoma SH-SY5Y cells under oxidative stress. Using buthionine sulfoximine (BSO) as an inhibitor of glutathione synthesis, we found that BSO treatment reduced the viability of SH-SY5Y cells. BSO induced cell death by increasing apoptosis, decreased the level of reduced glutathione (GSH), and increased ROS levels in SH-SY5Y cells. Addition of γT3 increased the viability of BSO-treated cells, suppressed apoptosis, and decreased the ROS level induced by BSO, while the GSH level was unaffected. These results suggest that decreasing GSH levels by BSO increased ROS levels, leading to apoptosis in SH-SY5Y cells. γT3 attenuated the BSO-induced cell death by scavenging free radicals.
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http://dx.doi.org/10.1080/01635581.2016.1153671DOI Listing
January 2017

Piper betle leaf extract enhances the cytotoxicity effect of 5-fluorouracil in inhibiting the growth of HT29 and HCT116 colon cancer cells.

J Zhejiang Univ Sci B 2014 Aug;15(8):692-700

Department of Biomedical Sciences, Faculty of Allied Health, Universiti Kebangsaan Malaysia (UKM), Jalan Raja Muda Abdul Aziz, 50300 Kuala Lumpur, Malaysia; UKM Medical Molecular Biology Institute (UMBI), Universiti Kebangsaan Malaysia (UKM), Jalan Yaacob Latiff, Bandar Tun Razak, Cheras, 56000 Kuala Lumpur, Malaysia; School of Biomedical Science, University of Nottingham Malaysia Campus, 43500 Semenyih, Selangor, Malaysia; Department of Biochemistry, Faculty of Medicine, Universiti Kebangsaan Malaysia (UKM), Jalan Raja Muda Abdul Aziz, 50300 Kuala Lumpur, Malaysia; Forest Research Institute Malaysia (FRIM), 52109 Kuala Lumpur, Kepong, Malaysia; School of Biosciences, Taylor's University, Lakeside Campus, 47500 Subang Jaya, Selangor, Malaysia.

Objective: The combination effect of Piper betle (PB) and 5-fluorouracil (5-FU) in enhancing the cytotoxic potential of 5-FU in inhibiting the growth of colon cancer cells was investigated.

Methods: HT29 and HCT116 cells were subjected to 5-FU or PB treatment. 5-FU and PB were then combined and their effects on both cell lines were observed after 24 h of treatment. PB-5-FU interaction was elucidated by isobologram analysis. Apoptosis features of the treated cells were revealed by annexin V/PI stain. High-performance liquid chromatography (HPLC) was performed to exclude any possible chemical interaction between the compounds.

Results: In the presence of PB extract, the cytotoxicity of 5-FU was observed at a lower dose (IC50 12.5 µmol/L) and a shorter time (24 h) in both cell lines. Both cell lines treated with 5-FU or PB alone induced a greater apoptosis effect compared with the combination treatment. Isobologram analysis indicated that PB and 5-FU interacted synergistically and antagonistically in inhibiting the growth of HT29 and HCT116 cells, respectively.

Conclusions: In the presence of PB, a lower dosage of 5-FU is required to achieve the maximum drug effect in inhibiting the growth of HT29 cells. However, PB did not significantly reduce 5-FU dosage in HCT116 cells. Our result showed that this interaction may not solely contribute to the apoptosis pathway.
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http://dx.doi.org/10.1631/jzus.B1300303DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4129089PMC
August 2014

Autogenic feeder free system from differentiated mesenchymal progenitor cells, maintains pluripotency of the MEL-1 human embryonic stem cells.

Differentiation 2013 Feb 28;85(3):110-8. Epub 2013 May 28.

UKM Medical Molecular Biology Institute, UKM Medical Center, Jalan Yaacob Latiff, Bandar Tun Razak, 56000 Kuala Lumpur, Malaysia.

Human embryonic stem cells (hESc) are known for its pluripotency and self renewal capability, thus possess great potential in regenerative medicine. However, the lack of suitable xenofree extracellular matrix substrate inhibits further applications or the use of hESc in cell-based therapy. In this study, we described a new differentiation method, which generates a homogeneous population of mesenchymal progenitor cells (hESc-MPC) from hESc via epithelial-mesenchymal transition. The extracellular matrix (ECM) proteins from hESc-MPC had in turn supported the undifferentiated expansion of hESc. Immunocytochemistry and flow cytometry characterization of hESc-MPC revealed the presence of early mesenchymal markers. Tandem mass spectometry analysis of ECM produced by hESc-MPC revealed the presence of a mixture of extracellular proteins which includes tenascin C, fibronectin, and vitronectin. The pluripotency of hESc (MEL-1) cultured on the ECM was maintained as shown by the expression of pluripotent genes (FoxD3, Oct-4, Tdgf1, Sox-2, Nanog, hTERT, Rex1), protein markers (SSEA-3, SSEA-4, TRA-1-81, TRA-1-60, Oct-4) and the ability to differentiate into cells representative of ectoderm, endoderm and mesoderm. In summary, we have established a xeno-free autogenic feeder free system to support undifferentiated expansion of hESc, which could be of clinical relevance.
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http://dx.doi.org/10.1016/j.diff.2013.01.004DOI Listing
February 2013

Association between vitamin A, vitamin E and apolipoprotein E status with mild cognitive impairment among elderly people in low-cost residential areas.

Nutr Neurosci 2013 Jan 22;16(1):6-12. Epub 2012 Oct 22.

Dietetics Program, Faculty of Health Sciences, School of Health Care Sciences, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia.

Rationale: The influence of nutritional parameters and genetic susceptibility on poor cognitive impairment has been documented; however, the association between lipid-soluble vitamins with genetic susceptibility on mild cognitive impairment (MCI) has not yet been studied extensively.

Objectives: The aim of the present study was (i) to determine the prevalence of MCI and its associated risk factors and (2) to investigate the influence of the apolipoprotein E (APOE) ε4 allele on peripheral vitamin A and E concentration in MCI and non-MCI groups.

Methods: A total of 333 subjects aged 60 years and above, residing in public housing areas in Kuala Lumpur, Malaysia were interviewed to obtain information on their neuropsychological status. Fasting venous blood was taken for determination of vitamin A and vitamin E concentration using high-performance liquid chromatography. Restriction fragment length polymorphism analysis was performed to determine the APOE genotypes.

Results: The prevalence of MCI was 21.1%. Binary logistic regression indicated that the predictors of MCI were being married, overweight or obesity, and had vitamin A deficiency. In non-MCI subjects, vitamin E levels were lower among APOEε4 allele carriers as compared to the non-carriers (P < 0.05).

Conclusion: The study highlighted the importance of maintaining good nutritional status and vitamin A status for optimal cognitive function. The presence of APOEε4 allele has a prominent role in affecting vitamin E levels, particularly among cognitively healthy elderly in our unique population.
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http://dx.doi.org/10.1179/1476830512Y.0000000013DOI Listing
January 2013

The role of long chain omega-3 polyunsaturated fatty acids in reducing lipid peroxidation among elderly patients with mild cognitive impairment: a case-control study.

J Nutr Biochem 2013 May 13;24(5):803-8. Epub 2012 Aug 13.

Nutrition Science Programme, School of Healthcare Sciences, Faculty of Health Sciences, Universiti Kebangsaan Malaysia, 50300 Kuala Lumpur, Malaysia.

The present work explores the effect of dietary omega-3 polyunsaturated fatty acids (PUFAs) intake on lipid peroxidation among mild cognitive impairment (MCI) patients. The plasma lipid hydroperoxide (LPO) levels in 67 MCI patients were compared to those of 134 healthy elderly controls. Omega-3 PUFA intake was assessed using an interviewer-administered food frequency questionnaire. Apolipoprotein E genotyping was performed using polymerase chain reaction and restriction enzyme digestion. The association between various confounders and lipid peroxidation was evaluated using regression analysis. The influence of docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) intake on LPO level was investigated. The results revealed that LPO levels were significantly higher in the MCI group than in the control group. Inverse correlations were found between DHA and EPA intake and LPO level among the MCI group. LPO levels decreased significantly with increasing DHA and EPA intake. In summary, the findings revealed that DHA and EPA can play a role in alleviating oxidative stress and reducing the risk of neurodegenerative diseases.
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http://dx.doi.org/10.1016/j.jnutbio.2012.04.014DOI Listing
May 2013

γ-Tocotrienol does not substantially protect DS neurons from hydrogen peroxide-induced oxidative injury.

Nutr Metab (Lond) 2012 Jan 5;9. Epub 2012 Jan 5.

UKM Medical Molecular Biology Institute (UMBI), Universiti Kebangsaan Malaysia (UKM), Kuala Lumpur, Malaysia.

Background: Down syndrome (DS) neurons are more susceptible to oxidative stress and previous studies have shown that vitamin E was able to reduce oxidative stress and improve DS neurons' viability. Therefore, this study was done to investigate the protective role of γ-tocotrienol (γT3) in DS neurons from hydrogen peroxide (H2O2) -induced oxidative stress. The pro-apoptosis tendency of γT3 was compared to α-tocopherol (αT) in non-stress condition as well.

Methods: Primary culture of DS and euploid neurons were divided into six groups of treatment: control, H2O2, γT3 pre-treatment with H2O2, γT3 only, αT pre-treatment with H2O2 and αT only. The treatments were assessed by MTS assay and apoptosis assay by single-stranded DNA (ssDNA) apoptosis ELISA assay, Hoechst and Neu-N immunofluorescence staining. The cellular uptake of γT3 and αT was determined by HPLC while protein expressions were determined by Western blot. Comparison between groups was made by the Student's t test, one-way ANOVA and Bonferroni adjustment as well as two-way ANOVA for multiple comparisons.

Results: One day incubation of γT3 was able to reduced apoptosis of DS neurons by 10%, however γT3 was cytotoxic at longer incubation period (14 days) and at concentrations ≥ 100 μM. Pre-treatment of αT and γT3 only attenuate apoptosis and increase cell viability in H2O2-treated DS and euploid neurons by 10% in which the effects were minimal to maintain most of the DS cells' morphology. γT3 act as a free radical scavenger by reducing ROS generated by H2O2. In untreated controls, DS neurons showed lower Bcl-2/Bax ratio and p53 expression compared to normal neurons, while cPKC and PKC-δ expressions were higher in DS neurons. On the other hand, pre-treatment of γT3 in H2O2-treated DS neurons have reduced Bcl-2/Bax ratio, which was not shown in euploid neurons. This suggests that pre-treatment of γT3 did not promote DS cell survival. Meanwhile γT3 and αT treatments without H2O2 as well as pre-treatment of γT3 and αT induced changes in cPKC and PKC-δ expression in DS neurons suggesting interaction of γT3 and αT with PKC activity.

Conclusion: Our study suggests that γT3 pre-treatment are not sufficient to protect DS neurons from H2O2-induced oxidative assault, instead induced the apoptosis process.
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http://dx.doi.org/10.1186/1743-7075-9-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3285086PMC
January 2012

Frequency of the HLA-B*1502 allele contributing to carbamazepine-induced hypersensitivity reactions in a cohort of Malaysian epilepsy patients.

Asian Pac J Allergy Immunol 2011 Sep;29(3):290-3

UKM Medical Molecular Biology Institute (UMBI), Universiti Kebangsaan Malaysia (UKM), Kuala Lumpur, Malaysia.

We describe the association of the HLA-B*1502 allele in 27 epilepsy patients (19 Malays, 8 Chinese) treated with carbamazepine (CBZ) at the UKM Medical Center (UKMMC), 6 with CBZ-Steven Johnson Syndrome (CBZ-SJS), 11 with CBZ-induced rash, 2 with suspected phenytoin-induced rash and 8 negative controls. Our study showed that 10 (6 Malay, 4 Chinese) patients were positive for HLA-B*1502. Out of the 10 patients, six were confirmed to have CBZ-SJS (p = 0.0006), while four patients developed a skin rash. However there were 6 Malay patients and 1 Chinese patient that developed a skin rash after CBZ administration who were not positive for the allele, indicating that there might be more that one allele associated with CBZ-induced hypersensitivity. Another 2 patients were suspected of having phenytoin-induced rash, instead of CBZ, and these patients did not have HLA-B*1502. In conclusion, this study confirmed the association of HLA-B*1502 with CBZ-SJS among Malaysian epilepsy patients, however there might be other genes that could be responsible for the CBZ-induced rash.
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September 2011

Is vitamin E toxic to neuron cells?

Cell Mol Neurobiol 2009 Jun 27;29(4):485-96. Epub 2009 Jan 27.

UKM Medical Molecular Biology Institute (UMBI), Universiti Kebangsaan Malaysia Medical Centre (UKMMC), Universiti Kebangsaan Malaysia, 7th Floor Clinical Block, Jalan Yaacob Latiff, Bandar Tun Razak, Cheras, Kuala Lumpur, Malaysia.

Besides acting as potent free radical scavengers, tocopherols and tocotrienols have been known to have non-antioxidant properties such as the involvement of alpha-tocopherol (alphaT) in PKC pathway and the anti-cancer properties of gamma-tocotrienol (gammaT3). This study aims to elucidate whether protective effects shown by alphaT and gammaT3 in H(2)O(2)-induced neuron cultures have anti-apoptotic or pro-apoptotic tendency toward the initiation of neuronal apoptosis. H(2)O(2) is used to induce apoptosis in primary cerebellar neuron cultures which is attenuated by pretreatment of alphaT or gammaT3 at concentrations < or =10 microM. Similar to our previous work, gammaT3 was found to be neurotoxic at concentrations > or =100 microM, whereas alphaT showed no neurotoxicity. Cellular uptake of gammaT3 was higher than that of alphaT. Treating cells simultaneously with either gammaT3 or alphaT and with then H(2)O(2) led to higher expression of Bax and Bcl-2 than in neurons exposed to H(2)O(2) alone. Analysis of Bcl-2/Bax ratio as 'survival index' showed that both pretreatment of gammaT3 and alphaT followed by H(2)O(2) increase the 'survival index' of Bcl-2/Bax ratio compared to H(2)O(2)-treated cells, while treatment of gammaT3 alone decrease the ratio compared to unchanged Bcl2/Bax ratio of similar treatment with alphaT alone. Similar treatment of gammaT3 decreased p53 expression and activates p38 MAPK phosphorylation, whereas alphaT did not alter its expression compared to H(2)O(2)-treated cells. Treating neurons with only gammaT3 or alphaT increased the expression of Bax, Bcl-2, p53, and p38 MAPK compared to control with gammaT3 exerting stronger expression for proteins involved than alphaT. In conclusion, low doses of gammaT3 and alphaT confer neuroprotection to H(2)O(2)-treated neurons via their antioxidant mechanism but gammaT3 has stronger pro-apoptosis tendency than alphaT by activating molecules involved in the neuronal apoptotic pathway in the absence of H(2)O(2).
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http://dx.doi.org/10.1007/s10571-008-9340-8DOI Listing
June 2009

Comparative effects of alpha-tocopherol and gamma-tocotrienol against hydrogen peroxide induced apoptosis on primary-cultured astrocytes.

J Neurol Sci 2006 Apr 27;243(1-2):5-12. Epub 2006 Jan 27.

Department of Biochemistry, Medical Faculty, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia.

Oxidative stress is thought to be one of the factors that cause neurodegeneration and that this can be inhibited by antioxidants. Since astrocytes support the survival of central nervous system (CNS) neurons, we compared the effect of alpha-tocopherol and gamma-tocotrienol in minimizing the cytotoxic damage induced by H(2)O(2), a pro-oxidant. Primary astrocyte cultures were pretreated with either alpha-tocopherol or gamma-tocotrienol for 1 h before incubation with 100 microM H(2)O(2) for 24 h. Cell viability was then assessed using the MTS assay while apoptosis was determined using a commercial ELISA kit as well as by fluorescent staining of live and apoptotic cells. The uptake of alpha-tocopherol and gamma-tocotrienol by astrocytes were also determined using HPLC. Results showed that gamma-tocotrienol is toxic at concentrations >200 microM but protects against H(2)O(2) induced cell loss and apoptosis in a dose dependent manner up to 100 microM. alpha-Tocopherol was not cytotoxic in the concentration range tested (up to 750 microM), reduced apoptosis to the same degree as that of gamma-tocotrienol but was less effective in maintaining the viable cell number. Since the uptake of alpha-tocopherol and gamma-tocotrienol by astrocytes is similar, this may reflect the roles of these 2 vitamin E subfamilies in inhibiting apoptosis and stimulating proliferation in astrocytes.
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http://dx.doi.org/10.1016/j.jns.2005.10.006DOI Listing
April 2006