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Targeting genes in insulin-associated signalling pathway, DNA damage, cell proliferation and cell differentiation pathways by tocotrienol-rich fraction in preventing cellular senescence of human diploid fibroblasts

Durani LW, Jaafar F, Tan JK, Tajul Arifin K, Mohd Yusof YA, Wan Ngah WZ, et al.

Clin Ter, 2016;166(6):e365-73.
PMID: 26794818 DOI: 10.7417/T.2015.1902

Tocotrienols have been known for their antioxidant properties besides their roles in cellular signalling, gene expression, immune response and apoptosis. This study aimed to determine the molecular mechanism of tocotrienol-rich fraction (TRF) in preventing cellular senescence of human diploid fibroblasts (HDFs) by targeting the genes in senescence-associated signalling pathways.
Tocotrienol-rich fraction prevents cellular aging by modulating cell proliferation signaling pathways

Khor SC, Mohd Yusof YA, Wan Ngah WZ, Makpol S

Clin Ter, 2015;166(2):e81-90.
PMID: 25945449 DOI: 10.7417/CT.2015.1825

BACKGROUND AND OBJECTIVE: Vitamin E has been suggested as nutritional intervention for the prevention of degenerative and age-related diseases. In this study, we aimed to elucidate the underlying mechanism of tocotrienol-rich fraction (TRF) in delaying cellular aging by targeting the proliferation signaling pathways in human diploid fibroblasts (HDFs).
MATERIALS AND METHODS: Tocotrienol-rich fraction was used to treat different stages of cellular aging of primary human diploid fibroblasts viz. young (passage 6), pre-senescent (passage 15) and senescent (passage 30). Several selected targets involved in the downstream of PI3K/AKT and RAF/MEK/ERK pathways were compared in total RNA and protein.
RESULTS: Different transcriptional profiles were observed in young, pre-senescent and senescent HDFs, in which cellular aging increased AKT, FOXO3, CDKN1A and RSK1 mRNA expression level, but decreased ELK1, FOS and SIRT1 mRNA expression level. With tocotrienol-rich fraction treatment, gene expression of AKT, FOXO3, ERK and RSK1 mRNA was decreased in senescent cells, but not in young cells. The three down-regulated mRNA in cellular aging, ELK1, FOS and SIRT1, were increased with tocotrienol-rich fraction treatment. Expression of FOXO3 and P21Cip1 proteins showed up-regulation in senescent cells but tocotrienol-rich fraction only decreased P21Cip1 protein expression in senescent cells.
CONCLUSIONS: Tocotrienol-rich fraction exerts gene modulating properties that might be responsible in promoting cell cycle progression during cellular aging.
Transcriptome analysis reveals the molecular mechanisms of combined gamma-tocotrienol and hydroxychavicol in preventing the proliferation of 1321N1, SW1783, and LN18 glioma cancer cells

Abdul Rahman A, Mokhtar NM, Harun R, Jamal R, Wan Ngah WZ

J Physiol Biochem, 2019 Nov;75(4):499-517.
PMID: 31414341 DOI: 10.1007/s13105-019-00699-z

Gamma-tocotrienol (GTT) and hydroxychavicol (HC) exhibit anticancer activity in glioma cancer cells, where the combination of GTT + HC was shown to be more effective than single agent. The aim of this study was to determine the effect of GTT + HC by measuring the cell cycle progression, migration, invasion, and colony formation of glioma cancer cells and elucidating the changes in gene expression mitigated by GTT + HC that are critical to the chemoprevention of glioma cell lines 1321N1 (grade II), SW1783 (grade III), and LN18 (grade IV) using high-throughput RNA sequencing (RNA-seq). Results of gene expression levels and alternative splicing transcripts were validated by qPCR. Exposure of glioma cancer cells to GTT + HC for 24 h promotes cell cycle arrest at G2M and S phases and inhibits cell migration, invasion, and colony formation of glioma cancer cells. The differential gene expression induced by GTT + HC clustered into response to endoplasmic reticulum (ER) stress, cell cycle regulations, apoptosis, cell migration/invasion, cell growth, and DNA repair. Subnetwork analysis of genes altered by GTT + HC revealed central genes, ATF4 and XBP1. The modulation of EIF2AK3, EDN1, and FOXM1 were unique to 1321N1, while CSF1, KLF4, and FGF2 were unique to SW1783. PLK2 and EIF3A gene expressions were only altered in LN18. Moreover, GTT + HC treatment dynamically altered transcripts and alternative splicing expression. GTT + HC showed therapeutic potential against glioma cancer as evident by the inhibition of cell cycle progression, migration, invasion, and colony formation of glioma cancer cells, as well as the changes in gene expression profiles with key targets in ER unfolded protein response pathway, apoptosis, cell cycle, and migration/invasion.
Piper betle Induced Cytoprotective Genes and Proteins via the Nrf2/ARE Pathway in Aging Mice

Aliahmat NS, Abdul Sani NF, Wan Hasan WN, Makpol S, Wan Ngah WZ, Mohd Yusof YA

J Nutrigenet Nutrigenomics, 2016;9(5-6):243-253.
PMID: 28002828 DOI: 10.1159/000452407

BACKGROUND/AIMS: The objective of this study was to elucidate the underlying antioxidant mechanism of aqueous extract of Piper betle (PB) in aging rats. The nuclear factor erythroid 2-related factor 2 (Nrf2)/ARE pathway involving phase II detoxifying and antioxidant enzymes plays an important role in the antioxidant system by reducing electrophiles and reactive oxygen species through induction of phase II enzymes and proteins.
METHODS: Genes and proteins of phase II detoxifying antioxidant enzymes were analyzed by QuantiGenePlex 2.0 Assay and Western blot analysis.
RESULTS: PB significantly induced genes and proteins of phase II and antioxidant enzymes, NAD(P)H quinone oxidoreductase 1, and catalase in aging mice (p < 0.05). The expression of these enzymes were stimulated via translocation of Nrf2 into the nucleus, indicating the involvement of ARE, a cis-acting motif located in the promoter region of nearly all phase II genes.
CONCLUSIONS: PB was testified for the first time to induce cytoprotective genes through the Nrf2/ARE signaling pathway, thus unraveling the antioxidant mechanism of PB during the aging process.
Suppression of colorectal cancer cell growth by combined treatment of 6-gingerol and γ-tocotrienol via alteration of multiple signalling pathways

Yusof KM, Makpol S, Fen LS, Jamal R, Wan Ngah WZ

J Nat Med, 2019 Sep;73(4):745-760.
PMID: 31177355 DOI: 10.1007/s11418-019-01323-6

Our previous study reported that combined treatment of γ-tocotrienol with 6-gingerol showed promising anticancer effects by synergistically inhibiting proliferation of human colorectal cancer cell lines. This study aimed to identify and elucidate molecular mechanisms involved in the suppression of SW837 colorectal cancer cells modulated by combined treatment of γ-tocotrienol and 6-gingerol. Total RNA from both untreated and treated cells was prepared for transcriptome analysis using RNA sequencing techniques. We performed high-throughput sequencing at approximately 30-60 million coverage on both untreated and 6G + γT3-treated cells. The results showed that cancer-specific differential gene expression occurred and functional enrichment pathway analysis suggested that more than one pathway was modulated in 6G + γT3-treated cells. Combined treatment with 6G + γT3 augmented its chemotherapeutic effect by interfering with the cell cycle process, downregulating the Wnt signalling pathway and inducing apoptosis mainly through caspase-independent programmed cell death through mitochondrial dysfunction, activation of ER-UPR, disruption of DNA repair mechanisms and inactivation of the cell cycle process through the downregulation of main genes in proliferation such as FOXM1 and its downstream genes. The combined treatment exerted its cytotoxic effect through upregulation of genes in stress response activation and cytostatic effects demonstrated by downregulation of main regulator genes in the cell cycle. Selected genes involved in particular pathways including ATF6, DDIT3, GADD34, FOXM1, CDK1 and p21 displayed concordant patterns of gene expression between RNA sequencing and RT-qPCR. This study provides new insights into combined treatment with bioactive compounds not only in terms of its pleiotropic effects that enhance multiple pathways but also specific target genes that could be exploited for therapeutic purposes, especially in suppressing cancer cell growth.
Fulltext The association between bone health indicated by calcaneal quantitative ultrasound and metabolic syndrome in Malaysian men

Chin KY, Ima-Nirwana S, Mohamed IN, Ahmad F, Mohd Ramli ES, Aminuddin A, et al.

J Diabetes Metab Disord, 2015;14:9.
PMID: 25789255 DOI: 10.1186/s40200-015-0136-3

BACKGROUND: Previous studies on the relationship between bone health and metabolic syndrome (MS) have revealed heterogeneous results. There are limited studies employing bone quantitative ultrasonometry in evaluating this relationship. This study aimed to determine the relationship between MS and bone health in a group of Malaysian middle-aged and elderly men using bone quantitative ultrasonometry.
METHODS: This cross-sectional study recruited 309 free living Chinese and Malay men aged 40 years and above residing in Klang Valley, Malaysia. Their demographic and anthropometric data were collected. Their calcaneal speed of sound (SOS) was measured using a CM-200 bone ultrasonometer. Their blood was collected for the evaluation of lipid profile, total testosterone and sex hormone-binding globulin. The joint interim MS definition was used for the classification of subjects. Multiple linear regression analysis was used to assess the association between SOS and indicators of MS and the presence of MS, with suitable adjustment for confounders.
RESULTS: There was no significant difference in SOS value between MS and non-MS subjects (p > 0.05). The SOS values among subjects with different MS scores did not differ significantly (p > 0.05). There were no significant associations between SOS values and indicators of MS or the presence of MS (p > 0.05).
CONCLUSIONS: The relationship between bone health and MS is not significant in Malaysian middle-aged and elderly men. A longitudinal study should be conducted to evaluate the association between bone loss and MS to confirm this finding.
Discrepancy between the quantitative ultrasound value of Malaysian men and the manufacturer's reference and the impact on classification of bone health status

Chin KY, Soelaiman IN, Mohamed IN, Mohamed N, Shuid AN, Muhammad N, et al.

J Clin Densitom, 2013 Apr-Jun;16(2):189-95.
PMID: 22572528 DOI: 10.1016/j.jocd.2012.03.004

The local normative value in quantitative ultrasound (QUS) equipment needs to be established for wider application and accurate classification of patients into respective fracture risk groups. The present study aimed to establish the calcaneal speed of sound (SOS) value for Chinese and Malay men in Malaysia and determine the difference between calcaneal SOS of the local population and the reference values provided by the manufacturer for each age group. This study will also determine the effect of using the manufacturer's young adult (20-29yr) reference or the local young adult reference to classify the subjects into the respective risk groups. Eight hundred forty Malay and Chinese men residing in central peninsular Malaysia were recruited and their calcaneal QUS value was determined using the CM-200 machine (Furuno Electric, Nishinomiya City, Japan). The results showed that the differences in SOS values between Chinese and Malay men were not significant across all the age groups studied (p>0.05). The age-dependent reduction of SOS value assumed a biphasic form, which was evident at 30-39yr and older than 60yr. The calcaneal SOS of the subject under study was significantly higher as compared with the manufacturer's reference (based on Japanese population) in all groups aged 40yr and older (p<0.05). A significant proportion of the subjects in the osteoporosis group was misclassified using the manufacturer's young adult reference as compared with using the local young adult reference (p<0.05). In conclusion, the overall normative value of SOS obtained was suitable for Chinese and Malay men in Malaysia, and a local reference value should be applied to avoid misclassification of subjects into the respective risk groups.
Fulltext Piper betle leaf extract enhances the cytotoxicity effect of 5-fluorouracil in inhibiting the growth of HT29 and HCT116 colon cancer cells

Ng PL, Rajab NF, Then SM, Mohd Yusof YA, Wan Ngah WZ, Pin KY, et al.

J Zhejiang Univ Sci B, 2014 Aug;15(8):692-700.
PMID: 25091987 DOI: 10.1631/jzus.B1300303

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.
KEYWORDS: 5-Fluorouracil; Herb-drug interaction; Isobologram analysis; Piper betle L.; Piperaceae
Fulltext Chlorella vulgaris triggers apoptosis in hepatocarcinogenesis-induced rats

Mohd Azamai ES, Sulaiman S, Mohd Habib SH, Looi ML, Das S, Abdul Hamid NA, et al.

J Zhejiang Univ Sci B, 2009 Jan;10(1):14-21.
PMID: 19198018 DOI: 10.1631/jzus.B0820168

Chlorella vulgaris (CV) has been reported to have antioxidant and anticancer properties. We evaluated the effect of CV on apoptotic regulator protein expression in liver cancer-induced rats. Male Wistar rats (200~250 g) were divided into eight groups: control group (normal diet), CDE group (choline deficient diet supplemented with ethionine in drinking water to induce hepatocarcinogenesis), CV groups with three different doses of CV (50, 150, and 300 mg/kg body weight), and CDE groups treated with different doses of CV (50, 150, and 300 mg/kg body weight). Rats were sacrificed at various weeks and liver tissues were embedded in paraffin blocks for immunohistochemistry studies. CV, at increasing doses, decreased the expression of anti-apoptotic protein, Bcl-2, but increased the expression of pro-apoptotic protein, caspase 8, in CDE rats, which was correlated with decreased hepatocytes proliferation and increased apoptosis as determined by bromodeoxy-uridine (BrdU) labeling and terminal deoxynucleotidyl transferase mediated dUTP nick-end labeling (TUNEL) assay, respectively. Our study shows that CV has definite chemopreventive effect by inducing apoptosis via decreasing the expression of Bcl-2 and increasing the expression of caspase 8 in hepatocarcinogenesis-induced rats.
Fulltext Effect of Age on the Protein Profile of Healthy Malay Adults and its Association with Cognitive Function Competency

Abu Bakar ZH, Damanhuri HA, Makpol S, Wan Kamaruddin WMA, Abdul Sani NF, Amir Hamzah AIZ, et al.

J Alzheimers Dis, 2019;70(s1):S43-S62.
PMID: 30594926 DOI: 10.3233/JAD-180511

BACKGROUND: Many studies on biochemical and psychological variables have aimed to elucidate the association between aging and cognitive function. Demographic differences and protein expression have been reported to play a role in determining the cognitive capability of a population.
OBJECTIVE: This study aimed to determine the effect of age on the protein profile of Malay individuals and its association with cognitive competency.
METHODS: A total of 160 individuals were recruited and grouped accordingly. Cognitive competency of each subject was assessed with several neuropsychological tests. Plasma samples were collected and analyzed with Q Exactive HF Orbitrap. Proteins were identified and quantitated with MaxQuant and further analyzed with Perseus to determine differentially expressed proteins. PANTHER, Reactome, and STRING were applied for bioinformatics output.
RESULTS: Our data showed that the Malay individuals are vulnerable to the deterioration of cognitive function with aging, and most of the proteins were differentially expressed in concordance. Several physiological components and pathways were shown to be involved, giving a hint of a promising interpretation on the induction of aging toward the state of the Malays' cognitive function. Nevertheless, some proteins have shown a considerable interaction with the generated protein network, which provides a direction of focus for further investigation.
CONCLUSION: This study demonstrated notable changes in the expression of several proteins as age increased. These changes provide a promising platform for understanding the biochemical factors affecting cognitive function in the Malay population. The exhibited network of protein-protein interaction suggests the possibility of implementing regulatory intervention in ameliorating Malay cognitive function.
Fulltext Tocotrienol Rich Fraction Supplementation Modulate Brain Hippocampal Gene Expression in APPswe/PS1dE9 Alzheimer's Disease Mouse Model

Wan Nasri WN, Makpol S, Mazlan M, Tooyama I, Wan Ngah WZ, Damanhuri HA

J Alzheimers Dis, 2019;70(s1):S239-S254.
PMID: 30507571 DOI: 10.3233/JAD-180496

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by loss of memory and other cognitive abilities. AD is associated with aggregation of amyloid-β (Aβ) deposited in the hippocampal brain region. Our previous work has shown that tocotrienol rich fraction (TRF) supplementation was able to attenuate the blood oxidative status, improve behavior, and reduce fibrillary-type Aβ deposition in the hippocampus of an AD mouse model. In the present study, we investigate the effect of 6 months of TRF supplementation on transcriptome profile in the hippocampus of APPswe/PS1dE9 double transgenic mice. TRF supplementation can alleviate AD conditions by modulating several important genes in AD. Moreover, TRF supplementation attenuated the affected biological process and pathways that were upregulated in the AD mouse model. Our findings indicate that TRF supplementation can modulate hippocampal gene expression as well as biological processes that can potentially delay the progression of AD.
Fulltext Modulation of Proteome Profile in AβPP/PS1 Mice Hippocampus, Medial Prefrontal Cortex, and Striatum by Palm Oil Derived Tocotrienol-Rich Fraction

Hamezah HS, Durani LW, Yanagisawa D, Ibrahim NF, Aizat WM, Makpol S, et al.

J Alzheimers Dis, 2019;72(1):229-246.
PMID: 31594216 DOI: 10.3233/JAD-181171

Tocotrienol-rich fraction (TRF) is a mixture of vitamin E analogs derived from palm oil. We previously demonstrated that supplementation with TRF improved cognitive function and modulated amyloid pathology in AβPP/PS1 mice brains. The current study was designed to examine proteomic profiles underlying the therapeutic effect of TRF in the brain. Proteomic analyses were performed on samples of hippocampus, medial prefrontal cortex (mPFC), and striatum using liquid chromatography coupled to Q Exactive HF Orbitrap mass spectrometry. From these analyses, we profiled a total of 5,847 proteins of which 155 proteins were differentially expressed between AβPP/PS1 and wild-type mice. TRF supplementation of these mice altered the expression of 255 proteins in the hippocampus, mPFC, and striatum. TRF also negatively modulated the expression of amyloid beta A4 protein and receptor-type tyrosine-protein phosphatase alpha protein in the hippocampus. The expression of proteins in metabolic pathways, oxidative phosphorylation, and those involved in Alzheimer's disease were altered in the brains of AβPP/PS1 mice that received TRF supplementation.
Tocotrienol-Rich Fraction Modulates Amyloid Pathology and Improves Cognitive Function in AβPP/PS1 Mice

Ibrahim NF, Yanagisawa D, Durani LW, Hamezah HS, Damanhuri HA, Wan Ngah WZ, et al.

J Alzheimers Dis, 2017;55(2):597-612.
PMID: 27716672

Alzheimer's disease (AD) is the most common cause of dementia. The cardinal neuropathological characteristic of AD is the accumulation of amyloid-β (Aβ) into extracellular plaques that ultimately disrupt neuronal function and lead to neurodegeneration. One possible therapeutic strategy therefore is to prevent Aβ aggregation. Previous studies have suggested that vitamin E analogs slow AD progression in humans. In the present study, we investigated the effects of the tocotrienol-rich fraction (TRF), a mixture of vitamin E analogs from palm oil, on amyloid pathology in vitro and in vivo. TRF treatment dose-dependently inhibited the formation of Aβ fibrils and Aβ oligomers in vitro. Moreover, daily TRF supplementation to AβPPswe/PS1dE9 double transgenic mice for 10 months attenuated Aβ immunoreactive depositions and thioflavin-S-positive fibrillar type plaques in the brain, and eventually improved cognitive function in the novel object recognition test compared with control AβPPswe/PS1dE9 mice. The present result indicates that TRF reduced amyloid pathology and improved cognitive functions, and suggests that TRF is a potential therapeutic agent for AD.
Fulltext Tocotrienol-Rich Fraction of Palm Oil Improves Behavioral Impairments and Regulates Metabolic Pathways in AβPP/PS1 Mice

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

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

We have recently shown that the tocotrienol-rich fraction (TRF) of palm oil, a mixture of vitamin E analogs, improves amyloid pathology in vitro and in vivo. However, precise mechanisms remain unknown. In this study, we examined the effects of long-term (10 months) TRF treatment on behavioral impairments and brain metabolites in (15 months old) AβPP/PS1 double transgenic (Tg) Alzheimer's disease (AD) mice. The open field test, Morris water maze, and novel object recognition tasks revealed improved exploratory activity, spatial learning, and recognition memory, respectively, in TRF-treated Tg mice. Brain metabolite profiling of wild-type and Tg mice treated with and without TRF was performed using ultrahigh performance liquid chromatography (UHPLC) coupled to high-resolution accurate mass (HRAM)-orbitrap tandem mass spectrometry (MS/MS). Metabolic pathway analysis found perturbed metabolic pathways that linked to AD. TRF treatment partly ameliorated metabolic perturbations in Tg mouse hippocampus. The mechanism of this pre-emptive activity may occur via modulation of metabolic pathways dependent on Aβ interaction or independent of Aβ interaction.
Silencing of PROS1 induces apoptosis and inhibits migration and invasion of glioblastoma multiforme cells

Che Mat MF, Abdul Murad NA, Ibrahim K, Mohd Mokhtar N, Wan Ngah WZ, Harun R, et al.

Int J Oncol, 2016 Dec;49(6):2359-2366.
PMID: 27840905 DOI: 10.3892/ijo.2016.3755

Glioblastoma multiforme (GBM) is an aggressive brain tumor and most patients have poor prognosis. Despite many advances in research, there has been no significant improvement in the patient survival rate. New molecular therapies are being studied and RNA interference (RNAi) therapy is one of the promising approaches to improve prognosis and increase survival in patients with GBM. We performed a meta‑analysis of five different microarray datasets and identified 460 significantly upregulated genes in GBM. Loss‑of‑function screening of these upregulated genes using LN18 cells was performed to identify the significant target genes for glioma. Further investigations were performed using siRNA in LN18 cells and various functional assays were carried out on the selected candidate gene to understand further its role in GBM. We identified PROS1 as a candidate gene for GBM from the meta‑analysis and RNAi screening. Knockdown of PROS1 in LN18 cells significantly induced apoptosis compared to siPROS1‑untreated cells (p<0.05). Migration in cells treated with siPROS1 was reduced significantly (p<0.05) and this was confirmed with wound-healing assay. PROS1 knockdown showed substantial reduction in cell invasion up to 82% (p<0.01). In addition, inhibition of PROS1 leads to decrease in cellular proliferation by 18%. Knockdown of PROS1 in LN18 cells caused activation of both of the extrinsic and intrinsic apoptotic pathways. It caused major upregulation of FasL which is important for death receptor signaling activation and also downregulation of GAS6 and other members of TAM family of receptors. PROS1 may play an important role in the development of GBM through cellular proliferation, migration and invasion as well as apoptosis. Targeting PROS1 in GBM could be a novel therapeutic strategy in GBM treatment.
Fulltext Lessons from the Bone Chapter of the Malaysian Aging Men Study

Chin KY, Wan Ngah WZ, Ima-Nirwana S

Int J Environ Res Public Health, 2016 05 25;13(6).
PMID: 27231930 DOI: 10.3390/ijerph13060531

Male osteoporosis in Malaysia is a largely neglected problem. Therefore, a bone health study in men using quantitative ultrasonometry was launched as part of the Malaysian Aging Men Study in 2009-2012. This review aimed to summarize the findings of the aforementioned bone health study. The study examined the bone health of Chinese and Malaysian men aged 20 years and above living in Kuala Lumpur using a quantitative ultrasound device. Participants answered a questionnaire on their demographic details and physical activity status. Body anthropometry of the participants was measured and their blood collected for biochemical analysis. Results showed that a significant proportion of the Malaysian Chinese and Malay men had suboptimal bone health indicated by calcaneal speed of sound and vitamin D status. Age-related decline of the calcaneal speed of sound in these men was gradual and biphasic without ethnic difference. Body anthropometry such as height, weight, body mass index, and body fat percentage contributed to the variation of the calcaneal speed of sound in Malaysian men. Age-related changes in testosterone, insulin-like growth factor 1, and thyroid stimulating hormone also influenced the calcaneal speed of sound in these men. This study serves as a reminder that male osteoporosis in Malaysia should be an issue of concern. It is also a basis for a more comprehensive study on bone health in men in the future.
Optimisation of glycaemic control during episodes of severe/acute hyperglycaemia in patients with type 2 diabetes mellitus

Huri HZ, Makmor-Bakry M, Hashim R, Mustafa N, Wan Ngah WZ

Int J Clin Pharm, 2012 Dec;34(6):863-70.
PMID: 22869200 DOI: 10.1007/s11096-012-9682-7

BACKGROUND: Patients with type 2 diabetes mellitus (T2DM) are frequently admitted to the hospital with severe or acute hyperglycaemia secondary to an acute illness or disease. Uncontrolled glycaemia is a significant problem during severe or acute hyperglycaemia.
OBJECTIVE: This study sought to identify demographic, clinical, and genetic factors that may contribute to increased insulin resistance or worsening of glycaemic control in patients with T2DM.
SETTING: This prospective cohort study included 156 patients with T2DM and severe or acute hyperglycaemia who were treated with insulin at any medical ward of the National University of Malaysia Medical Centre.
METHOD: Insulin resistance was determined using the homeostatic model assessment-insulin resistance index. Glycaemic control during the episode of hyperglycaemia was assessed as the degree to which the patient achieved the target glucose levels. The polymerase chain reaction-restriction fragment length polymorphism method was used to identify polymorphisms in insulin receptor substrate (IRS) genes.
MAIN OUTCOME MEASURE: Identification of possible predictors (demographic, clinical, or genetic) for insulin resistance and glycaemic control during severe/acute hyperglycaemia.
RESULTS: A polymorphism in IRS1, r.2963 G>A (p.Gly972Arg), was a significant predictor of both insulin resistance [odds ratios (OR) 4.48; 95 % confidence interval (CI) 1.2-16.7; P = 0.03) and worsening of glycaemic control (OR 6.04; 95 % CI 0.6-64.6; P = 0.02). The use of loop diuretics (P < 0.05) and antibiotics (P < 0.05) may indirectly predict worsening of insulin resistance or glycaemic control in patients with severe/acute hyperglycaemia.
CONCLUSION: Clinical and genetic factors contribute to worsening of insulin resistance and glycaemic control during severe/acute hyperglycaemia in patients with T2DM. Early identification of factors that may influence insulin resistance and glycaemic control may help to achieve optimal glycaemic control during severe/acute hyperglycaemia.
Different starting times of alpha-tocopherol and gamma-tocotrienol supplementation and tumor marker enzyme activities in the rat chemically induced with cancer

Makpol S, Shamaan NA, Jarien Z, Top AG, Khalid BA, Wan Ngah WZ

Gen. Pharmacol., 1997 Apr;28(4):589-92.
PMID: 9147029

1. alpha-Tocopherol (alpha-T) and gamma-tocotrienol (gamma-T) were supplemented continuously for 8 weeks in the diets of normal rats and rats chemically induced with cancer using diethylnitrosamine (DEN), 2-acetylaminofluorene (AAF) and partial hepatectomy. Hepatocarcinogenesis was followed by determining the plasma gamma-glutamyl-transpeptidase (GGT) and alkaline phosphatase (ALP) activities as well as placental glutathione S-transferase (PGST) and GGT activities histochemically, at 4-week intervals. 2. Male Rattus norvegicus were supplemented alpha-T and gamma-T at two different doses of 30 and 300 mg/kg diet. The supplementation was started at three different times: simultaneously with DEN administration; 4 weeks; and 8 weeks after DEN administration. 3. Elevation of plasma GGT activities and formation of PGST and GGT positive foci were attenuated significantly (P < 0.05) when alpha-T and gamma-T were supplemented simultaneously with cancer induction. Supplementation begun 4 and 8 weeks after cancer induction did not affect plasma enzyme activities and formation of enzyme-positive foci. 4. alpha-T was more effective than gamma-T, and a lower dose of 30 mg/kg was found to be more effective in reducing the severity of hepatocarcinogenesis.
Fulltext The Role of Oxidative Stress in Suicidal Behaviour Among Bipolar Patients: A Cross-Sectional Study in a Malaysian Sample

Loo JL, Mohamad Kamal NA, Goon JA, Ahmad Damanhuri H, Tan JAC, Abdul Murad NA, et al.

Front Psychiatry, 2021;12:698911.
PMID: 34916966 DOI: 10.3389/fpsyt.2021.698911

Background: Oxidative stress markers are found to be linked with depression and suicide attempts in bipolar disorder (BD), although the role of DNA damage as a marker of suicidal ideation and attempt has yet to be determined. We aim to investigate the association between DNA damage and suicidal behaviour, i.e., suicidal ideation and suicide attempt, among suicidal ideators in BD patients while accounting for clinical and psychosocial risk factors. Methods: A cross-sectional study was conducted in the Universiti Kebangsaan Malaysia Medical Centre on 62 consecutive BD patients diagnosed using the M.I.N.I. Neuropsychiatric Interview and 26 healthy control participants. Socio-demographic and clinical assessments were performed using the Columbia Suicide Severity Rating Scale (C-SSRS) for lifetime suicidal ideation and attempt, Quick Inventory of Depressive Symptomatology (QIDS) for depression severity, Clinical Global Impression for Bipolar Disorder (CGI-BD) for illness severity [both mania (CGI-Mania) and major depressive episode (CGI-MDE)], Social Readjustment Rating Scale (SRRS) for change in life events, and Barratt Impulsiveness Scale (BIS) for behavioural impulsivity. The degree of DNA damage in peripheral blood samples was determined using a standard protocol of comet assay. Results: Multivariable logistic regression revealed higher scores of CGI-MDE as the sole significant factor for lifetime suicidal ideation (OR = 1.937, 95% CI = 1.799-2.076). Although initial bivariate analysis showed a significant association between DNA damage, malondialdehyde (MDA), catalase (CAT), and suicidal behaviour, the findings were not seen in multivariable logistic regression. Bivariate subgroup analysis showed that moderate and severe DNA damage (p = 0.032 and p = 0.047, respectively) was significantly associated with lifetime suicide attempts among lifetime suicidal ideators. The study is the first to look at the connexion between DNA damage and suicidal risk in bipolar patients. It is limited by the small sample size and lack of information on illicit substance use. Conclusions: More severe DNA damage was significantly associated with lifetime suicide attempts among lifetime suicidal ideators in BD. However, the severity of depression was found to be independently associated with lifetime suicidal ideation per se rather than DNA damage in BD. Larger prospective studies are required to ascertain the potential of DNA damage as a biomarker for the transition from suicidal ideation to a suicide attempt.
Fulltext Mitochondrial DNA Mutations in Grade II and III Glioma Cell Lines Are Associated with Significant Mitochondrial Dysfunction and Higher Oxidative Stress

Soon BH, Abdul Murad NA, Then SM, Abu Bakar A, Fadzil F, Thanabalan J, et al.

Front Physiol, 2017;8:231.
PMID: 28484394 DOI: 10.3389/fphys.2017.00231

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 in-vitro 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-H2DCFDA, 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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