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Lack of association between TPH2 gene polymorphisms with major depressive disorder in multiethnic Malaysian population

Nazree NE, Loke AC, Zainal NZ, Mohamed Z

Asia Pac Psychiatry, 2015 Mar;7(1):72-7.
PMID: 24376086 DOI: 10.1111/appy.12118

Numerous association studies of candidate genes studies with major depressive disorder (MDD) have been conducted for many years; however, the evidence of association between genes and the risk of developing MDD still remains inconclusive. In this study, we aimed to investigate the association between the tryptophan hydroxylase 2 (TPH2) gene and MDD in three ethnic groups (Malay, Chinese and Indian) within the Malaysian population.
Fulltext Eating behaviour among multi-ethnic adolescents in a middle-income country as measured by the self-reported Children's Eating Behaviour Questionnaire

Loh DA, Moy FM, Zaharan NL, Mohamed Z

PLoS One, 2013;8(12):e82885.
PMID: 24349385 DOI: 10.1371/journal.pone.0082885

Escalating weight gain among the Malaysian paediatric population necessitates identifying modifiable behaviours in the obesity pathway.
Inhibitory effect of doxycycline against dengue virus replication in vitro

Rothan HA, Mohamed Z, Paydar M, Rahman NA, Yusof R

Arch Virol, 2014 Apr;159(4):711-8.
PMID: 24142271 DOI: 10.1007/s00705-013-1880-7

Doxycycline is an antibiotic derived from tetracycline that possesses antimicrobial and anti-inflammatory activities. Antiviral activity of doxycycline against dengue virus has been reported previously; however, its anti-dengue properties need further investigation. This study was conducted to determine the potential activity of doxycycline against dengue virus replication in vitro. Doxycycline inhibited the dengue virus serine protease (DENV2 NS2B-NS3pro) with an IC50 value of 52.3 ± 6.2 μM at 37 °C (normal human temperature) and 26.7 ± 5.3 μM at 40 °C (high fever temperature). The antiviral activity of doxycycline was first tested at different concentrations against DENV2 using a plaque-formation assay. The virus titter decreased significantly after applying doxycycline at levels lower than its 50 % cytotoxic concentration (CC50, 100 μM), showing concentration-dependent inhibition with a 50 % effective concentration (EC50) of approximately 50 μM. Doxycycline significantly inhibited viral entry and post-infection replication of the four dengue serotypes, with serotype-specific inhibition (high activity against DENV2 and DENV4 compared to DENV1 and DENV3). Collectively, these findings underline the need for further experimental and clinical studies on doxycycline, utilizing its anti-dengue and anti-inflammatory activities to attenuate the clinical symptoms of dengue virus infection.
Association of a functional FAAH polymorphism with methamphetamine-induced symptoms and dependence in a Malaysian population

Sim MS, Hatim A, Reynolds GP, Mohamed Z

Pharmacogenomics, 2013 Apr;14(5):505-14.
PMID: 23556448 DOI: 10.2217/pgs.13.25

FAAH is a membrane enzyme that terminates the activity of a large class of endogenous signaling lipids. Recent studies suggest that the FAAH Pro129Thr polymorphism is a common mutation in the FAAH gene that is significantly associated with drug-addictive traits. This study investigated the association of the Pro129Thr polymorphism of the FAAH gene with methamphetamine dependence, methamphetamine-induced psychosis, manic episodes and panic disorder in a Malaysian population.
Genetic association of SNPs in the FTO gene and predisposition to obesity in Malaysian Malays

Apalasamy YD, Ming MF, Rampal S, Bulgiba A, Mohamed Z

Braz. J. Med. Biol. Res., 2012 Dec;45(12):1119-26.
PMID: 22911346

The common variants in the fat mass- and obesity-associated (FTO) gene have been previously found to be associated with obesity in various adult populations. The objective of the present study was to investigate whether the single nucleotide polymorphisms (SNPs) and linkage disequilibrium (LD) blocks in various regions of the FTO gene are associated with predisposition to obesity in Malaysian Malays. Thirty-one FTO SNPs were genotyped in 587 (158 obese and 429 non-obese) Malaysian Malay subjects. Obesity traits and lipid profiles were measured and single-marker association testing, LD testing, and haplotype association analysis were performed. LD analysis of the FTO SNPs revealed the presence of 57 regions with complete LD (D' = 1.0). In addition, we detected the association of rs17817288 with low-density lipoprotein cholesterol. The FTO gene may therefore be involved in lipid metabolism in Malaysian Malays. Two haplotype blocks were present in this region of the FTO gene, but no particular haplotype was found to be significantly associated with an increased risk of obesity in Malaysian Malays.
Fulltext A comparative study on the expression, purification and functional characterization of human adiponectin in Pichia pastoris and Escherichia coli

Rothan HA, Teh SH, Haron K, Mohamed Z

Int J Mol Sci, 2012;13(3):3549-62.
PMID: 22489167 DOI: 10.3390/ijms13033549

Adiponectin is one of the most bioactive substances secreted by adipose tissue and is involved in the protection against metabolic syndrome, artherosclerosis and type II diabetes. Research into the use of adiponectin as a promising drug for metabolic syndromes requires production of this hormone in high quantities considering its molecular isoforms. The objective of this study is to produce recombinant human adiponectin by Pichia pastoris (P-ADP) as a cheap and convenient eukaryotic expression system for potential application in pharmaceutical therapy. For comparison, adiponectin was also expressed using the Escherichia coli (E-ADP) expression system. Adiponectin was constructed by overlap-extension PCR, and cloned in standard cloning vector and hosts. Recombinant expression vectors were cloned in the P. pastoris and E. coli host strains, respectively. SDS-PAGE and western blotting were used to detect and analyse expressed recombinant protein in both systems. Adiponectin was purified by affinity chromatography and quantified using the Bradford Assay. The results of this study indicated that P-ADP quantity (0.111 mg/mL) was higher than that of E-ADP (0.04 mg/mL) and both were produced in soluble form. However, P-ADP was able to form high molecular weights of adiponectin molecules, whilst E-ADP was not able to form isoforms higher than trimer. In addition, P-ADP was more active in lowering blood glucose compared with E-ADP. The two types of proteins were equally efficient and significantly decreased blood triglyceride and increased high density lipoprotein. We conclude that P. pastoris is able to produce high quantity of bioactive adiponectin for potential use in treatment of metabolic syndromes.
Association of the functional polymorphism in the catechol-O-methyltransferase gene with schizophrenia in the three ethnic groups of the Malaysian population

Wan CL, Zainal NZ, Lian LH, Mohamed Z

Psychiatry Res, 2011 Aug 30;189(1):67-71.
PMID: 21414668 DOI: 10.1016/j.psychres.2011.02.008

The catechol-O-methyltransferase (COMT) gene is a candidate gene for schizophrenia as its encoded enzyme is involved in the metabolic inactivation of dopamine and noradrenaline. Several molecular genetic studies thus far have demonstrated that the COMT functional polymorphism of Val158Met is susceptible with schizophrenia. Hence, the present study aims to determine this genetic association of this SNP in the three major ethnic groups of the Malaysian population. A total of 317 patients (79 Malays, 154 Chinese and 84 Indians) meeting DSM-IV criteria for schizophrenia and 417 healthy subjects (160 Malays, 164 Chinese and 93 Indians) were recruited. A PCR-RFLP method was used to determine the genotypes and alleles present. We found a significant association of genotypes within the total pooled samples, as well as in the female subgroup, with a higher frequency of heterozygotes in schizophrenia subjects. However, there were no significant differences in allele and genotype frequency between the schizophrenic patients and normal controls in all three ethnic groups. Our current findings suggest that the Val158Met polymorphism has a weak association with schizophrenia in the Malaysian population and does not play a major role in conferring susceptibility to the schizophrenia in any of the three major local ethnicities.
Gender-dependent association of a β(2)-adrenergic gene variant with obesity parameters in Malaysian Malays

Apalasamy YD, Ming MF, Rampal S, Bulgiba A, Mohamed Z

Asia Pac J Public Health, 2015 Mar;27(2):NP154-65.
PMID: 22199155 DOI: 10.1177/1010539511430250

Recent findings have shown that the rs1042714 (Gln27Glu) single-nucleotide polymorphism (SNP) on the β2-adrenoceptor gene may predispose to obesity. The findings from other studies carried on different populations, however, have been inconsistent. The authors investigated the association between the rs1042714 SNP with obesity-related parameters. DNA of 672 Malaysian Malays was analyzed using real-time polymerase chain reaction. Univariate and multivariate linear regression analyses revealed significant associations between rs1042714 and diastolic blood pressure in the pooled Malaysian Malay subjects under additive and recessive models. After gender stratification, however, a significant association was found between the rs1042714 and triglyceride and the rs1042714 and log-transformed high-density lipoprotein cholesterol levels in Malaysian Malay men. No significant association was found between the SNP and log-transformed body mass index. This polymorphism may have an important role in the development of obesity-related traits in Malaysian Malays. Gender is an effect modifier for the effect of the rs1042714 polymorphism on obesity-related traits in Malaysian Malays.
TT genotype of the methylenetetrahydrofolate reductase C677T polymorphism is an important determinant for homocysteine levels in multi-ethnic Malaysian ischaemic stroke patients

Mejia Mohamed EH, Tan KS, Ali JM, Mohamed Z

Ann Acad Med Singap, 2011 Apr;40(4):186-91.
PMID: 21678004

INTRODUCTION: The functional point mutation C677T in the methylenetetrahydrofolate reductase (MTHFR) gene, has been reported to contribute to hyperhomocysteinaemia which is a risk factor for atherothrombotic ischaemic strokes. This study evaluated the prevalence of the C677T polymorphism of the gene in Malaysian ischaemic stroke subjects of Malay, Chinese and Indian ethnicities, and its association with homocysteine levels (tHcy).
MATERIALS AND METHODS: A total of 292 subjects were recruited, comprising 150 ischaemic stroke patients and 142 control subjects who were age and sex matched. Plasma homocysteine, serum folate and vitamin B12 were measured in all subjects. Genotyping was carried out using PCR-RFLP.
RESULTS: The homocysteine levels were significantly higher (P = 0.001) in the stroke group (11.35 ± 2.75 μmol/L) compared to the control group (10.38 ± 2.79 μmol/L). The MTHFR C677T genotype distribution for the stroke group was 46%, 40% and 14%, respectively for CC, CT and TT genotypes and 59.9%, 33.8% and 6.3%, respectively for the control group. The genotype and allelic frequencies were significantly different between the 2 groups, with P = 0.02 and P = 0.004 respectively. No significant difference was seen in the genotype distribution inter-ethnically. An increasing tHcy was seen with every additional T allele, and the differences in the tHcy for the different genotypes were significant in both the control (P <0.001) and stroke groups (P <0.001).
CONCLUSION: This study shows that TT genotype of the methylenetetrahydrofolate reductase C677T polymorphic gene is an important determinant for homocysteine levels in Malaysian ischaemic stroke patients.
A bioequivalence comparison of two formulations of rifampicin (300- vs 150-mg capsules): An open-label, randomized, two-treatment, two-way crossover study in healthy volunteers

Chik Z, Basu RC, Pendek R, Lee TC, Mohamed Z

Clin Ther, 2010 Sep;32(10):1822-31.
PMID: 21194606 DOI: 10.1016/j.clinthera.2010.09.006

Rifampicin is a semisynthetic antibiotic derivative of rifamycin used worldwide for the treatment of various forms of tuberculosis.
Comparative bioavailability study of two salbutamol tablets in healthy adult volunteers

Chik Z, Basu RC, Pendek R, Lee TC, Mohamed Z

Int J Clin Pharmacol Ther, 2009 Jun;47(6):413-8.
PMID: 19473604

This study was carried out to compare the rate and extent of absorption of a generic salbutamol in oral dosage form (Brethmol, 4 mg) with the proprietary equivalent product (Ventolin, 4 mg), in healthy adult subjects, under fasting conditions. The study was a single dose, randomized, two way crossover study with a four-week washout period. It involved 22 healthy volunteers who received a single dose (4 mg) of the test and the reference products after an overnight fast of at least 10 hours. Blood samples were collected at pre-dose and a serial of 14 samples were collected from each of the subject from 1 h until 48 h post-dose. Plasma concentrations of salbutamol were analyzed using GCMS method. The mean AUC(0-yen) values were 91.26 and 96.45 h.ng/ml for reference and test product, respectively. The mean C(max) values were 12.26 and 12.38 ng/ml and the mean t(max) values were 2.80 and 2.33 hours for reference and test product, respectively. Analysis of variance showed that the 90% confidence intervals on the relative difference of the ratio for the AUC(0-yen) and the C(max) for the test and reference products were contained within the bioequivalence limit (80 - 125%) (C(max): 89.8 - 110.5% and AUC(0-yen): 91.6 - 121.5%). There was no statistically significant difference for the t(max) between the test and reference formulations (p = 0.30). The test formulation was found to be bioequivalent to the reference formulation with regard to AUC(0-yen) and C(max). There was no statistically significant difference in Brethmol and Ventolin t(max). In conclusion, Brethmol and Ventolin are bioequivalent in healthy subjects.
In vitro and in vivo evaluation of a novel testosterone transdermal delivery system (TTDS) using palm oil base

Haron DE, Chik Z, Noordin MI, Mohamed Z

Iran J Basic Med Sci, 2015 Dec;18(12):1167-75.
PMID: 26877845

Transdermal preparations for testosterone are becoming popular because of their unique advantages such as avoidance of first-pass effect, convenience, improved bioavailability, and reduction of systemic side effects. A novel testosterone transdermal delivery system (TDDS) was developed using a palm oil base called HAMIN™ (a commercial product) and tested using in vitro and in vivo skin permeability test methods.
Sugar-sweetened beverage intake and its associations with cardiometabolic risks among adolescents

Loh DA, Moy FM, Zaharan NL, Jalaludin MY, Mohamed Z

Pediatr Obes, 2017 02;12(1):e1-e5.
PMID: 26843446 DOI: 10.1111/ijpo.12108

BACKGROUND: Investigations on sugar-sweetened beverage (SSB) intake and cardiometabolic risks among Asians are scant.
OBJECTIVES: This study aimed to examine associations between SSB intake and cardiometabolic risks among Malaysian adolescents.
METHODS: Anthropometric data, blood pressure (BP), fasting blood glucose (FBG), lipid profiles and insulin levels measured involved 873 adolescents (aged 13 years). SSB intake, dietary patterns and physical activity level (PAL) were self-reported.
RESULTS: Mean SSB consumption was 177.5 mL day-1 with significant differences among ethnicities (Malay, Chinese, Indians and Others) (p
Genetic association of AKAP10 gene polymorphism with reduced risk of preterm birth

Langmia IM, Apalasamy YD, Suki SZ, Omar SZ, Mohamed Z

J Perinatol, 2015 Sep;35(9):700-4.
PMID: 26110499 DOI: 10.1038/jp.2015.68

Preterm birth (PTB) is a multifactorial complication in which genetic and environmental factors contribute to the phenotype. The AKAP10 protein encoded by AKAP10 gene has a vital role in the maintenance of myometrial quiescence and pregnancy. This study aimed to investigate whether polymorphisms in the AKAP10 gene are associated with the risk of PTB.
Disparities in health-related quality of life among healthy adolescents in a developing country - the impact of gender, ethnicity, socio-economic status and weight status

Loh DA, Moy FM, Zaharan NL, Mohamed Z

Child Care Health Dev, 2015 Nov;41(6):1216-26.
PMID: 25873448 DOI: 10.1111/cch.12252

Physical functioning and psychological resilience in adulthood is shaped during adolescence. Self-reported health-related quality of life (HRQoL) assessments during this life phase are important first-hand accounts of their well-being. This study aimed, firstly, to identify differences in HRQoL according to gender, ethnicity, socio-economic status and weight status; and secondly, to examine associations between weight status and HRQoL among an urban sample of multi-ethnic adolescents in Kuala Lumpur, Malaysia.
Growing dural sinus malformation with associated developmental venous anomaly, multiple cavernomas and facial venous malformation in an infant. An associated disease or a disease spectrum?

Mohamed Z, Batista LL, Sachet M, Mahadevan J, Alvarez H, Lasjaunias P

Interv Neuroradiol, 2002 Dec 22;8(4):421-30.
PMID: 20594504

This is an unusual case report of an infant, who initially presented with a facial haemangioma and was later diagnosed to have a dural sinus malformation (DSM) involving the torcula. The DSM increased in size lateralising to the right transverse sinus at three months of age. Postnatal enlargement of the dural sinus has not been described before suggesting a delay in the maturation of the dural sinus which normally would occur antenatally. There was a further association with a complex developmental venous anomaly (DVA) draining the right cerebral hemisphere into the deep cerebral vein and multiple cavernous malformations. The DVA was not clearly demonstrated at age one month but was more obvious at age three months. This would be the first reported case of DSM associated with a DVA. Increasing venous hypertension probably contributed to the poor opacification of the DVA on follow-up angiography at age six months and to the haemorrhagic changes within the cavernomas on magnetic resonance imaging (MRI). The therapeutic goal was to correct venous hypertension by partially embolising the dural shunts to remodel the cerebral vasculature and preserve the patent sinus. The treatment strategy and possible link between the complex disease entities presented in this infant are discussed. Despite these attemps, the lesion continued to grow compressing the posterior fossa structures. The infant died at nine months of age.
Fulltext Evaluation of Anti-Tumorigenic Effects of Diosmetin against Human Colon Cancer Xenografts in Athymic Nude Mice

Koosha S, Mohamed Z, Sinniah A, Alshawsh MA

Molecules, 2019 Jul 10;24(14).
PMID: 31295840 DOI: 10.3390/molecules24142522

Colon cancer is the third most common type of cancer in the world. Diosmetin (Dis), a natural O-methylated flavone, has been reported to have anti-cancer effects against different types of cancer. Although the mechanisms of action of Dis against several cancer cell lines are well reported, in vivo anti-tumorigenesis properties of this compound are still obscure. Therefore, this study aimed to investigate the anti-tumorigenesis properties of Dis against HCT-116 colon cancer xenografts in nude mice. HCT-116 colon cancer cells were injected in NCr nu/nu nude mice and treatment with Dis was initiated after the tumor volumes reached 100 mm3 and continued for four weeks. On the sacrificing date nude mice treated with 100 mg/kg of Dis showed significant lower tumor volume (264 ± 238.3 mm3) as compared to the untreated group (1428.8 ± 459.6 mm3). Anti-apoptotic Bcl-2 protein was significantly downregulated, while apoptotic protein (Bax) was significantly overexpressed in nude mice treated with 100 mg/kg Dis as compared to untreated mice. In conclusion, our in vivo results indicate that Dis significantly reduces tumor growth rate of HCT-116 colon cancer cells in nude mice at a dose of 100 mg/kg, and has no toxic effects in ICR mice up to 2000 mg/kg.
Cynometra cauliflora Linn. Attenuates metabolic abnormalities in high-fat diet-induced obese mice

Seyedan A, Mohamed Z, Alshagga MA, Koosha S, Alshawsh MA

J Ethnopharmacol, 2019 May 23;236:173-182.
PMID: 30851371 DOI: 10.1016/j.jep.2019.03.001

ETHNOPHARMACOLOGICAL RELEVANCE: Cynometra cauliflora Linn. belongs to the Fabaceae family and is known locally in Malaysia as nam-nam. Traditionally, a decoction of the C. cauliflora leaves is used for treating hyperlipidemia and diabetes.
AIM OF THE STUDY: This study aims to investigate the anti-obesity and lipid lowering effects of ethanolic extract of C. cauliflora leaves and its major compound (vitexin) in C57BL/6 obese mice induced by high-fat diet (HFD), as well as to further identify the molecular mechanism underlying this action.
METHODS AND MATERIAL: Male C57BL/6 mice were fed with HFD (60% fat) for 16 weeks to become obese. The treatment started during the last 8 weeks of HFD feeding and the obese mice were treated with C. cauliflora leaf extract at 200 and 400 mg/kg/day, orlistat (10 mg/kg) and vitexin (10 mg/kg).
RESULTS: The oral administration of C. cauliflora (400 and 200 mg/kg) and vitexin significantly reduced body weight, adipose tissue and liver weight and lipid accumulation in the liver compared to control HFD group. Both doses of C. cauliflora also significantly (P ≤ 0.05) decreased serum triglyceride, LDL, lipase, IL-6, peptide YY, resistin levels, hyperglycemia, hyperinsulinemia, and hyperleptinemia compared to the control HFD group. Moreover, C. cauliflora significantly up-regulated the expression of adiponectin, Glut4, Mtor, IRS-1 and InsR genes, and significantly decreased the expression of Lepr in white adipose tissue. Furthermore, C. cauliflora significantly up-regulated the expression of hypothalamus Glut4, Mtor and NF-kB genes. GC-MS analysis of C. cauliflora leaves detected the presence of phytol, vitamin E and β-sitosterol. Besides, the phytochemical evaluation of C. cauliflora leaves showed the presence of flavonoid, saponin and phenolic compounds.
CONCLUSION: This study shows interesting outcomes of C. cauliflora against HFD-induced obesity and associated metabolic abnormalities. Therefore, the C. cauliflora extract could be a potentially effective agent for obesity management and its related metabolic disorders such as insulin resistance and hyperlipidemia.
Association between microRNA-196A2 and microRNA-146A polymorphisms and progression to cirrhosis and hepatocellular carcinoma in patients with viral hepatitis B

Riazalhosseini B, Mohamed Z, Apalasamy YD, Eng HS, Mohamed R

Pharmacogenet Genomics, 2016 Feb;26(2):74-9.
PMID: 26529280 DOI: 10.1097/FPC.0000000000000187

MicroRNAs (miRNAs) are small noncoding RNAs that have been implicated in mechanisms underlying various types of cancers including hepatocellular carcinoma (HCC). Reports have indicated that single nucleotide polymorphisms in miRNA-196A2 and miRNA-146A genes may contribute to the risk of progression of hepatitis B virus (HBV) infection to cirrhosis and HCC. This study aimed to examine the effect of miRNA-196A2 and miRNA-146A polymorphisms on the progression of HBV infection to cirrhosis and/or HCC in HBV patients in the Malaysian population.
Phosphatidylethanolamine N-methyltransferase gene rs7946 polymorphism plays a role in risk of nonalcoholic fatty liver disease: evidence from meta-analysis

Tan HL, Mohamed R, Mohamed Z, Zain SM

Pharmacogenet Genomics, 2016 Feb;26(2):88-95.
PMID: 26636496 DOI: 10.1097/FPC.0000000000000193

Phosphatidylethanolamine N-methyltransferase (PEMT) governs the secretion of hepatic triglycerides in the form of very low-density lipoprotein and has been implicated in nonalcoholic fatty liver disease (NAFLD). Studies on the role of the PEMT rs7946 polymorphism as a genetic modifier of NAFLD have reported inconsistent results. This meta-analysis was carried out to evaluate and summarize the association of PEMT rs7946 with susceptibility to NAFLD.

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