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Fulltext Mutations of the p53 gene in gliomas from Malay patients

Jafri A, Aziz MY, Ros S, Nizam I

Med J Malaysia, 2003 Jun;58(2):236-42.
PMID: 14569744

This is the first investigation performed to detect the presence of the p53 mutation in Malay patients with gliomas. The p53 gene was amplified using polymerase chain reaction (PCR) from 33 fresh-frozen tumour tissues from patients histologically confirmed as glioma. Four hot spot areas that lie between exon 5 to 8 were screened for mutation by mean of non-isotopic "cold" single strand conformation polymorphism (SSCP) analysis and direct sequencing. The frequency of p53 gene mutation in gliomas examined was 33% (11 of 33). Five (45.5%) cases had mutation in exon 7, four (36.4%) had mutation in exon 8 and two (18.1%) had mutation in exon 6. Seven (63.6%) of 11 mutations were single nucleotide point mutations of which 5 were missense mutations, 1 was nonsense mutation and 1 was, silent mutation. Three (27.3%) showed insertion mutation and 1 (9.1%) showed deletion mutation. Of the point mutations, 57.1% were transitions and 42.9% were transversions. These results suggested that p53 mutations frequently occur in gliomas and this gene does play an important role in the tumourigenesis process of Malay patients with brain tumours.
Fulltext Liquid Chromatographic Tandem Mass Spectrometric (LC-MS/MS) Determination of Perfluorooctane Sulfonate (PFOS) and Perfluorooctanoic Acid (PFOA) in the Yolk of Poultry Eggs in Malaysia

Tahziz A, Mohamad Haron DE, Aziz MY

Molecules, 2020 May 16;25(10).
PMID: 32429475 DOI: 10.3390/molecules25102335

Perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) are widely used in products, and are known for their water and grease repellent properties. The persistence nature and potential toxicity of these substances have raised substantial concerns about health effects. Regarding humans, food consumption has reportedly been a significant source of exposure for both compounds. Hence, this study was performed to develop and validate an analytical method for PFOS and PFOA in egg yolks using liquid chromatographic tandem mass spectrometry (LC-MS/MS) followed by the determination of concentration of both compounds in the yolk of poultry eggs in Malaysia. A total of 47 poultry egg yolk samples were extracted by a simple protein precipitation technique using acetonitrile. The analytical method was developed using LC-MS/MS and validated based on the Food and Drug Administration (FDA)'s Bioanalytical Method Validation guidelines. The results revealed that PFOS was quantitatively detected in six samples, with the concentration range between 0.5 and 1.01 ng g-1. Among these, five samples were from home-produced chicken eggs, and one sample was from a quail egg. The levels of PFOA in all samples were below the quantifiable limit (<0.1 ng g-1). This indicated that the contamination of PFCs in poultry eggs were mostly attributed to the nature of free foraging animals, which had direct contact with the contaminants in soil and feed. In conclusion, a fast and robust analytical method for analyzing PFOS and PFOA in egg yolk samples using LC-MS/MS was successfully developed and validated. The presence of these emerging contaminants in this study signified widespread pollution in the environment.
Inhibition of CYP3A by Antimalarial Piperaquine and Its Metabolites in Human Liver Microsomes With IVIV Extrapolation

Aziz MY, Hoffmann KJ, Ashton M

J Pharm Sci, 2018 05;107(5):1461-1467.
PMID: 29352982 DOI: 10.1016/j.xphs.2018.01.009

The potential of the antimalarial piperaquine and its metabolites to inhibit CYP3A was investigated in pooled human liver microsomes. CYP3A activity was measured by liquid chromatography-tandem mass spectrometry as the rate of 1'-hydroxymidazolam formation. Piperaquine was found to be a reversible, potent inhibitor of CYP3A with the following parameter estimates (%CV): IC50 = 0.76 μM (29), Ki = 0.68 μM (29). In addition, piperaquine acted as a time-dependent inhibitor with IC50 declining to 0.32 μM (28) during 30-min pre-incubation. Time-dependent inhibitor estimates were kinact = 0.024 min-1 (30) and KI = 1.63 μM (17). Metabolite M2 was a highly potent reversible inhibitor with estimated IC50 and Ki values of 0.057 μM (17) and 0.043 μM (3), respectively. M1 and M5 metabolites did not show any inhibitory properties within the limits of assay used. Average (95th percentile) simulated in vivo areas under the curve of midazolam increased 2.2-fold (3.7-fold) on the third which is the last day of piperaquine dosing, whereas for its metabolite M2, areas under the curve of midazolam increased 7.7-fold (13-fold).
LC-MS/MS quantitation of antimalarial drug piperaquine and metabolites in human plasma

Aziz MY, Hoffmann KJ, Ashton M

J Chromatogr B Analyt Technol Biomed Life Sci, 2017 Sep 15;1063:253-258.
PMID: 28863865 DOI: 10.1016/j.jchromb.2017.06.035

PURPOSE: This study aimed to develop a sensitive, quantitative assay for the antimalarial piperaquine (PQ) and its metabolites M1 and M2 in human plasma.
RESULTS: Analytes were gradiently separated on a C18 column and detected with a Sciex API 4000 MS/MS with an ESI source operated in the positive ion mode with deuterated PQ as internal standard. The response was linear in the range 3.9-2508nM with a runtime of 7.0min per sample. The method was applied to clinical samples from healthy volunteers.
CONCLUSION: This LC-MS/MS method for the simultaneous quantitation of PQ and two of its metabolites in plasma may prove helpful for assessment of metabolite safety issues in vivo.
PFAS, bisphenol, and paraben in Malaysian food and estimated dietary intake

Mohamad Haron DE, Yoneda M, Ahmad ED, Aziz MY

Food Addit Contam Part B Surveill, 2023 Mar 23.
PMID: 36959529 DOI: 10.1080/19393210.2023.2188611

Endocrine disrupting chemicals (EDCs) such as per- and polyfluoroalkyl substances (PFAS), bisphenols, and parabens are used in food packaging or as preservatives and their unintended consumption has been associated with cancer and other diseases. Food EDCs data are scarce in Malaysia. Thus, liquid chromatography mass tandem spectrometry (LC-MS/MS) was utilised to analyse 18 EDCs from different food categories. Bisphenol was the most abundant EDC found, followed by PFAS and paraben. Bisphenol levels in canned foods, dairy products, canned drinks, fruits, and vegetables ranged from 1.16 to 183 ng/g. PFAS was found in almost every food category, with canned foods having the highest concentrations (0.18-34.5 ng/g). Only canned foods, fruits, and vegetables contained parabens, with mean concentrations ranging from 0.27 to 26.7 ng/g. PFOS, PFBA, PFHQA and bisphenol A all had hazard quotients (HQ) above 1, indicating that they can pose a risk to human health.
Damnacanthal: a promising compound as a medicinal anthraquinone

Abu N, Ali NM, Ho WY, Yeap SK, Aziz MY, Alitheen NB

Anticancer Agents Med Chem, 2014 Jun;14(5):750-5.
PMID: 24164045

The Noni fruit, or scientifically known as Morinda citrifolia can be found in various parts of the world, especially in the pacific region. It is a small evergreen bushy-like tree originated from the Rubiaceae family. The plant has been used by polynesians as a medicinal herb for more than 2000 years. A substantial amount of phytochemicals can be found in the roots of this plant. Among all, damnacanthal has been found to be the most interesting, versatile and potent compound. Damnacanthal or chemically known as,3- hydroxy-1-methoxyanthraquinone-2-caboxaldehyde (C16H10O5), appears as pale yellow crystals with a melting point of 210-211 °C. This compound is of particular interest due to its striking pharmacological properties. Damnacanthal was shown to inhibit the oncogene Ras, p56lck tyrosine kinase, NF-KB pathway and induce apoptosis in vitro. This review aims to discuss the biological properties of damnacanthal, specifically on its anti-cancer activity that has been reported.
Fulltext In vitro Anticancer Effects of Vernonia amygdalina Leaf Extract and Green-Synthesised Silver Nanoparticles

Joseph J, Khor KZ, Moses EJ, Lim V, Aziz MY, Abdul Samad N

Int J Nanomedicine, 2021;16:3599-3612.
PMID: 34079252 DOI: 10.2147/IJN.S303921

Purpose: Vernonia amygdalina (VA) is a traditional African herbal medicine that has been reported to possess anticancer properties. However, the anticancer properties of VA silver nanoparticles have not been studied. The aim of the study was to examine and evaluate the anticancer activities of VA leaf extracts and VA silver nanoparticles on the human breast cancer cell line, MCF-7.
Methods: VA leaves were extracted using sequential extraction assisted with ultrasound using three different solvents: ethanol, 50% ethanol, and deionized water. The silver nanoparticles were synthesised with VA aqueous extract.
Results: The ethanol extract and VA silver nanoparticles inhibit MCF-7 cell proliferation with an average half-maximal inhibitory concentration (IC50) value of 67µg/mL and 6.11µg/mL, respectively, after 72 hours of treatment. The ethanol extract and VA silver nanoparticles also caused G1 phase cell cycle arrest, induced apoptosis and nuclear fragmentation in MCF-7 cells.
Conclusion: VA ethanol extracts and VA silver nanoparticles decreased the cell viability in MCF-7 cells in a time and dose-dependent manner by inducing apoptosis and causing DNA damage. Further research is needed to elucidate the mechanism of action of VA leaf extracts and VA silver nanoparticles. This study is the first to report on the anticancer activity of VA silver nanoparticles in MCF-7 cells.
Assessment of 18 endocrine disrupting chemicals in tap water samples from Klang Valley, Malaysia

Haron DEM, Yoneda M, Hod R, Ramli MR, Aziz MY

Environ Sci Pollut Res Int, 2023 Nov;30(51):111062-111075.
PMID: 37801249 DOI: 10.1007/s11356-023-30022-9

Multiclass of endocrine disrupting chemicals (EDCs) such as nine perfluoroalkyl and polyfluoroalkyl substances (PFAS), five bisphenols, and four parabens were analysed in tap water samples from Malaysia's Klang Valley region. All samples were analysed using liquid chromatography mass tandem spectrometry (LC-MS/MS) with limit of quantitation (LOQ) ranged between 0.015 and 5 ng/mL. Fifteen of the 18 EDCs were tested positive in tap water samples, with total EDC concentrations ranging from 0.28 to 5516 ng/L for all 61 sampling point locations. In a specific area of the Klang Valley, the total concentration of EDCs was found to be highest in Hulu Langat, followed by Sepang, Putrajaya, Petaling, Kuala Lumpur, Seremban, and Gombak/Klang. PFAS and paraben were the most found EDCs in all tap water samples. Meanwhile, ethyl paraben (EtP) exhibited the highest detection rate, with 90.2% of all locations showing its presence. Over 60% of the regions showed the presence of perfluoro-n-butanoic acid (PFBA), perfluoro-n-hexanoic acid (PFHXA), perfluoro-n-octanoic acid (PFOA), perfluoro-n-nonanoic acid (PFNA), and perfluoro-1-octanesulfonate (PFOS), whereas the frequency of detection for other compounds was less than 40%. The spatial distribution and mean concentrations of EDCs in the Klang Valley regions revealed that Hulu Langat, Petaling Jaya, and Putrajaya exhibited higher levels of bisphenol A (BPA). On the other hand, Kuala Lumpur and Sepang displayed the highest mean concentrations of PFBA. In the worst scenario, the estimated daily intake (EDI) and risk quotient of some EDCs in this study exceeded the acceptable daily limits recommended by international standards, particularly for BPA, PFOA, PFOS, and PFNA, where the risk quotient (RQ) was found to be greater than 1, indicating a high risk to human health. The increasing presence of EDCs in tap water is undoubtedly a cause for concern as these substances can have adverse health consequences. This highlights the necessity for a standardised approach to evaluating EDC exposure and its direct impact on human populations' health.
Heavy Metal Concentrations in Malaysian Adults' Hair and Associated Variables in Bukit Mertajam, Penang, Malaysia

Aziz MY, Hussain SH, Ishak AR, Abdullah MA, Mohamed R, Ruzi II, et al.

Biol Trace Elem Res, 2021 Sep 30.
PMID: 34591221 DOI: 10.1007/s12011-021-02942-5

The presence of heavy metals in human hair is being tracked to predict health risk, forensics, and environmental monitoring. Heavy metals are typically non-biodegradable and have a lengthy half-life, allowing them to linger in humans and the environment for many years. Heavy metal exposure in hair has been attributed to multiple sources from the environment and food intake. In this study, copper (Cu), nickel (Ni), zinc (Zn), chromium (Cr), manganese (Mn), lead (Pb), and cadmium (Cd) levels were measured in the scalp hair of 50 individuals in Bukit Mertajam, Penang, Malaysia. In conjunction with sampling, subjects' age, gender, lifestyle, diet, and working environment were also obtained through the questionnaire. The Atomic Absorption Spectrometry (AAS) method was used to extract all the metals in the hair samples. The mean concentrations of heavy metals were found to be in the following order (unit of mg/kg): Cr > Zn > Pb > Ni > Cd > Cu. Manganese was detected below the limit of quantitation among the elements (
Damnacanthal is a potent inducer of apoptosis with anticancer activity by stimulating p53 and p21 genes in MCF-7 breast cancer cells

Aziz MY, Omar AR, Subramani T, Yeap SK, Ho WY, Ismail NH, et al.

Oncol Lett, 2014 May;7(5):1479-1484.
PMID: 24765160

Damnacanthal, an anthraquinone compound, is isolated from the roots of Morinda citrifolia L. (noni), which has been used for traditional therapy in several chronic diseases, including cancer. Although noni has long been consumed in Asian and Polynesian countries, the molecular mechanisms by which it exerts several benefits are starting to emerge. In the present study, the effect of damnacanthal on MCF-7 cell growth regulation was investigated. Treatment of MCF-7 cells with damnacanthal for 72 h indicated an antiproliferative activity. The MTT method confirmed that damnacanthal inhibited the growth of MCF-7 cells at the concentration of 8.2 μg/ml for 72 h. In addition, the drug was found to induce cell cycle arrest at the G1 checkpoint in MCF-7 cells by cell cycle analysis. Damnacanthal induced apoptosis, determined by Annexin V-fluorescein isothiocyanate/propidium iodide (PI) dual-labeling, acridine-orange/PI dyeing and caspase-7 expression. Furthermore, damnacanthal-mediated apoptosis involves the sustained activation of p21, leading to the transcription of p53 and the Bax gene. Overall, the present study provided significant evidence demonstrating that p53-mediated damnacanthal induced apoptosis through the activation of p21 and caspase-7.
Fulltext Pharmacokinetics and Biodistribution of Thymoquinone-loaded Nanostructured Lipid Carrier After Oral and Intravenous Administration into Rats

Zakarial Ansar FH, Latifah SY, Wan Kamal WHB, Khong KC, Ng Y, Foong JN, et al.

Int J Nanomedicine, 2020;15:7703-7717.
PMID: 33116496 DOI: 10.2147/IJN.S262395

Background: Thymoquinone (TQ), an active compound isolated from Nigella sativa, has been proven to exhibit various biological properties such as antioxidant. Although oral delivery of TQ is valuable, it is limited by poor oral bioavailability and low solubility. Recently, TQ-loaded nanostructured lipid carrier (TQ-NLC) was formulated with the aim of overcoming the limitations. TQ-NLC was successfully synthesized by the high-pressure homogenization method with remarkable physiochemical properties whereby the particle size is less than 100 nm, improved encapsulation efficiency and is stable up to 24 months of storage. Nevertheless, the pharmacokinetics and biodistribution of TQ-NLC have not been studied. This study determined the bioavailability of oral and intravenous administration of thymoquinone-loaded nanostructured lipid carrier (TQ-NLC) in rats and its distribution to organs.
Materials and Methods: TQ-NLC was radiolabeled with technetium-99m before the administration to the rats. The biodistribution and pharmacokinetics parameters were then evaluated at various time points. The rats were imaged at time intervals and the percentage of the injected dose/gram (%ID/g) in blood and each organ was analyzed.
Results: Oral administration of TQ-NLC exhibited greater relative bioavailability compared to intravenous administration. It is postulated that the movement of TQ-NLC through the intestinal lymphatic system bypasses the first metabolism and therefore enhances the relative bioavailability. However, oral administration has a slower absorption rate compared to intravenous administration where the AUC0-∞ was 4.539 times lower than the latter.
Conclusion: TQ-NLC had better absorption when administered intravenously compared to oral administration. However, oral administration showed greater bioavailability compared to the intravenous route. This study provides the pharmacokinetics and biodistribution profile of TQ-NLC in vivo which is useful to assist researchers in clinical use.
A simple and efficient sequential electrokinetic and hydrodynamic injections in micellar electrokinetic chromatography method for quantification of anticancer drug 5-fluorouracil and its metabolite in human plasma

Semail NF, Noordin SS, Keyon ASA, Waras MN, Saad B, Kamaruzaman S, et al.

Biomed Chromatogr, 2021 May;35(5):e5050.
PMID: 33314228 DOI: 10.1002/bmc.5050

A simple and sensitive preconcentration strategy using sequential electrokinetic and hydrodynamic injection modes in micellar electrokinetic chromatography with diode array detection was developed and applied for the separation and determination of anticancer agent, 5-fluorouracil and its metabolite, 5-fluoro-2'-deoxyuridine, in human plasma. Sequential injection modes with increased analyte loading capacity using the anionic pseudo-stationary phase facilitated collection of the dispersed neutral and charged analytes into narrow zones and improved sensitivity. Several important parameters affecting sample enrichment performance were evaluated and optimized in this study. Under the optimized experimental conditions, 614- and 643-fold and 782- and 803-fold sensitivity improvement were obtained for 5-fluorouracil and its metabolite when compared with normal hydrodynamic and electrokinetic injection, respectively. The method has good linearity (1-1,000 ng/ml) with acceptable coefficient of determination (r2 > 0.993), low limits of detection (0.11-0.14 ng/ml) and satisfactory analyte relative recovery (97.4-99.7%) with relative standard deviations of 4.6-9.3% (n = 6). Validation results as well as the application to analysis of human plasma samples from cancer patients demonstrate the applicability of the proposed method to clinical studies.
Population data and genetic characteristics of 12 X-STR loci using the Investigator® Argus X-12 Quality Sensor kit for the Kedayan population of Borneo in Malaysia

Hakim HM, Khan HO, Ismail SA, Lalung J, Kofi AE, Aziz MY, et al.

Int J Legal Med, 2021 Jul;135(4):1433-1435.
PMID: 33782746 DOI: 10.1007/s00414-021-02577-0

DNA profiling of X-chromosomal short tandem repeats (X-STR) has exceptional value in criminal investigations, especially for complex kinship and incest cases. In this study, Investigator® Argus X-12 Quality Sensor (QS) kits were successfully used to characterize 12 X-STR loci in 199 unrelated healthy Kedayan individuals living in Sabah and Sarawak, Malaysia. The LG1 haplogroup (DXS8378 - DXS10135 - DXS10148) has the largest HD (0.9799) as compared with all other closely linked haplotype groups examined (LG2; DXS7132-DXS10074-DXS10079, LG3; DXS10103-DXS10101-HPRTB and LG4; DXS10134-DXS7423-DXS10146). Data from statistical analysis showed that high combined of PDM, PDF, MEC_Krüger, MEC_Kishida, MEC_Desmarais, and MEC_Desmarais_duo values (0.999999994405922, 0.99999999999999, 0.999990463834938, 0.999999975914808, 0.999999975985006, and 0.999996491927194, respectively) in the Kedayan. In a two-dimensional scaling (MDS) plot and dendrogram constructed using allele frequencies at the 12 X-STR loci, Kedayan appear to be most closely related to their other Austronesian populations including the Malays and Filipinos as compared with other reference population groups. Findings from the present study thus demonstrate high genetic variability across the 12 tested X-STR loci and can be used for population studies and forensic applications.
Fulltext Population dataset for 21 simple tandem repeat loci in the Akan population of Ghana

Kofi AE, Hakim HM, Khan HO, Ismail SA, Ghansah A, Haslindawaty ARN, et al.

Data Brief, 2020 Aug;31:105746.
PMID: 32490095 DOI: 10.1016/j.dib.2020.105746

Short tandem repeat (STR) loci are widely used as genetic marker for ancestral and forensic analyses. The latter application includes for paternity testing and DNA profiling of samples collected from scenes of crime and suspects. This survey provides the first dataset for 21 STR loci across the Akan population in Ghana by genotyping of 109 unrelated healthy individuals using Investigator 24plex kit. None of the STR loci screened deviated from Hardy-Weinberg equilibrium after applying Bonferroni correction. Overall, 224 unique alleles were observed with allele frequencies ranging from 0.005 to 0.518. The combined match probability, combined power of exclusion and combined power discrimination were 1 in 4.07 × 10-25, 0.999999999 and 1, respectively. Principal coordinate analysis carried out using 21 STR allele frequency data mapped the Akans with Nigerian subpopulation groups (Hausa, Igbo and Yoruba), but separated from Thais of Thailand, Chechen of Jordan and Tijuana of Mexico.
Fulltext Combinatorial Cytotoxic Effects of Damnacanthal and Doxorubicin against Human Breast Cancer MCF-7 Cells in Vitro

Aziz MY, Abu N, Yeap SK, Ho WY, Omar AR, Ismail NH, et al.

Molecules, 2016 Sep 14;21(9).
PMID: 27649120 DOI: 10.3390/molecules21091228

Despite progressive research being done on drug therapy to treat breast cancer, the number of patients succumbing to the disease is still a major issue. Combinatorial treatment using different drugs and herbs to treat cancer patients is of major interest in scientists nowadays. Doxorubicin is one of the most used drugs to treat breast cancer patients. The combination of doxorubicin to other drugs such as tamoxifen has been reported. Nevertheless, the combination of doxorubicin with a natural product-derived agent has not been studied yet. Morinda citrifolia has always been sought out for its remarkable remedies. Damnacanthal, an anthraquinone that can be extracted from the roots of Morinda citrifolia is a promising compound that possesses a variety of biological properties. This study aimed to study the therapeutic effects of damnacanthal in combination with doxorubicin in breast cancer cells. Collectively, the combination of both these molecules enhanced the efficacy of induced cell death in MCF-7 as evidenced by the MTT assay, cell cycle, annexin V and expression of apoptosis-related genes and proteins. The effectiveness of doxorubicin as an anti-cancer drug was increased upon addition of damnacanthal. These results could provide a promising approach to treat breast cancer patients.
A genetic Study of the Ghanaian Population Using 15 Autosomal STR Loci

Kofi AE, Agyemang DA, Ghansah A, Awandare GA, Hakim HM, Khan HO, et al.

Biochem Genet, 2023 Oct;61(5):1850-1866.
PMID: 36869999 DOI: 10.1007/s10528-023-10347-3

Autosomal short tandem repeat (STR) population data collected from a well characterized population are needed to correctly assigning the weight of DNA profiles in the courtroom and widely used for ancestral analyses. In this study, allele frequencies for the 15 autosomal short tandem repeat (STR) loci included in the AmpFlSTR® Identifiler® plus kit (D8S1179, D21S11, D7S820, CSF1PO, D3S1358, TH01, D13S317, D16S539, D2S1338, D19S433, VWA, TPOX, D18S51, D5S818, FGA) were obtained by genotyping 332 unrelated individuals of Ghanaian origin. Statistical tests on STR genotype data showed no significant departure from Hardy-Weinberg equilibrium (HWE). The overall match probability, combined power of exclusion and combined power of discrimination for these loci were 1 in 3.85 × 1017, 0.99999893 and 0.99999998, respectively. Polymorphic information content (PIC) greater than 0.70 was observed for all loci except TH01 and D13S317. These statistical parameters confirm that this combination of loci is valuable for forensic identification and parentage analysis. Our results were also compared with those for 20 other human populations analyzed for the same set of markers. We observed that the Ghanaian population grouped with other African populations in two-dimensional principal coordinate (PCO) and a neighbor-joining (N-J) data mapping and placed closest to Nigerians. This observation reflects cultural similarities and geographical factors, coupled with the long history of migration and trading activities between Ghana and Nigeria. Our report provides what we believe to be the first published autosomal STR data for the general Ghanaian population using 15 loci genotyped using the AmpFlSTR® Identifiler® plus kit methodology. Our data show that the loci tested have sufficient power to be used reliably for DNA profiling in forensic casework and help to elucidate the genetic history of people living in the country.

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