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Fulltext Gamma-tocotrienol and hydroxy-chavicol synergistically inhibits growth and induces apoptosis of human glioma cells

Abdul Rahman A, Jamal AR, Harun R, Mohd Mokhtar N, Wan Ngah WZ

BMC Complement Altern Med, 2014;14:213.
PMID: 24980711 DOI: 10.1186/1472-6882-14-213

Gamma-tocotrienol (GTT), an isomer of vitamin E and hydroxy-chavicol (HC), a major bioactive compound in Piper betle, has been reported to possess anti-carcinogenic properties by modulating different cellular signaling events. One possible strategy to overcome multi-drug resistance and high toxic doses of treatment is by applying combinational therapy especially using natural bioactives in cancer treatment.
Fulltext Data for molecular recognition between polyamide thin film composite on the polymeric subtract by molecular dynamic

Wan Jusoh WZA, Abdul Rahman S, Ahmad AL, Mohd Mokhtar N

Data Brief, 2019 Jun;24:103910.
PMID: 31193576 DOI: 10.1016/j.dib.2019.103910

This paper focus to examine the best molecular interaction between Polyamide Thin Film Composite (PA TFC) layers with different properties of the support membrane. The support membrane of Nylon 66 (N66) and Polyvinylidene fluoride (PVDF) was chosen to represent the hydrophilic and hydrophobic model respectively in the Molecular Dynamic (MD) simulation. The Condensed-Phase Optimized Molecular Potential for Atomistic Simulation Studies (COMPASS) force field was used with the total simulation runs were set 1000 picoseconds run production ensembles. The temperature and pressure set for both ensembles were 298 K and 1 atm respectively. The validity of our model densities data was check and calculated where the deviation must be less than 6%. The comparison between hydrophobic and hydrophilic of the support membrane data was examined by the distance and magnitude of intensity of the Radial Distribution Function (RDF's) trends.
Fulltext Identification of Predictive DNA Methylation Biomarkers for Chemotherapy Response in Colorectal Cancer

Baharudin R, Ab Mutalib NS, Othman SN, Sagap I, Rose IM, Mohd Mokhtar N, et al.

Front Pharmacol, 2017;8:47.
PMID: 28243201 DOI: 10.3389/fphar.2017.00047

Resistance to 5-Fluorouracil (5-FU) is a major obstacle to the successful treatment of colorectal cancer (CRC) and posed an increased risk of recurrence. DNA methylation has been suggested as one of the underlying mechanisms for recurrent disease and its contribution to the development of drug resistance remains to be clarified. This study aimed to determine the methylation phenotype in CRC for identification of predictive markers for chemotherapy response. We performed DNA methylation profiling on 43 non-recurrent and five recurrent CRC patients using the Illumina Infinium HumanMethylation450 Beadchip assay. In addition, CRC cells with different genetic backgrounds, response to 5-FU and global methylation levels (HT29 and SW48) were treated with 5-FU and DNA methylation inhibitor 5-aza-2'-deoxycytidine (5-azadC). The singular and combined effects of these two drug classes on cell viability and global methylation profiles were investigated. Our genome-wide methylation study on the clinical specimens showed that recurrent CRCs exhibited higher methylation levels compared to non-recurrent CRCs. We identified 4787 significantly differentially methylated genes (P < 0.05); 3112 genes were hyper- while 1675 genes were hypomethylated in the recurrent group compared to the non-recurrent. Fifty eight and 47 of the significantly hypermethylated and hypomethylated genes have an absolute recurrent/non-recurrent methylation difference of ≥20%. Most of the hypermethylated genes were involved in the MAPK signaling pathway which is a key regulator for apoptosis while the hypomethylated genes were involved in the PI3K-AKT signaling pathway and proliferation process. We also demonstrate that 5-azadC treatment enhanced response to 5-FU which resulted in significant growth inhibition compared to 5-FU alone in hypermethylated cell lines SW48. In conclusion, we found the evidence of five potentially biologically important genes in recurrent CRCs that could possibly serve as a new potential therapeutic targets for patients with chemoresistance. We postulate that aberrant methylation of CCNEI, CCNDBP1, PON3, DDX43, and CHL1 in CRC might be associated with the recurrence of CRC and 5-azadC-mediated restoration of 5-FU sensitivity is mediated at least in part by MAPK signaling pathway.
Fulltext Implication of food insecurity on the gut microbiota and its potential relevance to a multi-ethnic population in Malaysia

Shafiee NH, Razalli NH, Muhammad Nawawi KN, Mohd Mokhtar N, Raja Ali RA

JGH Open, 2022 Feb;6(2):112-119.
PMID: 35155820 DOI: 10.1002/jgh3.12709

Food insecurity (FI) has an impact on food intake, and it can make it difficult for people to eat enough nutritious food at all times to sustain an active and healthy lifestyle. The COVID-19 outbreak has hampered people's capacity to obtain nutritious and affordable food. Although FI has been studied in Malaysia, the extent to which it is linked to gut microbiota has yet to be discovered. This review aimed to compile evidence of the relationship between FI and gut microbial changes and their potential relevance to a multi-ethnic population in Malaysia. FI is typically associated with cheaper and calorie-dense foods because of the high cost of quality food and financial constraints that hinder food-insecure people from adopting healthier dietary choices. As a result, they have started eating low-quality food such as simple carbohydrates, fats, and processed foods. These poor eating habits can reduce microbial diversity and influence changes in the composition and function of the gut microbiota. This review also explores the impact of ethnicity on the variation in composition of gut microbiota. In conclusion, the findings of this review may be utilized to develop and implement diet-related intervention programs to ensure that Malaysians get enough nutritious food to maintain a healthy gut microbiota and improve overall health.
The Effect of Surgical Intervention of Endometriosis to CA-125 and Pain

Abdul Karim AK, Abd Aziz NH, Md Zin RR, Mohd Mokhtar N, Shafiee MN

Malays J Med Sci, 2020 Dec;27(6):7-14.
PMID: 33447130 DOI: 10.21315/mjms2020.27.6.2

Endometriosis is an inflammatory condition characterised by the presence of endometrial growth beyond the uterine cavity. It is a debilitating disease requiring multiple modalities of treatment. In considering surgery as the option of treatment, the benefits should outweigh the risk. Besides direct surgical risk, intervention may lead to a reduction of ovarian reserve, in addition to premature menopause and low fecundity. To date, there is an inconclusive evidence to support any specific parameters in monitoring disease progression following surgical intervention. Serum cancer antigen (CA)-125 is expressed by coelomic epithelium and has been extensively studied as a biomarker for endometriosis. Elevated expression of CA-125 has been shown in endometrial tissues and the marker increased indirectly from peritoneal irritation that accompanies an extensive form of endometriosis. Additionally, the visual analogue scale (VAS) scores have been used as an objective measurement for measuring pain, especially in a complex disease such as endometriosis. This review aims to consolidate a series of clinical trials that utilised CA-125 level and VAS score as tools for monitoring patients undergoing surgery for endometriosis.
Fulltext Mobile Apps for Common Noncommunicable Disease Management: Systematic Search in App Stores and Evaluation Using the Mobile App Rating Scale

Cheah KJ, Abdul Manaf Z, Fitri Mat Ludin A, Razalli NH, Mohd Mokhtar N, Md Ali SH

JMIR Mhealth Uhealth, 2024 Mar 12;12:e49055.
PMID: 38532298 DOI: 10.2196/49055

BACKGROUND: The success of mobile apps in improving the lifestyle of patients with noncommunicable diseases through self-management interventions is contingent upon the emerging growth in this field. While users of mobile health (mHealth) apps continue to grow in number, little is known about the quality of available apps that provide self-management for common noncommunicable diseases such as diabetes, hypertension, and obesity.
OBJECTIVE: We aimed to investigate the availability, characteristics, and quality of mHealth apps for common noncommunicable disease health management that included dietary aspects (based on the developer's description), as well as their features for promoting health outcomes and self-monitoring.
METHODS: A systematic search of English-language apps on the Google Play Store (Google LLC) and Apple App Store (Apple Inc) was conducted between August 7, 2022, and September 13, 2022. The search terms used included weight management, obesity, diabetes, hypertension, cardiovascular diseases, stroke, and diet. The selected mHealth apps' titles and content were screened based on the description that was provided. Apps that were not designed with self-management features were excluded. We analyzed the mHealth apps by category and whether they involved health care professionals, were based on scientific testing, and had self-monitoring features. A validated and multidimensional tool, the Mobile App Rating Scale (MARS), was used to evaluate each mHealth app's quality based on a 5-point Likert scale from 1 (inadequate) to 5 (excellent).
RESULTS: Overall, 42 apps were identified. Diabetes-specific mHealth apps accounted for 7% (n=3) of the market, hypertension apps for 12% (n=5), and general noncommunicable disease management apps for 21% (n=9). About 38% (n=16) of the apps were for managing chronic diseases, while 74% (n=31) were for weight management. Self-management features such as weight tracking, BMI calculators, diet tracking, and fluid intake tracking were seen in 86% (n=36) of the apps. Most mHealth apps (n=37, 88%) did not indicate whether there was involvement of health professionals in app development. Additionally, none of the apps reported scientific evidence demonstrating their efficacy in managing health. The overall mean MARS score was 3.2 of 5, with a range of 2.0 to 4.1. Functionality was the best-rated category (mean score 3.9, SD 0.5), followed by aesthetics (mean score 3.2, SD 0.9), information (mean score 3.1, SD 0.7), and engagement (mean score 2.9, SD 0.6).
CONCLUSIONS: The quality of mHealth apps for managing chronic diseases was heterogeneous, with roughly half of them falling short of acceptable standards for both quality and content. The majority of apps contained scant information about scientific evidence and the developer's history. To increase user confidence and accomplish desired health outcomes, mHealth apps should be optimized with the help of health care professionals. Future studies on mHealth content analysis should focus on other diseases as well.
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 The Effects of Probiotics on Small Intestinal Microbiota Composition, Inflammatory Cytokines and Intestinal Permeability in Patients with Non-Alcoholic Fatty Liver Disease

Ayob N, Muhammad Nawawi KN, Mohamad Nor MH, Raja Ali RA, Ahmad HF, Oon SF, et al.

Biomedicines, 2023 Feb 20;11(2).
PMID: 36831176 DOI: 10.3390/biomedicines11020640

The prevalence of non-alcoholic fatty liver disease (NAFLD) has soared globally. As our understanding of the disease grows, the role of the gut-liver axis (GLA) in NAFLD pathophysiology becomes more apparent. Hence, we focused mainly on the small intestinal area to explore the role of GLA. We looked at how multi-strain probiotics (MCP® BCMC® strains) containing six different Lactobacillus and Bifidobacterium species affected the small intestinal gut microbiota, inflammatory cytokines, and permeability in NAFLD patients. After six months of supplementation, biochemical blood analysis did not show any discernible alterations in either group. Five predominant phyla known as Actinobacteria, Proteobacteria, Firmicutes, Bacteroidota and Fusobacteria were found in NAFLD patients. The probiotics group demonstrated a significant cluster formation of microbiota composition through beta-diversity analysis (p < 0.05). This group significantly reduced three unclassifiable species: unclassified_Proteobacteria, unclassified_Streptococcus, and unclassified_Stenotrophomonas. In contrast, the placebo group showed a significant increase in Prevotella_melaninogenica and Rothia_mucilaginosa, which were classified as pathogens. Real-time quantitative PCR analysis of small intestinal mucosal inflammatory cytokines revealed a significant decrease in IFN-γ (-7.9 ± 0.44, p < 0.0001) and TNF-α (-0.96 ± 0.25, p < 0.0033) in the probiotics group but an increase in IL-6 (12.79 ± 2.24, p < 0.0001). In terms of small intestinal permeability analysis, the probiotics group, unfortunately, did not show any positive changes through ELISA analysis. Both probiotics and placebo groups exhibited a significant increase in the level of circulating zonulin (probiotics: 107.6 ng/mL ± 124.7, p = 0.005 vs. placebo: 106.9 ng/mL ± 101.3, p = 0.0002) and a significant decrease in circulating zonula occluden-1 (ZO-1) (probiotics: -34.51 ng/mL ± 18.38, p < 0.0001 vs. placebo: -33.34 ng/mL ± 16.62, p = 0.0001). The consumption of Lactobacillus and Bifidobacterium suggested the presence of a well-balanced gut microbiota composition. Probiotic supplementation improves dysbiosis in NAFLD patients. This eventually stabilised the expression of inflammatory cytokines and mucosal immune function. To summarise, more research on probiotic supplementation as a supplement to a healthy diet and lifestyle is required to address NAFLD and its underlying causes.
Fulltext Profiling of Differentially Expressed MicroRNAs in Human Umbilical Vein Endothelial Cells Exposed to Hyperglycemia via RNA Sequencing

Othman NS, Aminuddin A, Zainal Abidin S, Syafruddin SE, Ahmad MF, Mohd Mokhtar N, et al.

Life (Basel), 2023 May 31;13(6).
PMID: 37374078 DOI: 10.3390/life13061296

Hyperglycemia is the hallmark of diabetes mellitus that results in oxidative stress, apoptosis, and diabetic vascular endothelial dysfunction. An increasing number of microRNAs (miRNAs) have been found to be involved in the pathogenesis of diabetic vascular complications. However, there is a limited number of studies that characterize the miRNA profile of endothelial cells exposed to hyperglycemia. Therefore, this study aims to analyze the miRNA profile of human umbilical-vein endothelial cells (HUVECs) exposed to hyperglycemia. HUVECs were divided into two groups: the control (treated with 5.5 mM glucose) and hyperglycemia (treated with 33.3 mM glucose) groups. RNA sequencing identified 17 differentially expressed miRNAs between the groups (p < 0.05). Of these, 4 miRNAs were upregulated, and 13 miRNAs were downregulated. Two of the most differentially expressed miRNAs (novel miR-1133 and miR-1225) were successfully validated with stem-loop qPCR. Collectively, the findings show that there is a differential expression pattern of miRNAs in HUVEC following exposure to hyperglycemia. These 17 differentially expressed miRNAs are involved in regulating cellular functions and pathways related to oxidative stress and apoptosis that may contribute to diabetic vascular endothelial dysfunction. The findings provide new clues on the role of miRNAs in the development of diabetic vascular endothelial dysfunction, which could be useful in future targeted therapy.
Aldosterone-Producing Adenomas: Histopathology-Genotype Correlation and Identification of a Novel CACNA1D Mutation

Tan GC, Negro G, Pinggera A, Tizen Laim NMS, Mohamed Rose I, Ceral J, et al.

Hypertension, 2017 07;70(1):129-136.
PMID: 28584016 DOI: 10.1161/HYPERTENSIONAHA.117.09057

Mutations in KCNJ5, ATP1A1, ATP2B3, CACNA1D, and CTNNB1 are thought to cause the excessive autonomous aldosterone secretion of aldosterone-producing adenomas (APAs). The histopathology of KCNJ5 mutant APAs, the most common and largest, has been thoroughly investigated and shown to have a zona fasciculata-like composition. This study aims to characterize the histopathologic spectrum of the other genotypes and document the proliferation rate of the different sized APAs. Adrenals from 39 primary aldosteronism patients were immunohistochemically stained for CYP11B2 to confirm diagnosis of an APA. Twenty-eight adenomas had sufficient material for further analysis and were target sequenced at hot spots in the 5 causal genes. Ten adenomas had a KCNJ5 mutation (35.7%), 7 adenomas had an ATP1A1 mutation (25%), and 4 adenomas had a CACNA1D mutation (14.3%). One novel mutation in exon 28 of CACNA1D (V1153G) was identified. The mutation caused a hyperpolarizing shift of the voltage-dependent activation and inactivation and slowed the channel's inactivation kinetics. Immunohistochemical stainings of CYP17A1 as a zona fasciculata cell marker and Ki67 as a proliferation marker were used. KCNJ5 mutant adenomas showed a strong expression of CYP17A1, whereas ATP1A1/CACNA1D mutant adenomas had a predominantly negative expression (P value =1.20×10-4). ATP1A1/CACNA1D mutant adenomas had twice the nuclei with intense staining of Ki67 than KCNJ5 mutant adenomas (0.7% [0.5%-1.9%] versus 0.4% [0.3%-0.7%]; P value =0.04). Further, 3 adenomas with either an ATP1A1 mutation or a CACNA1D mutation had >30% nuclei with moderate Ki67 staining. In summary, similar to KCNJ5 mutant APAs, ATP1A1 and CACNA1D mutant adenomas have a seemingly specific histopathologic phenotype.
Fulltext The role of probiotics in improving menstrual health in women with primary dysmenorrhoea: A randomized, double-blind, placebo-controlled trial (the PERIOD study)

Zakaria IA, Mohammed Zain NA, Teik CK, Abu MA, Zainuddin AA, Abdul Aziz NH, et al.

Womens Health (Lond), 2024;20:17455057241234524.
PMID: 38444064 DOI: 10.1177/17455057241234524

BACKGROUND: Primary dysmenorrhea is associated with poorer quality of life; however, the causal mechanism remains unclear. A vast body of literature supports the use of oral probiotics for relief from the symptoms of endometriosis; however, to our knowledge, no study has prescribed probiotics for primary dysmenorrhea.
OBJECTIVE: The aim of this study is to investigate the effects of 3-month supplementation with oral probiotics on quality of life and inflammatory markers in women with primary dysmenorrhea.
DESIGN: Randomized placebo-controlled trial.
METHODS: A total of 72 patients (36 patients in each arm) were randomized to receive either oral sachets containing 5 billion colony-forming units each of Lactobacillus acidophilus BCMC (BCrobes Microbial Cells) 12130, Lactobacillus casei subsp BCMC 12313, Lactobacillus lactis BCMC 12451, Bifidobacterium bifidum BCMC 02290, Bifidobacterium longum BCMC 02120, and Bifidobacterium infantis BCMC 02129 each or placebo twice daily for 3 months. Main outcome measures were visual analog scale, verbal rating scale, physical and mental health scores using Short-Form 12-Item version 2 questionnaire, frequency of nonsteroidal anti-inflammatory drug use, and changes in inflammatory markers (interleukin-6, interleukin-8, and tumor necrosis factor alpha) before and after treatment.
RESULTS: There was no significant difference in the quality of life scores between the probiotic and placebo groups. Both groups showed significant improvement in pain (visual analog scale) and severity (verbal rating scale) scores but the probiotic group had much lower nonsteroidal anti-inflammatory drug use (odds ratio: 0.69, 95% confidence interval: 0.26-1.83) and better mental health scores (mean change: 6.5, p = 0.03 versus 6.1, p = 0.08) than the placebo group. There was a significant confounding effect of nonsteroidal anti-inflammatory drug use on quality of life scores. No significant difference was found in inflammatory cytokines.
CONCLUSION: Tested oral probiotics improved mental health and potentially reduced the use of nonsteroidal anti-inflammatory drugs; however, there was no significant change in inflammatory markers. Further research with a larger sample size is needed to confirm the findings.
REGISTRATION: This study is registered under ClinicalTrials.gov (NCT04119011).

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