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Fulltext Annatto-Derived Tocotrienol Promotes Mineralization of MC3T3-E1 Cells by Enhancing BMP-2 Protein Expression via Inhibiting RhoA Activation and HMG-CoA Reductase Gene Expression

Wan Hasan WN, Chin KY, Abd Ghafar N, Soelaiman IN

Drug Des Devel Ther, 2020;14:969-976.
PMID: 32184566 DOI: 10.2147/DDDT.S224941

PURPOSE: Annatto-derived tocotrienol (AnTT) has been shown to improve bone formation in animal models of osteoporosis and promote differentiation of pre-osteoblastic cells. However, the mechanism of action of AnTT in achieving these effects is unclear. This study aims to investigate the mechanism of action of AnTT on MC3T3-E1 pre-osteoblasts via the mevalonate pathway.
METHODS: Murine pre-osteoblastic cells, MC3T3-E1, were cultured with the density of 1 × 104 cells/mL and treated with 4 concentrations of AnTT (0.001-1 µg/mL). Expression of HMG-CoA reductase (HMGR) gene was carried out using qPCR after treatment with AnTT for 21 days. RhoA activation and bone morphogenetic protein-2 (BMP-2) were measured using immunoassay after 9 and 15 days of AnTT treatment. Lovastatin was used as the positive control. Mineralized nodules were detected using Von Kossa staining after 21 days of AnTT treatment.
RESULTS: The results showed that HMGR was up-regulated in the lovastatin group on day 9 and 21 compared to the control. Lovastatin also inhibited RhoA activation (day 9 and 15) and increased BMP-2 protein (day 15). On the other hand, AnTT at 0.001 μg/mL (day 3) and 0.1 μg/mL (day 21) significantly down-regulated HMGR gene expression compared to the control. On day 21, HMGR gene expression was significantly reduced in all groups compared to day 15. AnTT at 0.1 μg/mL significantly decreased RhoA activation on day 9 compared to the control. AnTT at 1 μg/mL significantly increased BMP-2 protein on day 15 compared to the control (P<0.05). Mineralized calcium nodules were more abundant in AnTT treated groups compared to the control on day 21.
CONCLUSION: AnTT suppresses the mevalonate pathway by downregulating HMGR gene expression and inhibiting RhoA activation, leading to increased BMP-2 protein in MC3T3-E1 cells. This explains the stimulating effects of AnTT on osteoblast mineralization.
Fulltext Epidermal growth factor receptor (EGFR) gene alteration and protein overexpression in Malaysian triple-negative breast cancer (TNBC) cohort

Zakaria Z, Zulkifle MF, Wan Hasan WAN, Azhari AK, Abdul Raub SH, Eswaran J, et al.

Onco Targets Ther, 2019;12:7749-7756.
PMID: 31571924 DOI: 10.2147/OTT.S214611

Background: Epidermal growth factor receptor (EGFR) is a member of the ErbB family of tyrosine kinase receptor proteins that plays important roles in tumour cell survival and proliferation. EGFR has been reported to be overexpressed in up to 78% of triple-negative breast cancer (TNBC) cases suggesting it as a potential therapeutic target. The clinical trials of anti-EGFR agents in breast cancer showed low response rates. However, a subgroup of patients demonstrated response to EGFR inhibitors highlighting the necessity to stratify patients, who might benefit from effective combination therapy that could include anti EGFR-agents. Population variability in EGFR expression warrants systematic evaluation in specific populations.
Purpose: To study EGFR alterations and expressions in a multi ethnic Malaysian TNBC patient cohort to determine the possibility of using anti-EGFR combinatorial therapy for this population.
Patients and methods: In this study, we evaluated 58 cases of Malaysian TNBC patient samples for EGFR gene copy number alteration and EGFR protein overexpression using fluorescence in-situ hybridization (FISH) and immunohistochemistry (IHC) methods, respectively.
Results: EGFR protein overexpression was observed in about 30% while 15.5% displayed high EGFR copy number including 5.17% gene amplification and over 10% high polysomy. There is a positive correlation between EGFR protein overexpression and gene copy number and over expression of EGFR is observed in ten out of the 48 low copy number cases (20.9%) without gene amplification.
Conclusion: This study provides the first glimpse of EGFR alterations and expressions in a multi ethnic Malaysian TNBC patient cohort emphasising the need for the nationwide large scale EGFR expression evaluation in Malaysia.
Fulltext Piper betle induces phase I & II genes through Nrf2/ARE signaling pathway in mouse embryonic fibroblasts derived from wild type and Nrf2 knockout cells

Wan Hasan WN, Kwak MK, Makpol S, Wan Ngah WZ, Mohd Yusof YA

BMC Complement Altern Med, 2014;14:72.
PMID: 24559113 DOI: 10.1186/1472-6882-14-72

Nuclear factor-erythroid 2 p45 related factor 2 (Nrf2) is a primary transcription factor, protecting cells from oxidative stress by regulating a number of antioxidants and phase II detoxifying enzymes. Dietary components such as sulforaphane in broccoli and quercetin in onions have been shown to be inducers of Nrf2. Piper betle (PB) grows well in tropical climate and the leaves are used in a number of traditional remedies for the treatment of stomach ailments and infections among Asians. The aim of this study was to elucidate the effect of Piper betle (PB) leaves extract in Nrf2 signaling pathway by using 2 types of cells; mouse embryonic fibroblasts (MEFs) derived from wild-type (WT) and Nrf2 knockout (N0) mice.
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.
Fulltext Self-Calibration Algorithm for a Pressure Sensor with a Real-Time Approach Based on an Artificial Neural Network

Almassri AMM, Wan Hasan WZ, Ahmad SA, Shafie S, Wada C, Horio K

Sensors (Basel), 2018 Aug 05;18(8).
PMID: 30081581 DOI: 10.3390/s18082561

This paper presents a novel approach to predicting self-calibration in a pressure sensor using a proposed Levenberg Marquardt Back Propagation Artificial Neural Network (LMBP-ANN) model. The self-calibration algorithm should be able to fix major problems in the pressure sensor such as hysteresis, variation in gain and lack of linearity with high accuracy. The traditional calibration process for this kind of sensor is a time-consuming task because it is usually done through manual and repetitive identification. Furthermore, a traditional computational method is inadequate for solving the problem since it is extremely difficult to resolve the mathematical formula among multiple confounding pressure variables. Accordingly, this paper describes a new self-calibration methodology for nonlinear pressure sensors based on an LMBP-ANN model. The proposed method was achieved using a collected dataset from pressure sensors in real time. The load cell will be used as a reference for measuring the applied force. The proposed method was validated by comparing the output pressure of the trained network with the experimental target pressure (reference). This paper also shows that the proposed model exhibited a remarkable performance than traditional methods with a max mean square error of 0.17325 and an R-value over 0.99 for the total response of training, testing and validation. To verify the proposed model's capability to build a self-calibration algorithm, the model was tested using an untrained input data set. As a result, the proposed LMBP-ANN model for self-calibration purposes is able to successfully predict the desired pressure over time, even the uncertain behaviour of the pressure sensors due to its material creep. This means that the proposed model overcomes the problems of hysteresis, variation in gain and lack of linearity over time. In return, this can be used to enhance the durability of the grasping mechanism, leading to a more robust and secure grasp for paralyzed hands. Furthermore, the exposed analysis approach in this paper can be a useful methodology for the user to evaluate the performance of any measurement system in a real-time environment.
Investigating the performance of an amplitude-independent algorithm for detecting the hand muscle activity of stroke survivors

Hameed HK, Wan Hasan WZ, Shafie S, Ahmad SA, Jaafar H, Inche Mat LN

J Med Eng Technol, 2020 Apr;44(3):139-148.
PMID: 32396756 DOI: 10.1080/03091902.2020.1753838

To make robotic hand devices controlled by surface electromyography (sEMG) signals feasible and practical tools for assisting patients with hand impairments, the problems that prevent these devices from being widely used have to be overcome. The most significant problem is the involuntary amplitude variation of the sEMG signals due to the movement of electrodes during forearm motion. Moreover, for patients who have had a stroke or another neurological disease, the muscle activity of the impaired hand is weak and has a low signal-to-noise ratio (SNR). Thus, muscle activity detection methods intended for controlling robotic hand devices should not depend mainly on the amplitude characteristics of the sEMG signal in the detection process, and they need to be more reliable for sEMG signals that have a low SNR. Since amplitude-independent muscle activity detection methods meet these requirements, this paper investigates the performance of such a method on people who have had a stroke in terms of the detection of weak muscle activity and resistance to false alarms caused by the involuntary amplitude variation of sEMG signals; these two parameters are very important for achieving the reliable control of robotic hand devices intended for people with disabilities. A comparison between the performance of an amplitude-independent muscle activity detection algorithm and three amplitude-dependent algorithms was conducted by using sEMG signals recorded from six hemiparesis stroke survivors and from six healthy subjects. The results showed that the amplitude-independent algorithm performed better in terms of detecting weak muscle activity and resisting false alarms.
Fulltext Annatto-derived tocotrienol stimulates osteogenic activity in preosteoblastic MC3T3-E1 cells: a temporal sequential study

Wan Hasan WN, Abd Ghafar N, Chin KY, Ima-Nirwana S

Drug Des Devel Ther, 2018;12:1715-1726.
PMID: 29942115 DOI: 10.2147/DDDT.S168935

PURPOSE: Annatto-derived tocotrienol (AnTT) has been shown to improve bone formation in animal models of osteoporosis. However, detailed studies of the effects of AnTT on preosteoblastic cells were limited. This study was conducted to investigate the osteogenic effect of AnTT on preosteoblast MC3T3-E1 cells in a time-dependent manner.
MATERIALS AND METHODS: Murine MC3T3-E1 preosteoblastic cells were cultured in the different concentrations of AnTT (0.001-1 µg/mL) up to 24 days. Expression of osteoblastic differentiation markers was measured by qPCR (osterix [OSX], collagen 1 alpha 1 [COL1α1], alkaline phosphatase [ALP], and osteocalcin [OCN]) and by fluorometric assay for ALP activity. Detection of collagen and mineralized nodules was done via Direct Red staining and Alizarin Red staining, respectively.
RESULTS: The results showed that osteoblastic differentiation-related genes, such as OSX, COL1α1, ALP, and OCN, were significantly increased in the AnTT-treated groups compared to the vehicle group in a time-dependent manner (P<0.05). Type 1 collagen level was increased from day 3 to day 15 in the AnTT-treated groups, while ALP activity was increased from day 9 to day 21 in the AnTT-treated groups (P<0.05). Enhanced mineralization was observed in the AnTT-treated groups via increasing Alizarin Red staining from day 3 to day 21 (P<0.05).
CONCLUSION: Our results suggest that AnTT enhances the osteogenic activity by promoting the bone formation-related genes and proteins in a temporal and sequential manner.
Stressors in secondary boarding school students: association with stress, anxiety and depressive symptoms

Wahab S, Rahman FN, Wan Hasan WM, Zamani IZ, Arbaiei NC, Khor SL, et al.

Asia Pac Psychiatry, 2013 Apr;5 Suppl 1:82-9.
PMID: 23857842 DOI: 10.1111/appy.12067

Chronic stress in adolescents may cause physical, mental and emotional health issues which lead to poor outcomes if left untreated. The present study aimed to determine the prevalence of depression, anxiety and stress, and their association with stressors.
The relationship between circulating testosterone and inflammatory cytokines in men

Mohamad NV, Wong SK, Wan Hasan WN, Jolly JJ, Nur-Farhana MF, Ima-Nirwana S, et al.

Aging Male, 2019 Jun;22(2):129-140.
PMID: 29925283 DOI: 10.1080/13685538.2018.1482487

Testosterone is the predominant gonadal androgen in men. Low testosterone levels are found to be associated with an increased in metabolic risk and systematic inflammation. Since adipose tissue is a source of inflammatory cytokines, testosterone may regulate inflammation by acting on adipose tissue. This review aimed to explore the role of testosterone in inflammation and its mechanism of action. Both animal studies and human studies showed that (1) testosterone deficiency was associated with an increase in pro-inflammatory cytokines; (2) testosterone substitution reduced pro-inflammatory cytokines. The suppression of inflammation by testosterone were observed in patients with coronary artery disease, prostate cancer and diabetes mellitus through the increase in anti-inflammatory cytokines (IL-10) and the decrease in pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α). Despite these, some studies also reported a non-significant relationship. In conclusion, testosterone may possess anti-inflammatory properties but its magnitude is debatable. More evidence is needed to validate the use of testosterone as a marker and in the management of chronic inflammatory diseases.
Challenges and solutions of deep learning-based automated liver segmentation: A systematic review

Ghobadi V, Ismail LI, Wan Hasan WZ, Ahmad H, Ramli HR, Norsahperi NMH, et al.

Comput Biol Med, 2024 Dec 05;185:109459.
PMID: 39642700 DOI: 10.1016/j.compbiomed.2024.109459

The liver is one of the vital organs in the body. Precise liver segmentation in medical images is essential for liver disease treatment. The deep learning-based liver segmentation process faces several challenges. This research aims to analyze the challenges of liver segmentation in prior studies and identify the modifications made to network models and other enhancements implemented by researchers to tackle each challenge. In total, 88 articles from Scopus and ScienceDirect databases published between January 2016 and January 2022 have been studied. The liver segmentation challenges are classified into five main categories, each containing some subcategories. For each challenge, the proposed technique to overcome the challenge is investigated. The provided report details the authors, publication years, dataset types, imaging technologies, and evaluation metrics of all references for comparison. Additionally, a summary table outlines the challenges and solutions.