Publications by authors named "Badrul Hisham Yahaya"

22 Publications

  • Page 1 of 1

Synergistic Roles of Curcumin in Sensitising the Cisplatin Effect on a Cancer Stem Cell-Like Population Derived from Non-Small Cell Lung Cancer Cell Lines.

Molecules 2021 Feb 18;26(4). Epub 2021 Feb 18.

Lung Stem Cell and Gene Therapy Group, Regenerative Medicine Cluster, Advanced Medical and Dental Institute (IPPT), Universiti Sains Malaysia, Sains@Bertam Kepala Batas, Penang 13200, Malaysia.

Cancer stem cells (CSCs) represent a small subpopulation within a tumour. These cells possess stem cell-like properties but also initiate resistance to cytotoxic agents, which contributes to cancer relapse. Natural compounds such as curcumin that contain high amounts of polyphenols can have a chemosensitivity effect that sensitises CSCs to cytotoxic agents such as cisplatin. This study was designed to investigate the efficacy of curcumin as a chemo-sensitiser in CSCs subpopulation of non-small cell lung cancer (NSCLC) using the lung cancer adenocarcinoma human alveolar basal epithelial cells A549 and H2170. The ability of curcumin to sensitise lung CSCs to cisplatin was determined by evaluating stemness characteristics, including proliferation activity, colony formation, and spheroid formation of cells treated with curcumin alone, cisplatin alone, or the combination of both at 24, 48, and 72 h. The mRNA level of genes involved in stemness was analysed using quantitative real-time polymerase chain reaction. Liquid chromatography-mass spectrometry was used to evaluate the effect of curcumin on the CSC niche. A combined treatment of A549 subpopulations with curcumin reduced cellular proliferation activity at all time points. Curcumin significantly ( < 0.001) suppressed colonies formation by 50% and shrank the spheroids in CSC subpopulations, indicating inhibition of their self-renewal capability. This effect also was manifested by the down-regulation of , , and . Curcumin also regulated the niche of CSCs by inhibiting chemoresistance proteins, aldehyde dehydrogenase, metastasis, angiogenesis, and proliferation of cancer-related proteins. These results show the potential of using curcumin as a therapeutic approach for targeting CSC subpopulations in non-small cell lung cancer.
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http://dx.doi.org/10.3390/molecules26041056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7922800PMC
February 2021

Human umbilical cord mesenchymal stem cell-derived extracellular vesicles ameliorate airway inflammation in a rat model of chronic obstructive pulmonary disease (COPD).

Stem Cell Res Ther 2021 Jan 12;12(1):54. Epub 2021 Jan 12.

Lung Stem Cell and Gene Therapy Group, Regenerative Medicine Cluster, Advanced Medical and Dental Institute (IPPT), SAINS@BERTAM, Universiti Sains Malaysia, 13200, Bertam, Penang, Malaysia.

Background: Chronic obstructive pulmonary disease (COPD) is an incurable and debilitating chronic disease characterized by progressive airflow limitation associated with abnormal levels of tissue inflammation. Therefore, stem cell-based approaches to tackle the condition are currently a focus of regenerative therapies for COPD. Extracellular vesicles (EVs) released by all cell types are crucially involved in paracrine, extracellular communication. Recent advances in the field suggest that stem cell-derived EVs possess a therapeutic potential which is comparable to the cells of their origin.

Methods: In this study, we assessed the potential anti-inflammatory effects of human umbilical cord mesenchymal stem cell (hUC-MSC)-derived EVs in a rat model of COPD. EVs were isolated from hUC-MSCs and characterized by the transmission electron microscope, western blotting, and nanoparticle tracking analysis. As a model of COPD, male Sprague-Dawley rats were exposed to cigarette smoke for up to 12 weeks, followed by transplantation of hUC-MSCs or application of hUC-MSC-derived EVs. Lung tissue was subjected to histological analysis using haematoxylin and eosin staining, Alcian blue-periodic acid-Schiff (AB-PAS) staining, and immunofluorescence staining. Gene expression in the lung tissue was assessed using microarray analysis. Statistical analyses were performed using GraphPad Prism 7 version 7.0 (GraphPad Software, USA). Student's t test was used to compare between 2 groups. Comparison among more than 2 groups was done using one-way analysis of variance (ANOVA). Data presented as median ± standard deviation (SD).

Results: Both transplantation of hUC-MSCs and application of EVs resulted in a reduction of peribronchial and perivascular inflammation, alveolar septal thickening associated with mononuclear inflammation, and a decreased number of goblet cells. Moreover, hUC-MSCs and EVs ameliorated the loss of alveolar septa in the emphysematous lung of COPD rats and reduced the levels of NF-κB subunit p65 in the tissue. Subsequent microarray analysis revealed that both hUC-MSCs and EVs significantly regulate multiple pathways known to be associated with COPD.

Conclusions: In conclusion, we show that hUC-MSC-derived EVs effectively ameliorate by COPD-induced inflammation. Thus, EVs could serve as a new cell-free-based therapy for the treatment of COPD.
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http://dx.doi.org/10.1186/s13287-020-02088-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7805108PMC
January 2021

Acute Lung Injury: Disease Modelling and the Therapeutic Potential of Stem Cells.

Adv Exp Med Biol 2020 ;1298:149-166

Lung Stem Cell and Gene Therapy Group, Regenerative Medicine Cluster, Advanced Medical and Dental Institute (IPPT), Universiti Sains Malaysia, SAINS@Bertam, Penang, Malaysia.

Acute lung injury (ALI) is a severe clinical condition with high morbidity and mortality that usually results in the development of multiple organ dysfunction. The complex pathophysiology of ALI seems to provide a wide range of targets that offer numerous therapeutic options. However, despite extensive studies of ALI pathophysiology and treatment, no effective pharmacotherapy is available. Increasing evidence from both preclinical and clinical studies supports the preventive and therapeutic effects of mesenchymal stem cells (MSCs) for treating ALI. As cell-based therapy poses the risk of occlusion in microvasculature or unregulated growth, MSC-derived extracellular vesicles (MSC-EVs) have been extensively studied as a new therapeutic strategy for non-cell based therapy. It is widely accepted that the therapeutic properties of MSCs are derived from soluble factors with paracrine or endocrine effects, and EVs are among the most important paracrine or endocrine vehicles that can deliver various soluble factors with a similar phenotype as the parent cell. Therapeutic effects of MSCs have been reported for various delivery approaches, diverse doses, multiple origins, and different times of administration, and MSC-EVs treatment may include but is not limited to these choices. The mechanisms by which MSCs and MSC-EVs may contribute to ALI treatment remain elusive and need further exploration. This review provides an overview of preclinical studies that support the application of MSC-EVs for treating ALI, and it discusses emerging opportunities and their associated challenges.
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http://dx.doi.org/10.1007/5584_2020_538DOI Listing
November 2020

Transcriptomic Profiles of MV4-11 and Kasumi 1 Acute Myeloid Leukemia Cell Lines Modulated by Epigenetic Modifiers Trichostatin A and 5-Azacytidine.

Int J Hematol Oncol Stem Cell Res 2020 Jan;14(1):72-92

Department of Hematology, School of Medical Sciences, Universiti Sains Malaysia, 16150 Kubang Kerian, Kelantan, Malaysia.

Acute myeloid leukemia (AML) is the most common form of acute leukemias in adults which is clinically and molecularly heterogeneous. Several risk and genetic factors have been widely investigated to characterize AML. However, the concomitant epigenetic factors in controlling the gene expression lead to AML transformation was not fully understood. This study was aimed to identify epigenetically regulated genes in AML cell lines induced by epigenetic modulating agents, Trichostatin A (TSA) and 5-Azacytidine (5-Aza). MV4-11 and Kasumi 1 were treated with TSA and/or 5-Aza at IC concentration. Gene expression profiling by microarray was utilized using SurePrint G3 Human Gene Expression v3. Gene ontology and KEGG pathway annotations were analyzed by DAVID bioinformatics software using EASE enrichment score. mRNA expression of the differentially expressed genes were verified by quantitative real time PCR. Gene expression analysis revealed a significant changes in the expression of 24,822, 15,720, 15,654 genes in MV4-11 and 12,598, 8828, 18,026 genes in Kasumi 1, in response to TSA, 5-Aza and combination treatments, respectively, compared to non-treated (<0.05). 7 genes (, , , , , and ) and 4 genes (, , and ) shown to be predominantly expressed in MV4-11 and Kasumi 1, respectively (EASE<0.1). The analysis also revealed phagosome pathway commonly activated in both cell lines. Our data showed a distinct optimal biological characteristic and pathway in different types of leukemic cell lines. These finding may help in the identification of cell-specific epigenetic biomarker in the pathogenesis of AML.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7167603PMC
January 2020

Adipose-Derived Mesenchymal Stem Cells Promote Growth and Migration of Lung Adenocarcinoma Cancer Cells.

Adv Exp Med Biol 2020 ;1292:83-95

Regenerative Medicine Cluster, Advanced Medical & Dental Institute (AMDI), Universiti Sains Malaysia, Kepala Batas, Penang, Malaysia.

Introduction: Mesenchymal stem cells (MSCs) have been used in cancer therapy as vehicles to deliver therapeutic materials such as drugs, apoptosis inducers and cytokines due to their ability to migrate and home at the tumour site. Furthermore, MSCs have been genetically engineered to produce anticancer molecules such as TRAIL that can induce apoptosis of cancer cells. However, MSCs' presence in the tumour microenvironment has shown to be involved in promoting tumour growth and progression. Therefore, the roles of MSCs either promoting or suppressing tumorigenesis need to be investigated.

Methods: Human adipose-derived MSCs (Ad-MSCs) and A549 cells are co-cultured together in indirect co-culture system using Transwell insert. Following co-culture, both cells were analysed in terms of growth rate, migration ability, apoptosis and gene expression for genes involved in migration and stemness characteristics.

Results: The result shows that Ad-MSCs promoted the growth of A549 cells when indirectly co-cultured for 48 and 72 h. Furthermore, Ad-MSCs significantly enhanced the migration rate of A549 cells. The increased in migration rate was in parallel with the significant increase of MMP9. There are no significant changes observed in the expression of TWIST2, CDH2 and CDH1, genes involved in the epithelial-to-mesenchymal transition (EMT). Ad-MSCs also protect A549 cancer cells from undergoing apoptosis and increase the survival of cancer cells.

Conclusion: Secretion of soluble factors from Ad-MSCs has been shown to promote the growth and metastatic characteristics of A549 cancer cells. Therefore, the use of Ad-MSCs in cancer therapy needs to be carefully evaluated in the long-term aspect.
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http://dx.doi.org/10.1007/5584_2019_464DOI Listing
January 2021

Conditioned Medium of Human Menstrual Blood-Derived Endometrial Stem Cells Protects Against MPP-Induced Cytotoxicity .

Front Mol Neurosci 2019 5;12:80. Epub 2019 Apr 5.

Stem Cell and Biotherapy Engineering Research Center of Henan, College of Life, Science and Technology, Xinxiang Medical University, Xinxiang, China.

Mesenchymal stem cells (MSCs) showed the potential to treat Parkinson's disease (PD). However, it is unknown whether the conditioned medium of human menstrual blood-derived endometrial stem cells (MenSCs-CM) has the function to alleviate syndromes of PD. In this study, human neuroblastoma SH-SY5Y cells were exposed to neurotoxicant 1-methyl-4-phenylpyridinium (MPP) for inducing a range of response characteristics of PD. After culturing this cell model with 24 h/48 h collected MenSCs-CM for different days, cell viability, pro-inflammation cytokines, mitochondrial membrane potential (ΔΨm), oxidative stress, and cell apoptosis were detected. Finally, protein assay was performed to detect 12 kinds of neurotrophic factors inside MenSCs-CM. Our results showed that MPP caused SH-SY5Y cell viability reduction as an increasing dose and time dependent manner. MPP treatment resulted in inflammation, mitochondrial dysfunction, reactive oxygen species (ROS) production accumulation, and apoptosis of SH-SY5Y at its IC50 concentration. Forty-eight hours-collected MenSCs-CM and culturing with the MPP-treated SH-SY5Y for 2 days are the optimized condition to increase cell viability. Besides, MenSCs-CM was efficacious against MPP induced inflammation, ΔΨm loss, ROS generation, and it could significantly decrease cells numbers in late apoptosis stage. What's more, protein assay showed that MenSCs-CM contained various neuroprotective factors. Our study provided the first evidence that MenSCs-CM has a protective effect on MPP-induced cytotoxicity in various aspects, and firstly showed that MenSCs can release at least 12 kinds of neurotrophic factors to medium, which may contribute to the protective function of MenSCs-CM to treat PD. This research enlightening that MenSCs-CM is beneficial in the therapy for PD and probably also for other neurodegenerative diseases.
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http://dx.doi.org/10.3389/fnmol.2019.00080DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6460823PMC
April 2019

Inhibition of NF-κB Signaling Reduces the Stemness Characteristics of Lung Cancer Stem Cells.

Front Oncol 2018 17;8:166. Epub 2018 May 17.

Regenerative Medicine Cluster, Advanced Medical and Dental Institute, Universiti Sains Malaysia, Bertam, Penang, Malaysia.

Cancer stem cells (CSCs) are a subpopulation of cancer cells that play a pivotal role in tumor development, invasion, metastasis, and recurrence. We and others have reported significant involvement of the NF-κB pathway in regulating CSCs of non-small cell lung cancer (NSCLC). In this study, we evaluated the effects of NF-κB inhibition on self-renewal, stemness, migration, and expression of genes involved in the epithelial to mesenchymal transition (EMT) and apoptosis resistance in lung CSCs. Different concentrations of the NF-κB inhibitor BMS-345541 (0.4, 4.0, and 10.0 µM), an inhibitor the NF-κB upstream kinase IKKβ, were used to treat both lung CSCs (CD166CD44, CD166EpCAM) and non-CSC NSCLC cells (CD166CD44, CD166EpCAM) in A549 and H2170 cell lines. We assessed the impact of BMS-345541 on the ability to form tumorspheres (self-renewal assay), expression of stemness genes (, and ), migration, and expression of EMT and apoptosis-related genes. Inhibition of NF-κB by BMS-345541 effectively reduced the stemness, self-renewal, and migration capacity of lung CSCs. Moreover, expression of genes involved in the EMT ( and ) and apoptosis resistance (, and ) was significantly reduced following the treatments, suggesting that NF-κB inhibition is sufficient to prevent the EMT and induce apoptosis in lung CSCs. Our findings suggest that NF-κB inhibition could reduce the capability of CSCs to maintain their population within the tumor mass, potentially decelerating cancer progression, relapse, and chemotherapy resistance.
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http://dx.doi.org/10.3389/fonc.2018.00166DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5966538PMC
May 2018

Novel triple‑positive markers identified in human non‑small cell lung cancer cell line with chemotherapy-resistant and putative cancer stem cell characteristics.

Oncol Rep 2018 Aug 24;40(2):669-681. Epub 2018 May 24.

Stem Cell Laboratory, Haematology Unit, Cancer Research Centre, Institute for Medical Research (IMR), 50588 Kuala Lumpur, Malaysia.

Through the specific identification and direct targeting of cancer stem cells (CSCs), it is believed that a better treatment efficacy of cancer may be achieved. Hence, the present study aimed to identify a CSC subpopulation from adenocarcinoma cells (A549) as a model of non‑small cell lung cancer (NSCLC). Ιnitially, we sorted two subpopulations known as the triple‑positive (EpCAM+/CD166+/CD44+) and triple‑negative (EpCAM-/CD166-/CD44-) subpopulation using fluorescence-activated cell sorting (FACS). Sorted cells were subsequently evaluated for proliferation and chemotherapy-resistance using a viability assay and were further characterized for their clonal heterogeneity, self-renewal characteristics, cellular migration, alkaline dehydrogenase (ALDH) activity and the expression of stemness-related genes. According to our findings the triple‑positive subpopulation revealed significantly higher (P<0.01) proliferation activity, exhibited better clonogenicity, was mostly comprised of holoclones and had markedly bigger (P<0.001) spheroid formation indicating a better self-renewal capacity. A relatively higher resistance to both 5‑fluouracil and cisplatin with 80% expression of ALDH was observed in the triple‑positive subpopulation, compared to only 67% detected in the triple‑negative subpopulation indicated that high ALDH activity contributed to greater chemotherapy-resistance characteristics. Higher percentage of migrated cells was observed in the triple‑positive subpopulation with 56% cellular migration being detected, compared to only 19% in the triple‑negative subpopulation on day 2. This was similarly observed on day 3 in the triple‑positive subpopulation with 36% higher cellular migration compared to the triple‑negative subpopulation. Consistently, elevated levels of the stem cell genes such as REX1 and SSEA4 were also found in the triple‑positive subpopulation indicating that the subpopulation displayed a strong characteristic of pluripotency. In conclusion, our study revealed that the triple‑positive subpopulation demonstrated similar characteristics to CSCs compared to the triple‑negative subpopulation. It also confirmed the feasibility of using the triple‑positive (EpCAM+/CD166+/CD44+) marker as a novel candidate marker that may lead to the development of novel therapies targeting CSCs of NSCLC.
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http://dx.doi.org/10.3892/or.2018.6461DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6072294PMC
August 2018

The BRCA1 and BRCA2 Genes in Early-Onset Breast Cancer Patients.

Adv Exp Med Biol 2020 ;1292:1-12

Regenerative Medicine Cluster, Advanced Medical and Dental Institute, Universiti Sains Malaysia, Penang, Malaysia.

Approximately 5-10% of breast cancers are attributable to genetic susceptibility. Mutations in the BRCA1 and BRCA2 genes are the best known genetic factors to date. The goal of this study was to determine the structure and distribution of haplotypes of the BRCA1 and BRCA2 genes in early-onset breast cancer patients. We enrolled 70 patients diagnosed with early-onset breast cancer. A total of 21 SNPs (11 on BRCA1 and 10 on BRCA2) and 1 dinucleotide deletion on BRCA1 were genotyped using nested allele-specific PCR methods. Linkage disequilibrium (LD) analysis was conducted, and haplotypes were deduced from the genotype data. Two tightly linked LD blocks were observed on each of the BRCA1 and BRCA2 genes. Variant-free haplotypes (TAT-AG for BRCA1 and ATA-AAT for BRCA2) were observed at a frequency of more than 50% on each gene along with variable frequencies of derived haplotypes. The variant 3'-subhaplotype CGC displayed strong LD with 5'-subhaplotypes GA, AA, and GG on BRCA1 gene. Haplotypes ATA-AGT, ATC-AAT, and ATA-AAC were the variant haplotypes frequent on BRCA2 gene. Although the clinical significance of these derived haplotypes has not yet been established, it is expected that some of these haplotypes, especially the less frequent subhaplotypes, eventually will be shown to be indicative of a predisposition to early-onset breast cancer.
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http://dx.doi.org/10.1007/5584_2018_147DOI Listing
January 2021

Physico-Mechanical Properties of HA/TCP Pellets and Their Three-Dimensional Biological Evaluation In Vitro.

Adv Exp Med Biol 2019 ;1084:1-15

Regenerative Medicine Cluster, Advanced Medical and Dental Institute, Universiti Sains Malaysia, Kepala Batas, Penang, Malaysia.

The use of bioceramics, especially the combination of hydroxyapatite (HA) and β-tricalcium phosphate (β-TCP), as a three-dimensional scaffold in bone engineering is essential because together these elements constitute 60% of the bone content. Different ratios of HA and β-TCP were previously tested for their ability to produce suitable bioceramic scaffolds, which must be able to withstand high mechanical load. In this study, two ratios of HA/TCP (20:80 and 70:30) were used to create pellets, which then were evaluated in vitro to identify any adverse effects of using the material in bone grafting. Diametral tensile strength (DTS) and density testing was conducted to assess the mechanical strength and porosity of the pellets. The pellets then were tested for their toxicity to normal human fibroblast cells. In the toxicity assay, cells were incubated with the pellets for 3 days. At the end of the experiment, cell morphological changes were assessed, and the absorbance was read using PrestoBlue Cell Viability Reagent™. An inversely proportional relationship between DTS and porosity percentage was detected. Fibroblasts showed normal cell morphology in both treatments, which suggests that the HA/TCP pellets were not toxic. In the osteoblast cell attachment assay, cells were able to attach to the surface of both ratios, but cells were also able to penetrate inside the scaffold of the 70:30 pellets. This finding suggests that the 70:30 ratio had better osteoconduction properties than the 20:80 ratio.
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http://dx.doi.org/10.1007/5584_2017_130DOI Listing
September 2019

Stimulatory Secretions of Airway Epithelial Cells Accelerate Early Repair of Tracheal Epithelium.

Sci Rep 2017 09 15;7(1):11732. Epub 2017 Sep 15.

Regenerative Medicine Cluster, Advanced Medical and Dental Institute (AMDI), Universiti Sains Malaysia, Bandar Putra Bertam, 13200, Kepala Batas, Penang, Malaysia.

Airway stem/progenitor epithelial cells (AECs) are notable for their differentiation capacities in response to lung injury. Our previous finding highlighted the regenerative capacity of AECs following transplantation in repairing tracheal injury and reducing the severity of alveolar damage associated acute lung injury in a rabbit model. The goal of this study is to further investigate the potential of AECs to re-populate the tracheal epithelium and to study their stimulatory effect on inhibiting pro-inflammatory cytokines, epithelial cell migration and proliferation, and epithelial-to-mesenchymal transition (EMT) process following tracheal injury. Two in vitro culture assays were applied in this study; the direct co-culture assay that involved a culture of decellularised tracheal epithelium explants and AECs in a rotating tube, and indirect co-culture assay that utilized microporous membrane-well chamber system to separate the partially decellularised tracheal epithelium explants and AEC culture. The co-culture assays provided evidence of the stimulatory behaviour of AECs to enhance tracheal epithelial cell proliferation and migration during early wound repair. Factors that were secreted by AECs also markedly suppressed the production of IL-1β and IL-6 and initiated the EMT process during tracheal remodelling.
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http://dx.doi.org/10.1038/s41598-017-11992-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5601923PMC
September 2017

Direction of commissural axon projections in different regions of the spinal cord during chicken embryonic development.

Neuroscience 2017 09 4;358:269-276. Epub 2017 Jul 4.

College of Life Science and Technology, Henan Key Laboratory of Medical Tissue Regeneration, Xinxiang Medical University, Xinxiang 453003, China; Institute of Anatomy I, University of Jena School of Medicine, Jena University Hospital, Jena 07743, Germany; College of Biomedical Engineering, Xinxiang Medical University, Xinxiang 453003, China. Electronic address:

Few researchers have investigated the direction of commissural axon projections on the contralateral side of the vertebrate embryonic spinal cord, especially for comparison between its different regions. In this study, pCAGGS-GFP plasmid expression was limited to different regions of the chicken embryonic spinal cord (cervical, anterior limb, anterior thorax, posterior thorax and posterior limb) at E3 using in ovo electroporation with modified electrodes and optimal electroporation conditions. Then open-book technique was performed at E6 to analyze the direction of axon projections in different spinal cord regions. The results show that in the five investigated regions, most axons projected rostrally after crossing the floor plate while a minority projected caudally. And there was a significant difference between the rostral and caudal projection quantities (P<0.01). The ratio of rostral and caudal projections was significantly different between the five investigated regions (P<0.05), except between the cervical region and the anterior limb (P>0.05). The projections were most likely to be rostral for the posterior limb followed by the posterior thorax, cervical region, anterior limb and anterior thorax. Our data for the direction of the commissural axon projections will be helpful in the future analyses of axon projection mechanisms and spinal cord-brain circuit formation.
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http://dx.doi.org/10.1016/j.neuroscience.2017.06.053DOI Listing
September 2017

Targeting Lung Cancer Stem Cells: Research and Clinical Impacts.

Front Oncol 2017 5;7:80. Epub 2017 May 5.

Regenerative Medicine Cluster, Advanced Medical and Dental Institute (AMDI), Universiti Sains Malaysia, Kepala Batas, Penang, Malaysia.

Lung cancer is the most common cancer worldwide, accounting for 1.8 million new cases and 1.6 million deaths in 2012. Non-small cell lung cancer (NSCLC), which is one of two types of lung cancer, accounts for 85-90% of all lung cancers. Despite advances in therapy, lung cancer still remains a leading cause of death. Cancer relapse and dissemination after treatment indicates the existence of a niche of cancer cells that are not fully eradicated by current therapies. These chemoresistant populations of cancer cells are called cancer stem cells (CSCs) because they possess the self-renewal and differentiation capabilities similar to those of normal stem cells. Targeting the niche of CSCs in combination with chemotherapy might provide a promising strategy to eradicate these cells. Thus, understanding the characteristics of CSCs has become a focus of studies of NSCLC therapies.
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http://dx.doi.org/10.3389/fonc.2017.00080DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5418222PMC
May 2017

The use of mesenchymal stromal cells in treatment of lung disorders.

Regen Med 2017 03 17;12(2):203-216. Epub 2017 Feb 17.

Regenerative Medicine Cluster, Advanced Medical & Dental Institute (AMDI), Universiti Sains Malaysia, Bandar Putra Bertam, 13200 Kepala Batas, Pulau Pinang, Malaysia.

The therapeutic use of mesenchymal stromal cells (MSCs) represents a promising alternative clinical strategy for treating acute and chronic lung disorders. Several preclinical reports demonstrated that MSCs can secrete multiple paracrine factors and that their immunomodulatory properties can support endothelial and epithelial regeneration, modulate the inflammatory cascade and protect lungs from damage. The effects of MSC transplantation into patients suffering from lung diseases should be fully evaluated through careful assessment of safety and associated risks, which is a prerequisite for translation of preclinical research into clinical practice. In this article, we summarize the current status of preclinical research and review initial MSC-based clinical trials for treating lung injuries and lung disorders.
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http://dx.doi.org/10.2217/rme-2016-0112DOI Listing
March 2017

Kinetics Extraction Modelling and Antiproliferative Activity of Water Extract.

ScientificWorldJournal 2016 26;2016:7370536. Epub 2016 Dec 26.

School of Chemical Sciences and Food Technology, Faculty of Science and Technology, Universiti Kebangsaan Malaysia (UKM), 43600 Bangi, Selangor, Malaysia.

is widely grown in tropical Asia and locally known "belalai gajah" or Sabah snake grass. It has been used as a natural product to treat skin rashes, snake bites, lesion caused by herpes, diabetes, fever, and cancer. Therefore, the objectives of this research are to determine the maximum yield and time of exhaustive flavonoids extraction using Peleg's model and to evaluate potential of antiproliferative activity on human lung cancer cell (A549). The extraction process was carried out on fresh and dried leaves at 28 to 30°C with liquid-to-solid ratio of 10 mL/g for 72 hrs. The extracts were collected intermittently analysed using mathematical Peleg's model and RP-HPLC. The highest amount of flavonoids was used to evaluate the inhibitory concentration (IC) via 2D cell culture of A549. Based on the results obtained, the predicted maximum extract density was observed at 29.20 ± 14.54 hrs of extraction (). However, the exhaustive time of extraction to acquire maximum flavonoids content exhibited approximately 10 hrs earlier. Therefore, 18 hrs of extraction time was chosen to acquire high content of flavonoids. The best antiproliferative effect (IC) on A549 cell line was observed at 138.82 ± 0.60 g/mL. In conclusion, the flavonoids content in water extract possesses potential antiproliferative properties against A549, suggesting an alternative approach for cancer treatment.
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http://dx.doi.org/10.1155/2016/7370536DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5221343PMC
November 2017

Aerosol-Based Cell Therapy for Treatment of Lung Diseases.

Methods Mol Biol 2016 ;1516:243-255

Regenerative Medicine Cluster, Advanced Medical and Dental Institute (AMDI), Universiti Sains Malaysia, Bandar Putra Bertam, 13200, Kepala Batas, Penang, Malaysia.

Aerosol-based cell delivery technique via intratracheal is an effective route for delivering transplant cells directly into the lungs. An aerosol device known as the MicroSprayer(®) Aerosolizer is invented to transform liquid into an aerosol form, which then can be applied via intratracheal administration for drug delivery. The device produces a uniform and concentrated distribution of aerosolized liquid. Using the capability of MicroSprayer(®) Aerosolizer to transform liquid into aerosol form, our group has designed a novel method of cell delivery using an aerosol-based technique. We have successfully delivered skin-derived fibroblast cells and airway epithelial cells into the airway of a rabbit with minimum risk of cell loss and have uniformly distributed the cells into the airway. This chapter illustrates the application of aerosol device to deliver any type of cells for future treatment of lung diseases.
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http://dx.doi.org/10.1007/7651_2016_327DOI Listing
January 2018

Isolation and Characterization of Cancer Stem Cells of the Non-Small-Cell Lung Cancer (A549) Cell Line.

Methods Mol Biol 2016 ;1516:371-388

Regenerative Medicine Cluster, Advanced Medical and Dental Institute (AMDI), Universiti Sains Malaysia, Penang, 13200, Malaysia.

Cancer is a major health problem worldwide. The failure of current treatments to completely eradicate cancer cells often leads to cancer recurrence and dissemination. Studies have suggested that tumor growth and spread are driven by a minority of cancer cells that exhibit characteristics similar to those of normal stem cells, thus these cells are called cancer stem cells (CSCs). CSCs are believed to play an important role in initiating and promoting cancer. CSCs are resistant to currently available cancer therapies, and understanding the mechanisms that control the growth of CSCs might have great implications for cancer therapy. Cancer cells are consist of heterogeneous population of cells, thus methods of identification, isolation, and characterisation of CSCs are fundamental to obtain a pure CSC populations. Therefore, this chapter describes in detail a method for isolating and characterizing a pure population of CSCs from heterogeneous population of cancer cells and CSCs based on specific cell surface markers.
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http://dx.doi.org/10.1007/7651_2016_326DOI Listing
January 2018

Curcumin improves the efficacy of cisplatin by targeting cancer stem-like cells through p21 and cyclin D1-mediated tumour cell inhibition in non-small cell lung cancer cell lines.

Oncol Rep 2016 Jan 2;35(1):13-25. Epub 2015 Nov 2.

Regenerative Medicine Cluster, Advanced Medical and Dental Institute (AMDI), University Sains Malaysia, Kepala Batas, Penang 13200, Malaysia.

Natural compounds such as curcumin have the ability to enhance the therapeutic effectiveness of common chemotherapy agents through cancer stem-like cell (CSC) sensitisation. In the present study, we showed that curcumin enhanced the sensitivity of the double-positive (CD166+/EpCAM+) CSC subpopulation in non-small cell lung cancer (NSCLC) cell lines (A549 and H2170) to cisplatin-induced apoptosis and inhibition of metastasis. Our results revealed that initial exposure of NSCLC cell lines to curcumin (10-40 µM) markedly reduced the percentage of viability to an average of ~51 and ~54% compared to treatment with low dose cisplatin (3 µM) with only 94 and 86% in both the A549 and H2170 cells. Moreover, sensitisation of NSCLC cell lines to curcumin through combined treatment enhanced the single effect induced by low dose cisplatin on the apoptosis of the double-positive CSC subpopulation by 18 and 20% in the A549 and H2170 cells, respectively. Furthermore, we found that curcumin enhanced the inhibitory effects of cisplatin on the highly migratory CD166+/EpCAM+ subpopulation, marked by a reduction in cell migration to 9 and 21% in the A549 and H2170 cells, respectively, indicating that curcumin may increase the sensitivity of CSCs to cisplatin-induced migratory inhibition. We also observed that the mRNA expression of cyclin D1 was downregulated, while a substantial increased in p21 expression was noted, followed by Apaf1 and caspase-9 activation in the double-positive (CD166+/EpCAM+) CSC subpopulation of A549 cells, suggested that the combined treatments induced cell cycle arrest, therefore triggering CSC growth inhibition via the intrinsic apoptotic pathway. In conclusion, we provided novel evidence of the previously unknown therapeutic effects of curcumin, either alone or in combination with cisplatin on the inhibition of the CD166+/EpCAM+ subpopulation of NSCLC cell lines. This finding demonstrated the potential therapeutic approach of using curcumin that may enhance the effects of cisplatin by targeting the CSC subpopulation in NSCLC.
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http://dx.doi.org/10.3892/or.2015.4371DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4699625PMC
January 2016

Guidelines for nucleic acid detection and analysis in hematological disorders.

Malays J Pathol 2015 Aug;37(2):165-73

Universiti Sains Malaysia, School of Medical Sciences, Department of Haematology, 16150, Kubang Kerian, Kelantan, Malaysia.

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August 2015

A comparative study of non-viral gene delivery techniques to human adipose-derived mesenchymal stem cell.

Int J Mol Sci 2014 Aug 26;15(9):15044-60. Epub 2014 Aug 26.

Regenerative Medicine Cluster, Advanced Medical and Dental Institute (AMDI), Universiti Sains Malaysia, Penang 13200, Malaysia.

Mesenchymal stem cells (MSCs) hold tremendous potential for therapeutic use in stem cell-based gene therapy. Ex vivo genetic modification of MSCs with beneficial genes of interest is a prerequisite for successful use of stem cell-based therapeutic applications. However, genetic manipulation of MSCs is challenging because they are resistant to commonly used methods to introduce exogenous DNA or RNA. Herein we compared the effectiveness of several techniques (classic calcium phosphate precipitation, cationic polymer, and standard electroporation) with that of microporation technology to introduce the plasmid encoding for angiopoietin-1 (ANGPT-1) and enhanced green fluorescent protein (eGFP) into human adipose-derived MSCs (hAD-MSCs). The microporation technique had a higher transfection efficiency, with up to 50% of the viable hAD-MSCs being transfected, compared to the other transfection techniques, for which less than 1% of cells were positive for eGFP expression following transfection. The capability of cells to proliferate and differentiate into three major lineages (chondrocytes, adipocytes, and osteocytes) was found to be independent of the technique used for transfection. These results show that the microporation technique is superior to the others in terms of its ability to transfect hAD-MSCs without affecting their proliferation and differentiation capabilities. Therefore, this study provides a foundation for the selection of techniques when using ex vivo gene manipulation for cell-based gene therapy with MSCs as the vehicle for gene delivery.
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http://dx.doi.org/10.3390/ijms150915044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4200830PMC
August 2014

Molecular characterization of α- and β-thalassaemia among Malay patients.

Int J Mol Sci 2014 May 19;15(5):8835-45. Epub 2014 May 19.

Regenerative Medicine Cluster, Advanced Medical and Dental Institute, Universiti Sains Malaysia, Bertam, Kepala Batas, Penang 13200, Malaysia.

Both α- and β-thalassaemia syndromes are public health problems in the multi-ethnic population of Malaysia. To molecularly characterise the α- and β-thalassaemia deletions and mutations among Malays from Penang, Gap-PCR and multiplexed amplification refractory mutation systems were used to study 13 α-thalassaemia determinants and 20 β-thalassaemia mutations in 28 and 40 unrelated Malays, respectively. Four α-thalassaemia deletions and mutations were demonstrated. --SEA deletion and αCSα accounted for more than 70% of the α-thalassaemia alleles. Out of the 20 β-thalassaemia alleles studied, nine different β-thalassaemia mutations were identified of which βE accounted for more than 40%. We concluded that the highest prevalence of (α- and β-thalassaemia alleles in the Malays from Penang are --SEA deletion and βE mutation, respectively.
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http://dx.doi.org/10.3390/ijms15058835DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4057762PMC
May 2014

The rabbit as a model for studying lung disease and stem cell therapy.

Biomed Res Int 2013 8;2013:691830. Epub 2013 Apr 8.

Cluster for Regenerative Medicine, Advanced Medical & Dental Institute AMDI, Universiti Sains Malaysia, Bandar Putra Bertam, 13200 Kepala Batas, Malaysia.

No single animal model can reproduce all of the human features of both acute and chronic lung diseases. However, the rabbit is a reliable model and clinically relevant facsimile of human disease. The similarities between rabbits and humans in terms of airway anatomy and responses to inflammatory mediators highlight the value of this species in the investigation of lung disease pathophysiology and in the development of therapeutic agents. The inflammatory responses shown by the rabbit model, especially in the case of asthma, are comparable with those that occur in humans. The allergic rabbit model has been used extensively in drug screening tests, and this model and humans appear to be sensitive to similar drugs. In addition, recent studies have shown that the rabbit serves as a good platform for cell delivery for the purpose of stem-cell-based therapy.
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http://dx.doi.org/10.1155/2013/691830DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3638694PMC
December 2013