Publications by authors named "Hasnan Jaafar"

62 Publications

Significant transcriptomic changes are associated with differentiation of bone marrow-derived mesenchymal stem cells into neural progenitor-like cells in the presence of bFGF and EGF.

Cell Biosci 2020 Oct 28;10(1):126. Epub 2020 Oct 28.

Department of Pathology, School of Medical Sciences, Universiti Sains Malaysia Health Campus, Jalan Raja Perempuan Zainab II, 16150, Kubang Kerian, Kelantan, Malaysia.

Introduction: Mesenchymal stem cells (MSCs) isolated from bone marrow have different developmental origins, including neural crest. MSCs can differentiate into neural progenitor-like cells (NPCs) under the influence of bFGF and EGF. NPCs can terminally differentiate into neurons that express beta-III-tubulin and elicit action potential. The main aim of the study was to identify key genetic markers involved in differentiation of MSCs into NPCs through transcriptomic analysis.

Method: Total RNA was isolated from MSCs and MSCs-derived NPCs followed by cDNA library construction for transcriptomic analysis. Sample libraries that passed the quality and quantity assessments were subjected to high throughput mRNA sequencing using NextSeq®500. Differential gene expression analysis was performed using the DESeq2 R package with MSC samples being a reference group. The expression of eight differentially regulated genes was counter validated using real-time PCR.

Results: In total, of the 3,252 differentially regulated genes between MSCs and NPCs with two or more folds, 1,771 were upregulated genes, whereas 1,481 were downregulated in NPCs. Amongst these differential genes, 104 transcription factors were upregulated, and 45 were downregulated in NPCs. Neurogenesis related genes were upregulated in NPCs and the main non-redundant gene ontology (GO) terms enriched in NPCs were the autonomic nervous system, cell surface receptor signalling pathways), extracellular structure organisation, and programmed cell death. The main non-redundant GO terms enriched in MSCs included cytoskeleton organisation cytoskeleton structural constituent, mitotic cell cycle), and the mitotic cell cycle process Gene set enrichment analysis also confirmed cell cycle regulated pathways as well as Biocarta integrin pathway were upregulated in MSCs. Transcription factors enrichment analysis by ChEA3 revealed Foxs1 and HEYL, amongst the top five transcription factors, inhibits and enhances, respectively, the NPCs differentiation of MSCs.

Conclusions: The vast differences in the transcriptomic profiles between NPCs and MSCs revealed a set of markers that can identify the differentiation stage of NPCs as well as provide new targets to enhance MSCs differentiation into NPCs.
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http://dx.doi.org/10.1186/s13578-020-00487-zDOI Listing
October 2020

Significant transcriptomic changes are associated with differentiation of bone marrow-derived mesenchymal stem cells into neural progenitor-like cells in the presence of bFGF and EGF.

Cell Biosci 2020 28;10:126. Epub 2020 Oct 28.

Department of Pathology, School of Medical Sciences, Universiti Sains Malaysia Health Campus, Jalan Raja Perempuan Zainab II, 16150, Kubang Kerian, Kelantan Malaysia.

Introduction: Mesenchymal stem cells (MSCs) isolated from bone marrow have different developmental origins, including neural crest. MSCs can differentiate into neural progenitor-like cells (NPCs) under the influence of bFGF and EGF. NPCs can terminally differentiate into neurons that express beta-III-tubulin and elicit action potential. The main aim of the study was to identify key genetic markers involved in differentiation of MSCs into NPCs through transcriptomic analysis.

Method: Total RNA was isolated from MSCs and MSCs-derived NPCs followed by cDNA library construction for transcriptomic analysis. Sample libraries that passed the quality and quantity assessments were subjected to high throughput mRNA sequencing using NextSeq®500. Differential gene expression analysis was performed using the DESeq2 R package with MSC samples being a reference group. The expression of eight differentially regulated genes was counter validated using real-time PCR.

Results: In total, of the 3,252 differentially regulated genes between MSCs and NPCs with two or more folds, 1,771 were upregulated genes, whereas 1,481 were downregulated in NPCs. Amongst these differential genes, 104 transcription factors were upregulated, and 45 were downregulated in NPCs. Neurogenesis related genes were upregulated in NPCs and the main non-redundant gene ontology (GO) terms enriched in NPCs were the autonomic nervous system, cell surface receptor signalling pathways), extracellular structure organisation, and programmed cell death. The main non-redundant GO terms enriched in MSCs included cytoskeleton organisation cytoskeleton structural constituent, mitotic cell cycle), and the mitotic cell cycle process Gene set enrichment analysis also confirmed cell cycle regulated pathways as well as Biocarta integrin pathway were upregulated in MSCs. Transcription factors enrichment analysis by ChEA3 revealed Foxs1 and HEYL, amongst the top five transcription factors, inhibits and enhances, respectively, the NPCs differentiation of MSCs.

Conclusions: The vast differences in the transcriptomic profiles between NPCs and MSCs revealed a set of markers that can identify the differentiation stage of NPCs as well as provide new targets to enhance MSCs differentiation into NPCs.
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http://dx.doi.org/10.1186/s13578-020-00487-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7594431PMC
October 2020

Evaluation of NMU-Induced Breast Cancer Treated with Sirolimus and Sunitinib on Breast Cancer Growth.

Asian Pac J Cancer Prev 2020 Oct 1;21(10):2919-2925. Epub 2020 Oct 1.

Department of Chemical Pathology, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian, Malaysia.

Objective: To analyze the effect of sirolimus and sunitinib in blocking the tumor growth and to evaluate the expressions of estrogen receptor (ER), progesterone receptor (PgR), and human epidermal growth factor receptor-2 (HER2/neu) after treated with sirolimus and sunitinib.

Methods: Thirty-two female Sprague Dawley rats at age 21-days old were administered intraperitoneally with N-Methyl-N-Nitroso Urea (NMU), dosed at 70mg/kg body weight. The rats were divided into 4 groups; Group 1 (Control, n=8), Group 2 (Sirolimus, n=8), Group 3 (Sunitinib, n=8) and Group 4 (Sirolimus+Sunitinib, n=8), being treated twice when the tumor reached the size of 14.5±0.5 mm and subsequently sacrificed after 5 days. The protein expressions of ER, PgR and HER2/neu of the tumor tissues were evaluated by using immunohistochemistry analysis.

Results: Treatment with sirolimus alone lowered expressions of ER and PgR of breast cancer and reduced tumor size. There was no significant difference of ER and PgR expressions between control and sunitinib treated tumor. Sunitinib treated tumors reduce in diameter after the first treatment, however the diameter increases after the second treatment. Histologically, sunitinib treated tumor did not show any aggressive invasive carcinoma of no special type (NST) histological subtypes. In addition, all NMU-induced tumors are HER2/neu-negative scoring.

Conclusion: Sirolimus is neither synergistic nor additive with sunitinib for breast cancer treatment.
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http://dx.doi.org/10.31557/APJCP.2020.21.10.2919DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7798166PMC
October 2020

Microvessel density and vascular endothelial growth factor receptors in breast carcinoma under the influence of rapamycin and platelet factor 4.

Indian J Pathol Microbiol 2020 Apr-Jun;63(2):205-209

Department of Pathology, School of Medical Sciences, Universiti Sains Malaysia, Health Campus, Kubang Kerian, Kelantan, Malaysia.

Background: Vascular endothelial growth factor receptors (VEGFRs) are major endothelial growth factor receptors that influence the growth of a tumor. Microvessel density.

(: MVD) is the quantification method of various aspects of tumor vasculature that indicates angiogenic activity. This study aims to analyze the correlation between MVD to the expression of VEGFRs on breast cancer tissue.

Materials And Method: A total of 60 N-methyl-N-nitrosourea (MNU)-induced breast carcinomas in rats were suppressed by using antiangiogenic drugs. The rats were then sacrificed, and the tumor was fixed in 10% formalin, paraffin embedded, and immunohistochemistry stained using VEGFRs and CD34.

Result: One-way ANOVA test showed a significant difference in all markers that have been used (P < 0.05) on MNU-breast tumor treated with rapamycin (M= 90.1664, SD= 7.4487), PF4 (M= 93.7946, SD= 7.1303) and rapamycin + PF4 (M= 93.6990, SD= 1.8432). We obtained a significant reduction of MVD count on breast carcinoma for rapamycin group (M= 25.6786, SD= 9.7075) and rapamycin + PF4 group (M= 30.5250, SD= 13.6928) while PF4 group (M=47.7985, SD=4.8892) showed slightly increase compared to control (M= 45.1875, SD= 4.4786). There was a moderately strong, positive correlation between angiogenic markers; Flt-1 (r= 0.544, n=60, P < 0.005) and Flt-4 (r= 0.555, n= 60, P < 0.005) while Flk-1 (r= 0.797, n= 60, P < 0.005) showed a strong, positive correlation with MVD.

Conclusion: MVD was strongly correlated to the VEGFRs expression on breast carcinoma.
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http://dx.doi.org/10.4103/IJPM.IJPM_496_19DOI Listing
January 2021

Trkb-IP3 Pathway Mediating Neuroprotection in Rat Hippocampal Neuronal Cell Culture Following Induction of Kainic Acid.

Malays J Med Sci 2018 Nov 28;25(6):28-45. Epub 2018 Dec 28.

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

Background: Following brain injury, development of hippocampal sclerosis often led to the temporal lobe epilepsy which is sometimes resistant to common anti-epileptic drugs. Cellular and molecular changes underlying epileptogenesis in animal models were studied, however, the underlying mechanisms of kainic acid (KA) mediated neuronal damage in rat hippocampal neuron cell culture alone has not been elucidated yet.

Methods: Embryonic day 18 (E-18) rat hippocampus neurons were cultured with poly-L-lysine coated glass coverslips. Following optimisation, KA (0.5 μM), a chemoconvulsant agent, was administered at three different time-points (30, 60 and 90 min) to induce seizure in rat hippocampal neuronal cell culture. We examined cell viability, neurite outgrowth density and immunoreactivity of the hippocampus neuron culture by measuring brain derived neurotrophic factor (BDNF), γ-amino butyric acid A (GABA) subunit α-1 (GABRA1), tyrosine receptor kinase B (TrkB), and inositol trisphosphate receptor (IPR/IP3) levels.

Results: The results revealed significantly decreased and increased immunoreactivity changes in TrkB (a BDNF receptor) and IPR, respectively, at 60 min time point.

Conclusion: The current findings suggest that TrkB and IP3 could have a neuroprotective role which could be a potential pharmacological target for anti-epilepsy drugs.
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http://dx.doi.org/10.21315/mjms2018.25.6.4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6422567PMC
November 2018

Mesenchymal chondrosarcoma of maxilla in paediatric patient.

BMJ Case Rep 2019 Mar 9;12(3). Epub 2019 Mar 9.

Department of Otorhinolaryngology - Head and Neck Surgery, School of Medical Sciences, Universiti Sains Malaysia, Health Campus, Kota Bharu, Kelantan, Malaysia.

Chondrosarcoma (CS) is a malignant tumour of long and flat bone characterised by the formation of cartilage. Mesenchymal chondrosarcoma (MCS) is a rare subtype of CS that is more aggressive and may lead to erroneous diagnosis in a limited biopsy. The diagnosis is mainly based on the histopathological appearance of biphasic pattern of undifferentiated small round cells separated by islands of well-differentiated hyaline cartilage. We report a case of 13-year-old boy who initially presented with gum swelling and the biopsy result suggested a benign fibrous lesion. Following an extensive lesion shown in radiologic findings, the tumour excision was done and finally was diagnosed as an MCS of the maxilla. The patient was given postoperative chemotherapy (EURO-EWING 99 regimen), and now on regular follow-up for monitoring of local recurrence or tumour metastasis.
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http://dx.doi.org/10.1136/bcr-2018-228969DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6424280PMC
March 2019

Collapsed wall: destructive and reconstructive surgery of anterior abdominal wall tumour in a young girl.

J Surg Case Rep 2019 Feb 8;2019(2):rjy345. Epub 2019 Feb 8.

Hospital Universiti Sains Malaysia, Universiti Sains Malaysia, Kota Bharu, Malaysia.

Natural history of abdominal wall soft tissue sarcoma is still poorly understood due to its rarity. In unpublished data of our institution, only seven cases of abdominal wall soft sarcoma with ICD-10 coding of 49.4 were found for past 10 years. We illustrate a case of juvenile fibrosarcoma of anterior abdominal wall. This is a case of young girl with anterior abdominal wall tumour, underwent wide local excision with immediate reconstruction. There are few options of surgical treatment for this case, but which is the best. It is always a challenge in managing young patient with giant abdominal wall defect in view of long term effect namely weakened abdominal wall, pregnancy related issue and risk of herniation and surgical site recurrence as well.
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http://dx.doi.org/10.1093/jscr/rjy345DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6368141PMC
February 2019

Differential expression of entorhinal cortex and hippocampal subfields α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-D-aspartate (NMDA) receptors enhanced learning and memory of rats following administration of Centella asiatica.

Biomed Pharmacother 2019 Feb 20;110:168-180. Epub 2018 Nov 20.

Department of Neurosciences, School of Medical Sciences, Universiti Sains Malaysia, Jalan Hospital Universiti Sains Malaysia, 16150, Kubang Kerian, Kota Bharu, Kelantan, Malaysia. Electronic address:

Centella asiatica (CA) is a widely used traditional herb, notably for its cognitive enhancing effect and potential to increase synaptogenesis. The α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) and N-methyl-D-aspartate receptors (NMDARs) mediate fast excitatory neurotransmission with key roles in long-term potentiation which is believed to be the cellular mechanism of learning and memory. Improved learning and memory can be an indication to the surface expression level of these receptors. Our previous study demonstrated that administration of CA extract improved learning and memory and enhanced expression of AMPAR GluA1 subunit while exerting no significant effects on GABA receptors of the hippocampus in rats. Hence, to further elucidate the effects of CA, this study investigated the effects of CA extract in recognition memory and spatial memory, and its effects on AMPAR GluA1 and GluA2 subunit and NMDAR GluN2 A and GluN2B subunit expression in the entorhinal cortex (EC) and hippocampal subfields CA1 and CA3. The animals were administered with saline, 100 mg/kg, 300 mg/kg, and 600 mg/kg of CA extract through oral gavage for 14 days, followed by behavioural analysis through Open Field Test (OFT), Novel Object Recognition Task (NORT), and Morris Water Maze (MWM) and lastly morphological and immunohistochemical analysis of the surface expression of AMPAR and NMDAR subunits were performed. The results showed that 14 days of administration of 600 mg/kg of CA extract significantly improved memory assessed through NORT while 300 mg/kg of CA extract significantly improved memory of the animals assessed through MWM. Immunohistochemical analysis revealed differential modulation effects on the expressions of receptor subunits across CA1, CA3 and EC. The CA extract at the highest dose (600 mg/kg) significantly enhanced the expression of AMPAR subunit GluA1 and GluA2 in CA1, CA3 and EC, and NMDAR subunit GluN2B in CA1 and CA3 compared to control. At 300 mg/kg, CA significantly increased expression of AMPAR GluA1 in CA1 and EC, and GluA2 in CA1, CA3 and EC while 100 mg/kg of CA significantly increased expression of only AMPAR subunit GluA2 in CA3 and EC. Expression of NMDAR subunit GluN2 A was significantly reduced in the CA3 (at 100, 300, and 600 mg/kg) while no significant changes of subunit expression was observed in CA1 and EC compared to control. The results suggest that the enhanced learning and memory observed in animals administered with CA was mainly mediated through increased expression of AMPAR GluA1 and GluA2 subunits and differential expression of NMDAR GluN2 A and GluN2B subunits in the hippocampal subfields and EC. With these findings, the study revealed a new aspect of cognitive enhancing effect of CA and its therapeutic potentials through modulating receptor subunit expression.
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http://dx.doi.org/10.1016/j.biopha.2018.11.044DOI Listing
February 2019

Human tuberculosis brain promotes neuronal apoptosis but not in astrocytes with high expression of vascular endothelial growth factor.

Tuberculosis (Edinb) 2018 09 18;112:45-51. Epub 2018 Jul 18.

Department of Pathology, University Sains Malaysia, Malaysia. Electronic address:

The present study aimed to investigate the involvement of the angiogenic marker vascular endothelia growth factor (VEGF) and apoptotic markers of Bcl-2 and Bax in the neurons and astrocytes in the brain infected by Mycobacterium tuberculosis. The immunohistochemistry staining was performed to analyze the expression of the VEGF, Bcl-2 and Bax in the astrocytes and neurons. The expression of VEGF was high in neurons and astrocytes in both the infected brain and control tissues with no difference of angiogenic activity (p = 0.40). Higher Bcl-2 expression was seen in astrocytes of infected brain tissues compared to the control tissues (p = 0.004) promoted a higher anti-apoptotic activity in astrocytes. The neurons expressed strong Bax expression in the infected brain tissues compared to the control tissues (p < 0.001), which indicated more apoptosis in neurons. Thus, neuronal death and survival of infected astrocytes together with high expression of VEGF might be associated with formation of brain tuberculosis. In conclusion, neurons could be more vulnerable than astrocytes in human tuberculosis brain with high expression of VEGF.
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http://dx.doi.org/10.1016/j.tube.2018.07.007DOI Listing
September 2018

Hippocampal amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid GluA1 (AMPA GluA1) receptor subunit involves in learning and memory improvement following treatment with Centella asiatica extract in adolescent rats.

Brain Behav 2018 09 14;8(9):e01093. Epub 2018 Aug 14.

Center for Neuroscience Services and Research(P3Neuro), Universiti Sains Malaysia, Jalan Hospital Universiti Sains Malaysia, Kota Bharu, Kelantan, Malaysia.

Introduction: Centella asiatica is an herbal plant that contains phytochemicals that are widely believed to have positive effects on cognitive function. The adolescent stage is a critical development period for the maturation of brain processes that encompass changes in physical and psychological systems. However, the effect of C. asiatica has not been extensively studied in adolescents. The aim of this study was therefore to investigate the effects of a C. asiatica extract on the enhancement of learning and memory in adolescent rats.

Methods: The locomotor activity, learning, and memory were assessed by using open field test and water T-maze test. This study also examined changes in neuronal cell morphology using cresyl violet and apoptosis staining. We also performed immunohistochemical study to analyse the expression of the glutamate AMPA receptor (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) GluA1 subunit and the GABA receptor (γ-Aminobutyric Acid) subtype GABA α1 subunit in the hippocampus of the same animals.

Results: We found no significant changes in locomotor activity (p > 0.05). The water T-maze data showed that 30 mg/kg dose significantly (p < 0.05) improved learning, memory, and the memory consolidation phase but had no effect on reversal learning (p > 0.05). Histological data revealed no neuronal morphological changes. Immunohistochemical analysis revealed increased expression of the AMPA GluA1 receptor subunit but there was no effect on GABA receptor α1 subunit expression in the CA1 and CA2 subregions of the hippocampus.

Conclusions: The C. asiatica extract therefore improved hippocampus-dependent spatial learning and memory in a dose-dependent manner in rats through the GluA1-containing AMPA receptor in the CA1 and CA2 sub regions of the hippocampus.
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http://dx.doi.org/10.1002/brb3.1093DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6160644PMC
September 2018

Cellular and Molecular Changes in MNU-Induced Breast Tumours Injected with PF4 or bFGF

Asian Pac J Cancer Prev 2017 Dec 28;18(12):3231-3238. Epub 2017 Dec 28.

Department of Pathology, School of Medical Sciences, Universiti Sains Malaysia, Health Campus, 16150 Kota Bharu, Kelantan, Malaysia. Email:

Background: Angiogenic activity has been considered to reflect important molecular events during breast tumour development. The present study concerned cellular and molecular changes of MNU-induced breast tumours subjected to promotion and suppression of angiogenesis. Methods: Female Sprague Dawley rats at the age of 21 days received MNU at the dose 70 mg/kg of body weight by intraperitoneal injection. Three months post-carcinogen initiation, mammary tumours were palpated and their growth was monitored. When the tumour diameter reached 1.0 ± 0.05 cm, rats were given bFGF or PF4 intratumourally at a dose of 10 μg/tumour. Entire palpable tumour were subsequently excised and subjected to histology examination, IHC staining, and RT-PCR. Results: No critical morphological changes were observed between pro-angiogenic factor, bFGF, and control groups. However, increase of tumour size with more necrotic and diffuse areas was notable in tumours after anti-angiogenic PF4 intervention. ER and PR mRNA expression was significantly up- and down-regulated in bFGF and PF4 groups, respectively. The trends were significantly associated with peri- and intratumoural MVD counts. However, irrespective of whether we promoted or inhibited angiogenesis, the expression of EGFR and ERBB2 continued to be significantly increased but this was not significantly associated with the MVD score. No significant differences in E-cadherin and LR gene expression were noted between intervention and control groups. Conclusion: ER and PR receptor expression shows consistent responses when tumour angiogenesis is manipulated either positively or negatively. Our study adds to current understanding that not only do we need to target hormonal receptors, as presently practiced, but we also need to target endothelial receptors to successfully treat breast cancer.
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http://dx.doi.org/10.22034/APJCP.2017.18.12.3231DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5980876PMC
December 2017

Status epilepticus as the initial presentation of antibody-negative Goodpasture's syndrome.

BMJ Case Rep 2017 Aug 1;2017. Epub 2017 Aug 1.

Department of Pathology, University Sains Malaysia, Health Campus, Kubang Kerian, Malaysia.

Goodpasture's syndrome is a rare pulmonary-renal disease. It is characterised by presence of auto-antibodies directed against the glomerular basement membrane (GBM) antigen. These antibodies that bind to the GBM antigens cause rapidly progressive glomerulonephritis. The alveolar basement membrane also contains similar antigen, leading to pulmonary haemorrhage in active disease. We report a case of a young man who initially presented with status epilepticus and later was found to have rapidly progressive glomerulonephritis with pulmonary haemorrhage. Serum anti-GBM antibody was negative but the renal biopsy confirmed the diagnosis by showing typical linear IgG along the GBM on immunofluorescent study. He was treated with plasmapheresis and high-dose steroid in combination with oral cyclophosphamide. His renal function normalised after treatment.
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http://dx.doi.org/10.1136/bcr-2017-219628DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5612475PMC
August 2017

Tualang Honey Protects the Rat Midbrain and Lung against Repeated Paraquat Exposure.

Oxid Med Cell Longev 2017 3;2017:4605782. Epub 2017 Jan 3.

Department of Pharmacology, School of Medical Sciences, Health Campus, Universiti Sains Malaysia, Kubang Kerian, Kelantan, Malaysia.

Paraquat (PQ) is a dopaminergic neurotoxin and a well-known pneumotoxicant that exerts its toxic effect via oxidative stress-mediated cellular injuries. This study investigated the protective effects of Tualang honey against PQ-induced toxicity in the midbrain and lungs of rats. The rats were orally treated with distilled water (2 mL/kg/day), Tualang honey (1.0 g/kg/day), or ubiquinol (0.2 g/kg/day) throughout the experimental period. Two weeks after the respective treatments, the rats were injected intraperitoneally with saline (1 mL/kg/week) or PQ (10 mg/kg/week) once per week for four consecutive weeks. After four weekly exposures to PQ, the glutathione peroxidase activity and the number of tyrosine-hydroxylase immunopositive neurons in the midbrain were significantly decreased in animals from group PQ ( < 0.05). The lungs of animals from group PQ showed significantly decreased activity of superoxide dismutase and glutathione-S-transferase. Treatment with Tualang honey ameliorated the toxic effects observed in the midbrain and lungs. The beneficial effects of Tualang honey were comparable to those of ubiquinol, which was used as a positive control. These findings suggest that treatment with Tualang honey may protect against PQ-induced toxicity in the rat midbrain and lung.
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http://dx.doi.org/10.1155/2017/4605782DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5239975PMC
March 2017

Updates on Knowledge, Attitude and Preventive Practices on Tuberculosis among Healthcare Workers.

Malays J Med Sci 2016 Nov 7;23(6):25-34. Epub 2016 Dec 7.

Department of Pathology, National Institute of Medical Sciences and Nutrition "Salvador Zubiran", Avenida Vasco de Quiroga No. 15, Sección 16, Mexico, D.F. 14000.

Ranking as the most communicable disease killer worldwide, tuberculosis, has accounted with a total of 9.6 million new tuberculosis cases with 1.5 million tuberculosis-related deaths reported globally in 2014. Tuberculosis has remain as an occupational hazard for healthcare workers since 1920s and due to several tuberculosis outbreaks in healthcare settings in the early 1990s, the concern about the transmission to both patients and healthcare workers has been raised. Healthcare workers have two to three folds greater the risk of active tuberculosis than the general population. Several studies on knowledge, attitude and practices on tuberculosis among healthcare workers worldwide have revealed that majority of the participated healthcare workers had good knowledge on tuberculosis. Most of the healthcare workers from South India and South Africa also reported to have positive attitude whereas a study in Thailand reported that most of the healthcare providers have negative attitude towards tuberculosis patients. Nevertheless, majority of the healthcare workers have low level of practice on tuberculosis prevention. An improved communication between healthcare workers and the patients as well as their families is the key to better therapeutic outcomes with good knowledge, attitude and preventive practice towards tuberculosis.
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http://dx.doi.org/10.21315/mjms2016.23.6.3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5181989PMC
November 2016

Mouse model of intracerebellar haemorrhage.

Behav Brain Res 2016 10 17;312:374-84. Epub 2016 Jun 17.

Center for Neuroscience Services and Research(P3Neuro), Universiti Sains Malaysia, Jalan Hospital Universiti Sains Malaysia, 16150, Kubang Kerian, Kota Bharu, Kelantan,Malaysia; Department of Neurosciences, School of Medical Sciences, Universiti Sains Malaysia, Jalan Hospital Universiti Sains Malaysia, 16150, Kubang Kerian, Kota Bharu, Kelantan, Malaysia. Electronic address:

The present study aimed to investigate the behavior and neuronal morphological changes in the perihaemorrhagic tissue of the mouse intracerebellar haemorrhage experimental model. Adult male Swiss albino mice were stereotactically infused with collagenase type VII (0.4U/μl of saline) unilaterally in to the cerebellum, following anaesthesia. Motor deficits were assessed using open field and composite score for evaluating the mouse model of cerebellar ataxia at 1, 3, 7, 14 and 21 days after collagenase infusion. The animals were sacrificed at the same time interval for evaluation of perihaematomal neuronal degeneration using haematoxylin and eosin staining and Annexin V-FITC/Propidium iodide assay. At the end of the study, it was found that infusion of 0.4U collagenase produces significant locomotor and ataxic deficit in the mice especially within the first week post surgery, and that this gradually improved within three weeks. Neuronal degeneration evident by cytoplasmic shrinkage and nuclear pyknosis was observed at the perihaematomal area after one day; especially at 3 and 7 days post haemorrhage. By 21 days, both the haematoma and degenerating neurons in the perihaematomal area were phagocytosed and the remaining neuronal cells around the scar tissue appeared normal. Moreover, Annexin-V/propidium iodide-positive cells were observed at the perihaematomal area at 3 and 7 days implying that the neurons likely die via apoptosis. It was concluded that a population of potentially salvageable neurons exist in the perihaematomal area after cerebellar haemorrhage throughout a wide time window that could be amenable to treatment.
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http://dx.doi.org/10.1016/j.bbr.2016.06.034DOI Listing
October 2016

Neurogenic plasticity of mesenchymal stem cell, an alluring cellular replacement for traumatic brain injury.

Curr Stem Cell Res Ther 2016 ;11(2):149-57

Center for Neurosciences Services and Research, Universiti Sains Malaysia Hospital, Jalan Hospital Universiti Sains Malaysia, 16150 Kubang Kerian, Kelantan, Malaysia.

Traumatic brain injury (TBI) imposes horrendous neurophysiological alterations leading to most devastating forms of neuro-disability. Which includes impaired cognition, distorted locomotors activity and psychosomatic disability in both youths and adults. Emerging evidence from recent studies has identified mesenchymal stem cells (MSCs) as one of the promising category of stem cells having excellent neuroregenerative capability in TBI victims. Some of the clinical and animal studies reported that MSCs transplantation could cure neuronal damage as well as improve cognitive and locomotors behaviors in TBI. However, mechanism behind their broad spectrum neuroregenerative potential in TBI has not been reviewed yet. Therefore, in the present article, we present a comprehensive data on the important attributes of MSCs, such as neurotransdifferentiation, neuroprotection, axonal repair and plasticity, maintenance of blood-brain integrity, reduction of reactive oxygen species (ROS) and immunomodulation. We have reviewed in detail the crucial neurogenic capabilities of MSCs in vivo and provided consolidated knowledge regarding their cellular remodeling in TBI for future therapeutic implications.
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http://dx.doi.org/10.2174/1574888x10666151019120050DOI Listing
October 2016

MicroRNA expression profile of bone marrow mesenchymal stem cell-derived neural progenitor by microarray under the influence of EGF, bFGF and IGF-1.

Genom Data 2015 Sep 16;5:201-5. Epub 2015 Jun 16.

Department of Pathology, School of Medical Sciences, Universiti Sains Malaysia, Jalan Raja Perempuan Zainab II, 16150 Kubang Kerian, Kota Bharu, Kelantan, Malaysia.

Recently there has been growing interest in the differentiation of mesenchymal stem cells (MSCs) into neural lineages. Research suggests that MSCs can be differentiated into neural progenitor-like cells (NPCs) under the specific influence of paracrine factors particularly epidermal growth factor (EGF) and basic fibroblast growth factor (bFGF). Our recent research has found that the addition of insulin-like growth factor 1 (IGF-1) with the combination of the EGF and bFGF could significantly improve the growth and survivability of MSC-derived NPCs. To unravel the molecular mechanism of the improved differentiation we compared the microRNA expression profiles of the differentiation under various combinations of growth factors. MSCs were differentiated into neural lineage in 3 groups; Group A (EGF + bFGF), Group B (EGF + bFGF + IGF-1), and Group C (without growth factor). Regulated microRNAs during the early differentiation were identified by detailed microRNA profiling using Affymetrix GeneChip version 2.0 at three time intervals (day 1, day 3 and day 5). The data were deposited in the Gene Expression Omnibus, series GSE60060.
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http://dx.doi.org/10.1016/j.gdata.2015.06.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4583674PMC
September 2015

Overexpression of DNA methyltransferase 1 (DNMT1) protein in astrocytic tumour and its correlation with O6-methylguanine-DNA methyltransferase (MGMT) expression.

Int J Clin Exp Pathol 2015 1;8(6):6095-106. Epub 2015 Jun 1.

Department of Pathology, School of Medical Sciences, Universiti Sains Malaysia, Health Campus Kota Bharu 16150, Kelantan, Malaysia.

Background: The relationship between DNA methyltransferase (DNMT) and O6-methylguanine-DNA methyltransferase (MGMT) in mediating tumorigenesis is still poorly understood. This study was carried out to investigate a correlation between DNMT1 and MGMT immunoexpression in astrocytic tumour samples.

Methods: Formalin-fixed paraffin embedded tissues of astrocytic tumour patients was obtained from an observational study conducted in Hospital Universiti Sains Malaysia (USM), which was performed from January 1997 until May 2012. Patient's histological information was retrieved from the accessible Pathology Registry. Immunohistochemistry (IHC) staining was performed to assess DNMT1 and MGMT expressions in patients' tumours.

Results: Our data showed that DNMT1 was highly expressed in high grade astrocytic tumours. A multiple regression analysis demonstrated a significant association of DNMT1 overexpression with tumour grade III and IV (GIII: OR=5.802; 95% CI: 1.059, 31.785; p value=0.043; GIV: OR=40.663; 95% CI=4.069, 406.347; p value=0.002). The MGMT protein was downregulated in tumours with higher grade as evident by a reduction mean H-score for MGMT expression from GI to GIV [28.36 ± 43.88, 28.08 ± 33.67, 26.00 ± 48.70 and 16.20 ± 35.61]. However, a good negative correlation was observed between DNMT1 and MGMT in high grade tumour [Spearman correlation test: r=-0.561, p value ≤ 0.001 in percentage expression and r=-0.576, p value ≤ 0.001 in H score].

Conclusion: DNMT1 overexpression was seen correlated with a reduction of MGMT protein expression in high grade astrocytic tumour. Understanding the role of these markers could be important to overcome astrocytic tumour aggresiveness.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4525821PMC
May 2016

Subchronic toxicity study of standardized methanolic extract of Mitragyna speciosa Korth in Sprague-Dawley Rats.

Front Neurosci 2015 17;9:189. Epub 2015 Jun 17.

Department of Neurosciences, School of Medical Sciences, Universiti Sains Malaysia Kota Bharu, Malaysia ; Centre for Neuroscience Services and Research, Universiti Sains Malaysia, Jalan Hospital Universiti Sains Malaysia Kota Bharu, Malaysia ; Hospital Universiti Sains Malaysia, Jalan Hospital Universiti Sains Malaysia Kota Bharu, Malaysia.

Mitragyna speciosa Korth, or better known as ketum, has long been used by traditional folk around Southeast Asia to prevent fatigue from working under hot tropical weather and as a replacement of opium, which can then cause addiction. To date, no findings have been reported of the toxic effect of ketum subchronically (28 days). Hence, the aim of this study was to investigate the toxicity of subchronic effect of standardized methanolic extract of ketum (SMEMS) in Sprague-Dawley rats. Rats were orally administered with 100, 200, and 500 mg/kg of SMEMS for 28 days. Body weights were recorded daily. They were terminated at day 28 to obtain data for hematology, biochemistry, and histopathology of the brain, liver, kidney, lung, heart, sciatic nerve, and spinal cord. The SMEMS affected body weight compared to control group. Biochemistry findings showed that liver and kidney were affected with the abnormal values in AST, creatinine, globulin, glucose, total protein, and urea. However, SMEMS produced toxic effect more to liver, kidney, and lung than other organs as observed histopathologically. The results suggested subchronic exposure of ketum is toxic to the physiology of the animals.
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http://dx.doi.org/10.3389/fnins.2015.00189DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4470260PMC
July 2015

MicroRNA Expression Profile of Neural Progenitor-Like Cells Derived from Rat Bone Marrow Mesenchymal Stem Cells under the Influence of IGF-1, bFGF and EGF.

Int J Mol Sci 2015 Apr 29;16(5):9693-718. Epub 2015 Apr 29.

Department of Pathology, School of Medical Sciences, Universiti Sains Malaysia, Jalan Raja Perempuan Zainab II, 16150 Kubang Kerian, Kota Bharu, Kelantan, Malaysia.

Insulin-like growth factor 1 (IGF-1) enhances cellular proliferation and reduces apoptosis during the early differentiation of bone marrow derived mesenchymal stem cells (BMSCs) into neural progenitor-like cells (NPCs) in the presence of epidermal growth factor (EGF) and basic fibroblast growth factor (bFGF). BMSCs were differentiated in three groups of growth factors: (A) EGF + bFGF, (B) EGF + bFGF + IGF-1, and (C) without growth factor. To unravel the molecular mechanisms of the NPCs derivation, microarray analysis using GeneChip miRNA arrays was performed. The profiles were compared among the groups. Annotated microRNA fingerprints (GSE60060) delineated 46 microRNAs temporally up-regulated or down-regulated compared to group C. The expressions of selected microRNAs were validated by real-time PCR. Among the 46 microRNAs, 30 were consistently expressed for minimum of two consecutive time intervals. In Group B, only miR-496 was up-regulated and 12 microRNAs, including the let-7 family, miR-1224, miR-125a-3p, miR-214, miR-22, miR-320, miR-708, and miR-93, were down-regulated. Bioinformatics analysis reveals that some of these microRNAs (miR-22, miR-214, miR-125a-3p, miR-320 and let-7 family) are associated with reduction of apoptosis. Here, we summarize the roles of key microRNAs associated with IGF-1 in the differentiation of BMSCs into NPCs. These findings may provide clues to further our understanding of the mechanisms and roles of microRNAs as key regulators of BMSC-derived NPC maintenance.
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http://dx.doi.org/10.3390/ijms16059693DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4463612PMC
April 2015

Prognostic factors and survival rate of osteosarcoma: A single-institution study.

Asia Pac J Clin Oncol 2017 Apr 13;13(2):e104-e110. Epub 2015 Apr 13.

Department of Orthopaedics, Universiti Sains Malaysia, Kubang Kerian, Kelantan, Malaysia.

Aim: Osteosarcoma is a highly malignant primary bone tumor. The study aim to evaluate the prognostic factors influencing the survival rate in our center.

Methods: This was a retrospective cohort study of all patients treated between January 2005 and December 2010.

Results: We included 163 patients with an age range of 6-59 years (median = 19). The median follow-up was 47 months (range 36-84). The overall survival in patients who completed chemotherapy and surgery (n = 117) was 72% at 2 years and 44% at 5 years. Histologically, 99 (85%) had osteoblastic, 6 (5%) had chondroblastic and 3 (2.5%) had telangiectatic osteosarcoma. Limb salvage surgery was performed in 80 (49%) and 41 (25%) underwent amputation. However, 46 patients (28%) underwent no surgical intervention and incomplete chemotherapy. In total, 38/79 patients had a good chemotherapy response. There was a significantly better survival rate for limb salvage versus amputation. Independent prognostic factors for survival are compliance to treatment and presence of lung metastasis.

Conclusion: The overall survival of osteosarcoma patients was influenced by the presence of pulmonary metastases and compliance to treatment. Histological subtype, different chemotherapy regimens and histological necrosis after chemotherapy did not significantly influence survival. The patients who did not complete treatment had significantly poorer survival.
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http://dx.doi.org/10.1111/ajco.12346DOI Listing
April 2017

Effects of rapamycin on cell apoptosis in MCF-7 human breast cancer cells.

Asian Pac J Cancer Prev 2014 ;15(24):10659-63

Department of Pathology, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian, Malaysia E-mail :

Background: Rapamycin is an effective anti-angiogenic drug. However, the mode of its action remains unclear. Therefore, in this study, we aimed to elucidate the antitumor mechanism of rapamycin, hypothetically via apoptotic promotion, using MCF-7 breast cancer cells.

Materials And Methods: MCF-7 cells were plated at a density of 15105 cells/well in 6-well plates. After 24h, cells were treated with a series of concentrations of rapamycin while only adding DMEM medium with PEG for the control regiment and grown at 37oC, 5% CO2 and 95% air for 72h. Trypan blue was used to determine the cell viability and proliferation. Untreated and rapamycin-treated MCF-7 cells were also examined for morphological changes with an inverted-phase contrast microscope. Alteration in cell morphology was ascertained, along with a stage in the cell cycle and proliferation. In addition, cytotoxicity testing was performed using normal mouse breast mammary pads.

Results: Our results clearly showed that rapamycin exhibited inhibitory activity on MCF-7 cell lines. The IC50 value of rapamycin on the MCF-7 cells was determined as 0.4μg/ml (p<0.05). Direct observation by inverted microscopy demonstrated that the MCF-7 cells treated with rapamycin showed characteristic features of apoptosis including cell shrinkage, vascularization and autophagy. Cells underwent early apoptosis up to 24% after 72h. Analysis of the cell cycle showed an increase in the G0G1 phase cell population and a corresponding decrease in the S and G2M phase populations, from 81.5% to 91.3% and 17.3% to 7.9%, respectively.

Conclusions: This study demonstrated that rapamycin may potentially act as an anti-cancer agent via the inhibition of growth with some morphological changes of the MCF-7 cancer cells, arrest cell cycle progression at G0/G1 phase and induction of apoptosis in late stage of apoptosis. Further studies are needed to further characterize the mode of action of rapamycin as an anti-cancer agent.
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http://dx.doi.org/10.7314/apjcp.2014.15.24.10659DOI Listing
October 2015

Comparison on the Effects and Safety of Tualang Honey and Tribestan in Sperm Parameters, Erectile Function, and Hormonal Profiles among Oligospermic Males.

Evid Based Complement Alternat Med 2014 19;2014:126138. Epub 2014 Nov 19.

Hospital Raja Perempuan Zainab II, 15200 Kota Bharu, Kelantan, Malaysia.

Introduction. This study aims to evaluate the effectiveness of Tualang honey on sperm parameters, erectile function, and hormonal and safety profiles. Methodology. A randomized control trial was done using Tualang honey (20 grams) and Tribestan (750 mg) over a period of 12 weeks. Sperm parameters including sperm concentration, motility, and morphology were analyzed and erectile function was assessed using IIEF-5 questionnaire. Hormonal profiles of testosterone, FSH, and LH were studied. The volunteers were randomized into two groups and the outcomes were analyzed using SPSS version 18. Results. A total of 66 participants were involved. A significant increment of mean sperm concentration (P < 0.001), motility (P = 0.015) and morphology (P = 0.008) was seen in Tualang honey group. In Tribestan group, a significant increment of mean sperm concentration (P = 0.007), and morphology (P = 0.009) was seen. No significant differences of sperm concentration, motility, and morphology were seen between Tualang honey and Tribestan group and similar results were also seen in erectile function and hormonal profile. All safety profiles were normal and no adverse event was reported. Conclusion. Tualang honey effect among oligospermic males was comparable with Tribestan in improving sperm concentration, motility, and morphology. The usage of Tualang honey was also safe with no reported adverse event.
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http://dx.doi.org/10.1155/2014/126138DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4253697PMC
December 2014

Pattern of collagen fibers and localization of matrix metalloproteinase 2 and 9 during breast cancer invasion.

Tumori 2014 Sep-Oct;100(5):e204-11

Aims And Background: Parenchymal cells naturally interact, react and adapt with the environment including stromal components around them in order to maintain tissue architecture and function. However, studies have shown that this spontaneous interaction will become crucial in assisting cancer invasion. The purpose of the study was to analyze the pattern of collagen deposition and localization of matrix metalloproteinase 2 and matrix metalloproteinase 9 in the tumor microenvironment during breast cancer invasion.

Methods And Study Design: A standard transmission electron microscopy procedure was used together with the immunogold technique with a few modifications.

Results: The ultrastructure of fibroblasts in the vicinity of cancer cells was thick, elongated and spindle shaped with nuclear indentations. Desmoplasia was present near the cancer cells. Collagen fibers were still arranged parallel to the cancer cells and fibroblasts but were less dense than collagen fibers far from cancer cells and fibroblasts. Collagen fibers were less dense in the pericellular region because of proteolytic enzyme activity, which facilitates the invasion of breast cancer cells. In immunogold localization analysis, matrix metalloproteinase 9 had consistent localization throughout cancer cells, fibroblast and stroma. In matrix metalloproteinase 2 localization, gold conjugates were more heavily deposited in cancer cells and fibroblasts than in the stroma.

Conclusions: Invasive breast carcinoma is not an independent entity, and its survival depends on the surrounding microenvironment.
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http://dx.doi.org/10.1700/1660.18194DOI Listing
December 2014

Expression of DNA methylation marker of paired-like homeodomain transcription factor 2 and growth receptors in invasive ductal carcinoma of the breast.

Asian Pac J Cancer Prev 2014 ;15(19):8441-5

Department of Pathology, School of Medical Sciences, Universiti Sains Malaysia, Health Campus, Kelantan, Malaysia E-mail :

Background: Paired-like homeodomain transcription factor 2 (PITX2) is another new marker in breast carcinoma since hypermethylation at P2 promoter of this gene was noted to be associated with poor prognosis. We investigated the expression of PITX2 protein using immunohistochemistry in invasive ductal carcinoma and its association with the established growth receptors such as estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth receptor 2 (HER2).

Methods: We conducted a cross sectional study using 100 samples of archived formalin-fixed paraffin embedded tissue blocks of invasive ductal carcinoma and stained them with immunohistochemistry for PITX2, ER, PR and HER2. All HER2 with scoring of 2+ were confirmed with chromogenic in-situ hybridization (CISH).

Results: PITX2 protein was expressed in 53% of invasive ductal carcinoma and lack of PITX2 expression in 47%. Univariate analysis revealed a significant association between PITX2 expression with PR (p=0.001), ER (p=0.006), gland formation (p=0.044) and marginal association with molecular subtypes of breast carcinoma (p=0.051). Combined ER and PR expression with PITX2 was also significantly associated (p=0.003) especially in double positive cases. Multivariate analysis showed the most significant association between PITX2 and PR (RR 4.105, 95% CI 1.765-9.547, p=0.001).

Conclusion: PITX2 is another potential prognostic marker in breast carcinoma adding significant information to established prognostic factors of ER and PR. The expression of PITX2 together with PR may carry a very good prognosis.
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http://dx.doi.org/10.7314/apjcp.2014.15.19.8441DOI Listing
June 2015

MicroRNA profiling reveals unique miRNA signatures in IGF-1 treated embryonic striatal stem cell fate decisions in striatal neurogenesis in vitro.

Biomed Res Int 2014 1;2014:503162. Epub 2014 Sep 1.

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

The striatum is considered to be the central processing unit of the basal ganglia in locomotor activity and cognitive function of the brain. IGF-1 could act as a control switch for the long-term proliferation and survival of EGF+bFGF-responsive cultured embryonic striatal stem cell (ESSC), while LIF imposes a negative impact on cell proliferation. The IGF-1-treated ESSCs also showed elevated hTERT expression with demonstration of self-renewal and trilineage commitment (astrocytes, oligodendrocytes, and neurons). In order to decipher the underlying regulatory microRNA (miRNA)s in IGF-1/LIF-treated ESSC-derived neurogenesis, we performed in-depth miRNA profiling at 12 days in vitro and analyzed the candidates using the Partek Genome Suite software. The annotated miRNA fingerprints delineated the differential expressions of miR-143, miR-433, and miR-503 specific to IGF-1 treatment. Similarly, the LIF-treated ESSCs demonstrated specific expression of miR-326, miR-181, and miR-22, as they were nonsignificant in IGF-treated ESSCs. To elucidate the possible downstream pathways, we performed in silico mapping of the said miRNAs into ingenuity pathway analysis. Our findings revealed the important mRNA targets of the miRNAs and suggested specific interactomes. The above studies introduced a new genre of miRNAs for ESSC-based neuroregenerative therapeutic applications.
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http://dx.doi.org/10.1155/2014/503162DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4165568PMC
June 2015

Normobaric hyperoxia treatment prevents early alteration in dopamine level in mice striatum after fluid percussion injury: a biochemical approach.

Int J Neurosci 2015 2;125(9):686-92. Epub 2014 Oct 2.

1Center for Neuroscience Services and Research(P3Neuro), Universiti Sains Malaysia, Jalan Hospital Universiti Sains Malaysia, Kubang Kerian, Kota Bharu, Kelantan, Malaysia.

Dopamine (DA) is one of the key neurotransmitters in the striatum, which is functionally important for a variety of cognitive and motor behaviours. It is known that the striatum is vulnerable to damage from traumatic brain injury (TBI). However, a therapeutic approach has not yet been established to treat TBI. Hence, the present work aimed to evaluate the ability of Normobaric hyperoxia treatment (NBOT) to recover dopaminergic neurons following a fluid percussion injury (FPI) as a TBI experimental animal model. To examine this, mice were divided into four groups: (i) Control, (ii) Sham, (iii) FPI and (iv) FPI+NBOT. Mice were anesthetized and surgically prepared for FPI in the striatum and immediate exposure to NBOT at various time points (3, 6, 12 and 24 h). Dopamine levels were then estimated post injury by utilizing a commercially available ELISA method specific to DA. We found that DA levels were significantly reduced at 3 h, but there was no reduction at 6, 12 and 24 h in FPI groups when compared to the control and sham groups. Subjects receiving NBOT showed consistent increased DA levels at each time point when compared with Sham and FPI groups. These results suggest that FPI may alter DA levels at the early post-TBI stages but not in later stages. While DA levels increased in 6, 12 and 24 h in the FPI groups, NBOT could be used to accelerate the prevention of early dopaminergic neuronal damage following FPI injury and improve DA levels consistently.
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http://dx.doi.org/10.3109/00207454.2014.961065DOI Listing
May 2016

Relationship of angiogenic and apoptotic activities in soft-tissue sarcoma.

South Asian J Cancer 2014 Jul;3(3):171-4

Department of Pathology, Hospital Umum Sarawak, Jalan Hospital, 93586 Kuching, Sarawak, Malaysia.

Introduction: Angiogenesis and apoptosis play an essential role in tumor development and progression. Previous studies on apoptosis and angiogenesis of soft-tissue sarcoma (STS) were done separately. This is the first study of the relationship between apoptotic and angiogenic activity. Correlation of expression of anti-apoptotic protein (Bcl-2) and pro-apoptotic protein (Bax) in the tumor cells (TCs) with their expression in endothelial cell (EC) of the tumor blood vessels in STS were also carried out.

Materials And Methods: 101 cases of STS; consisting liposarcoma, malignant fibrous histiocytoma, synovial sarcoma, fibrosarcoma, leiomyosarcoma, rhabdomyosarcoma and malignant peripheral nerve sheath tumor; were collected and immunohistochemical reaction of vascular endothelial growth factor (VEGF), Bcl-2 and Bax were examined.

Results: Higher Bax expression in TCs (54.5%) was seen compared to Bcl-2 expression (44.6%). There was a significant association between Bcl-2 and Bax in TCs with ECs. Significant association was also seen between histological types of STS with Bcl-2 expression; however not with Bax expression. There was an association between VEGF and Bax with high VEGF expression and weak Bax expression. However, VEGF expression was not associated with Bcl-2 expression and histological types.

Conclusion: This study supports the role of ECs of tumor blood vessels and apoptosis of TCs in tumor management. Increased angiogenesis may inhibit apoptosis of TCs and lead to tumor growth. Therefore, inhibition of ECs survival or activation of ECs death is promising prospect for tumor therapy. Immunohistochemical antibodies in this study might be potential useful marker for the prognosis of STS.
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http://dx.doi.org/10.4103/2278-330X.136799DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4134609PMC
July 2014

IGF-1 enhances cell proliferation and survival during early differentiation of mesenchymal stem cells to neural progenitor-like cells.

BMC Neurosci 2014 Jul 22;15:91. Epub 2014 Jul 22.

Department of Pathology, School of Medical Sciences, Universiti Sains Malaysia, Jalan Hospital Universiti Sains Malaysia, 16150 Kubang Kerian, Kota Bharu, Kelantan, Malaysia.

Background: There has been increasing interest recently in the plasticity of mesenchymal stem cells (MSCs) and their potential to differentiate into neural lineages. To unravel the roles and effects of different growth factors in the differentiation of MSCs into neural lineages, we have differentiated MSCs into neural lineages using different combinations of growth factors. Based on previous studies of the roles of insulin-like growth factor 1 (IGF-1) in neural stem cell isolation in the laboratory, we hypothesized that IGF-1 can enhance proliferation and reduce apoptosis in neural progenitor-like cells (NPCs) during differentiation of MSCs into NCPs.We induced MSCs differentiation under four different combinations of growth factors: (A) EGF + bFGF, (B) EGF + bFGF + IGF-1, (C) EGF + bFGF + LIF, (D) EGF + bFGF + BDNF, and (E) without growth factors, as a negative control. The neurospheres formed were characterized by immunofluorescence staining against nestin, and the expression was measured by flow cytometry. Cell proliferation and apoptosis were also studied by MTS and Annexin V assay, respectively, at three different time intervals (24 hr, 3 days, and 5 days). The neurospheres formed in the four groups were then terminally differentiated into neuron and glial cells.

Results: The four derived NPCs showed a significantly higher expression of nestin than was shown by the negative control. Among the groups treated with growth factors, NPCs treated with IGF-1 showed the highest expression of nestin. Furthermore, NPCs derived using IGF-1 exhibited the highest cell proliferation and cell survival among the treated groups. The NPCs derived from IGF-1 treatment also resulted in a better yield after the terminal differentiation into neurons and glial cells than that of the other treated groups.

Conclusions: Our results suggested that IGF-1 has a crucial role in the differentiation of MSCs into neuronal lineage by enhancing the proliferation and reducing the apoptosis in the NPCs. This information will be beneficial in the long run for improving both cell-based and cell-free therapy for neurodegenerative diseases.
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http://dx.doi.org/10.1186/1471-2202-15-91DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4117972PMC
July 2014

Rapamycin and PF4 induce apoptosis by upregulating Bax and down-regulating survivin in MNU-induced breast cancer.

Asian Pac J Cancer Prev 2014 ;15(9):3939-44

Department of Pathology, School of Medical Sciences, Universiti Sains Malaysia, Kelantan, Malaysia E-mail :

Background: To elucidate the role of rapamycin and PF4 on apoptosis regulation via Bax (pro-apoptosis), Bcl-2 (anti-apoptosis) and survivin activation on the growth in the 1-methyl-1-nitrosourea -induced invasive breast carcinoma model.

Materials And Methods: Thirty five female Sprague Dawley rats at age 21-day old were divided into 4 groups; Group 1 (control, n=10), Group 2 (PF4, n=5), Group 3 (rapamycin, n=10) and Group 4 (rapamycin+PF4, n=10). MNU was administered intraperitionally, dosed at 70 mg/kg body weight. The rats were treated when the tumors reached the size of 14.5 ± 0.5 mm and subsequently sacrificed after 5 days. Rapamycin and PF4 were administered as focal intralesional injections at the dose of 20 μg/lesion. The tumor tissue was then subjected to histopathological examinations for morphological appraisal and immunohistochemical assessment of the pro-apoptotic marker, Bax and anti-apoptotic markers, Bcl-2 and survivin.

Results: The histopathological pattern of the untreated control cohort showed that the severity of the malignancy augments with mammary tumor growth. Tumors developing in untreated groups were more aggressive whilst those in treated groups demonstrated a transformation to a less aggressive subtype. Combined treatment resulted in a significant reduction of tumor size without phenotypic changes. Bax, the pro-apoptotic marker, was significantly expressed at higher levels in the rapamycin-treated and rapamycin+PF4-treated groups compared to controls (p<0.05). Consequently, survivin was also significantly downregulated in the rapamycin-treated and rapamycin+PF4-treated group and this was significantly different when compared to controls (p).

Conclusions: In our rat model, it could be clearly shown that rapamycin specifically affects Bax and survivin signaling pathways in activation of apoptosis. We conclude that rapamycin plays a critical role in the induction of apoptosis in MNU-induced mammary carcinoma.
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http://dx.doi.org/10.7314/apjcp.2014.15.9.3939DOI Listing
March 2016