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Fulltext Tocotrienol-Rich Fraction of Palm Oil Improves Behavioral Impairments and Regulates Metabolic Pathways in AβPP/PS1 Mice

Durani LW, Hamezah HS, Ibrahim NF, Yanagisawa D, Nasaruddin ML, Mori M, et al.

J Alzheimers Dis, 2018;64(1):249-267.
PMID: 29889072 DOI: 10.3233/JAD-170880

We have recently shown that the tocotrienol-rich fraction (TRF) of palm oil, a mixture of vitamin E analogs, improves amyloid pathology in vitro and in vivo. However, precise mechanisms remain unknown. In this study, we examined the effects of long-term (10 months) TRF treatment on behavioral impairments and brain metabolites in (15 months old) AβPP/PS1 double transgenic (Tg) Alzheimer's disease (AD) mice. The open field test, Morris water maze, and novel object recognition tasks revealed improved exploratory activity, spatial learning, and recognition memory, respectively, in TRF-treated Tg mice. Brain metabolite profiling of wild-type and Tg mice treated with and without TRF was performed using ultrahigh performance liquid chromatography (UHPLC) coupled to high-resolution accurate mass (HRAM)-orbitrap tandem mass spectrometry (MS/MS). Metabolic pathway analysis found perturbed metabolic pathways that linked to AD. TRF treatment partly ameliorated metabolic perturbations in Tg mouse hippocampus. The mechanism of this pre-emptive activity may occur via modulation of metabolic pathways dependent on Aβ interaction or independent of Aβ interaction.
Behavioral Assessment and Blood Oxidative Status of Aging Sprague Dawley Rats through a Longitudinal Analysis

Achin NA, Kit TJ, Ngah WZW, Makpol S, Mazlan M, Hamezah HS, et al.

Curr Aging Sci, 2018;11(3):182-194.
PMID: 30338748 DOI: 10.2174/1874609811666181019141217

BACKGROUND: Cognitive frailty emerges as one of the threats to healthy aging. It is in continuum with advancing of age with uncertain indicator between pathological and physiological changes. Alterations in pathways associated with the aging process have been observed including oxidative stress, lipid metabolism, and inflammation. However, the exact mechanisms leading to cognitive decline are still unclear.
OBJECTIVE: This study was sought to assess the level of cognitive functions and linked with blood oxidative status during normal aging in rats.
METHODS: A longitudinal study using male Sprague Dawley rats was performed starting from the age of 14 months old to 27 months old. Cognitive functions tests such as open field, Morris water maze and object recognition were determined at the age of 14, 18, 23, and 27 months old and were compared with group 3 months old. Blood was collected from the orbital venous sinus and oxidative status was determined by measuring the level of DNA damage, lipid peroxidation, protein oxidation and antioxidant enzymes activity.
RESULTS: Aged rats showed declining exploratory behavior and increased in the level of anxiety as compared to the young rats. The level of DNA damage increased with increasing age. Interestingly, our study found that both levels of malondialdehyde and plasma carbonyl content decreased with age. In addition, the level of superoxide dismutase activity was significantly decreased with age whereas catalase activity was significantly increased from 18 months of age. However, no significant difference was found in glutathione peroxidase activity among all age groups.
CONCLUSION: The progressions of cognitive impairment in normal aging rats are linked to the increment in the level of DNA damage.
Fulltext Targeting myomiRs by tocotrienol-rich fraction to promote myoblast differentiation

Razak AM, Khor SC, Jaafar F, Karim NA, Makpol S

Genes Nutr, 2018;13:31.
PMID: 30519366 DOI: 10.1186/s12263-018-0618-2

Background: Several muscle-specific microRNAs (myomiRs) are differentially expressed during cellular senescence. However, the role of dietary compounds on myomiRs remains elusive. This study aimed to elucidate the modulatory role of tocotrienol-rich fraction (TRF) on myomiRs and myogenic genes during differentiation of human myoblasts. Young and senescent human skeletal muscle myoblasts (HSMM) were treated with 50 μg/mL TRF for 24 h before and after inducing differentiation.
Results: The fusion index and myotube surface area were higher (p
A Review on Dietary Intervention in Obesity Associated Colon Cancer

Roslan NH, Makpol S, Mohd Yusof YA

Asian Pac J Cancer Prev, 2019 May 25;20(5):1309-1319.
PMID: 31127882

Background: Colorectal cancer (CRC) is one of the major causes of morbidity and mortality. According to National Cancer Registry, the incidence of colorectal cancer in Peninsular Malaysia increases with age. The incidence is highest among Chinese population but lower among Indians and Malays. Many reviews have suggested that obesity may be associated with a higher risk (>50%) of colorectal cancer. Methods: This study collects a comprehensive data from the literature review available from respective journals on dietary intervention and the chemo-protective mechanisms of a few natural resources in obesity -associated colon cancer based on previous and current studies. Results: In obesity-associated colon cancer, the genes of interest and pathways that are mainly involved include NFκB, P13K/Akt, and MAPK pathways, and FTO, leptin, Cyclin D, MMPs, and STAT3 genes. Dietary modification is one of the alternative steps in early prevention of colon cancer. It has been proposed that the components present in certain foods may have the ability to protect against many diseases including the prevention of cancer. Conclusion: There are many factors that lead to obesity-associated colon cancer and the mechanisms behind it is still undergoing intensive research. This review aims to scrutinize research as well as reviews that have been previously reported on obesity associated colorectal cancer and the beneficial effects of including antioxidants-rich foods such as vegetables and fruits in the diet to reduce the risk of obesity associated colorectal cancer.
Suppression of colorectal cancer cell growth by combined treatment of 6-gingerol and γ-tocotrienol via alteration of multiple signalling pathways

Yusof KM, Makpol S, Fen LS, Jamal R, Wan Ngah WZ

J Nat Med, 2019 Sep;73(4):745-760.
PMID: 31177355 DOI: 10.1007/s11418-019-01323-6

Our previous study reported that combined treatment of γ-tocotrienol with 6-gingerol showed promising anticancer effects by synergistically inhibiting proliferation of human colorectal cancer cell lines. This study aimed to identify and elucidate molecular mechanisms involved in the suppression of SW837 colorectal cancer cells modulated by combined treatment of γ-tocotrienol and 6-gingerol. Total RNA from both untreated and treated cells was prepared for transcriptome analysis using RNA sequencing techniques. We performed high-throughput sequencing at approximately 30-60 million coverage on both untreated and 6G + γT3-treated cells. The results showed that cancer-specific differential gene expression occurred and functional enrichment pathway analysis suggested that more than one pathway was modulated in 6G + γT3-treated cells. Combined treatment with 6G + γT3 augmented its chemotherapeutic effect by interfering with the cell cycle process, downregulating the Wnt signalling pathway and inducing apoptosis mainly through caspase-independent programmed cell death through mitochondrial dysfunction, activation of ER-UPR, disruption of DNA repair mechanisms and inactivation of the cell cycle process through the downregulation of main genes in proliferation such as FOXM1 and its downstream genes. The combined treatment exerted its cytotoxic effect through upregulation of genes in stress response activation and cytostatic effects demonstrated by downregulation of main regulator genes in the cell cycle. Selected genes involved in particular pathways including ATF6, DDIT3, GADD34, FOXM1, CDK1 and p21 displayed concordant patterns of gene expression between RNA sequencing and RT-qPCR. This study provides new insights into combined treatment with bioactive compounds not only in terms of its pleiotropic effects that enhance multiple pathways but also specific target genes that could be exploited for therapeutic purposes, especially in suppressing cancer cell growth.
Fulltext Effect of Age on the Protein Profile of Healthy Malay Adults and its Association with Cognitive Function Competency

Abu Bakar ZH, Damanhuri HA, Makpol S, Wan Kamaruddin WMA, Abdul Sani NF, Amir Hamzah AIZ, et al.

J Alzheimers Dis, 2019;70(s1):S43-S62.
PMID: 30594926 DOI: 10.3233/JAD-180511

BACKGROUND: Many studies on biochemical and psychological variables have aimed to elucidate the association between aging and cognitive function. Demographic differences and protein expression have been reported to play a role in determining the cognitive capability of a population.
OBJECTIVE: This study aimed to determine the effect of age on the protein profile of Malay individuals and its association with cognitive competency.
METHODS: A total of 160 individuals were recruited and grouped accordingly. Cognitive competency of each subject was assessed with several neuropsychological tests. Plasma samples were collected and analyzed with Q Exactive HF Orbitrap. Proteins were identified and quantitated with MaxQuant and further analyzed with Perseus to determine differentially expressed proteins. PANTHER, Reactome, and STRING were applied for bioinformatics output.
RESULTS: Our data showed that the Malay individuals are vulnerable to the deterioration of cognitive function with aging, and most of the proteins were differentially expressed in concordance. Several physiological components and pathways were shown to be involved, giving a hint of a promising interpretation on the induction of aging toward the state of the Malays' cognitive function. Nevertheless, some proteins have shown a considerable interaction with the generated protein network, which provides a direction of focus for further investigation.
CONCLUSION: This study demonstrated notable changes in the expression of several proteins as age increased. These changes provide a promising platform for understanding the biochemical factors affecting cognitive function in the Malay population. The exhibited network of protein-protein interaction suggests the possibility of implementing regulatory intervention in ameliorating Malay cognitive function.
Fulltext Tocotrienol Rich Fraction Supplementation Modulate Brain Hippocampal Gene Expression in APPswe/PS1dE9 Alzheimer's Disease Mouse Model

Wan Nasri WN, Makpol S, Mazlan M, Tooyama I, Wan Ngah WZ, Damanhuri HA

J Alzheimers Dis, 2019;70(s1):S239-S254.
PMID: 30507571 DOI: 10.3233/JAD-180496

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by loss of memory and other cognitive abilities. AD is associated with aggregation of amyloid-β (Aβ) deposited in the hippocampal brain region. Our previous work has shown that tocotrienol rich fraction (TRF) supplementation was able to attenuate the blood oxidative status, improve behavior, and reduce fibrillary-type Aβ deposition in the hippocampus of an AD mouse model. In the present study, we investigate the effect of 6 months of TRF supplementation on transcriptome profile in the hippocampus of APPswe/PS1dE9 double transgenic mice. TRF supplementation can alleviate AD conditions by modulating several important genes in AD. Moreover, TRF supplementation attenuated the affected biological process and pathways that were upregulated in the AD mouse model. Our findings indicate that TRF supplementation can modulate hippocampal gene expression as well as biological processes that can potentially delay the progression of AD.
Fulltext Modulation of Proteome Profile in AβPP/PS1 Mice Hippocampus, Medial Prefrontal Cortex, and Striatum by Palm Oil Derived Tocotrienol-Rich Fraction

Hamezah HS, Durani LW, Yanagisawa D, Ibrahim NF, Aizat WM, Makpol S, et al.

J Alzheimers Dis, 2019;72(1):229-246.
PMID: 31594216 DOI: 10.3233/JAD-181171

Tocotrienol-rich fraction (TRF) is a mixture of vitamin E analogs derived from palm oil. We previously demonstrated that supplementation with TRF improved cognitive function and modulated amyloid pathology in AβPP/PS1 mice brains. The current study was designed to examine proteomic profiles underlying the therapeutic effect of TRF in the brain. Proteomic analyses were performed on samples of hippocampus, medial prefrontal cortex (mPFC), and striatum using liquid chromatography coupled to Q Exactive HF Orbitrap mass spectrometry. From these analyses, we profiled a total of 5,847 proteins of which 155 proteins were differentially expressed between AβPP/PS1 and wild-type mice. TRF supplementation of these mice altered the expression of 255 proteins in the hippocampus, mPFC, and striatum. TRF also negatively modulated the expression of amyloid beta A4 protein and receptor-type tyrosine-protein phosphatase alpha protein in the hippocampus. The expression of proteins in metabolic pathways, oxidative phosphorylation, and those involved in Alzheimer's disease were altered in the brains of AβPP/PS1 mice that received TRF supplementation.
Fulltext Chlorella vulgaris Improves the Regenerative Capacity of Young and Senescent Myoblasts and Promotes Muscle Regeneration

Zainul Azlan N, Mohd Yusof YA, Alias E, Makpol S

Oxid Med Cell Longev, 2019;2019:3520789.
PMID: 31281573 DOI: 10.1155/2019/3520789

Sarcopenia is characterized by the loss of muscle mass, strength, and function with ageing. With increasing life expectancy, greater attention has been given to counteracting the effects of sarcopenia on the growing elderly population. Chlorella vulgaris, a microscopic, unicellular, green alga with the potential for various pharmaceutical uses, has been widely studied in this context. This study is aimed at determining the effects of C. vulgaris on promoting muscle regeneration by evaluating myoblast regenerative capacity in vitro. Human skeletal myoblast cells were cultured and underwent serial passaging into young and senescent phases and were then treated with C. vulgaris, followed by the induction of differentiation. The ability of C. vulgaris to promote myoblast differentiation was analysed through cellular morphology, real-time monitoring, cell proliferation, senescence-associated β-galactosidase (SA-β-gal) expression, myogenic differentiation, myogenin expression, and cell cycle profiling. The results obtained showed that senescent myoblasts exhibited an enlarged and flattened morphology, with increased SA-β-gal expression, reduced myogenic differentiation, decreased expression of myogenin, and an increased percentage of cells in the G0/G1 phase. Treatment with C. vulgaris resulted in decreased SA-β-gal expression and promotion of myogenic differentiation, as observed via an increased fusion index, maturation index, myotube size, and surface area and an increased percentage of cells that stained positive for myogenin. In conclusion, C. vulgaris improves the regenerative capacity of young and senescent myoblasts and promotes myoblast differentiation, indicating its potential to promote muscle regeneration.
Fulltext Chlorella vulgaris Modulates Genes and Muscle-Specific microRNAs Expression to Promote Myoblast Differentiation in Culture

Zainul Azlan N, Mohd Yusof YA, Alias E, Makpol S

Evid Based Complement Alternat Med, 2019;2019:8394648.
PMID: 31428175 DOI: 10.1155/2019/8394648

Background: Loss of skeletal muscle mass, strength, and function due to gradual decline in the regeneration of skeletal muscle fibers was observed with advancing age. This condition is known as sarcopenia. Myogenic regulatory factors (MRFs) are essential in muscle regeneration as its activation leads to the differentiation of myoblasts to myofibers. Chlorella vulgaris is a coccoid green eukaryotic microalga that contains highly nutritious substances and has been reported for its pharmaceutical effects. The aim of this study was to determine the effect of C. vulgaris on the regulation of MRFs and myomiRs expression in young and senescent myoblasts during differentiation in vitro.
Methods: Human skeletal muscle myoblast (HSMM) cells were cultured and serial passaging was carried out to obtain young and senescent cells. The cells were then treated with C. vulgaris followed by differentiation induction. The expression of Pax7, MyoD1, Myf5, MEF2C, IGF1R, MYOG, TNNT1, PTEN, and MYH2 genes and miR-133b, miR-206, and miR-486 was determined in untreated and C. vulgaris-treated myoblasts on Days 0, 1, 3, 5, and 7 of differentiation.
Results: The expression of Pax7, MyoD1, Myf5, MEF2C, IGF1R, MYOG, TNNT1, and PTEN in control senescent myoblasts was significantly decreased on Day 0 of differentiation (p<0.05). Treatment with C. vulgaris upregulated Pax7, Myf5, MEF2C, IGF1R, MYOG, and PTEN in senescent myoblasts (p<0.05) and upregulated Pax7 and MYOG in young myoblasts (p<0.05). The expression of MyoD1 and Myf5 in young myoblasts however was significantly decreased on Day 0 of differentiation (p<0.05). During differentiation, the expression of these genes was increased with C. vulgaris treatment. Further analysis on myomiRs expression showed that miR-133b, miR-206, and miR-486 were significantly downregulated in senescent myoblasts on Day 0 of differentiation which was upregulated by C. vulgaris treatment (p<0.05). During differentiation, the expression of miR-133b and miR-206 was significantly increased with C. vulgaris treatment in both young and senescent myoblasts (p<0.05). However, no significant change was observed on the expression of miR-486 with C. vulgaris treatment.
Conclusions: C. vulgaris demonstrated the modulatory effects on the expression of MRFs and myomiRs during proliferation and differentiation of myoblasts in culture. These findings may indicate the beneficial effect of C. vulgaris in muscle regeneration during ageing thus may prevent sarcopenia in the elderly.
Fulltext Ginger (Zingiber officinale Roscoe) in the Prevention of Ageing and Degenerative Diseases: Review of Current Evidence

Mohd Sahardi NFN, Makpol S

Evid Based Complement Alternat Med, 2019;2019:5054395.
PMID: 31531114 DOI: 10.1155/2019/5054395

Currently, the age of the population is increasing as a result of increased life expectancy. Ageing is defined as the progressive loss of physiological integrity, which can be characterized by functional impairment and high vulnerability to various types of diseases, such as diabetes, hypertension, Alzheimer's disease (AD), Parkinson's disease (PD), and atherosclerosis. Numerous studies have reported that the presence of oxidative stress and inflammation contributes to the development of these diseases. In general, oxidative stress could induce proinflammatory cytokines and reduce cellular antioxidant capacity. Increased oxidative stress levels beyond the production of antioxidant agents cause oxidative damage to biological molecules, including DNA, protein, and carbohydrates, which affects normal cell signalling, cell growth, differentiation, and apoptosis and leads to disease pathogenesis. Since oxidative stress and inflammation contribute to these diseases, ginger (Zingiber officinale Roscoe) is one of the potential herbs that can be used to reduce the level of oxidative stress and inflammation. Ginger consists of two major active components, 6-gingerol and 6-shogaol, which are essential for preventing oxidative stress and inflammation. Thus, this paper will review the effects of ginger on ageing and degenerative diseases, including AD, PD, type 2 diabetes mellitus (DM), hypertension, and osteoarthritis.
Chlorella vulgaris modulates the expression of senescence-associated genes in replicative senescence of human diploid fibroblasts

Jaafar F, Durani LW, Makpol S

Mol Biol Rep, 2020 Jan;47(1):369-379.
PMID: 31642042 DOI: 10.1007/s11033-019-05140-8

Human diploid fibroblasts (HDFs) cultured in vitro have limited capacity to proliferate after population doubling is repeated several times, and they enter into a state known as replicative senescence or cellular senescence. This study aimed to investigate the effect of Chlorella vulgaris on the replicative senescence of HDFs by determining the expression of senescence-associated genes. Young and senescent HDFs were divided into untreated control and C. vulgaris-treated groups. A senescence-associated gene transcription analysis was carried out with qRT-PCR. Treatment of young HDFs with C. vulgaris reduced the expression of SOD1, CAT and CCS (p
Fulltext Comparative Effects of Alpha- and Gamma-Tocopherol on Mitochondrial Functions in Alzheimer's Disease In Vitro Model

Pahrudin Arrozi A, Shukri SNS, Wan Ngah WZ, Mohd Yusof YA, Ahmad Damanhuri MH, Jaafar F, et al.

Sci Rep, 2020 06 02;10(1):8962.
PMID: 32488024 DOI: 10.1038/s41598-020-65570-4

Vitamin E acts as an antioxidant and reduces the level of reactive oxygen species (ROS) in Alzheimer's disease (AD). Alpha-tocopherol (ATF) is the most widely studied form of vitamin E besides gamma-tocopherol (GTF) which also shows beneficial effects in AD. The levels of amyloid-beta (Aβ) and amyloid precursor protein (APP) increased in the brains of AD patients, and mutations in the APP gene are known to enhance the production of Aβ. Mitochondrial function was shown to be affected by the increased level of Aβ and may induce cell death. Here, we aimed to compare the effects of ATF and GTF on their ability to reduce Aβ level, modulate mitochondrial function and reduce the apoptosis marker in SH-SY5Y cells stably transfected with the wild-type or mutant form of the APP gene. The Aβ level was measured by ELISA, the mitochondrial ROS and ATP level were quantified by fluorescence and luciferase assay respectively whereas the complex V enzyme activity was measured by spectrophotometry. The expressions of genes involved in the regulation of mitochondrial membrane permeability such as voltage dependent anion channel (VDAC1), adenine nucleotide translocase (ANT), and cyclophilin D (CYPD) were determined by quantitative real-time polymerase chain reaction (qRT-PCR), while the expressions of cyclophilin D (CypD), cytochrome c, Bcl2 associated X (BAX), B cell lymphoma-2 (Bcl-2), and pro-caspase-3 were determined by western blot. Our results showed that mitochondrial ROS level was elevated accompanied by decreased ATP level and complex V enzyme activity in SH-SY5Y cells expressing the mutant APP gene (p
Epigenetic Changes and Its Intervention in Age-Related Neurodegenerative Diseases

Mohd Murshid N, Aminullah Lubis F, Makpol S

Cell Mol Neurobiol, 2020 Oct 19.
PMID: 33074454 DOI: 10.1007/s10571-020-00979-z

Epigenetic mechanisms involving the modulation of gene activity without modifying the DNA bases are reported to have lifelong effects on mature neurons in addition to their impact on synaptic plasticity and cognition. Histone methylation and acetylation are involved in synchronizing gene expression and protein function in neuronal cells. Studies have demonstrated in experimental models of neurodegenerative disorders that manipulations of these two mechanisms influence the susceptibility of neurons to degeneration and apoptosis. In Alzheimer's disease (AD), the expression of presenilin 1 (PSEN1) is markedly increased due to decreased methylation at CpG sites, thus promoting the accumulation of toxic amyloid-β (Aβ) peptide. In Parkinson's disease (PD), dysregulation of α-synuclein (SNCA) expression is presumed to occur via aberrant methylation at CpG sites, which controls the activation or suppression of protein expression. Mutant Huntingtin (mtHTT) alters the activity of histone acetyltransferases (HATs), causing the dysregulation of transcription observed in most Huntington's disease (HD) cases. Folate, vitamin B6, vitamin B12, and S-adenosylmethionine (SAM) are vital cofactors involved in DNA methylation modification; 5-azacytidine (AZA) is the most widely studied DNA methyltransferase (DNMT) inhibitor, and dietary polyphenols are DNMT inhibitors in vitro. Drug intervention is believed to reverse the epigenetic mechanisms to serve as a regulator in neuronal diseases. Nevertheless, the biochemical effect of the drugs on brain function and the underlying mechanisms are not well understood. This review focuses on further discussion of therapeutic targets, emphasizing the potential role of epigenetic factors including histone and DNA modifications in the diseases.
Antioxidant Modulation of mTOR and Sirtuin Pathways in Age-Related Neurodegenerative Diseases

Abdullah A, Mohd Murshid N, Makpol S

Mol Neurobiol, 2020 Dec;57(12):5193-5207.
PMID: 32865663 DOI: 10.1007/s12035-020-02083-1

In the human body, cell division and metabolism are expected to transpire uneventfully for approximately 25 years. Then, secondary metabolism and cell damage products accumulate, and ageing phenotypes are acquired, causing the progression of disease. Among these age-related diseases, neurodegenerative diseases have attracted considerable attention because of their irreversibility, the absence of effective treatment and their relationship with social and economic pressures. Mechanistic (formerly mammalian) target of rapamycin (mTOR), sirtuin (SIRT) and insulin/insulin growth factor 1 (IGF1) signalling pathways are among the most important pathways in ageing-associated conditions, such as neurodegeneration. These longevity-related pathways are associated with a diversity of various processes, including metabolism, cognition, stress reaction and brain plasticity. In this review, we discuss the roles of sirtuin and mTOR in ageing and neurodegeneration, with an emphasis on their regulation of autophagy, apoptosis and mitochondrial energy metabolism. The intervention of neurodegeneration using potential antioxidants, including vitamins, phytochemicals, resveratrol, herbals, curcumin, coenzyme Q10 and minerals, specifically aimed at retaining mitochondrial function in the treatment of Alzheimer's disease, Parkinson's disease and Huntington's disease is highlighted.
Fulltext Zingiber Officinale Roscoe Prevents Cellular Senescence of Myoblasts in Culture and Promotes Muscle Regeneration

Mohd Sahardi NFN, Jaafar F, Mad Nordin MF, Makpol S

Evid Based Complement Alternat Med, 2020;2020:1787342.
PMID: 32419792 DOI: 10.1155/2020/1787342

Background: Ageing resulted in a progressive loss of muscle mass and strength. Increased oxidative stress in ageing affects the capacity of the myoblast to differentiate leading to impairment of muscle regeneration. Zingiber officinale Roscoe (ginger) has potential benefits in reversing muscle ageing due to its antioxidant property. This study aimed to determine the effect of ginger in the prevention of cellular senescence and promotion of muscle regeneration.
Methods: Myoblast cells were cultured into young and senescent state before treated with different concentrations of ginger standardised extracts containing different concentrations of 6-gingerol and 6-shogaol. Analysis on cellular morphology and myogenic purity was carried out besides determination of SA-β-galactosidase expression and cell cycle profile. Myoblast differentiation was quantitated by determining the fusion index, maturation index, and myotube size.
Results: Treatment with ginger extracts resulted in improvement of cellular morphology of senescent myoblasts which resembled the morphology of young myoblasts. Our results also showed that ginger treatment caused a significant reduction in SA-β-galactosidase expression on senescent myoblasts indicating prevention of cellular senescence, while cell cycle analysis showed a significant increase in the percentage of cells in the G0/G1 phase and reduction in the S-phase cells. Increased myoblast regenerative capacity was observed as shown by the increased number of nuclei per myotube, fusion index, and maturation index.
Conclusions: Ginger extracts exerted their potency in promoting muscle regeneration as indicated by prevention of cellular senescence and promotion of myoblast regenerative capacity.
Fulltext Gene Expression Profile in Different Age Groups and Its Association with Cognitive Function in Healthy Malay Adults in Malaysia

Abdul Sani NF, Amir Hamzah AIZ, Abu Bakar ZH, Mohd Yusof YA, Makpol S, Wan Ngah WZ, et al.

Cells, 2021 06 27;10(7).
PMID: 34199148 DOI: 10.3390/cells10071611

The mechanism of cognitive aging at the molecular level is complex and not well understood. Growing evidence suggests that cognitive differences might also be caused by ethnicity. Thus, this study aims to determine the gene expression changes associated with age-related cognitive decline among Malay adults in Malaysia. A cross-sectional study was conducted on 160 healthy Malay subjects, aged between 28 and 79, and recruited around Selangor and Klang Valley, Malaysia. Gene expression analysis was performed using a HumanHT-12v4.0 Expression BeadChip microarray kit. The top 20 differentially expressed genes at p < 0.05 and fold change (FC) = 1.2 showed that PAFAH1B3, HIST1H1E, KCNA3, TM7SF2, RGS1, and TGFBRAP1 were regulated with increased age. The gene set analysis suggests that the Malay adult's susceptibility to developing age-related cognitive decline might be due to the changes in gene expression patterns associated with inflammation, signal transduction, and metabolic pathway in the genetic network. It may, perhaps, have important implications for finding a biomarker for cognitive decline and offer molecular targets to achieve successful aging, mainly in the Malay population in Malaysia.
Fulltext A Link between Mitochondrial Dysregulation and Idiopathic Autism Spectrum Disorder (ASD): Alterations in Mitochondrial Respiratory Capacity and Membrane Potential

Hassan H, Zakaria F, Makpol S, Karim NA

Curr Issues Mol Biol, 2021 Dec 16;43(3):2238-2252.
PMID: 34940131 DOI: 10.3390/cimb43030157

Autism spectrum disorder (ASD) is a neurological disorder triggered by various factors through complex mechanisms. Research has been done to elucidate the potential etiologic mechanisms in ASD, but no single cause has been confirmed. The involvement of oxidative stress is correlated with ASD and possibly affects mitochondrial function. This study aimed to elucidate the link between mitochondrial dysregulation and idiopathic ASD by focusing on mitochondrial respiratory capacity and membrane potential. Our findings showed that mitochondrial function in the energy metabolism pathway was significantly dysregulated in a lymphoblastoid cell line (LCL) derived from an autistic child (ALCL). Respiratory capacities of oxidative phosphorylation (OXPHOS), electron transfer of the Complex I and Complex II linked pathways, membrane potential, and Complex IV activity of the ALCL were analyzed and compared with control cell lines derived from a developmentally normal non-autistic sibling (NALCL). All experiments were performed using high-resolution respirometry. Respiratory capacities of OXPHOS, electron transfer of the Complex I- and Complex II-linked pathways, and Complex IV activity of the ALCL were significantly higher compared to healthy controls. Mitochondrial membrane potential was also significantly higher, measured in the Complex II-linked pathway during LEAK respiration and OXPHOS. These results indicate the abnormalities in mitochondrial respiratory control linking mitochondrial function with autism. Correlating mitochondrial dysfunction and autism is important for a better understanding of ASD pathogenesis in order to produce effective interventions.
Fulltext Modulation of Ki67 and myogenic regulatory factor expression by tocotrienol-rich fraction ameliorates myogenic program of senescent human myoblasts

Tan CM, Najib NAM, Suhaimi NF, Halid NA, Cho VV, Abdullah SI, et al.

Arch Med Sci, 2021;17(3):752-763.
PMID: 34025846 DOI: 10.5114/aoms.2019.85449

Introduction: Replicative senescence results in dysregulation of cell proliferation and differentiation, which plays a role in the regenerative defects observed during age-related muscle atrophy. Vitamin E is a well-known antioxidant, which potentially ameliorates a wide range of age-related manifestations. The aim of this study was to determine the effects of tocotrienol-rich fraction (TRF) in modulating the expression of proliferation- and differentiation-associated proteins in senescent human myoblasts during the differentiation phase.
Material and methods: Human skeletal muscle myoblasts were cultured until senescence. Young and senescent cells were treated with TRF for 24 h before and after differentiation induction, followed by evaluation of cellular morphology and efficiency of differentiation. Expression of cell proliferation marker Ki67 protein and myogenic regulatory factors MyoD and myogenin were determined.
Results: Our findings showed that treatment with TRF significantly improved the morphology of senescent myoblasts. Promotion of differentiation was observed in young and senescent myoblasts with TRF treatment as shown by the increased fusion index and larger size of myotubes. Increased Ki67 and myogenin expression with TRF treatment was also observed in senescent myoblasts, suggesting amelioration of the myogenic program by TRF during replicative senescence.
Conclusions: TRF modulates the expression of regulatory factors related to proliferation and differentiation in senescent human myoblasts and could be beneficial for ameliorating the regenerative defects during aging.
Fulltext Zebrafish: A Pharmacological Model for Learning and Memory Research

Tan JK, Nazar FH, Makpol S, Teoh SL

Molecules, 2022 Oct 30;27(21).
PMID: 36364200 DOI: 10.3390/molecules27217374

Learning and memory are essential to organism survival and are conserved across various species, especially vertebrates. Cognitive studies involving learning and memory require using appropriate model organisms to translate relevant findings to humans. Zebrafish are becoming increasingly popular as one of the animal models for neurodegenerative diseases due to their low maintenance cost, prolific nature and amenability to genetic manipulation. More importantly, zebrafish exhibit a repertoire of neurobehaviors comparable to humans. In this review, we discuss the forms of learning and memory abilities in zebrafish and the tests used to evaluate the neurobehaviors in this species. In addition, the pharmacological studies that used zebrafish as models to screen for the effects of neuroprotective and neurotoxic compounds on cognitive performance will be summarized here. Lastly, we discuss the challenges and perspectives in establishing zebrafish as a robust model for cognitive research involving learning and memory. Zebrafish are becoming an indispensable model in learning and memory research for screening neuroprotective agents against cognitive impairment.

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