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Fulltext Elucidating the Pharmacological Properties of Zingiber officinale Roscoe (Ginger) on Muscle Ageing by Untargeted Metabolomic Profiling of Human Myoblasts

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

Nutrients, 2023 Oct 25;15(21).
PMID: 37960173 DOI: 10.3390/nu15214520

(1) Background: Muscle loss is associated with frailty and a reduction in physical strength and performance, which is caused by increased oxidative stress. Ginger (Zingiber officinale Roscoe) is a potential herb that can be used to reduce the level of oxidative stress. This study aimed to determine the effect of ginger on the expression of metabolites and their metabolic pathways in the myoblast cells to elucidate the mechanism involved and its pharmacological properties in promoting myoblast differentiation. (2) Methods: The myoblast cells were cultured into three stages (young, pre-senescent and senescent). At each stage, the myoblasts were treated with different concentrations of ginger extract. Then, metabolomic analysis was performed using liquid chromatography-tandem mass spectrometry (LCMS/MS). (3) Results: Nine metabolites were decreased in both the pre-senescent and senescent control groups as compared to the young control group. For the young ginger-treated group, 8-shogaol and valine were upregulated, whereas adipic acid and bis (4-ethyl benzylidene) sorbitol were decreased. In the pre-senescent ginger-treated group, the niacinamide was upregulated, while carnitine and creatine were downregulated. Ginger treatment in the senescent group caused a significant upregulation in 8-shogaol, octadecanamide and uracil. (4) Conclusions: Ginger extract has the potential as a pharmacological agent to reduce muscle loss in skeletal muscle by triggering changes in some metabolites and their pathways that could promote muscle regeneration in ageing.
Fulltext Preventative and therapeutic potential of tocotrienols on musculoskeletal diseases in ageing

Saud Gany SL, Chin KY, Tan JK, Aminuddin A, Makpol S

Front Pharmacol, 2023;14:1290721.
PMID: 38146461 DOI: 10.3389/fphar.2023.1290721

Musculoskeletal health is paramount in an ageing population susceptible to conditions such as osteoporosis, arthritis and fractures. Age-related changes in bone, muscle, and joint function result in declining musculoskeletal health, reduced mobility, increased risk of falls, and persistent discomfort. Preserving musculoskeletal wellbeing is essential for maintaining independence and enhancing the overall quality of life for the elderly. The global burden of musculoskeletal disorders is significant, impacting 1.71 billion individuals worldwide, with age-related muscle atrophy being a well-established phenomenon. Tocotrienols, a unique type of vitamin E found in various sources, demonstrate exceptional antioxidant capabilities compared to tocopherols. This characteristic positions them as promising candidates for addressing musculoskeletal challenges, particularly in mitigating inflammation and oxidative stress underlying musculoskeletal disorders. This review paper comprehensively examines existing research into the preventive and therapeutic potential of tocotrienols in addressing age-related musculoskeletal issues. It sheds light on the promising role of tocotrienols in enhancing musculoskeletal health and overall wellbeing, emphasizing their significance within the broader context of age-related health concerns.
Fulltext Effect of Vitamin E on Transcriptomic Alterations in Alzheimer's Disease

Ekeuku SO, Mohd Murshid N, Shukri SN, Mohd Sahardi NFN, Makpol S

Int J Mol Sci, 2023 Aug 03;24(15).
PMID: 37569747 DOI: 10.3390/ijms241512372

Research into ageing is focused on understanding why some people can maintain cognitive ability and others lose autonomy, affecting their quality of life. Studies have revealed that age-related neurodegenerative disorders like Alzheimer's disease (AD) are now major causes of death among the elderly, surpassing malignancy. This review examines the effects of vitamin E on transcriptomic changes in ageing and neurodegenerative diseases, using AD as an example, and how different transcriptome profiling techniques can shape the results. Despite mixed results from transcriptomic studies on AD patients' brains, we think advanced technologies could offer a more detailed and accurate tool for such analysis. Research has also demonstrated the role of antioxidant modifiers in preventing AD. This review will explore the key findings regarding AD and its modulation by vitamin E, emphasizing the shift in its epidemiology during the ageing process.
Fulltext Lipopolysaccharide-Induced Delirium-like Behaviour in a Rat Model of Chronic Cerebral Hypoperfusion Is Associated with Increased Indoleamine 2,3-Dioxygenase Expression and Endotoxin Tolerance

Ang HP, Makpol S, Nasaruddin ML, Ahmad NS, Tan JK, Wan Zaidi WA, et al.

Int J Mol Sci, 2023 Jul 31;24(15).
PMID: 37569622 DOI: 10.3390/ijms241512248

Indoleamine 2,3-dioxygenase (IDO) and the tryptophan-kynurenine pathway (TRP-KP) are upregulated in ageing and could be implicated in the pathogenesis of delirium. This study evaluated the role of IDO/KP in lipopolysaccharide (LPS)-induced delirium in an animal model of chronic cerebral hypoperfusion (CCH), a proposed model for delirium. CCH was induced by a permanent bilateral common carotid artery ligation (BCCAL) in Sprague Dawley rats to trigger chronic neuroinflammation-induced neurodegeneration. Eight weeks after permanent BCCAL, the rats were treated with a single systemic LPS. The rats were divided into three groups: (1) post-BCCAL rats treated with intraperitoneal (i.p.) saline, (2) post-BCCAL rats treated with i.p. LPS 100 μg/kg, and (3) sham-operated rats treated with i.p. LPS 100 μg/kg. Each group consisted of 10 male rats. To elucidate the LPS-induced delirium-like behaviour, natural and learned behaviour changes were assessed by a buried food test (BFT), open field test (OFT), and Y-maze test at 0, 24-, 48-, and 72 h after LPS treatment. Serum was collected after each session of behavioural assessment. The rats were euthanised after the last serum collection, and the hippocampi and cerebral cortex were collected. The TRP-KP neuroactive metabolites were measured in both serum and brain tissues using ELISA. Our data show that LPS treatment in CCH rats was associated with acute, transient, and fluctuated deficits in natural and learned behaviour, consistent with features of delirium. These behaviour deficits were mild compared to the sham-operated rats, which exhibited robust behaviour impairments. Additionally, heightened hippocampal IDO expression in the LPS-treated CCH rats was associated with reduced serum KP activity together with a decrease in the hippocampal quinolinic acid (QA) expression compared to the sham-operated rats, suggested for the presence of endotoxin tolerance through the immunomodulatory activity of IDO in the brain. These data provide new insight into the underlying mechanisms of delirium, and future studies should further explore the role of IDO modulation and its therapeutic potential in delirium.
Fulltext Tocotrienol-rich fraction, [6]-gingerol and epigallocatechin gallate inhibit proliferation and induce apoptosis of glioma cancer cells

Rahman AA, Makpol S, Jamal R, Harun R, Mokhtar N, Ngah WZ

Molecules, 2014 Sep 12;19(9):14528-41.
PMID: 25221872 DOI: 10.3390/molecules190914528

Plant bioactives [6]-gingerol (GING), epigallocatechin gallate (EGCG) and asiaticoside (AS) and vitamin E, such as tocotrienol-rich fraction (TRF), have been reported to possess anticancer activity. In this study, we investigated the apoptotic properties of these bioactive compounds alone or in combination on glioma cancer cells. TRF, GING, EGCG and AS were tested for cytotoxicity on glioma cell lines 1321N1 (Grade II), SW1783 (Grade III) and LN18 (Grade IV) in culture by the (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxy-phenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt) (MTS) assay. With the exception of AS, combinations of two compounds were tested, and the interactions of each combination were evaluated by the combination index (CI) using an isobologram. Different grades of glioma cancer cells showed different cytotoxic responses to the compounds, where in 1321N1 and LN18 cells, the combination of EGCG + GING exhibited a synergistic effect with CI = 0.77 and CI = 0.55, respectively. In contrast, all combinations tested (TRF + GING, TRF + EGCG and EGCG + GING) were found to be antagonistic on SW1783 with CI values of 1.29, 1.39 and 1.39, respectively. Combined EGCG + GING induced apoptosis in both 1321N1 and LN18 cells, as evidenced by Annexin-V FITC/PI staining and increased active caspase-3. Our current data suggests that the combination of EGCG + GING synergistically induced apoptosis and inhibits the proliferation 1321N1 and LN18 cells, but not SW1783 cells, which may be due to their different genetic profiles.
Fulltext γ-Tocotrienol and 6-Gingerol in Combination Synergistically Induce Cytotoxicity and Apoptosis in HT-29 and SW837 Human Colorectal Cancer Cells

Yusof KM, Makpol S, Jamal R, Harun R, Mokhtar N, Ngah WZ

Molecules, 2015 Jun 03;20(6):10280-97.
PMID: 26046324 DOI: 10.3390/molecules200610280

Numerous bioactive compounds have cytotoxic properties towards cancer cells. However, most studies have used single compounds when bioactives may target different pathways and exert greater cytotoxic effects when used in combination. Therefore, the objective of this study was to determine the anti-proliferative effect of γ-tocotrienol (γ-T3) and 6-gingerol (6G) in combination by evaluating apoptosis and active caspase-3 in HT-29 and SW837 colorectal cancer cells. MTS assays were performed to determine the anti-proliferative and cytotoxicity effect of γ-T3 (0-150 µg/mL) and 6G (0-300 µg/mL) on the cells. The half maximal inhibitory concentration (IC50) value of 6G+ γ-T3 for HT-29 was 105 + 67 µg/mL and for SW837 it was 70 + 20 µg/mL. Apoptosis, active caspase-3 and annexin V FITC assays were performed after 24 h of treatment using flow cytometry. These bioactives in combination showed synergistic effect on HT-29 (CI: 0.89 ± 0.02,) and SW837 (CI: 0.79 ± 0.10) apoptosis was increased by 21.2% in HT-29 and 55.4% in SW837 (p < 0.05) after 24 h treatment, while normal hepatic WRL-68 cells were unaffected. Increased apoptosis by the combined treatments was also observed morphologically, with effects like cell shrinkage and pyknosis. In conclusion, although further studies need to be done, γ-T3 and 6G when used in combination act synergistically increasing cytotoxicity and apoptosis in cancer cells.
Fulltext Combined ginger extract & Gelam honey modulate Ras/ERK and PI3K/AKT pathway genes in colon cancer HT29 cells

Tahir AA, Sani NF, Murad NA, Makpol S, Ngah WZ, Yusof YA

Nutr J, 2015;14:31.
PMID: 25889965 DOI: 10.1186/s12937-015-0015-2

The interconnected Ras/ERK and PI3K/AKT pathways play a central role in colorectal tumorigenesis, and they are targets for elucidating mechanisms involved in attempts to induce colon cancer cell death. Both ginger (Zingiber officinale) and honey have been shown to exhibit anti-tumor and anti-inflammation properties against many types of cancer, including colorectal cancer. However, there are currently no reports showing the combined effect of these two dietary compounds in cancer growth inhibition. The aim of this study was to evaluate the synergistic effect of crude ginger extract and Gelam honey in combination as potential cancer chemopreventive agents against the colorectal cancer cell line HT29.
Fulltext Piper betle induces phase I & II genes through Nrf2/ARE signaling pathway in mouse embryonic fibroblasts derived from wild type and Nrf2 knockout cells

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

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

Nuclear factor-erythroid 2 p45 related factor 2 (Nrf2) is a primary transcription factor, protecting cells from oxidative stress by regulating a number of antioxidants and phase II detoxifying enzymes. Dietary components such as sulforaphane in broccoli and quercetin in onions have been shown to be inducers of Nrf2. Piper betle (PB) grows well in tropical climate and the leaves are used in a number of traditional remedies for the treatment of stomach ailments and infections among Asians. The aim of this study was to elucidate the effect of Piper betle (PB) leaves extract in Nrf2 signaling pathway by using 2 types of cells; mouse embryonic fibroblasts (MEFs) derived from wild-type (WT) and Nrf2 knockout (N0) mice.
Fulltext Comparative effects of biodynes, tocotrienol-rich fraction, and tocopherol in enhancing collagen synthesis and inhibiting collagen degradation in stress-induced premature senescence model of human diploid fibroblasts

Makpol S, Jam FA, Khor SC, Ismail Z, Mohd Yusof YA, Ngah WZ

Oxid Med Cell Longev, 2013;2013:298574.
PMID: 24396567 DOI: 10.1155/2013/298574

Biodynes, tocotrienol-rich fraction (TRF), and tocopherol have shown antiaging properties. However, the combined effects of these compounds on skin aging are yet to be investigated. This study aimed to elucidate the skin aging effects of biodynes, TRF, and tocopherol on stress-induced premature senescence (SIPS) model of human diploid fibroblasts (HDFs) by determining the expression of collagen and MMPs at gene and protein levels. Primary HDFs were treated with biodynes, TRF, and tocopherol prior to hydrogen peroxide (H2O2) exposure. The expression of COL1A1, COL3A1, MMP1, MMP2, MMP3, and MMP9 genes was determined by qRT-PCR. Type I and type III procollagen proteins were measured by Western blotting while the activities of MMPs were quantified by fluorometric Sensolyte MMP Kit. Our results showed that biodynes, TRF, and tocopherol upregulated collagen genes and downregulated MMP genes (P < 0.05). Type I procollagen and type III procollagen protein levels were significantly increased in response to biodynes, TRF, and tocopherol treatment (P < 0.05) with reduction in MMP-1, MMP-2, MMP-3, and MMP-9 activities (P < 0.05). These findings indicated that biodynes, TRF, and tocopherol effectively enhanced collagen synthesis and inhibited collagen degradation and therefore may protect the skin from aging.
Fulltext Comparative effect of Piper betle, Chlorella vulgaris and tocotrienol-rich fraction on antioxidant enzymes activity in cellular ageing of human diploid fibroblasts

Makpol S, Yeoh TW, Ruslam FA, Arifin KT, Yusof YA

BMC Complement Altern Med, 2013;13:210.
PMID: 23948056 DOI: 10.1186/1472-6882-13-210

Human diploid fibroblasts (HDFs) undergo a limited number of cellular divisions in culture and progressively reach a state of irreversible growth arrest, a process termed cellular ageing. Even though beneficial effects of Piper betle, Chlorella vulgaris and tocotrienol-rich fraction (TRF) have been reported, ongoing studies in relation to ageing is of interest to determine possible protective effects that may reverse the effect of ageing. The aim of this study was to evaluate the effect of P. betle, C. vulgaris and TRF in preventing cellular ageing of HDFs by determining the activity of antioxidant enzymes viz.; catalase, superoxide dismutase (SOD) and glutathione peroxidase.
Differences in protein changes between stress-induced premature senescence and replicative senescence states

Aan GJ, Hairi HA, Makpol S, Rahman MA, Karsani SA

Electrophoresis, 2013 Aug;34(15):2209-17.
PMID: 23712505 DOI: 10.1002/elps.201300086

Replicative senescence and stress-induced premature senescence (SIPS) cells are known to share certain traits. However, whether these cells are different at the protein level is unclear. Thus, this study has utilized proteomics to identify differences in the proteomes of replicative senescence and SIPS cells compared to normal cells. Replicative senescence was induced by serial passage of normal cells in culture. SIPS was established by exposure to H2 O2 at a subcytotoxic concentration of 20 μM for two weeks. Following 2DE, protein profiles were compared and protein spots that changed in abundance were identified by MALDI-TOF MS. Quantitative real-time RT-PCR was then performed to evaluate the transcript expression of selected altered proteins. A total of 24 and 10 proteins were found to have changed in abundance in replicative senescence and SIPS cells, respectively, when compared to young cells. Quantitative RT-PCR revealed that nine genes showed the same direction of change as observed in the proteomics analysis. Very little overlap was observed between proteins that changed in replicative senescence and SIPS cells, suggesting that although both SIPS and replicative senescence cells share hallmarks of cellular senescence, they were different in terms of proteins that changed in abundance.
Fulltext Gamma-tocotrienol modulated gene expression in senescent human diploid fibroblasts as revealed by microarray analysis

Makpol S, Zainuddin A, Chua KH, Mohd Yusof YA, Ngah WZ

Oxid Med Cell Longev, 2013;2013:454328.
PMID: 23634235 DOI: 10.1155/2013/454328

The effect of γ -tocotrienol, a vitamin E isomer, in modulating gene expression in cellular aging of human diploid fibroblasts was studied. Senescent cells at passage 30 were incubated with 70 μ M of γ -tocotrienol for 24 h. Gene expression patterns were evaluated using Sentrix HumanRef-8 Expression BeadChip from Illumina, analysed using GeneSpring GX10 software, and validated using quantitative RT-PCR. A total of 100 genes were differentially expressed (P < 0.001) by at least 1.5 fold in response to γ -tocotrienol treatment. Amongst the genes were IRAK3, SelS, HSPA5, HERPUD1, DNAJB9, SEPR1, C18orf55, ARF4, RINT1, NXT1, CADPS2, COG6, and GLRX5. Significant gene list was further analysed by Gene Set Enrichment Analysis (GSEA), and the Normalized Enrichment Score (NES) showed that biological processes such as inflammation, protein transport, apoptosis, and cell redox homeostasis were modulated in senescent fibroblasts treated with γ -tocotrienol. These findings revealed that γ -tocotrienol may prevent cellular aging of human diploid fibroblasts by modulating gene expression.
Antioxidant modulation in restoring mitochondrial function in neurodegeneration

Pahrudin Arrozi A, Wan Ngah WZ, Mohd Yusof YA, Ahmad Damanhuri MH, Makpol S

Int J Neurosci, 2017 Mar;127(3):218-235.
PMID: 27074540 DOI: 10.1080/00207454.2016.1178261

Alzheimer's disease (AD) and Parkinson's disease (PD) are the leading causes of disability associated with neurodegeneration worldwide. These diseases are influenced by multiple genetic and environmental factors and share similar mechanisms as both are characterized by accumulation and aggregation of misfolded proteins - amyloid-beta (Aβ) in AD and α-synuclein in PD. Over the past decade, increasing evidence has shown that mitochondrial dysfunction and the generation of reactive oxygen species (ROS) are involved in the pathology of these diseases, and the contributions of these defects to the cellular and molecular changes that eventually cause neuronal death have been explored. Using mitochondrial protective agents, such as antioxidants, to combat ROS provides a new strategy for neurodegenerative treatment. In this review, we highlight the potential of multiple types of antioxidants, including vitamins, phytochemicals, fatty acids and minerals, as well as synthetic antioxidants specifically targeting the mitochondria, which can restore mitochondrial function, in the treatment of neurodegenerative disorders at both the pre-clinical and clinical stages by focusing on AD and PD.
Fulltext The Tocotrienol-Rich Fraction Is Superior to Tocopherol in Promoting Myogenic Differentiation in the Prevention of Replicative Senescence of Myoblasts

Khor SC, Razak AM, Wan Ngah WZ, Mohd Yusof YA, Abdul Karim N, Makpol S

PLoS One, 2016;11(2):e0149265.
PMID: 26885980 DOI: 10.1371/journal.pone.0149265

Aging results in a loss of muscle mass and strength. Myoblasts play an important role in maintaining muscle mass through regenerative processes, which are impaired during aging. Vitamin E potentially ameliorates age-related phenotypes. Hence, this study aimed to determine the effects of the tocotrienol-rich fraction (TRF) and α-tocopherol (ATF) in protecting myoblasts from replicative senescence and promoting myogenic differentiation. Primary human myoblasts were cultured into young and senescent stages and were then treated with TRF or ATF for 24 h, followed by an analysis of cell proliferation, senescence biomarkers, cellular morphology and differentiation. Our data showed that replicative senescence impaired the normal regenerative processes of myoblasts, resulting in changes in cellular morphology, cell proliferation, senescence-associated β-galactosidase (SA-β-gal) expression, myogenic differentiation and myogenic regulatory factors (MRFs) expression. Treatment with both TRF and ATF was beneficial to senescent myoblasts in reclaiming the morphology of young cells, improved cell viability and decreased SA-β-gal expression. However, only TRF treatment increased BrdU incorporation in senescent myoblasts, as well as promoted myogenic differentiation through the modulation of MRFs at the mRNA and protein levels. MYOD1 and MYOG gene expression and myogenin protein expression were modulated in the early phases of myogenic differentiation. In conclusion, the tocotrienol-rich fraction is superior to α-tocopherol in ameliorating replicative senescence-related aberration and promoting differentiation via modulation of MRFs expression, indicating vitamin E potential in modulating replicative senescence of myoblasts.
Mechanism of Chemoprevention against Colon Cancer Cells Using Combined Gelam Honey and Ginger Extract via mTOR and Wnt/β-catenin Pathways

Wee LH, Morad NA, Aan GJ, Makpol S, Wan Ngah WZ, Mohd Yusof YA

Asian Pac J Cancer Prev, 2015;16(15):6549-56.
PMID: 26434873

The PI3K-Akt-mTOR, Wnt/β-catenin and apoptosis signaling pathways have been shown to be involved in genesis of colorectal cancer (CRC). The aim of this study was to elucidate whether combination of Gelam honey and ginger might have chemopreventive properties in HT29 colon cancer cells by modulating the mTOR, Wnt/β-catenin and apoptosis signaling pathways. Treatment with Gelam honey and ginger reduced the viability of the HT29 cells dose dependently with IC50 values of 88 mg/ml and 2.15 mg/ml respectively, their while the combined treatment of 2 mg/ml of ginger with 31 mg/ml of Gelam honey inhibited growth of most HT29 cells. Gelam honey, ginger and combination induced apoptosis in a dose dependent manner with the combined treatment exhibiting the highest apoptosis rate. The combined treatment downregulated the gene expressions of Akt, mTOR, Raptor, Rictor, β-catenin, Gsk3β, Tcf4 and cyclin D1 while cytochrome C and caspase 3 genes were shown to be upregulated. In conclusion, the combination of Gelam honey and ginger may serve as a potential therapy in the treatment of colorectal cancer through inhibiton of mTOR, Wnt/β catenin signaling pathways and induction of apoptosis pathway.
Fulltext Profiling neuroprotective potential of trehalose in animal models of neurodegenerative diseases: a systematic review

Yap KH, Azmin S, Makpol S, Damanhuri HA, Mustapha M, Hamzah JC, et al.

Neural Regen Res, 2023 Jun;18(6):1179-1185.
PMID: 36453391 DOI: 10.4103/1673-5374.360164

Trehalose, a unique nonreducing crystalline disaccharide, is a potential disease-modifying treatment for neurodegenerative diseases associated with protein misfolding and aggregation due to aging, intrinsic mutations, or autophagy dysregulation. This systematic review summarizes the effects of trehalose on its underlying mechanisms in animal models of selected neurodegenerative disorders (tau pathology, synucleinopathy, polyglutamine tract, and motor neuron diseases). All animal studies on neurodegenerative diseases treated with trehalose published in Medline (accessed via EBSCOhost) and Scopus were considered. Of the 2259 studies screened, 29 met the eligibility criteria. According to the SYstematic Review Center for Laboratory Animal Experiment (SYRCLE) risk of bias tool, we reported 22 out of 29 studies with a high risk of bias. The present findings support the purported role of trehalose in autophagic flux and protein refolding. This review identified several other lesser-known pathways, including modifying amyloid precursor protein processing, inhibition of reactive gliosis, the integrity of the blood-brain barrier, activation of growth factors, upregulation of the downstream antioxidant signaling pathway, and protection against mitochondrial defects. The absence of adverse events and improvements in the outcome parameters were observed in some studies, which supports the transition to human clinical trials. It is possible to conclude that trehalose exerts its neuroprotective effects through both direct and indirect pathways. However, heterogeneous methodologies and outcome measures across the studies rendered it impossible to derive a definitive conclusion. Translational studies on trehalose would need to clarify three important questions: 1) bioavailability with oral administration, 2) optimal time window to confer neuroprotective benefits, and 3) optimal dosage to confer neuroprotection.
Fulltext Untargeted muscle tissue metabolites profiling in young, adult, and old rats supplemented with tocotrienol-rich fraction

Saud Gany SL, Tan JK, Chin KY, Hakimi NH, Ab Rani N, Ihsan N, et al.

Front Mol Biosci, 2022;9:1008908.
PMID: 36310588 DOI: 10.3389/fmolb.2022.1008908

The greatest significant influence on human life span and health is inevitable ageing. One of the distinguishing characteristics of ageing is the gradual decrease of muscle mass and physical function. There has been growing evidence that tocotrienol can guard against age-associated chronic diseases and metabolic disorders. This study aimed to elucidate the effects of tocotrienol-rich fraction (TRF) on muscle metabolomes and metabolic pathways in ageing Sprague Dawley (SD) rats. Three months, 9 months, and 21 months old male SD rats were divided into control and treated groups with 10 rats per group. Rats in control and treated groups were given 60 mg/kg body weight/day of palm olein and 60 mg/kg body weight/day of TRF, respectively, via oral gavage for 3 months. Muscle performance was assessed at 0 and 3 months of treatment by measuring muscle strength and function. Our results showed that TRF treatment caused a significant increase in the swimming time of the young rats. Comparison in the control groups showed that metabolites involved in lipid metabolisms such as L-palmitoyl carnitine and decanoyl carnitine were increased in ageing. In contrast, several metabolites, such as 3-phosphoglyceric acid, aspartic acid and aspartyl phenylalanine were decreased. These findings indicated that muscle metabolomes involved in lipid metabolism were upregulated in aged rats. In contrast, the metabolites involved in energy and amino acid metabolism were significantly downregulated. Comparison in the TRF-supplemented groups showed an upregulation of metabolites involved in energy and amino acid metabolism. Metabolites such as N6-methyl adenosine, spermine, phenylalanine, tryptophan, aspartic acid, histidine, and N-acetyl neuraminic acid were up-regulated, indicating promotion of amino acid synthesis and muscle regeneration. Energy metabolism was also improved in adult and old rats with TRF supplementation as indicated by the upregulation of nicotinamide adenine dinucleotide and glycerol 3-phosphate compared to the control group. In conclusion, the mechanism underlying the changes in skeletal muscle mass and functions in ageing was related to carbohydrate, lipid and amino acid metabolism. Tocotrienol supplementation showed beneficial effects in alleviating energy and amino acid synthesis that may promote the regeneration and renewal of skeletal muscle in ageing rats.
Fulltext Safety of Lidocaine During Wide-Awake Local Anesthesia No Tourniquet for Distal Radius Plating

Abdullah S, Tokiran MF, Ahmad AA, Soh EZF, Makpol S, Sapuan J

J Hand Surg Glob Online, 2023 Mar;5(2):196-200.
PMID: 36974291 DOI: 10.1016/j.jhsg.2022.12.003

PURPOSE: This study evaluated the clinical and biochemical safety profile of infiltration of lidocaine with adrenaline in wide-awake local anesthesia no tourniquet for distal radius plating.
METHODS: Twenty-four participants were randomly assigned to the therapeutic group (n = 19) (1% lidocaine in 1:100,000 adrenaline) and control group (n = 5) (2% lidocaine alone). Clinical parameters, including skin necrosis, duration of recovery of sensation, and lidocaine toxicity, were monitored. The serum lidocaine level was measured at different time intervals using a high-performance liquid chromatography reagent.
RESULTS: No lidocaine toxicity was recorded in any participant. The therapeutic group had a longer time for recovery of sensation. There was a significant difference in the serum lidocaine levels between both the groups at all time intervals up to 6 hours, with all participants exhibiting serum lidocaine levels below the mild toxicity level of 6.0 μg/mL.
CONCLUSIONS: Lidocaine used within a safe recommended dose in wide-awake local anesthesia no tourniquet for distal radius plating is clinically and biochemically safe.
CLINICAL RELEVANCE: Determining the clinical and biochemical safety profile of lidocaine with adrenaline in wide-awake local anesthesia no tourniquet can promote wider use of this technique.
Fulltext Altered Tryptophan-Kynurenine Pathway in Delirium: A Review of the Current Literature

Phing AH, Makpol S, Nasaruddin ML, Wan Zaidi WA, Ahmad NS, Embong H

Int J Mol Sci, 2023 Mar 15;24(6).
PMID: 36982655 DOI: 10.3390/ijms24065580

Delirium, a common form of acute brain dysfunction, is associated with increased morbidity and mortality, especially in older patients. The underlying pathophysiology of delirium is not clearly understood, but acute systemic inflammation is known to drive delirium in cases of acute illnesses, such as sepsis, trauma, and surgery. Based on psychomotor presentations, delirium has three main subtypes, such as hypoactive, hyperactive, and mixed subtype. There are similarities in the initial presentation of delirium with depression and dementia, especially in the hypoactive subtype. Hence, patients with hypoactive delirium are frequently misdiagnosed. The altered kynurenine pathway (KP) is a promising molecular pathway implicated in the pathogenesis of delirium. The KP is highly regulated in the immune system and influences neurological functions. The activation of indoleamine 2,3-dioxygenase, and specific KP neuroactive metabolites, such as quinolinic acid and kynurenic acid, could play a role in the event of delirium. Here, we collectively describe the roles of the KP and speculate on its relevance in delirium.
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.

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