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  1. 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.
  2. Fulltext A Review of L-Asparaginase Hypersensitivity in Paediatric Acute Lymphoblastic Leukaemia Patients with Regard to the Measurement of Anti-Asparaginase Antibodies and Their Genetic Predisposition
    Tan YQ, Loh CK, Makpol S
    Malays J Med Sci, 2023 Oct;30(5):40-51.
    PMID: 37928798 DOI: 10.21315/mjms2023.30.5.4
    L-asparaginase is effective as part of the first line childhood acute lymphoblastic leukaemia (ALL) treatment regimen but suffers the risk of antibody production causing immune-mediated sequelae. This article aimed to describe the clinical implication of L-asparaginase hypersensitivity and review the types of antibodies and genetic polymorphisms contributing to it. Clinical or subclinical L-asparaginase hypersensitivity may lead to suboptimum therapeutic effect and jeopardise the clinical outcome in ALL children. Anti-asparaginase antibodies immunoglobulin (Ig)G, IgM and IgE were identified in the L-asparaginase hypersensitivities. Enzyme-linked immunosorbent assay (ELISA) is commonly used to quantify the IgG and IgM levels. The role of IgE in mediating L-asparaginase hypersensitivity is contradictory. Moreover, the presence of antibodies may not necessarily correlate inversely with the L-asparaginase efficacies in some studies. Patients with specific genetic variants have been shown to be more susceptible to clinical hypersensitivity of L-asparaginase. With the advance of technology, gene polymorphisms have been identified among Caucasians using whole-genome or exon sequencing, but the evidence is scanty among Asians. There is lack of pre-clinical study models that could help in understanding the pathophysiological pathway co-relating the gene expression and anti-asparaginase antibody formation. In conclusion, future research studies are required to fill the current gap in understanding the immune mediated reactions towards L-asparaginase upon its administration and its potential impact to the disease outcome.
  3. Fulltext Effects of Vitamin E on the Gut Microbiome in Ageing and Its Relationship with Age-Related Diseases: A Review of the Current Literature
    Gothandapani D, Makpol S
    Int J Mol Sci, 2023 Sep 28;24(19).
    PMID: 37834115 DOI: 10.3390/ijms241914667
    Ageing is inevitable in all living organisms and is associated with physical deterioration, disease and eventually death. Dysbiosis, which is the alteration of the gut microbiome, occurs in individuals during ageing, and plenty of studies support that gut dysbiosis is responsible for the progression of different types of age-related diseases. The economic burden of age-linked health issues increases as ageing populations increase. Hence, an improvement in disease prevention or therapeutic approaches is urgently required. In recent years, vitamin E has garnered significant attention as a promising therapeutic approach for delaying the ageing process and potentially impeding the development of age-related disease. Nevertheless, more research is still required to understand how vitamin E affects the gut microbiome and how it relates to age-related diseases. Therefore, we gathered and summarized recent papers in this review that addressed the impact of the gut microbiome on age-related disease, the effect of vitamin E on age-related disease along with the role of vitamin E on the gut microbiome and the relationship with age-related diseases which are caused by ageing. Based on the studies reported, different bacteria brought on various age-related diseases with either increased or decreased relative abundances. Some studies have also reported the positive effects of vitamin E on the gut microbiome as beneficial bacteria and metabolites increase with vitamin E supplementation. This demonstrates how vitamin E is vital as it affects the gut microbiome positively to delay ageing and the progression of age-related diseases. The findings discussed in this review will provide a simplified yet deeper understanding for researchers studying ageing, the gut microbiome and age-related diseases, allowing them to develop new preclinical and clinical studies.
  4. 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.
  5. Fulltext Suppression of Inflamm-Aging by Moringa oleifera and Zingiber officinale Roscoe in the Prevention of Degenerative Diseases: A Review of Current Evidence
    Mohd Sahardi NFN, Makpol S
    Molecules, 2023 Aug 03;28(15).
    PMID: 37570837 DOI: 10.3390/molecules28155867
    Inflammation or inflamm-aging is a chronic low-grade inflammation that contributes to numerous types of degenerative diseases among the elderly and might be impeded by introducing an anti-inflammatory agent like Moringa oleifera Lam (moringa) and Zingiber officinale Roscoe (ginger). Therefore, this paper aims to review the role of moringa and ginger in suppressing inflamm-aging to prevent degenerative diseases. Various peer-reviewed publications were searched and downloaded using the reputed search engine "Pubmed" and "Google Scholar". These materials were reviewed and tabulated. A comparison between these previous findings was made based on the mechanism of action of moringa and ginger against degenerative diseases, focusing on their anti-inflammatory properties. Many studies have reported the efficacy of moringa and ginger in type 2 diabetes mellitus, neurodegenerative disease, cardiovascular disease, cancer, and kidney disease by reducing inflammatory cytokines activities, mainly of TNF-α and IL-6. They also enhanced the activity of antioxidant enzymes, including catalase, glutathione, and superoxide dismutase. The anti-inflammatory activities can be seen by inhibiting NF-κβ activity. Thus, the anti-inflammatory potential of moringa and ginger in various types of degenerative diseases due to inflamm-aging has been shown in many recent types of research.
  6. 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.
  7. Fulltext Alcohol Dependence Modulates Amygdalar mTORC2 and PKCε Expression in a Rodent Model
    Hanim A, Mohamed IN, Mohamed RMP, Mokhtar MH, Makpol S, Naomi R, et al.
    Nutrients, 2023 Jul 05;15(13).
    PMID: 37447362 DOI: 10.3390/nu15133036
    Multiple alcohol use disorder (AUD)-related behavioral alterations are governed by protein kinase C epsilon (PKCε), particularly in the amygdala. Protein kinase C (PKC) is readily phosphorylated at Ser729 before activation by the mTORC2 protein complex. In keeping with this, the current study was conducted to assess the variations in mTORC2 and PKCε during different ethanol exposure stages. The following groups of rats were employed: control, acute, chronic, ethanol withdrawal (EW), and EW + ethanol (EtOH). Ethanol-containing and non-ethanol-containing modified liquid diets (MLDs) were administered for 27 days. On day 28, either saline or ethanol (2.5 g/kg, 20% v/v) was intraperitoneally administered, followed by bilateral amygdala extraction. PKCε mRNA levels were noticeably increased in the amygdala of the EW + EtOH and EW groups. Following chronic ethanol consumption, the stress-activated map kinase-interacting protein 1 (Sin1) gene expression was markedly decreased. In the EW, EW + EtOH, and chronic ethanol groups, there was a profound increase in the protein expression of mTOR, Sin1, PKCε, and phosphorylated PKCε (Ser729). The PKCε gene and protein expressions showed a statistically significant moderate association, according to a correlation analysis. Our results suggest that an elevated PKCε protein expression in the amygdala during EW and EW + EtOH occurred at the transcriptional level. However, an elevation in the PKCε protein expression, but not its mRNA, after chronic ethanol intake warrants further investigation to fully understand the signaling pathways during different episodes of AUD.
  8. 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.
  9. 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.
  10. 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.

  11. Fulltext Effects of Microalgae on Metabolic Syndrome
    Tamel Selvan K, Goon JA, Makpol S, Tan JK
    Antioxidants (Basel), 2023 Feb 10;12(2).
    PMID: 36830009 DOI: 10.3390/antiox12020449
    Metabolic syndrome (MetS) is a cluster of metabolic disturbances, including abdominal obesity, hypertension, hypertriglyceridemia, reduced high-density lipoprotein cholesterol (HDL-C) and hyperglycemia. Adopting a healthier lifestyle and multiple drug-based therapies are current ways to manage MetS, but they have limited efficacy, albeit the prevalence of MetS is rising. Microalgae is a part of the human diet and has also been consumed as a health supplement to improve insulin sensitivity, inflammation, and several components of MetS. These therapeutic effects of microalgae are attributed to the bioactive compounds present in them that exhibit antioxidant, anti-inflammatory, anti-obesity, antihypertensive, hepatoprotective and immunomodulatory effects. Therefore, studies investigating the potential of microalgae in alleviating MetS are becoming more popular, but a review on this topic remains scarce. In this review, we discuss the effects of microalgae, specifically on MetS, by reviewing the evidence from scientific literature covering in vitro and in vivo studies. In addition, we also discuss the underlying mechanisms that modulate the effects of microalgae on MetS, and the limitations and future perspectives of developing microalgae as a health supplement for MetS. Microalgae supplementation is becoming a viable approach in alleviating metabolic disturbances and as a unique addition to the management of MetS.
  12. Fulltext A subcritical water extract of soil grown Zingiber officinale Roscoe: Comparative analysis of antioxidant and anti-inflammatory effects and evaluation of bioactive metabolites
    Razak AM, Zakaria SNA, Abdul Sani NF, Ab Rani N, Hakimi NH, Mohd Said M, et al.
    Front Pharmacol, 2023;14:1006265.
    PMID: 36843947 DOI: 10.3389/fphar.2023.1006265
    Introduction: Ginger (Zingiber officinale Roscoe) can scavenge free radicals, which cause oxidative damage and inflamm-ageing. This study aimed to evaluate the antioxidant and anti-inflammatory effects of soil ginger's sub-critical water extracts (SWE) on different ages of Sprague Dawley (SD) rats. The antioxidant properties and yield of SWE of soil- and soilless-grown ginger (soil ginger and soilless ginger will be used throughout the passage) were compared and evaluated. Methods: Three (young), nine (adult), and twenty-one (old) months old SD rats were subjected to oral gavage treatments with either distilled water or the SWE of soil ginger at a concentration of 200 mg/kg body weight (BW) for three months. Results: Soil ginger was found to yield 46% more extract than soilless ginger. While [6]-shogaol was more prevalent in soilless ginger, and [6]-gingerol concentration was higher in soil ginger (p < 0.05). Interestingly, soil ginger exhibited higher antioxidant activities than soilless ginger by using 2,2-diphenyl-1-(2,4,6-trinitrophenyl) hydrazyl (DPPH) and ferric reducing antioxidant power (FRAP) assay. With ginger treatment, a reduced levels of tumour necrosis factor-α (TNF-α) and C-reactive protein (CRP) but not interleukin-6 (IL-6) were observed in young rats. In all ages of SD rats, ginger treatment boosted catalase activity while lowering malondialdehyde (MDA). Reduction of urine 15-isoprostane F2t in young rats, creatine kinase-MM (CK-MM) in adult and old rats and lipid peroxidation (LPO) in young and adult rats were also observed. Discussion: The findings confirmed that the SWE of both soil and soilless grown ginger possessed antioxidant activities. Soil ginger produced a higher yield of extracts with a more prominent antioxidant activity. The SWE of soil ginger treatment on the different ages of SD rats ameliorates oxidative stress and inflammation responses. This could serve as the basis for developing a nutraceutical that can be used as a therapeutic intervention for ageing-related diseases.
  13. Fulltext Metabolomics Profiling of Age-Associated Metabolites in Malay Population
    Tan JK, Zakaria SNA, Gunasekaran G, Abdul Sani NF, Nasaruddin ML, Jaafar F, et al.
    Oxid Med Cell Longev, 2023;2023:4416410.
    PMID: 36785791 DOI: 10.1155/2023/4416410
    Aging is a complex process characterized by progressive loss of functional abilities due to the accumulation of molecular damages. Metabolomics could offer novel insights into the predictors and mechanisms of aging. This cross-sectional study is aimed at identifying age-associated plasma metabolome in a Malay population. A total of 146 (90 females) healthy participants aged 28-69 were selected for the study. Untargeted metabolomics profiling was performed using liquid chromatography-tandem mass spectrometry. Association analysis was based on the general linear model. Gender-associated metabolites were adjusted for age, while age-associated metabolites were adjusted for gender or analyzed in a gender-stratified manner. Gender-associated metabolites such as 4-hydroxyphenyllactic acid, carnitine, cortisol, and testosterone sulfate showed higher levels in males than females. Deoxycholic acid and hippuric acid were among the metabolites with a positive association with age after being adjusted for gender, while 9(E),11(E)-conjugated linoleic acid, cortisol, and nicotinamide were negatively associated with age. In gender-stratified analysis, glutamine was one of the common metabolites that showed a direct association with age in both genders, while metabolites such as 11-deoxy prostaglandin F2β, guanosine monophosphate, and testosterone sulfate were inversely associated with age in males and females. This study reveals several age-associated metabolites in Malays that could reflect the changes in metabolisms during aging and may be used to discern the risk of geriatric syndromes and disorders later. Further studies are required to determine the interplay between these metabolites and environmental factors on the functional outcomes during aging.
  14. 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.
  15. 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.
  16. Fulltext A review of the preclinical and clinical studies on the role of the gut microbiome in aging and neurodegenerative diseases and its modulation
    Hashim HM, Makpol S
    Front Cell Neurosci, 2022;16:1007166.
    PMID: 36406749 DOI: 10.3389/fncel.2022.1007166
    As the world population ages, the burden of age-related health problems grows, creating a greater demand for new novel interventions for healthy aging. Advancing aging is related to a loss of beneficial mutualistic microbes in the gut microbiota caused by extrinsic and intrinsic factors such as diet, sedentary lifestyle, sleep deprivation, circadian rhythms, and oxidative stress, which emerge as essential elements in controlling and prolonging life expectancy of healthy aging. This condition is known as gut dysbiosis, and it affects normal brain function via the brain-gut microbiota (BGM) axis, which is a bidirectional link between the gastrointestinal tract (GIT) and the central nervous system (CNS) that leads to the emergence of brain disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD). Here, we reviewed the role of the gut microbiome in aging and neurodegenerative diseases, as well as provided a comprehensive review of recent findings from preclinical and clinical studies to present an up-to-date overview of recent advances in developing strategies to modulate the intestinal microbiome by probiotic administration, dietary intervention, fecal microbiota transplantation (FMT), and physical activity to address the aging process and prevent neurodegenerative diseases. The findings of this review will provide researchers in the fields of aging and the gut microbiome design innovative studies that leverage results from preclinical and clinical studies to better understand the nuances of aging, gut microbiome, and neurodegenerative diseases.
  17. 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.
  18. Fulltext Alpha- and Gamma-Tocopherol Modulates the Amyloidogenic Pathway of Amyloid Precursor Protein in an in vitro Model of Alzheimer's Disease: A Transcriptional Study
    Pahrudin Arrozi A, Shukri SNS, Mohd Murshid N, Ahmad Shahzalli AB, Wan Ngah WZ, Ahmad Damanhuri H, et al.
    Front Cell Neurosci, 2022;16:846459.
    PMID: 35614968 DOI: 10.3389/fncel.2022.846459
    The amyloid precursor protein (APP) processing pathway was altered in Alzheimer's disease (AD) and contributed to abnormal amyloid-beta (Aβ) production, which forms insoluble interneuron protein aggregates known as amyloid plaques in the brain. Targeting the APP processing pathway is still fundamental for AD modifying therapy. Extensive research has evaluated the protective effects of vitamin E as an antioxidant and as a signaling molecule. The present study aimed to investigate the modulatory effects of different tocopherol isomers on the expression of genes involved in regulating the APP processing pathway in vitro. The screening for the effective tocopherol isomers in reducing APP expression and Aβ-42 was carried out in SH-SY5Y stably overexpressed APP Swedish. Subsequently, quantitative one-step real-time PCR was performed to determine the modulatory effects of selected tocopherol isomers on the expression of genes in SH-SY5Y stably overexpressed three different types of APP (wild-type, APP Swedish, and APP Swedish/Indiana). Our results showed that all tocopherol isomers, especially at higher concentrations (80-100 μM), significantly increased (p < 0.05) the cell viability in all cells group, but only α-tocopherol (ATF) and γ-tocopherol (GTF) significantly decreased (p < 0.05) the APP mRNA level without statistically significant APP protein level, accompanied with a reduced significance (p < 0.05) on the level of Aβ-42 in SH-SY5Y APP Swedish. On the other hand, β- and δ-tocopherol (BTF and DTF) showed no effects on the level of APP expression and Aβ-42. Subsequent results demonstrated that ATF and GTF significantly decreased (p < 0.05) the expression of gene beta-site APP cleaving enzyme (BACE1), APH1B, and Nicastrin (NCSTN), but significantly increased (p < 0.05) the expression of Sirtuin 1 (SIRT1) in SH-SY5Y stably expressed the mutant APP form. These findings suggested that ATF and GTF could modulate altered pathways and may help ameliorate the burden of amyloid load in AD.
  19. 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.
  20. 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.
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