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  1. Fulltext Fluorine-19 Magnetic Resonance Imaging for Detection of Amyloid β Oligomers Using a Keto Form of Curcumin Derivative in a Mouse Model of Alzheimer's Disease
    Yanagisawa D, Ibrahim NF, Taguchi H, Morikawa S, Tomiyama T, Tooyama I
    Molecules, 2021 Mar 04;26(5).
    PMID: 33806326 DOI: 10.3390/molecules26051362
    Recent evidence suggests that the formation of soluble amyloid β (Aβ) aggregates with high toxicity, such as oligomers and protofibrils, is a key event that causes Alzheimer's disease (AD). However, understanding the pathophysiological role of such soluble Aβ aggregates in the brain in vivo could be difficult due to the lack of a clinically available method to detect, visualize, and quantify soluble Aβ aggregates in the brain. We had synthesized a novel fluorinated curcumin derivative with a fixed keto form, named as Shiga-Y51, which exhibited high selectivity to Aβ oligomers in vitro. In this study, we investigated the in vivo detection of Aβ oligomers by fluorine-19 (19F) magnetic resonance imaging (MRI) using Shiga-Y51 in an APP/PS1 double transgenic mouse model of AD. Significantly high levels of 19F signals were detected in the upper forebrain region of APP/PS1 mice compared with wild-type mice. Moreover, the highest levels of Aβ oligomers were detected in the upper forebrain region of APP/PS1 mice in enzyme-linked immunosorbent assay. These findings suggested that 19F-MRI using Shiga-Y51 detected Aβ oligomers in the in vivo brain. Therefore, 19F-MRI using Shiga-Y51 with a 7 T MR scanner could be a powerful tool for imaging Aβ oligomers in the brain.
  2. Fluorine-19 magnetic resonance imaging probe for the detection of tau pathology in female rTg4510 mice
    Yanagisawa D, Ibrahim NF, Taguchi H, Morikawa S, Kato T, Hirao K, et al.
    J Neurosci Res, 2018 05;96(5):841-851.
    PMID: 29063641 DOI: 10.1002/jnr.24188
    Aggregation of tau into neurofibrillary tangles (NFTs) is characteristic of tauopathies, including Alzheimer's disease. Recent advances in tau imaging have attracted much attention because of its potential contributions to early diagnosis and monitoring of disease progress. Fluorine-19 magnetic resonance imaging (19 F-MRI) may be extremely useful for tau imaging once a high-quality probe has been formulated. In this investigation, a novel fluorine-19-labeling compound has been developed as a probe for tau imaging using 19 F-MRI. This compound is a buta-1,3-diene derivative with a polyethylene glycol side chain bearing a CF3 group and is known as Shiga-X35. Female rTg4510 mice (a mouse model of tauopathy) and wild-type mice were intravenously injected with Shiga-X35, and magnetic resonance imaging of each mouse's head was conducted in a 7.0-T horizontal-bore magnetic resonance scanner. The 19 F-MRI in rTg4510 mice showed an intense signal in the forebrain region. Analysis of the signal intensity in the forebrain region revealed a significant accumulation of fluorine-19 magnetic resonance signal in the rTg4510 mice compared with the wild-type mice. Histological analysis showed fluorescent signals of Shiga-X35 binding to the NFTs in the brain sections of rTg4510 mice. Data collected as part of this investigation indicate that 19 F-MRI using Shiga-X35 could be a promising tool to evaluate tau pathology in the brain.
  3. Fulltext The effect of α-tocopherol, α- and γ-tocotrienols on amyloid-β aggregation and disaggregation in vitro
    Ibrahim NF, Hamezah HS, Yanagisawa D, Tsuji M, Kiuchi Y, Ono K, et al.
    Biochem Biophys Rep, 2021 Dec;28:101131.
    PMID: 34541343 DOI: 10.1016/j.bbrep.2021.101131
    One of the neuropathological hallmarks of Alzheimer's disease (AD)-causing neurodegeneration and consequent memory deterioration, and eventually, cognitive decline-is amyloid-β (Aβ) aggregation forming amyloid plaques. Our previous study showed the potential of a tocotrienol-rich fraction-a mixture of naturally occurring of vitamin E analogs-to inhibit Aβ aggregation and restore cognitive function in an AD mouse model. The current study examined the effect of three vitamin E analogs-α-tocopherol (α-TOC), α-tocotrienol (α-T3), and γ-tocotrienol (γ-T3)-on Aβ aggregation, disaggregation, and oligomerization in vitro. Thioflavin T (ThT) assay showed α-T3 reduced Aβ aggregation at 10 μM concentration. Furthermore, both α-T3 and γ-T3 demonstrated Aβ disaggregation, as shown by the reduction of ThT fluorescence. However, α-TOC showed no significant effect. We confirmed the results for ThT assays with scanning electron microscopy imaging. Further investigation in photo-induced cross-linking of unmodified protein assay indicated a reduction in Aβ oligomerization by γ-T3. The present study thus revealed the individual effect of each tocotrienol analog in reducing Aβ aggregation and oligomerization as well as disaggregating preformed fibrils.
  4. Alternative sweeteners influence the biomass of oral biofilm
    Abdul Razak F, Baharuddin BA, Akbar EFM, Norizan AH, Ibrahim NF, Musa MY
    Arch Oral Biol, 2017 Aug;80:180-184.
    PMID: 28448807 DOI: 10.1016/j.archoralbio.2017.04.014
    OBJECTIVE: Compact-structured oral biofilm accumulates acids that upon prolonged exposure to tooth surface, causes demineralisation of enamel. This study aimed to assess the effect of alternative sweeteners Equal Stevia(®), Tropicana Slim(®), Pal Sweet(®) and xylitol on the matrix-forming activity of plaque biofilm at both the early and established stages of formation.

    METHODS: Saliva-coated glass beads (sGB) were used as substratum for the adhesion of a mixed-bacterial suspension of Streptococcus mutans, Streptococcus sanguinis and Streptococcus mitis. Biofilms formed on sGB at 3h and 24h represented the early and established-plaque models. The biofilms were exposed to three doses of the sweeteners (10%), introduced at three intervals to simulate the exposure of dental plaque to sugar during three consecutive food intakes. The treated sGB were (i) examined under the SEM and (ii) collected for turbidity reading. The absorbance indicated the amount of plaque mass produced. Analysis was performed comparative to sucrose as control.

    RESULTS: Higher rate of bacterial adherence was determined during the early compared to established phases of formation. Comparative to the sweeteners, sucrose showed a 40% increase in bacterial adherence and produced 70% more plaque-mass. Bacterial counts and SEM micrographs exhibited absence of matrix in all the sweetener-treated biofilms at the early phase of formation. At the established phase, presence of matrix was detected but at significantly lower degree compared to sucrose (p<0.05).

    CONCLUSION: Alternatives sweeteners promoted the formation of oral biofilm with lighter mass and lower bacterial adherence. Hence, suggesting alternative sweeteners as potential antiplaque agents.

  5. Fulltext Age-related changes in the metabolic profiles of rat hippocampus, medial prefrontal cortex and striatum
    Durani LW, Hamezah HS, Ibrahim NF, Yanagisawa D, Makpol S, Damanhuri HA, et al.
    Biochem Biophys Res Commun, 2017 11 25;493(3):1356-1363.
    PMID: 28970069 DOI: 10.1016/j.bbrc.2017.09.164
    We have recently shown that age-dependent regional brain atrophy and lateral ventricle expansion may be linked with impaired cognitive and locomotor functions. However, metabolic profile transformation in different brain regions during aging is unknown. This study examined metabolic changes in the hippocampus, medial prefrontal cortex (mPFC) and striatum of middle- and late-aged Sprague-Dawley rats using ultrahigh performance liquid chromatography coupled with high-resolution accurate mass-orbitrap tandem mass spectrometry. Thirty-eight potential metabolites were altered in hippocampus, 29 in mPFC, and 14 in striatum. These alterations indicated that regional metabolic mechanisms in lated-aged rats are related to multiple pathways including glutathione, sphingolipid, tyrosine, and purine metabolism. Thus, our findings might be useful for understanding the complexity of metabolic mechanisms in aging and provide insight for aging and health span.
  6. Fulltext Seasonal benthic species composition linked to coastal defense structures (CDS) in Kuala Nerus, Terengganu, Malaysia
    Ibrahim NF, Abd Hamid M, Mohd Akhir MF, Chuan Ong M, Wan Talaat WIA, Idris I
    PeerJ, 2023;11:e16203.
    PMID: 38025728 DOI: 10.7717/peerj.16203
    BACKGROUND: The natural hydrodynamic process of Kuala Nerus, Terengganu, has changed since the extension of Sultan Mahmud Airport runway in 2008. Consequently, severe coastal erosion has occurred in the area, particularly during the northeast monsoon season (NEM). Numerous types of coastal defense structures (CDS) have been constructed to protect the coastline. Despite the loss of esthetic values, the effect of CDS construction on marine organisms in the area remains unknown. Hence, this study aims to assess the ecological aspects of macrobenthic compositions at the CDS area of Kuala Nerus, Terengganu, based on the differences between the southwest (SWM) and northeast (NEM) monsoon seasons.

    METHODS: Macrobenthos were collected from the sediment in July (SWM) and December 2021 (NEM) using the Ponar grab at 12 substations from five sampling stations.

    RESULTS: The density of macrobenthos was higher in SWM (48,190.82 ind./m2) than in NEM (24,504.83 ind./m2), with phylum Mollusca recording the highest species composition (60-99.3%). The macrobenthos species had a low to moderate level of diversity (H' = 1.4-3.1) with the species were almost evenly distributed (J' = 0.2-0.8). Windward substations exhibited coarser grain sizes (38.56%-86.84%), whereas landward substations exhibited very fine grain sizes (44.26%-86.70%). The SWM season recorded a higher organic matter content (1.6%-6.33%) than the NEM season (0.4%-3.1%). However, metal concentrations in the surface sediment were within the safe range and permissible limits for both seasons, inferring that the macrobenthos composition was unaffected.

    DISCUSSION: This study demonstrated that the CDS associated with the monsoon system has controlled the hydrodynamics and nearshore sedimentary processes in the Kuala Nerus coastal zone, thereby affecting the macrobenthos population, in terms of richness and density. The ecological and energetic effects of the coastal structures in different seasons have resulted in a more significant result, with the SWM exhibiting a higher macrobenthos composition than the NEM.

  7. PERMA well-being and innovative work behaviour : A systematic literature review
    Ibrahim NF, Mohamad Sharif S, Saleh H, Mat Hasan NH, Jayiddin NF
    F1000Res, 2023;12:1338.
    PMID: 38152588 DOI: 10.12688/f1000research.141629.1
    Background: The purpose of this research is to examine at how the literature measures the relationship between PERMA (positive emotion, engagement, relationships, meaning, and accomplishments) well-being and innovative work behaviour (IWB). Methods: This systematic literature review examines peer-reviewed English research papers published in 2012 that investigate the relationship between PERMA well-being and IWB. A total of 37 publications were discovered in 32 journals. Results: A total of 220 articles were initially retrieved from the database. 37 studies out of 220 satisfied the inclusion criteria and were thoroughly examined. Our findings present a comprehensive overview of the types of PERMA well-being related to IWB in different countries and industries. Literature-based research approaches are also discussed. Research methods from the previous literature are also discussed. Conclusions: This study is one of the first to conduct a systematic literature review (PRISMA) method on the relationship between PERMA well-being and IWB. This review suggests constructive future research directions.
  8. Amyloid imaging using fluorine-19 magnetic resonance imaging ((19)F-MRI)
    Tooyama I, Yanagisawa D, Taguchi H, Kato T, Hirao K, Shirai N, et al.
    Ageing Res Rev, 2016 09;30:85-94.
    PMID: 26772439 DOI: 10.1016/j.arr.2015.12.008
    The formation of senile plaques followed by the deposition of amyloid-β is the earliest pathological change in Alzheimer's disease. Thus, the detection of senile plaques remains the most important early diagnostic indicator of Alzheimer's disease. Amyloid imaging is a noninvasive technique for visualizing senile plaques in the brains of Alzheimer's patients using positron emission tomography (PET) or magnetic resonance imaging (MRI). Because fluorine-19 ((19)F) displays an intense nuclear magnetic resonance signal and is almost non-existent in the body, targets are detected with a higher signal-to-noise ratio using appropriate fluorinated contrast agents. The recent introduction of high-field MRI allows us to detect amyloid depositions in the brain of living mouse using (19)F-MRI. So far, at least three probes have been reported to detect amyloid deposition in the brain of transgenic mouse models of Alzheimer's disease; (E,E)-1-fluoro-2,5-bis-(3-hydroxycarbonyl-4-hydroxy)styrylbenzene (FSB), 1,7-bis(4'-hydroxy-3'-trifluoromethoxyphenyl)-4-methoxycarbonylethyl-1,6-heptadiene3,5-dione (FMeC1, Shiga-Y5) and 6-(3',6',9',15',18',21'-heptaoxa-23',23',23'-trifluorotricosanyloxy)-2-(4'-dimethylaminostyryl)benzoxazole (XP7, Shiga-X22). This review presents the recent advances in amyloid imaging using (19)F-MRI, including our own studies.
  9. 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.
  10. Tocotrienol-Rich Fraction Modulates Amyloid Pathology and Improves Cognitive Function in AβPP/PS1 Mice
    Ibrahim NF, Yanagisawa D, Durani LW, Hamezah HS, Damanhuri HA, Wan Ngah WZ, et al.
    J Alzheimers Dis, 2017;55(2):597-612.
    PMID: 27716672
    Alzheimer's disease (AD) is the most common cause of dementia. The cardinal neuropathological characteristic of AD is the accumulation of amyloid-β (Aβ) into extracellular plaques that ultimately disrupt neuronal function and lead to neurodegeneration. One possible therapeutic strategy therefore is to prevent Aβ aggregation. Previous studies have suggested that vitamin E analogs slow AD progression in humans. In the present study, we investigated the effects of the tocotrienol-rich fraction (TRF), a mixture of vitamin E analogs from palm oil, on amyloid pathology in vitro and in vivo. TRF treatment dose-dependently inhibited the formation of Aβ fibrils and Aβ oligomers in vitro. Moreover, daily TRF supplementation to AβPPswe/PS1dE9 double transgenic mice for 10 months attenuated Aβ immunoreactive depositions and thioflavin-S-positive fibrillar type plaques in the brain, and eventually improved cognitive function in the novel object recognition test compared with control AβPPswe/PS1dE9 mice. The present result indicates that TRF reduced amyloid pathology and improved cognitive functions, and suggests that TRF is a potential therapeutic agent for AD.
  11. Fulltext Volumetric changes in the aging rat brain and its impact on cognitive and locomotor functions
    Hamezah HS, Durani LW, Ibrahim NF, Yanagisawa D, Kato T, Shiino A, et al.
    Exp Gerontol, 2017 12 01;99:69-79.
    PMID: 28918364 DOI: 10.1016/j.exger.2017.09.008
    Impairments in cognitive and locomotor functions usually occur with advanced age, as do changes in brain volume. This study was conducted to assess changes in brain volume, cognitive and locomotor functions, and oxidative stress levels in middle- to late-aged rats. Forty-four male Sprague-Dawley rats were divided into four groups: 14, 18, 23, and 27months of age. 1H magnetic resonance imaging (MRI) was performed using a 7.0-Tesla MR scanner system. The volumes of the lateral ventricles, medial prefrontal cortex (mPFC), hippocampus, striatum, cerebellum, and whole brain were measured. Open field, object recognition, and Morris water maze tests were conducted to assess cognitive and locomotor functions. Blood was taken for measurements of malondialdehyde (MDA), protein carbonyl content, and antioxidant enzyme activity. The lateral ventricle volumes were larger, whereas the mPFC, hippocampus, and striatum volumes were smaller in 27-month-old rats than in 14-month-old rats. In behavioral tasks, the 27-month-old rats showed less exploratory activity and poorer spatial learning and memory than did the 14-month-old rats. Biochemical measurements likewise showed increased MDA and lower glutathione peroxidase (GPx) activity in the 27-month-old rats. In conclusion, age-related increases in oxidative stress, impairment in cognitive and locomotor functions, and changes in brain volume were observed, with the most marked impairments observed in later age.
  12. 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.
  13. Fulltext Proteome profiling in the hippocampus, medial prefrontal cortex, and striatum of aging rat
    Hamezah HS, Durani LW, Yanagisawa D, Ibrahim NF, Aizat WM, Bellier JP, et al.
    Exp Gerontol, 2018 Oct 01;111:53-64.
    PMID: 29981398 DOI: 10.1016/j.exger.2018.07.002
    Decrease in multiple functions occurs in the brain with aging, all of which can contribute to age-related cognitive and locomotor impairments. Brain atrophy specifically in hippocampus, medial prefrontal cortex (mPFC), and striatum, can contribute to this age-associated decline in function. Our recent metabolomics analysis showed age-related changes in these brain regions. To further understand the aging processes, analysis using a proteomics approach was carried out. This study was conducted to identify proteome profiles in the hippocampus, mPFC, and striatum of 14-, 18-, 23-, and 27-month-old rats. Proteomics analysis using ultrahigh performance liquid chromatography coupled with Q Exactive HF Orbitrap mass spectrometry identified 1074 proteins in the hippocampus, 871 proteins in the mPFC, and 241 proteins in the striatum. Of these proteins, 97 in the hippocampus, 25 in mPFC, and 5 in striatum were differentially expressed with age. The altered proteins were classified into three ontologies (cellular component, molecular function, and biological process) containing 44, 38, and 35 functional groups in the hippocampus, mPFC, and striatum, respectively. Most of these altered proteins participate in oxidative phosphorylation (e.g. cytochrome c oxidase and ATP synthase), glutathione metabolism (e.g. peroxiredoxins), or calcium signaling pathway (e.g. protein S100B and calmodulin). The most prominent changes were observed in the oldest animals. These results suggest that alterations in oxidative phosphorylation, glutathione metabolism, and calcium signaling pathway are involved in cognitive and locomotor impairments in aging.
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