Displaying publications 1 - 20 of 27 in total

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  1. Transcorneal electrical stimulation enhances cognitive functions in aged and 5XFAD mouse models
    Yu WS, Aquili L, Wong KH, Lo ACY, Chan LLH, Chan YS, et al.
    Ann N Y Acad Sci, 2022 09;1515(1):249-265.
    PMID: 35751874 DOI: 10.1111/nyas.14850
    Dementia is a major burden on global health for which there are no effective treatments. The use of noninvasive visual stimulation to ameliorate cognitive deficits is a novel concept that may be applicable for treating dementia. In this study, we investigated the effects of transcorneal electrical stimulation (TES) on memory enhancement using two mouse models, in aged mice and in the 5XFAD model of Alzheimer's disease. After 3 weeks of TES treatment, mice were subjected to Y-maze and Morris water maze tests to assess hippocampal-dependent learning and memory. Immunostaining of the hippocampus of 5XFAD mice was also performed to examine the effects of TES on amyloid plaque pathology. The results showed that TES improved the performance of both aged and 5XFAD mice in memory tests. TES also reduced hippocampal plaque deposition in male, but not female, 5XFAD mice. Moreover, TES significantly reversed the downregulated level of postsynaptic protein 95 in the hippocampus of male 5XFAD mice, suggesting the effects of TES involve a postsynaptic mechanism. Overall, these findings support further investigation of TES as a potential treatment for cognitive dysfunction and mechanistic studies of TES effects in other dementia models.
    Matched MeSH terms: Mice, Transgenic
  2. Sex-specific pleiotropic changes in emotional behavior and alcohol consumption in human α-synuclein A53T transgenic mice during early adulthood
    Kalinichenko LS, Kohl Z, Mühle C, Hassan Z, Hahn A, Schmitt EM, et al.
    J Neurochem, 2024 Mar;168(3):269-287.
    PMID: 38284431 DOI: 10.1111/jnc.16051
    Point mutations in the α-synuclein coding gene may lead to the development of Parkinson's disease (PD). PD is often accompanied by other psychiatric conditions, such as anxiety, depression, and drug use disorders, which typically emerge in adulthood. Some of these point mutations, such as SNCA and A30T, have been linked to behavioral effects that are not commonly associated with PD, especially regarding alcohol consumption patterns. In this study, we investigated whether the familial PD point mutation A53T is associated with changes in alcohol consumption behavior and emotional states at ages not yet characterized by α-synuclein accumulation. The affective and alcohol-drinking phenotypes remained unaltered in female PDGF-hA53T-synuclein-transgenic (A53T) mice during both early and late adulthood. Brain region-specific activation of ceramide-producing enzymes, acid sphingomyelinase (ASM), and neutral sphingomyelinase (NSM), known for their neuroprotective properties, was observed during early adulthood but not in late adulthood. In males, the A53T mutation was linked to a reduction in alcohol consumption in both early and late adulthood. However, male A53T mice displayed increased anxiety- and depression-like behaviors during both early and late adulthood. Enhanced ASM activity in the dorsal mesencephalon and ventral hippocampus may potentially contribute to these adverse behavioral effects of the mutation in males during late adulthood. In summary, the A53T gene mutation was associated with diverse changes in emotional states and alcohol consumption behavior long before the onset of PD, and these effects varied by sex. These alterations in behavior may be linked to changes in brain ceramide metabolism.
    Matched MeSH terms: Mice, Transgenic
  3. Absence of beta-amyloid deposition in the central nervous system of a transgenic mouse model of distal myopathy with rimmed vacuoles
    Anada RP, Wong KT, Malicdan MC, Goh KJ, Hayashi Y, Nishino I, et al.
    Amyloid, 2014 Jun;21(2):138-9.
    PMID: 24601867 DOI: 10.3109/13506129.2014.889675
    Matched MeSH terms: Mice, Transgenic
  4. Fulltext Tocotrienol Rich Fraction Supplementation Modulate Brain Hippocampal Gene Expression in APPswe/PS1dE9 Alzheimer's Disease Mouse Model
    Wan Nasri WN, Makpol S, Mazlan M, Tooyama I, Wan Ngah WZ, Damanhuri HA
    J Alzheimers Dis, 2019;70(s1):S239-S254.
    PMID: 30507571 DOI: 10.3233/JAD-180496
    Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by loss of memory and other cognitive abilities. AD is associated with aggregation of amyloid-β (Aβ) deposited in the hippocampal brain region. Our previous work has shown that tocotrienol rich fraction (TRF) supplementation was able to attenuate the blood oxidative status, improve behavior, and reduce fibrillary-type Aβ deposition in the hippocampus of an AD mouse model. In the present study, we investigate the effect of 6 months of TRF supplementation on transcriptome profile in the hippocampus of APPswe/PS1dE9 double transgenic mice. TRF supplementation can alleviate AD conditions by modulating several important genes in AD. Moreover, TRF supplementation attenuated the affected biological process and pathways that were upregulated in the AD mouse model. Our findings indicate that TRF supplementation can modulate hippocampal gene expression as well as biological processes that can potentially delay the progression of AD.
    Matched MeSH terms: Mice, Transgenic
  5. Ciproxifan improves cholinergic transmission, attenuates neuroinflammation and oxidative stress but does not reduce amyloid level in transgenic mice
    Mani V, Jaafar SM, Azahan NSM, Ramasamy K, Lim SM, Ming LC, et al.
    Life Sci, 2017 Jul 01;180:23-35.
    PMID: 28501482 DOI: 10.1016/j.lfs.2017.05.013
    AIM: The present study is aimed to investigate the ability of ciproxifan, a histamine H3 receptor antagonist to inhibit β-amyloid (Aβ)-induced neurotoxicity in SK-N-SH cells and APP transgenic mouse model.

    MATERIALS AND METHODS: In vitro studies was designed to evaluate the neuroprotective effects of ciproxifan in Aβ25-35 - induced SK-N-SH cells. For the in vivo study, ciproxifan (1 and 3mg/kg, i.p.) was administrated to transgenic mice for 15days and behaviour was assessed using the radial arm maze (RAM). Brain tissues were collected to measure Aβ levels (Aβ1-40 and Aβ1-42), acetylcholine (ACh), acetylcholinesterase (AChE), nitric oxide (NO), lipid peroxidation (LPO), antioxidant activities, cyclooxygenases (COX) and cytokines (IL-1α, IL-1β and IL-6), while plasma was collected to measure TGF-1β.

    RESULTS: The in vitro studies demonstrated neuroprotective effect of ciproxifan by increasing cell viability and inhibiting reactive oxygen species (ROS) in Aβ25-35-induced SK-N-SH cells. Ciproxifan significantly improved the behavioural parameters in RAM. Ciproxifan however, did not alter the Aβ levels in APP transgenic mice. Ciproxifan increased ACh and showed anti-oxidant properties by reducing NO and LPO levels as well as enhancing antioxidant levels. The neuroinflammatory analysis showed that ciproxifan reduced both COX-1 and COX-2 activities, decreased the level of pro-inflammatory cytokines IL-1α, IL-1β and IL-6 and increased the level of anti-inflammatory cytokine TGF-1β.

    CONCLUSION: This present study provides scientific evidence of the use of ciproxifan via antioxidant and cholinergic pathways in the management of AD.

    Matched MeSH terms: Mice, Transgenic
  6. Fulltext Characterization and potential roles of bone marrow-derived stromal cells in cancer development and metastasis
    Kawai H, Tsujigiwa H, Siar CH, Nakano K, Takabatake K, Fujii M, et al.
    Int J Med Sci, 2018;15(12):1406-1414.
    PMID: 30275769 DOI: 10.7150/ijms.24370
    Background: The tumor microenvironment and its stromal cells play an important role in cancer development and metastasis. Bone marrow-derived cells (BMDCs), a rich source of hematopoietic and mesenchymal stem cells, putatively contribute to this tumoral stroma. However their characteristics and roles within the tumor microenvironment are unclear. In the present study, BMDCs in the tumor microenvironment were traced using the green fluorescent protein (GFP) bone marrow transplantation model. Methods: C57BL/6 mice were irradiated and rescued by bone marrow transplantation from GFP-transgenic mice. Lewis lung cancer cells were inoculated into the mice to generate subcutaneous allograft tumors or lung metastases. Confocal microscopy, immunohistochemistry for GFP, α-SMA, CD11b, CD31, CD34 and CD105, and double-fluorescent immunohistochemistry for GFP-CD11b, GFP-CD105 and GFP-CD31 were performed. Results: Round and dendritic-shaped GFP-positive mononuclear cells constituted a significant stromal subpopulation in primary tumor peripheral area (PA) and metastatic tumor area (MA) microenvironment, thus implicating an invasive and metastatic role for these cells. CD11b co-expression in GFP-positive cells suggests that round/dendritic cell subpopulations are possibly BM-derived macrophages. Identification of GFP-positive mononuclear infiltrates co-expressing CD31 suggests that these cells might be BM-derived angioblasts, whereas their non-reactivity for CD34, CD105 and α-SMA implies an altered vascular phenotype distinct from endothelial cells. Significant upregulation of GFP-positive, CD31-positive and GFP/CD31 double-positive cell densities positively correlated with PA and MA (P<0.05). Conclusion: Taken together, in vivo evidence of traceable GFP-positive BMDCs in primary and metastatic tumor microenvironment suggests that recruited BMDCs might partake in cancer invasion and metastasis, possess multilineage potency and promote angiogenesis.
    Matched MeSH terms: Mice, Transgenic
  7. Fulltext Predisposition to Alzheimer's and Age-Related Brain Pathologies by PM2.5 Exposure: Perspective on the Roles of Oxidative Stress and TRPM2 Channel
    Wang L, Wei LY, Ding R, Feng Y, Li D, Li C, et al.
    Front Physiol, 2020;11:155.
    PMID: 32174842 DOI: 10.3389/fphys.2020.00155
    Accumulating epidemiological evidence supports that chronic exposure to ambient fine particular matters of <2.5 μm (PM2.5) predisposes both children and adults to Alzheimer's disease (AD) and age-related brain damage leading to dementia. There is also experimental evidence to show that PM2.5 exposure results in early onset of AD-related pathologies in transgenic AD mice and development of AD-related and age-related brain pathologies in healthy rodents. Studies have also documented that PM2.5 exposure causes AD-linked molecular and cellular alterations, such as mitochondrial dysfunction, synaptic deficits, impaired neurite growth, neuronal cell death, glial cell activation, neuroinflammation, and neurovascular dysfunction, in addition to elevated levels of amyloid β (Aβ) and tau phosphorylation. Oxidative stress and the oxidative stress-sensitive TRPM2 channel play important roles in mediating multiple molecular and cellular alterations that underpin AD-related cognitive dysfunction. Documented evidence suggests critical engagement of oxidative stress and TRPM2 channel activation in various PM2.5-induced cellular effects. Here we discuss recent studies that favor causative relationships of PM2.5 exposure to increased AD prevalence and AD- and age-related pathologies, and raise the perspective on the roles of oxidative stress and the TRPM2 channel in mediating PM2.5-induced predisposition to AD and age-related brain damage.
    Matched MeSH terms: Mice, Transgenic
  8. Hydrogel-gauze dressing for moderate-to-severe atopic dermatitis: development and efficacy study on atopic dermatitis-like skin lesions in NC/Nga mice
    Ng SF, Lew PC, Sin YB
    Drug Dev Ind Pharm, 2014 Nov;40(11):1538-46.
    PMID: 24025072 DOI: 10.3109/03639045.2013.836214
    Topical emollients are known to provide symptomatic relief for atopic dermatitis. In hospitals, wet-wrap therapy has been shown to benefit children with moderate-to-severe atopic dermatitis (AD), but the application of wet-wraps is tedious and time-consuming. Topical emollients have low residence time and often dry out easily. The aim of this work was to develop a hydrogel-gauze dressing that is not only easy to apply but also rehydrates and traps moisture to provide longer relief for AD patients. In this study, a prototype hydrogel-gauze dressing was developed with varying ratios of sodium carboxymethylcellulose (NaCMC) and propylene glycol. The hydrogel-gauze dressings were assessed based on the moisture vapor transmission rate, moisture absorption, mechanical properties and storage stability over three months. Then, the efficacy of the hydrogel-gauze dressing was compared to topical emollients using transgenic NC/Nga mice with AD-like lesions. The NaCMC hydrogel-gauze dressings significantly lowered transepidermal water loss, and the animals displayed a faster recovery, which indicates that hydrogel-gauze dressings can trap moisture more effectively and accelerate AD healing. Hence, we propose that hydrogel-gauze dressings can potentially become an alternative to wet-wrap therapy due to the ease of application and the higher efficacy compared to topical products.
    Matched MeSH terms: Mice, Transgenic
  9. Fulltext Differential accumulation of tau pathology between reciprocal F1 hybrids of rTg4510 mice
    Yanagisawa D, Hamezah HS, Pahrudin Arrozi A, Tooyama I
    Sci Rep, 2021 May 05;11(1):9623.
    PMID: 33953293 DOI: 10.1038/s41598-021-89142-2
    Tau, a family of microtubule-associated proteins, forms abnormal intracellular inclusions, so-called tau pathology, in a range of neurodegenerative diseases collectively known as tauopathies. The rTg4510 mouse model is a well-characterized bitransgenic F1 hybrid mouse model of tauopathy, which was obtained by crossing a Camk2α-tTA mouse line (on a C57BL/6 J background) with a tetO-MAPT*P301L mouse line (on a FVB/NJ background). The aim of this study was to investigate the effects of the genetic background and sex on the accumulation of tau pathology in reciprocal F1 hybrids of rTg4510 mice, i.e., rTg4510 on the (C57BL/6 J × FVB/NJ)F1 background (rTg4510_CxF) and on the (FVB/NJ × C57BL/6 J)F1 background (rTg4510_FxC). As compared with rTg4510_CxF mice, the rTg4510_FxC mice showed marked levels of tau pathology in the forebrain. Biochemical analyses indicated that the accumulation of abnormal tau species was accelerated in rTg4510_FxC mice. There were strong effects of the genetic background on the differential accumulation of tau pathology in rTg4510 mice, while sex had no apparent effect. Interestingly, midline-1 (Mid1) was identified as a candidate gene associated with this difference and exhibited significant up/downregulation according to the genetic background. Mid1 silencing with siRNA induced pathological phosphorylation of tau in HEK293T cells that stably expressed human tau with the P301L mutation, suggesting the role of Mid1 in pathological alterations of tau. Elucidation of the underlying mechanisms will provide novel insights into the accumulation of tau pathology and is expected to be especially informative to researchers for the continued development of therapeutic interventions for tauopathies.
    Matched MeSH terms: Mice, Transgenic
  10. Lactobacillus Spp.-Enhanced Memory is Strain-Dependent and Associated, in Part, with Amyloidogenic and anti-Oxidant/Oxidative Stress Interplay in Amyloid Beta Precursor Protein Transgenic Mice
    Ahmad Alwi NA, Lim SM, Mani V, Ramasamy K
    J Diet Suppl, 2023;20(5):717-734.
    PMID: 35876040 DOI: 10.1080/19390211.2022.2103608
    This study explored mechanisms underpinning enhanced memory in amyloid precursor protein (APP) transgenic mice (male; 10-12 months; n = 6/group) supplemented with Lactobacillus plantarum LAB12 (LAB12)/Lactobacillus casei Shirota (LcS). Morris Water Maze test was performed before brains were harvested for gene expression and biochemical studies. LAB-supplemented mice exhibited reduced escape latency and distance but significant increased time spent in platform zone. This was associated with downregulated beta-site APP cleaving enzyme-1 (BACE1) mRNA and significant reduced nitric oxide in brains. LAB12 also significantly increased glutathione. The LAB-enhanced memory is strain-dependent and could be mediated, in part, through amyloidogenic pathway and anti-oxidant/oxidative stress interplay.
    Matched MeSH terms: Mice, Transgenic
  11. Fulltext Highly efficient Runx1 enhancer eR1-mediated genetic engineering for fetal, child and adult hematopoietic stem cells
    Koh CP, Bahirvani AG, Wang CQ, Yokomizo T, Ng CEL, Du L, et al.
    Gene, 2023 Jan 30;851:147049.
    PMID: 36384171 DOI: 10.1016/j.gene.2022.147049
    A cis-regulatory genetic element which targets gene expression to stem cells, termed stem cell enhancer, serves as a molecular handle for stem cell-specific genetic engineering. Here we show the generation and characterization of a tamoxifen-inducible CreERT2 transgenic (Tg) mouse employing previously identified hematopoietic stem cell (HSC) enhancer for Runx1, eR1 (+24 m). Kinetic analysis of labeled cells after tamoxifen injection and transplantation assays revealed that eR1-driven CreERT2 activity marks dormant adult HSCs which slowly but steadily contribute to unperturbed hematopoiesis. Fetal and child HSCs that are uniformly or intermediately active were also efficiently targeted. Notably, a gene ablation at distinct developmental stages, enabled by this system, resulted in different phenotypes. Similarly, an oncogenic Kras induction at distinct ages caused different spectrums of malignant diseases. These results demonstrate that the eR1-CreERT2 Tg mouse serves as a powerful resource for the analyses of both normal and malignant HSCs at all developmental stages.
    Matched MeSH terms: Mice, Transgenic
  12. Fulltext Vitamin E-Mediated Modulation of Glutamate Receptor Expression in an Oxidative Stress Model of Neural Cells Derived from Embryonic Stem Cell Cultures
    Abd Jalil A, Khaza'ai H, Nordin N, Mansor N, Zaulkffali AS
    Evid Based Complement Alternat Med, 2017;2017:6048936.
    PMID: 29348770 DOI: 10.1155/2017/6048936
    Glutamate is the primary excitatory neurotransmitter in the central nervous system. Excessive concentrations of glutamate in the brain can be excitotoxic and cause oxidative stress, which is associated with Alzheimer's disease. In the present study, the effects of vitamin E in the form of tocotrienol-rich fraction (TRF) and alpha-tocopherol (α-TCP) in modulating the glutamate receptor and neuron injury markers in an in vitro model of oxidative stress in neural-derived embryonic stem (ES) cell cultures were elucidated. A transgenic mouse ES cell line (46C) was differentiated into a neural lineage in vitro via induction with retinoic acid. These cells were then subjected to oxidative stress with a significantly high concentration of glutamate. Measurement of reactive oxygen species (ROS) was performed after inducing glutamate excitotoxicity, and recovery from this toxicity in response to vitamin E was determined. The gene expression levels of glutamate receptors and neuron-specific enolase were elucidated using real-time PCR. The results reveal that neural cells derived from 46C cells and subjected to oxidative stress exhibit downregulation of NMDA, kainate receptor, and NSE after posttreatment with different concentrations of TRF and α-TCP, a sign of neurorecovery. Treatment of either TRF or α-TCP reduced the levels of ROS in neural cells subjected to glutamate-induced oxidative stress; these results indicated that vitamin E is a potent antioxidant.
    Matched MeSH terms: Mice, Transgenic
  13. Melatonin in Alzheimer's disease and other neurodegenerative disorders
    Srinivasan V, Pandi-Perumal SR, Cardinali DP, Poeggeler B, Hardeland R
    Behav Brain Funct, 2006 May 04;2:15.
    PMID: 16674804
    Increased oxidative stress and mitochondrial dysfunction have been identified as common pathophysiological phenomena associated with neurodegenerative disorders such as Alzheimer's disease (AD), Parkinson's disease (PD) and Huntington's disease (HD). As the age-related decline in the production of melatonin may contribute to increased levels of oxidative stress in the elderly, the role of this neuroprotective agent is attracting increasing attention. Melatonin has multiple actions as a regulator of antioxidant and prooxidant enzymes, radical scavenger and antagonist of mitochondrial radical formation. The ability of melatonin and its kynuramine metabolites to interact directly with the electron transport chain by increasing the electron flow and reducing electron leakage are unique features by which melatonin is able to increase the survival of neurons under enhanced oxidative stress. Moreover, antifibrillogenic actions have been demonstrated in vitro, also in the presence of profibrillogenic apoE4 or apoE3, and in vivo, in a transgenic mouse model. Amyloid-beta toxicity is antagonized by melatonin and one of its kynuramine metabolites. Cytoskeletal disorganization and protein hyperphosphorylation, as induced in several cell-line models, have been attenuated by melatonin, effects comprising stress kinase downregulation and extending to neurotrophin expression. Various experimental models of AD, PD and HD indicate the usefulness of melatonin in antagonizing disease progression and/or mitigating some of the symptoms. Melatonin secretion has been found to be altered in AD and PD. Attempts to compensate for age- and disease-dependent melatonin deficiency have shown that administration of this compound can improve sleep efficiency in AD and PD and, to some extent, cognitive function in AD patients. Exogenous melatonin has also been reported to alleviate behavioral symptoms such as sundowning. Taken together, these findings suggest that melatonin, its analogues and kynuric metabolites may have potential value in prevention and treatment of AD and other neurodegenerative disorders.
    Matched MeSH terms: Mice, Transgenic
  14. Gene and protein expression profiles of JAK-STAT signalling pathway in the developing brain of the Ts1Cje down syndrome mouse model
    Lee HC, Md Yusof HH, Leong MP, Zainal Abidin S, Seth EA, Hewitt CA, et al.
    Int J Neurosci, 2019 Sep;129(9):871-881.
    PMID: 30775947 DOI: 10.1080/00207454.2019.1580280
    Aims: The JAK-STAT signalling pathway is one of the key regulators of pro-gliogenesis process during brain development. Down syndrome (DS) individuals, as well as DS mouse models, exhibit an increased number of astrocytes, suggesting an imbalance of neurogenic-to-gliogenic shift attributed to dysregulated JAK-STAT signalling pathway. The gene and protein expression profiles of JAK-STAT pathway members have not been characterised in the DS models. Therefore, we aimed to profile the expression of Jak1, Jak2, Stat1, Stat3 and Stat6 at different stages of brain development in the Ts1Cje mouse model of DS. Methods: Whole brain samples from Ts1Cje and wild-type mice at embryonic day (E)10.5, E15, postnatal day (P)1.5; and embryonic cortex-derived neurospheres were collected for gene and protein expression analysis. Gene expression profiles of three brain regions (cerebral cortex, cerebellum and hippocampus) from Ts1Cje and wild-type mice across four time-points (P1.5, P15, P30 and P84) were also analysed. Results: In the developing mouse brain, none of the Jak/Stat genes were differentially expressed in the Ts1Cje model compared to wild-type mice. However, Western blot analyses indicated that phosphorylated (p)-Jak2, p-Stat3 and p-Stat6 were downregulated in the Ts1Cje model. During the postnatal brain development, Jak/Stat genes showed complex expression patterns, as most of the members were downregulated at different selected time-points. Notably, embryonic cortex-derived neurospheres from Ts1Cje mouse brain expressed lower Stat3 and Stat6 protein compared to the wild-type group. Conclusion: The comprehensive expression profiling of Jak/Stat candidates provides insights on the potential role of the JAK-STAT signalling pathway during abnormal development of the Ts1Cje mouse brains.
    Matched MeSH terms: Mice, Transgenic
  15. Protein kinase D2 regulates epithelial sodium channel activity and aldosterone non-genomic responses in renal cortical collecting duct cells
    Thomas W, Dooley R, Quinn S, Robles MY, Harvey BJ
    Steroids, 2020 03;155:108553.
    PMID: 31836481 DOI: 10.1016/j.steroids.2019.108553
    Protein kinase D2 (PKD2) is a serine/threonine protein kinase which plays an important role in vesicle fission at the trans-Golgi network (TGN) to coordinate subcellular trafficking with gene expression. We found that in the rat kidney, PKD2 is specifically expressed in collecting duct principal cells predominantly at the apical membrane and with lower basal expression in cytosolic compartments. When rats were maintained on a Na+ depleted diet (<0.87 mmol Na+/kg) to increase plasma aldosterone levels, PKD2 became internalized to a cytoplasmic compartment. Treatment of murine M1 cortical collecting duct (M1-CCD) cells with aldosterone (10 nM) promoted PKD2 co-localization with the trans-Golgi network within 30 min. PKD2 underwent autophosphorylation at Ser876 within 10 min of aldosterone treatment and remained phosphorylated (active) for at least 24 h. A stable PKD2 shRNA knock-down (PKD2 KD) M1-CCD cell line was developed to study the role of PKD2 in epithelial Na+ channel (ENaC) trafficking and transepithelial Na+ transport (SCC) in epithelial monolayers grown in Ussing chambers. The PKD2 KD cells developed transepithelial resistance with kinetics equivalent to wild-type cells, however the transepithelial voltage and Na+ current were significantly elevated in PKD2 knock-down CCD epithelia. The higher basal SCC was due to increased ENaC activity. Aldosterone treatment for 24 h resulted in a decline in ENaC activity in the PKD2 KD cells as opposed to the increase observed in the wild-type cells. The paradoxical inhibition of SCC by aldosterone in PKD2 KD epithelium was attributed to a reduction in ENaC current and lower membrane abundance of ENaC, demonstrating that PKD2 plays a critical tonic role in ENaC trafficking and channel subunit stability. The rapid activation of PKD2 by aldosterone is synergistic with the transcriptional activity of MR and contributes to increased ENaC activity.
    Matched MeSH terms: Mice, Transgenic
  16. 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.
    Matched MeSH terms: Mice, Transgenic
  17. 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.
    Matched MeSH terms: Mice, Transgenic
  18. Fulltext Expression profile and down-regulation of argininosuccinate synthetase in hepatocellular carcinoma in a transgenic mouse model
    Shiue SC, Huang MZ, Tsai TF, Chang AC, Choo KB, Huang CJ, et al.
    J Biomed Sci, 2015;22:10.
    PMID: 25616743 DOI: 10.1186/s12929-015-0114-6
    Argininosuccinate synthetase (ASS) participates in urea and nitric oxide production and is a rate-limiting enzyme in arginine biosynthesis. Regulation of ASS expression appears complex and dynamic. In addition to transcriptional regulation, a novel post-transcriptional regulation affecting nuclear precursor RNA stability has been reported. Moreover, many cancers, including hepatocellular carcinoma (HCC), have been found not to express ASS mRNA; therefore, they are auxotrophic for arginine. To study when and where ASS is expressed and whether post-transcriptional regulation is undermined in particular temporal and spatial expression and in pathological events such as HCC, we set up a transgenic mouse system with modified BAC (bacterial artificial chromosome) carrying the human ASS gene tagged with an EGFP reporter.
    Matched MeSH terms: Mice, Transgenic
  19. 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.
    Matched MeSH terms: Mice, Transgenic
  20. Fulltext Pharmaceutical Potential of Casein-Derived Tripeptide Met-Lys-Pro: Improvement in Cognitive Impairments and Suppression of Inflammation in APP/PS1 Mice
    Matsuzaki Tada A, Hamezah HS, Pahrudin Arrozi A, Abu Bakar ZH, Yanagisawa D, Tooyama I
    J Alzheimers Dis, 2022;89(3):835-848.
    PMID: 35964178 DOI: 10.3233/JAD-220192
    BACKGROUND: Tripeptide Met-Lys-Pro (MKP), a component of casein hydrolysates, has effective angiotensin-converting enzyme (ACE) inhibitory activity. Brain angiotensin II enzyme activates the NADPH oxidase complex via angiotensin II receptor type 1 (AT1) and enhances oxidative stress injury. ACE inhibitors improved cognitive function in Alzheimer's disease (AD) mouse models and previous clinical trials. Thus, although undetermined, MKP may be effective against pathological amyloid-β (Aβ) accumulation-induced cognitive impairment.

    OBJECTIVE: The current study aimed to investigate the potential of MKP as a pharmaceutical against AD by examining MKP's effect on cognitive function and molecular changes in the brain using double transgenic (APP/PS1) mice.

    METHODS: Experimental procedures were conducted in APP/PS1 mice (n = 38) with a C57BL/6 background. A novel object recognition test was used to evaluate recognition memory. ELISA was used to measure insoluble Aβ40, Aβ42, and TNF-α levels in brain tissue. Immunohistochemical analysis allowed the assessment of glial cell activation in MKP-treated APP/PS1 mice.

    RESULTS: The novel object recognition test revealed that MKP-treated APP/PS1 mice showed significant improvement in recognition memory. ELISA of brain tissue showed that MKP significantly reduced insoluble Aβ40, Aβ42, and TNF-α levels. Immunohistochemical analysis indicated the suppression of the marker for microglia and reactive astrocytes in MKP-treated APP/PS1 mice.

    CONCLUSION: Based on these results, we consider that MKP could ameliorate pathological Aβ accumulation-induced cognitive impairment in APP/PS1 mice. Furthermore, our findings suggest that MKP potentially contributes to preventing cognitive decline in AD.

    Matched MeSH terms: Mice, Transgenic
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