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      • REM sleep deprivation impairs learning and memory by decreasing brain O-GlcNAc cycling in mouse

        Sang-Min Kim,Jiwon Park,Hyun Jae Sung,Ngan An Bui,Quynh T N Nguyen,Thuy-Duong Thi Tran,Dong Yeol Kim,Inn-Oc Han 한국당과학회 2022 한국당과학회 학술대회 Vol.2022 No.07

        Rapid eye movement (REM) sleep is associated with learning and memory (L/M) functions. Here, we demonstrate that REM sleep deprivation (REMSD)-induced impairment of contextual fear memory and spatial memory in mouse is linked to a downregulation in hexosamine biosynthetic pathway (HBP)/O-GlcNAc flux in mouse brain. In mice exposed to REMSD, O-GlcNAcylation proteins and O-GlcNAc transferase (OGT) were decreased while O-GlcNAcase was increased compared to control mouse brain. Foot shock fear conditioning (FC) induced activation of protein kinase A (PKA) and cAMP response element binding protein (CREB), which were significantly inhibited in brains of the REMSD group. Intriguingly, increasing O-GlcNAc cycling with glucosamine (GlcN) or OGA inhibitor, Thiamet G, restored defects in L/M functions and FC-induced PKA/CREB activation induced by REMSD. On behavior test, GlcN restored the contextual fear memory and spatial memory impairment induced by REMSD. Furthermore, Thiamet G restored the REMSD-induced decrease in dendritic spine density and learning and memory impairment. Suppression of O-GlcNAcylation by the glutamine fructose-6-phosphate amidotransferase (GFAT) inhibitor, 6‐diazo‐5‐oxo‐l‐norleucine (DON), or OGT inhibitor, OSMI-1, impaired memory function and inhibited FC-induced PKA/CREB activation. To our knowledge, this is the first study to provide comprehensive evidence of dynamic O-GlcNAcylation changes during the L/M process in mice and defects in this pathway in the brain of REM sleep-deprived mice. Our collective results highlight HBP/O-GlcNAc cycling as a novel molecular link between sleep and cognitive function.

      • SCIESCOPUS

        NEDD 4‐induced degradative ubiquitination of phosphatidylinositol 4‐phosphate 5‐kinase α and its implication in breast cancer cell proliferation

        Tran, Mai Hoang,Seo, Eunjeong,Min, Soohong,Nguyen, Quynh‐,Anh T.,Choi, Juyong,Lee, Uk‐,Jin,Hong, Soon‐,Sun,Kang, Hyuk,Mansukhani, Alka,Jou, Ilo,Lee, Sang Yoon John Wiley and Sons Inc. 2018 JOURNAL OF CELLULAR AND MOLECULAR MEDICINE Vol.22 No.9

        <P><B>Abstract</B></P><P>Phosphatidylinositol 4‐phosphate 5‐kinase (PIP5K) family members generate phosphatidylinositol 4,5‐bisphosphate (PIP2), a critical lipid regulator of diverse physiological processes. The PIP5K‐dependent PIP2 generation can also act upstream of the oncogenic phosphatidylinositol 3‐kinase (PI3K)/Akt pathway. Many studies have demonstrated various mechanisms of spatiotemporal regulation of PIP5K catalytic activity. However, there are few studies on regulation of PIP5K protein stability. Here, we examined potential regulation of PIP5Kα, a PIP5K isoform, via ubiquitin‐proteasome system, and its implication for breast cancer. Our results showed that the ubiquitin ligase NEDD4 (neural precursor cell expressed, developmentally down‐regulated gene 4) mediated ubiquitination and proteasomal degradation of PIP5Kα, consequently reducing plasma membrane PIP2 level. NEDD4 interacted with the C‐terminal region and ubiquitinated the N‐terminal lysine 88 in PIP5Kα. In addition, PIP5Kα gene disruption inhibited epidermal growth factor (EGF)‐induced Akt activation and caused significant proliferation defect in breast cancer cells. Notably, PIP5Kα K88R mutant that was resistant to NEDD4‐mediated ubiquitination and degradation showed more potentiating effects on Akt activation by EGF and cell proliferation than wild‐type PIP5Kα. Collectively, these results suggest that PIP5Kα is a novel degradative substrate of NEDD4 and that the PIP5Kα‐dependent PIP2 pool contributing to breast cancer cell proliferation through PI3K/Akt activation is negatively controlled by NEDD4.</P>

      • SCISCIESCOPUS
      • Forskolin rescues hypoxia-induced cognitive dysfunction in zebrafish: a potential role of HBP/O-GlcNAc cycling

        Quynh T N Nguyen,Jiwon Park,Dong Yeol Kim,Sang-Min Kim,Hyun Jae Sung,Thuy-Duong Thi Tran,Ngan An Bui,Inn-Oc Han 한국당과학회 2022 한국당과학회 학술대회 Vol.2022 No.07

        Repeated sublethal hypoxia exposure is reported to accelerate brain inflammation, and to affect the initiation and progression of cognitive dysfunction. Forskolin, an adenylate cyclase activator, is well-known as an inducer of the cAMP/PKA/CREB signaling. It has been shown that forskolin protects against various neuronal complications and induces long term memory; however, the underlying mechanism remains unclear. In this study, we showed that intraperitoneal administration of 200ng/g forskolin for 5 days on zebrafish notably recovered hypoxia-induced social interaction impairment and learning memory deficit. Forskolin suppressed hypoxia-induced neuroinflammation indicated by the decrease of NF-kB signaling and GFAP expression. On mouse neuroblastoma cell line, forskolin notably rescued hypoxia-induced cell death and dysfunction. The hypoxia model either in vivo or in vitro exerted a downregulation of PKA/CREB signaling and its downstream, c-Fos and BDNF expression, which was restored by forskolin. As previous studies proposed that hypoxia-induced hypo-O-GlcNAcylation could be an important causal factor for cognitive defect, we further investigated whether the HBP/O-GlcNAcylation cycling was changed by forskolin. Intriguingly, we observed that following forskolin treatment, OGT protein level (enzyme controls the addition of GlcNAc group to target proteins) induced considerably, which was accompanied by the upregulated O-GlcNAcylation level. Under forskolin treatment, O-GlcNAcylation flux on hypoxia-exposed zebrafish was reserved in line with the recovery of other inflammation and learning/memory markers. Next, we studied further about potential regulation of O-GlcNAcylation on the neuroprotective effect of forskolin. Zebrafish were treated with 500ng/g 6-diazo-5-oxo-L-norleucine (DON), an inhibitor of GFAT1 (enzyme that catalyzes the reaction from fructose-6-P to glucosamine-6-P), to downregulate the O-GlcNAcylation of proteins. It was observed that DON treatment led to learning/memory impairment, which was rescued by forskolin. Moreover, forskolin conserved hypo-O-GlcNAcylation and neuroinflammation following DON administration. Further experiments are being conducted to examine how HBP/O-GlcNAc flux is involved in the beneficial effect of forskolin on cognitive function.

      • Glucosamine relieves high fat diet-induced fatty liver through autophagy

        Jiwon Park,Quynh T N Nguyen,Dong Yeol Kim,Sang-Min Kim,Thuy-Duong Thi Tran,Hyun Jae Sung,Ngan An Bui,Inn-Oc Han 한국당과학회 2022 한국당과학회 학술대회 Vol.2022 No.07

        Glucosamine (GlcN) is the amino sugar that increases the protein O-GlcNAcylation level by going into the hexosamine biosynthesis pathway (HBP pathway). Previous studies have reported that GlcN regulates autophagy in various organs including the brain, cartilage, and retina. However, its regulating mechanism and role in the liver are still unclear. Here, we observed glucosamine induces autophagy in human hepatocytes (HepG2). Moreover, LC3, one of the most important factors of autophagy, was upregulated by GlcN at the transcriptional and protein levels. We hypothesized that the HBP pathway is involved in GlcN-induced autophagy. Therefore, examined with inhibition of two enzymes, O-GlcNacase and O-GlcNAc transferase, which have an opposite role in the HBP pathway. As a result, the autophagy process was regulated by O-GlcNAcylation levels. To provide the role of GlcN in the liver autophagy process, we conducted the GlcN effect on the fatty liver, known autophagy disrupted disease. Palmitic acid (PA) induced autophagy inhibition and fat accumulation was relieved by GlcN in HepG2 cells. In addition, high-fat diet-induced fatty liver was restored by GlcN through autophagy in mice. Our results indicate that GlcN increased autophagy flux and through this, lipid accumulation can be restored both in vivo and in vitro.

      • SCISCIESCOPUS
      • SCIESCOPUSKCI등재

        DEVELOPMENT AND EVALUATION OF A TEMPORARY PLACEMENT AND CONVEYANCE OPERATION SIMULATION SYSTEM USING AUGMENTED REALITY

        Yan, Weida,Aoyama, Shuhei,Ishii, Hirotake,Shimoda, Hiroshi,Sang, Tran T.,Inge, Solhaug Lars,Lygren, Toppe Aleksander,Terje, Johnsen,Izumi, Masanori Korean Nuclear Society 2012 Nuclear Engineering and Technology Vol.44 No.5

        When decommissioning a nuclear power plant, it is difficult to make an appropriate plan to ensure sufficient space for temporary placement and conveyance operations of dismantling targets. This paper describes a system to support temporary placement and conveyance operations using augmented reality (AR). The system employs a laser range scanner to measure the three-dimensional (3D) information of the environment and a dismantling target to produce 3D surface polygon models. Then, the operator simulates temporary placement and conveyance operations using the system by manipulating the obtained 3D model of the dismantling target in the work field. Referring to the obtained 3D model of the environment, a possible collision between the dismantling target and the environment is detectable. Using AR, the collision position is presented intuitively. After field workers evaluated this system, the authors concluded that the system is feasible and acceptable to verify whether spaces for passage and temporary storage are sufficient for temporary placement and conveyance operations. For practical use in the future, some new functions must be added to improve the system. For example, it must be possible for multiple workers to use the system simultaneously by sharing the view of dismantling work.

      • KCI등재

        DEVELOPMENT AND EVALUATION OF A TEMPORARY PLACEMENT AND CONVEYANCE OPERATION SIMULATION SYSTEM USING AUGMENTED REALITY

        WEIDA YAN,SHUHEI AOYAMA,HIROTAKE ISHII,HIROSHI SHIMODA,TRAN T. SANG,SOLHAUGLARS INGE,TOPPE ALEKSANDER LYGREN,JOHNSEN TERJE,MASANORI IZUMI 한국원자력학회 2012 Nuclear Engineering and Technology Vol.44 No.5

        When decommissioning a nuclear power plant, it is difficult to make an appropriate plan to ensure sufficient space for temporary placement and conveyance operations of dismantling targets. This paper describes a system to support temporary placement and conveyance operations using augmented reality (AR). The system employs a laser range scanner to measure the three-dimensional (3D) information of the environment and a dismantling target to produce 3D surface polygon models. Then,the operator simulates temporary placement and conveyance operations using the system by manipulating the obtained 3D model of the dismantling target in the work field. Referring to the obtained 3D model of the environment, a possible collision between the dismantling target and the environment is detectable. Using AR, the collision position is presented intuitively. After field workers evaluated this system, the authors concluded that the system is feasible and acceptable to verify whether spaces for passage and temporary storage are sufficient for temporary placement and conveyance operations. For practical use in the future, some new functions must be added to improve the system. For example, it must be possible for multiple workers to use the system simultaneously by sharing the view of dismantling work.

      • Wound-healing effect of ginsenoside Rd from leaves of Panax ginseng via cyclic AMP-dependent protein kinase pathway

        Kim, W.K.,Song, S.Y.,Oh, W.K.,Kaewsuwan, S.,Tran, T.L.,Kim, W.S.,Sung, J.H. North-Holland ; Elsevier Science Ltd 2013 european journal of pharmacology Vol.702 No.1

        Panax ginseng is considered as one of the most valuable medicinal herbs in traditional medicine, and ginsenoside Rd is one of the main active ingredients in P. ginseng leaf. Although there is significant number of evidences implicated on the beneficial effects of the ginsenosides with diverse associated mechanisms, reports on the skin regeneration by the ginsenoside Rd are not sufficient. Therefore, we examined the mitogenic and protective effects of the ginsenoside Rd in the keratinocyte progenitor cells (KPCs) and human dermal fibroblasts (HDFs). Furthermore, the signaling pathways involved in the activation of KPCs and HDFs were investigated, and wound-healing effect is evaluated in vivo through animal wound models. We found that the ginsenoside Rd significantly increased the proliferation and migration level of KPCs and HDFs in a dose-dependent manner. Additionally, the cell survival was significantly increased in H<SUB>2</SUB>O<SUB>2</SUB> treated KPCs. Moreover, the ginsenoside Rd effectively induced collagen type 1 and down-regulated matrix metalloprotinase-1 (MMP-1) in a dose-dependent manner. All of these beneficial effects are associated with an induction of intracellular cAMP levels and phosphorylated cAMP response element-binding protein expression in nucleus, which both attenuated by adenine 9-β-d-arabinofuranoside, an adenylate cyclase inhibitor. Application of the ginsenoside Rd to an excision wound in mice showed an effective healing process. As skin regeneration is mainly associated with the activation of HDFs and KPCs, P. ginseng leaf, an alternative source of the ginsenoside Rd, can be used as a natural source for skin regeneration.

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