• 동의신경정신과학회지
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• 제23권1호
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• pp.145-159
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• 2012

Objectives : This research investigates the effect of the JCT extract regarding Alzheimer's disease. Methods : The effects of the JCT extract on IL-$1{\beta}$, IL-6, TNF-${\alpha}$, COX-2, NOS-II mRNA, APP mRNA, BACE mRNA, Nitric oxide(NO), and ${\beta}A$ protein production in the BV2 microglia cell lines treated with LPS and ${\beta}A$ were investigated. Results : 1. The JCT extract suppressed the expression of IL-$1{\beta}$, IL-6, TNF-${\alpha}$, COX-2, and NOS-II mRNA in BV2 microglial cell line treated with LPS and ${\beta}A$. 2. The JCT extract suppressed the expression of BACE and APP mRNA in BV2 microglial cell line treated with LPS and ${\beta}A$. 3. The JCT extract suppressed the expression of Nitric oxide(NO) in BV2 microglial cell line treated with LPS and ${\beta}A$. 4. The JCT extract suppressed the expression of ${\beta}A$ protein production in BV2 microglial cell line treated with LPS and ${\beta}A$. Conclusions : These results suggest that the JCT group may be effective for the treatment of Alzheimer's disease. Thus, JCT could be considered among the future therapeutic drugs indicated for the treatment of Alzheimer's disease.

• Biomolecules & Therapeutics
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• 제28권2호
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• pp.131-136
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• 2020

Hippocampal synaptic dysfunction is a hallmark of Alzheimer's disease (AD). Many agents regulating hippocampal synaptic plasticity show an ameliorative effect on AD pathology, making them potential candidates for AD therapy. In the present study, we investigated spinosin as a regulating agent of synaptic plasticity in AD. Spinosin attenuated amyloid β (Aβ)-induced long-term potentiation (LTP) impairment, and improved plasmin activity and protein level in the hippocampi of 5XFAD mice, a transgenic AD mouse model. Moreover, the effect of spinosin on hippocampal LTP in 5XFAD mice was prevented by 6-aminocaproic acid, a plasmin inhibitor. These results suggest that spinosin improves synaptic function in the AD hippocampus by regulating plasmin activity.

• Molecules and Cells
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• 제43권8호
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• pp.671-685
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• 2020

The regulator of calcineurin (RCAN) was first reported as a novel gene called DSCR1, encoded in a region termed the Down syndrome critical region (DSCR) of human chromosome 21. Genome sequence comparisons across species using bioinformatics revealed three members of the RCAN gene family, RCAN1, RCAN2, and RCAN3, present in most jawed vertebrates, with one member observed in most invertebrates and fungi. RCAN is most highly expressed in brain and striated muscles, but expression has been reported in many other tissues, as well, including the heart and kidneys. Expression levels of RCAN homologs are responsive to external stressors such as reactive oxygen species, Ca²⁺, amyloid β, and hormonal changes and upregulated in pathological conditions, including Alzheimer's disease, cardiac hypertrophy, diabetes, and degenerative neuropathy. RCAN binding to calcineurin, a Ca²⁺/calmodulin-dependent phosphatase, inhibits calcineurin activity, thereby regulating different physiological events via dephosphorylation of important substrates. Novel functions of RCANs have recently emerged, indicating involvement in mitochondria homeostasis, RNA binding, circadian rhythms, obesity, and thermogenesis, some of which are calcineurin-independent. These developments suggest that besides significant contributions to DS pathologies and calcineurin regulation, RCAN is an important participant across physiological systems, suggesting it as a favorable therapeutic target.

• 한국자원식물학회지
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• 제28권6호
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• pp.675-681
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• 2015

β amyloid protein (Aβ) plays a critical role in the pathogenesis of Alzheimer's disease (AD) and possibly in Aβ-induced mitochondrial dysfunction and oxidative stress. Aβ can directly cause reactive oxygen species (ROS) production. Overproduction of ROS is considered to be involved in the pathogenesis of neurodegeneration of AD. Here, we investigated 9 kinds of ramie (Boehmeria nivea, (L.) Gaud., BN; hereafter denoted as BN) for their protective action against oxidative stress in a cellular system using C6 glial cells. We observed loss of cell viability and high levels of ROS generation after treatment with hydrogen peroxide (H₂O₂) and Aβ_25-35. However, treatments with BN extracts led to an increase in cell viability and decrease in ROS production induced by H2O2 and Aβ25-35. In particular, the extracts of BN-01 (seobang variety from Seocheon) and BN-09 (local variety from Yeonggwang) showed excellent anti-oxidative properties. This indicates that BN extracts could prevent neurodegeneration by reducing oxidative stress in cells.

• BMB Reports
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• 제54권6호
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• pp.295-304
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• 2021

Olfactory neuropathology is a cause of olfactory loss in Alzheimer's disease (AD). Olfactory dysfunction is also associated with memory and cognitive dysfunction and is an incidental finding of AD dementia. Here we review neuropathological research on the olfactory system in AD, considering both structural and functional evidence. Experimental and clinical findings identify olfactory dysfunction as an early indicator of AD. In keeping with this, amyloid-β production and neuroinflammation are related to underlying causes of impaired olfaction. Notably, physiological features of the spatial map in the olfactory system suggest the evidence of ongoing neurodegeneration. Our aim in this review is to examine olfactory pathology findings essential to identifying mechanisms of olfactory dysfunction in the development of AD in hopes of supporting investigations leading towards revealing potential diagnostic methods and causes of early pathogenesis in the olfactory system.

• Natural Product Sciences
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• 제27권1호
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• pp.28-35
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• 2021

The aim of this study was to anatomize the therapeutic potential of alaternin (=7-hydroxyemodin) against inflammation, advanced glycation end products (AGEs) formation, tyrosinase, and two cyclin-dependent kinases (CDKs), CDK2 and CDK4, and compare its potency with emodin. Alaternin showed lower cytotoxicity and higher dose-dependent inhibition against lipopolysaccharide (LPS) induced nitric oxide (NO) production with half maximal inhibitory concentration (IC50) of 18.68 µM. Similarly, alaternin efficaciously inhibited biotransformation of fluorescent AGEs and amyloid cross-β structure on the bovine serum albumin (BSA)-glucose-fructose system, five times more than emodin. Interestingly, alaternin also showed selective activity against CDK4 at 170 µM, whereas emodin inhibited both CDK2 and CDK4 at a concentration of 17 and 380 µM respectively. In addition, alaternin showed dose-dependent inhibitory activity against mushroom tyrosinase with inhibition percentage of 35.84 % at 400 µM. Altogether, alaternin with pronounced inhibition against inflammatory mediator (NO), glycated products formation, and targeted inhibition towards CDK4 receptor can be taken as an important candidate to target multiple diseases.

• 한국식품과학회지
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• 제53권6호
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• pp.715-721
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• 2021

인구의 고령화에 따른 노인 인구 증가로 지난 10년간 치매환자수와 경도인지장애 환자수가 급증하였다. 치매는 예방이 중요한 만큼 인지기능 향상에 도움을 줄 수 있는 기능성 소재 탐색에 대한 연구가 필요하다. 한편, PGG는 다양한 약용식물에 함유되어있는 gallotannins로 소교세포에서 항염증효과, amyloid beta 단백질 침착 억제효과, beta-secretase 억제효과가 알려져 있으나 인지 기능과 관련된 지표들에 대한 연구는 부족한 실정이다. 이에 본 연구에서는 PGG가 신경모세포주인 SK-N-SH세포에서 인지기능과 관련된 인자에 미치는 영향을 검토하고 관련 기전에 대해 평가하였다. 퇴행성질환 등에서 그 분비가 증가되는 AChE 효소활성이 PGG 처리에 의해 시험관실험과 세포실험에서 모두 억제되었다. 또한, PGG는 neurotrophin 중의 하나인 BDNF mRNA 및 단백질 발현을 증가하였다. 이러한 PGG의 BDNF 발현 증가에 대한 분자적 기전을 확인하기 위해 CAMKII-CREB 신호경로를 측정한 결과, PGG는 CAMKII를 인산화하였고, BDNF의 전사인자인 CREB를 활성화하였다. 이상의 결과로부터, hydrolyzed tannins의 하나인 PGG가 신경세포에서 CAMKII-CREB 경로를 활성화함으로써 BDNF의 발현을 증가시킬 뿐만 아니라 AChE 활성을 억제하는 것으로 나타났다(Fig. 8). 추가적으로 이러한 PGG의 효과가 인지기능이 저하된 동물모델 등에서도 효과가 있는지를 검토할 필요가 있다. 이러한 자료가 축적이 된다면 향후 PGG가 인지기능 개선을 위한 기능성 소재로서의 사용될 가능성이 있을 것으로 생각된다.

• Molecules and Cells
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• 제38권9호
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• pp.796-805
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• 2015

Gintonin is a novel ginseng-derived lysophosphatidic acid (LPA) receptor ligand. Oral administration of gintonin ameliorates learning and memory dysfunctions in Alzheimer's disease (AD) animal models. The brain cholinergic system plays a key role in cognitive functions. The brains of AD patients show a reduction in acetylcholine concentration caused by cholinergic system impairments. However, little is known about the role of LPA in the cholinergic system. In this study, we used gintonin to investigate the effect of LPA receptor activation on the cholinergic system in vitro and in vivo using wild-type and AD animal models. Gintonin induced $[Ca^{2+}]_i $ transient in cultured mouse hippocampal neural progenitor cells (NPCs). Gintonin-mediated $[Ca^{2+}]_i $ transients were linked to stimulation of acetylcholine release through LPA receptor activation. Oral administration of gintonin-enriched fraction (25, 50, or 100 mg/kg, 3 weeks) significantly attenuated scopolamine-induced memory impairment. Oral administration of gintonin (25 or 50 mg/kg, 1 2 weeks) also significantly attenuated amyloid-${\beta}$ protein ($A{\beta}$)-induced cholinergic dysfunctions, such as decreased acetylcholine concentration, decreased choline acetyltransferase (ChAT) activity and immunoreactivity, and increased acetylcholine esterase (AChE) activity. In a transgenic AD mouse model, long-term oral administration of gintonin (25 or 50 mg/kg, 3 months) also attenuated AD-related cholinergic impairments. In this study, we showed that activation of G protein-coupled LPA receptors by gintonin is coupled to the regulation of cholinergic functions. Furthermore, this study showed that gintonin could be a novel agent for the restoration of cholinergic system damages due to $A{\beta}$ and could be utilized for AD prevention or therapy.

• Biomolecules & Therapeutics
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• 제28권3호
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• pp.259-266
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• 2020

The present research work primarily investigated whether spinosin has the potential of improving the pathogenesis of Alzheimer's disease (AD) driven by β-amyloid (Aβ) overproduction through impacting the procession of amyloid precursor protein (APP). Wild type mouse Neuro-2a cells (N2a/WT) and N2a stably expressing human APP695 (N2a/APP695) cells were treated with spinosin for 24 h. The levels of APP protein and secreted enzymes closely related to APP procession were examined by western blot analysis. Oxidative stress related proteins, such as nuclear factor-erythroid 2-related factor 2 (Nrf2), and heme oxygenase-1 (HO-1) were detected by immunofluorescence assay and western blot analysis, respectively. The intracellular reactive oxygen species (ROS) level was analyzed by flow cytometry, the levels of Aβ_1-42 were determined by ELISA kit, and Thioflavin T (ThT) assay was used to detect the effect of spinosin on Aβ_1-42 aggregation. The results showed that ROS induced the expression of ADAM10 and reduced the expression of BACE1, while spinosin inhibited ROS production by activating Nrf2 and up-regulating the expression of HO-1. Additionally, spinosin reduced Aβ_1-42 production by impacting the procession of APP. In addition, spinosin inhibited the aggregation of Aβ_1-42. In conclusion, spinosin reduced Aβ_1-42 production by activating the Nrf2/HO-1 pathway in N2a/WT and N2a/APP695 cells. Therefore, spinosin is expected to be a promising treatment of AD.

• Molecules and Cells
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• 제42권6호
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• pp.480-494
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• 2019

Aggregates of disease-causing proteins dysregulate cellular functions, thereby causing neuronal cell loss in diverse neurodegenerative diseases. Although many in vitro or in vivo studies of protein aggregate inhibitors have been performed, a therapeutic strategy to control aggregate toxicity has not been earnestly pursued, partly due to the limitations of available aggregate models. In this study, we established a tetracycline (Tet)-inducible nuclear aggregate (${\beta}23$) expression model to screen potential lead compounds inhibiting ${\beta}23$-induced toxicity. High-throughput screening identified several natural compounds as nuclear ${\beta}23$ inhibitors, including peucedanocoumarin III (PCIII). Interestingly, PCIII accelerates disaggregation and proteasomal clearance of both nuclear and cytosolic ${\beta}23$ aggregates and protects SH-SY5Y cells from toxicity induced by ${\beta}23$ expression. Of translational relevance, PCIII disassembled fibrils and enhanced clearance of cytosolic and nuclear protein aggregates in cellular models of huntingtin and ${\alpha}$-synuclein aggregation. Moreover, cellular toxicity was diminished with PCIII treatment for polyglutamine (PolyQ)-huntingtin expression and ${\alpha}$-synuclein expression in conjunction with 6-hydroxydopamine (6-OHDA) treatment. Importantly, PCIII not only inhibited ${\alpha}$-synuclein aggregation but also disaggregated preformed ${\alpha}$-synuclein fibrils in vitro. Taken together, our results suggest that a Tet-Off ${\beta}23$ cell model could serve as a robust platform for screening effective lead compounds inhibiting nuclear or cytosolic protein aggregates. Brain-permeable PCIII or its derivatives could be beneficial for eliminating established protein aggregates.