• 동의신경정신과학회지
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• 제23권2호
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• pp.99-120
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• 2012

Objectives : The oriental medicine Jangwonhwan, a boiled extract of 12 medicinal herbs/mushrooms, has been prescribed to patients with cognitive dysfunction, as originally described in the Korean medical text, DonguiBogam(amnesia chapter). Recently, a modified formula of Jangwonhwan (LMK02-Jangwonhwan) consisting of seven medicinal plants/mushrooms, was shown to reduce the ${\beta}$-amyloid deposition in the brain of Tg-APPswe/PS1dE9 mouse model for Alzheimer's disease. The toxicity of LMK02-Jangwonhwan was investigated in SD rats, by a daily oral administration for 13 weeks and NOAEL(No observed adverse effect dose), a definite toxic dose and target organ, as well. Methods : Quality control of the tablet form of LMK02-Jangwonhwan was established by estimating the indicative components, Ginsenoside Rg3 of Red Ginseng and Decursin of Angelicagigas Nakai. The toxicity of LMK02-Jangwonhwan was investigated in 6 week old, specific pathogen free (SPF), Sprageu-Dawley rats by oral administration. Each test group consisted of 10 male and 10 female rats. The groups received doses of 500, 1,000 or 2,000 mg/kg/day of test substance for 13 weeks. The clinical signs, death rate, body weight, food consumption, ophthalmic examination, urinalysis, hematological and serum biochemistry, organ weight and pathological changes were examined and compared with those of the control group. Results : The 13-week repeated oral treatment doses didn't result in any specific symptoms or death. There were no significant changes in the rat's weight and food consumption. Further, ophthalmic examination, urinalysis, hematological, serum biochemistry test and organ weight revealed no significant differences. Conclusions : The no-observed-adverse-effect level(NOAEL) of LMK02 for male and female Sprague-Dawley rats was determined as 2,000mg/kg/day and the target organ wasn't confirmed. Because no significant adverse effects were observed, the target organ could not be determined.

• 동의생리병리학회지
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• 제24권6호
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• pp.1034-1041
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• 2010

The oriental medicine Jangwonhwan, which is a boiled extract of 12 medicinal herbs/mushroom, has been prescribed for patients with cognitive dysfunction and it is originally from the Korean medical text, DonguiBogam(amnesia chapter). Recently, a modified recipe of Jangwonhwan (LMK02-Jangwonhwan) consisting of seven medicinal plants/mushroom, was shown to reduce ${\beta}$-amyloid deposition in the brain of Tg-APPswe/PS1dE9 mouse model of Alzheimer disease. The toxicity of LMK02 was investigated in SD rats by oral repeated adminstration for 4 weeks and we tried to determine test does for 13 weeks repeated study. Quality control of tablet form of LMK02 was established by estimating indicative components, Ginsenoside Rg3 of Red Ginseng and Decursin of Angelicagigas Nakai. The toxicity of LMK02 was investigated in 6 weeks old specific pathogen free (SPF) Sprageu-Dawley rats by oral administration. Each test group were consist of 5 male and 5 female and they received doses of 500, 1,000 and 2,000 mg/kg/day of test substance for 4 weeks. The clinical signs, death rate, body weight, food consumption, ophthalmic examination, urinalysis, hematological and serum biochemistry, organ weight and pathological changes were examined and compared with those of control group. Urinalysis : We observed increase of PRO(p<0.01), SG(p<0.01) in female rats of 1,000 mg/kg/day and 2,000 mg/kg/day(p<0.01). Also, we observed increase of pH and KET in female rats of 1,000 mg/kg/day(p<0.05) and of 2,000 mg/kg/day(p<0.01). WBC in female rats in 1,000 mg/kg/day and 2,000 mg/kg/day were on increase. Hematological test : We observed increase of MCV in male rats of 250 mg/kg/day. (p<0.05) Serum biochemistry test : We found increase of CHO in female rats of 2,000 mg/kg/day(p<0.05). During the experimental period, there were no animals dead or moribund. There were no treatment related changes of general symptom, food and water consumption, organ weight and autopsy According to the results of 4-week repeated dose range finding study, the highest dose was established as 1000 mg/kg for 13-week repeated dose toxicity study and we determined to put 2 more groups by common ratio two.

• 대한약침학회지
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• 제9권2호
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• pp.17-37
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• 2006

Objectives : To observe the changes in the serum proteins after intravenous injection of cultivated wild ginseng pharmacopuncture. Methods : Blood was collected before and after the administration of cultivated wild ginseng pharmacopuncture and only the serum was taken. Then differences in the spots on the scanned image after carrying out 2-Dimensional electrophoresis were located and conducted mass analysis and protein identification. Results : Following results were obtained from the comparative analysis of serum proteins before and after the administration of cultivated wild ginseng pharmacopuncture. 1. 28 spots were identified before and after the administration. 2. In confirming manifestation degree, spots with more than two-times increase were 204, 1302, 2205, 3105, 7104, 8006, spots with more than one-time increase were 1101, 1505, 2013, 2403, 3009, 3010, 4002, 4009, 6704, 8101, and spots with decrease were 205, 801, 803, 3205, 5202, 6105, 6106, 7103, 9001, 9003. 3. After conducting protein identification, proteins 205, 804, 1302, 4009, 6105, 6106 are unidentified yet, and 1l01 is unnamed protein. Protein 204 is identified as complement receptor CR2-C3d, 801 as YAPl protein, 803 as antitrypsin polymer, 1505 as PRO0684, 2013 and 3010 as proapolipoprotein, 2205 as USP48, 2403 as vitamin D binding protein, 3009 as complement component 4A preprotein, 3105 as immunoglobulin lambda chain, 3205 as transthyretin, 4002 as Ras-related protein Ral-A, 4204 as beta actin, 5202 and 7104 as apolipoprotein Ll, 6704 as alpha 2 macroglobulin precursor, 7103 as complement component 3 precursor, 8006 as testis-specific protein Y, 8101 as transferrin, 9001 as (Alpha-Oxy, Beta-(Cl12g)deoxy) T-State Human Hemoglobin, and 9003 as human hemoglobin. 4. Immune protein CR2-C3d(204), which acts against microbes and pathogenic organisms, was increased by more than two-times after the administration of pharmacopuncture. 5. Antitrypsin(803), which is secreted with inflammatory response in the lungs, was reduced after the administration of pharmacopuncture. 6. Proapolipoprotein(2013, 3010) and apolipoprotein(7104), key components of the HDL-cholesterol which plays an important role in preventing arteriosclerosis, were increased after the administration of pharmacopuncture. 7. Vitamin D binding protein(DBP, 2403), protecting the lung at the time of inflammatory response, was increased after the administration of pharmacopuncture. 8. Transthyretin(TTR, 3205), which is the main protein causing familial amyloid polyneuropathy(FAP), was decreased after the administration of pharmacopuncture. 9. Ras-related protein Ral-A(4002) that controls phospholipid metabolism, cytoskeletal formation, and membrane traffic, was increased after the administration of pharmacopuncture. 10. Testis-specific protein Y(8006), which takes part in determination of the gender, was increased by more than two-times after the administration of pharmacopuncture. 11. Transferrin(8101), which balances the iron level in the body, was increased after the administration of pharmacopuncture. Conclusion : Above results support the notion that intravenous injection of cultivated wild ginseng pharmacopuncture induce changes in serum proteins and this research can be a pioneer work in finding biomarkers.

• 대한한방내과학회지
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• 제41권3호
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• pp.326-338
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• 2020

Background: Alzheimer's disease (AD) is a chronic neurodegenerative disease that causes disorientation, mood swings, problems with language, and difficulty remembering recent events. Acetylcholinesterase inhibitors (AchEIs) and memantine have been used to slow the course of the disease, but they can neither modify its progression nor prevent disease onset. Previous studies have suggested that Kami-guibi-tang (KGT) could be beneficial for supporting cognitive function in AD patients, but few clinical trials have been published. This pilot study aimed to evaluate the effect of KGT in improving cognitive function in AD patients. Methods: The study will be a randomized, placebo-controlled, double-blind, single-center trial conducted using subjects diagnosed with mild AD by neurologists. Study subjects will be randomly assigned to either a treatment or control group. The treatment group will receive KGT granules for 24 weeks, while the control group will receive placebo granules. AchEI administration will be maintained in both groups during the entirety of the study. Subjects will be assessed using the following exams: the Seoul Neuropsychologic Screening Battery (SNSB) for cognitive function; brain magnetic resonance imaging (MRI) for brain metabolite, neurotransmitter, and cerebral blood flow (CBF) measurements; the Korean version of Quality of Life-Alzheimer's Disease (KQol-AD) for quality of life; the Caregiver-Administered Neuropsychiatric Inventory (CGA-NPI) for neurobehavioral symptoms; blood tests for amyloid and tau proteins and general blood parameters; and electrocardiography (ECG) before and after taking the medication. Discussion: Our findings will provide insight into the feasibility of large-scale trials to consolidate evidence for the efficacy of KGT for dementia treatment. Registration ID in CRIS: KCT0002904 (Clinical Research Information Service of the Republic of Korea).

• 동의신경정신과학회지
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• 제16권1호
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• pp.97-117
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• 2005

This research investigates the effect of the Chaenomelis fructus(CMF) on Alzheimer's disease. Specifically, the effects of the CMF extract on (1) >$IL-1{\beta}$, IL-6, and $TNF-{\alpha}$ mRNA of PC-12 cells treated with LPS; (2) amyloid precursor proteins(APP), acetylcholinesterase(AChE), and glial fibrillary acidic protein(GFAP) mRNA of PC-12 cells treated with CT-105; (3) the AChE activity and the APP production of PC-12 cell treated with CT-105; (4) the behavior of AD mice with ${\beta}A$; (5) expression of $IL-1{\beta}$, $TNF-{\alpha}$, MDA, $IL-1{\beta}$ mRNA, $TNF-{\alpha}$ mRNA, and ROS; (6) the infarction area of the hippocampus, and brain tissue injury in Alzheimer's diseased mice induced with ${\beta}A$ were investigated. The results were summarized as follows; 1. The CMF extract suppressed the expression of $IL-1{\beta}$, IL-6 and $TNF-{\alpha}$ mRNA in THP-1 cells treated with LPS. 2. The CMF extract suppressed the expression of APP, AChE, and GFAP mRNA in PC-12 cells treated with CT-105. 3. The CMF extract suppressed the AChE activity, and the production of APP significantly in PC-12 cells treated with CT-105. 4. A significant inhibitory effect on the memory deficit was shown on the CMF extract group of the mice with Alzheimer's disease induced by ${\beta}A$ in the Morris water maze experiment, which measured stop-through latency, and distance movement-through latency. 5. The CMF extract suppressed the over-expression of $IL-1{\beta}$ protein, $TNF-{\alpha}$ protein, MDA, $IL-1{\beta}$ protein, mRNA, $TNF-{\alpha}$ mRNA, CD68/GFAP, and ROS in the mice with Alzheimer's disease induced by ${\beta}A$. 6. The CMF extract reduced the infarction area of hippocampus, and controlled the injury of brain tissue in the mice with Alzheimer’s disease induced by ${\beta}A$. These results suggest that the CMF extract may be effective for the treatment of Alzheimer’s disease. Investigation into the clinical use of the CMF extract for Alzheimer's disease is suggested for future research.

• 생명과학회지
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• 제26권7호
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• pp.868-874
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• 2016

수용체 상호작용 단백질 인산화 효소 RIPK1 (Receptor-interacting protein kinases 1)과 RIPK3은 고도로 보존된 인산화 효소 부위를 통하여 세린이나 트레오닌의 하이드록실기를 인산화하는 세린 또는 트레오닌-단백질 인산화 효소 군에 속한다. RIPK군은 염증이나 선천성 면역뿐 만 아니라 세포사멸이나 괴사와 같은 프로그램화된 세포사 멸을 중재하는데 중요한 역할을 담당한다. RIPK1과 다른 TNFR1 관련 단백질들의 상호작용은 TNF 수용체 1(TNFR1)에 사이토카인이 결합할 때 생존 촉진 전사인자 NF-κB의 활성을 조절하는 신호전달복합체 I을 조립하는 것으로 알려져 왔다. 뿐만 아니라, RIPK1과 RIPK3은 프로그램화된 세포괴사를 중재하는 RIP 동형 상호작용 모티브(RHIM)를 통하여 상호작용하고, 이러한 괴사는 세포사멸의 유형과는 다른 형태학적 특징을 가진 돌발적이고 제어되지 않는 세포사멸 유형으로 오랫동안 알려져 왔다. RIPK1과 RIPK3에 존재하는 RHIM의 고도로 보존된 서열들이 이들의 상호작용을 조절하며 이들은 necrosome이라 불리는 세포질 내 아밀로이드 복합체의 조립을 유도 한다. 또한 necrosome은 최근에 하위 신호전달을 조절하는 RIPK3의 기질로 확인된 혼합형 인산화 효소 도메인-유사 단백질(MLKL)을 포함한다. 본 리뷰는 TNF 신호전달에서 RIPK와 MLKL의 기능적, 생리적 특징들에 관한 개요를 제공한다.

• 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.

• 한국응용과학기술학회지
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• 제36권3호
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• pp.804-812
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• 2019

The purpose of this study was to investigate the effects of different types of exercise training on neurodegeneration and cognitive function in mice with impaired glucose tolerance (IGT). Thirty-six male C57BL/6 mice were randomly assigned to the control (CO, n = 9) and impaired glucose tolerance (IGT, n = 27) groups. The IGT group consumed 45% high fat diet for 4 weeks and received 40 mg/kg of streptozotocin twice in the lower abdomen to induce IGT. After the IGT induction period, the IGT group was subdivided into IGT + sedentary (IGT, n = 9), IGT + endurance exercise (IGTE, n = 9), and IGT + resistance exercise (IGTR, n = 9). The IGTE and IGTR groups performed treadmill and ladder climbing exercises 5 times per week for 8 weeks, respectively. Fasting glucose and glycated hemoglobin (HbA1c) levels were significantly higher in IGT group than in CO, IGTE, and IGTR groups (p < 0.05). HOMA-IR was significantly higher in IGT group than CO group (p < 0.05). Hippocampal catalase (CAT) was significantly lower in IGT group than in CO group (p < 0.05), while beta-amyloid ($A{\beta}$) was significantly higher in IGT group than in CO group (p < 0.05). Hippocampal tau was significantly higher in IGT group than in CO, IGTE, and IGTR groups (p < 0.05). The Y-maze test performance for cognitive function was significantly lower in IGT group than in CO, IGTE, and IGTR groups (p <0.05). These results suggest that IGT induces neurodegeneration and negatively affects cognitive function, while regular exercise may be effective in alleviating neurodegeneration and cognitive decline regardless of exercise type.

• Yonsei Medical Journal
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• 제59권9호
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• pp.1096-1106
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• 2018

Purpose: Alzheimer's disease (AD) is the sixth most common cause of death in the United States. MicroRNAs have been identified as vital players in neurodegenerative diseases, including AD. microRNA-128 (miR-128) has been shown to be dysregulated in AD. This study aimed to explore the roles and molecular mechanisms of miR-128 in AD progression. Materials and Methods: Expression patterns of miR-128 and peroxisome proliferator-activated receptor gamma ($PPAR-{\gamma}$) messenger RNA in clinical samples and cells were measured using RT-qPCR assay. $PPAR-{\gamma}$ protein levels were determined by Western blot assay. Cell viability was determined by MTT assay. Cell apoptotic rate was detected by flow cytometry via double-staining of Annexin V-FITC/PI. Caspase 3 and $NF-{\kappa}B$ activity was determined by a Caspase 3 Activity Assay Kit or $NF-{\kappa}B$ p65 Transcription Factor Assay Kit, respectively. Bioinformatics prediction and luciferase reporter assay were used to investigate interactions between miR-128 and $PPAR-{\gamma}$ 3'UTR. Results: MiR-128 expression was upregulated and $PPAR-{\gamma}$ expression was downregulated in plasma from AD patients and $amyloid-{\beta}$ $(A{\beta})-treated$ primary mouse cortical neurons (MCN) and Neuro2a (N2a) cells. Inhibition of miR-128 decreased $A{\beta}-mediated$ cytotoxicity through inactivation of $NF-{\kappa}B$ in MCN and N2a cells. Moreover, $PPAR-{\gamma}$ was a target of miR-128. $PPAR-{\gamma}$ upregulation attenuated $A{\beta}-mediated$ cytotoxicity by inactivating $NF-{\kappa}B$ in MCN and N2a cells. Furthermore, $PPAR-{\gamma}$ downregulation was able to abolish the effect of anti-miR-128 on cytotoxicity and $NF-{\kappa}B$ activity in MCN and N2a cells. Conclusion: MiR-128 inhibitor decreased $A{\beta}-mediated$ cytotoxicity by upregulating $PPAR-{\gamma}$ via inactivation of $NF-{\kappa}B$ in MCN and N2a cells, providing a new potential target in AD treatment.

• Journal of Ginseng Research
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• 제47권2호
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• pp.302-310
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• 2023

Background: The most common type of dementia, Alzheimer's disease (AD), is marked by the formation of extracellular amyloid beta (Aβ) plaques. The impairments of axons and synapses appear in the process of Aβ plaques formation, and this damage could cause neurodegeneration. We previously reported that non-saponin fraction with rich polysaccharide (NFP) from Korean Red Ginseng (KRG) showed neuroprotective effects in AD. However, precise molecular mechanism of the therapeutic effects of NFP from KRG in AD still remains elusive. Methods: To investigate the therapeutic mechanisms of NFP from KRG on AD, we conducted proteomic analysis for frontal cortex from vehicle-treated wild-type, vehicle-treated 5XFAD mice, and NFP-treated 5XFAD mice by using nano-LC-ESI-MS/MS. Metabolic network analysis was additionally performed as the effects of NFP appeared to be associated with metabolism according to the proteome analysis. Results: Starting from 5,470 proteins, 2,636 proteins were selected for hierarchical clustering analysis, and finally 111 proteins were further selected for protein-protein interaction network analysis. A series of these analyses revealed that proteins associated with synapse and mitochondria might be linked to the therapeutic mechanism of NFP. Subsequent metabolic network analysis via genome-scale metabolic models that represent the three mouse groups showed that there were significant changes in metabolic fluxes of mitochondrial carnitine shuttle pathway and mitochondrial beta-oxidation of polyunsaturated fatty acids. Conclusion: Our results suggested that the therapeutic effects of NFP on AD were associated with synaptic- and mitochondrial-related pathways, and they provided targets for further rigorous studies on precise understanding of the molecular mechanism of NFP.