• Clinical and Experimental Pediatrics
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• 제50권7호
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• pp.686-693
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• 2007

목 적 : Mycophenolate mofetil (MMF)의 활성 대사산물인 (MPA는 IMPDH의 잠재적인 반응 억제제로써 새로운 면역치료제로 사용되고 있다. 이러한 MPA는 신경계에서 흥분독성 손상 후 뇌세포를 보호하고, 미세아교세포에서는 세포사멸사(apoptosis)를 유도하지만, 저산소성 허혈성 뇌질환에서 MPA의 효과는 아직 알려지지 않아, 본 연구에서 Rice-Vannucci 모델을 이용한 신생 백서의 저산소성 허혈성 뇌 손상과 저산소 상태의 태아 백서 뇌세포 배양에서 MPA의 뇌보호 효과를 알아보고자 실험하였다. 방 법 : 생후 7일된 백서의 좌측 총 경동맥을 결찰한 후 저산소 (8% $O_2$) 상태에서 2시간 노출하여, 저산소성 허혈성 뇌 손상을 유발하고 뇌 손상 전후에 MPA(10 mg/kg)를 투여하여 대조군과 비교하였다. 또한, 재태기간 18일된 태아 백서의 대뇌피질 세포를 배양하여 1% $O_2$ 배양기에서 저산소 상태로 세포손상을 유도하여 저산소군, 손상 전후 MPA 투여군($10{\mu}g/mL$)으로 나누어 정상산소군과 비교하였다. 세포사멸사와의 관련을 알아보기 위해서 Bcl-2, Bax, caspase-3 항체로 western blotting하였고 Bcl-2, Bax, caspase-3 primer를 이용하여 real-time PCR을 하였다. 결 과 : 형태학적으로 H&E 염색상 MPA를 투여한 군에서 뇌 보호 효과를 보였다. Western blotting과 real-time PCR을 이용한 저산소성 허혈성 뇌손상 동물 모델뿐만 아니라 저산소 상태로 태아 백서 뇌세포 배양 실험에서도 MPA 투여한 경우 caspase-3의 발현과 Bax/Bcl-2의 비율이 감소함을 보였다. 결 론 : 본 연구에서 MPA가 anti-apoptosis 작용을 통하여 주산기 저산소성 허혈성 뇌 손상에 뇌보호 역할을 하는 것을 알 수 있었고 향후 신생아 저산소성 허혈성 뇌병증의 치료에 임상적 적용이 가능하리라 생각된다.

• The Korean Journal of Physiology and Pharmacology
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• 제21권5호
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• pp.475-485
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• 2017

The present study aimed to explore the neuroprotective effect and possible mechanisms of rhGLP-1 (7-36) against transient ischemia/reperfusion injuries induced by middle cerebral artery occlusion (MCAO) in type 2 diabetic rats. First, diabetic rats were established by a combination of a high-fat diet and low-dose streptozotocin (STZ) (30 mg/kg, intraperitoneally). Second, they were subjected to MCAO for 2 h, then treated with rhGLP-1 (7-36) (10, 20, $40{\mu}g/kg$ i.p.) at the same time of reperfusion. In the following 3 days, they were injected with rhGLP-1 (7-36) at the same dose and route for three times each day. After 72 h, hypoglycemic effects were assessed by blood glucose changes, and neuroprotective effects were evaluated by neurological deficits, infarct volume and histomorphology. Mechanisms were investigated by detecting the distribution and expression of the nuclear factor erythroid-derived factor 2 related factor 2 (Nrf2) in ischemic brain tissue, the levels of phospho-PI3 kinase (PI3K)/PI3K ratio and heme-oxygenase-1 (HO-l), as well as the activities of superoxide dismutase (SOD) and the contents of malondialdehyde (MDA). Our results showed that rhGLP-1 (7-36) significantly reduced blood glucose and infarction volume, alleviated neurological deficits, enhanced the density of surviving neurons and vascular proliferation. The nuclear positive cells ratio and expression of Nrf2, the levels of P-PI3K/PI3K ratio and HO-l increased, the activities of SOD increased and the contents of MDA decreased. The current results indicated the protective effect of rhGLP-1 (7-36) in diabetic rats following MCAO/R that may be concerned with reducing blood glucose, up-regulating expression of Nrf2/HO-1 and increasing the activities of SOD.

• 대한한의학회지
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• 제23권4호
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• pp.161-168
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• 2002

Objectives: Hwangryunhaedok-tang (Huang-lian-jie-du-tang, HRHDT, 黃連解毒湯) is a traditional Korean herbal medicine that is formulated with Coptidis Rhizoma, Phellodendri Cortex, Scutellariae Radix and Gardeniae Fructus. HRHDT is cold (寒) and bitter (苦) in nature and has general properties of clearing heat and detoxifying (淸熱解毒), strengthening the stomach and settling the liver (健胃平肝), and reducing inflammation, fever and swelling. This formula can prevent and treat artherosclerosis, hyperplasia of the endothelium, cerebral fluid circulation, cerebral vascular deterioration through aging, impairment of neurotransmitters, or disruption of the functioning of the cerebral cortex following infection or trauma. The purpose of the study reported here was to determine the neuroprotective effect of HRHDT on global ischemia induced by 4-vessel occlusion in Wistar rats. Methods: HRHDT extract was lyophilized after extraction with 85% methanol and 100% water. Rats were induced to 10 minutes of forebrain ischemia by 4-vessel occlusion (4-VO) and reperfused again. HRHDT was administered with a dose of 100 mg/kg, and 500 mg/kg of 85% methanol extracts and 100 mg/kg of 100% water extracts, respectively, at 0 min and 90 min after 4-VO. Rats were killed at 7 days after ischemia and the number of CA1 pyramidal neurons was counted in hippocampal sections stained with cresyl violet. Results: Body temperature of animals showed no significant difference between saline-treated groups and HRHDT extracts-treated groups until 5 hours of reperfusion. This result indicated that neuroprotective effects of HRHDT extracts were not due to hypothermic effects. The administration of HRHDT showed a significant neuroprotective effect on hippocampal CA1 neurons at 7 days after ischemia compared to the saline-treated group (P<0.001). HRHDT methanol extracts of 100 mg/kg, 500 mg/kg and HRHDT water extracts of 100 mg/kg showed 88.5%, 98.3% and 95.1 % neuroprotection, respectively. Conclusions: The results of this study demonstrate that administration of HRHDT is highly effective in reducing neuronal damage in response to transient global cerebral ischemia. HRHDT may involve many mechanisms that might account for its high degree of efficacy. A number of factors including free radicals, glutamate, calcium overload, NO, and various cytokines have been proposed to have an important role in causing neuronal death after short periods of global ischemia. Further studies are needed to know the neuroprotective mechanisms of HRHDT.

• Molecules and Cells
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• 제38권1호
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• pp.1-13
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• 2015

Recent technical developments have transformed how neuroscientists can probe brain function. What was once thought to be difficult and perhaps impossible, stimulating a single set of long range inputs among many, is now relatively straight-forward using optogenetic approaches. This has provided an avalanche of data demonstrating causal roles for circuits in a variety of behaviors. However, despite the critical role that neuropeptide signaling plays in the regulation of behavior and physiology of the brain, there have been remarkably few studies demonstrating how peptide release is causally linked to behaviors. This is likely due to both the different time scale by which peptides act on and the modulatory nature of their actions. For example, while glutamate release can effectively transmit information between synapses in milliseconds, peptide release is potentially slower [See the excellent review by Van Den Pol on the time scales and mechanisms of release (van den Pol, 2012)] and it can only tune the existing signals via modulation. And while there have been some studies exploring mechanisms of release, it is still not as clearly known what is required for efficient peptide release. Furthermore, this analysis could be complicated by the fact that there are multiple peptides released, some of which may act in contrast. Despite these limitations, there are a number of groups making progress in this area. The goal of this review is to explore the role of peptide signaling in one specific structure, the bed nucleus of the stria terminalis, that has proven to be a fertile ground for peptide action.

• 감성과학
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• 제24권2호
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• pp.39-48
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• 2021

국제통증연구학회(IASP)에 따르면, 신경병증성 통증은 정상 조건에서 중추신경계에 유해한 정보를 전달하는 신경계 기능 장애로 특징 지워진다. 이런 통증은 말초 혹은 중추 신경계에 확인 가능한 병변이 있는 질환과 어떠한 신경에도 병변이 없는 상태에서 발생하는 상황으로 나누어 볼 수 있다. 두 가지 상황 모두 장기적이고 만성적인 변화과정을 겪게 되며, 결과적으로 신경계가 부적절하게 적응하여 치유되기 어려운 만성통증 증후군으로 발전할 수 있다. 그러나 이러한 통증 치료는 진단에서부터 치료까지의 과정이 어려운 탓에 현재까지도 특별한 해결방안이 부족한 실정이다. 최근 자기공명영상(fMRI), 양전자방출단층촬영법(PET), 광영상(optical imaging) 등 영상분석기술이 발달함에 따라 통증을 유발할 수 있는 유해 자극에 대한 중추신경계의 반응을 영상화하는 연구가 증가하고 있다. 이러한 영상 기법들을 통해 통증을 해석하고 처리하는 뇌 영역에서 시냅스 간 가소성 변화가 일어나고 있음을 확인하였으며, 신경병증성 통증을 비롯한 만성통증과 학습과의 상호 작용을 이해하는 데 많은 도움을 주고 있다. 본 연구는 병리적 통증의 기전과 통증 자극에 따른 뇌의 구조적, 기능적 변화에 대해 최근까지 밝혀진 연구들을 소개하고자 한다. 만성적 통증의 정의와 발생기전을 되짚고 새로운 연구 동향을 살펴보는 것은 통증을 완화할 수 있는 방안을 강구하는 데 도움이 될 것으로 사료된다.

• Molecules and Cells
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• 제26권2호
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• pp.121-130
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• 2008

Methamphetamine, a commonly used addictive drug, is a powerful addictive stimulant that dramatically affects the CNS. Repeated METH administration leads to a rewarding effect in a state of addiction that includes sensitization, dependence, and other phenomena. It is well known that susceptibility to the development of addiction is influenced by sources of reinforcement, variable neuroadaptive mechanisms, and neurochemical changes that together lead to altered homeostasis of the brain reward system. These behavioral abnormalities reflect neuroadaptive changes in signal transduction function and cellular gene expression produced by repeated drug exposure. To provide a better understanding of addiction and the mechanism of the rewarding effect, it is important to identify related genes. In the present study, we performed gene expression profiling using microarray analysis in a reward effect animal model. We also investigated gene expression in four important regions of the brain, the nucleus accumbens, striatum, hippocampus, and cingulated cortex, and analyzed the data by two clustering methods. Genes related to signaling pathways including G-protein-coupled receptor-related pathways predominated among the identified genes. The genes identified in our study may contribute to the development of a gene modeling network for methamphetamine addiction.

• IMMUNE NETWORK
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• 제4권1호
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• pp.60-64
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• 2004

Background: Microglial cells, major immune effector cells in the central nervous system, become activated in neurodegenerative disorders. Activated microglial cells produce proinflammatory mediators such as nitric oxide (NO), tumor necrosis factor-$\alpha$ and interleukin-$1{\beta}$(IL-$1{\beta}$). These proinflammatory mediators have been shown to be significantly increased in the neurodegenerative disorders such as Alzhimer's disease and Pakinson's disease. It was known that one of the neurodegeneration source is stress and it is important to elucidate mechanisms of the stress response for understanding the stress-related disorders and developing improved treatments. Because one of the neuropeptide which plays a main role in regulating the stress response is corticotropin-releasing hormone (CRH), we analyzed the regulation of NO release by CRH in BV2 murine microglial cell as macrophage in the brain. Methods: First, we tested the CRH receptor expression in the mRNA levels by RT-PCR. To test the regulation of NO release by CRH, cells were treated with CRH and then NO release was measured by Griess reagent assay. Results: Our study demonstrated that CRH receptor 1 was expressed in BV2 murine microglial cells and CRH treatment enhanced NO production. Furthermore, additive effects of lipopolysaccaride (LPS) and CRH were confirmed in NO production time dependantly. Conclusion: Taken together, these data indicated that CRH is an important mediator to regulate NO release on microglial cells in the brain during stress.

• 대한한방내과학회지
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• 제32권4호
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• pp.530-541
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• 2011

Objectives : Categorized as 'cheongyeol' herbs, Herba Prunellae, Flos Lonicerae and Radix Scutellaria have been proven to have effect on degenerative brain disease, cerebrovascular disease and brain tumor because of their anti inflammation, antioxidant, or anticancer effects. In this study, we studied activity against reactive oxygen species and anti inflammation effect of these three 'Cheongyeol' herbs. Methods : We measured each herb's yield of ethanol extracts, phenolic contents and activities against DPPH, hydroxyl radical and superoxide anion. Also through 6-hydroxydopamine (6-OHDA) induced oxidative damage in SH-SY5Y human neuroblastoma cell line, we measured antioxidant effect and NO activity of the three herbs. From the three herbs, we chose Prunella Herba, which showed the highest antioxidant effect, and studied its cell survival rate and anti inflammation effect through COX-2 and iNOS. Results : All three herbs showed significant results, and especially Prunella Herba showed significant effect on phenol contents, antioxidant effect on various active oxygen and antioxidant, and anti inflammation effect through cell line. Conclusions : Further study of the origin concept of 'cheongyeol' and research into specific mechanisms and role in treatment of cranial nerve disease, seems warranted.

• Molecules and Cells
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• 제40권4호
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• pp.271-279
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• 2017

Ran-binding protein family member, RanBP9 has been reported in various basic cellular mechanisms and neuropathological conditions including schizophrenia. Previous studies have reported that RanBP9 is highly expressed in the mammalian brain and retina; however, the role of RanBP9 in retinal development is largely unknown. Here, we present the novel and regulatory roles of RanBP9 in retinal development of a vertebrate animal model, zebrafish. Zebrafish embryos exhibited abundant expression of ranbp9 in developing brain tissues as well as in the developing retina. Yeast two-hybrid screening demonstrated the interaction of RanBP9 with Mind bomb, a component of Notch signaling involved in both neurogenesis and neural disease autism. The interaction is further substantiated by co-localization studies in cultured cells. Knockdown of ranbp9 resulted in retinal dysplasia with defective proliferation of retinal cells, downregulation of neuronal differentiation marker huC, elevation of neural proliferation marker her4, and alteration of cell cycle marker p57kip2. Expression of the $M{\ddot{u}}ller$ glial cell marker glutamine synthase was also affected in knockdown morphants. Our results suggest that Mind bomb-binding partner RanBP9 plays a role during retinal cell development of zebrafish embryogenesis.

• Genomics & Informatics
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• 제10권1호
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• pp.33-39
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• 2012

High-throughput genomic technologies (HGTs), including next-generation DNA sequencing (NGS), microarray, and serial analysis of gene expression (SAGE), have become effective experimental tools for cancer genomics to identify cancer-associated somatic genomic alterations and genes. The main hurdle in cancer genomics is to identify the real causative mutations or genes out of many candidates from an HGT-based cancer genomic analysis. One useful approach is to refer to known cancer genes and associated information. The list of known cancer genes can be used to determine candidates of cancer driver mutations, while cancer gene-related information, including gene expression, protein-protein interaction, and pathways, can be useful for scoring novel candidates. Some cancer gene or mutation databases exist for this purpose, but few specialized tools exist for an automated analysis of a long gene list from an HGT-based cancer genomic analysis. This report presents a new web-accessible bioinformatic tool, called CaGe, a cancer genome annotation system for the assessment of candidates of cancer genes from HGT-based cancer genomics. The tool provides users with information on cancer-related genes, mutations, pathways, and associated annotations through annotation and browsing functions. With this tool, researchers can classify their candidate genes from cancer genome studies into either previously reported or novel categories of cancer genes and gain insight into underlying carcinogenic mechanisms through a pathway analysis. We show the usefulness of CaGe by assessing its performance in annotating somatic mutations from a published small cell lung cancer study.