Role of agmatine in the application of neural progenitor cell in central nervous system diseases: therapeutic potentials and effects

Agmatine, the primary decarboxylation product of L-arginine, generated from arginine decarboxylase. Since the discovery of agmatine in the mammalian brain in the 1990s, an increasing number of agmatine-mediated effects have been discovered, demonstrating the benefits of agmatine on ischemic strokes, traumatic brain injury and numerous psychological disorders such as depression, anxiety, and stress. Agmatine also has cellular protective effects and contributes to cell proliferation and differentiation in the central nervous system (CNS). Neural progenitor cells are an important component in the recovery and repair of many neurological disorders due to their ability to differentiate into functional adult neurons. Recent data has revealed that agmatine can regulate and increase proliferation and the fate of progenitor cells in the adult hippocampus. This review aims to summarise and discuss the role of agmatine in the CNS; specifically, the effects and relationship between agmatine and neural progenitor cells and how these ideas can be applied to potential therapeutic application.ope

Effects of Mutation in CG11426 Gene on Glial Population in the Drosophila Eye Imaginal Disc

학위논문(석사)--서울대학교 대학원 :사범대학 과학교육과(생물전공),2019. 8. 전상학.Glial cells have various functions such as guiding axon growth, supporting neuron, taking up neurotransmitters, and forming a blood-brain barrier. However, little is known about the mechanisms for regulating their population. Because Drosophila glial cells are highly similar to human glial cells in function and morphology, studying Drosophila glial cells is important in understanding the human nervous system. I characterized a novel Drosophila gene, CG11426 which is expressed in glia. CG11426 encodes lipid phosphate phosphatase (LPP). The known Drosophila LPP, Wunens are involved in germ cell migration and survival, and septate junction formation during tracheal development. In this study, I characterized a function of a new gene encoding Drosophila LPP, CG11426, which regulates glial cell population in the eye imaginal disc. The suppression of the CG11426 gene increased glial cell number while the ectopic expression of CG11426 gene reduced glial cell number in the eye imaginal disc. Also, I observed that CG11426 gene normally promotes apoptosis and inhibits ERK signaling in the eye imaginal disc. Moreover, a mutation in CG11426 gene caused defects in axon projection to the optic lobe in the larval eye-brain complexes and disruption of brain cortex in adult flies. Thus, the results in this study demonstrate that CG11426 gene negatively regulates ERK signaling to promote apoptosis and eventually maintains an appropriate glial population.신경계에서 신경교세포는 단순히 신경세포를 보호하는 것 이외에도 다양한 역할을 한다. 신경교세포는 신경 축삭돌기가 뻗어나가는 길을 안내하고, 뇌를 보호하는 장벽을 형성하며, 신경세포에 영양분을 공급하기도 한다. 따라서 신경계를 이해하고자 한다면 신경교세포에 대한 이해가 바탕이 되어야 한다. 초파리의 신경교세포는 사람의 신경교세포와 형태와 기능이 비슷하기 때문에 초파리는 신경교세포를 연구하기에 적합한 모델 동물이다. 이 연구에서는 초파리의 신경교세포에서 발현되는 CG11426 유전자를 탐색하였다. CG11426 유전자는 기존에 연구되지 않은 인지질 탈인산화효소를 암호화하는 유전자이다. 초파리의 인지질 탈인산화효소라고 알려진 Wunen은 생식세포의 이동과 생존, 정점 접합 형성 및 기관 발달에 영향을 미친다고 알려져 있다. 이 연구에서는 새로운 인지질 탈인산화효소를 암호화하는 CG11426 유전자를 탐색하였다. CG11426 유전자의 발현을 억제하였더니 신경교세포 수가 늘어났고, 반대로 CG11426 유전자의 발현을 증가시켰더니 신경교세포 수가 감소하였다. 또한, CG11426 유전자의 발현이 증가하였을 때 유충의 눈-뇌 복합체에서 신경 축삭 말단이 정확한 위치에 도달하지 못했고, 뇌에도 손상이 발견되었다. 이러한 연구의 결과들로 CG11426 유전자가 적절한 수의 신경교세포를 유지하도록 조절하며, 그 조절 기작은 ERK signaling 억제에 의한 세포 사멸 때문임을 밝혔다.Chapter 1. Introduction 1 1.1. Lipid phosphate phosphatase . 1 1.2. Glia in the eye imaginal disc. 4 1.3. ERK signaling pathway . 8 1.4. Purpose of the study 9 Chapter 2. Materials and Methods . 10 2.1. Plasmid construction and Drosophila transformation 10 2.2. Fly strains . 11 2.3. Immnuohistochemistry . 13 2.4. Histology . 15 2.5. Quantitative Real-time PCR. 15 Chapter 3. Results . 17 3.1. CG11426 gene was expressed in glia at embryonic and larval stage . 17 3.2. UAS-CG11426 flies were constructed . 22 3.3. CG11426 gene negatively regulated the number of glial cells in the eye imaginal disc 24 3.4. CG11426 expression levels were identified in the mutant flies 25 3.5. CG11426 knockdown in the SPG decreased the number of glial cells 30 3.6. CG11426 gene promoted glial cell death . 35 3.7. CG11426 gene suppressed ERK signaling 40 3.8. Mutation in CG11426 gene caused defects in axon projection 43 3.9. Increased CG11426 levels caused defects in integrity of brain 45 Chapter 4. Discussion 47 References . 53 국문초록 62Maste

Autophagy, Cellular Aging and Age-related Human Diseases

Macroautophagy/autophagy is a conserved degradation system that engulfs intracytoplasmic contents, including aggregated proteins and organelles, which is crucial for cellular homeostasis. During aging, cellular factors suggested as the cause of aging have been reported to be associated with progressively compromised autophagy. Dysfunctional autophagy may contribute to age-related diseases, such as neurodegenerative disease, cancer, and metabolic syndrome, in the elderly. Therefore, restoration of impaired autophagy to normal may help to prevent age-related disease and extend lifespan and longevity. Therefore, this review aims to provide an overview of the mechanisms of autophagy underlying cellular aging and the consequent disease. Understanding the mechanisms of autophagy may provide potential information to aid therapeutic interventions in age-related diseases.ope

The role of NOX inhibitors in neurodegenerative diseases

Oxidative stress is a key player in both chronic and acute brain disease due to the higher metabolic demand of the brain. Among the producers of free radicals, NADPH-oxidase (NOX) is a major contributor to oxidative stress in neurological disorders. In the brain, the superoxide produced by NOX is mainly found in leukocytes. However, recent studies have reported that it can be found in several other cell types. NOX has been reported to regulate neuronal signaling, memory processing, and central cardiovascular homeostasis. However, overproduction of NOX can contribute to neurotoxicity, CNS degeneration, and cardiovascular disorders. Regarding the above functions, NOX has been shown to play a crucial role in chronic CNS diseases like Parkinson's disease (PD), Alzheimer's disease (AD), Huntington's disease (HD), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS), and in acute CNS disorders such as stroke, spinal cord injury, traumatic brain injury (TBI), and related cerebrovascular diseases. NOX is a multi-subunit complex consisting of two membrane-associated and four cytosolic subunits. Thus, in recent years, inhibition of NOX activity has drawn a great deal of attention from researchers in the field of treating chronic and acute CNS disorders and preventing secondary complications. Mounting evidence has shown that NOX inhibition is neuroprotective and that inhibiting NOX in circulating immune cells can improve neurological disease conditions. This review summarizes recent studies on the therapeutic effects and pharmacological strategies regarding NOX inhibitors in chronic and acute brain diseases and focuses on the hurdles that should be overcome before their clinical implementation.ope

Maintenance of the Neuroprotective Function of the Amino Group Blocked Fluorescence-Agmatine

Agmatine, an endogenous derivative of arginine, has been found to be effective in treating idiopathic pain, convulsion, stress-mediated behavior, and attenuate the withdrawal symptoms of drugs like morphine. In the early stages of ischemic brain injury in animals, exogenous agmatine treatment was found to be neuroprotective. Agmatine is also considered as a putative neurotransmitter and is still an experimental drug. Chemically, agmatine is called agmatine 1-(4-aminobutyl guanidine). Crystallographic study data show that positively-charged guanidine can bind to the protein containing Gly and Asp residues, and the amino group can interact with the complimentary sites of Glu and Ser. In this study, we blocked the amino end of the agmatine by conjugating it with FITC, but the guanidine end was unchanged. We compared the neuroprotective function of the agmatine and agmatine-FITC by treating them in neurons after excitotoxic stimulation. We found that even the amino end blocked neuronal viability in the excitotoxic condition, by NMDA treatment for 1 h, was increased by agmatine-FITC, which was similar to that of agmatine. We also found that the agmatine-FITC treatment reduced the expression of nitric oxide production in NMDA-treated cells. This study suggests that even if the amino end of agmatine is blocked, it can perform its neuroprotective function.ope

Brain 11: what's new in stroke research?

The International Society for Cerebral Blood Flow and Metabolism promotes research centered on furthering the understanding of neurological conditions that result from ischemia and related injuries. This previous meeting (Brain 11) focused on state-of-the-art research, which shed light on the pathophysiology of these conditions as they pertained to the cerebral vasculature - including the BBB - and angiogenesis, immune mechanisms, regeneration and repair following such insults. The meeting also covered a variety of potential therapeutic strategies ranging from cell-based therapy, induced tolerance and the targeting of specific immune or cell death pathways. In addition, there was a focus on how the peripheral circulation contributes to such types of brain injury.ope

Neural induction with neurogenin1 increases the therapeutic effects of mesenchymal stem cells in the ischemic brain.

Mesenchymal stem cells (MSCs) have been shown to ameliorate a variety of neurological dysfunctions. This effect is believed to be mediated by their paracrine functions, since these cells rarely differentiate into neuronal cells. It is of clinical interest whether neural induction of MSCs is beneficial for the replacement therapy of neurological diseases. Here we report that expression of Neurogenin1 (Ngn1), a proneural gene that directs neuronal differentiation of progenitor cells during development, is sufficient to convert the mesodermal cell fate of MSCs into a neuronal one. Ngn1-expressing MSCs expressed neuron-specific proteins, including NeuroD and voltage-gated Ca2+ and Na+ channels that were absent in parental MSCs. Most importantly, transplantation of Ngn1-expressing MSCs in the animal stroke model dramatically improved motor functions compared with the parental MSCs. MSCs with Ngn1 populated the ischemic brain, where they expressed mature neuronal markers, including microtubule associated protein 2, neurofilament 200, and vesicular glutamate transporter 2, and functionally connected to host neurons. MSCs with and without Ngn1 were indistinguishable in reducing the numbers of Iba1+, ED1+ inflammatory cells, and terminal deoxynucleotidyl transferase dUTP nick-end labeling(+) apoptotic cells and in increasing the numbers of proliferating Ki67+ cells. The data indicate that in addition to the intrinsic paracrine functions of MSCs, motor dysfunctions were remarkably improved by MSCs able to transdifferentiate into neuronal cells. Thus, neural induction of MSCs is advantageous for the treatment of neurological dysfunctions.ope

경찰 중립화 제도 변화에 관한 연구

학위논문 (석사)-- 서울대학교 행정대학원 : 행정학과, 2015. 2. 김병섭.본 연구는 경찰중립화제도의 역사적 변화 과정을 치안국시대, 치안본부시대, 경찰청시대로 나누어 분석하였다. 이러한 분석을 위한 연구방법으로 사례연구방법을 적용하였으며 자료 수집을 위해 국회속기록, 국회공청회기록, 언론보도, 연구자료, 경찰편찬역사서, 경찰청장 취임사 및 신년사 등의 문헌자료와 함께 면접을 사용하였다. 분석틀을 구축하기 위한 선행연구 검토에서는 정치적 중립, 경찰중립화, 제도, 제도변화를 검토하였다. 정치적 중립과 경찰중립화의 다양한 의미를 확인하였고 다양한 제도의 개념과 제도 변화의 기제를 파악하였다. 또한 각 경찰중립화제도가 어떻게 정치적 중립성을 확보할 수 있는지 검토하였다. 이러한 검토 후 본 연구는 경찰중립화제도 변화에 관계하는 영향요인을 거시적 구조와 행위자로 설정하는 분석틀을 설정하였다. 거시적 구조는 정치적 환경을 통해 분석하였으며 행위자는 변화추진자와 변화반대자로 유형화하는 동시에 각 행위자의 주장과 정치적 중립에 대한 인식을 분석하였다. 또한 제도변화는 국회에 제출되고 통과된 법안을 중심으로 분석하였다. 이를 통해 거시적 구조 변화가 어떻게 행위자에게 기회 또는 제약으로 작용하는지 그리고 제도변화에 직접적으로는 어떤 영향을 미치는지와 각 행위자의 행동이 제도변화에 어떻게 영향을 미치는지를 파악하려고 하였다. 사례분석의 결과 경찰중립화제도는 거의 변화하지 않은 것으로 나타났다. 치안국시대‧치안본부시대‧경찰청시대에 경찰중립화제도 도입에 대한 많은 논의가 있었음에도 불구하고 경찰청의 설치, 경찰위원회 도입, 경찰청장 임기제 및 경찰청장 퇴직 후 정치활동 제한 등의 제도변화가 있었으나 실제 운영에 있어서는 경찰의 정치적 중립을 실질적으로 제고하는 역할을 하지 못하고 있다. 면접의 결과 경찰에 의한 적극적인 정치적 중립 훼손은 많이 감소하였으나 소극적인 정치적 중립 훼손은 언제든지 발생할 수 있다는 점을 고려할 때 향후 경찰의 정치적 중립을 확고히 하기 위해 국무총리 산하에 경찰에 실질적인 영향력을 행사할 수 있는 공안위원회를 설치하는 것, 공안위원회 구성에서 정치적 중립 확보를 위해 여당과 야당 또는 입법부․사법부․행정부에서 각각 위원을 추천하는 것 그리고 현재 제도화되어 있는 경찰청장 임기제를 실질적으로 지키는 것을 제안하며 궁극적으로는 자치경찰제도를 도입하고 경찰에 수사권을 부여하여 자치경찰과 중앙경찰 사이․경찰과 검찰 사이에 견제와 균형을 이룰 것을 제안한다.목 차 제1장 서론 ······························································ 1 제1절 연구의 필요성 및 연구목적 ····································· 1 제2절 연구범위 및 연구방법 ··········································· 2 제2장 선행연구의 검토 ············································· 4 제1절 정치적 중립과 경찰 중립화 ····································· 4 1. 정치적 중립 ·························································· 4 2. 경찰 중립화 ·························································· 7 제2절 제도와 제도변화 ················································ 11 1. 제도와 제도변화 ··················································· 11 1) 제도의 개념과 의의 ·············································· 11 2) 제도변화 ··························································· 14 2. 제도 변화에 대한 선행연구의 검토 ······························ 17 제3장 연구방법과 분석틀 ········································ 22 제1절 연구방법 ························································· 22 제2절 분석틀 ···························································· 22 1. 분석틀 ······························································· 23 2. 분석요소 : 거시적 구조, 행위자, 제도변화 ····················· 25 1) 거시적 구조 ······················································· 25 2) 행위자 ······························································ 26 3) 제도변화 ··························································· 28 제4장 사례분석 ······················································ 29 제1절 치안국 시대 ···················································· 29 1. 거시적 구조 ························································· 29 2. 행위자 ······························································· 31 1) 변화추진자 ························································ 31 (1) 야당 ······························································ 31 (2) 시민대표 ························································ 36 (3) 경찰 ······························································ 38 2) 변화반대자 ························································ 40 (1) 정부부문 ························································· 40 (2) 여당 ······························································ 44 3. 제도변화 : 제도변화의 내용 ······································ 45 4. 소결 ·································································· 48 제2절 치안본부 시대 ·················································· 47 1. 거시적 구조 ························································· 47 2. 행위자 ······························································· 49 1) 변화추진자 ························································ 49 (1) 야당 ······························································ 50 (2) 경찰 ······························································ 55 2) 변화반대자 ························································ 58 (1) 정부부문 ························································· 58 (2) 여당 ······························································ 61 3. 제도변화 : 제도변화의 내용 ······································ 62 4. 소결 ·································································· 63 제3절 경찰청 시대 ···················································· 65 1. 거시적 구조 ························································· 65 2. 행위자 ······························································· 66 1) 변화추진자 : 야당 ················································ 66 2) 변화반대자 ························································ 67 (1) 여당 ······························································ 67 (2) 경찰 ····························································· 69 3. 제도변화 : 제도변화의 내용 ······································ 70 4. 소결 ·································································· 71 제4절 분석결과 종합 ·················································· 72 1. 경찰 중립화 제도 ·················································· 72 1) 경찰 위원회 제도 ················································· 73 2) 자치경찰제도 ······················································ 74 3) 경찰의 수사권 보장 ·············································· 74 4) 경찰청장 퇴임 후 정당 활동 제한 및 경찰청장의 임기제 ·· 75 2. 시대별 논의의 종합 ················································ 75 제5장 결론 ····························································· 88 제1절 요약 ······························································· 88 제2절 연구의 시사점 및 한계 ········································· 90 1. 연구의 시사점 ······················································ 90 2. 연구의 한계 ························································· 91 ······························································· 92Maste

Expression of the γ-Aminobutyraldehyde Dehydrogenase in the Bovine Brain by Immunohistochemistry and in Situ Hybridization Methods

γ-Aminobutyrate (GABA), a four carbon amino acid, was discovered in brain tissue in 1950. GABA is an inhibitory neurotransmitter in the mammalian CNS. GABA is produced mainly through enzymaticdecarboxyIation of glutamic acid by glutamic acid decarboxylase (GAD), and synthesized by the degradation of putrescine (1,4-diaminobutane), one of the polyamines. It provides y aminobutyraldehyde (γ-ABAL), substrate for the synthesis of GABA by γ- minobutyraldehyde dehydrogenase (γ-ABALDH). We purified γ-ABALDH, another synthetic enzyme for GABA, from the bovine brain and prepared an antibody for γ-ABALDH from rabbits. We also attempted the NHrterminal sequencing of γ-ABALDH and were successful in producing the oligonucleotide probes based on the N-terminal sequence determined. 36 mer-oligonucleotides complementary to the mRNA were synthesized, and radiolabelled at the 5' end with 32P. Then an in situ hybridization technique was applied to detect γ-aminobutyraldehyde dehydrogenase mRNA in the bovine brain tissue. Cells containing mRNA of γ-ABALDH were found in many regions of bovine brain tissue, the results being similar to those from immunostaining.ope

The protective effect of melatonin on neural stem cell against LPS-induced inflammation

Stem cell therapy for tissue regeneration has several limitations in the fact that transplanted cells could not survive for a long time. For solving these limitations, many studies have focused on the antioxidants to increase survival rate of neural stem cells (NSCs). Melatonin, an antioxidant synthesized in the pineal gland, plays multiple roles in various physiological mechanisms. Melatonin exerts neuroprotective effects in the central nervous system. To determine the effect of melatonin on NSCs which is in LPS-induced inflammatory stress state, we first investigated nitric oxide (NO) production and cytotoxicity using Griess reagent assays, LDH assay, and neurosphere counting. Also, we investigated the effect of melatonin on NSCs by measuring the mRNA levels of SOX2, TLX, and FGFR-2. In addition, western blot analyses were performed to examine the activation of PI3K/Akt/Nrf2 signaling in LPS-treated NSCs. In the present study, we suggested that melatonin inhibits NO production and protects NSCs against LPS-induced inflammatory stress. In addition, melatonin promoted the expression of SOX2 and activated the PI3K/Akt/Nrf2 signaling under LPS-induced inflammation condition. Based on our results, we conclude that melatonin may be an important factor for the survival and proliferation of NSCs in neuroinflammatory diseasesope