Protection against RAGE-mediated neuronal cell death by sRAGE-secreting human mesenchymal stem cells in 5xFAD transgenic mouse model

Son, Myeongjoo,Oh, Seyeon,Park, Hyunjin,Ahn, Hyosang,Choi, Junwon,Kim, Hyungho,Lee, Hye Sun,Lee, Sojung,Park, Hye-Jeong,Kim, Seung U.,Lee, Bonghee,Byun, Kyunghee Elsevier 2017 Brain, behavior, and immunity Vol.66 No.-

<P><B>Abstract</B></P> <P>Alzheimer's disease (AD), which is the most commonly encountered neurodegenerative disease, causes synaptic dysfunction and neuronal loss due to various pathological processes that include tau abnormality and amyloid beta (Aβ) accumulation. Aβ stimulates the secretion and the synthesis of Receptor for Advanced Glycation End products (RAGE) ligand by activating microglial cells, and has been reported to cause neuronal cell death in Aβ<SUB>1–42</SUB> treated rats and in mice with neurotoxin-induced Parkinson’s disease.</P> <P>The soluble form of RAGE (sRAGE) is known to reduce inflammation, and to decrease microglial cell activation and Aβ deposition, and thus, it protects from neuronal cell death in AD. However, sRAGE protein has too a short half-life for therapeutic purposes. We developed sRAGE-secreting umbilical cord derived mesenchymal stem cells (sRAGE-MSCs) to enhance the inhibitory effects of sRAGE on Aβ deposition and to reduce the secretion and synthesis of RAGE ligands in 5xFAD mice. In addition, these cells improved the viability of injected MSCs, and enhanced the protective effects of sRAGE by inhibiting the binding of RAGE and RAGE ligands in 5xFAD mice. These findings suggest sRAGE protein from sRAGE-MSCs has better protection against neuronal cell death than sRAGE protein or single MSC treatment by inhibiting the RAGE cell death cascade and RAGE-induce inflammation.</P> <P><B>Highlights</B></P> <P> <UL> <LI> sRAGE enhanced viability of MSCs in 5xFAD mice. </LI> <LI> sRAGE-MSCs showed low Aβ<SUB>1–42</SUB> levels and protective effects from RAGE-mediated neuronal cell death microglia activation in 5xFAD mice. </LI> <LI> Comparing sRAGE protein and MSCs, the sRAGE protein effectively modulated expression of RAGE ligands and control MSC has protective effects from neuron apoptosis in 5xFAD mice. </LI> </UL> </P>

Gamma-aminobutyric acid-salt attenuated high cholesterol/high salt diet induced hypertension in mice

Myeongjoo Son,Seyeon Oh,Hye Sun Lee,Junwon Choi,Bae-Jin Lee,Joung-Hyun Park,Chul Hyun Park,Kuk Hui Son,Kyunghee Byun 대한약리학회 2021 The Korean Journal of Physiology & Pharmacology Vol.25 No.1

Excessive salt intake induces hypertension, but several gamma-aminobutyric acid (GABA) supplements have been shown to reduce blood pressure. GABAsalt, a fermented salt by L. brevis BJ20 containing GABA was prepared through the post-fermentation with refined salt and the fermented GABA extract. We evaluated the effect of GABA-salt on hypertension in a high salt, high cholesterol diet induced mouse model. We analyzed type 1 macrophage (M1) polarization, the expression of M1 related cytokines, GABA receptor expression, endothelial cell (EC) dysfunction, vascular smooth muscle cell (VSMC) proliferation, and medial thicknesses in mice model. GABA-salt attenuated diet-induced blood pressure increases, M1 polarization, and TNF-α and inducible nitric oxide synthase (NOS) levels in mouse aortas, and in salt treated macrophages in vitro. Furthermore, GABA-salt induced higher GABAB receptor and endothelial NOS (eNOS) and eNOS phosphorylation levels than those observed in salt treated ECs. In addition, GABA-salt attenuated EC dysfunction by decreasing the levels of adhesion molecules (E-selectin, Intercellular Adhesion Molecule-1 [ICAM-1], vascular cell adhesion molecule-1 [VCAM-1]) and of von Willebrand Factor and reduced EC death. GABA-salt also reduced diet-induced reductions in the levels of eNOS, phosphorylated eNOS, VSMC proliferation and medial thickening in mouse aortic tissues, and attenuated Endothelin-1 levels in salt treated VSMCs. In summary, GABA-salt reduced high salt, high cholesterol diet induced hypertension in our mouse model by reducing M1 polarization, EC dysfunction, and VSMC proliferation.

중증하지허혈 모델에서 골수유래 중간엽줄기세포가 혈관 형성에 미치는 영향

손명주(Myeongjoo Son),강웅철(Woong Chol Kang),변경희(Kyunghee Byun) 대한체질인류학회 2016 해부·생물인류학 (Anat Biol Anthropol) Vol.29 No.2

중증하지허혈 (Critical limb ischemia, CLI)은 동맥경화성 말초동맥질환의 가장 심한 임상 양상 중 하나로 혈전에 의해 유발되어 하지혈관을 통한 혈류를 감소시키고 피부궤양이나 조직괴사, 진행 정도에 따라 사지 절단을 초래할 수 있다. 질환 치료를 위해서 경피적 혈관 중재술 (percutaneous peripheral intervention) 등을 시도하고 있으나 이는 혈관을 뚫어줄 뿐 혈관 재협착률을 줄이지 못하며 새로운 혈관 생성을 하지 못하기 때문에 사지 절단률과 사망률을 유의하게 줄이지 못하고 있다. 최근 골수유래 줄기세포의 주변분비효능 (paracrine effect)을 통한 허혈성 질환에서의 치료 효과에 대해서 보고되었다. 본 연구에서는 중증하지허혈 동물 모델에서 골수유래 중간엽줄기세포의 치료 및 신혈관 형성 (angiogenesis) 효능을 확인하고자 한다. 이를 위해 사람의 골수에서 분리한 중간엽줄기세포의 특성을 유세포분석과 분화실험을 통해 확인하였다. 사람제 대정맥혈관내피세포에서 줄기세포의 배양 배지를 처리한 후 혈관 형성 확인을 통해 주변분비효능을 확인하였다. 또한 10% Ferric chloride (FeCl3)를 이용하여 흰쥐의 넙다리동맥 내에 혈전을 생성하여 중증하지허혈과 비슷한 조건을 만들었으며, 10만 개의 사람골수유래 중간엽줄기세포를 넙다리동맥의 주행에 따라 다리근육에 주입하였다. 28일 후에 줄기세포의 생착능, 다리혈관의 변화, 다리근육의 상태와 섬유화 등을 비교하여 주입한 줄기세포의 효능을 확인하였다. 실험 결과 줄기세포 배양 배지 처리 후 혈관내피세포의 혈관 형성능이 대조군보다 높았을 뿐만 아니라 주입한 중 간엽줄기세포를 주입한 흰쥐에서의 신생혈관 형성능이 높았다. 다리의 상태를 육안으로 확인한 허혈 정도 또한 좋아졌으며, 다리근육 세포의 조직학적 상태와 섬유화 정도에서도 유의미하게 호전되었다. 이상의 실험 결과를 통해 골수에서 분리 배양한 중간엽줄기세포는 중증하지허혈에서의 혈관 형성능뿐만 아니라 섬유화 억제 등의 효과로 중증하지허혈에서 하지 절단을 예방할 수 있음을 확인하였다. Critical limb ischemia (CLI) is the most severe peripheral artery disease and caused by thrombus formation in blood vessel. The current strategies for treating CLI does not protect limb amputation and reduction in the risk of mortality. Recently, human bone marrow derived mesenchymal stem cells (BD-MSC) were reported to have a paracrine effects on angiogenesis in several ischemic diseases. So, we validate to determine whether BD-MSC protect against ferric chloride treated CLI and induce angiogenesis. To characterized human bone marrow derived stem cell, BD-MSC differentiated to osteocytes and adipocytes and validated stemness using flow cytometry. Endothelial cell induced angiogenesis followed by mesenchymal stem cell cultured medium treatment in HUVEC in vitro. We also mimicked CLI patients condition using FeCl3 treated CLI mouse and injected one hundred thousand of BD-MSC along the femoral artery to leg muscle. We validated stem cell survival, blood vessel formation, leg muscle condition and fibrosis compared by saline injected mice 28 days later. In this study, BD-MSC cultured medium treatment increased migration and tube formation of HUVEC and BDMSC injection had an effective blood vessel formation in FeCl3 treated CLI. As well as blood vessel formation, limb salvage rate also improved and fibrosis area statistically decreased in BD-MSC injected mice. In conclusion, bone marrow derived mesenchymal stem cell improved not only blood

카데바를 이용한 해부학 실습의 효과에 관한 연구

손인아(Ina Son),손명주(Myeongjoo Son),정구보(Goo-Bo Jeong) 한국콘텐츠학회 2013 한국콘텐츠학회논문지 Vol.13 No.2

1급 응급구조사는 인체에 대한 해부학적 구조와 기능에 대한 이해를 바탕으로 정확한 임상술기를 수행해야 한다. 이러한 교육을 위해 응급구조(학)과 학생들은 기초의학 분야중 하나인 인체해부학을 이수해야 하며 카데바(cadaver)를 이용한 해부실습 교육이 통합적으로 필요하다. 따라서 본 연구는 응급구조(학)과 학생 255명에게 실시된 카데바를 이용한 해부학 실습의 효과를 조사 하였다. 그 결과 교육 만족도는 5점 척도 중 평균 4.50점으로 나타났으며, 주제별 시간의 적정도는 평균 3.61점이었고, 교육에 대한 이해도는 평균점으로 나타났다. 또한 93.3%의 학생이 재참여 혹은 다른 학생에게 추천할 의사가 있다고 응답하였고 학년별로 이해도 만족도 시간 적정도에 있어 통계적으로 유의한 차이가 있었다(P<.05). 결론적으로, 추후 학년별 맞춤형 카데바 해부실습 프로그램에 대한 연구가 지속되어야 할 것이고 고학년은 실습 시간을 늘리고 육안해부학(gross anatomy) 뿐만 아니라 임상술기를 접목한 임상해부학(clinical anatomy)에 대한 실습이 통합적으로 진행되어야 함을 제언하는 바이다. There are insufficient cadaver-used practice programs for paramedic student education. To provide the basic data for the effective cadaver practice program, the study interviewed 255 students in department of EMT, who attended cadaver practicum. The results indicated that the average satisfaction level in education was 4.5 out of 5 and in relation to allotted time was 3.61 out of 5. The average understanding level of was 4.5 out of 5. In conclusion, senior students who have already taken clinical education & clinical procedure are recommended to focus on clinical anatomy practice and lower grade students are recommended to focus on understanding human body structure in cadaver-used practice program.

sRAGE prolonged stem cell survival and suppressed RAGE-related inflammatory cell and T lymphocyte accumulations in an Alzheimer's disease model

Oh, Seyeon,Son, Myeongjoo,Choi, Junwon,Lee, Sojung,Byun, Kyunghee Academic Press 2018 Biochemical and biophysical research communication Vol. No.

<P><B>Abstract</B></P> <P>The main causes of Alzheimer's disease (AD) have not determined and effective treatment has not been developed yet, even though extensive researches and several clinical trials have been conducted.. Fortunately, stem cell transplantation is emerging as a potential therapeutic candidate for AD, but the success of stem cell based therapy depends on the survival of transplanted cells. Here, we generated sRAGE secreting mesenchymal stem cells (sRAGE-MSCs) and then injected these MSCs or control MSCs with amyloid beta 1–42 (Aβ<SUB>1-42</SUB>) into the entorhinal cortices of male Sprague Dawley rats. The survival of transplanted cell, the number of T lymphocytes and microglia, expression of RAGE and its ligands and neuronal cell death were determined, 4 weeks after sRAGE-MSC transplantation. Transplanted sRAGE-MSCs survived longer than control MSCs and sRAGE-MSCs showed reduced level of CD4 and CD3d positive T lymphocyte. Furthermore, the number of M1 microglia in MSCs was more than that of sRAGE-MSCs as well. On the other hand, the number of M2 microglia in sRAGE-MSCs was increased compared with that of MSCs. In addition, sRAGE-MSCs decreased RAGE and RAGE ligand expressions and their interactions more effectively than those of MSCs. Finally, sRAGE-MSC transplantation protected from apoptosis and prevented decreasing numbers of neuron in Aβ<SUB>1-42</SUB> treated rat brains. These observations suggest continuous sRAGE secretion from sRAGE-MSCs might appreciably improve the effectiveness of cell therapy in Aβ<SUB>1-42</SUB> injected rat brains.</P> <P><B>Highlights</B></P> <P> <UL> <LI> The interactions between RAGE and Aβ cause inflammatory responses and oxidative stress, and reduce cerebral blood flow. </LI> <LI> RAGE and its ligand interactions induce a cascade related to neuronal apoptosis and inflammation. </LI> <LI> The soluble form of RAGE (sRAGE) might suppress downregulation of the RAGE-mediated inflammatory/cell death pathway. </LI> <LI> sRAGE-MSCs enhanced survival more effectively than MSCs in an Aβ<SUB>1-42</SUB> induced rat model of AD. </LI> </UL> </P>

Ishige okamurae reduces blood glucose levels in high-fat diet mice and improves glucose metabolism in the skeletal muscle and pancreas

Yang, Hye-Won,Son, Myeongjoo,Choi, Junwon,Oh, Seyeon,Jeon, You-Jin,Byun, Kyunghee,Ryu, Bo Mi The Korean Society of Fisheries and Aquatic Scienc 2020 Fisheries and Aquatic Sciences Vol.23 No.1

Brown alga (Ishige okamurae; IO) dietary supplements have been reported to possess anti-diabetic properties. However, the effects of IO supplements have not been evaluated on glucose metabolism in the pancreas and skeletal muscle. C57BL/6 N male mice (age, 7 weeks) were arranged in five groups: a chow diet with 0.9% saline (NFD/saline group), high-fat diet (HFD) with 0.9% saline (HFD/saline group). high-fat diet with 25 mg/kg IO extract (HFD/25/IOE). high-fat diet with 50 mg/kg IO extract (HFD/50/IOE), and high-fat diet with 75 mg/kg IO extract (HFD/75/IOE). After 4 weeks, the plasma, pancreas, and skeletal muscle samples were collected for biochemical analyses. IOE significantly ameliorated glucose tolerance impairment and fasting and 2 h blood glucose level in HFD mice. IOE also stimulated the protein expressions of the glucose transporters (GLUTs) including GLUT2 and GLUT4 and those of their related transcription factors in the pancreases and skeletal muscles of HFD mice, enhanced glucose metabolism, and regulated blood glucose level. Our results suggest Ishige okamurae extract may reduce blood glucose levels by improving glucose metabolism in the pancreas and skeletal muscle in HFD-induced diabetes.

S-215 Prognostic value of soluble ST2 in patients with ST-segment elevation MI undergoing primary PCI

( Jongwook Yu ),( Pyung Chun Oh ),( Myeongjoo Son ),( Kyunghee Byun ),( Woong Chol Kang ) 대한내과학회 2016 대한내과학회 추계학술대회 Vol.2016 No.1

Background: Soluble ST2, an interleukin 33-related substance is a marker of biomechanical strain and has shown to be an independent predictor for adverse outcome in heart failure. We evaluated the prognostic value of soluble ST2 in ST-segment elevation myocardial infarction (STEMI) patients undergoing primary percutaneous coronary intervention (PCI). Methods: A total of 323 patients with STEMI undergoing primary PCI were enrolled and divided into two groups based on the median level of ST-2 measured at the time of presentation: the high ST2 group (ST2 ≥654 pg/mL, n=162) and the low ST2 group (ST2 <654 pg/mL, n=161). The primary endpoint was 1-year major adverse cardiovascular and cerebrovascular events (MACCE), defined as the composite of all-cause death, non-fatal MI, non-fatal stroke, and ischemia-driven revascularization. Results: Demographic, echocardiographic and angiographic characteristics were similar between the high and low ST2 groups. The cumulative incidence of MACCE at 1 year was significantly higher in the high ST2 group than in the low ST2 group (15.4% vs. 8.1%, p=0.044, Figure). By multivariate Cox regression analysis adjusting for age, sex, diabetes, anterior wall infarction, and systolic dysfunction (ejection fraction <40%), the high ST2 level was independently associated with 1-year MACCE (adjusted hazard ratio 2.09, 95% CI 1.01-4.29, p=0.046). Conclusions: The level of ST2 measured at the time of presentation can be a powerful, independent predictor of 1-year adverse clinical outcomes in patients with STEMI.

Activated microglial cells synthesize and secrete AGE-albumin

Kyunghee Byun,Enkhjaigal Bayarsaikhan,Daesik Kim,Myeongjoo Son,Junhee Hong,Goo-Bo Jeong,Sun Ha Paek,Moo-Ho Won,Bonghee Lee 대한해부학회 2012 Anatomy & Cell Biology Vol.45 No.1

A holy grail of curing neurodegenerative diseases is to identify the main causes and mechanisms underlying neuronal death. Many studies have sought to identify these targets in a wide variety of ways, but a more important task is to identify critical molecular targets and their origins. Potential molecular targets include advanced glycation end products (AGEs) that can promote neuronal cell death, thereby contributing to neurodegenerative disorders such as Alzheimer disease or Parkinson disease. In this study, we showed that AGE-albumin (glycated albumin) is synthesized in microglial cells and secreted in the human brain. Our results provide new insight into which microglial cells can promote the receptor for AGE-mediated neuronal cell death, eventually leading to neurodegenerative diseases.

Ciliogenesis is reciprocally regulated by PPARA and NR1H4/FXR through controlling autophagy in vitro and in vivo

Liu, Zhi-qiang,Lee, Joon No,Son, Myeongjoo,Lim, Jae-Young,Dutta, Raghbendra Kumar,Maharjan, Yunash,Kwak, SeongAe,Oh, Goo Taeg,Byun, Kyunghee,Choe, Seong-Kyu,Park, Raekil Landes Bioscience 2018 AUTOPHAGY Vol.14 No.6

<P>The primary cilia are evolutionarily conserved microtubule-based cellular organelles that perceive metabolic status and thus link the sensory system to cellular signaling pathways. Therefore, ciliogenesis is thought to be tightly linked to autophagy, which is also regulated by nutrient-sensing transcription factors, such as PPARA (peroxisome proliferator activated receptor alpha) and NR1H4/FXR (nuclear receptor subfamily 1, group H, member 4). However, the relationship between these factors and ciliogenesis has not been clearly demonstrated. Here, we present direct evidence for the involvement of macroautophagic/autophagic regulators in controlling ciliogenesis. We showed that activation of PPARA facilitated ciliogenesis independently of cellular nutritional states. Importantly, PPARA-induced ciliogenesis was mediated by controlling autophagy, since either pharmacological or genetic inactivation of autophagy significantly repressed ciliogenesis. Moreover, we showed that pharmacological activator of autophagy, rapamycin, recovered repressed ciliogenesis in ppara(-/-) cells. Conversely, activation of NR1H4 repressed cilia formation, while knockdown of NR1H4 enhanced ciliogenesis by inducing autophagy. The reciprocal activities of PPARA and NR1H4 in regulating ciliogenesis were highlighted in a condition where de-repressed ciliogenesis by NR1H4 knockdown was further enhanced by PPARA activation. The in vivo roles of PPARA and NR1H4 in regulating ciliogenesis were examined in greater detail in ppara(-/-) mice. In response to starvation, ciliogenesis was facilitated in wild-type mice via enhanced autophagy in kidney, while ppara(-/-) mice displayed impaired autophagy and kidney damage resembling ciliopathy. Furthermore, an NR1H4 agonist exacerbated kidney damage associated with starvation in ppara(-/-) mice. These findings indicate a previously unknown role for PPARA and NR1H4 in regulating the autophagy-ciliogenesis axis in vivo.</P>

Triboelectric-based rotating gate transistors

Hyunji Shin,Hang Chan Jo,Seul-Lee Lee,Dong-Jin Lee,Myeongjoo Son,Xue Zhang,Dae Yu Kim 한국차세대컴퓨팅학회 2022 한국차세대컴퓨팅학회 학술대회 Vol.2022 No.10

The rotating gate driving transistors based on the triboelectric mechanism has been developed. The fabricated device is switched on by triboelectricity without applying a gate voltage, and the output current increases as the gate rotation becomes faster or the friction layer becomes thicker.