• Yonsei Medical Journal
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• 제59권9호
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• pp.1079-1087
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• 2018

Purpose: Obstructive sleep apnea and chronic obstructive pulmonary disease are independent risk factors of cardiovascular disease (CVD), and their coexistence is known as overlap syndrome (OS). Endothelial dysfunction is the initial stage of CVD; however, underlying mechanisms linking OS and CVD are not well understood. The aim of this study was to explore whether OS can lead to more severe inflammation and endothelial apoptosis by promoting endothelial dysfunction, and to assess the intervention effects of antioxidant tempol. Materials and Methods: Male Wistar rats (n=66) were exposed to normal oxygen [normal control (NC) group], intermittent hypoxia (IH group), cigarette smoke (CH group), as well as cigarette smoke and IH (OS group). Tempol intervention was assessed in OS group treated with tempol (OST group) or NaCl (OSN group). After an 8-week challenge, lung tissues, serum, and fresh blood were harvested for analysis of endothelial markers and apoptosis. Results: The levels of intracellular adhesion molecule-1, vascular cellular adhesion molecule-1, and apoptosis in circulating epithelial cells were the highest in OS group and the lowest in NC group. These levels were all greater in IH group than in CH group, and were lower in OST group than in OS and OSN groups (all p<0.001). Conclusion: Synergistic effects of IH with cigarette smoke-induced emphysema produce a greater inflammatory status and endothelial apoptosis. OS-related inflammation and endothelial cell apoptosis may play important roles in promoting cardiovascular dysfunction, and antioxidant tempol could achieve a partial protective effect.

• BMB Reports
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• 제54권9호
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• pp.464-469
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• 2021

Cardiomyocyte differentiation occurs through complex and finely regulated processes including cardiac lineage commitment and maturation from pluripotent stem cells (PSCs). To gain some insight into the genome-wide characteristics of cardiac lineage commitment, we performed transcriptome analysis on both mouse embryonic stem cells (mESCs) and human induced PSCs (hiPSCs) at specific stages of cardiomyocyte differentiation. Specifically, the gene expression profiles and the protein-protein interaction networks of the mESC-derived platelet-derived growth factor receptor-alpha (PDGFRα)⁺ cardiac lineage-committed cells (CLCs) and hiPSC-derived kinase insert domain receptor (KDR)⁺ and PDGFRα⁺ cardiac progenitor cells (CPCs) at cardiac lineage commitment were compared with those of mesodermal cells and differentiated cardiomyocytes. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses revealed that the genes significantly upregulated at cardiac lineage commitment were associated with responses to organic substances and external stimuli, extracellular and myocardial contractile components, receptor binding, gated channel activity, PI3K-AKT signaling, and cardiac hypertrophy and dilation pathways. Protein-protein interaction network analysis revealed that the expression levels of genes that regulate cardiac maturation, heart contraction, and calcium handling showed a consistent increase during cardiac differentiation; however, the expression levels of genes that regulate cell differentiation and multicellular organism development decreased at the cardiac maturation stage following lineage commitment. Additionally, we identified for the first time the protein-protein interaction network connecting cardiac development, the immune system, and metabolism during cardiac lineage commitment in both mESC-derived PDGFRα⁺ CLCs and hiPSC-derived KDR⁺PDGFRα⁺ CPCs. These findings shed light on the regulation of cardiac lineage commitment and the pathogenesis of cardiometabolic diseases.

• Molecules and Cells
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• 제44권11호
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• pp.805-829
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• 2021

CCCTC-binding factor (CTCF) critically contributes to 3D chromatin organization by determining topologically associated domain (TAD) borders. Although CTCF primarily binds at TAD borders, there also exist putative CTCF-binding sites within TADs, which are spread throughout the genome by retrotransposition. However, the detailed mechanism responsible for masking the putative CTCF-binding sites remains largely elusive. Here, we show that the ATP-dependent chromatin remodeler, chromodomain helicase DNA-binding 4 (CHD4), regulates chromatin accessibility to conceal aberrant CTCF-binding sites embedded in H3K9me3-enriched heterochromatic B2 short interspersed nuclear elements (SINEs) in mouse embryonic stem cells (mESCs). Upon CHD4 depletion, these aberrant CTCF-binding sites become accessible and aberrant CTCF recruitment occurs within TADs, resulting in disorganization of local TADs. RNA-binding intrinsically disordered domains (IDRs) of CHD4 are required to prevent this aberrant CTCF binding, and CHD4 is critical for the repression of B2 SINE transcripts. These results collectively reveal that a CHD4-mediated mechanism ensures appropriate CTCF binding and associated TAD organization in mESCs.

• Journal of Gastric Cancer
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• 제22권4호
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• pp.348-368
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• 2022

Purpose: Chromosomal instability is a hallmark of gastric cancer (GC). It can be driven by single nucleotide variants (SNVs) in cell cycle genes. We investigated the associations between SNVs in candidate genes, PLK2, PLK3, and ATM, and GC risk and clinicopathological features. Materials and Methods: The genotyping study included 542 patients with GC and healthy controls. Generalized linear models were used for the risk and clinicopathological association analyses. Survival analysis was performed using the Kaplan-Meier method. The binding of candidate miRs was analyzed using a luciferase reporter assay. Results: The PLK2 C_rs15009-C_rs963615 haplotype was under-represented in the GC group compared to that in the control group (P_corr=0.050). Male patients with the PLK2 rs963615 CT genotype had a lower risk of GC, whereas female patients had a higher risk (P=0.023; P=0.026). The PLK2 rs963615 CT genotype was associated with the absence of vascular invasion (P=0.012). The PLK3 rs12404160 AA genotype was associated with a higher risk of GC in the male population (P=0.015). The ATM T_rs228589-A_rs189037-G_rs4585 haplotype was associated with a higher risk of GC (P<0.001). The ATM rs228589, rs189037, and rs4585 genotypes TA+AA, AG+GG, and TG+GG were associated with the absence of perineural invasion (P=0.034). In vitro analysis showed that the cancer-associated miR-23b-5p mimic specifically bound to the PLK2 rs15009 G allele (P=0.0097). Moreover, low miR-23b expression predicted longer 10-year survival (P=0.0066) in patients with GC. Conclusions: PLK2, PLK3, and ATM SNVs could potentially be helpful for the prediction of GC risk and clinicopathological features. PLK2 rs15009 affects the binding of miR-23b-5p. MiR-23b-5p expression status could serve as a prognostic marker for survival in patients with GC.

• Molecules and Cells
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• 제45권12호
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• pp.935-949
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• 2022

Liver cancer has a high prevalence, with majority of the cases presenting as hepatocellular carcinoma (HCC). The prognosis of metastatic HCC has hardly improved over the past decade, highlighting the necessity for liver cancer research. Studies have reported the ability of the KiSS1 gene to inhibit the growth or metastasis of liver cancer, but contradictory research results are also emerging. We, therefore, sought to investigate the effects of KiSS1 on growth and migration in human HCC cells. HepG2 human HCC cells were infected with lentivirus particles containing KiSS1. The overexpression of KiSS1 resulted in an increased proliferation rate of HCC cells. Quantitative polymerase chain reaction and immunoblotting revealed increased Akt activity, and downregulation of the G1/S phase cell cycle inhibitors. A significant increase in tumor spheroid formation with upregulation of β-catenin and CD133 was also observed. KiSS1 overexpression promoted the migratory, invasive ability, and metastatic capacity of the hepatocarcinoma cell line, and these effects were associated with changes in the expressions of epithelial mesenchymal transition (EMT)- related genes such as E-cadherin, N-cadherin, and slug. KiSS1 overexpression also resulted in dramatically increased tumor growth in the xenograft mouse model, and upregulation of proliferating cell nuclear antigen (PCNA) and Ki-67 in the HCC tumors. Furthermore, KiSS1 increased the angiogenic capacity by upregulation of the vascular endothelial growth factor A (VEGF-A) and CD31. Based on these observations, we infer that KiSS1 not only induces HCC proliferation, but also increases the metastatic potential by increasing the migratory ability and angiogenic capacity.

• Molecules and Cells
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• 제46권7호
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• pp.420-429
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• 2023

Age-related macular degeneration (AMD) is one of the leading causes of blindness in elderly individuals. However, the currently used intravitreal injections of anti-vascular endothelial growth factor are invasive, and repetitive injections are also accompanied by a risk of intraocular infection. The pathogenic mechanism of AMD is still not completely understood, but a multifactorial mechanism that combines genetic predisposition and environmental factors, including cellular senescence, has been suggested. Cellular senescence refers to the accumulation of cells that stop dividing due to the presence of free radicals and DNA damage. Characteristics of senescent cells include nuclear hypertrophy, increased levels of cell cycle inhibitors such as p16 and p21, and resistance to apoptosis. Senolytic drugs remove senescent cells by targeting the main characteristics of these cells. One of the senolytic drugs, ABT-263, which inhibits the antiapoptotic functions of Bcl-2 and Bcl-xL, may be a new treatment for AMD patients because it targets senescent retinal pigment epithelium (RPE) cells. We proved that it selectively kills doxorubicin (Dox)-induced senescent ARPE-19 cells by activating apoptosis. By removing senescent cells, the expression of inflammatory cytokines was reduced, and the proliferation of the remaining cells was increased. When ABT-263 was orally administered to the mouse model of senescent RPE cells induced by Dox, we confirmed that senescent RPE cells were selectively removed and retinal degeneration was alleviated. Therefore, we suggest that ABT-263, which removes senescent RPE cells through its senolytic effect, has the potential to be the first orally administered senolytic drug for the treatment of AMD.

• BMB Reports
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• 제57권4호
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• pp.167-175
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• 2024

Cancer progression is driven by genetic mutations, environmental factors, and intricate interactions within the tumor microenvironment (TME). The TME comprises of diverse cell types, such as cancer cells, immune cells, stromal cells, and neuronal cells. These cells mutually influence each other through various factors, including cytokines, vascular perfusion, and matrix stiffness. In the initial or developmental stage of cancer, neurotrophic factors such as nerve growth factor, brain-derived neurotrophic factor, and glial cell line-derived neurotrophic factor are associated with poor prognosis of various cancers by communicating with cancer cells, immune cells, and peripheral nerves within the TME. Over the past decade, research has been conducted to prevent cancer growth by controlling the activation of neurotrophic factors within tumors, exhibiting a novel attemt in cancer treatment with promising results. More recently, research focusing on controlling cancer growth through regulation of the autonomic nervous system, including the sympathetic and parasympathetic nervous systems, has gained significant attention. Sympathetic signaling predominantly promotes tumor progression, while the role of parasympathetic signaling varies among different cancer types. Neurotransmitters released from these signalings can directly or indirectly affect tumor cells or immune cells within the TME. Additionally, sensory nerve significantly promotes cancer progression. In the advanced stage of cancer, cancer-associated cachexia occurs, characterized by tissue wasting and reduced quality of life. This process involves the pathways via brainstem growth and differentiation factor 15-glial cell line-derived neurotrophic factor receptor alpha-like signaling and hypothalamic proopiomelanocortin neurons. Our review highlights the critical role of neurotrophic factors as well as central nervous system on the progression of cancer, offering promising avenues for targeted therapeutic strategies.

• Applied Microscopy
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• 제10권1_2호
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• pp.77-86
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• 1980

인삼의 근피층에서 확인된 분비관의 분포, 분비상피세포의 미세구조, 후형질성 함유물의 성분등을 광학 및 전자현미경을 이용하여 추구하였다. 1) 분비관은 배축, 근피층, 엽맥 유관속의 배축면과 향축면, 줄기의 유관속을 사이에 두고 피층과 수층 및 수내(髓內)에서 관찰되었다. 2) 근피층에 존재하는 분비관은 형성층에서 분화함이 확인되었고, 분비관의 환상배열층은 근령(根令)을 추정하는 구조적인 지표가 된다고 믿어진다. 3) 분비상피세포는 인(仁), 미토콘드리아, 소포체가 매우 발달되었으며, ribosome, chromoplast, leucoplast, dictyosome과 저장과립인 전분립이 관찰되었다. 4) 상피세포로는 단층이고 세포질과 분비관내에는 sudanophyl, osmophyl inclusion이 확인되었지만 Pyridin 및 alcohol로 lipid를 추출하였을 때에는 이들 함유물이 관찰되지 않았다. 5) Nile blue반응에서 상피세포내에는 oxazin에 반응하는 산성지질이, 분비관에는 oxazone에 반응하는 중성지질이 검출되었다. 6) 세포내 분비과립은 $OsO_4$단일고정시 전자밀도가 매우 높았다. 따라서 이 물질의 주성분은 불포화성지질인것 같으며 인삼의 분비관은 지질대사와 밀접한 관련성이 있는 것으로 믿어지므로 인삼이 지니는 분비관은 지질분비관(lipid canal 또는 lipid duct)으로 명명됨이 바람직하다.

• 환경생물
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• 제27권3호
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• pp.314-322
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• 2009

특산속 식물인 모데미풀의 자생지 식생을 비롯해 환경 및 토양 특성을 조사하여 보존 및 복원 시 기초자료를 제공하고자 하였다. 모데미풀의 자생지는 770~1,440m에 위치하고, 경사는 $0{\sim}20^{\circ}$로 완만하였으며, 주로 계곡부 북사면에 불연속적인 군락을 형성하고 있었다. 식생분석결과 78개 방형구 내에서 조사된 분류군은 총 111종류였다. 중요치는 모데미풀이 27.05%로 가장 높았으며, 모데미풀과 비슷한 환경을 선호하는 분류군으로는 박새 (5.67%), 현호색 (5.32%), 눈개승마 (4.35%), 벌깨덩굴(4.06%), 홀아비바람꽃(3.91%) 등으로 나타났다. 자생지 상층 수목 중 교목층은 층층나무, 가래나무, 신갈나무, 당단풍나무, 고로쇠나무 등이 우점종으로 나타났고, 아교목층은 당단풍나무와 까치박달이 높은 빈도를 보였으며, 관목층은 물참대와 귀룽나무가 우점하였다. 종다양도는 평균 1.16이었고, 우점도와 균등도는 각각 0.12와 0.81로 나타났다. 토양의 포장용수량은 평균 26.41%이었으며, 유기물 함량은 7.83%로 나타났고, pH는 5.83으로 확인되었다. 환경특성과 식생 및 토양 분석 결과에 기초한 상관분석에서는 경사와 pH, 경사와 유기물함량, 우점도와 중요치, 종다양도와 종풍부도가 정의 상관관계를, 우점도와 종다양도, 종다양도와 중요치는 부의 상관관계를 보였다.

• 한국자원식물학회지
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• 제29권4호
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• pp.419-433
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• 2016

행정구역상 충청남도 예산군 삽교읍과 덕산면, 홍성군 홍북면에 걸쳐있는 용봉산 및 수암산 일대의 식물상을 2010년도 3월부터 2016년 5월까지 총 23회에 걸쳐 조사하였다. 사진과 표본 등의 증거자료를 바탕으로 작성한 소산 관속식물은 105과 312속 468종 4아종 47변종 13품종의 총 532분류군으로 확인되었다. 한반도 특산식물은 은사시나무(식), 외대으아리, 할미밀망, 좀땅비싸리, 개나리(식), 오동나무(식), 병꽃나무, 벌개미취(식) 등 8분류군이 조사되었고, 산림청지정 희귀식물은 주목(식), 개지치, 두메부추(식), 꽃창포(식) 등 4분류군이 관찰되었으며, 환경부지정 멸종위기야생식물은 출현하지 않았다. 식물구계학적 특정식물종은 III~V등급에 해당하는 11분류군이 확인되었다. 귀화식물은 총 68분류군으로 귀화율은 12.8%, 도시화지수는 21.2%로 높은 수치를 보여주었다.