• The Korean Journal of Physiology and Pharmacology
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• 제22권6호
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• pp.607-616
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• 2018

The effect of melatonin on juveniles with cardio fibrosis is poorly understood. We investigated whether HDACs participate in the anti-fibrotic processes regulated by melatonin during hypertrophic remodeling. Abdominal aortic constriction (AAC) was employed in juvenile rats resulting in pressure overload-induced ventricular hypertrophy and melatonin was subsequently decreased via continuous light exposure for 5 weeks after surgery. AAC rats displayed an increased cross-sectional area of myocardial fibers and significantly elevated collagen deposition compared to sham-operated rats, as measured by HE and Masson Trichrome staining. Continuous light exposure following surgery exacerbated the increase in the cross-sectional area of myocardial fibers. The expression of HDAC1, HDAC2, HDAC3, HDAC4 and HDAC6 genes were all significantly enhanced in AAC rats with light exposure relative to the other rats. Moreover, the protein level of $TNF-{\alpha}$ was also upregulated in the AAC light exposure groups when compared with the sham. However, Smad4 protein expression was unchanged in the juveniles' hearts. In contrast, beginning 5 weeks after the operation, the AAC rats were treated with melatonin (10 mg/kg, intraperitoneal injection every evening) or vehicle 4 weeks, and sham rats were given vehicle. The changes in the histological measures of cardio fibrosis and the gene expressions of HDAC1, HDAC2, HDAC3, HDAC4 and HDAC6 were attenuated by melatonin administration. The results reveal that melatonin plays a role in the development of cardio fibrosis and the expression of HDAC1, HDAC2, HDAC3, HDAC4 and HDAC6 in cardiomyocytes.

• Journal of Microbiology and Biotechnology
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• 제34권3호
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• pp.606-621
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• 2024

This study evaluated the hepatoprotective effect of fermented Protaetia brevitarsis larvae (FPB) in ethanol-induced liver injury mice. As a result of amino acids in FPB, 18 types of amino acids including essential amino acids were identified. In the results of in vitro tests, FPB increased alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) activities. In addition, FPB treatment increased cell viability on ethanol- and H₂O₂-induced HepG2 cells. FPB ameliorated serum biomarkers related to hepatoxicity including glutamic oxaloacetic transaminase, glutamine pyruvic transaminase, total bilirubin, and lactate dehydrogenase and lipid metabolism including triglyceride, total cholesterol, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol. Also, FPB controlled ethanol metabolism enzymes by regulating the protein expression levels of ADH, ALDH, and cytochrome P450 2E1 in liver tissue. FPB protected hepatic oxidative stress by improving malondialdehyde content, reduced glutathione, and superoxide dismutase levels. In addition, FPB reversed mitochondrial dysfunction by regulating reactive oxygen species production, mitochondrial membrane potential, and ATP levels. FPB protected ethanol-induced apoptosis, fatty liver, and hepatic inflammation through p-AMP-activated protein kinase and TLR-4/NF-κB signaling pathways. Furthermore, FPB prevented hepatic fibrosis by decreasing TGF-β1/Smad pathway. In summary, these results suggest that FPB might be a potential prophylactic agent for the treatment of alcoholic liver disease via preventing liver injury such as fatty liver, hepatic inflammation due to chronic ethanol-induced oxidative stress.

• Journal of Veterinary Science
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• 제21권2호
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• pp.26.1-26.14
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• 2020

Pancreatic ductal adenocarcinoma is a lethal cancer type that is associated with multiple gene mutations in somatic cells. Genetically engineered mouse is hardly applicable for developing a pancreatic cancer model, and the xenograft model poses a limitation in the reflection of early stage pancreatic cancer. Thus, in vivo somatic cell gene engineering with clustered regularly interspaced short palindromic repeats is drawing increasing attention for generating an animal model of pancreatic cancer. In this study, we selected Kras, Trp53, Ink4a, Smad4, and Brca2 as target genes, and applied Campylobacter jejuni Cas9 (CjCas9) and Streptococcus pyogens Cas9 (SpCas9) for developing pancreatic cancer using adeno associated virus (AAV) transduction. After confirming multifocal and diffuse transduction of AAV2, we generated SpCas9 overexpression mice, which exhibited high double-strand DNA breakage (DSB) in target genes and pancreatic intraepithelial neoplasia (PanIN) lesions with two AAV transductions; however, wild-type (WT) mice with three AAV transductions did not develop PanIN. Furthermore, small-sized Cjcas9 was applied to WT mice with two AAV system, which, in addition, developed high extensive DSB and PanIN lesions. Histological changes and expression of cancer markers such as Ki67, cytokeratin, Mucin5a, alpha smooth muscle actin in duct and islet cells were observed. In addition, the study revealed several findings such as 1) multiple DSB potential of AAV-CjCas9, 2) peri-ductal lymphocyte infiltration, 3) multi-focal cancer marker expression, and 4) requirement of > 12 months for initiation of PanIN in AAV mediated targeting. In this study, we present a useful tool for in vivo cancer modeling that would be applicable for other disease models as well.

• 한국생물정보학회:학술대회논문집
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• 한국생물정보시스템생물학회 2006년도 Principles and Practice of Microarray for Biomedical Researchers
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• pp.83-89
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• 2006

Cellular functions are carried out by a concerted action of biochemical pathways whose components have genetic interactions. Abnormalities in the activity of the genes that constitute or modulate these pathways frequently have oncogenic implications. Therefore, identifying the upstream regulatory genes for major biochemical pathways and defining their roles in carcinogenesis can have important consequences in establishing an effective target-oriented antitumor strategy We have analyzed the gene expression profiles of human liver cancer samples using cDNA microarray chips enriched in liver and/or stomach-expressed cDNA elements, and identified groups of genes that can tell tumors from non-tumors or normal liver, or classify tumors according to clinical parameters such as tumor grade, age, and inflammation grade. We also set up a high-throughput cell-based assay system (cell chip) that can monitor the activity of major biochemical pathways through a reporter assay. Then, we applied the cell chip platform for the analysis of the HCC-associated genes discovered from transcriptome profiling, and found a number of cancer marker genes having a potential of modulating the activity of cancer-related biochemical pathways such as E2F, TCF, p53, Stat, Smad, AP-1, c-Myc, HIF and NF-kB. Some of these marker genes were previously blown to modulate these pathways, while most of the others not. Upon a fast-track phenotype analysis, a subset of the genes showed increased colony forming abilities in soft agar and altered cell morphology or adherence characteristics in the presence of purified matrix proteins. We are currently analyzing these selected marker genes in more detail for their effects on various biological Processes and for Possible clinical roles in liver cancer development.

• Tuberculosis and Respiratory Diseases
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• 제50권4호
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• pp.450-461
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• 2001

서 론 : 폐암의 치료에 사용되는 방사선 조사는 흉곽 및 여러장기에 다양한 합병증을 발생시키며, 특히 방사선 섬유화증과 방사선 폐렴을 일으킨다. 방사선 조사의 초기 효과는 보통 염증 세포들의 침윤, 간질 및 폐포 부종, 상피세포의 탈락에 의한 방사선 폐렴이며 후기 효과는 방사선 섬유화증을 초래한다. 방사선 조사는 폐장의 염증 세포에서 TGF-beta의 단백 합성 및 활성도를 증가시키고, 생체외 실험에서 TGF-beta는 mitogen activated protein kinases(MAPKs)를 활성화시킨다는 것이 알려져 있다. c-Jun N-terminal kinase(JNK)는 MAPKs중의 하나로 핵단백질인 c-Jun을 인산화(phosphorylation) 시켜 전사(transcription)를 증가시키는데 생체외 실험에서 자외선 조사후 대식 세포에서 JNK의 활성이 증가되는 것으로 알려져 있다. 하지만 현재 까지 생체내에서 JNK가 방사선 조사에 의해 활성화되는지 그리고 이들 활성화가 방사선 섬유화증의 병인에 관계하는 지는 알려진 바 없다. 본 연구는 흉부에 방사선을 조사한 백서를 이용하여 방사선 섬유화증의 병인에 JNK가 신호 전달 체계에서 주요한 역할을 담당하는 지를 알아보고자 시행하였다. 대상 및 방법 : C57BL/6 백서의 전 흉부에 14 Gy의 $^{60}CO{\gamma}$-ray를 조사한 후 일정한 간격(1주, 4주, 8주)으로 폐장의 세포 분석을 위한 기관지 폐포 세척술, elastin의 합성 정도를 측정하기 위한 Verhoeff stain, collagen 합성 양을 알기 위한 hydroxyproline의 측정, JNK 활성도를 알기 위한 in vitro JNK assay를 시행하였다. 결 과 : 폐장의 기관지 폐포 세척 소견상 총세포수는 방사선 조사 4주, 8주후에 증가하는 소견을 보였다. 세포의 감별 분석상 림프구는 4주후 증가되는 경향을 보였다. Verhoeff 염색상 폐포 조직의 특이 변화 소견은 없었으며 hydroxyproline의 양은 방사선 조사전에 비해 4주, 8주후에 증가하는 소견을 보였다. 방사선 조사 후 시간이 경과함에 따라 4주 후에 c-Jun N-terminal kinase(JNK)의 활성도가 가장 높았으며 8주 후에는 4주 후와 비슷한 활성도를 보였다. 결 론 : 흉곽에 방사선 조사 후 hydroxyproline양의 증가와 함께 JNK 활성도의 증가 소견을 보여 방사선 폐섬유화증의 병인에 JNK가 관여될 것으로 사료된다.