• 분석과학
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• 제24권6호
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• pp.533-543
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• 2011

hERG (human ether-a-go-go related gene) 이온채널은 심장 재분극의 중요 요소이며 이 채널의 저해제는 부정맥과 돌연사를 유발할 수 있다. 따라서, 신약개발과정에서 후보물질이 hERG 이온채널의 잠재적인 저해제일 경우에는 심장독성 부작용을 유발하므로, 이를 최소화하고자 많은 노력이 집중되고 있다. 본 연구는 HEK(인간 배아 신장)세포에서 얻은 202개 유기화합물의 $IC_{50}$ 데이터를 이용하여 2차원 구조-활성의 정량적 관계(2D-QSAR)방법으로 예측하는 모델을 개발하였다. hERG이온채널 저해제의 기계 학습방법으로는 다중선형회귀(Multiple Linear Regression), 서포트 벡터 머신(Support Vector Machine: SVM)방법과 인공신경망(Artificial Neural Network)방법이며, 교차검증을 적용한 모집단 기반 전진선택(forward selection)방법과 결합하여 각 학습모델에 적합한 최적의 표현자들을 결정하였다. 가장 우수한 방법은 14종의 표현자를 사용한 인공신경망방법($R^2_{CV}$=0.617, RMSECV=0.762, MAECV=0.583)이었고, 다중선형회귀방법을 통해서 hERG이온채널 저해물질의 구조적 특징과 수용체와의 상호작용을 설명할 수 있다. QSAR모델의 검증은 교차검증과 Y-scrambling test방법으로 수행하였다.

• Korean Circulation Journal
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• 제53권6호
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• pp.387-403
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• 2023

Background and Objectives: Myocardial ischemia and reperfusion injury (MIRI) has high morbidity and mortality worldwide. We aimed to explore the role of long noncoding RNA lysyl oxidase like 1 antisense RNA 1 (LOXL1-AS1) in cardiomyocyte pyroptosis. Methods: Hypoxia/reoxygenation (H/R) injury was constructed in human cardiomyocyte (HCM). The level of LOXL1-AS1, miR-761, phosphatase and tensin homolog (PTEN) and pyroptosis-related proteins was monitored by quantitative real-time polymerase chain reaction or western blot. Flow cytometry examined the pyroptosis level. Lactate dehydrogenase (LDH), creatine kinase-MB and cardiac troponin I levels were detected by test kits. Enzyme-linked immunosorbent assay measured the release of inflammatory cytokines. Dual-luciferase assay validated the binding relationship among LOXL1-AS1, miR-761, and PTEN. Finally, ischemia/reperfusion (I/R) animal model was constructed. Hematoxylin and eosin staining assessed morphological changes of myocardial tissue. NOD-like receptor pyrin domain-containing protein 3 (NLRP3) and casepase-1 expression was determined by immunohistochemistry. Results: After H/R treatment, LOXL1-AS1 and PTEN were highly expressed but miR-761 level was suppressed. LOXL1-AS1 inhibition or miR-761 overexpression increased cell viability, blocked the release of LDH and inflammatory cytokines (interleukin [IL]-1β, IL-18), inhibited pyroptosis level, and downregulated pyroptosis-related proteins (ASC, cleaved caspase-1, gasdermin D-N, NLRP3, IL-1β, and IL-18) levels in HCMs. LOXL1-AS1 sponged miR-761 to up-regulate PTEN. Knockdown of miR-761 reversed the effect of LOXL1-AS1 down regulation on H/R induced HCM pyroptosis. LOXL1-AS1 aggravated the MIRI by regulating miR-761/PTEN axis in vivo. Conclusions: LOXL1-AS1 targeted miR-761 to regulate PTEN expression, then enhance cardiomyocyte pyroptosis, providing a new alternative target for the treatment of MIRI.

• Journal of Chest Surgery
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• 제21권3호
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• pp.425-446
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• 1988

After 24 hours of preservation under 15 mmHg perfusion pressure the recovery rates of isolated canine hearts were determined. Preservation was performed in a cold room maintained at 4*C with 4 different types of perfusates bubbled with a mixture of 95% 0y and 5% CO~ using a modified perfusion unit designed in our institute. The perfusates used were as follows; Group 1: Krebs-Henseleit solution, Group 2: Krebs solution added by albumin and PGE1. Group 3: Modified Wicomb*s solution, Group 4: Modified Collin*s solution. The extent of myocardial recovery was evaluated using a modified isolated carmine perfusion model by measuring heart rate, systolic arterial pressure, left atrial pressure[LAP] and cardiac output. In addition to the above hemodynamic parameters, biochemical and enzymatic assays from perfusates and electron microscopic changes of the myocardium were also studied. The results were as follows; 1] The heart recovery rates were 41.6%, 53.4% and 108.9% in groups 1, 2 and 3, respectively, and group 3 elicited the best result[p< 0.001]. The heart beat was never recovered in group 4. 2] Recovered systolic arterial pressures[mmHg] were 63.3% in group 1, 94.9% in group 2 and 94.3% in group 3. 3] LAPs[mmHg] were 20 in group 1, 13.5 in group 2 and 11.2 in group 3, which suggested that the best myocardial preservation was elicited in group 3[p< 0.05]. 4] Cardiac output, the sum of aortic stroke volume and coronary leakage, were 69.1% in group 2, and 90.7% in group 3, but these were not statistically significant[p=0.24]. No aortic stroke output was measured in group 1 and 4. 5] The degree of myocardial edema increase was 17.5` in group 1, 24.6% in group 2, 20.9% in group 3 and 55.3% in group 4. But there were no statistical differences in each group[p= 0.08]. 6] CPK-MB[U/L] levels were increased 750% and 332%[p< 0.05], glucose levels[mg/dl] 60.5% and 78.2% and SGOT[U/L] levels 523% and 333%, in groups 2 and 3, respectively. Biochemical and enzymatic assays could not be performed in group 1 and group 4, because of poor recovery of heart beat. 7] Electron microscopic findings in the myocardium of most groups revealed slight to moderate muscle cell and mitochondrial edema. But all these findings were within the limits of reversible change. From these above results, it is suggested that modified Wicomb*s solution seems to be the most useful physiologic salt solution for preservation of the heart. We propose that after further study and improvement, our portable continuous hypothermic perfusion system will contribute to the development of a better preservation method for donor hearts for human heart transplantation.