• Journal of Chest Surgery
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• 제32권4호
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• pp.333-340
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• 1999

배경: PAI-1은 t-PA의 억제인자로서 섬유소융해계에 작용을 하여 혈전형성을 유발한다. PAI-1은 동맥경화된 혈관벽에서 분비가 된다. PAI-1의 증가는 동맥경화증의 위험인자가 되는 당뇨병과 고혈압이 동반된 환자에서 보이며 혈전증유발에 위험인자가 될 수 있다. 본 연구는 고혈당과 인슐린 및 angiotensin II가 PAI-1의 생성 및 평활근세포의 증식에 미치는 영향을 규명하고자 하였다. 대상 및 방법:흰쥐 대동맥평활근세포를 5.5 mM과 22 mM의 포도당 배양액을 사용하여 배양하였다. 배양액에 angiotensin II 및 인슐린을 농도 및 배양시간에 따라 첨가하여 Northern blotting방법으로 PAI-1 유전자발현을 나타내었다. 또한 세포 증식에 대한 포도당, 인슐린 및 angiotensin II의 영향을 규명하기 위하여 MTT assay를 사용하였다. 결과: 5.5 mM과 22 mM의 포도당 배양액에서 angiotensin II(100 nM)를 첨가하여 배양한 결과, 22 mM 포도당 배양액에서 PAI-1 mRNA 발현이 증가되었으며 angiotensin II 투여 4시간에 최고치에 도달하였고 6시간까지 지속되었다. 5.5 mM, 22 mM의 포도당 배양액에 angiotensin II의 농도를 0, 10, 100, 200 nM 투여하여 배양한 결과, PAI-1 mRNA의 발현은 angiotensin II 농도에 따른 증가를 보였으며 22 mM 포도당 배양액시 더욱 뚜렷하게 증가되었다. 배양액에 angiotensin II(100 nM)과 인슐린(100 nM)을 투여하여 배양한 결과, PAI-1 mRNA의 발현은 angiotensin II 단독으로 투여시 증가하였으나 인슐린을 첨가하였을 때는 감소하였다. 5.5 mM과 22 mM의 포도당 배양액에 1, 10, 100 nM의 인슐린과 1, 10, 100 nM의 angiotensin II를 첨가한 후 대동맥평활근세포의 성장속도를 비교한 결과, 5.5 mM보다 22 mM의 포도당이 든 배양액에서 대동맥평활근세포의 성장이 촉진되었으며, 인슐린 및 angiotensin II를 첨가한 경우도 대동맥평활근세포의 성장이 증가되었다. 결론:흰쥐 대동맥평활근세포에서 PAI-1 mRNA의 발현은 포도당 농도가 높을수록 증가되며 angiotensin II의 농도 및 배양시간에 따라 증가되고 인슐린 투여로 감소하였다. 또한 angiotensin II의 투여는 22 mM의 고농도 포도당 투여 후 증가된 PAI-1 mRNA 발현 증가를 더욱 증가시켜 PAI-1 mRNA 발현 증가에 상승작용이 있음을 알 수 있다. 그리고 22 mM의 고농도 포도당, 인슐린 및 angiotensin II는 흰쥐의 대동맥평활근세포의 성장을 촉진시켰다.

• Tuberculosis and Respiratory Diseases
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• 제75권4호
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• pp.140-149
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• 2013

Background: Plasminogen activator inhibitor type 1 (PAI-1), an important regulator of plasminogen activator system which controls degradation of extracellular membrane and progression of tumor cells, and PAI-1 gene polymorphic variants have been known as the prognostic biomarkers of non-small cell lung cancer patients. Recently, experimental in vitro study revealed that transforming growth factor-${\beta}1$ initiated PAI-1 transcription through epithelial growth factor receptor (EGFR) signaling pathway. However, there is little clinical evidence on the association between PAI-1 A15T gene polymorphism and prognosis of Korean population with pulmonary adenocarcinoma and the influence of activating mutation of EGFR kinase domain. Methods: We retrospectively reviewed the medical records of 171 patients who were diagnosed with pulmonary adenocarcinoma and undergone EGFR mutation analysis from 1995 through 2009. Results: In all patients with pulmonary adenocarcinoma, there was no significant association between PAI-1 A15T polymorphic variants and prognosis for overall survival. However, further subgroup analysis showed that the group with AG/AA genotype had a shorter 3-year survival time than the group with GG genotype in patients with EGFR mutant-type pulmonary adenocarcinoma (mean survival time, 24.9 months vs. 32.5 months, respectively; p=0.015). In multivariate analysis of 3-year survival for patients with pulmonary adenocarcinoma harboring mutant-type EGFR, the AG/AA genotype carriers had poorer prognosis than the GG genotype carriers (hazard ratio, 7.729; 95% confidence interval, 1.414-42.250; p=0.018). Conclusion: According to our study of Korean population with pulmonary adenocarcinoma, AG/AA genotype of PAI-1 A15T would be a significant predictor of poor short-term survival in patients with pulmonary adenocarcinoma harboring mutant-type EGFR.

• BMB Reports
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• 제44권1호
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• pp.34-39
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• 2011

Resistance to PAI-1 is a factor which confers clinical benefits in thrombolytic therapy. The only US FDA approved PAI-1 resistant drug is Tenecteplase$^{(R)}$. Deletion variants of t-PA have the advantage of fewer disulfide bonds in addition to higher plasma half lives. A new variant was developed by deletion of the first three domains in t-PA in addition to substitution of KHRR 128-131 amino acids with AAAA in truncated t-PA. The specific activity of this new variant, $570\;IU/{\mu}g$, was found to be similar to those found in full length t-PA (Alteplase$^{(R)}$), $580\;IU/{\mu}g$. A 65% and 85% residual activity after inhibition by rPAI-1 was observed for full length and truncated-mutant form, respectively. This new variant as the first PAI-1 resistant truncated t-PA may offer more advantages in clinical conditions in which high PAI-1 levels makes the thrombolytic system prone to re-occlusion.

• Radiation Oncology Journal
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• 제24권1호
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• pp.58-66
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• 2006

목적: 방사선에 의한 신장손상은 궁극적으로 신장 섬유화로 인한 신부전으로 나타나며 여기에는 세포외기질의 변화가 동반된다. 방사선 신장손상에서 신사구체 상피세포의 역할을 알아보기 위하여 방사선에 의한 세포외기질과 연관된 여러 유전자 발현의 변화를 알아보고자 하였다. 대상 및 방법 : 백서 사구체 상피세포 (rat glomerular epithelial cell: GEpC) 에 6 MV 선형가속기 (Siemens, USA)를 이용하여 0, 2, 5, 10, 20 Gy 의 단일 방사선량을 조사한 후 각각 6, 24, 48, 72 시간에 시료를 채취하였다. Northern blot, Western blot, Zymography를 이용하여 fibronectin (Fn), plasminogen activator inhibitor-1 (Pai-1), matrix metalloproteinases-2, 9 (MMP-2, 9), tissue inhibitor of matrix metallproteinase-2 (TIMP-2), tissue-type plasminogen activator (t-PA), Urokinase-type plasminogen activator (u-PA)의 발현을 측정하였다. 결과: GEpC 에 대한 10 Gy 단일 방사선 조사후 24 시간부터 Fn mRNA 가 유의한 증가를 나타냈으며 48 시간에 측정한 Fn 단백질은 5, 10 Gy 의 방사선량에서 유의하게 증가되었다. 방사선조사에 의해서 Pai-1 유전자의 발현도 mRNA 및 단백질 단계에서 증가되었으며, 특히 10Gy 조사 후 24, 48 시간에 측정한 mRNA 의 증가는 통계적으로 유의하였다. GEpC에 방사선조사 후 24 시간에 측정한 MMP-2 활성형은 방사선량에 따라 증가하였으나 통계학적 유의성은 없었다. 그밖의 MMP-9, TIMP-2, t-PA 와 u-PA 는 아무런 변화를 나타내지 않았다. 결론 : 방사선에 의하여 GEpC에서 세포외 기질과 관련된 유전자 발현의 번화가 관찰되었으며 이는 방사선 신장 손상에 GEpC가 관여함을 나타낸다.

• Genomics & Informatics
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• 제21권1호
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• pp.4.1-4.18
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• 2023

Coronavirus disease 2019 (COVID-19) is an inflammatory and infectious disease caused by severe acute respiratory syndrome coronavirus 2 virus with a complex pathophysiology. While COVID-19 vaccines and boosters are available, treatment of the disease is primarily supportive and symptomatic. Several research have suggested the potential of herbal medicines as an adjunctive treatment for the disease. A popular herbal medicine approved in the Philippines for the treatment of acute respiratory disease is Vitex negundo L. In fact, the Department of Science and Technology of the Philippines has funded a clinical trial to establish its potential as an adjunctive treatment for COVID-19. Here, we utilized network pharmacology and molecular docking in determining pivotal targets of Vitex negundo compounds against COVID-19. The results showed that significant targets of Vitex negundo compounds in COVID-19 are CSB, SERPINE1, and PLG which code for cathepsin B, plasminogen activator inhibitor-1, and plasminogen, respectively. Molecular docking revealed that α-terpinyl acetate and geranyl acetate have good binding affinity in cathepsin B; 6,7,4-trimethoxyflavanone, 5,6,7,8,3',4',5'-heptamethoxyflavone, artemetin, demethylnobiletin, gardenin A, geranyl acetate in plasminogen; and 7,8,4-trimethoxyflavanone in plasminogen activator inhibitor-1. While the results are promising, these are bound to the limitations of computational methods and further experimentation are needed to completely establish the molecular mechanisms of Vitex negundo against COVID-19.

• Animal cells and systems
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• 제10권2호
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• pp.79-83
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• 2006

Tissue plasminogen activator (tPA) is used to lyse clots and reperfuse brain in ischemic stroke. However, sideeffects of intracerebral hemorrhage (ICH) and edema limit their clinical application. In part, these phenomena has been linked with elevations in matrix metalloproteinase-9 (MMP-9) in neurovascular unit. However little is known about their regulatory signaling pathways in brain cells. Here, I examine the role of MAP kinase pathways in tPA-induced MMP-9 regulation in rat cortical astrocytes. tPA $(1-10\;{\mu}g/ml)$ induced dose-dependent elevations in MMP-9 and MMP-2 in conditioned media. Although tPA increased phosphorylation in two MAP kinases (ERK, JNK), only inhibition of the JNK pathway by the JNK inhibitor SP600126 significantly reduced MMP-9 upregulation. Neither ERK inhibition with U0126 nor p38 inhibition with SB203580 had any significant effects. Taken together, these results suggest that c-jun N-terminal kinase (JNK) plays an essential role for tPA-induced MMP-9 upregulation.

• Animal cells and systems
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• 제7권3호
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• pp.249-253
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• 2003

Abnormalities in fibrinolysis system is associated with risk of hypertension. In this report, the Alu repeat insertion/deletion (I/D) polymorphism of tissue plasminogen activator (t-PA) and the Hind III RFLP of plasminogen activator inhibitor-1 (PAI-1) genes were investigated in 115 normotensives and 83 patients with hypertension, and their association with anthropometrical data and plasma biochemical parameters were analyzed. There were no significant differences in the gene frequencies of the two candidate genes between normotensives and hypertensives, respectively. Our results indicate lack of associations between the two polymorph isms in t-PA and PAI-1 genes and risk of hypertension in the population under study. However, the Hind III RFLP of PAI-1 gene was significantly associated with plasma glucose level, suggesting its role in glucose metabolism. It needs to be tested whether this RFLP of PAI-1 gene is associated with insulin resistance syndrome or non-insulin dependent diabetes mellitus (NIDDM) in the Korean population.

• BMB Reports
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• 제47권7호
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• pp.376-381
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• 2014

Enzymatic oxidation of pyrogallol was efficiently transformed to an oxidative product, purpurogallin (PPG). Here, the anticoagulant activities of PPG were examined by monitoring activated partial thromboplastin time (aPTT), prothrombin time (PT), and the activities of thrombin and activated factor X (FXa). And, the effects of PPG on expression of plasminogen activator inhibitor type 1 (PAI-1) and tissue-type plasminogen activator (t-PA) were evaluated in tumor necrosis factor (TNF)-${\alpha}$ activated human umbilical vein endothelial cells (HUVECs). Treatment with PPG resulted in prolonged aPTT and PT and inhibition of the activities of thrombin and FXa, as well as inhibited production of thrombin and FXa in HUVECs. In addition, PPG inhibited thrombin-catalyzed fibrin polymerization and platelet aggregation. PPG also elicited anticoagulant effects in mice. In addition, treatment with PPG resulted in significant reduction of the PAI-1 to t-PA ratio. Collectively, PPG possesses antithrombotic activities and offers a basis for development of a novel anticoagulant.

• KSBB Journal
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• 제19권5호
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• pp.335-340
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• 2004

Mesangial expansion caused by cell proliferation and glomerular extracellular matrix accumulation is one of the earliest renal abnormalties observed at the onset of hyperglycemia in diabetes mellitus. Transcription factor Sp1 is implicated in the transcriptional regulation of a wide range of genes participating in cell proliferation, and is assumed to play an essential role in mesangial expansion, transforming growth factor (TGF)-$\beta$1, plasminogen activator inhibitor (PAI)-1. We have generated a phosphorothioated double-stranded Sp1-decoy oligodeoxynucleotide that effectively blocks Sp1 binding to the promoter region for transcriptional regulation of TGF-$\beta$1 and PAI-1. The Sp1 decoy oligodeoxynucleotide suppressed transcription of these cytokines and proliferation of primary rat mesangial cells in response to serum stimulation. These results suggest that the Sp1 decoy oligodeoxynucleotide could bea powerful tool in preventing the pathogenesis of renal hypertrophy.

• Food Science and Biotechnology
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• 제18권5호
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• pp.1284-1287
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• 2009

Tumor necrosis factor (TNF)-${\alpha}$ is chronically elevated in adipose tissues of obese rodents and humans. Increased levels of TNF-${\alpha}$ have been implicated in both the induction of atherogenic adipokines, such as plasminogen activator inhibitor (PAI)-1, and the inhibition of the anti-atherogenic adipokine, adiponectin. In this study, we investigated the effects of trans-stilbene, piceatannol, rhaponticin, and piceid on the TNF-${\alpha}$-induced atherogenic changes of adipokines in 3T3-L1 cells. Exposure to TNF-${\alpha}$ for 24 hr increased PAI-1 secretion and decreased adiponectin secretion. Among stilbenoids, piceatannol significantly inhibited the increased secretion of PAI-1 induced by TNF-${\alpha}$. Adiponectin secretion decreased by TNF-${\alpha}$ was recovered after trans-stilbene and rhaponticin treatments. Our results showed that stilbenoids exerted different effects on TNF-${\alpha}$-induced changes in adipokines secretion in 3T3-L1 adipocytes according to their structural characteristics.