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Article ; Online: Ligand-mediated PAI-1 inhibition in a mouse model of peritoneal carcinomatosis.

Hendrikson, Josephine / Liu, Ying / Ng, Wai Har / Lee, Jing Yi / Lim, Abner Herbert / Loh, Jui Wan / Ng, Cedric C Y / Ong, Whee Sze / Tan, Joey Wee-Shan / Tan, Qiu Xuan / Ng, Gillian / Shannon, Nicholas B / Lim, Weng Khong / Lim, Tony K H / Chua, Clarinda / Wong, Jolene Si Min / Tan, Grace Hwei Ching / So, Jimmy Bok Yan / Yeoh, Khay Guan /

Teh, Bin Tean / Chia, Claramae Shulyn / Soo, Khee Chee / Kon, Oi Lian / Tan, Iain Beehuat / Chan, Jason Yongsheng / Teo, Melissa Ching Ching / Ong, Chin-Ann J

Cell reports. Medicine

2022 Volume 3, Issue 2, Page(s) 100526

Abstract: ... in a prospective study (n = 149). Via single-cell sequencing experiments, we uncover that PAI-1, a key component ... stratification of ascites using PAI-1 levels and STAT3 activation in ascites-treated cells highlight ...

Abstract	Peritoneal carcinomatosis (PC) present a ubiquitous clinical conundrum in all intra-abdominal malignancies. Via functional and transcriptomic experiments of ascites-treated PC cells, we identify STAT3 as a key signaling pathway. Integrative analysis of publicly available databases and correlation with clinical cohorts (n = 7,359) reveal putative clinically significant activating ligands of STAT3 signaling. We further validate a 3-biomarker prognostic panel in ascites independent of clinical covariates in a prospective study (n = 149). Via single-cell sequencing experiments, we uncover that PAI-1, a key component of the prognostic biomarker panel, is largely secreted by fibroblasts and mesothelial cells. Molecular stratification of ascites using PAI-1 levels and STAT3 activation in ascites-treated cells highlight a therapeutic opportunity based on a phenomenon of paracrine addiction. These results are recapitulated in patient-derived ascites-dependent xenografts. Here, we demonstrate therapeutic proof of concept of direct ligand inhibition of a prognostic target within an enclosed biological space.
MeSH term(s)	Animals ; Ascites ; Disease Models, Animal ; Humans ; Ligands ; Mice ; Peritoneal Neoplasms ; Plasminogen Activator Inhibitor 1/genetics ; Prospective Studies
Chemical Substances	Ligands ; Plasminogen Activator Inhibitor 1
Language	English
Publishing date	2022-02-15
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	2666-3791
ISSN (online)	2666-3791
DOI	10.1016/j.xcrm.2022.100526
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Article ; Online: The development of nasal polyps involves early middle meatus mucous remodeling via TGF-β1 mediated PAI-1 reduction.

Liu, Yijun / Shu, Longlan / Jiang, Xiaocong / Zhang, Yue / Chen, Qian / Shen, Yang / Yang, Yucheng

Brazilian journal of otorhinolaryngology

2023 Volume 89, Issue 3, Page(s) 366–373

Abstract: Objective: Our study aimed to elucidate the effect of PAI-1 (Plasminogen Activator Inhibitor-1 ... treated with TGF-β1 (Transforming Growth Factor-beta 1) activator, TGF-β1 inhibitor (SB431542), and PAI-1 ... The immunohistochemistry and immunofluorescence showed that PAI-1 expression decreased in eNP and mNP, mainly in epithelium ...

Abstract	Objective: Our study aimed to elucidate the effect of PAI-1 (Plasminogen Activator Inhibitor-1) and t-PA (Tissue-type Plasminogen Activator) in tissue remodeling in nasal polyps patients. Methods: Samples were streamed as early Nasal Polyps (eNP, n=10) and inferior tissue from the same patient, mature Nasal Polyps (mNP, n=14), and Control group (n=15), respectively. Immunohistochemistry and immunofluorescence were applied to detect localization. Quantitative Real-Time Polymerase Chain Reaction (qRT-PCR) and Western blot were used to measure different levels among three groups. The mNP tissue was cultured in vitro and treated with TGF-β1 (Transforming Growth Factor-beta 1) activator, TGF-β1 inhibitor (SB431542), and PAI-1 inhibitor (TM5275); then Western blot, qRT-PCR, and ELISA were used to assess changes. Results: The immunohistochemistry and immunofluorescence showed that PAI-1 expression decreased in eNP and mNP, mainly in epithelium and glands. The transcriptional expression and protein level of TGF-β1/t-PA/PAI-1/Collagen1 were lower in eNP than IT while mNP group demonstrated lower mRNA expression and protein level of TGF-β1/t-PA/PAI-1/Collagen1 than Control group. In mNP tissue culture in vitro, TGF-β1 activator elevated t-PA, PAI-1, and Collagen1 with higher release of PAI-1 and Collagen1 in supernatant, whereas SB431542 suppressed above reactions; TM5275 lowered transcriptional and protein level of Collagen1 in supernatant. Conclusion: Early Nasal polyps' formation in middle meatus mucous is related with fibrillation system PAI-1/t-PA and tissue remodeling; moreover, nasal polyps' development is regulated by TGF-β1-mediated PAI-1 reduction. Level of evidence: 3b.
MeSH term(s)	Humans ; Nasal Polyps ; Plasminogen Activator Inhibitor 1/genetics ; Plasminogen Activator Inhibitor 1/metabolism ; Transforming Growth Factor beta1/metabolism
Chemical Substances	4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide ; 5-chloro-2-(((2-(4-(diphenylmethyl)piperazin-1-yl)-2-oxoethoxy)acetyl)amino)benzoate ; Plasminogen Activator Inhibitor 1 ; Transforming Growth Factor beta1 ; SERPINE1 protein, human ; TGFB1 protein, human
Language	English
Publishing date	2023-02-14
Publishing country	Brazil
Document type	Journal Article
ZDB-ID	2428110-4
ISSN	1808-8686 ; 1808-8694
ISSN (online)	1808-8686
ISSN	1808-8694
DOI	10.1016/j.bjorl.2023.01.007
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Article ; Online: PAI-1 Regulation of p53 Expression and Senescence in Type II Alveolar Epithelial Cells.

Rana, Tapasi / Jiang, Chunsun / Banerjee, Sami / Yi, Nengjun / Zmijewski, Jaroslaw W / Liu, Gang / Liu, Rui-Ming

Cells

2023 Volume 12, Issue 15

Abstract: ... of plasminogen activator inhibitor 1 (PAI-1), a serine protease inhibitor, promotes ATII cell senescence through inducing ... In this study, we further show that PAI-1 binds to proteasome components and inhibits proteasome activity and ... that, although overexpression of wild-type PAI-1 (wtPAI-1) or a secretion-deficient, mature form of PAI-1 (sdPAI-1) alone ...

Abstract	Cellular senescence contributes importantly to aging and aging-related diseases, including idiopathic pulmonary fibrosis (IPF). Alveolar epithelial type II (ATII) cells are progenitors of alveolar epithelium, and ATII cell senescence is evident in IPF. Previous studies from this lab have shown that increased expression of plasminogen activator inhibitor 1 (PAI-1), a serine protease inhibitor, promotes ATII cell senescence through inducing p53, a master cell cycle repressor, and activating p53-p21-pRb cell cycle repression pathway. In this study, we further show that PAI-1 binds to proteasome components and inhibits proteasome activity and p53 degradation in human lung epithelial A549 cells and primary mouse ATII cells. This is associated with a senescence phenotype of these cells, manifested as increased p53 and p21 expression, decreased phosphorylated retinoblastoma protein (pRb), and increased senescence-associated beta-galactose (SA-β-gal) activity. Moreover, we find that, although overexpression of wild-type PAI-1 (wtPAI-1) or a secretion-deficient, mature form of PAI-1 (sdPAI-1) alone induces ATII cell senescence (increases SA-β-gal activity), only wtPAI-1 induces p53, suggesting that the premature form of PAI-1 is required for the interaction with the proteasome. In summary, our data indicate that PAI-1 can bind to proteasome components and thus inhibit proteasome activity and p53 degradation in ATII cells. As p53 is a master cell cycle repressor and PAI-1 expression is increased in many senescent cells, the results from this study will have a significant impact not only on ATII cell senescence/lung fibrosis but also on the senescence of other types of cells in different diseases.
MeSH term(s)	Animals ; Humans ; Mice ; Alveolar Epithelial Cells/metabolism ; Idiopathic Pulmonary Fibrosis/metabolism ; Plasminogen Activator Inhibitor 1/metabolism ; Proteasome Endopeptidase Complex/metabolism ; Tumor Suppressor Protein p53/metabolism
Chemical Substances	Plasminogen Activator Inhibitor 1 ; Proteasome Endopeptidase Complex (EC 3.4.25.1) ; Tumor Suppressor Protein p53 ; SERPINE1 protein, human ; TP53 protein, human ; Trp53 protein, mouse
Language	English
Publishing date	2023-08-05
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2661518-6
ISSN	2073-4409 ; 2073-4409
ISSN (online)	2073-4409
ISSN	2073-4409
DOI	10.3390/cells12152008
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Article ; Online: SIRT6-PAI-1 axis is a promising therapeutic target in aging-related bone metabolic disruption.

Aobulikasimu, Alkebaier / Liu, Tao / Piao, Jinying / Sato, Shingo / Ochi, Hiroki / Okawa, Atsushi / Tsuji, Kunikazu / Asou, Yoshinori

Scientific reports

2023 Volume 13, Issue 1, Page(s) 7991

Abstract: ... expression of Sost, Fgf23 and senescence inducing gene Pai-1 and the senescence markers p16 and Il-6 ... that were a cross of PAI-1-null mice with cKO mice. Furthermore, senescence induction in MLO-Y4 cells ... binding to the Fgf23 enhancer sequence. Bone mass and serum phosphate levels were higher in PAI-1-null ...

Abstract	The mechanistic regulation of bone mass in aged animals is poorly understood. In this study, we examined the role of SIRT6, a longevity-associated factor, in osteocytes, using mice lacking Sirt6 in Dmp-1-expressing cells (cKO mice) and the MLO-Y4 osteocyte-like cell line. cKO mice exhibited increased osteocytic expression of Sost, Fgf23 and senescence inducing gene Pai-1 and the senescence markers p16 and Il-6, decreased serum phosphate levels, and low-turnover osteopenia. The cKO phenotype was reversed in mice that were a cross of PAI-1-null mice with cKO mice. Furthermore, senescence induction in MLO-Y4 cells increased the Fgf23 and Sost mRNA expression. Sirt6 knockout and senescence induction increased HIF-1α binding to the Fgf23 enhancer sequence. Bone mass and serum phosphate levels were higher in PAI-1-null aged mice than in wild-type mice. Therefore, SIRT6 agonists or PAI-1 inhibitors may be promising therapeutic options for aging-related bone metabolism disruptions.
MeSH term(s)	Animals ; Mice ; Cell Line ; Osteocytes/metabolism ; Phosphates/metabolism ; Plasminogen Activator Inhibitor 1/genetics ; Plasminogen Activator Inhibitor 1/metabolism ; Sirtuins/genetics ; Sirtuins/metabolism
Chemical Substances	Phosphates ; Plasminogen Activator Inhibitor 1 ; Sirt6 protein, mouse (EC 2.4.2.31) ; Sirtuins (EC 3.5.1.-) ; Serpine2 protein, mouse
Language	English
Publishing date	2023-05-17
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-023-33297-7
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Article ; Online: Eupatilin Ameliorates Hepatic Fibrosis and Hepatic Stellate Cell Activation by Suppressing β-catenin/PAI-1 Pathway.

Hu, Jinyuan / Liu, Yuanyuan / Pan, Zheng / Huang, Xuekuan / Wang, Jianwei / Cao, Wenfu / Chen, Zhiwei

International journal of molecular sciences

2023 Volume 24, Issue 6

Abstract: The activation of hepatic stellate cells (HSCs) has proved to be pivotal in hepatic fibrosis. Therefore, the suppression of HSC activation is an effective anti-fibrotic strategy. Although studies have indicated that eupatilin, a bioactive flavone found ... ...

Abstract	The activation of hepatic stellate cells (HSCs) has proved to be pivotal in hepatic fibrosis. Therefore, the suppression of HSC activation is an effective anti-fibrotic strategy. Although studies have indicated that eupatilin, a bioactive flavone found in
MeSH term(s)	Humans ; Mice ; Animals ; Hepatic Stellate Cells/metabolism ; Plasminogen Activator Inhibitor 1/genetics ; Plasminogen Activator Inhibitor 1/metabolism ; Liver Cirrhosis/metabolism ; Flavonoids/adverse effects ; Fibrosis
Chemical Substances	eupatilin (4D58O05490) ; Plasminogen Activator Inhibitor 1 ; Flavonoids
Language	English
Publishing date	2023-03-21
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms24065933
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Article ; Online: The simulation, regulation capacity assessment and coping strategy of rainstorm runoff waterlogging in Zhu pai-chong Basin of Nanning, China.

Li, Qianyun / Yang, Yunchuan / Liao, Haixiang / Liu, Miaoqing / Liao, Liping / Huang, Shanqi / Sun, Guikai / Mo, Chongxun / Li, Xungui

Journal of environmental management

2023 Volume 332, Page(s) 117395

Abstract: ... management. Therefore, this paper selected the Zhu pai-chong watershed in Nanning with frequent waterlogging ...

Abstract	Currently, China is experiencing a phase of rapid urbanization. With the frequent occurrence of extreme rainfall events within the context of climate change, the problem of heavy rainfall and waterlogging in many cities is very prominent. In November 2020, China issued a proposal for the construction of sponge cities across the entire region to significantly enhance the rainfall flood prevention and drainage capacity of cities and effectively improve the resilience of sponge city systems for flooding management. Therefore, this paper selected the Zhu pai-chong watershed in Nanning with frequent waterlogging disasters as an example. Based on underlying surface information, We used a coupled SWMM-LISFOOD model to simulate runoff and waterlogging processes and analyze the spatial and temporal evolution characteristics of the basin under 10 designed rainstorm return periods (0.25a-50a). The results confirm the substantial spatial and temporal variabilities of the runoff coefficient in the study area; impermeability was the main factor contributing to high runoff coefficient values. The spatial distribution characteristics of inundation area was general dispersion and local linear aggregation. Furthermore, this study assessed the effect of the control rate of blue‒green‒gray facilities on the actual storms, and the value ranged from only 48.6% (0.25a)-24.05% (50a). This study quantified the two-dimensional distribution of rainfall storage volume thresholds with or without considering the discharged from the pipe network. Quantitative mapping between the elements of "rainfall-storage volume of blue‒green‒gray facilities-runoff-drainage capacity of the pipe network-waterlogging level" was conducted within the study area as an example. Finally, an overall technical process scheme for rainfall and waterlogging management was proposed. The scheme covered the hydrological‒hydraulic mechanism, storage function of sponge facilities, engineering control response, nonengineering measures and intelligent management of rainfall and waterlogging during sponge city construction, which could provide critical scientific support for effective promotion of the construction of sponge cities in China.
MeSH term(s)	Rain ; Water Movements ; China ; Cities ; Adaptation, Psychological
Language	English
Publishing date	2023-02-02
Publishing country	England
Document type	Journal Article
ZDB-ID	184882-3
ISSN	1095-8630 ; 0301-4797
ISSN (online)	1095-8630
ISSN	0301-4797
DOI	10.1016/j.jenvman.2023.117395
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Article ; Online: Integrative identification of human serpin PAI-1 inhibitors from Dracaena dragon blood and molecular implications for inhibitor-induced PAI-1 allosterism.

Xu, Chong / Liu, Xia / Shen, Jie / Sun, Quan / Guo, Xiaohong / Yang, Min / Leng, Jing

Biotechnology and applied biochemistry

2021 Volume 69, Issue 1, Page(s) 221–229

Abstract: Human plasminogen activator inhibitor-1 (PAI-1) is an important component of the coagulation system ... inhibitory activity against PAI-1, but it is unclear which constituents directly participate ... in the inhibition and how do they regulate PAI-1 at molecular level. Here, we describe an integrated strategy ...

Abstract	Human plasminogen activator inhibitor-1 (PAI-1) is an important component of the coagulation system and has been recognized as a potential therapeutic target of diverse cardiovascular disorders. Previously, it was found that the extracts from the Chinese medicine Dracaena dragon blood have potent inhibitory activity against PAI-1, but it is unclear which constituents directly participate in the inhibition and how do they regulate PAI-1 at molecular level. Here, we describe an integrated strategy to identify the dragon blood's chemical constituents that can directly target PAI-1. With the strategy, five compounds 1-5 are hit as promising PAI-1 inhibitor candidates, from which three are measured to have high or moderate activity against PAI-1. In particular, the compound 3 is determined to exhibit the highest potency; this value is roughly comparable with the widely used PAI-1 inhibitor Tiplaxtinin. We further examine the molecular effect of compound 3 on PAI-1 conformation at structural level. It is supposed that small-molecule inhibitor regulates the reactive center loop (RCL) of PAI-1 through an allosterism, that is, binding of compound 3 to PAI-1 can allosterically stabilize RCL in latent form, thus promoting PAI-1 conformational conversion from metastable active form to the inactive latent form. Long-term atomistic simulations also demonstrate that removal of compound 3 can destabilize the structured β-stranded conformation of RCL in latent form, although the current simulations are still not sufficient to characterize the full conversion dynamics trajectory.
MeSH term(s)	Dracaena ; Humans ; Plasminogen Activator Inhibitor 1 ; Protein Conformation ; Serpins
Chemical Substances	Plasminogen Activator Inhibitor 1 ; Serpins
Language	English
Publishing date	2021-01-26
Publishing country	United States
Document type	Journal Article
ZDB-ID	883433-7
ISSN	1470-8744 ; 0885-4513
ISSN (online)	1470-8744
ISSN	0885-4513
DOI	10.1002/bab.2100
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Zs.A 1865: Show issues

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Article ; Online: Clinical value of echocardiography combined with serum Cav-1, NFATc1, and PAI-1 in the diagnosis of Kawasaki disease complicated with coronary artery lesions.

Zhang, Yanxia / Liu, Jieqiong

Heart and vessels

2023 Volume 39, Issue 1, Page(s) 18–24

Abstract: ... activated T cell nuclear factor C1 (NFATc1), and plasminogen activator inhibitor-1 (PAI-1) in the diagnosis ... of Cav-1, NFATc1, and PAI-1 were detected by enzyme-linked immunosorbent assay. Echocardiography was ... with serum Cav-1, NFATc1, and PAI-1 in the diagnosis of KD complicated with CAL were analyzed ...

Abstract	To analyze the clinical value of echocardiography combined with serum lacuna protein-1 (Cav-1), activated T cell nuclear factor C1 (NFATc1), and plasminogen activator inhibitor-1 (PAI-1) in the diagnosis of Kawasaki disease (KD) complicated with coronary artery lesions (CAL). A total of 200 children with KD treated in our hospital from January 2019 to October 2021 were grouped as the KD alone group (n = 56) and the KD complicated with CAL group (n = 144) according to the results of coronary angiography. The levels of Cav-1, NFATc1, and PAI-1 were detected by enzyme-linked immunosorbent assay. Echocardiography was performed and the internal diameters of left and right coronary arteries were compared between the two groups. The area under the curve (AUC), sensitivity, and specificity of echocardiography combined with serum Cav-1, NFATc1, and PAI-1 in the diagnosis of KD complicated with CAL were analyzed with receiver operating characteristic (ROC) curve. Coronary angiography, as the gold standard, showed that the sensitivity of echocardiography in diagnosing KD with CAL was 88.19% (127/144), the specificity was 66.07% (37/56), and the accuracy was 82.00% (164/200). ROC curve analysis revealed that the AUC of KD complicated with CAL diagnosed by echocardiography, Cav-1, NFATc1, and PAI-1 was 0.819, 0.715, 0.688, and 0.663, respectively, and the AUC of combined diagnosis of the four was 0.896. The combination of echocardiography, Cav-1, NFATc1, and PAI-1 has high value in diagnosing KD complicated with CAL, which can be widely used in clinical practice.
MeSH term(s)	Child ; Humans ; Coronary Artery Disease/diagnosis ; Coronary Artery Disease/diagnostic imaging ; Echocardiography ; Mucocutaneous Lymph Node Syndrome/complications ; Mucocutaneous Lymph Node Syndrome/diagnosis ; Plasminogen Activator Inhibitor 1
Chemical Substances	Plasminogen Activator Inhibitor 1 ; SERPINE1 protein, human
Language	English
Publishing date	2023-09-27
Publishing country	Japan
Document type	Journal Article
ZDB-ID	89678-0
ISSN	1615-2573 ; 0910-8327 ; 0935-736X
ISSN (online)	1615-2573
ISSN	0910-8327 ; 0935-736X
DOI	10.1007/s00380-023-02315-z
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Article ; Online: Wnt5a/β-catenin axis is involved in the downregulation of AT2 lineage by PAI-1.

Jain, Krishan G / Zhao, Runzhen / Liu, Yang / Guo, Xuan / Yi, Guohua / Ji, Hong-Long

American journal of physiology. Lung cellular and molecular physiology

2022 Volume 323, Issue 5, Page(s) L515–L524

Abstract: ... in coronavirus disease 2019 (COVID-19). How elevated plasminogen activator inhibitor-1 (PAI-1) regulates ... to examine the role of PAI-1-Wnt5a-β catenin cascades in AT2 fate. Dramatic reduction in AT2 yield was ...

Abstract	Failure to regenerate injured alveoli functionally and promptly causes a high incidence of fatality in coronavirus disease 2019 (COVID-19). How elevated plasminogen activator inhibitor-1 (PAI-1) regulates the lineage of alveolar type 2 (AT2) cells for re-alveolarization has not been studied. This study aimed to examine the role of PAI-1-Wnt5a-β catenin cascades in AT2 fate. Dramatic reduction in AT2 yield was observed in
MeSH term(s)	Animals ; Mice ; Antibodies, Neutralizing ; beta Catenin/metabolism ; COVID-19 ; Down-Regulation ; Wnt Signaling Pathway/physiology ; Wnt-5a Protein/metabolism ; Plasminogen Activator Inhibitor 1/metabolism ; Pulmonary Alveoli/cytology ; Cell Proliferation
Chemical Substances	Antibodies, Neutralizing ; beta Catenin ; Wnt-5a Protein ; Plasminogen Activator Inhibitor 1
Language	English
Publishing date	2022-09-13
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	1013184-x
ISSN	1522-1504 ; 1040-0605
ISSN (online)	1522-1504
ISSN	1040-0605
DOI	10.1152/ajplung.00202.2022
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Article ; Online: Shitsan Pai: the establishment of the first biophysics department in the world.

Liu, Rui

Protein & cell

2018 Volume 10, Issue 10, Page(s) 701–704

MeSH term(s)	Academies and Institutes/history ; Biophysics/history ; China ; History, 20th Century
Language	English
Publishing date	2018-06-26
Publishing country	Germany
Document type	Biography ; Historical Article ; Journal Article ; Portrait
ZDB-ID	2543451-2
ISSN	1674-8018 ; 1674-800X
ISSN (online)	1674-8018
ISSN	1674-800X
DOI	10.1007/s13238-018-0557-0
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