1.The expression and significance of PAI-1,t-PA,u-PA and u-PAR in induced sputum in patients with asthma
Chinese Journal of Postgraduates of Medicine 2009;32(1):1-3
Objective To detect the levels of plasminogen activator inhibitor(PAI)-1,tissue plasminogen activator(t-PA),urokinase-type plasminogen activator(u-PA)and urokinase-type plasminogen activator receptor(u-PAR)in induced sputum in patients with asthma and analyze their clinical significances in pathogenesis of asthlna.Methods The induced sputum was isolated from 15 normal subjects(control group),29 patients with acute attack of asthma(attack group)and 26 stable asthma patients(stable group).The levels of PAl-1,t-PA,u-PA and u-PAR were measured by ELISA.Meanwhile FEV1%pred of all groups were evaluated.Results The levels of PAI-1 and u-PAR of induced sputum were significandy higher in at-tack group[(23.32±21.64),(0.766±0.272)μg/L]and stable group[(17.23±9.40),(0.700±0.271)μg/L]than those in control group[(5.99±5.04),(0.516±0.197)μg/L](P<0.05).As for the induced sputum concentrations of u-PA and t-PA,there were no significant differences among the attack group[(0.287±0.235),(7.68±3.46)μg/L],stable group[(0.251±0.276),(9.88±4.68)μg/L]and control group[(0.239±0.322),(10.35±7.47)μg/L].In stable group,the level of PAI-1 had a negative correlation with the FEV1%pred(r=-0.756,P<0.01).In stable group,the level of PAI-1 had a positive correlation with the length of disease course(r=0.454,P<0.05).Conclusion PAI-1 and u-PAR maybe involved in pathophysiologic change of asthma.
2.A redox-responsive self-assembling COA-4-arm PEG prodrug nanosystem for dual drug delivery suppresses cancer metastasis and drug resistance by downregulating hsp90 expression.
Yi ZHOU ; Yingling MIAO ; Qiudi HUANG ; Wenwen SHI ; Jiacui XIE ; Jiachang LIN ; Pei HUANG ; Chengfeng YUE ; Yuan QIN ; Xiyong YU ; He WANG ; Linghao QIN ; Jianhai CHEN
Acta Pharmaceutica Sinica B 2023;13(7):3153-3167
Metastasis and resistance are main causes to affect the outcome of the current anticancer therapies. Heat shock protein 90 (Hsp90) as an ATP-dependent molecular chaperone takes important role in the tumor metastasis and resistance. Targeting Hsp90 and downregulating its expression show promising in inhibiting tumor metastasis and resistance. In this study, a redox-responsive dual-drug nanocarrier was constructed for the effective delivery of a commonly used chemotherapeutic drug PTX, and a COA-modified 4-arm PEG polymer (4PSC) was synthesized. COA, an active component in oleanolic acid that exerts strong antitumor activity by downregulating Hsp90 expression, was used as a structural and functional element to endow 4PSC with redox responsiveness and Hsp90 inhibitory activity. Our results showed that 4PSC/PTX nanomicelles efficiently delivered PTX and COA to tumor locations without inducing systemic toxicity. By blocking the Hsp90 signaling pathway, 4PSC significantly enhanced the antitumor effect of PTX, inhibiting tumor proliferation and invasiveness as well as chemotherapy-induced resistance in vitro. Remarkable results were further confirmed in vivo with two preclinical tumor models. These findings demonstrate that the COA-modified 4PSC drug delivery nanosystem provides a potential platform for enhancing the efficacy of chemotherapies.
3.Gli1 promotes epithelial-mesenchymal transition and metastasis of non-small cell lung carcinoma by regulating snail transcriptional activity and stability.
Xueping LEI ; Zhan LI ; Yihang ZHONG ; Songpei LI ; Jiacong CHEN ; Yuanyu KE ; Sha LV ; Lijuan HUANG ; Qianrong PAN ; Lixin ZHAO ; Xiangyu YANG ; Zisheng CHEN ; Qiudi DENG ; Xiyong YU
Acta Pharmaceutica Sinica B 2022;12(10):3877-3890
Metastasis is crucial for the mortality of non-small cell lung carcinoma (NSCLC) patients. The epithelial-mesenchymal transition (EMT) plays a critical role in regulating tumor metastasis. Glioma-associated oncogene 1 (Gli1) is aberrantly active in a series of tumor tissues. However, the molecular regulatory relationships between Gli1 and NSCLC metastasis have not yet been identified. Herein, we reported Gli1 promoted NSCLC metastasis. High Gli1 expression was associated with poor survival of NSCLC patients. Ectopic expression of Gli1 in low metastatic A549 and NCI-H460 cells enhanced their migration, invasion abilities and facilitated EMT process, whereas knock-down of Gli1 in high metastatic NCI-H1299 and NCI-H1703 cells showed an opposite effect. Notably, Gli1 overexpression accelerated the lung and liver metastasis of NSCLC in the intravenously injected metastasis model. Further research showed that Gli1 positively regulated Snail expression by binding to its promoter and enhancing its protein stability, thereby facilitating the migration, invasion and EMT of NSCLC. In addition, administration of GANT-61, a Gli1 inhibitor, obviously suppressed the metastasis of NSCLC. Collectively, our study reveals that Gli1 is a critical regulator for NSCLC metastasis and suggests that targeting Gli1 is a prospective therapy strategy for metastatic NSCLC.