Objective To investigate the effects and potential mechanisms of tolvaptan on chronic intermittent hypoxia(CIH)-induced atrial remodeling in rats.Methods A total of 45 Sprague-Dawley rats were divided into 3 groups by...Objective To investigate the effects and potential mechanisms of tolvaptan on chronic intermittent hypoxia(CIH)-induced atrial remodeling in rats.Methods A total of 45 Sprague-Dawley rats were divided into 3 groups by the random number table:control group,CIH group(6 h/d for 30 days),CIH plus tolvaptan group(8 mg·kg-1·d-1 per gavage for 30 days).Echocardiography examination was performed after 30 days.Thereafter,5 rats were randomly chosen for histology evaluation,5 for molecular biological examinations and another 5 rats underwent isolated heart electrophysiology study in each group.Protein and mRNA expression levels of miRNA-21,Spry1,PTEN,ERK/p-ERK,MMP-9,PI3K,AKT/p-AKT were detected.Results Compared to the rats in control group,rats in the CIH group showed higher atrial interstitial collagen deposition(P<0.001),increased atrial fibrillation inducibility(P=0.022).The results of immunohistochemistry staining showed that the mean optical density(MOD)of ERK,p-ERK and MMP-9 were significantly increased(all P<0.05),the MOD of Spry1 and PTEN were significantly decreased(both P<0.05),above changes could be significantly reversed by cotreatment with tolvaptan.No significant differences were detected in PI3K and AKT among the three groups(P>0.05).展开更多
Ubiquitin specific peptidase 28(USP28) is closely associated to the occurrence and development of various malignancies, and thus has been validated as a promising therapeutic target for cancer therapy. To date,only fe...Ubiquitin specific peptidase 28(USP28) is closely associated to the occurrence and development of various malignancies, and thus has been validated as a promising therapeutic target for cancer therapy. To date,only few USP28 inhibitors with moderate inhibitory activity have been reported, highly potent and selective USP28 inhibitors with new chemotypes remain to be discovered for pathologically investigating the roles of deubiquitinase. In this current study, we reported the synthesis and biological evaluation of new [1,2,3]triazolo[4,5-d]pyrimidine derivatives as potent USP28 inhibitors. Especially, compound 19 potently inhibited USP28(IC50=1.10 ± 0.02 μmol/L, Kd=40 nmol/L), showing selectivity over USP7 and LSD1(IC50> 100 μmol/L). Compound 19 was cellularly engaged to USP28 in gastric cancer cells. Compound 19 reversibly bound to USP28 and directly affected its protein levels, thus inhibiting the proliferation, cell cycle at S phase, and epithelial-mesenchymal transition(EMT) progression in gastric cancer cell lines. Docking studies were performed to rationalize the potency of compound 19. Collectively, compound 19 could serve as a new tool compound for the development of new USP28 inhibitors for exploring the roles of deubiquitinase in cancers.展开更多
文摘Objective To investigate the effects and potential mechanisms of tolvaptan on chronic intermittent hypoxia(CIH)-induced atrial remodeling in rats.Methods A total of 45 Sprague-Dawley rats were divided into 3 groups by the random number table:control group,CIH group(6 h/d for 30 days),CIH plus tolvaptan group(8 mg·kg-1·d-1 per gavage for 30 days).Echocardiography examination was performed after 30 days.Thereafter,5 rats were randomly chosen for histology evaluation,5 for molecular biological examinations and another 5 rats underwent isolated heart electrophysiology study in each group.Protein and mRNA expression levels of miRNA-21,Spry1,PTEN,ERK/p-ERK,MMP-9,PI3K,AKT/p-AKT were detected.Results Compared to the rats in control group,rats in the CIH group showed higher atrial interstitial collagen deposition(P<0.001),increased atrial fibrillation inducibility(P=0.022).The results of immunohistochemistry staining showed that the mean optical density(MOD)of ERK,p-ERK and MMP-9 were significantly increased(all P<0.05),the MOD of Spry1 and PTEN were significantly decreased(both P<0.05),above changes could be significantly reversed by cotreatment with tolvaptan.No significant differences were detected in PI3K and AKT among the three groups(P>0.05).
基金supported by the National Key Research Program of Proteins(No.2016YFA0501800 for Hongmin Liu,China)National Natural Science Foundation of China(Nos.81430085 and 81773562 for Hongmin Liu and Nos.81703326 and 81973177 for Bin Yu)+2 种基金Scientific Program of Henan Province(No.19A350012 for Xiaojing Shi,China)China Postdoctoral Science Foundation(No.2018M630840 and 2019T120641 for Bin Yu)the Henan Scientific Innovation Talent Team,Department for Education(No.19ITSTHN001 for Wen Zhao,China)
文摘Ubiquitin specific peptidase 28(USP28) is closely associated to the occurrence and development of various malignancies, and thus has been validated as a promising therapeutic target for cancer therapy. To date,only few USP28 inhibitors with moderate inhibitory activity have been reported, highly potent and selective USP28 inhibitors with new chemotypes remain to be discovered for pathologically investigating the roles of deubiquitinase. In this current study, we reported the synthesis and biological evaluation of new [1,2,3]triazolo[4,5-d]pyrimidine derivatives as potent USP28 inhibitors. Especially, compound 19 potently inhibited USP28(IC50=1.10 ± 0.02 μmol/L, Kd=40 nmol/L), showing selectivity over USP7 and LSD1(IC50> 100 μmol/L). Compound 19 was cellularly engaged to USP28 in gastric cancer cells. Compound 19 reversibly bound to USP28 and directly affected its protein levels, thus inhibiting the proliferation, cell cycle at S phase, and epithelial-mesenchymal transition(EMT) progression in gastric cancer cell lines. Docking studies were performed to rationalize the potency of compound 19. Collectively, compound 19 could serve as a new tool compound for the development of new USP28 inhibitors for exploring the roles of deubiquitinase in cancers.
