RESUMO
Modulating Tankyrases (TNKS), interactions with USP25 to promote TNKS degradation, rather than inhibiting their enzymatic activities, is emerging as an alternative/specific approach to inhibit the Wnt/β-catenin pathway. Here, we identified UAT-B, a novel neoantimycin analog isolated from Streptomyces conglobatus, as a small-molecule inhibitor of TNKS-USP25 protein-protein interaction (PPI) to overcome multi-drug resistance in colorectal cancer (CRC). The disruption of TNKS-USP25 complex formation by UAT-B led to a significant decrease in TNKS levels, triggering cell apoptosis through modulation of the Wnt/β-catenin pathway. Importantly, UAT-B successfully inhibited the CRC cells growth that harbored high TNKS levels, as demonstrated in various in vitro and in vivo studies utilizing cell line-based and patient-derived xenografts, as well as APCmin/+ spontaneous CRC models. Collectively, these findings suggest that targeting the TNKS-USP25 PPI using a small-molecule inhibitor represents a compelling therapeutic strategy for CRC treatment, and UAT-B emerges as a promising candidate for further preclinical and clinical investigations.
RESUMO
OBJECTIVE:To study the protective effects of Polygonum hydropiper extract on acute gastric mucosal lesion (AGML)in rats. METHODS:48 rats were randomly divided into normal group(normal saline),model group(normal saline), positive group(ranitidine hydrochloride,0.05 g/kg),P. hydropiper extract low-dose,medium-dose and high-dose groups(2.7, 8.1,24.3 g/kg by crude drug),i.g. for consecutive 7 d,once a day. Except for normal group,other groups were given absolute ethyl alcohol to induce AGMI model after 1 h of last administration. 1.5 h after modeling,gastric mucosal lesion index of rats was calculated;the pathological changes of gastric tissue in rats were observed;nuclear factor E2 related factor 2(Nrf2)content and SOD activity in gastric tissue of rats were determined by ELISA. RESULTS:Compared with normal group,the gastric mucosa of model group was damaged obviously,there was blood capillary rupture in submucosa,gastric mucosal lesion index was increased significantly(P<0.01);Nrf2 content and SOD activity were significantly decreased in gastric tissue of rats(P<0.05 or P<0.01). Compared with model group,gastric mucosal lesion of rats was relieved to different extent;in positive group,P. hydropiper extract medium-dose and high-dose groups,gastric mucosal lesion index was decreased significantly(P<0.05),and Nrf2 content and SOD activity were increased significantly(P<0.05 or P<0.01). CONCLUSIONS:P. hydropiper extract has good protective effect on absolute ethyl alcohol-induce AGMI,the mechanism of which may be associated with raising Nrf2 content and enhancing SOD activity in gastric mucosal tissue.