As a significant co-activator involved in cell cycle and cell growth, differentiation and development, p300/CBP has shown extraordinary potential target in cancer therapy. Herein we designed new compounds from the lead compound A-485 based on molecular dynamic simulations. A series of new spirocyclic chroman derivatives was prepared, characterized and proven to be a potential treatment of prostate cancer. The most potent compound B16 inhibited the proliferation of enzalutamide-resistant 22Rv1 cells with an IC50 value of 96 nM. Furthermore, compounds B16–P2 displayed favorable overall pharmacokinetic profiles, and better tumor growth inhibition than A-485 in an in vivo xenograft model.
ObjectiveThe aim of this study was to investigate the effect of IL‐10 on the phenotype polarization of macrophages and osteogenesis in diabetes mellitus type 2 (T2DM) rat jaw defects.MethodsLipopolysaccharide (LPS) and interleukin‐10 (IL‐10) were chosen to induce the polarization of macrophages. In vitro assessment included wound‐healing assay, western blotting, and alizarin red staining after co‐culture of the bone marrow‐derived mesenchymal stem cells (BMSCs) and induced macrophages. For in vivo study, IL‐10 was loaded on GelMA‐Heparin and applied to bone defects of the alveolar ridge in diabetic rats, while Bio‐Oss Collagen, simple GelMA‐Heparin, and blank control groups were set for contrast experiment. The mandibles of rats were processed for micro‐computed tomography, histology, and immunohistochemistry 1 week and 4 weeks after the operation.ResultsIL‐10 induced expression of arginase 1, TGF‐β1, EGR2, and Mannose Receptor (CD206), whereas LPS induced expression of iNOS, TNF‐α, IL‐6, CD80. The BMSCs co‐cultured with macrophages induced by IL‐10 showed increased migration, osteogenic differentiation, and mineralization in vitro. Notably, the IL‐10‐laden GelMA‐Heparin group showed quicker new bone formation and a higher M2/M1 ratio of macrophages in the jawbone defect area compared with the control groups.ConclusionsIL‐10 can stably induce macrophages to M2 type, thereby influencing BMSCs and improving the osteogenesis of jaw bone defects.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.