Abstract Background: Promoting bone marrow mesenchymal stem cell (BMSC) osteoblastic differentiation is a promising therapeutic strategy for osteoporosis (OP). The present study demonstrates that miR-483-5p inhibits the osteogenic differentiation of BMSCs. Therefore, selectively delivering the nanoparticles carrying antagomir-483-5p (miR-483-5p inhibitor) to BMSCs is expected to become an effective treatment drug for OP. Methods: Real-time PCR assays were used to analyse miR-483-5p, ALP and Bglap levels in BMSCs of ovariectomized and aged osteoporotic mice. To selectively and efficiently deliver antagomir-483-5p to BMSCs in vivo, immunoglobulin G and poloxamer-188 were used to encapsulate the functional small molecules, and BMSC-targeting aptamer was employed to confirm the direction of the nanoparticles. Luciferase assays were used to determine the target genes of miR-483-5p. Western blot assays and immunohistochemistry staining were used to detect the targets in vitro and vivo. Results: miR-483-5p levels were increased in BMSCs of ovariectomized and aged osteoporotic mice. Inhibition of miR-483-5p levels in BMSCs by antagomir-483-5p in vitro promoted the expression of bone formation markers, such as ALP and Bglap. The FAM-BMSC-aptamer-nanoparticles carrying antagomir-483-5p were taken up by BMSCs, resulting in stimulation of BMSC osteoblastic differentiation in vitro and osteoporosis prevention in vivo. Furthermore, our research demonstrated that mitogen-activated protein kinase 1 (MAPK1) and SMAD family member 5 (Smad5) were direct targets of miR-483-5p in regulating BMSC osteoblastic differentiation and osteoporosis pathological processes. Conclusions: The important therapeutic role of FAM-BMSC-aptamer-nanoparticles carrying antagomir-483-5p in osteoporosis was established in our study. These nanoparticles are novel candidate for the clinical prevention and treatment of osteoporosis. The optimized targeted drug delivery platform for small molecules will provide new ideas for the treatment of clinical diseases.
Estrogen/ERα signaling is critical for breast cancer progression and therapeutic treatments. Thus, identifying new regulators of this pathway will help to develop new therapeutics to overcome chemotherapy resistance of the breast cancer cells. Here, we report Ajuba directly interacts with ERα to potentiate ERα target gene expression, and biologically Ajuba promotes breast cancer cell growth and contributes to tamoxifen resistance of these cells. Ajuba constitutively binds the DBD and AF2 regions of ERα, and these interactions can be markedly enhanced by estrogen treatment. Mechanistically, Ajuba recruits DBC1 and CBP/p300 and forms a ternary complex to co-activate ERα transcriptional activity and concomitantly enhances ERα acetylation. Moreover, components of this complex can be found at endogenous promoters containing functional ERα responsive elements. Taken together, these data demonstrate that Ajuba functions as a novel co-activator of ERα and that Ajuba/DBC1/CBP/p300 ternary complex may be a new target for developing therapeutics to treat breast cancer.
Abstract Bone mass is determined by the balance between bone formation, carried out by mesenchymal stem cell-derived osteoblasts, and bone resorption, carried out by monocyte-derived osteoclasts. Here we investigated the potential roles of p38 MAPKs, which are activated by growth factors and cytokines including RANKL and BMPs, in osteoclastogenesis and bone resorption by ablating p38α MAPK in LysM+monocytes. p38α deficiency promoted monocyte proliferation but regulated monocyte osteoclastic differentiation in a cell-density dependent manner, with proliferating p38α −/− cultures showing increased differentiation. While young mutant mice showed minor increase in bone mass, 6-month-old mutant mice developed osteoporosis, associated with an increase in osteoclastogenesis and bone resorption and an increase in the pool of monocytes. Moreover, monocyte-specific p38α ablation resulted in a decrease in bone formation and the number of bone marrow mesenchymal stem/stromal cells, likely due to decreased expression of PDGF-AA and BMP2. The expression of PDGF-AA and BMP2 was positively regulated by the p38 MAPK-Creb axis in osteoclasts, with the promoters of PDGF-AA and BMP2 having Creb binding sites. These findings uncovered the molecular mechanisms by which p38α MAPK regulates osteoclastogenesis and coordinates osteoclastogenesis and osteoblastogenesis.
The merits of retaining the subvalvular apparatus during mitral valve replacement (MVR) for chronic mitral regurgitation have been demonstrated in clinical investigations. This study was to investigate the feasibility of total preservation of the leaflet and subvalvular apparatus at the native anatomic position during MVR in a rheumatic population with enlarged left ventricular chamber.The techniques of valvular apparatus preservation used during MVR with or without aortic valve replacement were investigated in 128 patients with an enlarged left ventricular chamber suffering from rheumatic mitral regurgitation between October 2003 and December 2007. Seventy patients had the anterior leaflet and subvalvular apparatus excised but the posterior leaflet and subvlvular apparatus preserved during the mitral valve replacement (P-MVR group), and 58 patients had the anterior and posterior mitral leaflets and the subvalvalur apparatus completely preserved at the native anatomical position during the mitral valve replacement (C-MVR group). Echocardiography was performed preoperatively, at discharge, and after 3 months, 1 year, and 3 years to determine the left ventricular dimensions and function.There were 2 cases (3.4%) of early death in the C-MVR group, and there were 4 cases (5.7%) of early death in the P-MVR group. There were 3 cases of late death 1 year after surgery, of which 1 case in the C-MVR group was caused by congestive heart failure and the other 2 cases in the P-MVR group were due to sudden death. Both groups exhibited significant improvement (P < .05) in left ventricular function instantly and late postoperatively. The reduction of the left ventricular end-diastolic diameter was more significant in the C-MVR group as compared to the P-MVR group (P < .05). A statistically significant increase in fractional shortening (FS) occurred in the C-MVR group compared to the P-MVR group.This study shows that complete mitral leaflet preservation at the native anatomical position during MVR is feasible in rheumatic patients with an enlarged left ventricular chamber and confers significant short-term and long-term advantages by preserving left ventricular function and geometry. Therefore, it is a safe, simple, and effective surgical technique and should be individualized during clinical use.
DNA damage and the elicited cellular response underlie the etiology of tumorigenesis and ageing. Yet, how this response integrates inputs from cells' environmental cues remains underexplored. Here we report that the BMP-Smad1 pathway, which is essential for embryonic development and tissue homeostasis, has an important role in the DNA damage response and oncogenesis. On genotoxic stress, Atm phosphorylates BMPs-activated Smad1 in the nucleus on S239, which disrupts Smad1 interaction with protein phosphatase PPM1A, leading to enhanced activation and upregulation of Smad1. Smad1 then interacts with p53 and inhibits Mdm2-mediated p53 ubiquitination and degradation to regulate cell proliferation and survival. Enhanced Smad1 S239 phosphorylation, and Smad1 mutations causing S239 substitution were detected in oesophageal and gastric cancer samples, respectively. These findings suggest that BMP-Smad1 signalling participates in the DNA damage response via the Atm-p53 pathway, thus providing a molecular mechanism whereby BMP-Smad1 loss-of-function leads to tumorigenesis, for example, juvenile polyposis and Cowden syndromes. The bone morphogenetic protein (BMP) and Smad1 signalling pathway is required for embryogenesis. In this study, Smad1 is shown to be phosphorylated by Atm in response to DNA damage and this results in elevated Smad1 signalling, thus uncovering a new role for this pathway in the DNA damage response.
The organ system-centered teaching model breaks the clear-cut disciplinary boundary in the traditional teaching and reflects the continuity,comprehensiveness and clinical practicality of disciplines.Therefore,it is the development orientation of training medical personnel for the new century.By taking for example the digestive system teaching in our hospital's Surgery Teaching and Research Section,this paper discusses the merits,integration method and related reforms of the organ system-centered teaching.
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