miR-532-3p is a widely documented microRNA (miRNA) involved in multifaceted processes of cancer tumorigenesis and metastasis. However, the clinical significance and biological functions of miR-532-3p in bone metastasis of prostate cancer (PCa) remain largely unknown. Herein, we report that miR-532-3p was downregulated in PCa tissues with bone metastasis, and downexpression of miR-532-3p was significantly associated with Gleason grade and serum prostate-specific antigen (PSA) levels and predicted poor bone metastasisfree survival in PCa patients. Upregulating miR-532-3p inhibited invasion and migration abilities of PCa cells in vitro, while silencing miR-532-3p yielded an opposite effect on invasion and migration abilities of PCa cells. Importantly, upregulating miR-532-3p repressed bone metastasis of PCa cells in vivo. Our results further demonstrated that overexpression of miR-532-3p inhibited activation of nuclear facto kB (NF-kB) signaling via simultaneously targeting tumor necrosis factor receptor-associated factor 1 (TRAF1), TRAF2, and TRAF4, which further promoted invasion, migration, and bone metastasis of PCa cells. Therefore, our findings reveal a novel mechanism contributing to the sustained activity of NF-kB signaling underlying the bone metastasis of PCa.
Though diabetes mellitus (DM) is one of the known causes of osteoporosis, it is also realized that ketogenic diet (KD), an effective regimen for epilepsy, impairs bone microstructures. However, the similarities and differences of effects between these two factors are still unknown. The purpose of this study is to identify different effects between hyperglycemia and hyperketonemia, which are manifestations of DM and KD, on bone in rats. Thirty male Sprague-Dawley rats were randomly divided into three groups: the sham, DM, and KD groups. Hyperglycemia was achieved by intravenous injection of streptozotocin in DM group, while hyperketonemia was induced by application of ketogenic diet (carbohydrates-to-fat as 1:3) in KD group. The body weight, blood ketone body, and blood glucose were recorded, and the bone turnover markers, bone length, bone microstructures, bone biomechanics and histomorphology were measured after 12 weeks intervention. Compared with the control and KD groups, a significant body weight loss was found in the DM group, and the bone lengths of tibia and femur of the group were shortened. The blood glucose and blood ketone were noticeably increased in the DM and KD rats, respectively. Microstructures and properties of cancellous bone were significantly deteriorated in both the DM and KD groups compared with the sham group, as the bone volumes were decreased and the bone trabecula structures were disturbed. Meanwhile, the thickness and strength of cortical bone was reduced more in the DM group than those in the sham and KD groups. The HE staining showed that bone trabecula was significantly decreased in both the DM and KD groups, and more adipose tissue was observed in the KD rats. The activity of osteoblasts was decreased more in both the KD and DM groups than that in the sham group, while the activity of osteoclasts of the two groups was remarkably increased. The present study indicates that both hyperglycemia and hyperketonemia have adverse effects on bone. Therefore, it is worth paying more attention to the bone status of patients with hyperglycemia and hyperketonemia in clinic.
Icaritin, a metabolite of icariin, is a potent promoter of bone marrow-derived mesenchymal stem cells (BMScs) osteogenesis, but the underlying mechanisms remain unclear. To examine the effects of icaritin on osteogenic differentiation, BMScs were exposed to osteogenic induction medium with or without icaritin pretreatment in the present study. It was identified that icaritin (0.01-1 µM) exhibited no cytotoxicity on the proliferative abilities of the BMScs. Icaritin at 1 µM increased alkaline phosphatase activity, mineral deposition and osteoblast-specific gene expression. Treatment with 1 µM Icaritin upregulated osteocalcin, RUNX family transcription factor 2, tissue-nonspecific alkaline phosphatase and β-catenin, and suppressed sclerostin (SOST) gene expression in different stages of osteogenic differentiation. It was also demonstrated that SOST overexpression inhibited icaritin-induced osteogenesis. The western blot analysis data suggested that IcI 182780, which causes estrogen receptor α (ERα) degradation, reversed the icaritin-induced decrease in SOST expression, which was inconsistent with the results of immunofluorescence analysis. In conclusion, icaritin was demonstrated to promote the osteogenesis of hBMScs by downregulating SOST expression, and icaritin-induced suppression of SOST was regulated in part via the Wnt/β-catenin/ERα axis.
Granulocyte colony-stimulating factor (G-CSF) is one of the most critical cytokines used for the treatment of acute radiation syndrome (ARS). In addition to the hematopoietic effects of G-CSF on the differentiation and proliferation of myeloid progenitor cells, G-CSF is also known to have immunomodulatory effects. The aim of the present study was to investigate whether G-CSF could accelerate central and peripheral T lymphocyte recovery after a sublethal dose of irradiation. Female BALB/c mice were subjected to 6 Gy of total body irradiation and then were treated with either 100 μg/kg G-CSF or an equal volume of PBS once daily for 14 days. Percentages of thymocyte subpopulations including CD4 − CD8 − , CD4 + CD8 + , CD4 + CD8− and CD4 − CD8+ T cells, peripheral CD3 + , CD4+ and CD8+ cells were analyzed by flow cytometry. Recent thymic emigrants (RTEs) were assessed by real-time polymerase chain reaction (PCR) using primers specific to the 257-bp T cell receptor rearrangement excision circles (sjTRECs). The proliferative capacity of splenic mononuclear cells upon exposure to ConA was measured by using the Cell Count Kit-8 (CCK-8). G-CSF treatment promoted thymocyte regeneration, accelerated the recovery of CD4 + CD8+ cells and increased the frequency of thymocyte sjTRECs. These effects were more prominent at early time points (Day 28) after irradiation. G-CSF also increased the rate of recovery of peripheral CD3 + , CD4+ and CD8+ cells and shortened the period of severe lymphopenia following irradiation. G-CSF also increased the splenic mononuclear cell mitotic responsiveness to ConA more than control-treated cells. Our results show that G-CSF accelerates T cell recovery through both thymic-dependent and thymic-independent pathways, which could be used to increase the rate of immune reconstitution after sublethal irradiation.
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