Forkhead box-O (FOXO) transcription factors have a fundamental role in the development and differentiation of immune cells. FOXO1 and FOXO3 are FOXO members that are structurally similar and bind to the same conserved consensus DNA sequences to induce transcription. FOXO1 has been studied in detail in the activation of dendritic cells (DCs), where it plays an important role through the regulation of target genes such as ICAM-1, CCR7, and the integrin αvβ3. FOXO1 is activated by bacteria challenge in DCs and promotes DC bacterial phagocytosis, migration, homing to lymph nodes, DC stimulation of CD4+ T cells and resting B cells, and antibody production. Deletion of FOXO1 in DCs enhances susceptibility to bacteria-induced periodontal disease. FOXO1 and FOXO3 maintain naive T cell quiescence and survival. FOXO1 and FOXO3 enhance the formation of regulatory T cells and inhibit the formation of T-helper 1 (Th1) and Th17 cells. FOXO1 promotes differentiation, proliferation, survival, immunoglobulin gene rearrangement, and class switching in B cells, but FOXO3 has little effect. Both FOXO1 and FOXO3 are important in the maintenance of hematopoietic stem cells by protecting them from oxidative stress. This review examines FOXO1/FOXO3 in the adaptive immune response, key target genes, and FOXO inhibition by the phosphoinositide 3-kinase/AKT pathway.
In an attempt to overcome the limitations of titanium in dental and orthopaedic clinical applications, a new method has been developed to prepare calcium carbonate coatings on sandblasted and acid-etched (SA) titanium implants. The purpose of this study was to investigate the effect of calcium carbonate-SA (CC-SA) implants on osseointegration in vivo. The surfaces of SA and CC-SA implants were characterised for surface morphology and surface chemistry. Subsequently, these two kinds of implants were implanted in the femoral condyles of rabbits. The implants were retrieved and prepared for histological and histomorphometric evaluation 1, 2, 4, 8 and 12 weeks after implantation. Significantly higher values of bone-to-implant contact of the entire implant except the gap area (BIC_ALL) and the bone-to-implant contact of the gap area (BIC_GAP) were found in animals with the CC-SA implants than in those with the SA implants at 4 weeks. Higher values of total gap bone were found in those with the CC-SA implants than in those with the SA implants at 1, 2 and 4 weeks. In conclusion, the current findings demonstrate that the calcium carbonate coating can improve and accelerate the early ingrowth of bone and osseointegration at the early healing phase. This may reduce clinical healing times and thus improve implant success rates.
Mesenchymal stemXin cells (MSCs) are a great cell source for bone regeneration. Although combining MSCs with growth factors and scaffolds provides a useful clinical strategy for bone tissue engineering, the efficiency of MSC osteogenic differentiation remains to be improved. Epigenetic modification is related to the differentiation ability of MSCs during osteogenic induction. In this study, we evaluate the effect of Chaetocin, an inhibitor of lysine-specific histone methyltransferases, on the differentiation of MSCs. We found that MSCs treated with Chaetocin demonstrated increased osteogenic ability and reduced adipogenic ability. The expression of osteogenic markers (Runx2 and OPN) was induced in MSCs by Chaetocin during osteogenic induction. Moveover, treatment of Chaetocin in MSCs improves Wnt/β-catenin signaling pathways and its downstream targets. Finally, we showed increased bone formation of MSC and Wnt/β-catenin signaling activity by treatment of Chaetocin using in vivo bone formation assays. Our data uncovered a critical role of Chaetocin in MSC osteogenic differentiation and provide new insights into bone tissue regeneration and repair.
BackgroundRenal cell carcinoma (RCC) is the most common kidney cancer, accounting for approximately 80–90% of all primary kidney cancer. Treatment for patients with advanced RCC remains unsatisfactory. Rare cancer stem cells (CSCs) are proposed to be responsible for failure of current treatment.MethodsOncoLnc was used as a tool for interactively exploring survival correlations. Gene manipulation and expression analysis were carried out using siRNA, RT-PCR and Western blotting. Wound healing and invasion assays were used for phenotypical characterization. Aldefluor assay and FACS sorting Sphere culture were used to determine the “stemness” of CSCs. Co-Immunoprecipitation (Co-IP) was used to examine the interaction between OCT4 and CBFA2T2. Student’s t-test and Chi square test was used to analyze statistical significance.ResultsCBFA2T2 expression can significantly predict the survival of RCC patients. Knocking-down of CBFA2T2 can inhibit cell migration and invasion in RCC cells in vitro, and reduce ALDHhigh CSCs populations. CBFA2T2 expression is necessary for sphere-forming ability and cancer stem cells marker expression in RCC cell lines.ConclusionsOur data suggest that CBFA2T2 expression correlates with aggressive characteristics of RCC and CBFA2T2 is required for maintenance of “stemness” through regulation of stem cells factors, thereby highlighting CBFA2T2 as a potential therapeutic target for RCC treatment.Electronic supplementary materialThe online version of this article (10.1186/s12935-017-0473-z) contains supplementary material, which is available to authorized users.
Both LIF and LIFR exist in the periodontal tissue, and continuous orthodontic forces induce the upregulation of LIF/LIFR production, suggesting that LIF/LIFR may play important roles in periodontium remodeling.
This research investigated osteogenic potencies of Farthing-Fray-Chen Titanium (FFcTi) implant with transitional porous-solid structure. The material characteristics, biomechanical property, osteogenic performances were assessed. FFcTi showed similar roughness as sand-blasted and acid etched titanium (SA), but was more hydrophilic than SA and machined commercial pure titanium (MA). Young's modulus of FFcTi implant in compressive tests was 15.8 ± 6.3 GPa, which was close to bone. In vitro observations manifested excellent spreading abilities of MC3T3-E1 cell on FFcTi and SA. Adhesion rates of MC3T3-E1 cells at 4 h gradually decreased on MA, SA, and FFcTi surfaces (MA > SA, p < 0.01; SA > FFcTi, p < 0.05), while cell proliferation ability on FFcTi was weaker than MA during 1-6 days (p < 0.01) and similar to MA and SA in day 11. ALP activity of cells on FFcTi at 14 day was higher than MA and lower than SA (p < 0.01). In a bone defect model of rabbits, BIC and bone volum ratio within 50 μm were significantly higher for FFcTi than MA (BIC, p < 0.01; BT0.05, p < 0.05) while bone volume ratio within 100 and 500 μm were of no differences. Micro CT analysis also showed similar results to the histomorphometric data. Thus, we conclude that FFcTi with melting sphere based multiporous structure has a hydrophilic, rough surface, and close modulus to bone. In vitro, its low proliferation and ALP activity promotion were similar to other micro scale roughed surface. In vivo test showed better osteogenesis ability when compared with MA at least in 2 weeks. Thus, this Farthing-Fray-Chen Titanium implant seems to hold considerable potential for bone implant applications.
Objective. Transplantation of bone marrow-derived mesenchymal stem cells (BMSCs) remains a hopeful therapeutic approach for bone defect reconstruction. Herein, we investigated the effects and mechanisms of leukemia inhibitory factor (LIF) in the function and viability of hypoxic BMSCs as well as bone defect repair. Methods. The effects of LIF on apoptosis (flow cytometry, TUNEL staining), mitochondrial activity (JC-1 staining), proliferation (colony formation, EdU staining), and differentiation (CD105, CD90, and CD29 via flow sorting) were examined in hypoxic BMSCs. LIF, LIFR, gp130, Keap1, Nrf2, antioxidant enzymes (SOD1, catalase, GPx-3), bone-specific matrix proteins (ALP, BSP, OCN), PI3K, and Akt were detected via immunoblotting or immunofluorescent staining. BMSCs combined with biphasic calcium phosphate scaffolds were implanted into calvarial bone defect mice, and the therapeutic effect of LIF on bone defect was investigated. Results. Hypoxic BMSCs had increased apoptosis and oxidative stress and reduced mitochondrial activity. Additionally, LIF, LIFR, and gp130 were upregulated and PI3K/Akt activity was depressed in hypoxic BMSCs. Upregulated LIF alleviated apoptosis and oxidative stress and heightened mitochondrial activity and PI3K/Akt signaling in hypoxic BMSCs. Additionally, LIF overexpression promoted self-renewal and osteogenic differentiation of BMSCs with hypoxic condition. Mechanically, LIF facilitated self-renewal and differentiation as well as attenuated oxidative stress of BMSCs through enhancing PI3K/AKT signaling activity. Implantation of LIF-overexpressed BMSC-loaded BCP scaffolds promoted osteogenesis as well as alleviated oxidative stress and apoptosis through PI3K/Akt signaling. Conclusion. Our findings demonstrate that LIF facilitates self-renewal and differentiation and attenuates oxidative stress of BMSCs by PI3K/AKT signaling.
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