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The hypoxia-inducible factors have recently been identified as critical regulators of angiogenic-osteogenic coupling. Mice overexpressing HIFalpha subunits in osteoblasts produce abundant VEGF and develop extremely dense, highly v...
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The hypoxia-inducible factors have recently been identified as critical regulators of angiogenic-osteogenic coupling. Mice overexpressing HIFalpha subunits in osteoblasts produce abundant VEGF and develop extremely dense, highly vascularized long bones. In this study, we investigated the individual contributions of Hif-1alpha and Hif-2alpha in angiogenesis and osteogenesis by individually disrupting each Hifalpha gene in osteoblasts using the Cre-loxP method. Mice lacking Hif-1alpha demonstrated markedly decreased trabecular bone volume, reduced bone formation rate, and altered cortical bone architecture. By contrast, mice lacking Hif-2alpha had only a modest decrease in trabecular bone volume. Interestingly, long bone blood vessel development measured by angiography was decreased by a similar degree in both DeltaHif-1alpha and DeltaHif-2alpha mice suggesting a common role for these Hifalpha subunits in skeletal angiogenesis. In agreement with this idea, osteoblasts lacking either Hif-1alpha or Hif-2alpha had profound reductions in VEGF mRNA expression but only the loss of Hif-1alpha impaired osteoblast proliferation. These findings indicate that expression of both Hif-1alpha and Hif-2alpha by osteoblasts is required for long bone development. We propose that both Hif-1alpha and Hif-2alpha function through cell non-autonomous modes to promote vascularization of bone and that Hif-1alpha also promotes bone formation by exerting direct actions on the osteoblast.
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Doping with different trace elements can significantly change the original degradability, mineralization, and biological properties of bone repair material. According to the fundamental research on prepared calcium polyphosphate (...
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Doping with different trace elements can significantly change the original degradability, mineralization, and biological properties of bone repair material. According to the fundamental research on prepared calcium polyphosphate (CPP) as a bone repair material by our group, this article began further exploration on the effect of doping different trace elements (K, Na, Mg, Zn, Sr) into CPP on its degradability and mineralization soaking in simulated body fluids. The results indicated that doped elements significantly changed the lattice parameters and cell volume of crystal, resulted in different types of crystal defect and surface charge distribution, and consequently changed the original degradability and mineralization of CPP. The conclusion is that doped ions with relatively smaller ionic radius and equivalent positive charge compared with Ca(2+) can greatly promote the degradability and mineralization of CPP, whereas doped ions with equivalent ionic radius and diverse positive charges compared with Ca(2+) provide less contribution on promoting the degradability and mineralization or even counteract.
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To identify new biomarkers that facilitate the accurate early diagnosis of osteosarcoma and that may possibly include novel therapeutic candidates, we performed a proteomic approach to compare osteosarcoma cells and human primary ...
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To identify new biomarkers that facilitate the accurate early diagnosis of osteosarcoma and that may possibly include novel therapeutic candidates, we performed a proteomic approach to compare osteosarcoma cells and human primary cultured osteoblastic cells. Image analysis of silver-stained 2-DE gels revealed that the level of 12 protein spots was significantly different between the two groups of samples (p < .004). After mass spectroscopic identification and database searches, we found that in osteosarcoma cells, the level of HSP70, actin capping protein, ATP synthase, Mthsp75, UQCRC1, Ras-related nuclear protein, UCH-L1, and PRDX4 was elevated. However, the level of pyruvate dehydrogenase E1, Prohibitin, and Annexin V was decreased. Subsequent Western blot analyses of UQCRC1, UCH-L1, and PRDX4 in osteosarcoma tissues confirmed the results obtained by the proteomic analyses. These identified proteins may be potential molecular targets for osteosarcomatous diagnostics and therapeutics.
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Skeletal trauma and impaired skeletal healing is commonly associated with diminished vascularity. Hypoxia inducible factor alpha (HIF-1) is a key transcription factor responsible for activating angiogenic factors during developmen...
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Skeletal trauma and impaired skeletal healing is commonly associated with diminished vascularity. Hypoxia inducible factor alpha (HIF-1) is a key transcription factor responsible for activating angiogenic factors during development and tissue repair. Small molecule inhibitors of the prolyl hydroxylase enzyme (PHD), the key enzyme responsible for degrading HIF-1, have been shown to activate HIF-1, and are effective in inducing angiogenesis. Here we examined the effects of several commercially available PHD inhibitors on bone marrow mesenchymal stromal cells (MSCs) in vitro and in a stabilized fracture model in vivo. Three PHD inhibitors [Desferrioxamine (DFO), L-mimosine (L-mim), and Dimethyloxalylglycine (DMOG)] effectively activated a HIF-1 target reporter, induced expression of vascular endothelial growth factor (VEGF) mRNA in vitro, and increased capillary sprouting in a functional angiogenesis assay. DFO and DMOG were applied by direct injection at the fracture site in a stabilized murine femur fracture model. PHD inhibition increased the vascularity at 14 days and increased callus size as assessed by microCT at 28 days. These results suggest that HIF activation is a viable approach to increase vascularity and bone formation following skeletal trauma.
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Classical swine fever virus (CSFV) is capable of counteracting innate cellular antiviral responses by inhibiting type I interferon (IFN)-alpha/beta induction. A function associated with CSFV N(pro), with respect to the inhibition ...
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Classical swine fever virus (CSFV) is capable of counteracting innate cellular antiviral responses by inhibiting type I interferon (IFN)-alpha/beta induction. A function associated with CSFV N(pro), with respect to the inhibition of IFN-beta production, has been clearly elucidated. In this study, we explored the role of CSFV E(rns) in IFN-beta induction by exogenous double-stranded (ds) RNA. Synthetic dsRNA (poly (IC)) was used as an exogenous stimulus to trigger IFN-beta induction. CSFV E(rns) inhibited IFN-beta promoter-driven luciferase activity induced by poly (IC) in different cell lines, and the inhibitory effect was dose-dependent. Moreover, E(rns) reduced IFN-beta mRNA synthesis and blocked IFN-alpha/beta production induced by poly (IC), suggesting that this inhibition occurs at the transcriptional level. Furthermore, E(rns) counteracted poly (IC)-mediated IFN-beta induction independent of its ribonuclease activity. In conclusion, CSFV E(rns) antagonizes extracellular dsRNA-mediated IFN-beta expression. These findings contribute to our understanding of the pathogenesis of CSFV.
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BACKGROUND AND OBJECTIVE: Extreme haemodilution occurring with cardiopulmonary bypass imposes a primary risk factor for blood transfusion in small adult cardiac surgical patients. Priming of the cardiopulmonary bypass circuit with...
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BACKGROUND AND OBJECTIVE: Extreme haemodilution occurring with cardiopulmonary bypass imposes a primary risk factor for blood transfusion in small adult cardiac surgical patients. Priming of the cardiopulmonary bypass circuit with patients' own blood [retrograde autologous priming (RAP)] is a technique used to limit haemodilution and reduce transfusion requirements. We designed this study to evaluate the effects of RAP on reducing perioperative blood transfusion in small adults. METHODS: One hundred and twenty patients with a body surface area of less than 1.5 m undergoing first-time, nonemergency cardiac surgery were randomized to either the standard priming group or the RAP group. All patients followed strict transfusion criteria. Homologous transfusion, haematocrit, plasma colloid osmotic pressure and postoperative clinical outcomes were evaluated perioperatively. RESULTS: Patient characteristics and operative parameters were equal for patients in both groups. With autologous priming, a mean volume of 614.8 +/- 138.8 ml of priming solution was replaced with autologous blood. This allowed a significantly higher haematocrit value during cardiopulmonary bypass (P < 0.05). Red blood cell transfusion was necessary in 83.3% of patients of the standard priming group on pump, whereas only 26.7% of patients of the RAP group required transfusion (P < 0.01). The overall transfusion rate of the RAP group was significantly less than that in the standard priming group during the hospitalization (90.0 vs. 50.0%, P < 0.01). Amongst patients who received transfusion on pump, the number of homologous units of packed red blood cells was less in the RAP group than that in the standard priming group intraoperatively and perioperatively (0.94 +/- 0.32 vs. 1.48 +/- 0.68 units, P = 0.03; 1.24 +/- 0.54 vs. 1.69 +/- 0.69 units, P = 0.15). Ten minutes after aortic cross-clamp, colloid osmotic pressure was reduced by 39.7 +/- 2.8% in the standard priming group and by 28.6 +/- 3.2% in the RAP group (P < 0.05). Clinical outcomes were similar with respect to pulmonary, renal and hepatic function, length of ICU stay and hospital stay. CONCLUSION: RAP resulted in a significant decrease in intraoperative haemodilution and conserved the use of blood. This technique should be considered for patients with a small body surface area (<1.5 m) undergoing open heart surgery.
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Host cells sense double-stranded RNA (dsRNA) produced during viral replication and initiate type I interferon (IFN-alpha/beta) production, leading to subsequent antiviral responses. Many viruses, including classical swine fever vi...
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Host cells sense double-stranded RNA (dsRNA) produced during viral replication and initiate type I interferon (IFN-alpha/beta) production, leading to subsequent antiviral responses. Many viruses, including classical swine fever virus (CSFV), have developed strategies for counteracting the IFN-alpha/beta response. In this study, we explored the role of the CSFV E(rns) glycoprotein in the inhibition of IFN-beta production induced by dsRNA [poly(IC)]. Our results demonstrated that CSFV E(rns) could bind to exogenous dsRNA and inhibit dsRNA-induced IFN-beta production but failed to inhibit TRIF-triggered IFN-beta production. Our data suggest that the inhibition of IFN-beta induction occurred at the initial step of the TLR3 signaling pathway. We also showed that deglycosylation of E(rns) rendered it unable to bind to dsRNA, and thus unable to inhibit dsRNA-induced IFN-beta production. Taken together, these results indicated that N-glycan of CSFV E(rns) is essential for E(rns) blocking of IFN-beta induction.
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