Experimental cell research
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FGF23 is a bone-derived hormone that regulates systemic phosphate homeostasis, vitamin D metabolism and α-Klotho expression through a novel bone-kidney axis. FGF23 inhibits renal tubular reabsorption of phosphate through mechanisms independent of PTH as well as reduces circulating 1, 25(OH)(2)D through its dual effects to suppress Cyp27b1 production and to stimulate Cyp24 catabolism of 1,25(OH)(2)D. 1,25(OH)(2)D and other factors regulating bone remodeling/mineralization are the major physiological regulators of FGF23 expression. FGF23 also suppresses the gene transcription of α-klotho by the kidney, which exists as a membrane and soluble protein. ⋯ In addition, the prevalent thought that CKD is a functional "vitamin D deficient state" requiring therapy with 1,25(OH)(2)D analogs is challenged by effects of FGF23 to potentially lower both 25(OH)D and 1,25(OH)D by induction of Cyp24-mediated degradation. Finally, increments in FGF23 are associated with increased cardiovascular mortality in CKD. Whether these effects represent direct effects of FGF23 or represent a marker of other abnormalities in CKD remains to be determined.
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Angiopoietins are ligands of the Tie2 receptor that control angiogenic remodeling in a context-dependent manner. Tie signaling is involved in multiple steps of the angiogenic remodeling process during development, including destabilization of existing vessels, endothelial cell migration, tube formation and the subsequent stabilization of newly formed tubes by mesenchymal cells. ⋯ Signaling through the Tie1 receptor is not well understood, but Tie1 may have both angiopoietin-dependent and ligand-independent functions. Changes in the expression of Tie receptors and angiopoietins occur in many pathological conditions, and mutations in the Tie2 gene are found in familial cases of vascular disease.
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Currently, most of the approved clinical gene therapy protocols involve cancer patients and several of the therapies are designed to treat brain tumors. Two factors promoting the use of gene therapy for gliomas are the failure and toxicity of conventional therapies and the identification of the genetic abnormalities that contribute to the malignancy of gliomas. During the malignant progression of astrocitic tumors several tumor suppressor genes are inactivated, and numerous growth factors and oncogenes are overexpressed progressively. ⋯ In the second part, we will review the evolution of adenoviruses as gene vehicles. In addition, we will examine the role of recombinant mutant oncolytic adenoviruses as anticancer tools. From the results to date it is clear that gene therapy strategies for brain tumors are quite promising but more critical research is required, mainly in the vector field, if the strategies are to achieve their true potential in ameliorating patients with gliomas.