Journal of molecular medicine : official organ of the "Gesellschaft Deutscher Naturforscher und Ärzte"
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MicroRNAs (miRNAs) are about 20-22 nucleotide conserved non-coding RNA molecules that post-transcriptionally regulate gene expression by targeting the 3'-untranslated region of specific messenger RNAs (mRNAs) for degradation or translational repression. During the last two decades, miRNAs have emerged as critical regulators of a range of biological processes including immune cell lineage commitment, differentiation, maturation, and immune signaling pathways. The endoribonucleases such as Dicer, which is required for miRNA biogenesis, has also been shown to play an important role in inflammatory response and autoimmunity. ⋯ In this review, we will discuss recent advances in miRNAs mediated regulation of inflammatory responses and autoimmune pathogenesis. Specifically, we will discuss how miRNAs regulate autoimmunity through affecting the development, differentiation, and function of various cell types such as innate immune cells, adaptive immune cells and local resident cells. The identification of distinct miRNA expression patterns, and a comprehensive understanding of the roles of those dysregulated miRNAs in inflammatory autoimmune pathogenesis offers inspirations of not only potential molecular diagnostic markers but also novel therapeutic strategies for treating inflammatory autoimmune diseases.
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Glioblastoma multiforme (GBM) is the most malignant brain tumor and highly resistant to intensive combination therapies. GBM is one of the most vascularized tumors and vascular endothelial growth factor (VEGF) produced by tumor cells is a major factor regulating angiogenesis. Successful results of preclinical studies of anti-angiogenic therapies using xenograft mouse models of human GBM cell lines encouraged clinical studies of anti-angiogenic drugs, such as bevacizumab (Avastin), an anti-VEGF antibody. ⋯ Enhanced invasiveness is one such resistance mechanism and recent works report the contribution of activated MET signaling induced by inhibition of VEGF signaling. On the other hand, tumor cell-originated neovascularization including tumor-derived endothelial cell-induced angiogenesis and vasculogenic mimicry has been suggested to be involved in the resistance to anti-VEGF therapy. Therefore, these mechanisms should be targeted in addition to anti-angiogenic therapies to achieve better results for patients with GBM.
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Congenital polycythemias have diverse etiologies, including mutations in the hypoxia sensing pathway. These include HIF2A at exon 12, VHL gene (Chuvash polycythemia), and PHD2 mutations, which in one family was also associated with recurrent pheochromocytoma/paraganglioma (PHEO/PGL). ⋯ We show that this is a gain-of-function mutation and demonstrate no loss-of-heterozygosity or additional somatic mutation of HIF2A in the tumor, indicating HIF2A (F374Y) may be predisposing rather than causative of PHEO/PGL. This report, in view of two other concomitantly reported PHEO/PGL patients with somatic mutations of HIF2A and polycythemia, underscores the PHEO/PGL-promoting potential of mutations of HIF2A that alone are not sufficient for PHEO/PGL development.
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In Chuvash polycythemia, a homozygous 598C>T mutation in the von Hippel-Lindau gene (VHL) leads to an R200W substitution in VHL protein, impaired degradation of α-subunits of hypoxia-inducible factor (HIF)-1 and HIF-2, and augmented hypoxic responses during normoxia. Chronic hypoxia of high altitude is associated with decreased serum glucose and insulin concentrations. Other investigators reported that HIF-1 promotes cellular glucose uptake by increased expression of GLUT1 and increased glycolysis by increased expression of enzymes such as PDK. ⋯ Hepatic expression of Glut2 and G6pc, but not Pdk2, was decreased, and skeletal muscle expression of Glut1, Pdk1, and Pdk4 was increased. These results suggest that both decreased hepatic gluconeogenesis and increased skeletal uptake and glycolysis contribute to the decreased glucose concentrations. Further study is needed to determine whether pharmacologically manipulating HIF expression might be beneficial for treatment of diabetic patients.