Current Issue : July - September Volume : 2017 Issue Number : 3 Articles : 6 Articles
Background: Antiangiogenic therapies are considered promising for the treatment of glioblastoma (GB). The noncollagenous\nC-terminal globular NC1 domain of type VIII collagen a1 chain, Vastatin, is an endogenous antiangiogenic\npolypeptide. Sustained enhanced expression of Vastatin was shown to inhibit tumour growth and metastasis in murine\nhepatocellular carcinoma models. In this study, we further explored the efficacy of Vastatin in the treatment of GB\nxenografts.\nMethod: Treatment of Vastatin was carried out using a nanopolymer gene vector PEI600-CyD-Folate (H1). Antiangiogenic\neffect of Vastatin was tested in vitro by using co-culture system and conditioned medium. An orthotopic GB murine\nmodel was established to examine the in vivo therapeutic effect of Vastatin alone treatment and its combination with\ntemozolomide.\nResults: Vastatin gene transfection mediated by H1 could target tumour cells specifically and suppress the\nproliferation of microvessel endothelial cells (MECs) through a paracrine inhibition manner. Enhancing Vastatin\nexpression by intracerebral injection of H1-Vastatin significantly prolonged animal survival from 48 to 75 days in\nGB murine model, which was comparable to the effect of Endostatin, the most studied endogenous antiangiogenic\npolypeptide. The diminished presence of CD34 positive cells in the GB xenografts suggested that Vastatin induced\nsignificant antiangiogenesis. Moreover, a synergistic effect in extending survival was detected when H1-Vastatin was\nadministered with temozolomide (TMZ) in GB chemoresistant murine models.\nConclusion: Our results suggest, for the first time, that Vastatin is an antiangiogenic polypeptide with significant potential\ntherapeutic benefit for GB. H1-Vastatin gene therapy may have important implications in re-sensitizing recurrent GB to\nstandard chemotherapeutic agents....
Fibroblast growth factor 21 (FGF21) is a metabolic hormone with multiple beneficial effects on lipid and glucose homeostasis.\nPrevious study demonstrated that FGF21 might be one of the Sp1 target genes. However, the transcriptional role of Sp1 on FGF21\nin adipose tissue and liver has not been reported. In this study, we found that the proximal promoter of mouse FGF21 is located\nbetween âË?â??63 and âË?â??20 containing two putative Sp1-binding sites. Sp1 is a mammalian transcription factor involved in the regulation\nof many genes during physiological and pathological processes. Our study showed that overexpression of Sp1 or suppressing Sp1\nexpression resulted in increased or reduced FGF21 promoter activity, respectively. Mutation analysis demonstrated that the Sp1-\nbinding site located between âË?â??46 and âË?â??38 plays a primary role in transcription of FGF21. Electrophoretic mobility shift assay and\nchromatin immunoprecipitation analysis indicated that Sp1 specifically bound to this region. Furthermore, the binding activity of\nSp1 was significantly increased in adipose tissues of HFD-induced obese mouse and liver of DEN-treated mouse.Thus, our results\ndemonstrate that Sp1 positively regulates the basal transcription of FGF21 in the liver and adipose tissue and contributes to the\nobesity-induced FGF21 upregulation in mouse adipose tissue and hepatic FGF21 upregulation in hepatocarcinogenesis....
Background: The purpose of this study was to investigate the therapeutic efficacy of intravenously administered\nimmunoselected STRO-3 + mesenchymal precursor cells (MPCs) on clinical scores, joint pathology and cytokine\nproduction in an ovine model of monoarthritis.\nMethods: Monoarthritis was established in 16 adult merino sheep by administration of bovine type II collagen into\nthe left hock joint following initial sensitization to this antigen. After 24 h, sheep were administered either 150\nmillion allogeneic ovine MPCs (n = 8) or saline (n = 8) intravenously (IV). Lameness, joint swelling and pain were\nmonitored and blood samples for leukocytes and cytokine levels were collected at intervals following arthritis\ninduction. Animals were necropsied 14 days after arthritis induction and gross and histopathological evaluations\nwere undertaken on tissues from the arthritic (left) and contralateral (right) joints.\nResults: MPC-treated sheep demonstrated significantly reduced clinical signs of lameness, joint pain and swelling\ncompared with saline controls. They also showed decreased cartilage erosions, synovial stromal cell activation and\nangiogenesis. This was accompanied by decreased infiltration of the synovial tissues by CD4+ lymphocytes and CD14+\nmonocytes/macrophages. Over the 3 days following joint arthropathy induction, the numbers of neutrophils circulating in\nthe blood and plasma concentrations of activin A were significantly reduced in animals administered MPCs.\nConclusions: The results of this study have demonstrated the capacity of IV-administered MPCs to mitigate the clinical\nsigns and some of the inflammatory mediators responsible for joint tissue destruction in a large animal model of\nmonoarthritis....
Background: MicroRNAs have emerged as an important class of modulators of gene expression. These molecules\ninfluence protein synthesis through translational repression or degradation of mRNA transcripts. Herein, we investigated\nthe potential role of miR-142a isoforms, miR-142a-3p and miR-142a-5p, in the context of autoimmune neuroinflammation.\nMethods: The expression levels of two mature isoforms of miR-142 were measured in the brains of patients with multiple\nsclerosis (MS) and the CNS tissues from mice with experimental autoimmune encephalomyelitis (EAE), an animal model\nof MS. Expression analyses were also performed in mitogen and antigen-stimulated splenocytes, as well as macrophages\nand astrocytes using real-time RT-PCR. The role of the mature miRNAs was then investigated in T cell differentiation by\ntransfection of CD4+ T cells, followed by flow cytometric analysis of intracellular cytokines. Luciferase assays using vectors\ncontaining the 3�UTR of predicted targets were performed to confirm the interaction of miRNA sequences with transcripts.\nExpression of targets were then analyzed in activated splenocytes and MS/EAE tissues.\nResults: Expression of miR-142-5p was significantly increased in the frontal white matter from MS patients\ncompared with white matter from non-MS controls. Likewise, expression levels of miR-142a-5p and miR-142a-3p showed\nsignificant upregulation in the spinal cords of EAE mice at days 15 and 25 post disease induction. Splenocytes stimulated\nwith myelin oligodendrocyte glycoprotein (MOG) peptide or anti-CD3/anti-CD28 antibodies showed upregulation\nof miR-142a-5p and miR-142a-3p isoforms, whereas stimulated bone marrow-derived macrophages and primary\nastrocytes did not show any significant changes in miRNA expression levels. miR-142a-5p overexpression in activated\nlymphocytes shifted the pattern of T cell differentiation towards Th1 cells. Luciferase assays revealed SOCS1 and\nTGFBR1 as direct targets of miR-142a-5p and miR-142a-3p, respectively, and overexpression of miRNA mimic sequences\nsuppressed the expression of these target transcripts in lymphocytes. SOCS1 levels were also diminished in MS white\nmatter and EAE spinal cords.\nConclusions: Our findings suggest that increased expression of miR-142 isoforms might be involved in the pathogenesis\nof autoimmune neuroinflammation by influencing T cell differentiation, and this effect could be mediated by interaction\nof miR-142 isoforms with SOCS1 and TGFBR-1 transcripts....
Background: Cardiac fibrosis play a key role in the atrial fibrillation pathogenesis but the underlying potential\nmolecular mechanism is still understood. However, potential mechanisms for miR-21 upregulation and its role in\ncardiac fibrosis remain unclear. The controls cell proliferation and processes fundamental to disease progression.\nMethods: In this study, immunohistochemistry, real-time RT-PCR, cell transfection, cell cycle, cell proliferation and\nWestern blot were used, respectively.\nResults: Here we have been demonstrated that the tumor suppressor cell adhesion molecule 1 (CADM1) is the\npotential target of miR-21. Our study revealed that miR-21 regulation of CADM1 expression, which was decreased\nin cardiac fibroblasts and fibrosis tissue. The cardiac fibroblasts transfected with miR-21 mimic promoted miR-21\noverexpression enhanced STAT3 expression and decreased CADM1 expression. Nevertheless, the cardiac fibroblasts\ntransfected with miR-21 inhibitor obtained the opposite expression result. Furthermore, downexpression of miR-21\nsuppressed cardiac fibroblast proliferation.\nConclusions: These results suggested that miR-21 overexpression promotes cardiac fibrosis via STAT3 signaling\npathway by decrease CADM1 expression, indicating miR-21 as an important signaling molecule for cardiac fibrotic\nremodeling and AF....
Acute liver failure is a complex and fatal disease. Cell-based therapies are a promising alternative therapeutic approach for liver\nfailure due to relatively simple technique and lower cost. The use of semipermeable microcapsules has become an interesting tool\nfor evaluating paracrine effects in vivo. In this study, we aimed to assess the paracrine effects of bone marrow mononuclear cells\n(BMMC) encapsulated in sodium alginate to treat acute liver failure in an animal model of 90% partial hepatectomy (90% PH).\nEncapsulated BMMC were able to increase 10-day survival without enhancing liver regeneration markers. Gene expression of Il-6\nand Il-10 in the remnant liver was markedly reduced at 6 h after 90% PH in animals receiving encapsulated BMMC compared to\ncontrols. This difference, however, was neither reflected by changes in the number of CD68+ cells nor by serum levels of IL6. On\nthe other hand, treated animals presented increased caspase activity and gene expression in the liver. Taken together, these results\nsuggest that BMMCregulate immune response and promote apoptosis in the liver after 90%PHby paracrine factors. These changes\nultimately may be related to the higher survival observed in treated animals, suggesting thatBMMCmay be a promising alternative\nto treat acute liver failure....
Loading....