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Osteoporosis, a leading cause of morbidity in the elderly, is characterized by progressive loss of bone mass resulting from excess osteoclastic bone resorption relative to osteoblastic bone formation. Here we identify Vav3, a Rho family guanine nucleotide exchange factor, as essential for stimulated osteoclast activation and bone density in vivo. Vav3-deficient osteoclasts show defective actin cytoskeleton organization, polarization, spreading and resorptive activity resulting from impaired signaling downstream of the M-CSF receptor and [alpha][sub.v][beta][sub.3] integrin. Vav3-deficient mice have increased bone mass and are protected from bone loss induced by systemic bone resorption stimuli such as parathyroid hormone or RANKL. Moreover, we provide genetic and biochemical evidence for the role of Syk tyrosine kinase as a crucial upstream regulator of Vav3 in osteoclasts. Thus, Vav3 is a potential new target for antiosteoporosis therapy., Author(s): Roberta Faccio [1, 2, 3]; Steven L Teitelbaum [1]; Keiko Fujikawa [1, 5]; Jean Chappel [1]; Alberta Zallone [3]; Victor L Tybulewicz [4]; F Patrick Ross (corresponding author) [1]; [...]

Multiple system atrophy (MSA) is a sporadic neurodegenerative disease that is pathologically characterized by α-synuclein positive glial cytoplasmic inclusions in oligodendrocytes. The clinical diagnosis of MSA is often challenging as there are no established biomarkers and diagnoses are now based on clinical findings alone. At present, the etiology and pathogenesis of MSA are unclear. It has been reported that dysregulation of microRNA (miRNA/miR) serves an important role in neurodegenerative disorders including Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis. The miRNA profile of patients with MSA remains to be established. The present study investigated the serum miRNA expression level of 10 patients with MSA, using microarray chips including 668 miRNAs. It was identified that 50 miRNAs were significantly upregulated and 17 miRNAs were significantly downregulated in the serum of the patients with MSA. The most upregulated miRNA was miR-16, which may induce the accumulation of α-synuclein. The target genes of some miRNAs upregulated in MSA (including miR-17, 20a, 24, 25, 30d and 451) were associated with autophagy-associated molecules. The present study concluded that the expression pattern of miRNAs may be a clinical biomarker for MSA and targeting these miRNAs may provide a novel treatment for MSA. [ABSTRACT FROM AUTHOR]

The Vav family of Rho-guanine nucleotide exchange factors (GEFs) is thought to control a diverse array of signaling pathways emanating from antigen receptors in lymphocytes, although the exact mechanism by which Vav exerts its function is only beginning to emerge. Vav proteins are modular and contain the Dbl-homology domain, typical of all known Rho-GEFs, in addition to several other structural domains characteristic of proteins involved in signal transduction. Recently, our laboratory generated mice congenitally lacking all three Vav isoforms, providing genetic evidence that the Vav family is critical and nonredundant in T-and B-lymphocyte development and function and is essential in the formation of the adaptive immune system. These experimental also demonstrated that Vav proteins are indispensable for both T-cell receptor—and B-cell receptr-induced Ca++ fluxes. However, detailed analyses of Vav-deficient mice revealed unexpected complexity of Vav involvement in cellular activation. Notably, we observed lineage-specific Vav regulation of mitogen-activated protein kinase signaling, in which Vav was required in T-cell, but not in B-cells. Moreover, the three Vav proteins appear to function specifically in distinct signaling pathways emanating from activating receptors of natural killer cells that trigger natural cytotoxicity. [ABSTRACT FROM AUTHOR]

Abstract: The interaction between interleukin-10 (IL-10) and interleukin-6 (IL-6) was investigated in the inflammatory response to Rhodococcus aurantiacus (R. aurantiacus) infection, in which both cytokines act as anti-inflammatory cytokines. Compared with wild-type (WT) counterparts, IL-6 gene-deficient (IL-6−/−) mice mounted a more robust production of IL-10 and tumor necrosis factor-alpha (TNF-α) during the initial phase of infection. Administration of anti-IL-10 antibody resulted in all the mice dying within 3days post-infection as well as a further elevated TNF-α release. In vitro challenge of the macrophages from IL-6−/− and WT mice with heat-killed R. aurantiacus also showed similar results. Addition of exogenous IL-6 depressed IL-10 and TNF-α production by either IL-6−/− mice or IL-6−/− mouse macrophages. Likewise, WT mouse macrophages pretreated with anti-IL-10 or anti-IL-6 antibody exhibited increased production of TNF-α and IL-6 or IL-10 respectively. Moreover, neutralization of both IL-10 and IL-6 induced a further increase in TNF-α production by WT mouse cells. Overall, we conclude that IL-10 is a key element in protecting mice against mortality, and that IL-10 and IL-6 production are negatively regulated by each other although they are additive in suppressing TNF-α release in R. aurantiacus-infected mouse model. [Copyright &y& Elsevier]

Gastric cancer is the second-leading cause of cancer-related mortality worldwide, and the prognosis of advanced gastric cancer remains poor. Galectin-9 (Gal-9) is a tandem-repeat-type galectin that has recently been demonstrated to exert anti-proliferative effects on various types of cancer cells. The aim of our present study was to evaluate the effects of Gal-9 on human gastric cancer cells and the expression levels of microRNAs (miRNAs) associated with the antitumor effects of Gal-9 in vitro. In our initial experiments, Gal-9 suppressed the proliferation of gastric cancer cell lines in vitro. Our data further revealed that Gal-9 increased caspase-cleaved keratin 18 (CCK18) levels in gastric cancer cells. Additionally, Gal-9 reduced the phosphorylation of vascular endothelial growth factor receptor-3 (VEGFR-3) and insulin-like growth factor-1 receptor (IGF-1R). Furthermore, miRNA expression levels were markedly altered with Gal-9 treatment in vitro. In conclusion, Gal-9 suppressed the proliferation of human gastric cancer cells by inducing apoptosis. These findings suggest that Gal-9 could be a potential therapeutic target in the treatment of gastric cancer.