1,724,670 research outputs found
MiR-3606-3p inhibits systemic sclerosis through targeting TGF-β type II receptor
No full textSystemic sclerosis (SSc) is a multisystemic fibrotic disease characterized by excessive collagen deposition and extracellular matrix synthesis. Though transforming growth factor-β (TGF-β) plays a fundamental role in the pathogenesis of SSc, the mechanism by which TGF-β signaling acts in SSc remains largely unclear. Here, we showed that TGF-β type II receptor (TGFBR2) was significantly upregulated in both human SSc dermal tissues and primary fibroblasts. In fibroblasts, siRNA-induced knockdown of TGFBR2 resulted in a reduction of p-SMAD2/3 levels and reduced production of type I collagen. Additionally, functional experiments revealed that downregulation of TGFBR2 yielded an anti-growth effect on fibroblasts through inhibiting cell cycle progression. Further studies showed that miR-3606-3p could directly target the 3′-UTR of TGFBR2 and significantly decrease the levels of both TGFBR2 mRNA and protein. Furthermore, SSc dermal tissues and primary fibroblasts contain significantly reduced amounts of miR-3606-3p, and the overexpression of miR-3606-3p in fibroblasts replicates the phenotype of TGFBR2 downregulation. Collectively, our findings demonstrated that increased TGFBR2 could be responsible for the hyperactive TGF-β signaling observed in SSc. Moreover, we identified a pivotal role for miR-3606-3p in SSc, which acts, at least partly, through the attenuation of TGF-β signaling via TGFBR2 repression, suggesting that the regulation of miR-3606-3p/TGFBR2 could be a promising therapeutic target that could improve the treatment strategy for fibrosis.</p
Bay 61–3606 is a sensitizer of TRAIL-induced apoptosis.
No full text<p>(A) Assay plate where Bay 61–3606 was identified as a sensitizer of TRAIL. After pre-incubation of test compounds (5 μM), cells were exposed to TRAIL (50 ng/ml). Cell survival was measured as a percentage of the control sample. The arrow indicates Bay 61–3606 (5 μM). (B) MCF-7 cells were exposed to TRAIL (indicated concentrations) with or without Bay 61–3606 (2.5 μM) for 24 h (upper) and Bay 61–3606 (indicated concentrations) with or without TRAIL (50 ng/ml) for 24 h (lower). (C) After exposure to the agents for 12 h, MCF-7 cells were subjected to immunocytochemistry using an active Bak antibody. (D) Caspase activity in MCF-7 cells exposed to Bay 61–3606 (5 μM) with or without TRAIL (50 ng/ml) for 24 h. (E) DNA fragmentation in MCF-7 cells was treated as seen in (D). Values are the mean ± SE from three separate experiments performed in triplicate. Asterisks indicate significant differences compared with the control (* <i>P</i> <0.05, and *** <i>P</i>-values < 0.001).</p
Identification and attempted validation of BAY61-3606 targets.
No full text<p>(<b>a</b>) TREEspot image representing the inhibitory activity of BAY61-3606. Kinases that are inhibited for ATP binding by BAY61-3606 are indicated by red dots on the phylogenetic tree of kinases. The size of the red dot corresponds to the amount of inhibition by 1 μM BAY61-3606. The identity of the individual kinases can be found in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0041343#pone.0041343.s008" target="_blank">Table S1</a>. (<b>b</b>) Cell viability quantified by Syto60 after shRNA-mediated knockdown of the potential BAY61-3606 targets in DLD-1 (red) or DKs-8 (blue) cell lines. Relative cell viability is normalized to the parental cell lines infected with vector only. Error bars represent SEM for 2 independent experiments.</p
Bay 61-3606 Sensitizes TRAIL-Induced Apoptosis by Downregulating Mcl-1 in Breast Cancer Cells.
No full textBreast cancer cells generally develop resistance to TNF-Related Apoptosis-Inducing Ligand (TRAIL) and, therefore, assistance from sensitizers is required. In our study, we have demonstrated that Spleen tyrosine kinase (Syk) inhibitor Bay 61-3606 was identified as a TRAIL sensitizer. Amplification of TRAIL-induced apoptosis by Bay 61-3606 was accompanied by the strong activation of Bak, caspases, and DNA fragmentation. In mechanism of action, Bay 61-3606 sensitized cells to TRAIL via two mechanisms regulating myeloid cell leukemia sequence-1 (Mcl-1). First, Bay 61-3606 triggered ubiquitin-dependent degradation of Mcl-1 by regulating Mcl-1 phosphorylation. Second, Bay 61-3606 downregulates Mcl-1 expression at the transcription level. In this context, Bay 61-3606 acted as an inhibitor of Cyclin-Dependent Kinase (CDK) 9 rather than Syk. In summary, Bay 61-3606 downregulates Mcl-1 expression in breast cancer cells and sensitizes cancer cells to TRAIL-mediated apoptosis
Block Card 3606 Torrance Drive
No full textThis image was produced by the Auditor's Office in Lucas County, Ohio for tax assessment purposes. Associated dates are approximate. Descriptive terms related to this photograph include: dwelling | 3606 Torrance Drive (Toledo, Ohio) | Colonial Revival Style | Almeda Heights (Toledo, Ohio) | Willys Park area (Toledo, Ohio) | West Toledo (Toledo, Ohio
Block Card 3606 Camille Drive
No full textThis image was produced by the Auditor's Office in Lucas County, Ohio for tax assessment purposes. Associated dates are approximate. Descriptive terms related to this photograph include: Ranch houses | 3606 Camille Drive (Toledo, Ohio) | Dwelling | Albert J. Corey Company Beverly Downs (Toledo, Ohio) | South Toledo Area (Toledo, Ohio
Block Card 3606 Denise Drive
No full textThis image was produced by the Auditor's Office in Lucas County, Ohio for tax assessment purposes. Associated dates are approximate. Descriptive terms related to this photograph include: Ranch houses | 3606 Denise Drive (Toledo, Ohio) | Dwelling | Albert J. Corey Company Beverly Downs (Toledo, Ohio) | South Toledo Area (Toledo, Ohio
Viral inhibition and cytotoxicity assays using BAY61-3606.
No full textViral inhibition and cytotoxicity assays using BAY61-3606.</p
Block Card 3606 Cavalear Drive
No full textThis image was produced by the Auditor's Office in Lucas County, Ohio for tax assessment purposes. Associated dates are approximate. Descriptive terms related to this photograph include: Dwelling | 3606 Cavalear Drive (Toledo, Ohio) | Ranch houses | Cavalear Estates (Toledo, Ohio) | Westgate Area (Toledo, Ohio) | West Toledo area (Toledo, Ohio
Block Card 3606 Claudia Drive
No full textThis image was produced by the Auditor's Office in Lucas County, Ohio for tax assessment purposes. Associated dates are approximate. Descriptive terms related to this photograph include: Ranch houses | 3606 Claudia Drive (Toledo, Ohio) | Dwelling | Albert J. Corey Company Beverly Downs (Toledo, Ohio) | South Toledo Area (Toledo, Ohio
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