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  • EdU is a thymidine analog

    2022-09-29

    EdU is a thymidine analog that is incorporated into replicated chromosomal DNA during the S phase of the cell cycle. DAPI is a fluorescent dye that binds strongly to A-T-rich regions in DNA and is commonly used for cell nucleus staining. We used the EdU incorporation assay, which is a highly sensitive and specific method, to investigate the inhibitory effects of 7b. As shown in , treatment of Hep3B cells with (10 µM) for 12 h reduced the percentage of EdU-positive cells compared with the vehicle-treated cells (A), indicating that inhibits Hep3B cell proliferation . We also performed clonogenic assays to determine the long-term anti-proliferative activity of . We observed a dose-dependent reduction in colony formation by -treated compared with control Hep3B cells (B). A series of UA derivatives containing an aminoguanidine moiety were designed, synthesized, and evaluated for their biological activity as HIF-1α inhibitors. Among the compounds tested, was the most active inhibitor of HIF-1α (IC 4.0 μM) and did not show significant cytotoxic activity against any of the tested cell lines. We investigated the mechanism of action of compound and found that it reduced HIF-1α protein levels without affecting its transcription or degradation. Moreover, inhibited hypoxia-induced expression of VEGF at both the mRNA and protein levels. Compound was confirmed to inhibit the proliferation of cancer cells . These results provide initial support for the development of as a potential anti-cancer agent. Acknowledgements The work was supported by the National Science Foundation of China (No. 81260468, 81660608, 81760657) and the Natural Science Foundation of Jilin Province (No. 20160101218JC). We thank Anne M. O’Rourke, PhD, from Liwen Bianji, Edanz Group China (www.liwenbianji.cn/ac), for editing the English text of a draft of this manuscript.
    Introduction B cells have been found to suppress inflammation in T cell-mediated autoimmune diseases by secreting immune-regulatory cytokines, including interleukin 10 (IL-10), transforming growth factor β, and IL-35 (Mauri and Blair, 2014; Rosser and Mauri, 2015; Wei et al., 2019). In mice, multiple subsets of YM178 have been identified as the regulatory B cells (Bregs) to affect CD4+ T cell response through the production of IL-10, such as CD5+CD1dhi B10 B cells, CD21hiCD23hiCD24hi transitional 2 marginal-zone precursor cells, Tim-1+ B cells, and CD138+ plasma cells (Rosser and Mauri, 2015). Our published data demonstrated that a subset of B cells expressing CD11b displayed a regulatory function by inhibiting CD4+T effect cell response in an experimental autoimmune hepatitis (EAH) model (Liu et al., 2015), and Peyer’s patches (PP)-derived CD11b+ B cells recruited regulatory T (Treg) cells by secreting CXCL9 in DSS-induced colitis (Wang et al., 2019), indicating that CD11b may play a regulatory function for regulatory B cells. CD11b encoded by integrin subunit alpha M (Itgam) is an integrin αM subunit of Mac-1 that dimerizes with CD18 and is widely expressed on the surface of various immune cells (Farokhzad et al., 1996). Multiple studies have demonstrated that CD11b has a pivotal role in suppressive regulation. CD11b expressed on antigen-presenting cells (APCs) negatively regulated T cell activation (Wang et al., 2015) and T-helper 17 (Th17) differentiation (Ehirchiou et al., 2007). Furthermore, CD11b expressed on APCs inhibited inflammatory responses through Toll-like receptor (TLR) suppression (Ding et al., 2013; Rosetti and Mayadas, 2016; Wang et al., 2010) and provoke innate anti-tumor immunity (Schmid et al., 2018) while expressed on macrophages. CD11b-null mice exhibited severer colitis compared to the wildtype (WT) mice (Abdelbaqi et al., 2006). Furthermore, CD11b activation reduced TLR-dependent inflammation, reduced type I interferon response, and protected mice from severe sepsis in systemic lupus erythematosus (Faridi et al., 2017). Regarding B cells, CD11b was reported to regulate immunoglobulin heavy chain class switch recombination via the induced expression of AID in activated B2 B cells (Park et al., 2017). CD11b expression on B cells was up-regulated in liver and spleen during the pathological process of EAH (Liu et al., 2015) and in the PPs in IBD (Wang et al., 2019). These studies imply that CD11b, as an integrin subunit, not only is a surface marker of Breg cells but may also function as a regulatory molecule in B cell-mediated suppressive response. However, it is still unknown whether CD11b is systemically expressed in inflammatory bowel disease (IBD) and how CD11b is induced to express on B cells in gut-related autoimmune diseases.