Indole derivative 1 interferes with the interaction of the HIV surface protein gp120 with the host cell receptor CD4. The 4-fluoro derivative 2 exhibited markedly enhanced potency and was bioavailable in the rat, dog, and cynomolgus monkey when administered orally as a solution formulation. However, aqueous suspensions of 2 were poorly bioavailable, indicative of dissolution-limited absorption. The 7-azaindole derivative 3, BMS-378806, exhibited improved pharmaceutical properties while retaining the HIV-1 inhibitory profile of 2.
M2 polarization of macrophages is essential for their function in immunologic tolerance, which might promote tumorigenesis. However, the molecular mechanism behind the polarization process is not fully understood. Given that several lines of evidence have suggested that long noncoding RNAs (lncRNAs) could be involved in regulating immune cell differentiation and function, the current study aimed to identify the lncRNAs that specifically modulate M2 macrophage polarization. By utilizing a series of cellbased M2 macrophage polarization models, a total of 25 lncRNAs with altered expression were documented based on lncRNA microarray-based profiling assays. Among them, lncRNA-MM2P was the only lncRNA upregulated during M2 polarization but downregulated in M1 macrophages. Knockdown of lncRNA-MM2P blocked cytokine-driven M2 polarization of macrophages and weakened the angiogenesis-promoting feature of M2 macrophages by reducing phosphorylation on STAT6. Moreover, manipulating lncRNA-MM2P in macrophages impaired macrophagemediated promotion of tumorigenesis, tumor growth in vivo, and tumor angiogenesis. Collectively, our study identifies lncRNA-MM2P as a modulator required for macrophage M2 polarization and uncovers its role in macrophage-promoted tumorigenesis.
Stress granules (SGs) are primarily composed of mRNAs that stall at translation initiation and usually appear in the cytoplasm under unusual physiological or pathological conditions such as hypoxia, oxidative stress, and viral infection. Recent studies have indicated that several components of SGs participate in tumourigenesis and cancer metastasis through tumour-associated signalling pathways as well as other mechanisms. Furthermore, some chemotherapy drugs have been reported to induce SGs.Thus, the roles of SGs in cancer treatment have attracted considerable interest.Importantly, disturbing the recruitment of SGs components or microtubule polymerization, as well as other strategies that can abolish SGs formation, is reported to inhibit tumour progression, suggesting that targeting SGs could be a promising strategy for cancer treatment. In this review, we summarize the relationship between SGs and cancer, as well as recent advances in targeting SGs, in the interest of providing new opportunities for cancer treatment. | INTRODUCTIONDuring the eukaryotic gene expression process, RNA translation is thought to be a key process that regulates RNA modification, stability, location, protein function, and chromatin structure (Rizvi & Smith, 2017). Stresses such as hypoxia, viral infection, heat shock, and oxidative stress can induce multiple tissue and organ damages, as well as disordered protein translation, all of which are called "integrated stress responses (ISRs)" (Anderson, Kedersha, & Ivanov, 2015). Composed of non-translated mRNAs, cytoplasmic messenger ribonucleoprotein particles (mRNPs) are components of the ISR and emerge when translation initiation is stalled, subsequently forming granules to ensure cell adaptation to stress conditions. These RNA granules can usually be divided into four types: processing bodies, stress granules (SGs), neuronal granules, and germ cell granules (Anderson & Kedersha, 2006). Among these granules, SGs are the most well studied. Given that SGs assemble when translation initiation is stalled, they usually occur in the cytoplasm, containing various RNA-binding proteins (RBPs), non-translated RNAs, types of translation initiation factors, poly(A)binding protein, and ribosomal subunits.SGs assemble immediately once stresses are encountered and are cleaned up once the stresses disappear (Reineke & Neilson, 2019).As SGs are a non-typical type of multifunctional membrane-less organelles, the formation of SGs is a highly regulated and dynamic process. SGs are usually triggered by the serine 51 phosphorylation of eukaryotic initiator factor 2A (eIF2A; Buchan & Parker, 2009;Gilks et al., 2004), which represents the initiation of 48-s ribosomal subunit disassembly and translation arrest. Considered to be one of the most pivotal components of SGs, the phosphorylation of Ras-GTPaseactivating protein SH3 domain-binding protein 1 (G3BP1) affects SG formation (Mahboubi & Stochaj, 2017). Moreover, the post-translation modifications (PTMs) of mRNPs components are also closely associated with SGs a...
Low-coordinate organometallic complexes are important in structure and catalysis, and hemilability or secondary interactions such as hydrogen bonding enabled by hybrid ligands are receiving increasing attention. To study the factors controlling these phenomena, three new imidazol-2-ylphosphine ligands, L, were made. In these ligands, the bulk around P and the hindrance at the basic and potentially coordinating imidazole N-3 were varied. Remarkably, L(2)Pd(0) complexes 3a-c were shown to be two-coordinate, 12-electron species, despite the availability of imidazole N-3 to enter into eta(2)-P,N chelation. In oxidative additions of C-X bonds to the Pd(0) complexes, reaction rates and products could be controlled by the nature of the C and X groups and the R groups on the phosphine. Most significantly, whereas 4c-PhI and 4c-MeOTf from 3c are normal trans-bis(phosphine)Pd(R)(X) species, 5a-PhI, 5a-PhBr, and 5b-PhI from 3a and 3b were shown by X-ray diffraction to be a monomeric species with a single eta(2)-P,N-chelating phosphine. From 3a and methyl triflate, an ionic complex [6a-Me](+)[OTf](-) with one chelating and one nonchelating phosphine was formed, with temperature-dependent windshield-wiper exchange of the two, showing hemilability. Thus, large phosphine substituents (R = tert-butyl rather than isopropyl) favor chelation. The chelate Pd-imidazole N-3 bond is longer when the heterocyclic nitrogen is hindered by an adjacent tert-butyl group at C-4 (comparing 5a-PhI and 5b-PhI). Finally, whereas in [8b-Ph](+)[OTf](-) from 5b-PhI and isopropylamine, the amine coordinates without chelate opening or hydrogen bonding, in [10c-Me](+)[OTf](-) made from 4c-MeOTf and isopropylamine, the amine is not only coordinated at N but also donates a hydrogen bond to each phosphine imidazol-2-yl substituent.
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