Sterile inflammatory insults are known to activate innate immunity and propagate organ damage through the recognition of extracellular Damage Associated Molecular Pattern (DAMP) molecules. Although DAMPs, such as endogenous DNA and nuclear High Mobility Group Box 1, have been shown to be critical in sterile inflammation, the role of nuclear histone proteins has not yet been investigated. We report that endogenous histones function as DAMPs following ischemic injury through the pattern recognition receptor Toll-Like Receptor 9 (TLR9) to initiate inflammation. Using an in vivo model of hepatic ischemia/reperfusion (I/R) injury, we show that levels of circulating histones are significantly higher after I/R, and that histone neutralization significantly protects against injury. Injection of exogenous histones exacerbates I/R injury through cytotoxic effects mediated by TLR9 and MyD88. In addition, histone administration increases TLR9 activation, while neither TLR9 nor MyD88 mutant mice respond to exogenous histones. Furthermore, we demonstrate in vitro that extracellular histones enhance DNA-mediated TLR9 activation in immune cells through a direct interaction. Conclusions these novel findings reveal that histones represent a new class of DAMP molecules and they serve as a crucial link between initial damage and activation of innate immunity during sterile inflammation.

High expression of estrogen receptor a (ERa) is associated with a poor prognosis that correlates closely with cellular proliferation in breast cancer. However, the exact molecular mechanism by which ERa controls breast cancer cell proliferation is not clear. Here we report that ERa regulates the cell cycle by suppressing p53/p21 and up-regulating proliferating cell nuclear antigen (PCNA) and proliferation-related Ki-67 antigen (Ki-67) to promote proliferation of MCF-7 cells. In addition, 17-b-estradiol (E2) enhances ERa-induced proliferation of MCF-7 cells by stimulating expression of PCNA and Ki-67. Knockdown of ERa significantly affects PCNA/ Ki-67 and p53/p21 expression. Furthermore, ERa inhibits the transcriptional activity of p53/p21 in an estrogen response element-dependent manner. More importantly, we provide new evidence that ERa mediates proliferation of MCF-7 cells by up-regulating miR-17 to silence the expression of p21. Thus, these data provide new insights into the underlying effect of ERa on breast cancer proliferation.

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Background:The JAK-STAT3 signaling pathway is one of the critical pathways regulating cell proliferation and differentiation. Results: Knockdown of endogenous STAT3 enhances VSMC contractile phenotype by promoting the association of the myocardin-SRF-CArG complex. Conclusion:The JAK-STAT3 signaling pathway is a central regulator of the phenotypic switch of VSMCs. Significance: The phenotypic switch of VSMCs can be controlled by modulation of JAK-STAT3 signaling.

Signal transducer and activator of transcription 3 (STAT3) controls cell survival, growth, migration, and invasion. Here, we observed that STAT3 exerted anti-apoptotic effects in breast cancer cells. On the other hand, miR-17-5p induced apoptosis in breast cancer cells, and overexpression of miR-17-5p sensitized MCF-7 cells to paclitaxel-induced apoptosis via STAT3. Overexpression of STAT3 in MCF-7 cells decreased paclitaxel-induced apoptosis, but STAT3 knockout abolished the miR-17-5p-induced increases in apoptosis. Finally, miR-17-5p promoted apoptosis by increasing p53 expression, which was inhibited by STAT3. These results demonstrate a novel pathway via which miR-17-5p inhibits STAT3 and increases p53 expression to promote apoptosis in breast cancer cells.

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SummaryMicroRNAs (miRNAs) are a class of endogenous, highly conserved, small noncoding RNAs that regulate gene expression post-transcriptionally. Recent studies have demonstrated that miRNAs are aberrantly expressed in the cardiovascular system. The implications of miRNAs in cardiovascular disease have recently been recognized, representing the most rapidly evolving research field. Gain-and loss-of-function studies in mice models have identified distinct roles for specific miRNAs during cardiac hypertrophy, heart failing, and myocardial infarction. In the present article, the currently relevant findings on the role of miRNAs in cardiac hypertrophy and heart failure will be summarized and the target genes and signaling pathways linking these miRNAs will be discussed. Furthermore, we focus on the use of miRNA mimics and antagonists (antagomirs) as tools for disease therapy in the cardiovascular system in the future. Taken together, the recent studies showed that miRNAs are key regulators of gene expression in cardiovascular biology and suggested the potential importance of miRNAs as diagnostic markers and therapeutic targets for cardiovascular disease.2009 IUBMB IUBMB Life, 61(6): 566-571, 2009

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