1. Experiments were conducted using the whole-cell patch clamp technique to 7. These results suggest that there are at least two populations of isolated AV nodal cells with distinct action potentials and ionic current profiles that may contribute to the complex electrophysiological properties observed in the intact AV node.

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Background: Mesenchymal stem cells (MSCs) are suspected to exert neuroprotective effects in brain injury, in part through the secretion of extracellular vesicles like exosomes containing bioactive compounds. We now investigate the mechanism by which bone marrow MSCs (BMSCs)-derived exosomes harboring the small non-coding RNA miR-29b-3p protect against hypoxic-ischemic brain injury in rats. Methods:We established a rat model of middle cerebral artery occlusion (MCAO) and primary cortical neuron or brain microvascular endothelial cell (BMEC) models of oxygen and glucose deprivation (OGD). Exosomes were isolated from the culture medium of BMSCs. We treated the MCAO rats with BMSC-derived exosomes in vivo, and likewise the OGD-treated neurons and BMECs in vitro. We then measured apoptosis-and angiogenesis-related features using TUNEL and CD31 immunohistochemical staining and in vitro Matrigel angiogenesis assays. Results: The dual luciferase reporter gene assay showed that miR-29b-3p targeted the protein phosphatase and tensin homolog (PTEN). miR-29b-3p was downregulated and PTEN was upregulated in the brain of MCAO rats and in OGD-treated cultured neurons. MCAO rats and OGD-treated neurons showed promoted apoptosis and decreased angiogenesis, but overexpression of miR-29b-3p or silencing of PTEN could reverse these alterations. Furthermore, miR-29b-3p could negatively regulate PTEN and activate the Akt signaling pathway. BMSCs-derived exosomes also exerted protective effects against apoptosis of OGD neurons and cell apoptosis in the brain samples from MCAO rats, where we also observed promotion of angiogenesis.Conclusion: BMSC-derived exosomal miR-29b-3p ameliorates ischemic brain injury by promoting angiogenesis and suppressing neuronal apoptosis, a finding which may be of great significance in the treatment of hypoxic-ischemic brain injury.

We have previously reported the oncogenic properties of the gene amplified in breast cancer 1 (AIB1), a member of the p160 family of hormone receptor coactivators. In a transgenic mouse model, AIB1 overexpression resulted in a high incidence of tumors in various tissues, including mammary gland, uterus, lung, and pituitary. To determine whether the AIB1 oncogenicity in this model depended on its function as an estrogen receptor (ER) coactivator, we abolished ER signaling through two independent approaches, by performing ovariectomy on AIB1 transgenic (AIB1-tg) mice to prevent gonadal estrogen production and by crossing AIB1-tg mice with ERα-null mutant mice. Ovariectomized (ovx) mice, but not AIB1 × ERα−/− mice, still developed mammary gland hyperplasia and ductal carcinoma in situ. Both approaches, however, completely prevented the development of invasive mammary tumors, indicating that invasive mammary tumor formation is strictly estrogen dependent. Once developed, AIB1-induced mammary tumors can subsequently lose their dependence on estrogen: Injection of ERα(+) tumor cell lines derived from such tumors into ovx or untreated wild-type mice resulted in a similar rate of tumor growth in both groups. Surprisingly, however, ovx mice had an ∼4-fold higher rate of metastasis formation, suggesting that estrogen provided some protection from metastasis formation. Lastly, our experiments identified oncogenic functions of AIB1 that are independent of its ER coactivation, as both approaches, ovariectomy and ER−/− crosses, still resulted in a high incidence of tumors in the lung and pituitary. We therefore conclude that AIB1 can exert its oncogenicity through tissuespecific estrogen-dependent and estrogen-independent functions. Cancer Res; 70(10); 4102-11. ©2010 AACR.

The role of angiotensin II (Ang II) in the early embryonic development of the heart has not been examined. We have used RT-PCR to identify mRNA for angiotensinogen, angiotensin-converting enzyme, and the Ang II AT1 and AT2 receptors in embryonic day 10.25 Sprague-Dawley rats, and have used confocal microscopy to localize the AT1 receptor to the greater curvature of the developing ventricle in these animals at embryonic days (ED) 9.25 and 10.25. The antibodies used in immunolocalization studies did not distinguish between the AT1a and AT1b receptor subtypes. In whole embryo culture, Ang II added to the culture media resulted in increased ventricular growth and myocyte hypertrophy when treated embryos were compared to cultured littermate controls. Use of Losartan and PD123,319 to block the Ang II AT1 and AT2 receptors resulted in reduced ventricular development and cardiac dilation when compared to control and Ang II-treated embryos. Addition of Ang II and PD123,319 to the culture media also resulted in cardiac loop inversions which may be associated with disruption of normal myofibrillar development. These results clearly indicate an important role for Ang II in the early embryonic development of the heart.