Doxorubicin is believed to cause dose-dependent cardiotoxicity through redox cycling and the generation of reactive oxygen species (ROS). Here we show that cardiomyocyte-specific deletion of Top2b (encoding topoisomerase-IIβ) protects cardiomyocytes from doxorubicin-induced DNA double-strand breaks and transcriptome changes that are responsible for defective mitochondrial biogenesis and ROS formation. Furthermore, cardiomyocyte-specific deletion of Top2b protects mice from the development of doxorubicin-induced progressive heart failure, suggesting that doxorubicin-induced cardiotoxicity is mediated by topoisomerase-IIβ in cardiomyocytes.

SUMOylation is a dynamic process, catalyzed by SUMO-specific ligases and reversed by Sentrin/SUMO-specific proteases (SENPs). The physiologic consequences of SUMOylation and deSUMOylation are not fully understood. Here we investigate the phenotypes of mice lacking SENP1 and find that SENP1(-/-) embryos show severe fetal anemia stemming from deficient erythropoietin (Epo) production and die midgestation. We determine that SENP1 controls Epo production by regulating the stability of hypoxia-inducible factor 1alpha (HIF1alpha) during hypoxia. Hypoxia induces SUMOylation of HIF1alpha, which promotes its binding to a ubiquitin ligase, von Hippel-Lindau (VHL) protein, through a proline hydroxylation-independent mechanism, leading to its ubiquitination and degradation. In SENP1(-/-) MEFs, hypoxia-induced transcription of HIF1alpha-dependent genes such as vascular endothelial growth factor (VEGF) and glucose transporter 1 (Glut-1) is markedly reduced. These results show that SENP1 plays a key role in the regulation of the hypoxic response through regulation of HIF1alpha stability and that SUMOylation can serve as a direct signal for ubiquitin-dependent degradation.

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Background-Adult human peripheral blood cells have been shown to differentiate into mature cells of nonhematopoietic tissues, such as hepatocytes and epithelial cells of the skin and gastrointestinal track. We investigated whether these cells could also transdifferentiate into human cardiomyocytes, mature endothelial cells, and smooth muscle cells in vivo. Methods and Results-Myocardial infarction was created in SCID mice by occluding the left anterior descending coronary artery, after which adult peripheral blood CD34 ϩ cells were injected into the tail vein. Hearts were harvested 2 months after injection and stained for human leukocyte antigen (HLA) and markers for cardiomyocytes, endothelial cells, and smooth muscle cells. Cardiomyocytes, endothelial cells, and smooth muscle cells that bear HLA were identified in the infarct and peri-infarct regions of the mouse hearts. In a separate experiment, CD34 ϩ cells were injected intraventricularly into mice without experimental myocardial infarction. HLA-positive myocytes and smooth muscle cells could only be identified in 1 of these mice killed at different time points. Conclusions-Adult peripheral blood CD34ϩ cells can transdifferentiate into cardiomyocytes, mature endothelial cells, and smooth muscle cells in vivo. However, transdifferentiation is augmented significantly by local tissue injury. The use of peripheral blood CD34 ϩ cells for cell-based therapy should greatly simplify the procurement of cells for the regeneration of damaged myocardium.

A novel dual-modification strategy, including (1) the cross-linking and construction of a GO framework by ethylenediamine (EDA) and (2) the amine-enrichment modification by hyperbranched polyethylenimine (HPEI), has been proposed to design stable and highly charged GO framework membranes with the GO selective layer thickness of 70 nm for effective heave metal removal via nanofiltration (NF). Results from sonication experiments and positron annihilation spectroscopy confirmed that EDA cross-linking not only enhanced structural stability but also enlarged the nanochannels among the laminated GO nanosheets for higher water permeability. HPEI 60K was found to be the most effective post-treatment agent that resulted in GO framework membranes with a higher surface charge and lower transport resistance. The newly developed membrane exhibited a high pure water permeability of 5.01 L m(-2) h(-1) bar(-1) and comparably high rejections toward Mg(2+), Pb(2+), Ni(2+), Cd(2+), and Zn(2+). These results have demonstrated the great potential of GO framework materials in wastewater treatment and may provide insights for the design and fabrication of the next generation two-dimensional (2D)-based NF membranes.

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Bone is the most common site of metastases from prostate cancer. The mechanism by which prostate cancer cells metastasize to bone is not fully understood, but interactions between prostate cancer cells and bone cells are thought to initiate the colonization of metastatic cells at that site. Here, we show that cadherin-11 (also known as osteoblast-cadherin) was highly expressed in prostate cancer cell line derived from bone metastases and had strong homophilic binding to recombinant cadherin-11 in vitro. Down-regulation of cadherin-11 in bone metastasis -derived PC3 cells with cadherin-11 -specific short hairpin RNA (PC3-shCad-11) significantly decreased the adhesion of those cells to cadherin-11 in vitro. In a mouse model of metastasis, intracardiac injection of PC3 cells led to metastasis of those cells to bone. However, the incidence of PC3 metastasis to bone in this model was reduced greatly when the expression of cadherin-11 by those cells was silenced. The clinical relevance of cadherin-11 in prostate cancer metastases was further studied by examining the expression of cadherin-11 in human prostate cancer specimens. Cadherin-11 was not expressed by normal prostate epithelial cells but was detected in prostate cancer, with its expression increasing from primary to metastatic disease in lymph nodes and especially bone. Cadherin-11 expression was not detected in metastatic lesions that occur in other organs. Collectively, these findings suggest that cadherin-11 is involved in the metastasis of prostate cancer cells to bone. (Mol Cancer Res 2008;6(8):1259 -67)

Membrane technology has gained great interest in industrial separation processing over the past few decades owing to its high energy efficiency, small capital investment, environmentally benign characteristics, and the continuous operation process. Among various types of membranes, mixed matrix membranes (MMMs) combining the merits of the polymer matrix and inorganic/organic fillers have been extensively investigated. With the rapid development of chemistry and materials science, recent studies have shifted toward the design and application of advanced porous materials as promising fillers to boost the separation performance of MMMs. Here, first a comprehensive overview is provided on the choices of advanced porous materials recently adopted in MMMs, including metal-organic frameworks, porous organic frameworks, and porous molecular compounds. Novel trends in MMMs induced by these advanced porous fillers are discussed in detail, followed by a summary of applying these MMMs for gas and liquid separations. Finally, a concise conclusion and current challenges toward the industrial implementation of MMMs are outlined, hoping to provide guidance for the design of high-performance membranes to meet the urgent needs of clean energy and environmental sustainability.