RETRACTED: MMP-9 induces CD44 cleavage and CD44 mediated cell migration in glioblastoma xenograft cells.

This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/our-business/policies/article-withdrawal). This article has been retracted at the request of the Editor in Chief. On behalf the University of Illinois at Chicago, the Associate Vice Chancellor and Research Integrity Officer requested retraction of the article because of the elements listed here that were deemed false: Figure 5B, bottom row, Columns 1, 2, 4 and 5, top panel; Figure 5B, Row 1, Columns 1 and 2, bottom panel; Figure 5B, Row 2, Columns 3 and 4 bottom panel. Based on these circumstances the Editor in Chief has therefore decided to retract the paper. The corresponding author has been non-responsive to approaches from the Publisher.

Human umbilical cord blood derived stem cells repair doxorubicin-induced pathological cardiac hypertrophy in mice.

In the present study, we investigated the cardiomyogenic potential of human umbilical cord blood (hUCB)-derived stem cells and whether stem cell treatment repairs the pathological hypertrophy induced by doxorubicin (DOX) in cultured neonatal rat cardiomyocytes (NRCM) and in mouse hearts. hUCB, which were labeled with cell tracker dye, were co-cultured with isolated NRCM in vitro. After 48h of incubation, the red stained hUCB cells (30%) contracted rhythmically and synchronously (physical examination). These differentiated hUCB also expressed cardiac specific alpha-actinin and showed diffused expression of connexin 43 and N-cadherin, thereby suggesting a tight electrical coupling among hUCB cells and myocytes. When co-cultured, hUCB also reversed the pathological effects induced by DOX in NRCM and in mice as seen by RT-PCR, immunoblot analysis and immunocytochemistry. hUCB migrated and integrated into the hearts of mice that were treated with DOX after intravenous injection and reversed the expression of pathological hypertrophic markers induced by DOX in mice. Further, we observed a shift from pathological hypertrophy towards physiological hypertrophy by hUCB in DOX-challenged mice. hUCB treatment in mice decreased DOX-induced increase of heart weight to body mass ratio and fibrosis. Taken together, these findings suggest the potential therapeutic use of hUCB in reversing heart failure conditions.

Doxorubicin-mediated apoptosis in glioma cells requires NFAT3.

Nuclear factor of activated T cells (NFAT), a family of transcription factors, has been implicated in many cellular processes, including some cancers. Here, we characterize, for the first time, the role of NFAT3 in doxorubicin (DOX)-mediated apoptosis, migration, and invasion in SNB19 and U87 glioma cells. This study demonstrates that the specific knockdown of NFAT3 results in a dramatic inhibition of the apoptotic effect induced by DOX and favors cell survival. Inhibition of NFAT3 activation by shNFAT3 (shNF3) significantly downregulated tumor necrosis factor (TNF)-alpha induction, its receptor TNFR1, caspase 10, caspase 3, and poly (ADP-ribose) polymerase, abrogating DOX-mediated apoptosis in glioma cells. DOX treatment resulted in NFAT3 translocation to the nucleus. Similarly, shNF3 treatment in SNB19 and U87 cells reversed DOX-induced inhibition of cell migration and invasion, as determined by wound healing and matrigel invasion assays. Taken together, these results indicate that NFAT3 is a prerequisite for the induction of DOX-mediated apoptosis in glioma cells.

Effect of human umbilical cord blood cells on Ang-II-induced hypertrophy in mice.

We have assessed the capacity of human umbilical cord blood (hUCB)-derived stem cells to differentiate into cardiomyocytes and repair angiotensin II induced insult in culture and in mouse hearts when injected. hUCB were able to differentiate into cardiomyocyte-like cells, when induced with 5-azacytidine or co-cultured with rat neonatal cardiomyocytes (NRCM). When co-cultured, hUCB reversed the pathological effects induced by angiotensin II (Ang-II) in NRCM and in mice injected after Ang-II infusion. As assessed by increased heart weight to body mass ratio and Ang-II-induced fibrosis, cardiac hypertrophy was also reduced after hUCB were injected. hUCB also reversed the pathological heart failure markers induced by Ang-II in mice. Further, we observed a shift from pathological hypertrophy towards physiological hypertrophy by hUCB in Ang-II-challenged mice. Our findings support hUCB as a feasible model for experimentation in stem cell therapy and emphasize the relevance of the hUCB in reversing heart failure conditions.

Blockade of tumor growth due to matrix metalloproteinase-9 inhibition is mediated by sequential activation of beta1-integrin, ERK, and NF-kappaB.

We previously showed that matrix metalloproteinase (MMP)-9 inhibition using an adenovirus-mediated delivery of MMP-9 small interfering RNA (Ad-MMP-9), caused senescence in medulloblastoma cells. Regardless of whether or not Ad-MMP-9 would induce apoptosis, the possible signaling mechanism is still obscure. In this report, we demonstrate that Ad-MMP-9 induced apoptosis in DAOY cells as determined by propidium iodide and terminal deoxynucleotidyltransferase-mediated nick end labeling staining. Ad-MMP-9 infection induced the release of cytochrome c, activation of caspase-9 and -3, and cleavage of poly(ADP-ribose) polymerase. Ad-MMP-9 infection stimulated ERK, and electrophoretic mobility shift assay indicated an increase in NF-kappaB activation. ERK inhibition, using a kinase-dead mutant for ERK, ameliorated NF-kappaB activation and caspase-mediated apoptosis in Ad-MMP-9-infected cells. beta1-Integrin expression in Ad-MMP-9-infected cells also increased, and this increase was reversed by the reintroduction of MMP-9. We found that the addition of beta1 blocking antibodies inhibited Ad-MMP-9-induced ERK activation. Taken together, our results indicate that MMP-9 inhibition induces apoptosis due to altered beta1-integrin expression in medulloblastoma. In addition, ERK activation plays an active role in this process and functions upstream of NF-kappaB activation to initiate the apoptotic signal.

Doxorubicin activates nuclear factor of activated T-lymphocytes and Fas ligand transcription: role of mitochondrial reactive oxygen species and calcium.

Doxorubicin (DOX), a widely used antitumour drug, causes dose-dependent cardiotoxicity. Cardiac mitochondria represent a critical target organelle of toxicity during DOX chemotherapy. Proposed mechanisms include generation of ROS (reactive oxygen species) and disturbances in mitochondrial calcium homoeostasis. In the present study, we probed the mechanistic link between mitochondrial ROS and calcium in the embryonic rat heart-derived H9c2 cell line and in adult rat cardiomyocytes. The results show that DOX stimulates calcium/calcineurin-dependent activation of the transcription factor NFAT (nuclear factor of activated T-lymphocytes). Pre-treatment of cells with an intracellular calcium chelator abrogated DOX-induced nuclear NFAT translocation, Fas L (Fas ligand) expression and caspase activation, as did pre-treatment of cells with a mitochondria-targeted antioxidant, Mito-Q (a mitochondria-targeted antioxidant consisting of a mixture of mitoquinol and mitoquinone), or with adenoviral-over-expressed antioxidant enzymes. Treatment with GPx-1 (glutathione peroxidase 1), MnSOD (manganese superoxide dismutase) or a peptide inhibitor of NFAT also inhibited DOX-induced nuclear NFAT translocation. Pre-treatment of cells with a Fas L neutralizing antibody abrogated DOX-induced caspase-8- and -3-like activities during the initial stages of apoptosis. We conclude that mitochondria-derived ROS and calcium play a key role in stimulating DOX-induced 'intrinsic and extrinsic forms' of apoptosis in cardiac cells with Fas L expression via the NFAT signalling mechanism. Implications of ROS- and calcium-dependent NFAT signalling in DOX-induced apoptosis are discussed.

Human transcobalamin II receptor binds to Staphylococcus aureus protein A: implications as to its structure and function.

Purified human placental transcobalamin II receptor (TC II-R) dimer of molecular mass 124 kDa bound to Sepharose-linked bacterial immunoglobulin (IgG) binding proteins protein A, protein G, and protein A/G. TC II-R dimer was detected directly, by blotting human placental and rabbit and rat kidney membrane proteins with 125I-protein A, or indirectly, using antiserum to TC II-R or IgG-Fc region and 125I-protein. TC II-R antiserum, but not protein A, protein G, protein A/G, or antiserum to the IgG-Fc region, when added to culture medium of human intestinal epithelial Caco-2 cells or umbilical vein endothelial cells, inhibited ligand binding. However, protein A, protein G, protein A/G, or antiserum to the Fc region inhibited the internalization of the ligand TC II-[57Co]cyanocobalamin. Taken together, these studies strongly suggest TC II-R is an IgG-like molecule that contains an Fc-like region which is important in ligand internalization but not binding.