Intended for use in high performance applications where electrical conductivity is required, we developed a CNT-TPU composite. Such a composite can be prepared by melt processing (extrusion) on an industrial scale. Due to the known hazard upon inhalation of CNTs, we assessed three degradation scenarios that may lead to the release of CNTs from the composite: normal use, machining and outdoor weathering. Unexpectedly, we find that the relative softness of the material actually enhances the embedding of CNTs also in its degradation fragments. A release of free CNTs was not detected under any condition using several detection methods. However, since machining may induce a high acute dose of human exposure, we assessed the cytotoxicity potential of released fragments in the in vitro model of precision-cut lung slices, and found no additional toxicity due to the presence of CNTs. At very low rates over years, weathering degrades the polymer matrix as expected for polyurethanes, thus exposing a network of entangled CNTs. In a preliminary risk assessment, we conclude that this material is safe for humans in professional and consumer use.
Fas/CD95-induced apoptosis of hepatocytes in vivo proceeds through the so-called type II pathway, requiring the proapoptotic BH3-only Bcl-2 family member Bid for mitochondrial death signaling. Consequently, Bid-deficient mice are protected from anti-Fas antibody injection induced fatal hepatitis. We report the unexpected finding that freshly isolated mouse hepatocytes, cultured on collagen or Matrigel, become independent of Bid for Fas-induced apoptosis, thereby switching death signaling from type II to type I. In such in vitro cultures, Fas ligand (FasL) activates caspase-3 without Bid cleavage, Bax/Bak activation or cytochrome c release, and neither Bid ablation nor Bcl-2 overexpression is protective. The type II to type I switch depends on extracellular matrix adhesion, as primary hepatocytes in suspension die in a Bid-dependent manner. Moreover, the switch is specific for FasL-induced apoptosis as collagen-plated Bid-deficient hepatocytes are protected from tumor necrosis factor alpha/actinomycin D (TNF␣/ ActD)-induced apoptosis. Conclusion: Our data suggest a selective crosstalk between extracellular matrix and Fas-mediated signaling that favors mitochondria-independent type I apoptosis induction. (HEPATOLOGY 2008;48:1942-1953
Loss of p53-dependent apoptosis contributes to the development of hematologic malignancies and failure to respond to treatment. Proapoptotic Bcl-2 family member Puma is essential for apoptosis in HoxB8-immortalized interleukin-3 (IL-3)-dependent myeloid cell lines (FDM cells) provoked by IL-3 deprivation. p53 and FoxO3a can transcriptionally regulate Puma. To investigate which transcriptional regulator is responsible for IL-3 deprivation-induced Puma expression and apoptosis, we generated wild-type (WT), p53 ؊/؊ , and FoxO3a ؊/؊ FDM cells and found that p53 ؊/؊ but not FoxO3a ؊/؊ cells were protected against IL-3 withdrawal. Loss of p21 cip/waf , which is critical for p53-mediated cell-cycle arrest, afforded no protection against IL-3 deprivation. A survival advantage was also observed in untransformed p53 ؊/؊ hemato poietic progenitor cells cultured in the presence or absence of cytokines. In response to IL-3 deprivation, increased Puma protein levels in p53 ؊/؊ cells were substantially delayed compared with WT cells. Increased p53 transcriptional activity was detected after cytokine deprivation. This was substantially less than that induced by DNA damage and associated not with increased p53 protein levels but with loss of the p53 regulator, MDM2. Thus, we conclude that p53 protein is activated after IL-3 deprivation by loss of MDM2. Activated p53 transcriptionally upregulates Puma, which initiates apoptosis. (Blood. 2010;115:344-352) IntroductionThe maintenance of hematopoietic stem and progenitor cells depends on lineage-specific growth factors, such as interleukin-3 (IL-3). In the absence of cytokine signals, hematopoietic cells exit the cell cycle and commit to apoptosis by pathways regulated by the Bcl-2 family of apoptosis regulators. Evading this commitment permits cells to survive and proliferate in the absence of cytokines and constitutes an important step to tumor formation. 1 Understanding the pathways by which cytokine signaling regulates proliferation and suppresses apoptosis in hematopoietic cells provides insight to the abnormal regulation of these responses in hematologic malignancies.Acute myeloid leukemia (AML) with 17p deletions or mutations lose p53 function. This is associated with poorer outcomes and response to treatment, in part, as a result of loss of p53-dependent apoptosis. 2,3 In chronic lymphocytic leukemia (CLL) or AML, loss of p53 may also promote clonogenic proliferation and generation of malignant cells with a stem cell-like phenotype. 4 The p53 tumor suppressor functions to regulate the cell cycle and apoptosis in response to a range of cellular stresses such as double-stranded DNA breaks, exposure to genotoxic drugs commonly used to treat malignancies, and abnormal regulation of the cell cycle. 5 Other evidence indicates p53 also regulates apoptosis in response to cytokine and substrate deprivation. 6,7 p53 also functions to limit the capacity of somatic cells to produce induced pluripotential stem cells through unknown mechanisms. [8][9][10][11] The mechanism of p53-dependen...
The applicability of rat precision-cut lung slices (PCLuS) in detecting nanomaterial (NM) toxicity to the respiratory tract was investigated evaluating sixteen OECD reference NMs (TiO₂, ZnO, CeO₂, SiO₂, Ag, multi-walled carbon nanotubes (MWCNTs)). Upon 24-hour test substance exposure, the PCLuS system was able to detect early events of NM toxicity: total protein, reduction in mitochondrial activity, caspase-3/-7 activation, glutathione depletion/increase, cytokine induction, and histopathological evaluation. Ion shedding NMS (ZnO and Ag) induced severe tissue destruction detected by the loss of total protein. Two anatase TiO₂ NMs, CeO₂ NMs, and two MWCNT caused significant (determined by trend analysis) cytotoxicity in the WST-1 assay. At non-cytotoxic concentrations, different TiO₂ NMs and one MWCNT increased GSH levels, presumably a defense response to reactive oxygen species, and these substances further induced a variety of cytokines. One of the SiO₂ NMs increased caspase-3/-7 activities at non-cytotoxic levels, and one rutile TiO₂ only induced cytokines. Investigating these effects is, however, not sufficient to predict apical effects found in vivo. Reproducibility of test substance measurements was not fully satisfactory, especially in the GSH and cytokine assays. Effects were frequently observed in negative controls pointing to tissue slice vulnerability even though prepared and handled with utmost care. Comparisons of the effects observed in the PCLuS to in vivo effects reveal some concordances for the metal oxide NMs, but less so for the MWCNT. The highest effective dosages, however, exceeded those reported for rat short-term inhalation studies. To become applicable for NM testing, the PCLuS system requires test protocol optimization.
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