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The hazards of various types of nanoparticles with high functionality have not been fully assessed. We investigated the usefulness of biopersistence as a hazard indicator of nanoparticles by performing inhalation and intratracheal instillation studies and comparing the biopersistence of two nanoparticles with different toxicities: NiO and TiO2 nanoparticles with high and low toxicity among nanoparticles, respectively. In the 4-week inhalation studies, the average exposure concentrations were 0.32 and 1.65 mg/m³ for NiO, and 0.50 and 1.84 mg/m³ for TiO2. In the instillation studies, 0.2 and 1.0 mg of NiO nanoparticles and 0.2, 0.36, and 1.0 mg of TiO2 were dispersed in 0.4 mL water and instilled to rats. After the exposure, the lung burden in each of five rats was determined by Inductively Coupled Plasma-Atomic Emission Spectrometer (ICP-AES) from 3 days to 3 months for inhalation studies and to 6 months for instillation studies. In both the inhalation and instillation studies, NiO nanoparticles persisted for longer in the lung compared with TiO2 nanoparticles, and the calculated biological half times (BHTs) of the NiO nanoparticles was longer than that of the TiO2 nanoparticles. Biopersistence also correlated with histopathological changes, inflammatory response, and other biomarkers in bronchoalveolar lavage fluid (BALF) after the exposure to nanoparticles. These results suggested that the biopersistence is a good indicator of the hazards of nanoparticles. [ABSTRACT FROM AUTHOR]

Aurora kinase B (AURKB) inhibitors are regarded as potential molecular-targeting drugs for cancer therapy. The present study evaluated the cytotoxic effect of a combination of AZD1152-hQPA, an AURKB inhibitor, and various anticancer agents on the HeLa human cervical cancer cell line, as well as its cisplatin-resistant equivalent HCP4 cell line. It was demonstrated that AZD1152-hQPA had an antagonistic effect on the cytotoxicity of cisplatin, etoposide and doxorubicin, but had a synergistic effect on that of all-trans-retinoic acid (ATRA), Am80 and TAC-101, when tested on HeLa cells. Cisplatin, etoposide and doxorubicin were shown to increase the cellular expression of AURKB, while ATRA, Am80 and TAC-101 downregulated its expression. These results suggested that AURKB expression is regulated by these anticancer agents at the transcriptional level, and that the level of expression of AURKB may influence the cytotoxic effect of AZD1152-hQPA. Therefore, when using anticancer agents, decreasing the expression of AURKB using a molecular-targeting drug may be an optimal therapeutic strategy. [ABSTRACT FROM AUTHOR]

We conducted inhalation and intratracheal instillation studies of zinc oxide (ZnO) nanoparticles in order to examine their pulmonary toxicity. F344 rats were received intratracheal instillation at 0.2 or 1 mg of ZnO nanoparticles with a primary diameter of 35 nm that were well-dispersed in distilled water. Cell analysis and chemokines in bronchoalveolar lavage fluid (BALF) were analyzed at three days, one week, one month, three months, and six months after the instillation. As the inhalation study, rats were exposed to a concentration of inhaled ZnO nanoparticles (2 and 10 mg/m³) for four weeks (6 h/day, 5 days/week). The same endpoints as in the intratracheal instillation study were analyzed at three days, one month, and three months after the end of the exposure. In the intratracheal instillation study, both the 0.2 and the 1.0 mg ZnO groups had a transient increase in the total cell and neutrophil count in the BALF and in the expression of cytokine-induced neutrophil chemoattractant (CINC)-1, CINC-2, chemokine for neutrophil, and heme oxygenase-1 (HO-1), an oxidative stress marker, in the BALF. In the inhalation study, transient increases in total cell and neutrophil count, CINC-1,-2 and HO-1 in the BALF were observed in the high concentration groups. Neither of the studies of ZnO nanoparticles showed persistent inflammation in the rat lung, suggesting that well-dispersed ZnO nanoparticles have low toxicity. [ABSTRACT FROM AUTHOR]

Background: WNT/β-catenin signaling plays an important role in the pathogenesis of idiopathic pulmonary fibrosis (IPF); however, the role of WNT10A via transforming growth factor (TGF)-β signaling remains unclear.Methods: We evaluated the expression of WNT10A and TGF-β in bleomycin (BLM)-treated mice and the interactions between TGF-β or BLM and WNT10A in vitro. Additionally, we investigated IPF patients who underwent video-assisted thoracoscopic surgery to determine whether the WNT10A expression is related to the survival.Results: Increased WNT10A and TGF-β expressions were noted in the BLM-treated mice. Real-time PCR and luciferase reporter assays demonstrated the levels of WNT10A and collagen in the fibroblasts cells to increase after TGF-β administration. Conversely, WNT10A siRNA treatment inhibited the synthesis of collagen in the transfected fibroblasts cells. A Kaplan-Meier survival analysis demonstrated a tendency toward a poor survival among the IPF patients with a WNT10A-positive expression compared to those with a negative expression (Hazard ratio 5.351, 95 % CI 1.703-16.82; p = 0.0041). An overexpression of WNT10A was found to be significantly predictive of an acute exacerbation of IPF (AE-IPF) (Odds ratio 13.69, 95 % CI 1.728-108.5; p = 0.013).Conclusions: WNT10A plays an important role in the pathogenesis of IPF via TGF-β activation and it may also be a sensitive predictor for the onset of an AE-IPF. [ABSTRACT FROM AUTHOR]

Mitochondria are important cellular organelles that function as control centers of the energy supply for highly proliferative cancer cells and regulate apoptosis after cancer chemotherapy. Cisplatin is one of the most important chemotherapeutic agents and a key drug in therapeutic regimens for a broad range of solid tumors. Cisplatin may directly interact with mitochondria, which can induce apoptosis. The direct interactions between cisplatin and mitochondria may account for our understanding of the clinical activity of cisplatin and development of resistance. However, the basis for the roles of mitochondria under treatment with chemotherapy is poorly understood. In this review, we present novel aspects regarding the unique characteristics of the mitochondrial genome in relation to the use of platinum-based chemotherapy and describe our recent work demonstrating the importance of the mitochondrial transcription factor A (mtTFA) expression in cancer cells. [ABSTRACT FROM AUTHOR]

Background The Y-box binding protein 1 (YB-1) possesses pleiotropic functions through its interactions with various cellular proteins, and its high expression levels make it a potential useful prognostic biomarker for cancer cells. Eukaryotic DNA topoisomerases, such as DNA topoisomerase 1 (TOPO1) and DNA topoisomerase 2 (TOPO2), are the essential DNA metabolism regulators that usually overexpressed in cancer cells, and multiple proteins have been reported to regulate the enzyme activity and the clinical efficacy of their inhibitors. The present study unraveled the interaction of YB-1 with TOPO1, and further investigated the related function and potential mechanisms during the interaction. Methods The direct association of TOPO1 with specific domain of YB-1 was explored by coimmunoprecipitation and GST pull-down assays. The interaction function was further clarified by DNA relaxation assays, co-immunoprecipitation and WST-8 assays with in vitro gain- and loss- of function models. Results We found that YB-1 interacts directly with TOPO1 (but not with TOPO2) and promotes TOPO1 catalytic activity. Interactions between YB-1 and TOPO1 increased when cancer cells were treated with the TOPO1 inhibitor, camptothecin (CPT), but not with the TOPO2 inhibitor, adriamycin (ADM). Furthermore, we found that the interaction is prevented by pretreatment with the antioxidant agent, N-acetyl cysteine, and that YB-1 downregulation renders cells resistant to CPT. Conclusions Our findings suggest that nuclear YB-1 serves as an intracellular promoter of TOPO1 catalytic activity that enhances CPT sensitivity through its direct interaction with TOPO1. [ABSTRACT FROM AUTHOR]

It is thought that inhaled dusts such as asbestos and man-made mineral fibers in the lung repeatedly induce persistent inflammation and finally lead to pulmonary fibrosis and respiratory cancer. There have been many studies about whether a variety of factors, such as oxidative stress including free radicals, chemokines, inflammatory cytokines, and fibrosis-related cytokines are related to pulmonary fibrosis, lung cancer and malignant mesothelioma. In this paper, we introduce the relationship between these factors and these diseases. It is important to determine what physicochemical properties of fibrous materials such as asbestos are related to asbestos-related diseases. We show the relationship between the physicochemical properties of not only asbestos but also other fibrous materials and inflammation, fibrosis and biopersistence in the lung. [ABSTRACT FROM AUTHOR]

Pulmonary inflammation, especially persistent inflammation, has been found to play a key role in respiratory disorders induced by nanoparticles in animal models. In inhalation studies and instillation studies of nanomaterials, persistent inflammation is composed of neutrophils and alveolar macrophages, and its pathogenesis is related to chemokines such as the cytokine-induced neutrophil chemoattractant (CINC) family and macrophage inflammatory protein-lα and oxidant stress-related genes such as heme oxygenase-1 (HO-1). DNA damages occur chemically or physically by nanomaterials. Chemical and physical damage are associated with point mutation by free radicals and double strand brake, respectively. The failure of DNA repair and accumulation of mutations might occur when inflammation is prolonged, and finally normal cells could become malignant. These free radicals can not only damage cells but also induce signaling molecules containing immunoreaction. Nanoparticles and asbestos also induce the production of free radicals. In allergic responses, nanoparticles act as Th2 adjuvants to activate Th2 immune responses such as activation of eosinophil and induction of IgE. Taken together, the presence of persistent inflammation may contribute to the pathogenesis of a variety of diseases induced by nanomaterials. [ABSTRACT FROM AUTHOR]

Angiogenic stimuli induce tubular morphogenesis and angiogenesis in vascular endothelial cells, but these cells are highly vulnerable to cytokines, oxidative stress, and genotoxic anticancer agents. A transcription factor, NF-κB, is involved in the protection against apoptosis and in angiogenesis in response to stimuli that could induce cell death. NF-κB was specifically activated by the genotoxic anticancer therapeutic agents etoposide and doxorubicin, but not by bleomycin, mitomycin C and cisplatin, in human vascular endothelial cells in three independent assay systems: nuclear translocation of NF-κB, binding of NF-κB to its consensus sequence, and NF-κB -dependent transcription. Exposure to etoposide and doxorubicin induced tubular morphogenesis by vascular endothelial cells in type I collagen gel at rates comparable to tumor necrosis factor-α. Co-administration of NF-κB antisense oligonucleotides inhibited the angiogenesis by doxorubicin and etoposide. In contrast, bleomycin, mitomycin C, and cisplatin did not induce angiogenesis. An angiogenic factor, interleukin 8, was dramatically induced in vascular endothelial cells treated with doxorubicin, but not in cells treated with cisplatin. Co-administration of anti-interleukin 8 antibody almost completely blocked the doxorubicin-induced angiogenesis in vitro, suggesting a paracrine/autocrine control through drug-induced angiogenic factor(s). The presence or absence of NF-κB activation may have an essential role in tubular morphogenesis by vascular endothelial cells during chemotherapeutic treatment, possibly through interleukin 8. [ABSTRACT FROM AUTHOR]