Exposure to titanium dioxide and other metallic oxide nanoparticles induces cytotoxicity on human neural cells and fibroblasts

The use of titanium dioxide (TiO2) in various industrial applications (eg, production of paper, plastics, cosmetics, and paints) has been expanding thereby increasing the occupational and other environmental exposure of these nanoparticles to humans and other species. However, the health effects of exposure to TiO2 nanoparticles have not been systematically assessed even though recent studies suggest that such exposure induces inflammatory responses in lung tissue and cells. Because the effects of such nanoparticles on human neural cells are unknown, we have determined the putative cytotoxic effects of these nanoparticles on human astrocytes-like astrocytoma U87 cells and compared their effects on normal human fibroblasts. We found that TiO2 micro- and nanoparticles induced cell death on both human cell types in a concentration-related manner. We further noted that zinc oxide (ZnO) nanoparticles were the most effective, TiO2 nanoparticles the second most effective, and magnesium oxide (MgO) nanoparticles the least effective in inducing cell death in U87 cells. The cell death mechanisms underlying the effects of TiO2 micro- and nanoparticles on U87 cells include apoptosis, necrosis, and possibly apoptosis-like and necrosis-like cell death types. Thus, our findings may have toxicological and other pathophysiological implications on exposure of humans and other mammalian species to metallic oxide nanoparticles

Structure-Templated Predictions of Novel Protein Interactions from Sequence Information

The multitude of functions performed in the cell are largely controlled by a set of carefully orchestrated protein interactions often facilitated by specific binding of conserved domains in the interacting proteins. Interacting domains commonly exhibit distinct binding specificity to short and conserved recognition peptides called binding profiles. Although many conserved domains are known in nature, only a few have well-characterized binding profiles. Here, we describe a novel predictive method known as domain–motif interactions from structural topology (D-MIST) for elucidating the binding profiles of interacting domains. A set of domains and their corresponding binding profiles were derived from extant protein structures and protein interaction data and then used to predict novel protein interactions in yeast. A number of the predicted interactions were verified experimentally, including new interactions of the mitotic exit network, RNA polymerases, nucleotide metabolism enzymes, and the chaperone complex. These results demonstrate that new protein interactions can be predicted exclusively from sequence information

Proteins associated with pancreatic cancer survival in patients with resectable pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease with a dismal prognosis. However, while most patients die within the first year of diagnosis, very rarely, a few patients can survive for >10 years. Better understanding the molecular characteristics of the pancreatic adenocarcinomas from these very-long-term survivors (VLTS) may provide clues for personalized medicine and improve current pancreatic cancer treatment. To extend our previous investigation, we examined the proteomes of individual pancreas tumor tissues from a group of VLTS patients (survival ≥10 years) and short-term survival patients (STS, survival <14 months). With a given analytical sensitivity, the protein profile of each pancreatic tumor tissue was compared to reveal the proteome alterations that may be associated with pancreatic cancer survival. Pathway analysis of the differential proteins identified suggested that MYC, IGF1R and p53 were the top three upstream regulators for the STS-associated proteins, and VEGFA, APOE and TGFβ-1 were the top three upstream regulators for the VLTS-associated proteins. Immunohistochemistry analysis using an independent cohort of 145 PDAC confirmed that the higher abundance of ribosomal protein S8 (RPS8) and prolargin (PRELP) were correlated with STS and VLTS, respectively. Multivariate Cox analysis indicated that 'High-RPS8 and Low-PRELP' was significantly associated with shorter survival time (HR=2.69, 95% CI 1.46-4.92, P=0.001). In addition, galectin-1, a previously identified protein with its abundance aversely associated with pancreatic cancer survival, was further evaluated for its significance in cancer-associated fibroblasts. Knockdown of galectin-1 in pancreatic cancer-associated fibroblasts dramatically reduced cell migration and invasion. The results from our study suggested that PRELP, LGALS1 and RPS8 might be significant prognostic factors, and RPS8 and LGALS1 could be potential therapeutic targets to improve pancreatic cancer survival if further validated

Acetaminophen use and risk of asthma, rhinoconjunctivitis and eczema in adolescents : ISAAC Phase Three

Rationale: There is epidemiological evidence that the use of acetaminophen may increase the risk of developing asthma. Objectives: To investigate the risk of asthma and other allergic disorders associated with the current use of acetaminophen in 13- to 14-year-old children in different populations worldwide. Methods: As part of the International Study of Asthma and Allergies in Childhood (ISAAC) Phase Three, 13- to 14-year-old children completed written and video questionnaires obtaining data on current symptoms of asthma, rhinoconjunctivitis, and eczema, and a written environmental questionnaire obtaining data on putative risk factors, including acetaminophen use in the past 12 months. Measurements and Main Results: The primary outcome measure was the odds ratio (OR) of current asthma symptoms associated with acetaminophen use calculated by logistic regression. A total of 322,959 adolescent children from 113 centers in 50 countries participated. In the multivariate analyses the recent use of acetaminophen was associated with an exposure-dependent increased risk of current asthma symptoms (OR, 1.43 [95% confidence interval, 1.33–1.53] and 2.51 [95% confidence interval, 2.33–2.70] for medium and high versus no use, respectively). Acetaminophen use was also associated with an exposure-dependent increased risk of current symptoms of rhinoconjunctivitis and eczema. Conclusions: Acetaminophen use may represent an important risk factor for the development and/or maintenance of asthma, rhinoconjunctivitis, and eczema in adolescent children.peer-reviewe

Global variation in the prevalence and severity of asthma symptoms : phase three of the International Study of Asthma and Allergies in Childhood (ISAAC)

Background: Phase Three of the International Study of Asthma and Allergies in Childhood (ISAAC) measured the global prevalence and severity of asthma symptoms in children. Methods: A cross-sectional questionnaire survey of 798 685 children aged 13–14 years from 233 centres in 97 countries, and 388 811 children aged 6–7 years from 144 centres in 61 countries, was conducted between 2000 and 2003 in .90% of the centres. Results: The prevalence of wheeze in the past 12 months (current wheeze) ranged from 0.8% in Tibet (China) to 32.6% in Wellington (New Zealand) in the 13–14 year olds, and from 2.4% in Jodhpur (India) to 37.6% in Costa Rica in the 6–7 year olds. The prevalence of symptoms of severe asthma, defined as >4 attacks of wheeze or >1 night per week sleep disturbance from wheeze or wheeze affecting speech in the past 12 months, ranged from 0.1% in Pune (India) to 16% in Costa Rica in the 13–14 year olds and from 0% to 20.3% in the same two centres, respectively, in the 6–7 year olds. Ecological economic analyses revealed a significant trend towards a higher prevalence of current wheeze in centres in higher income countries in both age groups, but this trend was reversed for the prevalence of severe symptoms among current wheezers, especially in the older age group. Conclusion: Wide variations exist in the symptom prevalence of childhood asthma worldwide. Although asthma symptoms tend to be more prevalent in more affluent countries, they appear to be more severe in less affluent countries.peer-reviewe

Treatment of human astrocytoma U87 cells with silicon dioxide nanoparticles lowers their survival and alters their expression of mitochondrial and cell signaling proteins

Recent evidence suggests silicon dioxide micro- and nanoparticles induce cytotoxic effects on lung cells. Thus, there is an increasing concern regarding their potential health hazard. Nevertheless, the putative toxicity of nanoparticles in mammalian cells has not yet been systematically investigated. We previously noted that several metallic oxide nanoparticles exert differential cytotoxic effects on human neural and nonneural cells. Therefore, we hypothesized that silicon dioxide nanoparticles induce cytotoxicity in U87 cells by lowering their survival by decreasing cell survival signaling and disturbing mitochondrial function. To investigate this hypothesis, we determined the activities of the key mitochondrial enzymes, citrate synthase and malate dehydrogenase, in astrocytoma U87 cells treated with silicon dioxide nanoparticles. In addition, we studied the expression of the mitochondrial DNA-encoded proteins, cytochrome C oxidase II and nicotinamide adenine dinucleotide (NADPH) dehydrogenase subunit 6, and cell signaling pathway protein extracellular signal-regulated kinase (ERK) and phosphorylated ERK in treated U87 cells. The activated form of ERK controls cell growth, differentiation, and proliferation. In parallel, we determined survival of U87 cells after treating them with various concentrations of silicon dioxide nanoparticles. Our results indicated that treatment with silicon dioxide nanoparticles induced decreases in U87 cell survival in a dose-related manner. The activities of citrate synthase and malate dehydrogenase in treated U87 cells were increased, possibly due to an energetic compensation in surviving cells. However, the expression of mitochondrial DNA-encoded cytochrome C oxidase subunit II and NADH dehydrogenase subunit 6 and the cell signaling protein ERK and phosphorylated ERK were altered in the treated U87 cells, suggesting that silicon dioxide nanoparticles induced disruption of mitochondrial DNA-encoded protein expression, leading to decreased mitochondrial energy production and decreased cell survival/proliferation signaling. Thus, our results strongly suggest that the cytotoxicity of silicon dioxide nanoparticles in human neural cells implicates altered mitochondrial function and cell survival/proliferation signaling

Evidence for a correlation between the sizes of quiescent galaxies and local environment to z ~ 2

We present evidence for a strong relationship between galaxy size and environment for the quiescent population in the redshift range 1 < z < 2. Environments were measured using projected galaxy overdensities on a scale of 400 kpc, as determined from ~ 96,000 K-band selected galaxies from the UKIDSS Ultra Deep Survey (UDS). Sizes were determined from ground-based K-band imaging, calibrated using space-based CANDELS HST observations in the centre of the UDS field, with photometric redshifts and stellar masses derived from 11-band photometric fitting. From the resulting size-mass relation, we confirm that quiescent galaxies at a given stellar mass were typically ~ 50 % smaller at z ~ 1.4 compared to the present day. At a given epoch, however, we find that passive galaxies in denser environments are on average significantly larger at a given stellar mass. The most massive quiescent galaxies (M_stellar > 2 x 10^11 M_sun) at z > 1 are typically 50 % larger in the highest density environments compared to those in the lowest density environments. Using Monte Carlo simulations, we reject the null hypothesis that the size-mass relation is independent of environment at a significance > 4.8 sigma for the redshift range 1 < z < 2. In contrast, the evidence for a relationship between size and environment is much weaker for star-forming galaxies.Comment: Accepted for publication in MNRAS. 16 pages, 11 figures, 6 table

S100A8 and S100A9 Are Associated with Doxorubicin-Induced Cardiotoxicity in the Heart of Diabetic Mice

© 2016 Pei, Tam, Sin, Wang, Yung, Chan, Wong, Ying, Lai and Siu. Cardiomyopathy is a clinical problem that occurs in the hearts of type 2 diabetic patients as well as cancer patients undergoing doxorubicin chemotherapy. The number of diabetic cancer patients is increasing but surprisingly the cardiac damaging effects of doxorubicin, a commonly used chemotherapeutic drug, on diabetic hearts have not been well-examined. As the signaling mechanisms of the doxorubicin-induced cardiomyopathy in type 2 diabetic heart are largely unknown, this study examined the molecular signaling pathways that are responsible for the doxorubicin-induced cardiotoxicity in type 2 diabetic hearts. Male 14- to 18-week-old db/db mice were used as the type 2 diabetic model, and age-matched non-diabetic db/+ mice served as controls. The db/+ non-diabetic and db/db diabetic mice were randomly assigned to the following groups: db/+CON, db/+DOX-5d, db/+DOX-7d, db/dbCON, db/dbDOX-5d, and db/dbDOX-7d. Mice assigned to doxorubicin (DOX) group were exposed to an intraperitoneal (i.p.) injection of DOX at a dose of 15 mg/kg to induce cardiomyopathy. Mice in control (CON) groups were i.p. injected with the same volume of saline instead of DOX. Mice were euthanized by overdose of ketamine and xylazine 5 or 7 days after the DOX injection. Microarray analysis was adopted to examine the changes of the whole transcriptional profile in response to doxorubicin exposure in diabetic hearts. Ventricular fractional shortening was examined as an indicator of cardiac function by transthoracic echocardiography. The presence of diabetic cardiomyopathy in db/db mice was evident by the reduction of fractional shortening. There was a further impairment of cardiac contractile function 7 days after the DOX administration in db/db diabetic mice. According to our microarray analysis, we identified a panel of regulatory genes associated with cardiac remodeling, inflammatory response, oxidative stress, and metabolism in the DOX-induced cardiac injury in diabetic heart. The microarray results of selected genes were confirmed by real time PCR. Notably, S100A8 and S100A9 were found to have a unique specific expression pattern that was coincident with the DOX-induced cardiomyopathy in diabetic hearts. Correspondingly, NF-κB expression in diabetic hearts was increased together with the elevation of S100A8/9 and activation of p38 MAPK signaling after DOX administration, which induced cardiac inflammation as demonstrated by the elevation of cardiac IL-6 level. These findings provide novel pre-clinical information for revealing the S100A8/A9-associated molecular signaling pathways that mediate the doxorubicin-induced cardiotoxicity in diabetic hearts.Link_to_subscribed_fulltex

Self-Reported Truck Traffic on the Street of Residence and Symptoms of Asthma and Allergic Disease: A Global Relationship in ISAAC Phase 3

BACKGROUND: Associations between traffic pollution on the street of residence and a range of respiratory and allergic outcomes in children have been reported in developed countries, but little is known about such associations in developing countries. METHODS: The third phase of the International Study of Asthma and Allergies in Childhood (ISAAC) was carried out in 13- to 14-year-old and 6- to 7-year-old children across the world. A question about frequency of truck traffic on the street of residence was included in an additional questionnaire. We investigated the association between self-reported truck traffic on the street of residence and symptoms of asthma, rhinoconjunctivitis, and eczema with logistic regression. Adjustments were made for sex, region of the world, language, gross national income, and 10 other subject-specific covariates. RESULTS: Frequency of truck traffic on the street of residence was positively associated with the prevalence of symptoms of asthma, rhinoconjunctivitis, and eczema with an exposure-response relationship. Odds ratios (95% confidence intervals) for "current wheeze" and "almost the whole day" versus "never" truck traffic were 1.35 (1.23-1.49) for 13- to 14-year-olds and 1.35 (1.22-1.48) for 6- to 7-year-olds. CONCLUSIONS: Higher exposure to self-reported truck traffic on the street of residence is associated with increased reports of symptoms of asthma, rhinitis, and eczema in many locations in the world. These findings require further investigation in view of increasing exposure of the world's children to traffic