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Leiss V.,University of Tubingen | Flockerzie K.,University of Tubingen | Novakovic A.,University of Tubingen | Rath M.,German Institute of Human Nutrition | And 5 more authors.
American Journal of Physiology - Endocrinology and Metabolism | Year: 2014

Bordetella pertussis toxin (PTx), also known as islet-activating protein, induces insulin secretion by ADP-ribosylation of inhibitory G proteins. PTx-induced insulin secretion may result either from inactivation of Gαo proteins or from combined inactivation of Gαo, Gαi1, Gαi2, and Gαi3 isoforms. However, the specific role of Gαi2 in pancreatic β-cells still remains unknown. In global (Gαi2 −/−) and β-cell-specific (Gαi2 βcko) gene-targeted Gαi2 mouse models, we studied glucose homeostasis and islet functions. Insulin secretion experiments and intracellular Ca2+ measurements were used to characterize Gαi2 function in vitro. Gαi2 −/− and Gαi2 βcko mice showed an unexpected metabolic phenotype, i.e., significantly lower plasma insulin levels upon intraperitoneal glucose challenge in Gαi2 −/− and Gαi2 βcko mice, whereas plasma glucose concentrations were unchanged in Gαi2 −/− but significantly increased in Gαi2 βcko mice. These findings indicate a novel albeit unexpected role for Gαi2 in the expression, turnover, and/or release of insulin from islets. Detection of insulin secretion in isolated islets did not show differences in response to high (16 mM) glucose concentrations between control and β-cell-specific Gαi2-deficient mice. In contrast, the two- to threefold increase in insulin secretion evoked by L-arginine or L-ornithine (in the presence of 16 mM glucose) was significantly reduced in islets lacking Gαi2. In accord with a reduced level of insulin secretion, intracellular calcium concentrations induced by the agonistic amino acid L-arginine did not reach control levels in β-cells. The presented analysis of gene-targeted mice provides novel insights in the role of β-cell Gαi2 showing that amino acid-induced insulin-release depends on Gαi2. © 2014 the American Physiological Society.

Gonzalez N.L.,National Institute of Environmental Health science
Epidemiology | Year: 2016

BACKGROUND:: Douching was recently reported to be associated with elevated levels of urinary metabolites of endocrine disrupting phthalates, but there is no literature on douching in relation to ovarian cancer. Numerous case-control studies of genital talc use have reported an increased risk of ovarian cancer, but prospective cohort studies have not uniformly confirmed this association. Behavioral correlation between talc use and douching could produce confounding. METHODS:: The Sister Study (2003-2009) enrolled and followed 50,884 women in the US and Puerto Rico who had a sister diagnosed with breast cancer. At baseline participants were asked about douching and talc use during the previous 12 months. During follow-up (median of 6.6 years) 154 participants reported a diagnosis of ovarian cancer. We computed adjusted hazard ratios (HR) and 95% confidence intervals (CI) for ovarian cancer risk using the Cox proportional hazards model. RESULTS:: There was little association between baseline perineal talc use and subsequent ovarian cancer (HR: 0.73 CI: 0.44, 1.2). Douching was more common among talc users (OR: 2.1 CI: 2.0, 2.3), and douching at baseline was associated with increased subsequent risk of ovarian cancer (HR: 1.8 CI: 1.2, 2.8). CONCLUSIONS:: Douching but not talc use was associated with increased risk of ovarian cancer in the Sister Study. Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.

Chen W.-Y.,Kaohsiung Medical University | Cheng Y.-H.,National Taiwan University | Hsieh N.-H.,Institute of Labor | Wu B.-C.,National Taiwan University | And 5 more authors.
International Journal of Nanomedicine | Year: 2015

Zinc oxide nanoparticles (ZnO NPs) have been widely used in consumer products, therapeutic agents, and drug delivery systems. However, the fate and behavior of ZnO NPs in living organisms are not well described. The purpose of this study was to develop a physiologically based pharmacokinetic model to describe the dynamic interactions of65ZnO NPs in mice. We estimated key physicochemical parameters of partition coefficients and excretion or elimination rates, based on our previously published data quantifying the biodistributions of 10 nm and 71 nm65ZnO NPs and zinc nitrate(65Zn(NO3)2) in various mice tissues. The time-dependent partition coefficients and excretion or elimination rates were used to construct our physiologically based pharmacokinetic model. In general, tissue partition coefficients of65ZnO NPs were greater than those of65Zn(NO3)2, particularly the lung partition coefficient of 10 nm65ZnO NPs. Sensitivity analysis revealed that 71 nm65ZnO NPs and65Zn(NO3)2 were sensitive to excretion and elimination rates in the liver and gastrointestinal tract. Although the partition coefficient of the brain was relative low, it increased time-dependently for65ZnO NPs and65Zn(NO3)2. The simulation of65Zn(NO3)2 was well fitted with the experimental data. However, replacing partition coefficients of65ZnO NPs with those of65Zn(NO3)2 after day 7 greatly improved the fitness of simulation, suggesting that ZnO NPs might decompose to zinc ion after day 7. In this study, we successfully established a potentially predictive dynamic model for slowly decomposed NPs. More caution is suggested for exposure to65ZnO NPs <10 nm because those small65ZnO NPs tend to accumulate in the body for a relatively longer time than 71 nm65ZnO NPs and65Zn(NO3)2 do. © 2015 Chen et al.

Ekenga C.C.,National Institute of Environmental Health science | Parks C.G.,National Institute of Environmental Health science | Sandler D.P.,National Institute of Environmental Health science
International Journal of Cancer | Year: 2015

We investigated the relationship between workplace chemical exposures and breast cancer risk among women enrolled in the Sister Study, a prospective cohort study of US and Puerto Rican women. A total of 47,640 participants reported work outside of the home. Workplace exposure to eleven agents (acids, dyes or inks, gasoline or other petroleum products, glues or adhesives, lubricating oils, metals, paints, pesticides, soldering materials, solvents and stains or varnishes) was characterized based on self-reports of frequency and duration of use. Approximately 14% of the study population reported exposure to only one agent and 11% reported working with two or more of the 11 agents in their lifetime. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated for each agent, adjusting for established breast cancer risk factors. During follow-up, 1,966 cases of breast cancer were reported. Although there were no significant associations between ever use of the eleven agents evaluated and breast cancer risk, women with cumulative exposure to gasoline or petroleum products at or above the highest quartile cutoff had an elevated risk of total (HR: 2.3, 95%CI: 1.1-4.9) and invasive (HR: 2.5, 95%CI: 1.1-5.9) breast cancer compared with women in the lowest quartile group (ptrend=0.03). Workplace exposure to soldering materials was associated with an increased risk of premenopausal breast cancer (HR=1.8, 95% CI=1.1-3.0). Findings support the need for further studies to elucidate the role of occupational chemicals in breast cancer etiology. © 2015 UICC.

Luo Y.-H.,National Institute of Environmental Health science | Wu Z.W.,National Health Research Institute | Tsai H.-T.,National Institute of Environmental Health science | Lin S.-Y.,National Health Research Institute | Lin P.,National Institute of Environmental Health science
Nano Letters | Year: 2015

In this study, we sought to control the assembly of an endotoxin known as the biologically supramolecular lipopolysaccharide (LPS, which consists of three portions: an O antigen, a core carbohydrate, and a lipid A molecule) in order to modulate immunological responses in a manner that has the potential for utilization in vaccine development. Changing the structures of LPS aggregates from lamellas to specific nonlamellas (i.e., cubosomes and hexosomes) can dramatically enhance the strength of LPS in causing inflammatory responses, leading to highly active responses. In order to control the formation of cubosome-free and hexosome-free nonlamellas, we designed a simple strategy based on the use of hydrophilic gold nanodots (AuNDs) to control LPS assembly to facilitate the formation of stable endotoxin nanovesicles, which are stable precursors of cubosomes and hexosomes with specific immunological effects. Structurally, the wall thicknesses of these nanovesicles are exactly twice the lengths of a single LPS molecule, indicating that the LPS molecules adopt a tail-to-tail arrangement (with the lipid A portions acting as the tail domain). The involvement of the hydrophilic AuNDs to laterally link polar domains of LPS can result in the progressive extension of an endotoxically active zone of lipid A assembly, leading to the eventual formation of large-size nanovesicles. Our results showed that endotoxin nanovesicles with such dense lipid A units can elicit the stronger inflammatory gene expressions, including interleukin 6 (IL-6), IL-1A, TNF-α, C-X-C chemokine ligand (CXCL) 1, 2, and 11, which have characteristics of T-helper 1 adjuvants. These findings provide evidence that the concept of manipulating the surface hydrophilicity of AuNDs to control LPS assembly in order to avoid the formation of highly active cubosomes and hexosomes, and thereby modulate immunological responses appropriately, could prove useful in vaccine development. © 2015 American Chemical Society.

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