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Cross-linking of thioredoxin reductase by the sulfur mustard analogue mechlorethamine (methylbis(2-chloroethyl)amine) in human lung epithelial cells and rat lung: selective inhibition of disulfide reduction but not redox cycling.

Jeffrey D. Laskin, Ph.D. - 16 hours 26 min ago

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Cross-linking of thioredoxin reductase by the sulfur mustard analogue mechlorethamine (methylbis(2-chloroethyl)amine) in human lung epithelial cells and rat lung: selective inhibition of disulfide reduction but not redox cycling.

Chem Res Toxicol. 2014 Jan 21;27(1):61-75

Authors: Jan YH, Heck DE, Malaviya R, Casillas RP, Laskin DL, Laskin JD

Abstract
Oxidative stress plays a key role in mechlorethamine (methylbis(2-chloroethyl)amine, HN2) toxicity. The thioredoxin system, consisting of thioredoxin reductase (TrxR), thioredoxin, and NADPH, is important in redox regulation and protection against oxidative stress. HN2 contains two electrophilic side chains that can react with nucleophilic sites in proteins, leading to changes in their structure and function. We report that HN2 inhibits the cytosolic (TrxR1) and mitochondrial (TrxR2) forms of TrxR in A549 lung epithelial cells. TrxR exists as homodimers under native conditions; monomers can be detected by denaturing and reducing SDS-PAGE followed by western blotting. HN2 treatment caused marked decreases in TrxR1 and TrxR2 monomers along with increases in dimers and oligomers under reducing conditions, indicating that HN2 cross-links TrxR. Cross-links were also observed in rat lung after HN2 treatment. Using purified TrxR1, NADPH reduced, but not oxidized, enzyme was inhibited and cross-linked by HN2. LC-MS/MS analysis of TrxR1 demonstrated that HN2 adducted cysteine- and selenocysteine-containing redox centers forming monoadducts, intramolecule and intermolecule cross-links, resulting in enzyme inhibition. HN2 cross-links two dimeric subunits through intermolecular binding to cysteine 59 in one subunit of the dimer and selenocysteine 498 in the other subunit, confirming the close proximity of the N- and C-terminal redox centers of adjacent subunits. Despite cross-linking and inhibition of TrxR activity by HN2, TrxR continued to mediate menadione redox cycling and generated reactive oxygen species. These data suggest that disruption of the thioredoxin system contributes to oxidative stress and tissue injury induced by HN2.

PMID: 24274902 [PubMed - indexed for MEDLINE]

Categories: Publications from UCDPER Members

Quantitative assessment of inhalation exposure and deposited dose of aerosol from nanotechnology-based consumer sprays.

Paul J. Lioy, Ph.D. - Fri, 01/30/2015 - 15:00

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Quantitative assessment of inhalation exposure and deposited dose of aerosol from nanotechnology-based consumer sprays.

Environ Sci Nano. 2014 Apr;1(2):161-171

Authors: Nazarenko Y, Lioy PJ, Mainelis G

Abstract
This study provides a quantitative assessment of inhalation exposure and deposited aerosol dose in the 14 nm to 20 μm particle size range based on the aerosol measurements conducted during realistic usage simulation of five nanotechnology-based and five regular spray products matching the nano-products by purpose of application. The products were also examined using transmission electron microscopy. In seven out of ten sprays, the highest inhalation exposure was observed for the coarse (2.5-10 μm) particles while being minimal or below the detection limit for the remaining three sprays. Nanosized aerosol particles (14-100 nm) were released, which resulted in low but measurable inhalation exposures from all of the investigated consumer sprays. Eight out of ten products produced high total deposited aerosol doses on the order of 10(1)-10(3) ng kg(-1) bw per application, ~85-88% of which were in the head airways, only <10% in the alveolar region and <8% in the tracheobronchial region. One nano and one regular spray produced substantially lower total deposited doses (by 2-4 orders of magnitude less), only ~52-64% of which were in the head while ~29-40% in the alveolar region. The electron microscopy data showed nanosized objects in some products not labeled as nanotechnology-based and conversely did not find nano-objects in some nano-sprays. We found no correlation between nano-object presence and abundance as per the electron microscopy data and the determined inhalation exposures and deposited doses. The findings of this study and the reported quantitative exposure data will be valuable for the manufacturers of nanotechnology-based consumer sprays to minimize inhalation exposure from their products, as well as for the regulators focusing on protecting the public health.

PMID: 25621175 [PubMed - as supplied by publisher]

Categories: Publications from UCDPER Members

The World Health Organization (WHO) Recommends Vaccine Composition for the 2011-2012 Northern Hemisphere Influenza Season

PandemicFlu.gov - Fri, 01/30/2015 - 15:00

The World Health Organization (WHO) Recommends Vaccine Composition for the 2011-2012 Northern Hemisphere Influenza Season

Categories: Government Agency News

Soboba Band of Luiseño Indians Severe Storms, Flooding, and Mudslides

FEMA Disaster Declarations - Tue, 01/27/2015 - 12:01

Major Disaster Declaration number 4206 issued Tue, 01/27/2015 - 12:24

Categories: Government Agency News

Gunmen kill at least 8, take hostages at Tripoli hotel

Homeland Security News - Tue, 01/27/2015 - 10:04

A Libyan security official says that gunmen have stormed on of the most exclusive hotels in Tripoli and have taken an unknown number of hostages after killing at least eight. Essam Al-Naas, a spokesman for a Tripoli security agency, told the Associated Press that a standoff was ongoing Tuesday at the Corinthia Hotel, which sits […]

This story comes to us via Homeland Security - National Terror Alert. National Terror Alert is America's trusted source for homeland security news and information.

Gunmen kill at least 8, take hostages at Tripoli hotel

Categories: Homeland Security News

Secret Service investigating small drone on White House grounds

Homeland Security News - Mon, 01/26/2015 - 10:26

The U.S. Secret Service is investigating after a drone crashed on the White House grounds early Monday morning. The Secret Service locked down the White House shortly after 3 a.m. after an officer on the south grounds of the White House spotted the drone, described as a two-foot wide “quad copter,” flying above the White […]

This story comes to us via Homeland Security - National Terror Alert. National Terror Alert is America's trusted source for homeland security news and information.

Secret Service investigating small drone on White House grounds

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Variability in bioreactivity linked to changes in size and zeta potential of diesel exhaust particles in human immune cells.

Paul J. Lioy, Ph.D. - Mon, 01/26/2015 - 03:00

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Variability in bioreactivity linked to changes in size and zeta potential of diesel exhaust particles in human immune cells.

PLoS One. 2014;9(5):e97304

Authors: Sarkar S, Zhang L, Subramaniam P, Lee KB, Garfunkel E, Strickland PA, Mainelis G, Lioy PJ, Tetley TD, Chung KF, Zhang J, Ryan M, Porter A, Schwander S

Abstract
Acting as fuel combustion catalysts to increase fuel economy, cerium dioxide (ceria, CeO2) nanoparticles have been used in Europe as diesel fuel additives (Envirox™). We attempted to examine the effects of particles emitted from a diesel engine burning either diesel (diesel exhaust particles, DEP) or diesel doped with various concentrations of CeO2 (DEP-Env) on innate immune responses in THP-1 and primary human peripheral blood mononuclear cells (PBMC). Batches of DEP and DEP-Env were obtained on three separate occasions using identical collection and extraction protocols with the aim of determining the reproducibility of particles generated at different times. However, we observed significant differences in size and surface charge (zeta potential) of the DEP and DEP-Env across the three batches. We also observed that exposure of THP-1 cells and PBMC to identical concentrations of DEP and DEP-Env from the three batches resulted in statistically significant differences in bioreactivity as determined by IL-1β, TNF-α, IL-6, IFN-γ, and IL-12p40 mRNA (by qRT-PCR) and protein expression (by ELISPOT assays). Importantly, bioreactivity was noted in very tight ranges of DEP size (60 to 120 nm) and zeta potential (-37 to -41 mV). Thus, these physical properties of DEP and DEP-Env were found to be the primary determinants of the bioreactivity measured in this study. Our findings also point to the potential risk of over- or under- estimation of expected bioreactivity effects (and by inference of public health risks) from bulk DEP use without taking into account potential batch-to-batch variations in physical (and possibly chemical) properties.

PMID: 24825358 [PubMed - indexed for MEDLINE]

Categories: Publications from UCDPER Members