Adverse outcome pathway (AOP): α2u-globulin nephropathy and kidney tumors in male rats.

The National Research Council's vision of using adverse outcome pathways (AOPs) as a framework to assist with toxicity assessment for regulatory requirements of chemical assessment has continued to gain traction since its release in 2007. The need to expand the AOP knowledge base has gained urgency, with the U.S.

Inhaled carbon nanotubes reach the subpleural tissue in mice.

Carbon nanotubes are shaped like fibres and can stimulate inflammation at the surface of the peritoneum when injected into the abdominal cavity of mice, raising concerns that inhaled nanotubes may cause pleural fibrosis and/or mesothelioma. Here, we show that multiwalled carbon nanotubes reach the subpleura in mice after a single inhalation exposure of 30 mg m(-3) for 6 h. Nanotubes were embedded in the subpleural wall and within subpleural macrophages.

Bacterial lipopolysaccharide enhances PDGF signaling and pulmonary fibrosis in rats exposed to carbon nanotubes.

Engineered multi-walled carbon nanotubes (MWCNT) represent a possible health risk for pulmonary fibrosis due to their fiber-like shape and potential for persistence in the lung. We postulated that bacterial lipopolysaccharide (LPS), a ubiquitous agent in the environment that causes lung inflammation, would enhance fibrosis caused by MWCNT. Rats were exposed to LPS and then intratracheally instilled with MWCNT or carbon black (CB) nanoparticles 24 hours later.

Inhaled multiwalled carbon nanotubes potentiate airway fibrosis in murine allergic asthma.

Carbon nanotubes are gaining increasing attention due to possible health risks from occupational or environmental exposures. This study tested the hypothesis that inhaled multiwalled carbon nanotubes (MWCNT) would increase airway fibrosis in mice with allergic asthma. Normal and ovalbumin-sensitized mice were exposed to a MWCNT aerosol (100 mg/m(3)) or saline aerosol for 6 hours.

STAT-1 signaling in human lung fibroblasts is induced by vanadium pentoxide through an IFN-beta autocrine loop.

The inhalation of vanadium pentoxide (V(2)O(5)) results in bronchitis and airway fibrosis. The lung fibrotic response to V(2)O(5) partially resolves where fibroblasts first proliferate and deposit collagen, but then undergo growth arrest and apoptosis. STAT-1 mediates fibroblast growth arrest and apoptosis.

Variables influencing interactions of untargeted quantum dot nanoparticles with skin cells and identification of biochemical modulators.

Skin cells (NHEK) take up untargeted quantum dots (QD) with surface polyethylene glycol (PEG), amines, and carboxylic acids, but the mechanisms are unknown. Time courses of QD-NHEK interactions were determined and effects of QD surface coating, temperature, culture medium supplements and inhibitors of the cell cycle and endocytosis identified. The magnitude of QD-NHEK interactions was coating dependent.

Effects of mechanical flexion on the penetration of fullerene amino acid-derivatized peptide nanoparticles through skin.

Dermatomed porcine skin was fixed to a flexing device and topically dosed with 33.5 mg.mL-1 of an aqueous solution of a fullerene-substituted phenylalanine (Baa) derivative of a nuclear localization peptide sequence (Baa-Lys(FITC)-NLS).

Functional selectivity of dopamine D1 receptor agonists in regulating the fate of internalized receptors.

Recently, we demonstrated that D(1) agonists can cause functionally selective effects when the endpoints of receptor internalization and adenylate cyclase activation are compared. The present study was designed to probe the phenomenon of functional selectivity at the D(1) receptor further by testing the hypothesis that structurally dissimilar agonists with efficacies at these endpoints that equal or exceed those of dopamine would differ in ability to influence receptor fate after internalization, a functional endpoint largely unexplored for the D(1) receptor. We selected two novel agonists of therapeutic interest that meet these criteria (the isochroman A-77636, and the isoquinoline dinapsoline), and compared the fates of the D(1) receptor after internalization in response to these two compounds with that of dopamine.

Surface coatings determine cytotoxicity and irritation potential of quantum dot nanoparticles in epidermal keratinocytes.

Quantum dot (QD) nanoparticles have potential applications in nanomedicine as drug delivery vectors and diagnostic agents, but the skin toxicity and irritation potential of QDs are unknown. Human epidermal keratinocytes (HEKs) were used to assess if QDs with different surface coatings would cause differential effects on HEK cytotoxicity, proinflammatory cytokine release, and cellular uptake. Commercially available QDs of two different sizes, QD 565 and QD 655, with neutral (polyethylene glycol (PEG)), cationic (PEG-amine), or anionic (carboxylic acid) coatings were utilized.

Penetration of intact skin by quantum dots with diverse physicochemical properties.

Skin is the largest organ of the body and is a potential route of exposure to engineered nanomaterials, but the permeability of the skin to these nanomaterials is unknown. We selected commercially available quantum dots (QD) of two core/shell sizes and shapes and three different surface coatings to determine if QD could penetrate intact skin in a size- or coating-dependent manner. Spherical 4.

Differential activation of adenylate cyclase and receptor internalization by novel dopamine D1 receptor agonists.

Structurally dissimilar dopamine D(1) receptor agonists were compared with dopamine in their ability to activate adenylate cyclase and to internalize hemagglutinin-tagged human D(1) receptors in a stably transfected human embryonic kidney cell line. Thirteen dopamine D(1) receptor agonists were selected rationally from three different structural classes: rigid fused ring compounds [dihydrexidine, dinapsoline, dinoxyline, apomorphine, and (5aR,11bS)-4,5,5a,6,7,11b-hexahydro-2-propyl-3-thia-5-azacyclopent-1-ena[c]-phenanthrene-9,10-diol (A86929)]; isochromans [(1R,3S)-3-(1'adamantyl)-1-aminomethyl-3,4-dihydo-5,6-dihydroxy-1H-2-benzopyran (A77636) and (1R,3S)-3-phenyl-1-aminomethyl-3,4-dihydo-5,6-dihydroxy-1H-2-benzopyran (A68930)]; and benzazepines [7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine (SKF38393), (+/-)-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine (SKF77434), 6-chloro-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine (SKF82958), 3-methyl-6-chloro-7,8-hydroxy-1-[3-methylphenyl]-2,3,4,5-tetrahydro-]H-3-benzazepine (SKF83959), R(+)-6-chloro-7,8,-dihydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine (SKF82957), and R(+)-6-chloro-7,8,-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine (SKF81297)]. The working hypothesis was that some agonists have differential effects on adenylate cyclase versus receptor internalization that could be correlated to the structural class of the agonist.