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Alcohol use disorders are common both in the United States and globally, and are associated with a variety of co-morbid, inflammation-linked diseases. The pathogenesis of many of these ailments are driven by the activation of the NLRP3 inflammasome, a multi-protein intracellular pattern recognition receptor complex that facilitates the cleavage and secretion of the pro-inflammatory cytokines IL-1β and IL-18. We hypothesized that protracted exposure of leukocytes to ethanol would amplify inflammasome activation, which would help to implicate mechanisms involved in diseases associated with both alcoholism and aberrant NLRP3 inflammasome activation. Here we show that long-term ethanol exposure of human peripheral blood mononuclear cells and a mouse macrophage cell line (J774) amplifies IL-1β secretion following stimulation with NLRP3 agonists, but not with AIM2 or NLRP1b agonists. The augmented NRLP3 activation was mediated by increases in iNOS expression and NO production, in conjunction with increases in mitochondrial membrane depolarization, oxygen consumption rate, and ROS generation in J774 cells chronically exposed to ethanol (CE cells), effects that could be inhibited by the iNOS inhibitor SEITU, the NO scavenger carboxy-PTIO, and the mitochondrial ROS scavenger MitoQ. Chronic ethanol exposure did not alter K + efflux or Zn 2+ homeostasis in CE cells, although it did result in a lower intracellular concentration of NAD + . Prolonged administration of acetaldehyde, the product of alcohol dehydrogenase (ADH) mediated metabolism of ethanol, mimicked chronic ethanol exposure, whereas ADH inhibition prevented ethanol-induced IL-1β hypersecretion. Together, these results indicate that increases in iNOS and mitochondrial ROS production are critical for chronic ethanol-induced IL-1β hypersecretion, and that protracted exposure to the products of ethanol metabolism are probable mediators of NLRP3 inflammasome hyperactivation., (Copyright © 2017. Published by Elsevier B.V.)

Immunosuppression is a major complication of alcoholism that contributes to increased rates of opportunistic infections and sepsis in alcoholics. The NLRP3 inflammasome, a multiprotein intracellular pattern recognition receptor complex that facilitates the cleavage and secretion of the proinflammatory cytokines IL-1β and IL-18, can be inhibited by ethanol, and we sought to better understand the mechanism through which this occurs and whether chemically similar molecules exert comparable effects. We show that ethanol can specifically inhibit activation of the NLRP3 inflammasome, resulting in attenuated IL-1β and caspase-1 cleavage and secretion, as well as diminished apoptosis-associated speck-like protein containing a CARD (ASC) speck formation, without affecting potassium efflux, in a mouse macrophage cell line (J774), mouse bone marrow-derived dendritic cells, mouse neutrophils, and human PBMCs. The inhibitory effects on the Nlrp3 inflammasome were independent of γ-aminobutyric acid A receptor activation or N-methyl-d-asparate receptor inhibition but were associated with decreased oxidant production. Ethanol treatment markedly decreased cellular tyrosine phosphorylation, whereas administration of the tyrosine phosphatase inhibitor sodium orthovanadate prior to ethanol restored tyrosine phosphorylation and IL-1β secretion subsequent to ATP stimulation. Furthermore, sodium orthovanadate-induced phosphorylation of ASC Y144, necessary and sufficient for Nlrp3 inflammasome activation, and secretion of phosphorylated ASC were inhibited by ethanol. Finally, multiple alcohol-containing organic compounds exerted inhibitory effects on the Nlrp3 inflammasome, whereas 2-methylbutane (isopentane), the analogous alkane of the potent inhibitor isoamyl alcohol (isopentanol), did not. Our results demonstrate that ethanol antagonizes the NLRP3 inflammasome at an apical event in its activation through the stimulation of protein tyrosine phosphatases, an effect shared by other short-chain alcohols., (Copyright © 2016 by The American Association of Immunologists, Inc.)

A facile sonochemical approach was used to deposit 3-5 nm monodisperse gold nanoparticles on porous SiO2-WO3 composite spheres, as confirmed by powder X-ray diffraction (XRD) and transmission electron microscopy (TEM). High-resolution TEM (HR-TEM) and energy dispersive X-ray spectroscopy (EDS) further characterized the supported Au nanoparticles within the Au-SiO2-WO3 composite. These analyses showed isolated Au nanoparticles within both SiO2- and WO3-containing regions. Selective etching of the SiO2 matrix from Au-SiO2-WO3 yielded a pure Au-WO3 material with well-dispersed 10 nm Au nanoparticles and moderate porosity. This combined sonochemical-nanocasting technique has not been previously used to synthesize Au-WO3 photocatalysts. Methylene blue (MB) served as a probe for the adsorption capacity and visible light photocatalytic activity of these WO3-containing catalysts. Extensive MB demethylation (azures A, B, C, and thionine) and polymerization of these products occurred over WO3 under dark conditions, as confirmed by electrospray ionization mass spectrometry (ESI-MS). Photoirradiation of these suspensions led to further degradation primarily through demethylation and polymerization pathways, regardless of the presence of Au nanoparticles. Ring-opening sulfur oxidation to the sulfone was a secondary photocatalytic pathway. According to UV-vis spectroscopy, pure WO3 materials showed superior MB adsorption compared to SiO2-WO3 composites. Compared to their respective nonloaded catalysts, Au-SiO2-WO3 and Au-WO3 catalysts exhibited enhanced visible light photocatalytic activity toward the degradation of MB. Specifically, the rates of MB degradation over Au-WO3 and Au-SiO2-WO3 during 300 min of irradiation were faster than those over their nonloaded counterparts (WO3 and SiO2-WO3). These studies highlight the ability of Au-WO3 to serve as an excellent adsorbant and photodegradation catalyst toward MB.