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Two groups of facts have been established in previous drug development studies of the non-benzodiazepine anxiolytic fabomotizole. First, fabomotizole prevents stress-induced decrease in binding ability of the GABAA receptor's benzodiazepine site. Second, fabomotizole is a Sigma1R chaperone agonist, and exposure to Sigma1R antagonists blocks its anxiolytic effect. To prove our main hypothesis of Sigma1R involvement in GABAA receptor-dependent pharmacological effects, we performed a series of experiments on BALB/c and ICR mice using Sigma1R ligands to study anxiolytic effects of benzodiazepine tranquilizers diazepam (1 mg/kg i.p.) and phenazepam (0.1 mg/kg i.p.) in the elevated plus maze test, the anticonvulsant effects of diazepam (1 mg/kg i.p.) in the pentylenetetrazole-induced seizure model, and the hypnotic effects of pentobarbital (50 mg/kg i.p.). Sigma1R antagonists BD-1047 (1, 10, and 20 mg/kg i.p.), NE-100 (1 and 3 mg/kg i.p.), and Sigma1R agonist PRE-084 (1, 5, and 20 mg/kg i.p.) were used in the experiments. Sigma1R antagonists have been found to attenuate while Sigma1R agonists can enhance GABAARs-dependent pharmacological effects. [ABSTRACT FROM AUTHOR]

Sulfur mustard (SM) inhalation causes debilitating pulmonary injury in humans which progresses to fibrosis. Herein, we developed a rat model of SM toxicity which parallels pathological changes in the respiratory tract observed in humans. SM vapor inhalation caused dose (0.2–0.6 mg/kg)-related damage to the respiratory tract within 3 days of exposure. At 0.4–0.6 mg/kg, ulceration of the proximal bronchioles, edema and inflammation were observed, along with a proteinaceous exudate containing inflammatory cells in alveolar regions. Time course studies revealed that the pathologic response was biphasic. Thus, changes observed at 3 days post-SM were reduced at 7–16 days; this was followed by more robust aberrations at 28 days, including epithelial necrosis and hyperplasia in the distal bronchioles, thickened alveolar walls, enlarged vacuolated macrophages, and interstitial fibrosis. Histopathologic changes were correlated with biphasic increases in bronchoalveolar lavage (BAL) cell and protein content and proliferating cell nuclear antigen expression. Proinflammatory proteins receptor for advanced glycation end product (RAGE), high-mobility group box protein (HMGB)-1, and matrix metalloproteinase (MMP)-9 also increased in a biphasic manner following SM inhalation, along with surfactant protein-D (SP-D). Tumor necrosis factor (TNF)-α and inducible nitric oxide synthase (iNOS), inflammatory proteins implicated in mustard lung toxicity, and the proinflammatory/profibrotic protein, galectin (Gal)-3, were upregulated in alveolar macrophages and in bronchiolar regions at 3 and 28 days post-SM. Inflammatory changes in the lung were associated with oxidative stress, as reflected by increased expression of heme oxygenase (HO)-1. These data demonstrate a similar pathologic response to inhaled SM in rats and humans suggesting that this rodent model can be used for mechanistic studies and for the identification of efficacious therapeutics for mitigating toxicity. [ABSTRACT FROM AUTHOR]

Inflammatory macrophages are known to contribute to ozone toxicity. Farnesoid X receptor (FXR) is a nuclear receptor involved in regulating bile acid and lipid homeostasis; it also exerts anti-inflammatory activity by suppressing macrophage NF-κB. Herein, we analyzed the role of FXR in regulating macrophage activation in the lung following ozone exposure. Treatment of wild-type (WT) mice with ozone (0.8 ppm, 3 h) resulted in increases in proinflammatory (F4/80+CD11c+CD11b+Ly6CHi) and anti-inflammatory (F4/80+CD11c+CD11b+Ly6CLo) macrophages in the lung. The accumulation of proinflammatory macrophages was increased in FXR−/− mice compared with WT mice; however, anti-inflammatory macrophage activation was blunted as reflected by reduced arginase and mannose receptor expression, a response correlated with decreased Nur77. This was associated with prolonged oxidative stress, as measured by 4-hydroxynonenal-modified proteins in the lung. Loss of FXR was accompanied by protracted increases in lung NF-κB activity and its target, inducible nitric oxide synthase in response to ozone. Levels of Tnf-α , Il-1β , Ccr2 , Ccl2 , Cx3cr1 , and Cx3cl1 were also increased in lungs of FXR−/− relative to WT mice; conversely, genes regulating lipid homeostasis including Lxrα , Apoe , Vldlr , Abcg1 , and Abca1 were downregulated, irrespective of ozone exposure. In FXR−/− mice, ozone caused an increase in total lung phospholipids, with no effect on SP-B or SP-D. Dyslipidemia was correlated with blunting of ozone-induced increases in positive end-expiratory pressure-dependent quasi-static pressure volume curves indicating a stiffer lung in FXR−/− mice. These findings identify FXR as a regulator of macrophage activation following ozone exposure suggesting that FXR ligands may be useful in mitigating inflammation and oxidative stress induced by pulmonary irritants. [ABSTRACT FROM AUTHOR]

Macrophages and inflammatory mediators have been implicated in ozone toxicity. In these studies, we used splenectomized (SPX) mice to assess the contribution of splenic monocytes to pulmonary inflammation and injury induced by ozone. Cells and tissue were collected 24-72h after exposure of mice to air or ozone (0.8 ppm, 3 h). Following ozone exposure, increased numbers of pro-inflammatory CD11b + Ly6CHi and anti-inflammatory CD11b + Ly6CLo monocytes were observed in spleens of control (CTL) mice. CD11b + Ly6CHi and MMP-9+pro-inflammatory macrophages were also observed in lungs of CTL mice after ozone, along with CD11b + Ly6CLo and mannose receptor (MR)+ anti-inflammatory macrophages. This was accompanied by increased lung expression of proteins involved in monocyte/macrophage trafficking including CCL3, CCL4, CCR1, and AT1R. Splenectomy resulted in decreases in pro-inflammatory macrophages in the lung and down regulation of CCR2, CCL2, and CCL4, but increases in CD11b + Ly6CLo anti-inflammatory macrophages. CD11b+Ly6G+Ly6C+ granulocytic (G)- and monocytic (M)-myeloid derived suppressor cells (MDSC)s were also detected in the lungs and spleens of CTL mice; these increased after ozone exposure. Splenectomy was associated with a decrease in G-MDSCs in the lung, with no effect on M-MDSCs. Changes in lung macrophage subpopulations and MDSCs in SPX mice were correlated with reduced ozone toxicity, as measured by decreases in bronchoalveolar lavage protein content and reduced 4-hydroxynonenal expression in the lung. These data suggest that the spleen is a source of pro-inflammatory/cytotoxic macrophages that contribute to ozone-induced lung injury, inflammation, and oxidative stress. [ABSTRACT FROM AUTHOR]

The transannular addition of SeCl2 and SeBr2 to cis,cis-cycloocta-1,5-diene affords 2,6-dihalo-9-selenabicyclo[3.3.1]nonanes in high yields. The latter react with SeCl2 and SeBr2 to form the 2 : 1 complexes, which are the first representatives of coordination compounds with the Se…Se…Se bonds. X-ray crystallographic data of the obtained compounds are discussed. In contrast to 2,6-dihalo-9-selenabicyclo[3.3.1]nonanes, tetrahydroselenophene does not form complexes with SeCl2 and SeBr2 giving 1,1-dihalotetrahydroselenophenes. [ABSTRACT FROM AUTHOR]

Sigma-1 receptor (chaperone Sigma1R) is an intracellular protein with chaperone functions, which is expressed in various organs, including the brain. Sigma1R participates in the regulation of physiological mechanisms of anxiety (Su, T. P. et al., 2016) and reactions to emotional stress (Hayashi, T., 2015). In 2006, fabomotizole (ethoxy-2-[2-(morpholino)-ethylthio]benzimidazole dihydrochloride) was registered in Russia as an anxiolytic (Seredenin S. and Voronin M., 2009). The molecular targets of fabomotizole are Sigma1R, NRH: quinone reductase 2 (NQO2), and monoamine oxidase A (MAO-A) (Seredenin S. and Voronin M., 2009). The current study aimed to clarify the dependence of fabomotizole anxiolytic action on its interaction with Sigma1R and perform a docking analysis of fabomotizole interaction with Sigma1R. An elevated plus maze (EPM) test revealed that the anxiolytic-like effect of fabomotizole (2.5 mg/kg i.p.) administered to male BALB/c mice 30 min prior EPM exposition was blocked by Sigma1R antagonists BD-1047 (1.0 mg/kg i.p.) and NE-100 (1.0 mg/kg i.p.) pretreatment. Results of initial in silico study showed that fabomotizole locates in the active center of Sigma1R, reproducing the interactions with the site's amino acids common for established Sigma1R ligands, with the ΔGbind value closer to that of agonist (+)-pentazocine in the 6DK1 binding site. [ABSTRACT FROM AUTHOR]