BackgroundAnesthetic propofol has immunomodulatory effects, particularly in the area of anti-inflammation. Bacterial endotoxin lipopolysaccharide (LPS) induces inflammation through toll-like receptor (TLR) 4 signaling. We investigated the molecular actions of propofol against LPS/TLR4-induced inflammatory activation in murine RAW264.7 macrophages.Methodology/Principal FindingsNon-cytotoxic levels of propofol reduced LPS-induced inducible nitric oxide synthase (iNOS) and NO as determined by western blotting and the Griess reaction, respectively. Propofol also reduced the production of tumor necrosis factor-α (TNF-α), interleukin (IL)-6, and IL-10 as detected by enzyme-linked immunosorbent assays. Western blot analysis showed propofol inhibited LPS-induced activation and phosphorylation of IKKβ (Ser180) and nuclear factor (NF)-κB (Ser536); the subsequent nuclear translocation of NF-κB p65 was also reduced. Additionally, propofol inhibited LPS-induced Akt activation and phosphorylation (Ser473) partly by reducing reactive oxygen species (ROS) generation; inter-regulation that ROS regulated Akt followed by NF-κB activation was found to be crucial for LPS-induced inflammatory responses in macrophages. An in vivo study using C57BL/6 mice also demonstrated the anti-inflammatory properties against LPS in peritoneal macrophages.Conclusions/SignificanceThese results suggest that propofol reduces LPS-induced inflammatory responses in macrophages by inhibiting the interconnected ROS/Akt/IKKβ/NF-κB signaling pathways.

there is a link between autophagy and both IFN-␥ signaling and cellular inflammation and that autophagy, because it inhibits the expression of reactive oxygen species and SHP2, is pivotal for Jak2-STAT1 activation.Autophagy, or autophagocytosis, is required for cellular regulation in response to a variety of stimuli, including starvation, pathogen-associated molecular patterns that are recognized by pattern-recognition receptors such as Toll-like receptors, and cytokines such as tumor necrosis factor (TNF)-␣ and interferon (IFN)-␥ (1, 2). In addition to maintaining cell survival and metabolic homeostasis (3), autophagy provides a cell-autonomous defense system for recognizing viral infections (4, 5) and eliminating intracellular pathogens via the autophagosome-lysosome pathway (6 -8).Proinflammatory cytokine IFN-␥, a type II IFN produced by T cells and natural killer cells, is involved in promoting diverse bioactivities, including antigen processing, intracellular microbial killing, and proinflammation (9). After binding with IFN-␥ receptors (IFNGRs), 2 IFN-␥ typically activates Jak2-STAT1 signaling and then regulates its bioactivities. For Jak2-STAT1 activation, Jak2 is first autophosphorylated at its tyrosine residues (Tyr 1007 /Tyr 1008 ) and then leads to Jak1 transphosphorylation (Tyr 1022 /Tyr 1023 ). The activation of Jak1 then phosphorylates IFNGR1 (Tyr 440 ), which induces the recruitment and activation of STAT1 through Jak2-mediated phosphorylation (Tyr 701 ). SOCS1 (suppressor of cytokine signaling-1), SOCS3, and SHP2 (dual-phosphatase Src homology-2 domain-containing phosphatase) provide feedback regulation by suppressing Jak2-STAT1 signaling (9, 10). SOCS1 and SOCS3 interact with IFNGRs, and SHP2 causes the dephosphorylation of Jak2 and STAT1. IFN-␥ induces, STAT1-dependently, SOCS1 and SOCS3 expression; however, the mechanisms for SHP2 activation remain undocumented.IFN-␥ uses a process that involves autophagy to increase the eradication of intracellular mycobacteria and chlamydia (6, 11). IFN-inducible immunity-related GTPases (Irgs (immunoreactive glucagons)), such as Irgm1 and Irga6 (6, 11), and IFN-inducible eukaryotic initiation factor (eIF)-2␣ kinase, protein kinase R (12), are potential autophagic regulators; however, the mechanisms for IFN-␥-induced autophagy are currently undocumented. In addition, the functions of autophagic machinery for IFN-␥-activated Jak2-STAT1 signaling and bioactivities require further investigation. In this study, we examined the role of autophagy and its molecular actions in the IFN-␥-induced Jak2-STAT1 activation and cellular inflammation. EXPERIMENTAL PROCEDURES

Emerging azole resistance in Aspergillus fumigatus poses a serious threat to human health. This nationwide surveillance study investigated the prevalence and molecular characteristics of azole-resistant A. fumigatus environmental isolates in Taiwan, an island country with increasing use of azole fungicides. Of the 2760 air and soil samples screened from 2014 to 2016, 451 A. fumigatus isolates were recovered from 266 samples and 34 isolates from 29 samples displayed resistance to medical azoles (itraconazole, voriconazole or posaconazole). The resistance prevalence was 10.9% and 7.5% in A. fumigatus-positive samples and isolates respectively. Most (29, 85.3%) azole-resistant isolates harboured TR /L98H mutations, which were widely distributed, clustered genetically with clinical isolates, and had growth rates that were similar to those of the wild-type isolates. Microsatellite genotyping revealed both the global spread of the TR /L98H isolates and the occurrence of TR /L98H/S297T/F495I isolates belonging to local microsatellite genotypes. AfuMDR3 and atrF, two efflux transporter genes, were constitutively upregulated in two individual resistant isolates without cyp51A mutations, highlighting their potential roles in azole resistance. These results emphasize the need for periodic environmental surveillance at the molecular level in regions in which azole fungicides are applied, and agricultural fungicide management strategies that generate less selective pressure should be investigated.

Background:Overdose propofol treatment with a prolong time causes injury to multiple cell types; however, its molecular mechanisms remain unclear. Activation of glycogen synthase kinase (GSK)-3␤ is proapoptotic under death stimuli.

Isolation of Brucella melitensis biovar 3 from a chamois (Rupicapra rupicapra) in the southern French Alps. J Wildl Dis. 8. Maquart M, Le Flèche P, Foster G, Tryland M, Ramisse F, Djønne B, et al. MLVA-16 typing of 295 marine mammal Brucella isolates from different animal and geographic origins identifies 7 major groups within Brucella ceti and Brucella pinnipedialis. BMC Microbiol. 2009;9:145. https://doi.