The multi-targeted kinase inhibitor sorafenib inhibits human cytomegalovirus replication

Human cytomegalovirus (HCMV) is a major pathogen in immunocompromised individuals. Here, non-toxic concentrations of the anti-cancer kinase inhibitor sorafenib were shown to inhibit replication of different HCMV strains (including a ganciclovir-resistant strain) in different cell types. In contrast to established anti-HCMV drugs, sorafenib inhibited HCMV major immediate early promoter activity and HCMV immediate early antigen (IEA) expression. Sorafenib is known to inhibit Raf. Comparison of sorafenib with the MEK inhibitor U0126 suggested that sorafenib inhibits HCMV IEA expression through inhibition of Raf but independently of signaling through the Raf downstream kinase MEK 1/2. In concordance, siRNA-mediated depletion of Raf but not of MEK-reduced IEA expression. In conclusion, sorafenib diminished HCMV replication in clinically relevant concentrations and inhibited HCMV IEA expression, a pathophysiologically relevant event that is not affected by established anti-HCMV drugs. Moreover, we demonstrated for the first time that Raf activation is involved in HCMV IEA expression

Selective abrogation of BiP/GRP78 blunts activation of NF-kappaBeta through the ATF6 branch of the UPR: involvement of C/EBPbeta and mTOR-dependent dephosphorylation of Akt

Subtilase cytotoxin (SubAB) that selectively cleaves BiP/GRP78 triggers the unfolded protein response (UPR) and protects mice from endotoxic lethality and collagen arthritis. We found that pretreatment of cells with SubAB suppressed tumor necrosis alpha (TNF-α)-induced activation of NF-κB and NF-κB-dependent chemokine expression. To elucidate underlying mechanisms, the involvement of C/EBP and Akt, putative regulators of NF-κB, was investigated. Among members of the C/EBP family, SubAB preferentially induced C/EBPβ. Overexpression of C/EBPβ suppressed TNF-α-induced NF-κB activation, and knockdown of C/EBPβ attenuated the suppressive effect of SubAB on NF-κB. We identified that the ATF6 branch of the UPR plays a crucial role in the induction of C/EBPβ. In addition to this effect, SubAB depressed basal and TNF-α-induced phosphorylation of Akt via the UPR. It was mediated by the induction of ATF6 and consequent activation of mTOR that dephosphorylated Akt. Inhibition of Akt attenuated activation of NF-κB by TNF-α, suggesting that the mTOR-Akt pathway is another target for SubAB-initiated, UPR-mediated NF-κB suppression. These results elucidated that SubAB blunts activation of NF-κB through ATF6-dependent mechanisms, i.e., preferential induction of C/EBPβ and mTOR-dependent dephosphorylation of Akt.Shotaro Nakajima, Nobuhiko Hiramatsu, Kunihiro Hayakawa, Yukinori Saito, Hironori Kato, Tao Huang, Jian Yao, Adrienne W. Paton, James C. Paton, and Masanori Kitamur

Sources and mass flows of xenobiotics in urban water cycles: an overview on current knowledge and data gaps.

In this study, the current most relevant compounds in waste water are discussed in relation to data available on their sources and mass flows in waste water treatment. In most western European situations, the highest contributions to the mass flow of xenobiotics stem from household and services applications (e.g. personal care compounds, pharmaceuticals, steroid hormones, fluorinated detergents etc.) as well as building and constructing environments (e.g. flame retardants, plasticizers, UV-Blockers and biocides), while the contribution from industrial point sources such as incineration industries e.g. coal, tar, steel and gas production (such as PAHs, PCBs, dioxins, etc.) as well as chemical industries are decreasing in relevance in terms of input and are of more local relevance nowadays. This paper considers current data and management strategies: such as mitigation and strategies for controlling xenobiotics at the source. However it also identifies major knowledge gaps relating to the behaviour and fate of organic pollutants in stormwater management, in bank- and soil infiltration as well as underground and soil passage of polluted waters. It also gives the major sources for a multitude of current day pollutants as well as emerging ones in a qualitative way. Keywords: xenobiotics, sources fluxes, mitigation, urban waters, source contro