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41.
Suyoung Yoon Sung-Eun Kim Jong Hyun Kim Ina Yoon Phuong-Thao Tran Jihyae Ann Changhoon Kim Woong Sub Byun Sangkook Lee Sunghoon Kim Jiyoun Lee Jeewoo Lee 《Bioorganic & medicinal chemistry》2019,27(6):1099-1109
Leucyl-tRNA synthetase (LRS) plays an important role in amino acid-dependent mTORC1 signaling, which is known to be associated with cellular metabolism and proliferation. Therefore, LRS-targeting small molecules that can suppress mTORC1 activation may provide an alternative strategy to current anticancer therapy. In this work, we developed a library of leucyladenylate sulfate analogues by extensively modifying three different pharmacophoric regions comprising adenine, ribose and leucine. Several effective compounds were identified by cell-based mTORC1 activation assays and further tested for anticancer activity. The selected compounds mostly exhibited selective cytotoxicity toward five different cancer cell lines, supporting the hypothesis that the LRS-mediated mTORC1 pathway is a promising alternative target to current therapeutic approaches. 相似文献
42.
Kristine von Bargen Mirella Scraba Ina Krmer Maren Ketterer Christian Nehls Sina Krokowski Urska Repnik Michaela Wittlich Anna Maaser Pia Zapka Madeleine Bunge Martin Schlesinger Gitta Huth Annette Klees Philipp Hansen Andreas Jeschke Gerd Bendas Olaf Utermhlen Gareth Griffiths Thomas Gutsmann Jens Wohlmann Albert Haas 《Cellular microbiology》2019,21(1)
Professional phagocytic cells such as macrophages are a central part of innate immune defence. They ingest microorganisms into membrane‐bound compartments (phagosomes), which acidify and eventually fuse with lysosomes, exposing their contents to a microbicidal environment. Gram‐positive Rhodococcus equi can cause pneumonia in young foals and in immunocompromised humans. The possession of a virulence plasmid allows them to subvert host defence mechanisms and to multiply in macrophages. Here, we show that the plasmid‐encoded and secreted virulence‐associated protein A (VapA) participates in exclusion of the proton‐pumping vacuolar‐ATPase complex from phagosomes and causes membrane permeabilisation, thus contributing to a pH‐neutral phagosome lumen. Using fluorescence and electron microscopy, we show that VapA is also transferred from phagosomes to lysosomes where it permeabilises the limiting membranes for small ions such as protons. This permeabilisation process is different from that of known membrane pore formers as revealed by experiments with artificial lipid bilayers. We demonstrate that, at 24 hr of infection, virulent R. equi is contained in a vacuole, which is enriched in lysosome material, yet possesses a pH of 7.2 whereas phagosomes containing a vapA deletion mutant have a pH of 5.8 and those with virulence plasmid‐less sister strains have a pH of 5.2. Experimentally neutralising the macrophage endocytic system allows avirulent R. equi to multiply. This observation is mirrored in the fact that virulent and avirulent R. equi multiply well in extracts of purified lysosomes at pH 7.2 but not at pH 5.1. Together these data indicate that the major function of VapA is to generate a pH‐neutral and hence growth‐promoting intracellular niche. VapA represents a new type of Gram‐positive virulence factor by trafficking from one subcellular compartment to another, affecting membrane permeability, excluding proton‐pumping ATPase, and consequently disarming host defences. 相似文献
43.
Roberto Menzel Samuel Dorey Tanja Maier Ina Pahl Armin Hauk 《Biotechnology progress》2022,38(1):e3214
The biopharmaceutical industry gains enormous flexibility in production processes by using sterilized preassembled single-use devices. Gamma irradiation is an established sterilization technology that may be restricted in the future by the availability of 60Co as irradiation source and irradiation capacities. X-ray technology is considered an alternative type of radiation for sterilizing SU equipment. In the context of extractables and leachables—one concern connected with the use of single-use process equipment—the effect of X-ray irradiation on the extractables profile of the materials needs to be compared to established gamma irradiation to qualify this alternative technology. An approach is presented to obtain robust and comprehensive extractables data for materials used in SU devices after sterilization either using X-ray or gamma irradiation. A careful selection of the test items and the test design allows a one-to-one comparison of data obtained from a combination of orthogonal analytical techniques. The extractables of a modern SU film material and the copolyester Tritan™ are evaluated. The data presented allow a risk evaluation on the safety of this new sterilization modality for biopharmaceutical applications. It is demonstrated that the extractables profile of a polymer is not affected by the type of irradiation used for sterilization. 相似文献
44.
Determination of drug permeability and prediction of drug absorption in Caco-2 monolayers 总被引:2,自引:0,他引:2
Permeability coefficients across monolayers of the human colon carcinoma cell line Caco-2, cultured on permeable supports, are commonly used to predict the absorption of orally administered drugs and other xenobiotics. This protocol describes our method for the cultivation, characterization and determination of permeability coefficients of xenobiotics (which are, typically, drug-like compounds) in the Caco-2 model. A few modifications that have been introduced over the years are incorporated in the protocol. The method can be used to trace the permeability of a test compound in two directions, from the apical to the basolateral side or vice versa, and both passive and active transport processes can be studied. The permeability assay can be completed within one working day, provided that the Caco-2 monolayers have been cultured and differentiated on the permeable supports 3 weeks in advance. 相似文献
45.
46.
Ferreira Jéssica Cristina Barbosa de Araújo Silva-Cardoso Inaê Mariê Meira Rennan Oliveira da Silva Costa Frederico Henrique Scherwinski-Pereira Jonny Everson 《In vitro cellular & developmental biology. Plant》2022,58(5):750-768
In Vitro Cellular & Developmental Biology - Plant - An efficient, reproducible, and unprecedented protocol of somatic embryogenesis (SE) was developed from leaf tissues of adult plants of... 相似文献
47.
Low sodium isocyanurate concentrations as a substitute to medium autoclaving in plant tissue culture
da Costa Urtiga Caio de Araújo Silva-Cardoso Inaê Mariê Araujo Figueiredo Sergio 《Plant Cell, Tissue and Organ Culture》2019,139(3):601-604
Plant Cell, Tissue and Organ Culture (PCTOC) - An optimization for a medium sterilization method, capable of substituting autoclaving, was developed using low concentrations of sodium isocyanurate... 相似文献
48.
Antonia Piazzesi Yiru Wang Joshua Jackson Lena Wischhof Viktoria ZeislerDiehl Enzo Scifo Ina Oganezova Thorben Hoffmann Pablo Gmez Martín Fabio Bertan Chester J J Wrobel Frank C Schroeder Dan Ehninger Kristian Hndler Joachim L Schultze Lukas Schreiber Gerhild van EchtenDeckert Pierluigi Nicotera Daniele Bano 《EMBO reports》2022,23(5)
49.
50.
M Brugna W Nitschke M Asso B Guigliarelli D Lemesle-Meunier C Schmidt 《The Journal of biological chemistry》1999,274(24):16766-16772
The Rieske proteins of two phylogenetically distant acidophilic organisms, i.e. the proteobacterium Thiobacillus ferrooxidans and the crenarchaeon Sulfolobus acidocaldarius, were studied by EPR. Redox titrations at a range of pH values showed that the Rieske centers of both organisms are characterized by redox midpoint potential-versus-pH curves featuring a common pK value of 6.2. This pK value is significantly more acidic (by almost 2 pH units) than that of Rieske proteins in neutrophilic species. The orientations of the Rieske center's g tensors with respect to the plane of the membrane were studied between pH 4 and 8 using partially ordered samples. At pH 4, the Sulfolobus Rieske cluster was found in the "typical" orientation of chemically reduced Rieske centers, whereas this orientation changed significantly on going toward high pH values. The Thiobacillus protein, by contrast, appeared to be in the "standard" orientation at both low and high pH values. The results are discussed with respect to the molecular parameters conveying acid resistance and in light of the recently demonstrated long-range conformational movement of the Rieske protein during enzyme turnover in cytochrome bc1 complexes. 相似文献