@phdthesis{Blankenburg2010,
  author    = {Blankenburg, Robert},
  title     = {Longitudinale Untersuchungen der kardialen Morphologie von knockin-M{\"a}usen mit humanen Myosinmutationen},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-71417},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2010},
  abstract  = {Longitudinale Untersuchungen der kardialen Morphologie von knockin-M{\"a}usen mit humanen Myosinmutationen},
  subject      = {Kardiomyopathie},
  language  = {de}
}
@phdthesis{Hupp2012,
  author    = {Hupp, Sabrina},
  title     = {Modulation of Actin Dynamics by the Cholesterol-Dependent Cytolysin Pneumolysin - a novel mechanism beyond pore formation},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-70889},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2012},
  abstract  = {Streptococcus pneumoniae is one of the major causes of bacterial meningitis, which mainly affects young infants in the developing countries of Africa, Asia (esp. India) and South America, and which has case fatality rates up to 50\% in those regions. Bacterial meningitis comprises an infection of the meninges and the sub-meningeal cortex tissue of the brain, whereat the presence of pneumolysin (PLY), a major virulence factor of the pneumococcus, is prerequisite for the development of a severe outcome of the infection and associated tissue damage (e. g. apoptosis, brain edema, and ischemia). Pneumolysin belongs to the family of pore forming, cholesterol-dependent cytolysins (CDCs), bacterial protein toxins, which basically use membrane-cholesterol as receptor and oligomerize to big aggregates, which induce cell lysis and cell death by disturbance of membrane integrity. Multiple recent studies, including this work, have revealed a new picture of pneumolysin, whose cell-related properties go far beyond membrane binding, pore formation and the induction of cell death and inflammatory responses. For a long time, it has been known that bacteria harm the tissues of their hosts in order to promote their own survival and proliferation. Many bacterial toxins aim to rather hijack cells than to kill them, by interacting with cellular components, such as the cytoskeleton or other endogenous proteins. This study was able to uncover a novel capacity of pneumolysin to interact with components of the actin machinery and to promote rapid, actin-dependent cell shape changes in primary astrocytes. The toxin was applied in disease-relevant concentrations, which were verified to be sub-lytic. These amounts of toxin induced a rapid actin cortex collapse in horizontal direction towards the cell core, whereat membrane integrity was preserved, indicating an actin severing function of pneumolysin, and being consistent with cell shrinkage, displacement, and blebbing observed in live cell imaging experiments. In contrast to neuroblastoma cells, in which pneumolysin led to cytoskeleton remodeling and simultaneously to activation of Rac1 and RhoA, in primary astrocytes the cell shape changes were seen to be primarily independent of small GTPases. The level of activated Rac1 and RhoA did not increase at the early time points after toxin application, when the initial shape changes have been observed, but at later time points when the actin-dependent displacement of cells was slower and less severe, probably presenting the cell's attempt to re-establish proper cytoskeleton function. A GUV (giant unilamellar vesicle) approach provided insight into the effects of pneumolysin in a biomimetic system, an environment, which is strictly biochemical, but still comprises cellular components, limited to the factors of interest (actin, Arp2/3, ATP, and Mg2+ on one side, and PLY on the other side). This approach was able to show that the wildtype-toxin, but not the Δ6 mutant (mutated in the unfolding domain, and thus non-porous), had the capacity to exhibit its functions through a membrane bilayer, meaning it was able to aggregate actin, which was located on the other side of the membrane, either via direct interaction with actin or in an Arp2/3 activating manner. Taking a closer look at these two factors with the help of several different imaging and biochemical approaches, this work unveiled the capacity of pneumolysin to bind and interact both with actin and Arp2 of the Arp2/3 complex. Pneumolysin was capable to slightly stabilize actin in an actin-pyrene polymerization assay. The same experimental setup was applied to show that the toxin had the capacity to lead to actin polymerization through activation of the Arp2/3 complex. This effect was additionally confirmed with the help of fluorescent microscopy of rhodamine (TRITC)-tagged actin. Strongest Arp2/3 activation, and actin nucleation/polymerization is achieved by the VCA domain of the WASP family proteins. However, addition of PLY to the Arp2/3-VCA system led to an enhanced actin nucleation, suggesting a synergistic activation function of pneumolysin. Hence, two different effects of pneumolysin on the actin cytoskeleton were observed. On the one hand an actin severing property, and on the other hand an actin stabilization property, both of which do not necessarily exclude each other. Actin remodeling is a common feature of bacterial virulence strategies. This is the first time, however, that these properties were assigned to a toxin of the CDC family. Cytoskeletal dysfunction in astrocytes leads to dysfunction and unregulated movement of these cells, which, in context of bacterial meningitis, can favor bacterial penetration and spreading in the brain tissue, and thus comprises an additional role of pneumolysin as a virulence factor of Streptococcus pneumonia in the context of brain infection.},
  subject      = {Hirnhautentz{\"u}ndung},
  language  = {en}
}
@phdthesis{Foertsch2012,
  author    = {F{\"o}rtsch, Christina},
  title     = {Pneumolysin: the state of pore-formation in context to cell trafficking and inflammatory responses of astrocytes},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-70892},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2012},
  abstract  = {Pneumolysin, a protein toxin, represents one of the major virulence factors of Streptococcus pneumoniae. This pathogen causes bacterial meningitis with especially high disease rates in young children, elderly people and immunosuppressed patients. The protein toxin belongs to the family of cholesterol-dependent cytolysins, which require membrane cholesterol in order to bind and to be activated. Upon activation, monomers assemble in a circle and undergo conformational change. This conformational change leads to the formation of a pore, which eventually leads to cell lysis. This knowledge was obtained by studies that used a higher concentration compared to the concentration of pneumolysin found in the cerebrospinal fluid of meningitis patients. Thus, a much lower concentration of pneumolysin was used in this work in order to investigate effects of this toxin on primary mouse astrocytes. Previously, a small GTPase activation, possibly leading to cytoskeletal changes, was found in a human neuroblastoma cell line. This led to the hypothesis that pneumolysin can lead to similar cytoskeletal changes in primary cells. The aim of this work was to investigate and characterise the effects of pneumolysin on primary mouse astrocytes in terms of a possible pore formation, cellular trafficking and immunological responses. Firstly, the importance of pore-formation on cytoskeletal changes was to be investigated. In order to tackle this question, wild-type pneumolysin and two mutant variants were used. One variant was generated by exchanging one amino acid in the cholesterol recognising region, the second variant was generated by deleting two amino acids in a protein domain that is essential for oligomerisation. These variants should be incapable of forming a pore and were compared to the wild-type in terms of lytic capacities, membrane binding, membrane depolarisation, pore-formation in artificial membranes (planar lipid bilayer) and effects on the cytoskeleton. These investigations resulted in the finding that the pore-formation is required for inducing cell lysis, membrane depolarisation and cytoskeletal changes in astrocytes. The variants were not able to form a pore in planar lipid bilayer and did not cause cell lysis and membrane depolarisation. However, they bound to the cell membrane to the same extent as the wild-type toxin. Thus, the pore-formation, but not the membrane binding was the cause for these changes. Secondly, the effect of pneumolysin on cellular trafficking was investigated. Here, the variants showed no effect, but the wild-type led to an increase in overall endocytotic events and was itself internalised into the cell. In order to characterise a possible mechanism for internalisation, a GFP-tagged version of pneumolysin was used. Several fluorescence-labelled markers for different endocytotic pathways were used in a co-staining approach with pneumolysin. Furthermore, inhibitors for two key-players in classical endocytotic pathways, dynamin and myosin II, were used in order to investigate classical endocytotic pathways and their possible involvement in toxin internalisation. The second finding of this work is that pneumolysin is taken up into the cell via dynamin- and caveolin-independent pinocytosis, which could transfer the toxin to caveosomes. From there, the fate of the toxin remains unknown. Additionally, pneumolysin leads to an overall increase in endocytotic events. This observation led to the third aim of this work. If the toxin increases the overall rate of endocytosis, the question arises whether toxin internalisation favours bacterial tissue penetration of the host or whether it serves as a defence mechanism of the cell in order to degrade the protein. Thus, several proinflammatory cytokines were investigated, as previous studies describe an effect of pneumolysin on cytokine production. Surprisingly, only interleukin 6-production was increased after toxin-treatment and no effect of endocytotic inhibitors on the interleukin 6-production was observed. The conclusion from this finding is that pneumolysin leads to an increase of interleukin 6, which would not depend on the endocytotic uptake of pneumolysin. The production of interleukin 6 would enhance the production of acute phase proteins, T-cell activation, growth and differentiation. On the one hand, this activation could serve pathogen clearance from infected tissue. On the other hand, the production of interleukin 6 could promote a further penetration of pathogen into host tissue. This question should be further investigated.},
  subject      = {Streptococcus pneumoniae},
  language  = {en}
}
@article{StopperKuehnelPodschun1994,
  author    = {Stopper, Helga and K{\"u}hnel, A. and Podschun, B.},
  title     = {Combination of the chemotherapeutic agent 5-fluorouracil with an inhibitor of its catabolism results in increased micronucleus induction},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-63383},
  year      = {1994},
  abstract  = {The rate limiting step in 5-fluorouracil catabolism is catalyzed by the enzyme dihydropyrimidine dehydrogenase. Since degradation of 5-fluorouracil decreases its efficacy in chemotherapy, the inhibition of its catabolism is a promising tool. We investigated the formation of micronuclei in vitro in mouse L5178Y cells. 5-fluorouracil induced an increase in micronucleus frequency, which could significantly be enhanced by the concurrent application of 2,6-dihydroxypyridine, an inhibitor of dihydropyrimidine dehydrogenase. The 5-fluorouracil concentration necessary to reach maximal genotoxic effects could be reduced to half in the presence of inhibitor. 2,6-Dihydroxypyridine alone and the naturally occuring enzyme substrate uracil did not induce micronucleus formation. Combined application of the chemotherapeutic agent 5-fluorouracil and an inhibitor of its could reduce side-effects by lowering the effective dose of the active drug. With this study we provide further support for the usefulness of this concept.},
  subject      = {Toxikologie},
  language  = {en}
}
@article{StopperEckertSchiffmannetal.1994,
  author    = {Stopper, Helga and Eckert, I. and Schiffmann, D. and Spencer, D. L. and Caspary, W. J.},
  title     = {Is micronucleus induction by aneugens an early event leading to mutagenesis?},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-63390},
  year      = {1994},
  abstract  = {This study was designed to investigate a previously unidentified potential mechanism for mutation induction as well as to clarify a biological comequence of micronucleus formation. We compared the induction of micronuclei with mutation inductioo as measured by trißuorothymidine (TFI') resistance in mouse L5178Y cells using four aneugens: colcemid, diethylstilbestrol, griseofulvin and vioblastine. AU four compounds induced micronuclei which appeared in the first cell cycle after treatment. More than 85\% of the micronuclei induced by each compound stained positive for the presence of kinetochores implying that the micronuclei contained wbole cbromosomes. However, these same compounds were unable to induce TFf resistance under tbree different treatment regimes. We concluded that tbese compounds, under conditions where tbey induce primarily kinetochore positive micronuclel, were not able to induce mutations. Thus, the induction of micronuclei containing wbole chromosomes barborlog a select.able gene is not an early event leadlog to mutations in these cells.},
  subject      = {Toxikologie},
  language  = {en}
}
@article{StopperKoerberSpenceretal.1993,
  author    = {Stopper, Helga and K{\"o}rber, C. and Spencer, D. L. and Kirchner, S. and Caspary, W.J. and Schiffmann, D.},
  title     = {An investigation of micronucleus and mutation induction by oxazepam in mammalian cells},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-63404},
  year      = {1993},
  abstract  = {Tbe benzodiazepines are a class of d.rugs that are widely used in the treatment of various psychiatric disorders. One member of um ~' oxazepam, is also a common metabolite of sevmd other benzod.iazepines. Since the evidence for the genetic toxicity and carcinogenic properties of these compounds is incol:lsb1ent, we investigated the oxazepam-induced fonnation of micronuclei in Syrian Hamster embryo fibroblast (SHE) cells, human amniotic fluid fibroblast-like (AFFL) cells and LS178Y mouse cells. A dose-dependent increase in micronucleus fractions was found in all tbree ceU llnes. The time course of micronucleus induction in L5178Y cells showed a maximum at 5 h after treatment, suggesting that the micronuclei were fonned in the first mitosis after treatment. Kinetochore staining (CREST -antiserum) revealed the presence of kinetochores in -SO\% of the micronuclei in aU tbree ceU types. ThJs resu1t was further confinned by in situ bybridization in LS178Y cells and indicates tbe presence of wbole Chromosomes or centric fragments as weU as acentric fragments in the oxazepam-induced micronuclei. The LS178Y cells did not show a mutagenic response to oxazepam at any of the doses or expression times used.},
  subject      = {Toxikologie},
  language  = {en}
}
@article{StopperKoerberSchiffmannetal.1993,
  author    = {Stopper, Helga and K{\"o}rber, C. and Schiffmann, D. and Caspary, W. J.},
  title     = {Cell-cycle dependent micronucleus formation and mitotic disturbances induced by 5-azacytidine in mammalian cells},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-63411},
  year      = {1993},
  abstract  = {5-Azacytidine was originally developed to treat human myelogenous leukemia. However, interest in this compound has expanded because of reports of its ability to affect cell differentiation and to alter eukaryotic gene expression. In an ongoing attempt to understand the biochemical effects of this compound, we examined the effects of 5-azacytidine on mitosis and on micronucleus formation in mammalian cells. In L5178Y mouse cells, 5-azacytidine induced micronuclei at concentrations at which we and others have already reported its mutagenicity at the tk locus. Using CREST staining and C-banding studies, we showed that the induced micronuclei contained mostly chromosomal fragments although some may have contained whole chromosomes. By incorporating BrdU into the DNA of SHE cells, we determined that micronuclei were induced only when the compound was added while the cells were in S phase. Microscopically visible effects due to 5-azacytidine treatment were not observed until anaphase of the mitosis following treatment or thereafter. 5-Azacytidine did not induce micronuclei via interference with formation of the metaphase chromosome arrangement in mitosis, a common mechanism leading to aneuploidy. SupravitalUV microscopy revealed that chromatid bridges were observed in anaphase and, in some cases, were sustained into interphase. In the first mitosis after 5-azacytidine treatment we observed that many cells were unable to perform anaphase separation. All of these observations indicate that 5-azacytidine is predominantly a clastogen through its incorporation into DNA.},
  subject      = {Toxikologie},
  language  = {en}
}
@article{AdamAhrweilerSahaMoelleretal.1993,
  author    = {Adam, W. and Ahrweiler, M. and Saha-M{\"o}ller, C. R. and Sauter, M. and Sch{\"o}nberger, A. and Epe, B. and M{\"u}ller, E. and Schiffmann, D. and Stopper, Helga and Wild, D.},
  title     = {Genotoxicity studies of benzofuran dioxetanes and epoxides with isolated DNA, bacteria and mammalian cells},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-63420},
  year      = {1993},
  abstract  = {1.2-Dioxetanes, very reactive and high energy molecules. are involved as labile intermediates in dioxygenase- activated aerobic metabolism and in physiological processes. Various toxico1ogica1 tests reveal that dioxetanes are indeed genotoxic. In supercoiled DNA of bacteriophage PM2 they induce endonucleasesensitive sites, most of them are FPG protein-sensitive base modifications (8-hydroxyguanine, fonnamidopyrimidines). Pyrimidinedimersand sites ofbase loss (AP sites) which were probed by UV endonuclease and exonuclease 111 are minor lesions in this system. While the alky1-substituted dioxetanes do not show any significant mutagenic activity in different Salmonella typhimurium strains, heteroarene dioxetanes such as benzofuran and furocoumarin dioxetanes are strongly mutagenic in S. typhimurium strain TA I 00. DNA adducts formed with an intermediary alkyJating agent appear to be responsible for the mutagenic activity of benzofuran dioxetane. We assume that the benzofuran epoxides, generated in situ from benzofuran dioxetanes by deoxygenation are the ultimate mutagens of the latter. since benzofuran epoxides are highly mutagenic in the S. typhimurium strain TAIOO and they form DNA adducts. as detected by the 212Ppostlabelling technique. Our results imply that the type of D NA darnage promoted by dioxetanes is dependent on the structural feature of dioxetanes. Furthermore, the direct photochemical DNA darnage by energy transfer. i.e., pyrimidine dimers, plays a minor role in the genotoxicity of dioxetanes. Instead, photooxidation dominates in isolated DNA. while radical darnage and alkylation prevail in the cellular system.},
  subject      = {Toxikologie},
  language  = {en}
}
@phdthesis{Fischer2010,
  author    = {Fischer, Thomas Horst},
  title     = {Die transkriptionelle Regulation der microRNA-21 im Herzen},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-50702},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2010},
  abstract  = {MicroRNAs sind kleine, nicht kodierende RNA-Molek{\"u}le, die posttranskriptionell die Genexpression regulieren. Sie binden hierf{\"u}r spezifisch an 3'-UTRs von messenger-RNAs und f{\"u}hren entweder direkt zu deren Abbau oder inhibieren deren Translation. {\"U}ber die Mechanismen, die die Expression von microRNAs regulieren, ist jedoch noch wenig bekannt. Die Tatsache, dass sie als lange Vorl{\"a}ufermolek{\"u}le (pri-microRNAs) durch die RNA-Polymerase-II transkribiert werden, legt die Existenz eines Promotorbereiches nahe, der dem proteinkodierender Gene {\"a}hnelt. Mit Hilfe von microRNA-Arrays konnten wir im linksventrikul{\"a}ren Myokard mehrere bei Herzinsuffizienz deutlich ver{\"a}ndert exprimierte microRNAs identifizieren. Die microRNA-21 ist dabei bereits im Fr{\"u}hstadium der Herzinsuffizienz verst{\"a}rkt exprimiert (Northern Blot). Auch in prim{\"a}ren, kardialen Zellen (Fibroblasten, Kardiomyozyten) wird die microRNA-21 nach Induktion einer Hypertrophie verst{\"a}rkt exprimiert. Weiterf{\"u}hrendes Ziel dieser Arbeit war es nun, diejenigen Mechanismen aufzukl{\"a}ren, die der starken Induktion der microRNA-21 im erkrankten Myokard zu Grunde liegen. Durch bioinformatische Analyse des zugeh{\"o}rigen Promotorbereiches (Trans-Spezies-Konservierung) und Klonierung danach ausgerichteter Fragmente in Luciferase-basierte Reporter-Plasmide konnte ein 118 Basen langer Bereich identifiziert werden, der maßgeblich die Expression der microRNA-21 im Herzen bedingt. Durch Deaktivierung einzelner cis-Elemente konnte die kardiale Expression auf zwei essentielle Transkriptionsfaktorbindungsstellen zur{\"u}ckgef{\"u}hrt werden. Es handelt sich dabei um Erkennungssequenzen f{\"u}r die im Herz bedeutsamen Transkriptionsfaktoren CREB und SRF. Sie liegen in enger r{\"a}umlicher Nachbarschaft ungef{\"a}hr 1150 bp vor der Transkriptionsstartstelle. Die Suppression der Expression dieser beiden Transkriptionsfaktoren mittels geeigneter siRNAs f{\"u}hrte jeweils zu einer signifikanten Aktivit{\"a}tsminderung des microRNA-21-Promotors und konnte somit die vorangehenden Ergebnisse validieren. Durch Generierung einer transgenen Tierlinie, die lacZ unter der Kontrolle des microRNA-21-Promotors exprimiert, werden in naher Zukunft n{\"a}here Aufschl{\"u}sse {\"u}ber die gewebsspezifische Verteilung der microRNA-21-Expresssion in vivo m{\"o}glich sein. Zusammenfassend beschreiben wir hier erstmals den Mechanismus der transkriptionellen Regulation der microRNA-21 im Herzen. Dieser Mechanismus bedingt wahrscheinlich die starke Induktion dieser microRNA bei kardialer Hypertrophie und Herzinsuffizienz.},
  subject      = {Small RNA},
  language  = {de}
}
@phdthesis{Moro2011,
  author    = {Moro, Sabrina},
  title     = {Identification of target proteins of furan reactive metabolites in rat liver},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-57617},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2011},
  abstract  = {Furan was recently found to be present in a variety of food items that undergo heat treatment. It is known to act as a potent hepatotoxin and liver carcinogen in rodents. In a 2-year bioassay, chronic furan administration to rats was shown to cause hepatocellular adenomas and carcinomas and very high incidences of cholangiocarcinomas even at the lowest furan dose tested (2.0 mg/kg bw). However, the mechanisms of furan-induced tumor formation are poorly understood. Furan is metabolized by cytochrome P450 (CYP) enzymes, predominantly CYP2E1, to its major metabolite cis-2-butene-1,4-dial (BDA). BDA is thought to be the key mediator of furan toxicity and carcinogenicity and was shown to react with cellular nucleophiles such as nucleosides and amino acid residues in vitro. It is well known that covalent protein binding may lead to cytotoxicity, but the cellular mechanisms involved remain to be elucidated. Since covalent binding of reactive intermediates to a target protein may result in loss of protein function and subsequent damage to the cell, the aim of this study was to identify furan target proteins to establish their role in the pathogenesis of furan-associated liver toxicity and carcinogenicity. In order to identify target proteins of furan reactive metabolites, male F344/N rats were administered [3,4-14C]-furan. Liquid scintillation counting of protein extracts revealed a dose-dependent increase of radioactivity covalently bound to liver proteins. After separation of the liver protein extracts by two-dimensional gel electrophoresis and subsequent detection of radioactive spots by fluorography, target proteins of reactive furan intermediates were identified by mass spectrometry and database search via Mascot. A total of 61 putative target proteins were consistently found to be adducted in 3 furan-treated rats. The identified proteins represent - among others - enzymes, transport proteins, structural proteins and chaperones. Pathway mapping tools revealed that target proteins are predominantly located in the cytosol and mitochondria and participate in glucose metabolism, mitochondrial β-oxidation of fatty acids, and amino acid degradation. These findings together with the fact that ATP synthase β subunit was also identified as a putative target protein strongly suggest that binding of furan reactive metabolites to proteins may result in mitochondrial injury, impaired cellular energy production, and altered redox state, which may contribute to cell death. Moreover, several proteins involved in the regulation of redox homeostasis represent putative furan target proteins. Loss of function of these proteins by covalent binding of furan reactive metabolites may impair cellular defense mechanisms against oxidative stress, which may also result in cell death. Besides the potential malfunction of whole pathways due to loss of functions of several participating proteins, loss of function of individual proteins which are involved in various cellular processes such as transport processes across the mitochondrial membranes, cell signaling, DNA methylation, blood coagulation, and bile acid transport may also contribute to furan-induced cytotoxicity and carcinogenicity. Covalent binding of reactive metabolites to cellular proteins may result in accumulation of high amounts of unfolded or damaged proteins in the endoplasmic reticulum (ER). In response to this ER stress, the cell can activate the unfolded protein response (UPR) to repair or degrade damaged proteins. To address whether binding of furan reactive metabolites to cellular proteins triggers activation of the UPR, semiquantitative PCR and TaqMan® real-time PCR were performed. In the case of UPR activation, semiquantitative PCR should show enhanced splicing of X-box binding protein-1 (XBP1) mRNA (transcription factor and key regulator of the UPR) and TaqMan® real-time PCR should determine an increased expression of UPR target genes. However, our data showed no evidence for activation of the UPR in the livers of rats treated either with a single hepatotoxic dose or with a known carcinogenic dose for 4 weeks. This suggests either that furan administration does not induce ER stress through accumulation of damaged proteins or that activation of the UPR is disrupted. Consistent with the latter, glucose-regulated protein 78 (GRP78), identified as a target protein in our study, represents an important mediator involved in activation of the UPR whose inhibition was shown to impair induction of the UPR. Thus, adduct formation and inactivation of GRP78 by furan metabolites may disturb activation of the UPR. In addition to impaired activation of UPR, protein repair and degradation functions may be altered, because several proteins involved in these processes also represent target proteins of furan and thus may show impaired functionality. Taken together...},
  subject      = {Furan},
  language  = {en}
}