@phdthesis{Loske2000,
  author    = {Loske, Claudia},
  title     = {Metabolische Ver{\"a}nderungen und Zelltod in neuralen Zellen durch "Advanced Glycation Endproducts"},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-1707},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2000},
  abstract  = {Advanced Glycation Endproducts (AGEs) entstehen aus nicht-enzymatisch glykierten Proteinen. In einer Folge von Dehydratations-, Kondensations- und Oxidationsschritten entsteht ein heterogenes Gemisch aus farbigen, fluoreszierenden Verbindungen. AGE-modifizierte Proteine sind unl{\"o}slich und proteaseresistent, bei ihrer Bildung entstehen freie Radikale und andere reaktive Intermediate. Von der AGE-Bildung betroffen sind vor allem langlebige Proteine mit geringem Umsatz wie Kollagen und Kristallin aber auch pathologische Proteinablagerungen, z.B. in der Alzheimer´schen Demenz (AD). Die Akkumulation von AGEs spielt in der Pathogenese von Komplikationen des Diabetes und der H{\"a}modialyse eine Rolle, f{\"u}r die AD wird eine Beteiligung von AGEs am Krankheitsverlauf diskutiert. Die Alzheimer´sche Demenz ist gekennzeichnet durch den histologischen Nachweis seniler Plaques und neurofibrill{\"a}rer B{\"u}ndel in Hirngewebe der Patienten. Auf Ebene des Stoffwechsels kommt es zu einer Verringerung des zerebralen Glukoseumsatzes, es finden sich Marker sowohl f{\"u}r eine Akutphasenreaktion als auch f{\"u}r oxidativen Stress. In dieser Arbeit wurde gezeigt, dass die AGE-Bildung in vitro die Aggregation von ßA4, dem Hauptbestandteil der senilen Plaques in der AD, beschleunigt. Der geschwindigkeits-bestimmende Schritt ist dabei die Glykierung des ßA4-Monomers. Durch Zugabe von {\"U}bergangsmetall-ionen kann die Vernetzung weiter beschleunigt werden. Dies deutet darauf hin, dass AGEs zur Plaquebildung in der AD beitragen, redox-aktive Eisenionen sind in der AD mit den Plaques assoziiert. Mit Hilfe von Metallchelatoren, Antioxidantien oder mit Substanzen, welche die zur Vernetzung notwendigen Aminogruppen abblocken, l{\"a}sst sich die Aggregation von ßA4 verlangsamen oder verhindern. AGEs wirken zytotoxisch auf BHK 21 Fibroblasten und humane SH-SY5Y Neuroblastoma Zellen. Die Toxizit{\"a}t unterschiedlicher Modell-AGEs ist abh{\"a}ngig von verschiedenen Faktoren, u.a. von dem zur Herstellung verwendeten Protein und vom Zucker. Die LD50 der Modell-AGEs korreliert mit dem AGE-Gehalt und der Radikalproduktion der Pr{\"a}parationen in vitro. Die AGE-Toxizit{\"a}t ist haupts{\"a}chlich radikalvermittelt. Oxidativer Stress l{\"a}sst sich in AGE-behandelten Zellen durch die Bildung intrazellul{\"a}rer Lipidperoxidationsprodukte nachweisen. Auf Ebene der Signaltransduktion konnte die Aktivierung des Transkriptions-faktors NfkB als Zeichen der Stressabwehr nachgewiesen werden. Die Gabe von Antioxidantien vor oder gleichzeitig mit den AGEs verringerte den Zelltod. Auch durch das Blockieren des Rezeptors f{\"u}r AGEs (RAGE) mit spezifischen Antik{\"o}rpern konnte die Zahl {\"u}berlebender Zellen gesteigert werden. Durch AGEs ausgel{\"o}ster Stress f{\"u}hrt in Neuroblastoma Zellen bereits in Konzentrationen unterhalb der LD50 zu St{\"o}rungen im Redoxstatus, es kommt zur Depletion von GSH und zu Verschiebungen im Verh{\"a}ltnis GSH/GSSG. Damit einher gehen Ver{\"a}nderungen im Energiestoffwechsel der Zelle, nach anf{\"a}nglich erh{\"o}hter Glukoseaufnahme kommt es im weiteren Verlauf der Inkubation zu einer Verringerung der Aufnahme von Glukose aus dem Medium, gefolgt von einer Zunahme der Laktataussch{\"u}ttung. Ausserdem wurde eine Depletion von ATP um bis zu 50 Prozent nachgewiesen. Antioxidantien k{\"o}nnen die St{\"o}rungen im Metabolismus der Zellen verhindern oder abschw{\"a}chen, die meisten der getesteten Substanzen konnten Redoxstatus und ATP-Gehalt der Zellen zu normalisieren. Obwohl sich in AGE-gestressten Zellkulturen durch Annexin-Fluorescein-Markierung ein geringf{\"u}gig erh{\"o}hter Prozentsatz apoptotischer Zellen nachweisen ließ und AGEs auch die Freisetzung von Cytochrom c ins Zytoplasma induzieren, verl{\"a}uft der durch AGEs ausgel{\"o}ste Zelltod verl{\"a}uft offenbar insgesamt nekrotisch. Sowohl durch Radikalproduktion als auch {\"u}ber rezeptorvermittelte Signalwege verursachen AGEs oxidativen Stress und induzieren Ver{\"a}nderungen im Metabolismus der Zelle. Dies f{\"u}hrt u. a. dazu, dass f{\"u}r die antioxidativen Schutzmechanismen der Zelle nicht mehr gen{\"u}gend Energie zur Verf{\"u}gung steht. AGE-Stress tr{\"a}gt damit in einer selbstverst{\"a}rkenden Reaktionskaskade zur Neurodegeneration bei und kann so an der Pathogenese der AD beteiligt sein. Antioxidantien und auch AGE-Inhibitoren k{\"o}nnten einen interessanten Ansatz zur Entwicklung alternativer Therapien in der AD darstellen.},
  subject      = {Alzheimer-Krankheit},
  language  = {de}
}
@phdthesis{Luehrmann2002,
  author    = {L{\"u}hrmann, Anja},
  title     = {Analyse der Reifung von Afipien- und Rhodokokken-enthaltenden Phagosomen in Makrophagen},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-1619},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2002},
  abstract  = {Die Isolierung von Phagosomen erm{\"o}glicht die biochemische Analyse der Phagosomen-Zusammensetzung sowie der an der Phagosomenreifung beteiligten Molek{\"u}le. Deshalb wurde im Rahmen dieser Promotionsarbeit eine Methode entwickelt, die es erm{\"o}glicht, Bakterien-enthaltende Phagosomen zu isolieren. Diese Methode erzielt im Vergleich zu anderen in der Literatur beschriebenen Methoden eine gute Ausbeute (fast 40 Prozent) und vor allem eine h{\"o}here Reinheit an Bakterien-enthaltenden Phagosomen. So besteht keine Kontamination mit Teilen des Golgi-Apparates und nur eine sehr geringe Kontamination mit endosomalen und lysosomalen Proteinen sowie Plasmamembranbestandteilen. Allerdings wurde eine Kontamination mit Mitochondrien und ER detektiert. Letzteres muss nicht unbedingt eine Kontamination darstellen, sondern k{\"o}nnte ein wichtiger Bestandteil von Phagosomen sein. Afipia felis ist ein Gram-negatives Bakterium, das f{\"u}r einige F{\"a}lle der Katzen-Kratz Krankheit verantwortlich ist. Es kann innerhalb von Makrophagen {\"u}berleben und sich vermehren. Die genaue Kompartimentierung der Afipia felis-enthaltenden Phagosomen in Makrophagen war allerdings unbekannt und sollte deshalb in der vorliegenden Promotionsarbeit analysiert werden. Ovalbumin Texas Red, mit dem Lysosomen vor der Infektion markiert wurden, gelangt nicht in die Afipien-enthaltenden Phagosomen, und die Afipien-enthaltenden Phagosomen sind auch nicht zug{\"a}nglich f{\"u}r Ovalbumin Texas Red, mit dem das gesamte endozytische System nach der etablierten Infektion markiert wurde. Außerdem sind etablierte, isolierte Afipia felis-enthaltende Phagosomen nur in geringem Umfang positiv f{\"u}r sp{\"a}t endosomale/lysosomale Markerproteine und negativ f{\"u}r fr{\"u}h endosomale Markerproteine. Die Afipien, die ein nicht endozytisches Kompartiment etablieren, werden vom Makrophagen in ein EEA1-negatives Kompartiment aufgenommen, das auch zu sp{\"a}teren Zeitpunkten negativ f{\"u}r LAMP-1 ist. Nur die circa 30 Prozent der Afipien, die sich in einem Kompartiment befinden, das zum endozytischen System geh{\"o}rt, gelangen nach der Aufnahme durch den Makrophagen in ein EEA1-positives Kompartiment, das zu einem sp{\"a}teren Zeitpunkt positiv f{\"u}r LAMP-1 wird. T{\"o}tung der Afipien oder Opsonisierung mit Antik{\"o}rpern vor der Infektion normalisiert die Reifung der Afipia felis-enthaltenden Phagosomen in den J774E-Makrophagen. Somit konnte nachgewiesen werden, dass die Mehrzahl der Phagosomen (70 Prozent), die Afipia felis enthalten, nicht zum endozytischen System geh{\"o}ren. Diese ungew{\"o}hnliche Kompartimentierung besteht bereits bei der Aufnahme und kann nur von lebenden Afipien etabliert werden. Rhodococcus equi ist ein Gram-positives Bakterium, das unter anderem Bronchopneumonien beim Fohlen verursacht. Aber auch Menschen und andere S{\"a}ugetiere sind von Infektionen mit R. equi betroffen. Die F{\"a}higkeit der Rhodokokken, innerhalb der Makrophagen zu {\"u}berleben und sich zu vermehren, ist mit dem Vorhandensein eines 85 kbp Plasmids assoziiert. Da {\"u}ber die genaue Kompartimentierung von R. equi im Mausmakrophagen wenig bekannt war, und der Frage, ob es einen Unterschied zwischen der Kompartimentierung von R. equi(+)- und R. equi(-)-enthaltenden Phagosomen gibt, noch nicht nachgegangen wurde, war beides Thema dieser Promotionsarbeit. Dabei zeigt sich, dass R. equi(-)-enthaltende Phagosomen wesentlich st{\"a}rker mit den sp{\"a}t endosomalen/lysosomalen Markerproteinen vATPase und LAMP-1 assoziiert sind sowie eine h{\"o}here ß-Galaktosidase-Aktivit{\"a}t aufweisen als die R. equi(+)-enthaltenden Phagosomen. Da sowohl die isolierten R. equi(-)- als auch die R. equi(+)-enthaltenden Phagosomen mit dem fr{\"u}h endosomalen Markerprotein rab5 assoziiert sind, ist anzunehmen, dass Rhodokokken unabh{\"a}ngig vom Vorhandensein des 85 kbp Plasmids in der Lage sind, die Phagosomenreifung zu verz{\"o}gern. Aber R. equi(-) kann die Reifung zwar verz{\"o}gern, aber letztendlich nicht verhindern. Wahrscheinlich reifen die Phagosomen, die R. equi(-) enthalten, zu einem sp{\"a}teren Zeitpunkt zu Phagolysosomen, wohingegen R. equi(+) ein ungew{\"o}hnliches Kompartiment etabliert und dadurch die Phagosomenreifung endg{\"u}ltig zu verhindern scheint. Somit ist anzunehmen, dass mindestens ein vom 85 kbp Plasmid kodiertes Molek{\"u}l f{\"u}r die Etablierung dieses ungew{\"o}hnlichen, R. equi(+)-enthaltenden Kompartimentes, verantwortlich ist. Da eine Infektion mit Rhodococcus equi zytotoxisch f{\"u}r die infizierte Zelle sein kann, wurde die von den Rhodokokken vermittelte Zytotoxizit{\"a}t n{\"a}her analysiert. Die in dieser vorliegenden Promotionsarbeit dargestellten Ergebnisse zeigen deutlich, dass nur die Plasmid-enthaltenden Rhodokokken zur Nekrose, aber nicht zur Apoptose ihrer Wirtszellen f{\"u}hren, w{\"a}hrend R. equi(-) keinen Einfluss auf die Vitalit{\"a}t ihrer Wirtszellen haben. Dieses Ph{\"a}nomen ist allerdings abh{\"a}ngig vom Wirtszelltyp. So sind R. equi(-) als auch R. equi(+) f{\"u}r humane Monozyten nur geringf{\"u}gig zytotoxisch.},
  subject      = {Afipia},
  language  = {de}
}
@phdthesis{Chan2002,
  author    = {Chan, Gordon},
  title     = {The Role of Vav-1, Vav-2 and Lsc in NK T cell development and NK cell cytotoxicity},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-3645},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2002},
  abstract  = {The hematopoietic-specific Rho-family GTP exchange factor (GEF) Vav-1 is a regulator of lymphocyte antigen receptor signaling and mediates normal maturation and activation of B and T cells. Recent findings suggest that Vav-1 also forms part of signaling pathways required for natural and antibody dependent cellular cytotoxicity (ADCC) of human NK cells. In this study, I show that Vav-1 is also expressed in murine NK cells. Vav-1-/- mice had normal numbers of splenic NK cells, and these displayed a similar expression profile of NK cell receptors as cells from wild type mice. Unexpectedly, IL-2-activated Vav-1-/- NK cells retained normal ADCC. Fc-receptor mediated activation of ERK, JNK, and p38 was also normal. In contrast, Vav-1-/- NK cells exhibited reduced natural cytotoxicity against EL4, C4.4.25, RMA and RMA/S. Together, these results demonstrate that Vav-1 is dispensable for mainstream NK cell development, but is required for NK cell natural cytotoxicity. Vav-2, a protein homologous to Vav-1 has also been implicated in NK cell functions. However, NK cells from Vav-2-/- mice have normal cytotoxic activities and NK cells that lack both Vav-1 and Vav-2 exhibit similar defect as Vav-1-/- cells. Thus Vav-2 has no apparent function in the development and the activation of NK cells. Although NK cell development is normal in Vav-1-/- mice, their numbers of NKT cells were dramatically diminished. Furthermore, NKT cells from Vav-1 mutant mice failed to produce IL-4 and IFNg following in vivo CD3 stimulation. A similar loss of NKT cells was observed in Vav-1-/-Vav-2-/- mice, but not in Vav-2-/- mice, suggesting that only Vav-1, and not Vav-2, is an essential regulator of NKT cell development and NK cell cytotoxicity. Similar to Vav-1, Lsc is a Rho GEF that is expressed specifically in the hematopoietic system. It contains a regulator of G-protein signaling (RGS) domain which negatively regulates the Ga12 and Ga13 subunits of G-protein coupled receptors (GPCRs). This study shows that NK and NKT cell development are normal in Lsc-/- mice. However, NK cells from mutant mice display enhanced cytotoxic responses towards a panel of tumor cells. These data implicate for the first time a RGS-containing Rho GEF in cytotoxic responses and suggest that Lsc down-modulate NK cell activation.},
  subject      = {Maus},
  language  = {en}
}
@phdthesis{Glueckermann2004,
  author    = {Gl{\"u}ckermann, Susanne Karola},
  title     = {Zytotoxizit{\"a}tspr{\"u}fung verschiedener Silbertitanlegierungen auf Titanbasis mittels humaner Osteoblasten},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-11021},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2004},
  abstract  = {In der vorliegenden Arbeit wurde die Zytotoxizit{\"a}t verschiedener Schichten bestehend aus Silber-Titanlegierungen auf Titanbasis mittels der humanen Osteoblastenzelllinie hFOB 1.19 gepr{\"u}ft. Es sollte der Einfluß des Silberanteils in der Beschichtung auf die Zellen getestet werden. Es wurde die Wirkung auf die Proliferations- und Differenzierungsleistung der Zellen mit standardisierten Untersuchungsmethoden getestet. Des weiteren wurde die Aktivit{\"a}t der alkalischen Phosphatase und die Biomassebestimmung vorgenommen.Als Kontrolluntersuchung wurde der gleiche Versuch mit der bronchialen Epithelzelllinie HBE 16 durchgef{\"u}hrt. Die Zellkultivierung erfolgte {\"u}ber einen 14-t{\"a}gigen Zeitraum. Als Referenzoberfl{\"a}che wurde konventionelles Zellkultur-Polystyrol verwendet. Die Zellvitalit{\"a}t wurde mit Hilfe des WST-1-Tests, der Differenzierungstatus anhand der Aktivit{\"a}t der alkalischen Phosphatase und der Proteingehalt mittels der Proteinbestimmung nach Bradford erfaßt. Es zeigten sich bei allen Messungen starke Schwankungen der Zellzahl, Zellvitalit{\"a}t, der spezifischen Aktivit{\"a}t der alkalischen Phosphatase und des Proteingehalts auf den Oberfl{\"a}chen. Eine Proportionalit{\"a}t zwischen den verschiedenen Silberkonzentrationen und den Proliferationszahlen war nicht zu beobachten. Mit dem Wissen {\"u}ber die hervorragende Biokompatibilit{\"a}t von Titan und der nachgewiesenen bakteriostatischen Wirkung von Silber ist dies ein hervorragender Werkstoff , welcher sch{\"a}dliche Bakterien um das Implantat herum eliminiert und trotzdem ein ungehindertes Einwachsen des Implantats in den Knochen erlaubt.},
  language  = {de}
}
@phdthesis{Seystahl2010,
  author    = {Seystahl, Katharina Gertrud},
  title     = {Einfluss von Dasatinib auf die Expansion, Zytotoxizit{\"a}t und Zytokinproduktion von humanen Nat{\"u}rlichen Killer-Zellen},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-51843},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2010},
  abstract  = {NK-Zellen spielen eine wichtige Rolle im menschlichen Immunsystem, insbesondere durch die Zerst{\"o}rung von virusinfizierten Zellen und Tumorzellen sowie durch die Produktion von Zytokinen. Eine gezielte Modulation der Effektorfunktionen von NK-Zellen kann den Weg f{\"u}r neue Therapiestrategien gegen{\"u}ber malignen Erkrankungen oder auch Autoimmunerkrankungen bahnen. Dasatinib ist ein potenter Inhibitor einer Vielzahl von Kinasen, die an der Regulation von NK-Zelleffektorfunktionen beteiligt sind und f{\"u}r die bereits eine Inhibition von T-Zelleffektorfunktionen gezeigt werden konnte [Schade et al. 2008; Weichsel et al. 2008]. Ein besseres Verst{\"a}ndnis der immunmodulatorischen Eigenschaften von Dasatinib kann nicht nur neue Einsatzbereiche identifizieren, sondern auch die bereits bew{\"a}hrte Therapie der CML optimieren. Daher wurde im Rahmen dieser Arbeit der Einfluss von Dasatinib auf die Expansion, Zytotoxizit{\"a}t und Zytokinproduktion von humanen NK-Zellen analysiert. Dazu wurden aus peripheren Blutlymphozyten gesunder Spender polyklonale NK-Zellen in Kokultur mit bestrahlten RPMI 8866-Zellen mit und ohne Dasatinib expandiert und NK-Zelleffektorfunktionen mit Durchfluszytometrie-basierten Experimenten untersucht. Im Detail wurde die Zytotoxizit{\"a}t nach dem Prinzip des FATAL-Experiments [Sheehy et al. 2001], die Degranulationsaktivit{\"a}t {\"u}ber die Expression von CD107a/b, die Produktion von TNF-α bzw. IFN-γ mit einer intrazellul{\"a}ren F{\"a}rbung und die Apoptose- und Zelltodanalyse {\"u}ber Annexin-V und 7-AAD gemessen. Die Daten dieser Arbeit zeigen, dass Dasatinib die Haupteffektorfunktionen von NK-Zellen gesunder Blutspender in vitro reguliert: Die Expansionskapazit{\"a}t von NK-Zellen wird dosisabh{\"a}ngig und bei 50 nM Dasatinib vollst{\"a}ndig inhibiert, ohne dass dies durch ein Absterben der NK-Zellen bedingt ist. Die Zytotoxizit{\"a}t von NK-Zellen, die unter 10 nM Dasatinib expandiert sind, ist nach Entfernen des Medikamentes restauriert, und die Degranulationskapazit{\"a}t und die Zytokinproduktion sind gesteigert. Bei unbehandelt expandierten NK-Zellen f{\"u}hrt die direkte Anwesenheit von Dasatinib zu einer dosisabh{\"a}ngigen Hemmung der Zytotoxizit{\"a}t gegen{\"u}ber K562-Zellen. Dar{\"u}ber hinaus inhibiert Dasatinib dosisabh{\"a}ngig die Degranulation und Zytokinproduktion von NK-Zellen bei einer Stimulation mit K562-Zellen nicht aber bei einer Stimulation mit PMA/Ca2+Ionophor. Eine indirekte Ver{\"a}nderung des Lyseverhaltens der NK-Zellen durch Effekte von Dasatinib auf die K562-Zellen zeigt sich nicht nach 4h, aber nach 24h im Sinne einer erh{\"o}hten Spontanlyse, aber geringeren spezifischen Lyse. Eine 24h-Vorbehandlung von K562-Zellen mit Dasatinib f{\"u}hrt außerdem zu einer verminderten Degranulationsaktivit{\"a}t und Zytokinproduktion von unbehandelten NK-Zellen. Die Hemmung der NK-Zelleffektorfunktionen bei direkter Anwesenheit von Dasatinib und deren Restauration respektive Steigerung nach Entfernen des Medikaments ist am ehesten auf eine reversible Inhibition von Src-Kinase-abh{\"a}ngigen Prozessen der intrazellul{\"a}ren Signal{\"u}bertragung zur{\"u}ckzuf{\"u}hren. Eine kompromittierte NK-Zellfunktion k{\"o}nnte w{\"a}hrend einer Behandlung mit Dasatinib zu einer Verminderung der Infektabwehr und der immunologischen Tumor{\"u}berwachung f{\"u}hren. M{\"o}glicherweise lassen sich jedoch die unerw{\"u}nschten Wirkungen durch ein ver{\"a}ndertes Dosisregime, wie eine Hochdosispulstherapie, bei guter Therapieeffizienz minimieren. Eine supprimierte Aktivit{\"a}t der NK-Zellen durch Dasatinib k{\"o}nnte dagegen bei der Therapie von NK-Zelllymphomen oder auch von Autoimmunerkrankungen eine neue Behandlungsoption darstellen. Aufgrund der bereits bekannten inhibitorischen Wirkung auf T-Zellfunktionen gibt es dabei m{\"o}glicherweise Synergien in der immunsuppressiven Wirkung. Das immunmodulatorische Potential von Dasatinib birgt daher große Chancen sowohl im Einsatz als Immunsuppressivum, als auch in der Optimierung der bereits bew{\"a}hrten Therapie der CML.},
  subject      = {Nat{\"u}rliche Killerzelle},
  language  = {de}
}
@phdthesis{Plochmann2011,
  author    = {Plochmann, Kathrin},
  title     = {Bioassays zur Untersuchung der biologischen Aktivit{\"a}t von Flavonoiden und Ermittlung eines zellul{\"a}ren Rezeptormolek{\"u}ls von foamyviralen Vektoren},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-65183},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2011},
  abstract  = {Aufgrund ihrer gut dokumentierten, umfangreichen gesundheitsf{\"o}rdernden biologischen Aktivit{\"a}ten wird den Flavonoiden eine große Bedeutung zugeordnet. Die Ergebnisse von in vitro- und Tierstudien deuten zudem darauf hin, dass diese Verbindungen bei der Pr{\"a}vention und Therapie von Erkrankungen wie Krebs oder Alzheimer Krankheit (AD) positive Effekte zeigen. Zur besseren Charakterisierung der Interaktion von Flavonoiden mit Krebszellen wurden von uns die Cytotoxizit{\"a}t verschiedener Flavonoide auf T-Lymphoblastomzellen untersucht und Strukturelemente identifiziert, welche f{\"u}r einen Flavonoid-induzierten Zelltod relevant sind. Weitere Studien waren der potentiell neuroprotektiven Wirkung von Flavonoiden gewidmet. Die sowohl in neuronalen Zellkulturen als auch in transgenen Alzheimer-M{\"a}usen (TgAPPsw) festgestellte Erh{\"o}hung der sAPPα Produktion und Reduktion von Aβ-Bildung wurden mit Aktivit{\"a}ts- und Expressionssteigerung der α-Sekretase ADAM-10 assoziiert. Um herauszufinden, ob Flavonoide eine neuroprotektive Wirkung zeigen, wurden erste Vorbereitungen f{\"u}r ein Flavonoid-Screening mit einer sowohl hAPP alsauch ADAM-10 stabil transfizierten HT1080 Zellen getroffen. Dies beinhaltete die Suche nach einer potenten siRNA/shRNA und einem effektiven Flavonoid. Im zweiten Teil der Arbeit wurden Experimente durchgef{\"u}hrt, um die Rolle von Heparansulfat (HS) bei der foamyviralen Anbindung an die Wirtszelle zu untersuchen. Foamyviren (FV) sind Spumaviren und geh{\"o}ren zur Familie der Retroviren. Bei unseren Studien wurde die Bindung von FV an Heparin, die Korrelation der Suszeptibilit{\"a}t verschiedener Zellen mit zellul{\"a}rem HS und die Reduktion der Infektion durch l{\"o}sliches Heparin sowie durch enzymatischen HS-Abbau festgestellt.},
  subject      = {Flavonoide},
  language  = {de}
}
@phdthesis{Pfeiffer2012,
  author    = {Pfeiffer, Hendrik},
  title     = {Synthesis and biological activity of molybdenum carbonyl complexes and their peptide conjugates},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-71199},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2012},
  abstract  = {Molybdenum carbonyl complexes with different polypyridyl coligands were prepared and conjugated to peptides by mild bioorthogonal coupling reactions like the oxime ligation and a catalyst-free azide-alkyne click reaction utilized for the first time in such a context. The biological activity of some of the new complexes and conjugates, including their CO release properties, cytotoxicity on human cancer cells, and mode of induction of cell death was studied.},
  subject      = {Molybd{\"a}ncarbonyle},
  language  = {en}
}
@article{RascheDuellMorgneretal.2013,
  author    = {Rasche, Leo and Duell, Johannes and Morgner, Charlotte and Chatterjee, Manik and Hensel, Frank and Rosenwald, Andreas and Einsele, Hermann and Topp, Max S. and Br{\"a}ndlein, Stephanie},
  title     = {The Natural Human IgM Antibody PAT-SM6 Induces Apoptosis in Primary Human Multiple Myeloma Cells by Targeting Heat Shock Protein GRP78},
  series = {PLoS ONE},
  volume    = {8},
  journal   = {PLoS ONE},
  number    = {5},
  doi       = {10.1371/journal.pone.0063414},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-130125},
  pages     = {e63414},
  year      = {2013},
  abstract  = {In contrast to other haematological malignancies, targeted immunotherapy has not entered standard treatment regimens for de novo or relapsed multiple myeloma (MM) yet. While a number of IgG-formatted monoclonal antibodies are currently being evaluated in clinical trials in MM, our study aimed to investigate whether the fully human IgM monoclonal antibody PAT-SM6 that targets a tumour-specific variant of the heat shock protein GRP78 might be an attractive candidate for future immunotherapeutic approaches. We here show that GRP78 is stably and consistently expressed on the surface on tumour cells from patients with de novo, but also relapsed MM and that binding of PAT-SM6 to MM cells can specifically exert cytotoxic effects on malignant plasma cells, whereas non-malignant cells are not targeted. We demonstrate that the induction of apoptosis and, to a lesser extent, complement dependent cytotoxicity is the main mode of action of PAT-SM6, whereas antibody dependent cellular cytotoxicity does not appear to contribute to the cytotoxic properties of this antibody. Given the favourable safety profile of PAT-SM6 in monkeys, but also in a recent phase I trial in patients with malignant melanoma, our results form the basis for a planned phase I study in patients with relapsed MM.},
  language  = {en}
}
@article{ShityakovSalvadorPastorinetal.2015,
  author    = {Shityakov, Sergey and Salvador, Ellaine and Pastorin, Giorgia and F{\"o}rster, Carola},
  title     = {Blood-brain barrier transport studies, aggregation, and molecular dynamics simulation of multiwalled carbon nanotube functionalized with fluorescein isothiocyanate},
  series = {International Journal of Nanomedicine},
  volume    = {10},
  journal   = {International Journal of Nanomedicine},
  doi       = {10.2147/IJN.S68429},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-149233},
  pages     = {1703-1713},
  year      = {2015},
  abstract  = {In this study, the ability of a multiwalled carbon nanotube functionalized with fluorescein isothiocyanate (MWCNT-FITC) was assessed as a prospective central nervous system-targeting drug delivery system to permeate the blood-brain barrier. The results indicated that the MWCNT-FITC conjugate is able to penetrate microvascular cerebral endothelial monolayers; its concentrations in the Transwell® system were fully equilibrated after 48 hours. Cell viability test, together with phase-contrast and fluorescence microscopies, did not detect any signs of MWCNT-FITC toxicity on the cerebral endothelial cells. These microscopic techniques also revealed presumably the intracellular localization of fluorescent MWCNT-FITCs apart from their massive nonfluorescent accumulation on the cellular surface due to nanotube lipophilic properties. In addition, the 1,000 ps molecular dynamics simulation in vacuo discovered the phenomenon of carbon nanotube aggregation driven by van der Waals forces via MWCN-TFITC rapid dissociation as an intermediate phase.},
  language  = {en}
}
@article{GlaserSchultheisMolletal.2015,
  author    = {Glaser, Jan and Schultheis, Martina and Moll, Heidrun and Hazra, Banasri and Holzgrabe, Ulrike},
  title     = {Antileishmanial and Cytotoxic Compounds from Valeriana wallichii and Identification of a Novel Nepetolactone Derivative},
  series = {Molecules},
  volume    = {20},
  journal   = {Molecules},
  number    = {4},
  doi       = {10.3390/molecules20045740},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-125320},
  pages     = {5740-5753},
  year      = {2015},
  abstract  = {The chloroform extract of Valeriana wallichii (V. wallichii) rhizomes was investigated to elucidate the structures responsible for reported antileishmanial activity. Besides bornyl caffeate (1, already been reported by us previously), bioassay-guided fractionation resulted in two additional cinnamic acid derivatives 2-3 with moderate leishmanicidal activity. The structure of a novel nepetolactone derivative 4 having a cinnamic acid moiety was elucidated by means of spectral analysis. To the best of our knowledge villoside aglycone (5) was isolated from this plant for the first time. The bioassay-guided fractionation yielded two new (compounds 6-7) and two known valtrates (compounds 8-9) with leishmanicidal potential against Leishmania major (L. major) promastigotes. In addition, β-bisabolol (10), α-kessyl alcohol (11), valeranone (12), bornyl isovalerate (13) and linarin-2-O-methylbutyrate (14) were identified. This is the first report on the isolation of 4'-demethylpodophyllotoxin (15), podophyllotoxin (16) and pinoresinol (17) in V. wallichii. In total thirteen known and four new compounds were identified from the extract and their cytotoxic and antileishmanial properties were evaluated.},
  language  = {en}
}
@article{GordonDaneshianBouwstraetal.2015,
  author    = {Gordon, Sarah and Daneshian, Mardas and Bouwstra, Joke and Caloni, Francesca and Constant, Samuel and Davies, Donna E. and Dandekar, Gudrun and Guzman, Carlos A. and Fabian, Eric and Haltner, Eleonore and Hartung, Thomas and Hasiwa, Nina and Hayden, Patrick and Kandarova, Helena and Khare, Sangeeta and Krug, Harald F. and Kneuer, Carsten and Leist, Marcel and Lian, Guoping and Marx, Uwe and Metzger, Marco and Ott, Katharina and Prieto, Pilar and Roberts, Michael S. and Roggen, Erwin L. and Tralau, Tewes and van den Braak, Claudia and Walles, Heike and Lehr, Claus-Michael},
  title     = {Non-animal models of epithelial barriers (skin, intestine and lung) in research, industrial applications and regulatory toxicology},
  series = {ALTEX: Alternatives to Animal Experimentation},
  volume    = {32},
  journal   = {ALTEX: Alternatives to Animal Experimentation},
  number    = {4},
  doi       = {10.14573/altex.1510051},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-144275},
  pages     = {327-378},
  year      = {2015},
  abstract  = {Models of the outer epithelia of the human body namely the skin, the intestine and the lung have found valid applications in both research and industrial settings as attractive alternatives to animal testing. A variety of approaches to model these barriers are currently employed in such fields, ranging from the utilization of ex vivo tissue to reconstructed in vitro models, and further to chip-based technologies, synthetic membrane systems and, of increasing current interest, in silico modeling approaches. An international group of experts in the field of epithelial barriers was convened from academia, industry and regulatory bodies to present both the current state of the art of non-animal models of the skin, intestinal and pulmonary barriers in their various fields of application, and to discuss research-based, industry-driven and regulatory-relevant future directions for both the development of new models and the refinement of existing test methods. Issues of model relevance and preference, validation and standardization, acceptance, and the need for simplicity versus complexity were focal themes of the discussions. The outcomes of workshop presentations and discussions, in relation to both current status and future directions in the utilization and development of epithelial barrier models, are presented by the attending experts in the current report.},
  language  = {en}
}
@article{BlaettnerDasPaprotkaetal.2016,
  author    = {Bl{\"a}ttner, Sebastian and Das, Sudip and Paprotka, Kerstin and Eilers, Ursula and Krischke, Markus and Kretschmer, Dorothee and Remmele, Christian W. and Dittrich, Marcus and M{\"u}ller, Tobias and Schuelein-Voelk, Christina and Hertlein, Tobias and Mueller, Martin J. and Huettel, Bruno and Reinhardt, Richard and Ohlsen, Knut and Rudel, Thomas and Fraunholz, Martin J.},
  title     = {Staphylococcus aureus Exploits a Non-ribosomal Cyclic Dipeptide to Modulate Survival within Epithelial Cells and Phagocytes},
  series = {PLoS Pathogens},
  volume    = {12},
  journal   = {PLoS Pathogens},
  number    = {9},
  doi       = {10.1371/journal.ppat.1005857},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-180380},
  year      = {2016},
  abstract  = {Community-acquired (CA) Staphylococcus aureus cause various diseases even in healthy individuals. Enhanced virulence of CA-strains is partly attributed to increased production of toxins such as phenol-soluble modulins (PSM). The pathogen is internalized efficiently by mammalian host cells and intracellular S. aureus has recently been shown to contribute to disease. Upon internalization, cytotoxic S. aureus strains can disrupt phagosomal membranes and kill host cells in a PSM-dependent manner. However, PSM are not sufficient for these processes. Here we screened for factors required for intracellular S. aureus virulence. We infected escape reporter host cells with strains from an established transposon mutant library and detected phagosomal escape rates using automated microscopy. We thereby, among other factors, identified a non-ribosomal peptide synthetase (NRPS) to be required for efficient phagosomal escape and intracellular survival of S. aureus as well as induction of host cell death. By genetic complementation as well as supplementation with the synthetic NRPS product, the cyclic dipeptide phevalin, wild-type phenotypes were restored. We further demonstrate that the NRPS is contributing to virulence in a mouse pneumonia model. Together, our data illustrate a hitherto unrecognized function of the S. aureus NRPS and its dipeptide product during S. aureus infection.},
  language  = {en}
}
@article{OttoHahlbrockEichetal.2016,
  author    = {Otto, Christoph and Hahlbrock, Theresa and Eich, Kilian and Karaaslan, Ferdi and J{\"u}rgens, Constantin and Germer, Christoph-Thomas and Wiegering, Armin and K{\"a}mmerer, Ulrike},
  title     = {Antiproliferative and antimetabolic effects behind the anticancer property of fermented wheat germ extract},
  series = {BMC Complementary and Alternative Medicine},
  volume    = {16},
  journal   = {BMC Complementary and Alternative Medicine},
  number    = {160},
  doi       = {10.1186/s12906-016-1138-5},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-146013},
  year      = {2016},
  abstract  = {Background Fermented wheat germ extract (FWGE) sold under the trade name Avemar exhibits anticancer activity in vitro and in vivo. Its mechanisms of action are divided into antiproliferative and antimetabolic effects. Its influcence on cancer cell metabolism needs further investigation. One objective of this study, therefore, was to further elucidate the antimetabolic action of FWGE. The anticancer compound 2,6-dimethoxy-1,4-benzoquinone (DMBQ) is the major bioactive compound in FWGE and is probably responsible for its anticancer activity. The second objective of this study was to compare the antiproliferative properties in vitro of FWGE and the DMBQ compound. Methods The IC\(_{50}\) values of FWGE were determined for nine human cancer cell lines after 24 h of culture. The DMBQ compound was used at a concentration of 24 μmol/l, which is equal to the molar concentration of DMBQ in FWGE. Cell viability, cell cycle, cellular redox state, glucose consumption, lactic acid production, cellular ATP levels, and the NADH/NAD\(^+\) ratio were measured. Results The mean IC\(_{50}\) value of FWGE for the nine human cancer cell lines tested was 10 mg/ml. Both FWGE (10 mg/ml) and the DMBQ compound (24 μmol/l) induced massive cell damage within 24 h after starting treatment, with changes in the cellular redox state secondary to formation of intracellular reactive oxygen species. Unlike the DMBQ compound, which was only cytotoxic, FWGE exhibited cytostatic and growth delay effects in addition to cytotoxicity. Both cytostatic and growth delay effects were linked to impaired glucose utilization which influenced the cell cycle, cellular ATP levels, and the NADH/NAD\(^+\) ratio. The growth delay effect in response to FWGE treatment led to induction of autophagy. Conclusions FWGE and the DMBQ compound both induced oxidative stress-promoted cytotoxicity. In addition, FWGE exhibited cytostatic and growth delay effects associated with impaired glucose utilization which led to autophagy, a possible previously unknown mechanism behind the influence of FWGE on cancer cell metabolism.},
  language  = {en}
}
@article{IckrathWagnerScherzadetal.2017,
  author    = {Ickrath, Pascal and Wagner, Martin and Scherzad, Agmal and Gehrke, Thomas and Burghartz, Marc and Hagen, Rudolf and Radeloff, Katrin and Kleinsasser, Norbert and Hackenberg, Stephan},
  title     = {Time-Dependent Toxic and Genotoxic Effects of Zinc Oxide Nanoparticles after Long-Term and Repetitive Exposure to Human Mesenchymal Stem Cells},
  series = {International Journal of Environmental Research and Public Health},
  volume    = {14},
  journal   = {International Journal of Environmental Research and Public Health},
  number    = {12},
  doi       = {10.3390/ijerph14121590},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-169932},
  pages     = {1590},
  year      = {2017},
  abstract  = {Zinc oxide nanoparticles (ZnO-NP) are widely spread in consumer products. Data about the toxicological characteristics of ZnO-NP is still under controversial discussion. The human skin is the most important organ concerning ZnO-NP exposure. Intact skin was demonstrated to be a sufficient barrier against NPs; however, defect skin may allow NP contact to proliferating cells. Within these cells, stem cells are the most important toxicological target for NPs. The aim of this study was to evaluate the genotoxic and cytotoxic effects of ZnO-NP at low-dose concentrations after long-term and repetitive exposure to human mesenchymal stem cells (hMSC). Cytotoxic effects of ZnO-NP were measured by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. Furthermore, genotoxicity was evaluated by the comet assay. For long-term observation over 6 weeks, transmission electron microscopy (TEM) was applied. The results of the study indicated cytotoxic effects of ZnO-NP beginning at high concentrations of 50 μg/mL and genotoxic effects in hMSC exposed to 1 and 10 μg/mL ZnO-NP. Repetitive exposure enhanced cyto- but not genotoxicity. Intracellular NP accumulation was observed up to 6 weeks. The results suggest cytotoxic and genotoxic potential of ZnO-NP. Even low doses of ZnO-NP may induce toxic effects as a result of repetitive exposure and long-term cellular accumulation. This data should be considered before using ZnO-NP on damaged skin.},
  language  = {en}
}
@article{GrebinykPrylutskaBuchelnikovetal.2019,
  author    = {Grebinyk, Anna and Prylutska, Svitlana and Buchelnikov, Anatoliy and Tverdokhleb, Nina and Grebinyk, Sergii and Evstigneev, Maxim and Matyshevska, Olga and Cherepanov, Vsevolod and Prylutskyy, Yuriy and Yashchuk, Valeriy and Naumovets, Anton and Ritter, Uwe and Dandekar, Thomas and Frohme, Marcus},
  title     = {C60 fullerene as an effective nanoplatform of alkaloid Berberine delivery into leukemic cells},
  series = {Pharmaceutics},
  volume    = {11},
  journal   = {Pharmaceutics},
  number    = {11},
  issn      = {1999-4923},
  doi       = {10.3390/pharmaceutics11110586},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-193216},
  pages     = {586},
  year      = {2019},
  abstract  = {A herbal alkaloid Berberine (Ber), used for centuries in Ayurvedic, Chinese, Middle-Eastern, and native American folk medicines, is nowadays proved to function as a safe anticancer agent. Yet, its poor water solubility, stability, and bioavailability hinder clinical application. In this study, we have explored a nanosized carbon nanoparticle—C60 fullerene (C60)—for optimized Ber delivery into leukemic cells. Water dispersions of noncovalent C60-Ber nanocomplexes in the 1:2, 1:1, and 2:1 molar ratios were prepared. UV-Vis spectroscopy, dynamic light scattering (DLS), and atomic force microscopy (AFM) evidenced a complexation of the Ber cation with the negatively charged C60 molecule. The computer simulation showed that π-stacking dominates in Ber and C\(_{60}\) binding in an aqueous solution. Complexation with C\(_{60}\) was found to promote Ber intracellular uptake. By increasing C\(_{60}\) concentration, the C\(_{60}\)-Ber nanocomplexes exhibited higher antiproliferative potential towards CCRF-CEM cells, in accordance with the following order: free Ber < 1:2 < 1:1 < 2:1 (the most toxic). The activation of caspase 3/7 and accumulation in the sub-G1 phase of CCRF-CEM cells treated with C\(_{60}\)-Ber nanocomplexes evidenced apoptosis induction. Thus, this study indicates that the fast and easy noncovalent complexation of alkaloid Ber with C\(_{60}\) improved its in vitro efficiency against cancer cells.},
  language  = {en}
}
@article{GrebinykPrylutskaGrebinyketal.2019,
  author    = {Grebinyk, Anna and Prylutska, Svitlana and Grebinyk, Sergii and Prylutskyy, Yuriy and Ritter, Uwe and Matyshevska, Olga and Dandekar, Thomas and Frohme, Marcus},
  title     = {Complexation with C\(_{60}\) fullerene increases doxorubicin efficiency against leukemic cells in vitro},
  series = {Nanoscale Research Letters},
  volume    = {14},
  journal   = {Nanoscale Research Letters},
  number    = {61},
  doi       = {10.1186/s11671-019-2894-1},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-228257},
  year      = {2019},
  abstract  = {Conventional anticancer chemotherapy is limited because of severe side effects as well as a quickly evolving multidrug resistance of the tumor cells. To address this problem, we have explored a C\(_{60}\) fullerene-based nanosized system as a carrier for anticancer drugs for an optimized drug delivery to leukemic cells.Here, we studied the physicochemical properties and anticancer activity of C\(_{60}\) fullerene noncovalent complexes with the commonly used anticancer drug doxorubicin. C\(_{60}\)-Doxorubicin complexes in a ratio 1:1 and 2:1 were characterized with UV/Vis spectrometry, dynamic light scattering, and high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). The obtained analytical data indicated that the 140-nm complexes were stable and could be used for biological applications. In leukemic cell lines (CCRF-CEM, Jurkat, THP1 and Molt-16), the nanocomplexes revealed 3.5 higher cytotoxic potential in comparison with the free drug in a range of nanomolar concentrations. Also, the intracellular drug's level evidenced C\(_{60}\) fullerene considerable nanocarrier function.The results of this study indicated that C\(_{60}\) fullerene-based delivery nanocomplexes had a potential value for optimization of doxorubicin efficiency against leukemic cells.},
  language  = {en}
}
@article{ScherzadMeyerIckrathetal.2019,
  author    = {Scherzad, Agmal and Meyer, Till and Ickrath, Pascal and Gehrke, Thomas Eckhart and Bregenzer, Maximillian and Hagen, Rudolf and Dembski, Sofia and Hackenberg, Stephan},
  title     = {Cultivation of hMSCs in human plasma prevents the cytotoxic and genotoxic potential of ZnO-NP in vitro},
  series = {Applied Sciences},
  volume    = {9},
  journal   = {Applied Sciences},
  number    = {23},
  issn      = {2076-3417},
  doi       = {10.3390/app9234994},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-193063},
  year      = {2019},
  abstract  = {Zinc oxide nanoparticles (ZnO-NPs) are commonly used for industrial applications. Consequently, there is increasing exposure of humans to them. The in vitro analysis of cytotoxicity and genotoxicity is commonly performed under standard cell culture conditions. Thus, the question arises of how the results of genotoxicity and cytotoxicity experiments would alter if human plasma was used instead of cell culture medium containing of fetal calf serum (FCS). Human mesenchymal stem cells (hMSCs) were cultured in human plasma and exposed to ZnO-NPs. A cultivation in expansion medium made of DMEM consisting 10\% FCS (DMEM-EM) served as control. Genotoxic and cytotoxic effects were evaluated with the comet and MTT assay, respectively. hMSC differentiation capacity and ZnO-NP disposition were evaluated by histology and transmission electron microscopy (TEM). The protein concentration and the amount of soluble Zn2+ were measured. The cultivation of hMSCs in plasma leads to an attenuation of genotoxic and cytotoxic effects of ZnO-NPs compared to control. The differentiation capacity of hMSCs was not altered. The TEM showed ZnO-NP persistence in cytoplasm in both groups. The concentrations of protein and Zn2+ were higher in plasma than in DMEM-EM. In conclusion, the cultivation of hMSCs in plasma compared to DMEM-EM leads to an attenuation of cytotoxicity and genotoxicity in vitro.},
  language  = {en}
}
@article{AbdelhameedEltamanyHaletal.2020,
  author    = {Abdelhameed, Reda F. A. and Eltamany, Enas E. and Hal, Dina M. and Ibrahim, Amany K. and AboulMagd, Asmaa M. and Al-Warhi, Tarfah and Youssif, Khayrya A. and Abd El-kader, Adel M. and Hassanean, Hashim A. and Fayez, Shaimaa and Bringmann, Gerhard and Ahmed, Safwat A. and Abdelmohsen, Usama Ramadan},
  title     = {New cytotoxic cerebrosides from the Red Sea cucumber Holothuria spinifera supported by in-silico studies},
  series = {Marine Drugs},
  volume    = {18},
  journal   = {Marine Drugs},
  number    = {8},
  issn      = {1660-3397},
  doi       = {10.3390/md18080405},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-211089},
  year      = {2020},
  abstract  = {Bioactivity-guided fractionation of a methanolic extract of the Red Sea cucumber Holothuria spinifera and LC-HRESIMS-assisted dereplication resulted in the isolation of four compounds, three new cerebrosides, spiniferosides A (1), B (2), and C (3), and cholesterol sulfate (4). The chemical structures of the isolated compounds were established on the basis of their 1D NMR and HRMS spectral data. Metabolic profiling of the H. spinifera extract indicated the presence of diverse secondary metabolites, mostly hydroxy fatty acids, diterpenes, triterpenes, and cerebrosides. The isolated compounds were tested for their in vitro cytotoxicities against the breast adenocarcinoma MCF-7 cell line. Compounds 1, 2, 3, and 4 displayed promising cytotoxic activities against MCF-7 cells, with IC\(_{50}\) values of 13.83, 8.13, 8.27, and 35.56 µM, respectively, compared to that of the standard drug doxorubicin (IC\(_{50}\) 8.64 µM). Additionally, docking studies were performed for compounds 1, 2, 3, and 4 to elucidate their binding interactions with the active site of the SET protein, an inhibitor of protein phosphatase 2A (PP2A), which could explain their cytotoxic activity. This study highlights the important role of these metabolites in the defense mechanism of the sea cucumber against fouling organisms and the potential uses of these active molecules in the design of new anticancer agents.},
  language  = {en}
}
@article{EltamanyAbdelmohsenHaletal.2021,
  author    = {Eltamany, Enas E. and Abdelmohsen, Usama Ramadan and Hal, Dina M. and Ibrahim, Amany K. and Hassanean, Hashim A. and Abdelhameed, Reda F. A. and Temraz, Tarek A. and Hajjar, Dina and Makki, Arwa A. and Hendawy, Omnia Magdy and AboulMagd, Asmaa M. and Youssif, Khayrya A. and Bringmann, Gerhard and Ahmed, Safwat A.},
  title     = {Holospiniferoside: A New Antitumor Cerebroside from The Red Sea Cucumber Holothuria spinifera: In Vitro and In Silico Studies},
  series = {Molecules},
  volume    = {26},
  journal   = {Molecules},
  number    = {6},
  issn      = {1420-3049},
  doi       = {10.3390/molecules26061555},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-234058},
  year      = {2021},
  abstract  = {Chemical investigation of the methanolic extract of the Red Sea cucumber Holothuria spinifera led to the isolation of a new cerebroside, holospiniferoside (1), together with thymidine (2), methyl-α-d-glucopyranoside (3), a new triacylglycerol (4), and cholesterol (5). Their chemical structures were established by NMR and mass spectrometric analysis, including gas chromatography-mass spectrometry (GC-MS) and high-resolution mass spectrometry (HRMS). All the isolated compounds are reported in this species for the first time. Moreover, compound 1 exhibited promising in vitro antiproliferative effect on the human breast cancer cell line (MCF-7) with IC\(_{50}\) of 20.6 µM compared to the IC50 of 15.3 µM for the drug cisplatin. To predict the possible mechanism underlying the cytotoxicity of compound 1, a docking study was performed to elucidate its binding interactions with the active site of the protein Mdm2-p53. Compound 1 displayed an apoptotic activity via strong interaction with the active site of the target protein. This study highlights the importance of marine natural products in the design of new anticancer agents.},
  language  = {en}
}
@article{StelznerBoynyHertleinetal.2021,
  author    = {Stelzner, Kathrin and Boyny, Aziza and Hertlein, Tobias and Sroka, Aneta and Moldovan, Adriana and Paprotka, Kerstin and Kessie, David and Mehling, Helene and Potempa, Jan and Ohlsen, Knut and Fraunholz, Martin J. and Rudel, Thomas},
  title     = {Intracellular Staphylococcus aureus employs the cysteine protease staphopain A to induce host cell death in epithelial cells},
  series = {PLoS Pathogens},
  volume    = {17},
  journal   = {PLoS Pathogens},
  number    = {9},
  doi       = {10.1371/journal.ppat.1009874},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-263908},
  year      = {2021},
  abstract  = {Staphylococcus aureus is a major human pathogen, which can invade and survive in non-professional and professional phagocytes. Uptake by host cells is thought to contribute to pathogenicity and persistence of the bacterium. Upon internalization by epithelial cells, cytotoxic S. aureus strains can escape from the phagosome, replicate in the cytosol and induce host cell death. Here, we identified a staphylococcal cysteine protease to induce cell death after translocation of intracellular S. aureus into the host cell cytoplasm. We demonstrated that loss of staphopain A function leads to delayed onset of host cell death and prolonged intracellular replication of S. aureus in epithelial cells. Overexpression of staphopain A in a non-cytotoxic strain facilitated intracellular killing of the host cell even in the absence of detectable intracellular replication. Moreover, staphopain A contributed to efficient colonization of the lung in a mouse pneumonia model. In phagocytic cells, where intracellular S. aureus is exclusively localized in the phagosome, staphopain A did not contribute to cytotoxicity. Our study suggests that staphopain A is utilized by S. aureus to exit the epithelial host cell and thus contributes to tissue destruction and dissemination of infection. Author summary Staphylococcus aureus is an antibiotic-resistant pathogen that emerges in hospital and community settings and can cause a variety of diseases ranging from skin abscesses to lung inflammation and blood poisoning. The bacterium can asymptomatically colonize the upper respiratory tract and skin of humans and take advantage of opportune conditions, like immunodeficiency or breached barriers, to cause infection. Although S. aureus was not regarded as intracellular bacterium, it can be internalized by human cells and subsequently exit the host cells by induction of cell death, which is considered to cause tissue destruction and spread of infection. The bacterial virulence factors and underlying molecular mechanisms involved in the intracellular lifestyle of S. aureus remain largely unknown. We identified a bacterial cysteine protease to contribute to host cell death of epithelial cells mediated by intracellular S. aureus. Staphopain A induced killing of the host cell after translocation of the pathogen into the cell cytosol, while bacterial proliferation was not required. Further, the protease enhanced survival of the pathogen during lung infection. These findings reveal a novel, intracellular role for the bacterial protease staphopain A.},
  language  = {en}
}
@article{AbdElAzizElMaghrabyEwaldetal.2021,
  author    = {Abd El-Aziz, Asmaa M. and El-Maghraby, Azza and Ewald, Andrea and Kandil, Sherif H.},
  title     = {In-vitro cytotoxicity study: cell viability and cell morphology of carbon nanofibrous scaffold/hydroxyapatite nanocomposites},
  series = {Molecules},
  volume    = {26},
  journal   = {Molecules},
  number    = {6},
  issn      = {1420-3049},
  doi       = {10.3390/molecules26061552},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-234037},
  year      = {2021},
  abstract  = {Electrospun carbon nanofibers (CNFs), which were modified with hydroxyapatite, were fabricated to be used as a substrate for bone cell proliferation. The CNFs were derived from electrospun polyacrylonitrile (PAN) nanofibers after two steps of heat treatment: stabilization and carbonization. Carbon nanofibrous (CNF)/hydroxyapatite (HA) nanocomposites were prepared by two different methods; one of them being modification during electrospinning (CNF-8HA) and the second method being hydrothermal modification after carbonization (CNF-8HA; hydrothermally) to be used as a platform for bone tissue engineering. The biological investigations were performed using in-vitro cell counting, WST cell viability and cell morphology after three and seven days. L929 mouse fibroblasts were found to be more viable on the hydrothermally-modified CNF scaffolds than on the unmodified CNF scaffolds. The biological characterizations of the synthesized CNF/HA nanofibrous composites indicated higher capability of bone regeneration.},
  language  = {en}
}
@article{ZahoranovaLuxenhofer2021,
  author    = {Zahoranov{\´a}, Anna and Luxenhofer, Robert},
  title     = {Poly(2-oxazoline)- and Poly(2-oxazine)-Based Self-Assemblies, Polyplexes, and Drug Nanoformulations—An Update},
  series = {Advanced Healthcare Materials},
  volume    = {10},
  journal   = {Advanced Healthcare Materials},
  number    = {6},
  doi       = {10.1002/adhm.202001382},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-225833},
  year      = {2021},
  abstract  = {For many decades, poly(2-oxazoline)s and poly(2-oxazine)s, two closely related families of polymers, have led the life of a rather obscure research topic with only a few research groups world-wide working with them. This has changed in the last five to ten years, presumably triggered significantly by very promising clinical trials of the first poly(2-oxazoline)-based drug conjugate. The huge chemical and structural toolbox poly(2-oxazoline)s and poly(2-oxazine)s has been extended very significantly in the last few years, but their potential still remains largely untapped. Here, specifically, the developments in macromolecular self-assemblies and non-covalent drug delivery systems such as polyplexes and drug nanoformulations based on poly(2-oxazoline)s and poly(2-oxazine)s are reviewed. This highly dynamic field benefits particularly from the extensive synthetic toolbox poly(2-oxazoline)s and poly(2-oxazine)s offer and also may have the largest potential for a further development. It is expected that the research dynamics will remain high in the next few years, particularly as more about the safety and therapeutic potential of poly(2-oxazoline)s and poly(2-oxazine)s is learned.},
  language  = {en}
}
@article{WilhelmsBroscheitShityakov2023,
  author    = {Wilhelms, Benedikt and Broscheit, Jens and Shityakov, Sergey},
  title     = {Chemical analysis and molecular modelling of cyclodextrin-formulated propofol and its sodium salt to improve drug solubility, stability and pharmacokinetics (cytogenotoxicity)},
  series = {Pharmaceuticals},
  volume    = {16},
  journal   = {Pharmaceuticals},
  number    = {5},
  issn      = {1424-8247},
  doi       = {10.3390/ph16050667},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-313705},
  year      = {2023},
  abstract  = {Propofol is a widely used general anesthetic in clinical practice, but its use is limited by its water-insoluble nature and associated pharmacokinetic and pharmacodynamic limitations. Therefore, researchers have been searching for alternative formulations to lipid emulsion to address the remaining side effects. In this study, novel formulations for propofol and its sodium salt Na-propofolat were designed and tested using the amphiphilic cyclodextrin (CD) derivative hydroxypropyl-β-cyclodextrin (HPβCD). The study found that spectroscopic and calorimetric measurements suggested complex formation between propofol/Na-propofolate and HPβCD, which was confirmed by the absence of an evaporation peak and different glass transition temperatures. Moreover, the formulated compounds showed no cytotoxicity and genotoxicity compared to the reference. The molecular modeling simulations based on molecular docking predicted a higher affinity for propofol/HPβCD than for Na-propofolate/HPβCD, as the former complex was more stable. This finding was further confirmed by high-performance liquid chromatography. In conclusion, the CD-based formulations of propofol and its sodium salt may be a promising option and a plausible alternative to conventional lipid emulsions.},
  language  = {en}
}