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The in vivo toxicity of QDs in animals has been broadly studied; however, their reproductive toxicity towards lactating rodents is currently unknown. This study therefore aims to assess the potential toxicity against dams and offspring after postnatal QD exposure at two doses (5 and 1 nmol per rat) and unravel whether QDs can translocate to pups via breastfeeding. The dose-dependent systemic toxicity of QDs in dams was observed by examining the body weight, hematology, biochemistry, histopathological changes, and sex hormone levels. It was found that the QDs primarily accumulated in the liver and spleen of dams at 1 day post injection (dpi), but the highest concentrations were found in the kidneys at 18 dpi. A few QDs were detected in breast milk and stomach and intestine of pups; this suggested that the QDs were transmitted to breast milk via blood circulation and then transferred to pups via breastfeeding. High-dose QDs induced severe growth inhibition and a 71.08% offspring mortality, while pups showed growth restriction within 90 dpi in the low-dose group. Moreover, the hematology, biochemistry, and histology results showed limited chronic toxicity against offspring in the long term. This study provides a theoretical foundation for the exposure assessment of nanomaterials in lactating animals and for the advancement of QDs in the biomedical field.

Das Wechselspiel von Monozyten und glatten Gefäßmuskelzellen (VSMC) spielt eine bedeutende Rolle bei den Vorgängen nach Gefäßwandverletzung. Vor allem geschieht dies über eine Modulation des funktionellen Verhaltens der VSMC, die über eine Interaktion von monozytärem urokinase Plasminogenaktivator (uPA) und ihrem uPA Rezeptor (uPAR) realisiert wird. Es konnte gezeigt werden, dass der Jak/Stat-Signalweg die uPA/uPAR-induzierte Migration und Proliferation von VSMC vermittelt. Die vorliegende Arbeit untersucht molekulare Mechanismen, die bisher noch nicht vollständig verstanden waren. Im Einzelnen hatte diese Arbeit die Identifizierung der Kinase zum Ziel, die innerhalb der Signalkaskade zur Phosphorylierung von Stat1 durch monozytäres uPA und den damit verbundenen Einfluss auf das Zellwachstum führt. VSMC, die die kinasedomäne-defiziente Mutante von Jak1 und Tyk2 exprimieren wurden in einem Monozyten-Kokulturmodell verwendet, das die Vorgänge nach Gefäßwandverletzung nachahmte. Die Arbeit zeigt auf, dass Tyk2, nicht hingegen Jak1, die monozyten-induzierte uPA-vermittelte Phosphorylierung von Stat1 und die VSMC- Wachstumshemmung bewirkt und legt eine neuartige Funktion für Tyk2 als wichtigen Modulator der monozyteninduzierten Funktionsänderung von VSMC am Ort der Gefäßwandverletzung nahe., The interaction between monocytes and vascular smooth muscle cells (VSMC) plays an important role in the response of the vessel wall to injury, presumably by modulating VSMC functional behaviour via an interaction of monozytic urokinase plasminogen (uPA) and its uPA receptor (uPAR). The Jak/Stat signaling pathway has been implicated to mediate the uPA/uPAR- directed cell migration and proliferation in VSMC. This work investigates the underlying molecular mechanisms, which remained not completely understood. In particular, this work aimed at identification of the kinase involved in the signaling cascade leading to Stat1 phosphorylation by monozytic uPA and its impact on VSMC growth. VSMC expressing kinase-deficient mutant forms of the Janus kinases Jak1 and Tyk2 were used in a monocyte coculture model imitating the response to vascular injury. This work provides evidence that Tyk2, but not Jak1, mediates moncyte-induced Stat1 phosphorylation and VSMC growth inhibition via secretion of uPA and suggests a novel function for Tyk2 as an important modulator of the monocyte-directed VSMC functional behaviour at the place of injury.

Human pancreatic ductal adenocarcinoma is a highly malignant disease with a very poor prognosis due to a lack of sufficient therapeutic options. Some observations indicate the important role of oncogenes, tumour suppressor genes and growth factors in its pathogenesis. Pancreatic carcinoma shows an overexpression of fibroblast growth factors (FGFs), which activate tumour progression by autocrine and paracrine loops. FGFs are a group of homologous heparin-binding polypeptides which signal via the according tyrosine-kinase-receptors (=FGFRs). In this study we characterized the expression and functionality of the human FGFR1-IIIb mRNA splice variant in pancreatic ductal cells and tissues. A cDNA encoding the human full-length 2,55 kB FGFR1-IIIb was expressed in a stable manner in well-differentiated TAKA-1 pancreatic ductal cells which are not expressing endogenous FGFR1 as well as in PANC-1 pancreatic carcinoma cells which are expressing little FGFR1. Immunoblot analysis of FGFR1-IIIb-expressing clones revealed that this FGFR is a glycosylated 110 kDa protein. MTT-assays evidenced that human FGFR1-IIIb is a functional receptor which enhances cell proliferation significantly after stimulation by FGF-1, -2 and -4. Further growth assays (MTT and soft agar) in complete medium with 10% FBS demonstrated that anchorage-dependent as well as anchorage-independent growth of TAKA-1 and PANC-1 is inhibited by the expression of FGFR1-IIIb. Growth inhibition is induced by still unknown signalling pathways. Our data demonstrate that human FGFR1-IIIb is a functional transmembrane FGF receptor expressed in the human pancreas and that several FGFs can exert mitogenic effects via FGFR1-IIIb. However, this receptor can also inhibit cell growth.

After organ transplantation recurrence of hepatoma occurs in over 50% in patients with high tumor stage. Sirolimus has been shown to inhibit the cell cycle in various cell systems. We examined the effect on growth of the human hepatoma cell lines SK-Hepl and Hep3B using sirolimus, tacrolimus, and a combination of both. FACS Analysis were done to reveal apoptotic cell death. There was a dose dependent growth inhibition of both cancer cell lines after treatment with sirolimus after 5 days ranging from 16% at 1 ng/ml in Hep3B cells to 74% at 100 ng/ml in SK-Hepl and Hep3B cells. Treatment with tacrolimus showed a growth stimulating effect on both tumor cell lines. The combination of sirolimus and tacrolimus at equal doses resulted in growth inhibition of both cell lines. FACS analysis showed an increase of apoptotic Hep3B cells from 6 to 16% when sirolimus and tacrolimus were combined. In SK-Hepl cells, we found a cell cycle arrest in this treatment group from 61 to 82%. No changes were seen in cells treated with tacrolimus alone. Western Blot analysis showed a down-regulation of bcl-2 in Hep3B by 80%, but not in SK-Hepl cells when combined with tacrolimus. We conclude that sirolimus exerts strong inhibition of hepatoma cell growth in contrast to tacrolimus, which stimulates hepatoma cell growth. Sirolimus inhibits the tacrolimus-induced cell proliferation. Immunosuppression including sirolimus may reduce the incidence of tumor recurrence after liver transplantation for hepatoma.