Astrid Kersten

Publications of Astrid Kersten

• Triterpenes Promote Keratinocyte Differentiation In Vitro, Ex Vivo and In Vivo: A Role for the Transient Receptor Potential Canonical (subtype) 6.

  Authors: Ute Woelfle, Melanie N Laszczyk, Margarethe Kraus, Kristina Leuner, Astrid Kersten, Birgit Simon-Haarhaus, Armin Scheffler, Stefan F Martin, Walter E Müller, Dorothee Nashan, Christoph M Schempp

  The Journal of investigative dermatology. 09/2009;

  It has been shown recently that triterpenes inhibit cancer cell growth of various cell types in vitro. In this work, the effect of highly purified triterpenes (TE) with betulin as the major compoundIt has been shown recently that triterpenes inhibit cancer cell growth of various cell types in vitro. In this work, the effect of highly purified triterpenes (TE) with betulin as the major compound (>80% w/w) on cell proliferation, apoptosis, and differentiation of human keratinocytes was analyzed in vitro, ex vivo, and in vivo. In vitro, TE increased calcium influx into primary keratinocytes and upregulated various differentiation markers including keratin 10. TE also specifically increased the expression of the non-selective transient receptor potential canonical (subtype) 6 (TRPC6) in keratinocytes, and knocking down TRPC6 inhibited keratin 10 upregulation. Ex vivo, in human skin explants TE induced the expression of TRPC6 in the epidermis and increased DNA fragmentation of terminally differentiating keratinocytes. Topical treatment with TE of actinic keratoses, that represent in situ squamous cell carcinomas with disturbed epithelial differentiation, resulted in downgrading of aberrant Ki67 expression and upregulation of keratin 10 in vivo. Our data indicate that TE promotes keratinocyte differentiation in vitro and in vivo. This effect seems to be mediated at least in part by TRPC6.Journal of Investigative Dermatology advance online publication, 13 August 2009; doi:10.1038/jid.2009.248.

• Treatment of actinic keratoses with a novel betulin-based oleogel. A prospective, randomized, comparative pilot study.

  Authors: Constance Huyke, Juliane Reuter, Mirko Rodig, Astrid Kersten, Melanie Laszczyk, Armin Scheffler, Dorothee Nashan, Christoph Schempp

  Journal der Deutschen Dermatologischen Gesellschaft = Journal of the German Society of Dermatology : JDDG. 09/2008;

  Background: Actinic keratoses (AK) are squamous cell carcinomas in situ and require treatment. Betulin-based oleogel prepared from a standardized triter-pene dry extract from birch bark represents aBackground: Actinic keratoses (AK) are squamous cell carcinomas in situ and require treatment. Betulin-based oleogel prepared from a standardized triter-pene dry extract from birch bark represents a new topical agent with anti-inflammatory and anti-tumor potential. Patients and Methods: In the prospective, randomized, monocentric phase 2a study 45 patients with < 10 AK were included and randomly assigned to one of the three treatment groups. Intervention consisted of topical betulin-based oleogel twice daily versus cryotherapy with liquid nitrogen versus the combination of cryotherapy with topical betulin-based oleogel.Treatment response was assessed clinically after three months. The clinical response was graded into complete clearing (100 %), therapy responders (> 75 % clearing of the lesions) and non-responders (< 75 % clearing). Additionally, punch biopsies were obtained from some patients before and at the end of treatment. Results: Therapy with betulin-based oleogel was well tolerated.Three patients discontinued therapy because of personal reasons. After three months, the 100% (and > 75%) clearing rates of the lesions were as follows: 64% (86%) with betulin-based oleogel (n = 14),79% (93%) with cryotherapy (n = 14),and 71% (71%) with the combined therapy (n = 14). Histological analysis of biopsies taken before and after treatment (n = 8) showed a reduced degree of dys-plasia in the epidermis in all study arms. Conclusions: Betulin-based oleogel seems to be an effective novel approach in the topical treatment of actinic keratoses. However,the clinical and histological findings of the present pilot study have to be verified against placebo with larger case numbers.

• NK cell-mediated immunopathology during an acute viral infection of the CNS.

  Authors: Mohammed Alsharifi, Mario Lobigs, Markus M Simon, Astrid Kersten, Klaus Müller, Aulikki Koskinen, Eva Lee, Arno Müllbacher

  European journal of immunology. 05/2006; 36(4):887-96.

  Natural killer (NK) and cytotoxic T (Tc) cells are prime effector populations in the antiviral response of the host. Tc cells are essential for recovery from many viral diseases but may also beNatural killer (NK) and cytotoxic T (Tc) cells are prime effector populations in the antiviral response of the host. Tc cells are essential for recovery from many viral diseases but may also be responsible for immunopathology. The role of NK cells in recovery from viral infections is less well established. We have studied acute virulent Semliki Forest virus (vSFV) infection of the central nervous system in C57BL/6J mice, which was mainly controlled by NK cells without marked Tc cell involvement. We show that mice with defects in the Fas and/or granule exocytosis pathways of cytotoxicity are more resistant to lethal vSFV infection than wild-type mice. On the other hand, mice defective in the IFN-gamma response are more sensitive than wild-type mice, whereas mice lacking the Tc cell compartment (beta-2 microglobulin-deficient mice) exhibit susceptibility similar to wild-type mice. The additional finding that depletion of NK cells significantly delayed the mean time to death but did not prevent mortality in SFV-infected B6 mice suggests that cytolytic activity of NK cells is detrimental, while IFN-gamma production is beneficial for recovery from SFV infection. This is the first study illustrating an NK cell-mediated immunopathological outcome to an acute viral infection.

• Perforin and Fas act together in the induction of apoptosis, and both are critical in the clearance of lymphocytic choriomeningitis virus infection.

  Authors: Miriam Rode, Sandra Balkow, Vera Sobek, Reina Brehm, Praxedis Martin, Astrid Kersten, Tilman Dumrese, Thomas Stehle, Arno Müllbacher, Reinhard Wallich, Markus M Simon

  Journal of virology. 12/2004; 78(22):12395-405.

  In this report we questioned the current view that the two principal cytotoxic pathways, the exocytosis and the Fas ligand (FasL)/Fas-mediated pathway, have largely nonoverlapping biological roles.In this report we questioned the current view that the two principal cytotoxic pathways, the exocytosis and the Fas ligand (FasL)/Fas-mediated pathway, have largely nonoverlapping biological roles. For this purpose we have analyzed the response of mice that lack Fas as well as granzyme A (gzmA) and gzmB (FasxgzmAxB(-/-)) to infection with lymphocytic choriomeningitis virus (LCMV). We show that FasxgzmAxB(-/-) mice, in contrast to B6, Fas(-/-), and gzmAxB(-/-) mice, do not recover from a primary infection with LCMV, in spite of the expression of comparable numbers of LCMV-immune and gamma interferon-producing cytotoxic T lymphocytes (CTL) in all mouse strains tested. Ex vivo-derived FasxgzmAxB(-/-) CTL lacked nucleolytic activity and expressed reduced cytolytic activity compared to B6 and Fas(-/-) CTL. Furthermore, virus-immune CTL with functional FasL and perforin (gzmAxB(-/-)) are more potent in causing target cell apoptosis in vitro than those expressing FasL alone (perfxgzmAxB(-/-)). This synergistic effect of perforin on Fas-mediated nucleolysis of target cells is indicated by the fact that, compared to perfxgzmAxB(-/-) CTL, gzmAxB(-/-) CTL induced (i) an accelerated decrease in mitochondrial transmembrane potential, (ii) increased generation of reactive oxygen species, and (iii) accelerated phosphatidylserine exposure on plasma membranes. We conclude that perforin does not mediate recovery from LCMV by itself but plays a vital role in both gzmA/B and FasL/Fas-mediated CTL activities, including apoptosis and control of viral infections.

• Brown tumor of the mandible as first manifestation of atypical parathyroid adenoma.

  Authors: Maria Mercedes Suarez-Cunqueiro, Ralf Schoen, Astrid Kersten, Joachim Klisch, Rainer Schmelzeisen

  Journal of oral and maxillofacial surgery : official journal of the American Association of Oral and Maxillofacial Surgeons. 09/2004; 62(8):1024-8.

• Inhibition of tumour cell growth by hyperforin, a novel anticancer drug from St. John's wort that acts by induction of apoptosis.

  Authors: Christoph M Schempp, Vladimir Kirkin, Birgit Simon-Haarhaus, Astrid Kersten, Judit Kiss, Christian C Termeer, Bernhard Gilb, Thomas Kaufmann, Christoph Borner, Jonathan P Sleeman, Jan C Simon

  Oncogene. 03/2002; 21(8):1242-50.

  Hyperforin is a plant derived antibiotic from St. John's wort. Here we describe a novel activity of hyperforin, namely its ability to inhibit the growth of tumour cells by induction of apoptosis.Hyperforin is a plant derived antibiotic from St. John's wort. Here we describe a novel activity of hyperforin, namely its ability to inhibit the growth of tumour cells by induction of apoptosis. Hyperforin inhibited the growth of various human and rat tumour cell lines in vivo, with IC(50) values between 3-15 microM. Treatment of tumour cells with hyperforin resulted in a dose-dependent generation of apoptotic oligonucleosomes, typical DNA-laddering and apoptosis-specific morphological changes. In MT-450 mammary carcinoma cells hyperforin increased the activity of caspase-9 and caspase-3, and hyperforin-mediated apoptosis was blocked by the broad-range caspase inhibitor zVAD.fmk. When added to MT-450 cells, hyperforin, but not paclitaxel, induced a rapid loss of the mitochondrial transmembrane potential Deltapsi(m), and subsequent morphological changes such as homogenization and vacuolization of mitochondria. Monitoring of Deltapsi(m) revealed that the hyperforin-mediated mitochondrial permeability transition can not be prevented by zVAD.fmk. This indicates that mitochondrial permeabilization is a cause rather than a consequence of caspase activation. Moreover, hyperforin was capable of releasing cytochrome c from isolated mitochondria. These findings suggest that hyperforin activates a mitochondria-mediated apoptosis pathway. In vivo, hyperforin inhibited the growth of autologous MT-450 breast carcinoma in immunocompetent Wistar rats to a similar extent as the cytotoxic drug paclitaxel, without any signs of acute toxicity. Owing to the combination of significant antitumour activity, low toxicity in vivo and natural abundance of the compound, hyperforin holds the promise of being an interesting novel antineoplastic agent that deserves further laboratory and in vivo exploration.