@phdthesis{RamirezPineda2003,
  author    = {Ramirez Pineda, Jos{\´e} Robinson},
  title     = {Dendritic cells activated by CpG motifs are potent inducers of a Th1 immune response that protects mice against leishmaniasis},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-8410},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2003},
  abstract  = {The present investigation report a protocol to obtain dendritic cells (DC) that protects mice against fatal leishmaniasis. DC were generated from bone marrow precursors, pulsed with leishmanial antigen and activated with CpG oligodeoxinucleotides. Mice that were vaccinated with these cells were strongly protected against the clinical and parasitological manifestations of leishmaniasis and developed a Th1 immune response. protection was solid and long-lasting, and was also dependent of the via of administration. Whe the mechanism of protection was studied, it was observed that the availability of the cytokine interleukin-12 at the time of vaccination was a key requirement, but that the source of this cytokine is not the donor cells but unidentified cells from the recipients.},
  subject      = {Leishmaniose},
  language  = {en}
}
@article{MasicValenciaHernandezHazraetal.2015,
  author    = {Masic, Anita and Valencia Hernandez, Ana Maria and Hazra, Sudipta and Glaser, Jan and Holzgrabe, Ulrike and Hazra, Banasri and Schurigt, Uta},
  title     = {Cinnamic Acid Bornyl Ester Derivatives from Valeriana wallichii Exhibit Antileishmanial In Vivo Activity in Leishmania major-Infected BALB/c Mice},
  series = {PLoS One},
  volume    = {10},
  journal   = {PLoS One},
  number    = {11},
  doi       = {10.1371/journal.pone.0142386},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-125354},
  pages     = {e0142386},
  year      = {2015},
  abstract  = {Human leishmaniasis covers a broad spectrum of clinical manifestations ranging from self-healing cutaneous leishmaniasis to severe and lethal visceral leishmaniasis caused among other species by Leishmania major or Leishmania donovani, respectively. Some drug candidates are in clinical trials to substitute current therapies, which are facing emerging drug-resistance accompanied with serious side effects. Here, two cinnamic acid bornyl ester derivatives (1 and 2) were assessed for their antileishmanial activity. Good selectivity and antileishmanial activity of bornyl 3-phenylpropanoate (2) in vitro prompted the antileishmanial assessment in vivo. For this purpose, BALB/c mice were infected with Leishmania major promastigotes and treated with three doses of 50 mg/kg/day of compound 2. The treatment prevented the characteristic swelling at the site of infection and correlated with reduced parasite burden. Transmitted light microscopy and transmission electron microscopy of Leishmania major promastigotes revealed that compounds 1 and 2 induce mitochondrial swelling. Subsequent studies on Leishmania major promastigotes showed the loss of mitochondrial transmembrane potential (ΔΨm) as a putative mode of action. As the cinnamic acid bornyl ester derivatives 1 and 2 had exhibited antileishmanial activity in vitro, and compound 2 in Leishmania major-infected BALB/c mice in vivo, they can be regarded as possible lead structures for the development of new antileishmanial therapeutic approaches.},
  language  = {en}
}
@article{KochCappelNockeretal.2013,
  author    = {Koch, Oliver and Cappel, Daniel and Nocker, Monika and J{\"a}ger, Timo and Floh{\´e}, Leopold and Sotriffer, Christoph A. and Selzer, Paul M.},
  title     = {Molecular Dynamics Reveal Binding Mode of Glutathionylspermidine by Trypanothione Synthetase},
  series = {PLoS ONE},
  volume    = {8},
  journal   = {PLoS ONE},
  number    = {2},
  doi       = {10.1371/journal.pone.0056788},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-131070},
  pages     = {e56788},
  year      = {2013},
  abstract  = {The trypanothione synthetase (TryS) catalyses the two-step biosynthesis of trypanothione from spermidine and glutathione and is an attractive new drug target for the development of trypanocidal and antileishmanial drugs, especially since the structural information of TryS from Leishmania major has become available. Unfortunately, the TryS structure was solved without any of the substrates and lacks loop regions that are mechanistically important. This contribution describes docking and molecular dynamics simulations that led to further insights into trypanothione biosynthesis and, in particular, explains the binding modes of substrates for the second catalytic step. The structural model essentially confirm previously proposed binding sites for glutathione, ATP and two \(Mg^{2+}\) ions, which appear identical for both catalytic steps. The analysis of an unsolved loop region near the proposed spermidine binding site revealed a new pocket that was demonstrated to bind glutathionylspermidine in an inverted orientation. For the second step of trypanothione synthesis glutathionylspermidine is bound in a way that preferentially allows \(N^1\)-glutathionylation of \(N^8\)-glutathionylspermidine, classifying \(N^8\)-glutathionylspermidine as the favoured substrate. By inhibitor docking, the binding site for \(N^8\)-glutathionylspermidine was characterised as druggable.},
  language  = {en}
}
@phdthesis{GonzalezLeal2014,
  author    = {Gonzalez-Leal, Iris Janet},
  title     = {Roles of cathepsins B and L in the Th1/Th2 polarization by dendritic cells},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-114397},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2014},
  abstract  = {Leishmaniasis is a neglected tropical disease that can be manifested through different clinical forms, ranging from cutaneous to visceral. The host response against Leishmania spp. is greatly dependent on T cell-mediated immunity, in which T helper 1 responses are associated with macrophage activation and elimination of the parasite, while regulatory T cells and T helper 2 responses are correlated with parasite survival and persistence of infection. Leishmania uses different virulence factors as strategies for evading the immune response of the host. One of them are cathepsin-like cysteine proteases, which are currently under extensive investigation as targets for drug development. Previous studies with inhibitors of cathepsins B and L in vivo revealed an outstanding modulation of the host T helper cell response. However, the mechanisms behind these observations were not further investigated. Given the urgent need for better treatments against leishmaniasis, the aim of this study was to investigate the effects that the lack of cathepsin B and L activity have on the signals that dendritic cells use to instruct T helper cell polarization in response to infection with Leishmania major. The cathepsin inhibitors tested showed low or no cytotoxicity in bone marrow-derived dendritic cells, and dendritic cells and macrophages could be generated from cathepsin B and cathepsin L-deficient mice without apparent alterations in their phenotype in comparison to wild-type controls. Furthermore, lack of cathepsin B and L activity showed no impact in the rate of promastigote processing by dendritic cells. Cathepsin B and cathepsin L-deficient macrophages showed no differences in parasite proliferation and capacity to produce nitric oxide in comparison to wild-type macrophages. In response to the parasite, dendritic cells treated with a cathepsin B inhibitor and dendritic cells from cathepsin B-deficient mice showed higher levels of expression of major histocompatibility complex (MHC) class II molecules than dimethyl sulfoxide (DMSO) or wild-type controls, but it was not accompanied by changes in the expression of costimulatory molecules. Wild-type dendritic cells and macrophages are not able to express the pro-inflammatory cytokine interleukin (IL)-12 in response to promastigotes. However, cells treated with a cathepsin B inhibitor or cells deficient for cathepsin B were able to express IL-12, whilethe expression of other cytokines -including IL-6 and tumor necrosis factor (TNF)-alpha-remained unchanged. These characteristics point towards a more "pro-Th1" profile of dendritic cells in the absence of cathepsin B. This data is the first report on IL-12 regulation depending on cathepsin B. The IL-12 up-regulation observed was already present at the transcriptional level. Furthermore, it was also present in macrophages and dendritic cells in response to LPS, and the latter had a higher capacity to induce T cell helper 1 polarization in vitro than wild-type dendritic cells. The activation of different signaling pathways was analyzed, but the up-regulation of IL-12 could not be attributed to modulation of nuclear factor-kappaB (NFkappaB), p38 mitogen activated protein kinase (MAPK) and extra-cellular signal-regulated kinase (ERK)1/2 pathways. Thus, the mechanism behind IL-12 regulation by cathepsin B remains to be elucidated, and the impact of these effects is yet to be confirmed in vivo. Altogether it is tempting to speculate that cathepsin B, in addition to its role in processing endocytosed material, is involved in the modulation of the pro-inflammatory cytokine IL-12.},
  subject      = {Leishmaniose},
  language  = {en}
}
@article{GlaserSchultheisHazraetal.2014,
  author    = {Glaser, Jan and Schultheis, Martina and Hazra, Sudipta and Hazra, Banazri and Moll, Heidrun and Schurigt, Uta and Holzgrabe, Ulrike},
  title     = {Antileishmanial Lead Structures from Nature: Analysis of Structure-Activity Relationships of a Compound Library Derived from Caffeic Acid Bornyl Ester},
  doi       = {10.3390/molecules19021394},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-112835},
  year      = {2014},
  abstract  = {Bioassay-guided fractionation of a chloroform extract of Valeriana wallichii (V. wallichii) rhizomes lead to the isolation and identification of caffeic acid bornyl ester (1) as the active component against Leishmania major (L. major) promastigotes (IC50 = 48.8 µM). To investigate the structure-activity relationship (SAR), a library of compounds based on 1 was synthesized and tested in vitro against L. major and L. donovani promastigotes, and L. major amastigotes. Cytotoxicity was determined using a murine J774.1 cell line and bone marrow derived macrophages (BMDM). Some compounds showed antileishmanial activity in the concentration range of pentamidine and miltefosine which are the standard drugs in use. In the L. major amastigote assay compounds 15, 19 and 20 showed good activity with relatively low cytotoxicity against BMDM, resulting in acceptable selectivity indices. Molecules with adjacent phenolic hydroxyl groups exhibited elevated cytotoxicity against murine cell lines J774.1 and BMDM. The Michael system seems not to be essential for antileishmanial activity. Based on the results compound 27 can be regarded as new lead structure for further structure optimization},
  language  = {en}
}