TY - JOUR A1 - Alb, Miriam A1 - Sie, Christopher A1 - Adam, Christian A1 - Chen, Suzie A1 - Becker, Jürgen C. A1 - Schrama, David T1 - Cellular and cytokine-dependent immunosuppressive mechanisms of grm1-transgenic murine melanoma JF - Cancer Immunology, Immunotherapy N2 - Grm1-transgenic mice spontaneously develop cutaneous melanoma. This model allowed us to scrutinize the generic immune responses over the course of melanoma development. To this end, lymphocytes obtained from spleens, unrelated lymph nodes and tumor-draining lymph nodes of mice with no evidence of disease, and low or high tumor burden were analyzed ex vivo and in vitro. Thereby, we could demonstrate an increase in the number of activated CD4\(^+\) and CD8+ lymphocytes in the respective organs with increasing tumor burden. However, mainly CD4\(^+\) T cells, which could constitute both T helper as well as immunosuppressive regulatory T cells, but not CD8\(^+\) T cells, expressed activation markers upon in vitro stimulation when obtained from tumor-bearing mice. Interestingly, these cells from tumor-burdened animals were also functionally hampered in their proliferative response even when subjected to strong in vitro stimulation. Further analyses revealed that the increased frequency of regulatory T cells in tumor-bearing mice is an early event present in all lymphoid organs. Additionally, expression of the immunosuppressive cytokines TGF-β1 and IL-10 became more evident with increased tumor burden. Notably, TGF-β1 is strongly expressed in both the tumor and the tumor-draining lymph node, whereas IL-10 expression is more pronounced in the lymph node, suggesting a more complex regulation of IL-10. Thus, similar to the situation in melanoma patients, both cytokines as well as cellular immune escape mechanisms seem to contribute to the observed immunosuppressed state of tumor-bearing grm1-transgenic mice, suggesting that this model is suitable for preclinical testing of immunomodulatory therapeutics. KW - regulatory T cell KW - melanoma KW - immune suppression KW - tumor-draining lymph node Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-125096 VL - 61 IS - 12 ER - TY - THES A1 - Chen, Christian T1 - Wirkungsunterschiede von AT-1-Rezeptorantagonisten und ACE-Hemmern auf die endotheliale Dysfunktion bei Herzinsuffizienz T1 - Comparison between AT-1-Receptorantagonists and ACE-Inhibitors on endothelial dysfunction occuring on heartfailure N2 - Untersucht wurde die Wirkungsunterschiede von dem AT-1-Rezeptorantagonist Irbesartan und dem ACE-Hemmer Trandolapril auf die endotheliale Dysfunktion bei herzinsuffizienzten Ratten nach Herzinfarkt. Zusammenfassend zeigte sich ein Vorteil des AT-1-Rezeptorantagonisten gegenüber dem ACE-Hemmer. N2 - We studied the different effect of the AT-1-receptorantagonist Irbesartan and the ACE-inhibitor Trandolapril on the endothelial dysfunction on rats with heartfailure. It showed that the AT-1-receptorantagonist improoves the dysfunction more effective than the ACE-inhibitor. KW - Endotheliale Dysfunktion KW - AT-1-Rezeptorantagonist KW - ACE-Hemmer KW - Herzinsuffizienz KW - endothelial dysfunction KW - AT-1-Receptorantagonist KW - ACE-Inhibitors KW - heartfailure Y1 - 2005 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-18880 ER - TY - JOUR A1 - Wegener, Christian A1 - Chen, Jiangtian T1 - Allatostatin A signalling: progress and new challenges from a paradigmatic pleiotropic invertebrate neuropeptide family JF - Frontiers in Physiology N2 - Neuropeptides have gained broad attraction in insect neuroscience and physiology, as new genetic tools are increasingly uncovering their wide-ranging pleiotropic functions with high cellular resolution. Allatostatin A (AstA) peptides constitute one of the best studied insect neuropeptide families. In insects and other panarthropods, AstA peptides qualify as brain-gut peptides and have regained attention with the discovery of their role in regulating feeding, growth, activity/sleep and learning. AstA receptor homologs are found throughout the protostomia and group with vertebrate somatostatin/galanin/kisspeptin receptors. In this review, we summarise the current knowledge on the evolution and the pleiotropic and cell-specific non-allatostatic functions of AstA. We speculate about the core functions of AstA signalling, and derive open questions and challengesfor future research on AstA and invertebrate neuropeptides in general. KW - neuropeptide signalling KW - feeding KW - intestinal control KW - sleep/activity KW - kisspeptin/galanin/spexin signalling KW - metabolism and growth KW - learning KW - cardioactive factor Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-278749 SN - 1664-042X VL - 13 ER - TY - JOUR A1 - Gentzsch, Christian A1 - Chen, Xinyu A1 - Spatz, Philipp A1 - Košak, Urban A1 - Knez, Damijan A1 - Nose, Naoko A1 - Gobec, Stanislav A1 - Higuchi, Takahiro A1 - Decker, Michael T1 - Synthesis and Initial Characterization of a Reversible, Selective \(^{18}\)F-Labeled Radiotracer for Human Butyrylcholinesterase JF - Molecular Imaging and Biology N2 - Purpose A neuropathological hallmark of Alzheimer's disease (AD) is the presence of amyloid-β (Aβ) plaques in the brain, which are observed in a significant number of cognitively normal, older adults as well. In AD, butyrylcholinesterase (BChE) becomes associated with A\(_{β}\) aggregates, making it a promising target for imaging probes to support diagnosis of AD. In this study, we present the synthesis, radiochemistry, in vitro and preliminary ex and in vivo investigations of a selective, reversible BChE inhibitor as PET-tracer for evaluation as an AD diagnostic. Procedures Radiolabeling of the inhibitor was achieved by fluorination of a respective tosylated precursor using K[\(^{18}\)F]. IC\(_{50}\) values of the fluorinated compound were obtained in a colorimetric assay using recombinant, human (h) BChE. Dissociation constants were determined by measuring hBChE activity in the presence of different concentrations of inhibitor. Results Radiofluorination of the tosylate precursor gave the desired radiotracer in an average radiochemical yield of 20 ± 3 %. Identity and > 95.5 % radiochemical purity were confirmed by HPLC and TLC autoradiography. The inhibitory potency determined in Ellman's assay gave an IC\(_{50}\) value of 118.3 ± 19.6 nM. Dissociation constants measured in kinetic experiments revealed lower affinity of the inhibitor for binding to the acylated enzyme (K2 = 68.0 nM) in comparison to the free enzyme (K\(_{1}\) = 32.9 nM). Conclusions The reversibly acting, selective radiotracer is synthetically easily accessible and retains promising activity and binding potential on hBChE. Radiosynthesis with \(^{18}\)F labeling of tosylates was feasible in a reasonable time frame and good radiochemical yield. KW - Alzheimer’s disease KW - amyloid-β (Aβ) KW - butyrylcholinesterase Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-269870 SN - 1860-2002 VL - 23 IS - 4 ER - TY - JOUR A1 - Selcho, Mareike A1 - Millán, Carola A1 - Palacios-Muñoz, Angelina A1 - Ruf, Franziska A1 - Ubillo, Lilian A1 - Chen, Jiangtian A1 - Bergmann, Gregor A1 - Ito, Chihiro A1 - Silva, Valeria A1 - Wegener, Christian A1 - Ewer, John T1 - Central and peripheral clocks are coupled by a neuropeptide pathway in Drosophila JF - Nature Communications N2 - Animal circadian clocks consist of central and peripheral pacemakers, which are coordinated to produce daily rhythms in physiology and behaviour. Despite its importance for optimal performance and health, the mechanism of clock coordination is poorly understood. Here we dissect the pathway through which the circadian clock of Drosophila imposes daily rhythmicity to the pattern of adult emergence. Rhythmicity depends on the coupling between the brain clock and a peripheral clock in the prothoracic gland (PG), which produces the steroid hormone, ecdysone. Time information from the central clock is transmitted via the neuropeptide, sNPF, to non-clock neurons that produce the neuropeptide, PTTH. These secretory neurons then forward time information to the PG clock. We also show that the central clock exerts a dominant role on the peripheral clock. This use of two coupled clocks could serve as a paradigm to understand how daily steroid hormone rhythms are generated in animals. KW - circadian clock KW - Drosophila KW - neuropeptide pathway KW - peripheral clocks KW - central clocks Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-170831 VL - 8 IS - 15563 ER - TY - JOUR A1 - Gentzsch, Christian A1 - Hoffmann, Matthias A1 - Ohshima, Yasuhiro A1 - Nose, Naoko A1 - Chen, Xinyu A1 - Higuchi, Takahiro A1 - Decker, Michael T1 - Synthesis and Initial Characterization of a Selective, Pseudo‐irreversible Inhibitor of Human Butyrylcholinesterase as PET Tracer JF - ChemMedChem N2 - The enzyme butyrylcholinesterase (BChE) represents a promising target for imaging probes to potentially enable early diagnosis of neurodegenerative diseases like Alzheimer's disease (AD) and to monitor disease progression in some forms of cancer. In this study, we present the design, facile synthesis, in vitro and preliminary ex vivo and in vivo evaluation of a morpholine‐based, selective inhibitor of human BChE as a positron emission tomography (PET) tracer with a pseudo‐irreversible binding mode. We demonstrate a novel protecting group strategy for 18F radiolabeling of carbamate precursors and show that the inhibitory potency as well as kinetic properties of our unlabeled reference compound were retained in comparison to the parent compound. In particular, the prolonged duration of enzyme inhibition of such a morpholinocarbamate motivated us to design a PET tracer, possibly enabling a precise mapping of BChE distribution. KW - carbamate KW - enzyme kinetics KW - fluorine-18 KW - positron emission tomography KW - radiotracers Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-239904 VL - 16 IS - 9 SP - 1427 EP - 1437 ER -