@article{VetrivelZhangEngeletal.2021, author = {Vetrivel, Sharmilee and Zhang, Ru and Engel, Mareen and Altieri, Barbara and Braun, Leah and Osswald, Andrea and Bidlingmaier, Martin and Fassnacht, Martin and Beuschlein, Felix and Reincke, Martin and Chen, Alon and Sbiera, Silviu and Riester, Anna}, title = {Circulating microRNA Expression in Cushing's Syndrome}, series = {Frontiers in Endocrinology}, volume = {12}, journal = {Frontiers in Endocrinology}, issn = {1664-2392}, doi = {10.3389/fendo.2021.620012}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-229761}, year = {2021}, abstract = {Context Cushing's syndrome (CS) is a rare disease of endogenous hypercortisolism associated with high morbidity and mortality. Diagnosis and classification of CS is still challenging. Objective Circulating microRNAs (miRNAs) are minimally invasive diagnostic markers. Our aim was to characterize the circulating miRNA profiles of CS patients and to identify distinct profiles between the two major CS subtypes. Methods We included three groups of patients from the German Cushing's registry: ACTH-independent CS (Cortisol-Producing-Adenoma; CPA), ACTH-dependent pituitary CS (Cushing's Disease; CD), and patients in whom CS had been ruled out (controls). Profiling of miRNAs was performed by next-generation-sequencing (NGS) in serum samples of 15 CS patients (each before and after curative surgery) and 10 controls. Significant miRNAs were first validated by qPCR in the discovery cohort and then in an independent validation cohort of 20 CS patients and 11 controls. Results NGS identified 411 circulating miRNAs. Differential expression of 14 miRNAs were found in the pre- and postoperative groups. qPCR in the discovery cohort validated 5 of the significant miRNAs from the preoperative group analyses. Only, miR-182-5p was found to be significantly upregulated in the CD group of the validation cohort. Comparing all CS samples as a group with the controls did not reveal any significant differences in expression. Outcome In conclusion, our study identified miR-182-5p as a possible biomarker for CD, which has to be validated in a prospective cohort. Furthermore, our results suggest that presence or absence of ACTH might be at least as relevant for miRNA expression as hypercortisolism itself.}, language = {en} } @article{AdolfBraunFussetal.2020, author = {Adolf, Christian and Braun, Leah T. and Fuss, Carmina T. and Hahner, Stefanie and K{\"u}nzel, Heike and Handgriff, Laura and Sturm, Lisa and Heinrich, Daniel A. and Schneider, Holger and Bidlingmaier, Martin and Reincke, Martin}, title = {Spironolactone reduces biochemical markers of bone turnover in postmenopausal women with primary aldosteronism}, series = {Endocrine}, volume = {69}, journal = {Endocrine}, number = {3}, issn = {1355-008X}, doi = {10.1007/s12020-020-02348-8}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-315966}, pages = {625-633}, year = {2020}, abstract = {Context Primary aldosteronism (PA) is the most frequent form of endocrine hypertension. Besides its deleterious impact on cardiovascular target organ damage, PA is considered to cause osteoporosis. Patients and methods We assessed bone turnover in a subset of 36 postmenopausal women with PA. 18 patients had unilateral PA and were treated by adrenalectomy, whereas 18 patients had bilateral PA and received mineralocorticoid receptor antagonist (MRA) therapy respectively. 18 age- and BMI-matched females served as controls. To estimate bone remodeling, we measured the bone turnover markers intact procollagen 1 N-terminal propeptide, bone alkaline phosphatase, osteocalcin and tartrate resistant acid phosphatase 5b in plasma by chemiluminescent immunoassays at time of diagnosis and one year after initiation of treatment. Study design Observational longitudinal cohort study. Setting Tertiary care hospital. Results Compared with controls, patients with PA had mildly elevated osteocalcin at baseline (p = 0.013), while the other bone markers were comparable between both groups. There were no differences between the unilateral and the bilateral PA subgroup. One year after initiation of MRA treatment with spironolactone bone resorption and bone formation markers had significantly decreased in patients with bilateral PA. In contrast, patients adrenalectomized because of unilateral PA showed no significant change of bone turnover markers. Conclusion This study shows that aldosterone excess in postmenopausal women with PA is not associated with a relevant increase of bone turnover markers at baseline. However, we observed a significant decrease of bone markers in patients treated with spironolactone, but not in patients treated by adrenalectomy.}, language = {en} } @article{EisenhardtSprengerRoeringetal.2016, author = {Eisenhardt, Anja E. and Sprenger, Adrian and R{\"o}ring, Michael and Herr, Ricarda and Weinberg, Florian and K{\"o}hler, Martin and Braun, Sandra and Orth, Joachim and Diedrich, Britta and Lanner, Ulrike and Tscherwinski, Natalja and Schuster, Simon and Dumaz, Nicolas and Schmidt, Enrico and Baumeister, Ralf and Schlosser, Andreas and Dengjel, J{\"o}rn and Brummer, Tilman}, title = {Phospho-proteomic analyses of B-Raf protein complexes reveal new regulatory principles}, series = {Oncotarget}, volume = {7}, journal = {Oncotarget}, number = {18}, doi = {10.18632/oncotarget.8427}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-166529}, pages = {26628-26652}, year = {2016}, abstract = {B-Raf represents a critical physiological regulator of the Ras/RAF/MEK/ERK-pathway and a pharmacological target of growing clinical relevance, in particular in oncology. To understand how B-Raf itself is regulated, we combined mass spectrometry with genetic approaches to map its interactome in MCF-10A cells as well as in B-Raf deficient murine embryonic fibroblasts (MEFs) and B-Raf/Raf-1 double deficient DT40 lymphoma cells complemented with wildtype or mutant B-Raf expression vectors. Using a multi-protease digestion approach, we identified a novel ubiquitination site and provide a detailed B-Raf phospho-map. Importantly, we identify two evolutionary conserved phosphorylation clusters around T401 and S419 in the B-Raf hinge region. SILAC labelling and genetic/biochemical follow-up revealed that these clusters are phosphorylated in the contexts of oncogenic Ras, sorafenib induced Raf dimerization and in the background of the V600E mutation. We further show that the vemurafenib sensitive phosphorylation of the T401 cluster occurs in trans within a Raf dimer. Substitution of the Ser/Thr-residues of this cluster by alanine residues enhances the transforming potential of B-Raf, indicating that these phosphorylation sites suppress its signaling output. Moreover, several B-Raf phosphorylation sites, including T401 and S419, are somatically mutated in tumors, further illustrating the importance of phosphorylation for the regulation of this kinase.}, language = {en} } @article{ChristlBraun1989, author = {Christl, Manfred and Braun, Martin}, title = {Generation and interception of 1-OXA-2,3-Cyclohexadiene and 1,2,4-Cyclohexatriene}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-56566}, year = {1989}, abstract = {The cycloadducts 6 and 7 of tricyc1o[4.1.0.0 2 ,7)hepta- 3,4-diene (~) with styrene and 1,3-butadiene rearrange to unusual products on thermolysis, namely the cycloheptatriene derivatives ~ and 10. 1-0xa-3,4-cyclohexadiene (20) is generated smoothly from 6,6-dichloro-3-oxabicyclo[3.1.0]hexane (22) and n-butyllithium. 1-0xa-2,3-cyclohexadiene (11) is formed from 6-exo-bromo-6-endo-fluoro-2-oxabicyclo[ 3.1.0]hexane (30) and methyllithium. In the presence of activated olefins, this reaction provides an efficient route to 28 and 33 - 38, the trapping products of 21. Interestingly, [2+2]-cycloadditions do not take place at the same double bond of 21 as [4+2]-cycloadditions. The reactions of 1,3-cyclopentadiene and indene with bromofluorocarbene afford 6-exo-bromo-6-endo-fluorobicyclo[3.1.0]hex-2-ene (50) and its benzo derivative ~, respectively. On treatment of these compounds with methyl lithium in the presence of styrene, the interception products 53 and 47 of 1,2,4-cyc10- hexatriene (44) and its benzo derivative 43, respectively, are formed in good yields.}, subject = {Chemie}, language = {en} } @article{ChristlBraun1989, author = {Christl, Manfred and Braun, Martin}, title = {Freisetzung und Abfangreaktionen von 1-Oxa-2,3-cyclohexadien}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-58517}, year = {1989}, abstract = {Umsetzung von 6,6-Dichlor-2-oxabicyclo[3.1.0)hexan (4a) in Styrol mit n-Butyllithium lieferte neben Polystyrol und t-Chlor-1- pbenylhexan (6) in geringer Ausbeute die Tet~hydrocyclobutapyrane 5, die Abfangprodukte des aus 4a generierten t-Oxa-2,3- cyclobexadiens (3). Das unbest{\"a}ndige 6,6-Dibrom-2-oxabicyclo( J.l.O]hexan (4b) wurde bei -60°C erzeugt un~ bei -30°C mit Methyllithium in Gegenwart von Styrol umgesetzt, woraus die Produkte 5 mit 24\% Ausbeute hervorgingen. Als bei 20°C best{\"a}ndige Quelle f{\"u}r 3 erwies sich exo-6-Brom-e~o-6-fluor-2-oxabicyclo[ J.t.O]bexan (9), das aus 2,3-Dihydrofuran und Bromßuorcarben mit 25\% Ausbeute bereitet wurde. Behandlung von 9 in Styrol,  C within the 5-HT4 receptor gene \(HTR4\) to be predominantly present in diarrhoea-IBS patients (IBS-D). It affects a binding site for the miR-16 family and miR-103/miR-107 within the isoforms \({HTR4b/i}\) and putatively impairs \(HTR4\) expression. Subsequent miRNA profiling revealed downregulation of miR-16 and miR-103 in the jejunum of IBS-D patients correlating with symptoms. \(In\) \(vitro\) assays confirmed expression regulation via three 3′UTR binding sites. The novel isoform \(HTR4b\_2\) lacking two of the three miRNA binding sites escapes miR-16/103/107 regulationin SNP carriers. We provide the first evidence that \(HTR4\) expression is fine-tuned by miRNAs, and that this regulation is impaired either by the SNP c.*61 T > C or bydiminished levels of miR-16 and miR-103 suggesting that \(HTR4\) might be involved in the development of IBS-D.}, language = {en} } @article{MaassDuezelBrigadskietal.2016, author = {Maass, Anne and D{\"u}zel, Sandra and Brigadski, Tanja and Goerke, Monique and Becke, Andreas and Sobieray, Uwe and Neumann, Katja and L{\"o}vd{\´e}n, Martin and Lindenberger, Ulman and B{\"a}ckman, Lars and Braun-Dullaeus, R{\"u}diger and Ahrens, D{\"o}rte and Heinze, Hans-Jochen and M{\"u}ller, Notger G. and Lessmann, Volkmar and Sendtner, Michael and D{\"u}zel, Emrah}, title = {Relationships of peripheral IGF-1, VEGF and BDNF levels to exercise-related changes in memory, hippocampal perfusion and volumes in older adults}, series = {NeuroImage}, volume = {131}, journal = {NeuroImage}, doi = {10.1016/j.neuroimage.2015.10.084}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-189219}, pages = {142-154}, year = {2016}, abstract = {Animal models point towards a key role of brain-derived neurotrophic factor (BDNF), insulin-like growth factor-I (IGF-I) and vascular endothelial growth factor (VEGF) in mediating exercise-induced structural and functional changes in the hippocampus. Recently, also platelet derived growth factor-C (PDGF-C) has been shown to promote blood vessel growth and neuronal survival. Moreover, reductions of these neurotrophic and angiogenic factors in old age have been related to hippocampal atrophy, decreased vascularization and cognitive decline. In a 3-month aerobic exercise study, forty healthy older humans (60 to 77 years) were pseudo-randomly assigned to either an aerobic exercise group (indoor treadmill, n = 21) or to a control group (indoor progressive-muscle relaxation/stretching, n = 19). As reported recently, we found evidence for fitness-related perfusion changes of the aged human hippocampus that were closely linked to changes in episodic memory function. Here, we test whether peripheral levels of BDNF, IGF-I, VEGF or PDGF-C are related to changes in hippocampal blood flow, volume and memory performance. Growth factor levels were not significantly affected by exercise, and their changes were not related to changes in fitness or perfusion. However, changes in IGF-I levels were positively correlated with hippocampal volume changes (derived by manual volumetry and voxel-based morphometry) and late verbal recall performance, a relationship that seemed to be independent of fitness, perfusion or their changes over time. These preliminary findings link IGF-I levels to hippocampal volume changes and putatively hippocampus-dependent memory changes that seem to occur over time independently of exercise. We discuss methodological shortcomings of our study and potential differences in the temporal dynamics of how IGF-1, VEGF and BDNF may be affected by exercise and to what extent these differences may have led to the negative findings reported here.}, language = {en} } @article{Prieto‐GarciaHartmannReisslandetal.2020, author = {Prieto-Garcia, Cristian and Hartmann, Oliver and Reissland, Michaela and Braun, Fabian and Fischer, Thomas and Walz, Susanne and Sch{\"u}lein-V{\"o}lk, Christina and Eilers, Ursula and Ade, Carsten P. and Calzado, Marco A. and Orian, Amir and Maric, Hans M. and M{\"u}nch, Christian and Rosenfeldt, Mathias and Eilers, Martin and Diefenbacher, Markus E.}, title = {Maintaining protein stability of ∆Np63 via USP28 is required by squamous cancer cells}, series = {EMBO Molecular Medicine}, volume = {12}, journal = {EMBO Molecular Medicine}, number = {4}, doi = {10.15252/emmm.201911101}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-218303}, year = {2020}, abstract = {The transcription factor ∆Np63 is a master regulator of epithelial cell identity and essential for the survival of squamous cell carcinoma (SCC) of lung, head and neck, oesophagus, cervix and skin. Here, we report that the deubiquitylase USP28 stabilizes ∆Np63 and maintains elevated ∆NP63 levels in SCC by counteracting its proteasome-mediated degradation. Impaired USP28 activity, either genetically or pharmacologically, abrogates the transcriptional identity and suppresses growth and survival of human SCC cells. CRISPR/Cas9-engineered in vivo mouse models establish that endogenous USP28 is strictly required for both induction and maintenance of lung SCC. Our data strongly suggest that targeting ∆Np63 abundance via inhibition of USP28 is a promising strategy for the treatment of SCC tumours.}, language = {en} }