TY  - INPR
A1  - Löffler, Mona C.
A1  - Mayer, Alexander E.
A1  - Trujillo Viera, Jonathan
A1  - Loza Valdes, Angel
A1  - El-Merahib, Rabih
A1  - Ade, Carsten P.
A1  - Karwen, Till
A1  - Schmitz, Werner
A1  - Slotta, Anja
A1  - Erk, Manuela
A1  - Janaki-Raman, Sudha
A1  - Matesanz, Nuria
A1  - Torres, Jorge L.
A1  - Marcos, Miguel
A1  - Sabio, Guadalupe
A1  - Eilers, Martin
A1  - Schulze, Almut
A1  - Sumara, Grzegorz
T1  - Protein kinase D1 deletion in adipocytes enhances energy dissipation and protects against adiposity
T2  - The EMBO Journal
N2  - Nutrient overload in combination with decreased energy dissipation promotes obesity and diabetes. Obesity results in a hormonal imbalance, which among others, activates G-protein coupled receptors utilizing diacylglycerol (DAG) as secondary messenger. Protein kinase D1 (PKD1) is a DAG effector which integrates multiple nutritional and hormonal inputs, but its physiological role in adipocytes is unknown. Here, we show that PKD1 promotes lipogenesis and suppresses mitochondrial fragmentation, biogenesis, respiration, and energy dissipation in an AMP-activated protein kinase (AMPK)-dependent manner. Moreover, mice lacking PKD1 in adipocytes are resistant to diet-induced obesity due to elevated energy expenditure. Beiging of adipocytes promotes energy expenditure and counteracts obesity. Consistently, deletion of PKD1 promotes expression of the β3-adrenergic receptor (ADRB3) in a CCAAT/enhancerbinding protein (C/EBP)-α and δ-dependent manner, which leads to the elevated expression of beige markers in adipocytes and subcutaneous adipose tissue. Finally, deletion of PKD1 in adipocytes improves insulin sensitivity and ameliorates liver steatosis. Thus, loss of PKD1 in adipocytes increases energy dissipation by several complementary mechanisms and might represent an attractive strategy to treat obesity and its related complications.
KW  - AMP-activated protein kinase (AMPK)
KW  - Beige adipocytes
KW  - β3 adrenergic receptor (ADRB3)
KW  - C/EBP
KW  - Protein kinase D1 (PKD1)
Y1  - 2018
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-176093
ER  - 
TY  - JOUR
A1  - Bechtle, Philip
A1  - Bringmann, Torsten
A1  - Desch, Klaus
A1  - Dreiner, Herbi
A1  - Hamer, Matthias
A1  - Hensel, Carsten
A1  - Krämer, Michael
A1  - Nguyen, Nelly
A1  - Porod, Werner
A1  - Prudent, Xavier
A1  - Sarrazin, Björn
A1  - Uhlenbrock, Mathias
A1  - Wienemann, Peter
T1  - Constrained supersymmetry after two years of LHC data: a global view with Fittino
JF  - Journal of High Energy Physics
N2  - We perform global fits to the parameters of the Constrained Minimal Super-symmetric Standard Model (CMSSM) and to a variant with non-universal Higgs masses (NUHM1). In addition to constraints from low-energy precision observables and the cosmological dark matter density, we take into account the LHC exclusions from searches in jets plus missing transverse energy signatures with about 5 fb\(^{−1}\) of integrated luminosity. We also include the most recent upper bound on the branching ratio B\(_s\)  → μμ from LHCb. Furthermore, constraints from and implications for direct and indirect dark matter searches are discussed. The best fit of the CMSSM prefers a light Higgs boson just above the experimentally excluded mass. We find that the description of the low-energy observables, (g − 2)\(_μ\) in particular, and the non-observation of SUSY at the LHC become more and more incompatible within the CMSSM. A potential SM-like Higgs boson with mass around 126 GeV can barely be accommodated. Values for B(B\(_s\)→μμ) just around the Standard Model prediction are naturally expected in the best fit region. The most-preferred region is not yet affected by limits on direct WIMP searches, but the next generation of experiments will probe this region. Finally, we discuss implications from fine-tuning for the best fit regions.
KW  - supersymmetry phenomenology
Y1  - 2012
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-129573
VL  - 06
IS  - 098
ER  - 
TY  - JOUR
A1  - Bothe, Friederike
A1  - Deubel, Anne-Kathrin
A1  - Hesse, Eliane
A1  - Lotz, Benedict
A1  - Groll, Jürgen
A1  - Werner, Carsten
A1  - Richter, Wiltrud
A1  - Hagmann, Sebastien
T1  - Treatment of focal cartilage defects in minipigs with zonal chondrocyte/mesenchymal progenitor cell constructs
JF  - International Journal of Molecular Sciences
N2  - Despite advances in cartilage repair strategies, treatment of focal chondral lesions remains an important challenge to prevent osteoarthritis. Articular cartilage is organized into several layers and lack of zonal organization of current grafts is held responsible for insufficient biomechanical and biochemical quality of repair-tissue. The aim was to develop a zonal approach for cartilage regeneration to determine whether the outcome can be improved compared to a non-zonal strategy. Hydrogel-filled polycaprolactone (PCL)-constructs with a chondrocyte-seeded upper-layer deemed to induce hyaline cartilage and a mesenchymal stromal cell (MSC)-containing bottom-layer deemed to induce calcified cartilage were compared to chondrocyte-based non-zonal grafts in a minipig model. Grafts showed comparable hardness at implantation and did not cause visible signs of inflammation. After 6 months, X-ray microtomography (µCT)-analysis revealed significant bone-loss in both treatment groups compared to empty controls. PCL-enforcement and some hydrogel-remnants were retained in all defects, but most implants were pressed into the subchondral bone. Despite important heterogeneities, both treatments reached a significantly lower modified O’Driscoll-score compared to empty controls. Thus, PCL may have induced bone-erosion during joint loading and misplacement of grafts in vivo precluding adequate permanent orientation of zones compared to surrounding native cartilage.
KW  - cartilage repair
KW  - osteochondral defect
KW  - tissue engineering
KW  - starPEG hydrogel
KW  - chondrocyte
KW  - MSC
KW  - zonal construct
KW  - minipig
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-285118
SN  - 1422-0067
VL  - 20
IS  - 3
ER  - 
TY  - JOUR
A1  - Schwaab, Bernhard
A1  - Bjarnason-Wehrens, Birna
A1  - Meng, Karin
A1  - Albus, Christian
A1  - Salzwedel, Annett
A1  - Schmid, Jean-Paul
A1  - Benzer, Werner
A1  - Metz, Matthes
A1  - Jensen, Katrin
A1  - Rauch, Bernhard
A1  - Bönner, Gerd
A1  - Brzoska, Patrick
A1  - Buhr-Schinner, Heike
A1  - Charrier, Albrecht
A1  - Cordes, Carsten
A1  - Dörr, Gesine
A1  - Eichler, Sarah
A1  - Exner, Anne-Kathrin
A1  - Fromm, Bernd
A1  - Gielen, Stephan
A1  - Glatz, Johannes
A1  - Gohlke, Helmut
A1  - Grilli, Maurizio
A1  - Gysan, Detlef
A1  - Härtel, Ursula
A1  - Hahmann, Harry
A1  - Herrmann-Lingen, Christoph
A1  - Karger, Gabriele
A1  - Karoff, Marthin
A1  - Kiwus, Ulrich
A1  - Knoglinger, Ernst
A1  - Krusch, Christian-Wolfgang
A1  - Langheim, Eike
A1  - Mann, Johannes
A1  - Max, Regina
A1  - Metzendorf, Maria-Inti
A1  - Nebel, Roland
A1  - Niebauer, Josef
A1  - Predel, Hans-Georg
A1  - Preßler, Axel
A1  - Razum, Oliver
A1  - Reiss, Nils
A1  - Saure, Daniel
A1  - von Schacky, Clemens
A1  - Schütt, Morten
A1  - Schultz, Konrad
A1  - Skoda, Eva-Maria
A1  - Steube, Diethard
A1  - Streibelt, Marco
A1  - Stüttgen, Martin
A1  - Stüttgen, Michaela
A1  - Teufel, Martin
A1  - Tschanz, Hansueli
A1  - Völler, Heinz
A1  - Vogel, Heiner
A1  - Westphal, Ronja
T1  - Cardiac rehabilitation in German speaking countries of Europe — evidence-based guidelines from Germany, Austria and Switzerland LLKardReha-DACH — part 2
JF  - Journal of Clinical Medicine
N2  - Background: Scientific guidelines have been developed to update and harmonize exercise based cardiac rehabilitation (ebCR) in German speaking countries. Key recommendations for ebCR indications have recently been published in part 1 of this journal. The present part 2 updates the evidence with respect to contents and delivery of ebCR in clinical practice, focusing on exercise training (ET), psychological interventions (PI), patient education (PE). In addition, special patients' groups and new developments, such as telemedical (Tele) or home-based ebCR, are discussed as well. Methods: Generation of evidence and search of literature have been described in part 1. Results: Well documented evidence confirms the prognostic significance of ET in patients with coronary artery disease. Positive clinical effects of ET are described in patients with congestive heart failure, heart valve surgery or intervention, adults with congenital heart disease, and peripheral arterial disease. Specific recommendations for risk stratification and adequate exercise prescription for continuous-, interval-, and strength training are given in detail. PI when added to ebCR did not show significant positive effects in general. There was a positive trend towards reduction in depressive symptoms for “distress management” and “lifestyle changes”. PE is able to increase patients’ knowledge and motivation, as well as behavior changes, regarding physical activity, dietary habits, and smoking cessation. The evidence for distinct ebCR programs in special patients’ groups is less clear. Studies on Tele-CR predominantly included low-risk patients. Hence, it is questionable, whether clinical results derived from studies in conventional ebCR may be transferred to Tele-CR. Conclusions: ET is the cornerstone of ebCR. Additional PI should be included, adjusted to the needs of the individual patient. PE is able to promote patients self-management, empowerment, and motivation. Diversity-sensitive structures should be established to interact with the needs of special patient groups and gender issues. Tele-CR should be further investigated as a valuable tool to implement ebCR more widely and effectively.
KW  - cardiac rehabilitation
KW  - scientific guidelines
KW  - secondary prevention
KW  - physical activity
KW  - exercise training
KW  - psychological interventions
KW  - education
KW  - gender
KW  - frailty
KW  - migration
KW  - old patients
KW  - young patients
KW  - tele-medicine
KW  - home-based-rehabilitation
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-242645
SN  - 2077-0383
VL  - 10
IS  - 14
ER  - 
TY  - JOUR
A1  - Berges, Carsten
A1  - Kerkau, Thomas
A1  - Werner, Sandra
A1  - Wolf, Nelli
A1  - Winter, Nadine
A1  - Hünig, Thomas
A1  - Einsele, Hermann
A1  - Topp, Max S.
A1  - Beyersdorf, Niklas
T1  - Hsp90 inhibition ameliorates CD4\(^{+}\) T cell-mediated acute Graft versus Host disease in mice
JF  - Immunity, Inflammation and Disease
N2  - Introduction:
For many patients with leukemia only allogeneic bone marrow transplantion provides a chance of cure. Co‐transplanted mature donor T cells mediate the desired Graft versus Tumor (GvT) effect required to destroy residual leukemic cells. The donor T cells very often, however, also attack healthy tissue of the patient inducing acute Graft versus Host Disease (aGvHD)—a potentially life‐threatening complication.

Methods:
Therefore, we used the well established C57BL/6 into BALB/c mouse aGvHD model to evaluate whether pharmacological inhibition of heat shock protein 90 (Hsp90) would protect the mice from aGvHD.

Results:
Treatment of the BALB/c recipient mice from day 0 to +2 after allogeneic CD4\(^{+}\) T cell transplantation with the Hsp90 inhibitor 17‐(dimethylaminoethylamino)‐17‐demethoxygeldanamycin (DMAG) partially protected the mice from aGvHD. DMAG treatment was, however, insufficient to prolong overall survival of leukemia‐bearing mice after transplantation of allogeneic CD4\(^{+}\) and CD8\(^{+}\) T cells. Ex vivo analyses and in vitro experiments revealed that DMAG primarily inhibits conventional CD4\(^{+}\) T cells with a relative resistance of CD4\(^{+}\) regulatory and CD8\(^{+}\) T cells toward Hsp90 inhibition.

Conclusions:
Our data, thus, suggest that Hsp90 inhibition might constitute a novel approach to reduce aGvHD in patients without abrogating the desired GvT effect.
KW  - Hsp90
KW  - leukemia
KW  - acute Graft versus Host Disease
KW  - Graft versus Tumor
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-168318
VL  - 4
IS  - 4
ER  - 
TY  - JOUR
A1  - Meinert, Madlen
A1  - Jessen, Christina
A1  - Hufnagel, Anita
A1  - Kreß, Julia Katharina Charlotte
A1  - Burnworth, Mychal
A1  - Däubler, Theo
A1  - Gallasch, Till
A1  - Da Xavier Silva, Thamara Nishida
A1  - Dos Santos, Ancély Ferreira
A1  - Ade, Carsten Patrick
A1  - Schmitz, Werner
A1  - Kneitz, Susanne
A1  - Friedmann Angeli, José Pedro
A1  - Meierjohann, Svenja
T1  - Thiol starvation triggers melanoma state switching in an ATF4 and NRF2-dependent manner
JF  - Redox Biology
N2  - The cystine/glutamate antiporter xCT is an important source of cysteine for cancer cells. Once taken up, cystine is reduced to cysteine and serves as a building block for the synthesis of glutathione, which efficiently protects cells from oxidative damage and prevents ferroptosis. As melanomas are particularly exposed to several sources of oxidative stress, we investigated the biological role of cysteine and glutathione supply by xCT in melanoma. xCT activity was abolished by genetic depletion in the Tyr::CreER; Braf\(^{CA}\); Pten\(^{lox/+}\) melanoma model and by acute cystine withdrawal in melanoma cell lines. Both interventions profoundly impacted melanoma glutathione levels, but they were surprisingly well tolerated by murine melanomas in vivo and by most human melanoma cell lines in vitro. RNA sequencing of human melanoma cells revealed a strong adaptive upregulation of NRF2 and ATF4 pathways, which orchestrated the compensatory upregulation of genes involved in antioxidant defence and de novo cysteine biosynthesis. In addition, the joint activation of ATF4 and NRF2 triggered a phenotypic switch characterized by a reduction of differentiation genes and induction of pro-invasive features, which was also observed after erastin treatment or the inhibition of glutathione synthesis. NRF2 alone was capable of inducing the phenotypic switch in a transient manner. Together, our data show that cystine or glutathione levels regulate the phenotypic plasticity of melanoma cells by elevating ATF4 and NRF2.
KW  - thiol starvation
KW  - ATF4
KW  - NRF2
KW  - melanoma
Y1  - 2024
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-350328
VL  - 70
ER  -