TY - JOUR AB - Background/Objectives: A relevant subgroup of post-COVID-19 syndrome (PCS) patients suffers from post-exertional malaise (PEM) and cardiovascular or neurological symptoms, impairing daily functioning up to becoming even house- or bedbound. Recent data suggest that PCS summarizes different subgroups, one of them being characterized by an impaired microcirculation. Thus, the aim of the present study was to investigate local deoxygenation, measured with non-invasive near-infrared regional spectroscopy (NIRS), and its association with self-reported fatigue in patients with PCS compared to controls in light exercise. Methods: 150 participants (100 PCS patients and 50 controls) were recruited. PEM was assessed using FACIT, Chalder, and Bell scoring and Canadian Criteria. NIRS was used to measure local oxygenation while kneading a stress ball and during recovery. Results: PCS patients showed fatigue scores of 30 (Bell score), 20.6 (FACIT fatigue score), and 9.914 (Chalder fatigue score). Decreased deoxygenation peaks at the start of exercise were observed in patients with PCS, compared to controls (p = 0.0002). Multivariate analysis identified a subgroup, showing an association between strong fatigue and restricted oxygenation dynamics. Conclusions: NIRS could be a potential tool to assess deoxygenation deficits even in moderate to severely impaired PCS patients using light exercise protocols. AU - Ladek, A.-M.* AU - Lucio, M. AU - Weiß, A.* AU - Knauer, T.E.* AU - Sarmiento, H.* AU - Ilgner, M.* AU - Jakobi, M.* AU - Barteczko, L.* AU - Ganslmayer, M.* AU - Rech, J.* AU - Bergua, A.* AU - Mardin, C.Y.* AU - Hohberger, B.* C1 - 74872 C2 - 57646 CY - Mdpi Ag, Grosspeteranlage 5, Ch-4052 Basel, Switzerland SP - 1371 - 1371 TI - Deoxygenation trends and their multivariate association with self-reported fatigue in post-COVID syndrome. JO - Biomedicines VL - 13 IS - 6 PB - Mdpi PY - 2025 SN - 2227-9059 ER - TY - JOUR AB - Background: Microbeam radiation therapy (MRT) is an advanced preclinical approach in radiotherapy that utilizes spatially fractionated dose distributions by collimating x-rays into micrometer-wide, planar beams. While the benefits of temporal fractionation are well established and widely incorporated into conventional radiotherapy protocols, the interplay between MRT and temporal dose fractionation remains largely unexplored. In this study, we investigate the effects of combining temporal and spatial dose fractionation by assessing clonogenic cell survival following temporally fractionated MRT with varying irradiation angles, compared to conventional broad-beam (BB) irradiation. Methods: A lung tumor cell line (A549) and a normal lung cell line (MRC-5) were irradiated with a total number of four fractions with a 24 h interval between each fraction. We compared a temporally fractionated BB regime to two temporally fractionated MRT schemes with either overlapping MRT fields or MRT fields with a 45° rotation per fraction. Subsequently, the clonogenic cell survival assay was used by analyzing the corresponding survival fractions (SFs). Results: The clonogenic survival of A549 tumor cells differed significantly between microbeam radiation therapy with rotation (MRT + R) and overlapping MRT. However, neither MRT + R nor overlapping MRT showed statistically significant differences compared to the broad-beam (BB) irradiation for A549. In contrast, the normal tissue cell line MRC-5 exhibited significantly higher clonogenic survival following both MRT + R and overlapping MRT compared to BB. Conclusions: This study demonstrates that combining temporal and spatial fractionation enhances normal tissue cell survival while maintaining equivalent tumor cell kill, potentially increasing the therapeutic index. Our findings support the feasibility of delivering temporally fractionated doses using different MRT modalities and provide clear evidence of the therapeutic benefits of temporally fractionated MRT. AU - Stolz, J. AU - Rogal, K. AU - Bicher, S. AU - Winter, J. AU - Ahmed, M. AU - Raulefs, S. AU - Combs, S.E. AU - Bartzsch, S. AU - Schmid, T.E. C1 - 73792 C2 - 57226 CY - Mdpi Ag, Grosspeteranlage 5, Ch-4052 Basel, Switzerland TI - The combination of temporal and spatial dose fractionation in microbeam radiation therapy. JO - Biomedicines VL - 13 IS - 3 PB - Mdpi PY - 2025 SN - 2227-9059 ER - TY - JOUR AB - The concept of redirecting metabolic pathways in cancer cells for therapeutic purposes has become a prominent theme in recent research. Now, with the advent of ferroptosis, a new chink in the armor has evolved that allows for repurposing of ferroptosis-sensitive lipids in order to trigger cell death. This review presents the historical context of lipidomic and metabolic alterations in cancer cells associated with ferroptosis sensitization. The main proferroptotic genes and pathways are identified as therapeutic targets for increasing susceptibility to ferroptosis. In this review, a particular emphasis is given to pathways in cancer cells such as de novo lipogenesis, which has been described as a potential target for ferroptosis sensitization. Additionally, we propose a connection between ketolysis inhibition and sensitivity to ferroptosis as a new vulnerability in cancer cells. The main proferroptotic genes and pathways have been identified as therapeutic targets for increasing susceptibility to ferroptosis. Proferroptotic metabolic pathways and vulnerable points, along with suggested agonists or antagonists, are also discussed. Finally, general therapeutic strategies for ferroptosis sensitization based on the manipulation of the lipidome in ferroptosis-resistant cancer cell lines are proposed. AU - Varynskyi, B. AU - Schick, J.A. C1 - 70378 C2 - 55397 CY - St Alban-anlage 66, Ch-4052 Basel, Switzerland TI - Hacking the lipidome: New ferroptosis strategies in cancer therapy. JO - Biomedicines VL - 12 IS - 3 PB - Mdpi PY - 2024 SN - 2227-9059 ER - TY - JOUR AB - The perception of circulating granulocytes as cells with a predetermined immune response mainly triggered by pathogens is evolving, recognizing their functional heterogeneity and adaptability, particularly within the neutrophil subset. The involvement of these cells in the pathophysiology of autoimmune uveitis has become increasingly clear, yet their exact role remains elusive. We used an equine model for autoimmune-mediated recurrent pan-uveitis to investigate early responses of granulocytes in different inflammatory environments. For this purpose, we performed differential proteomics on granulocytes from healthy and diseased horses stimulated with IL8, LPS, or PMA. Compared to healthy horses, granulocytes from the recurrent uveitis model significantly changed the cellular abundance of 384 proteins, with a considerable number of specific changes for each stimulant. To gain more insight into the functional impact of these stimulant-specific proteome changes in ERU pathogenesis, we used Ingenuity Pathway Analysis for pathway enrichment. This resulted in specific reaction patterns for each stimulant, with IL8 predominantly promoting Class I MHC-mediated antigen processing and presentation, LPS enhancing processes in phospholipid biosynthesis, and PMA, clearly inducing neutrophil degranulation. These findings shed light on the remarkably differentiated responses of neutrophils, offering valuable insights into their functional heterogeneity in a T-cell-driven disease. Raw data are available via ProteomeXchange with identifier PXD013648. AU - Degroote, R.L.* AU - Schmalen, A. AU - Hauck, S.M. AU - Deeg, C.A.* C1 - 69858 C2 - 54997 TI - Unveiling differential responses of granulocytes to distinct immunostimulants with implications in autoimmune uveitis. JO - Biomedicines VL - 12 IS - 1 PY - 2023 SN - 2227-9059 ER - TY - JOUR AB - Laminin α4 (LAMA4) is one of the main structural adipocyte basement membrane (BM) components that is upregulated during adipogenesis and related to obesity in mice and humans. We conducted RNA-seq-based gene expression analysis of LAMA4 in abdominal subcutaneous (SC) and visceral (VIS) adipose tissue (AT) depots across three human sub-cohorts of the Leipzig Obesity BioBank (LOBB) to explore the relationship between LAMA4 expression and obesity (N = 1479) in the context of weight loss (N = 65) and metabolic health (N = 42). We found significant associations of LAMA4 with body fat mass (p < 0.001) in VIS AT; higher expression in VIS AT compared to SC AT; and significant relation to metabolic health parameters e.g., body fat in VIS AT, waist (p = 0.009) and interleukin 6 (p = 0.002) in male VIS AT, and hemoglobin A1c (p = 0.008) in male SC AT. AT LAMA4 expression was not significantly different between subjects with or without obesity, metabolically healthy versus unhealthy, and obesity before versus after short-term weight loss. Our results support significant associations between obesity related clinical parameters and elevated LAMA4 expression in humans. Our work offers one of the first references for understanding the meaning of LAMA4 expression specifically in relation to obesity based on large-scale RNA-seq data. AU - Hagemann, T. AU - Czechowski, P. AU - Ghosh, A.* AU - Sun, W.* AU - Dong, H.* AU - Noé, F.* AU - Wolfrum, C.* AU - Blüher, M. AU - Hoffmann, A. C1 - 68689 C2 - 54898 CY - St Alban-anlage 66, Ch-4052 Basel, Switzerland TI - Laminin α4 expression in human adipose tissue depots and its association with obesity and obesity related traits. JO - Biomedicines VL - 11 IS - 10 PB - Mdpi PY - 2023 SN - 2227-9059 ER - TY - JOUR AB - Adipokines are signaling proteins involved in metabolic, endocrinological, vascular and immunogenic processes. Associations of various adipokines with not only insulin resistance but also with increased insulin sensitivity, increased systolic blood pressure, and atherosclerosis highlight the significance of adipokines in several components of metabolic syndrome and metabolic diseases in general. As pregnancy presents a unique metabolic state, the role of adipokines in pregnancy, and even in various pregnancy complications, appears to be key to elucidating these metabolic processes. Many studies in recent years have attempted to clarify the role of adipokines in pregnancy and gestational pathologies. In this review, we aim to investigate the changes in maternal adipokine levels in physiological gestation, as well as the association of adipokines with pregnancy pathologies, such as gestational diabetes mellitus (GDM) and preeclampsia (PE). Furthermore, we will analyze the association of adipokines in both maternal serum and cord blood with parameters of intrauterine growth and various pregnancy outcomes. AU - Kabbani, N.* AU - Blüher, M. AU - Stepan, H.* AU - Stumvoll, M.* AU - Ebert, T.* AU - Tönjes, A.* AU - Schrey-Petersen, S.* C1 - 67880 C2 - 54358 CY - St Alban-anlage 66, Ch-4052 Basel, Switzerland TI - Adipokines in pregnancy: A systematic review of clinical data. JO - Biomedicines VL - 11 IS - 5 PB - Mdpi PY - 2023 SN - 2227-9059 ER - TY - JOUR AB - Transforming growth factor beta-1 (TGFβ1) is an adipokine secreted from adipose tissue, placental tissue and immune cells with a role in cell proliferation, cell apoptosis and angiogenic proliferation. The role of TGFβ1 in pregnancy and child growth and the source of cord TGFβ1 are yet unknown. In this study, we sought to clarify the correlation of TGFβ1 levels with parameters of intrauterine growth and child growth during the first year of life, and to determine whether their source is primarily of fetal or maternal origin. Serum samples and anthropometric measurements were obtained from the LIFE Child cohort of 79 healthy mother-child pairs. Measurements were conducted using enzyme-linked immunosorbent assays. Statistical analyses including Mann-Whitney U-test, correlation analyses and linear regression analyses were performed using GraphPad Prism and R. TGFβ1 levels were significantly higher in cord than in maternal serum, suggesting a fetal origin. Multivariate regression analyses revealed strong positive associations between cord TGFβ1 levels at birth and child weight at U6. Furthermore, cord TGFβ1 was significantly correlated with child weight at approximately one year of age. An increase of 10,000 pg/mL in cord TGFβ1 concentrations at birth was associated with a higher body weight of 201 g at roughly one year of age when adjusted for sex. AU - Kabbani, N.* AU - Stepan, H.* AU - Blüher, M. AU - Ebert, T.* AU - Baber, R.* AU - Vogel, M.* AU - Kiess, W.* AU - Stumvoll, M.* AU - Breitfeld, J.* AU - Lössner, U.* AU - Tönjes, A.* AU - Schrey-Petersen, S.* C1 - 67951 C2 - 54429 CY - St Alban-anlage 66, Ch-4052 Basel, Switzerland TI - Association between TGFβ1 levels in cord blood and weight progress in the first year of life. JO - Biomedicines VL - 11 IS - 8 PB - Mdpi PY - 2023 SN - 2227-9059 ER - TY - JOUR AB - The successful development of effective viral vaccines depends on well-known correlates of protection, high immunogenicity, acceptable safety criteria, low reactogenicity, and well-designed immune monitoring and serology. Virus-neutralizing antibodies are often a good correlate of protective immunity, and their serum concentration is a key parameter during the pre-clinical and clinical testing of vaccine candidates. Viruses are inherently infectious and potentially harmful, but we and others developed replication-defective SARS-CoV-2 virus-like-particles (VLPs) as surrogates for infection to quantitate neutralizing antibodies with appropriate target cells using a split enzyme-based approach. Here, we show that SARS-CoV-2 and Epstein-Barr virus (EBV)-derived VLPs associate and fuse with extracellular vesicles in a highly specific manner, mediated by the respective viral fusion proteins and their corresponding host receptors. We highlight the capacity of virus-neutralizing antibodies to interfere with this interaction and demonstrate a potent application using this technology. To overcome the common limitations of most virus neutralization tests, we developed a quick in vitro diagnostic assay based on the fusion of SARS-CoV-2 VLPs with susceptible vesicles to quantitate neutralizing antibodies without the need for infectious viruses or living cells. We validated this method by testing a set of COVID-19 patient serum samples, correlated the results with those of a conventional test, and found good sensitivity and specificity. Furthermore, we demonstrate that this serological assay can be adapted to a human herpesvirus, EBV, and possibly other enveloped viruses. AU - Rössler, J. AU - Pich, D. AU - Krähling, V.* AU - Becker, S.* AU - Keppler, O.T.* AU - Zeidler, R. AU - Hammerschmidt, W. C1 - 68906 C2 - 53760 CY - St Alban-anlage 66, Ch-4052 Basel, Switzerland TI - SARS-CoV-2 and Epstein-Barr Virus-like particles associate and fuse with extracellular vesicles in virus neutralization tests. JO - Biomedicines VL - 11 IS - 11 PB - Mdpi PY - 2023 SN - 2227-9059 ER - TY - JOUR AB - Adipokines provide an outstanding role in the comprehensive etiology of obesity and may link adipose tissue dysfunction to further metabolic and cardiovascular complications. Although several adipokines have been identified in terms of their physiological roles, many regulatory circuits remain unclear and translation from experimental studies to clinical applications has yet to occur. Nevertheless, due to their complex metabolic properties, adipokines offer immense potential for their use both as obesity-associated biomarkers and as relevant treatment strategies for overweight, obesity and metabolic comorbidities. To provide an overview of the current clinical use of adipokines, this review summarizes clinical studies investigating the potential of various adipokines with respect to diagnostic and therapeutic treatment strategies for obesity and linked metabolic disorders. Furthermore, an overview of adipokines, for which a potential for clinical use has been demonstrated in experimental studies to date, will be presented. In particular, promising data revealed that fibroblast growth factor (FGF)-19, FGF-21 and leptin offer great potential for future clinical application in the treatment of obesity and related comorbidities. Based on data from animal studies or other clinical applications in addition to obesity, adipokines including adiponectin, vaspin, resistin, chemerin, visfatin, bone morphogenetic protein 7 (BMP-7) and tumor necrosis factor alpha (TNF-α) provide potential for human clinical application. AU - Würfel, M.* AU - Blüher, M. AU - Stumvoll, M.* AU - Ebert, T.* AU - Kovacs, P.* AU - Tönjes, A.* AU - Breitfeld, J.* C1 - 67879 C2 - 54357 CY - St Alban-anlage 66, Ch-4052 Basel, Switzerland TI - Adipokines as clinically relevant therapeutic targets in obesity. JO - Biomedicines VL - 11 IS - 5 PB - Mdpi PY - 2023 SN - 2227-9059 ER - TY - JOUR AB - KRAS (KRAS proto-oncogene, GTPase) inhibitors perform less well than other targeted drugs in vitro and fail clinical trials. To investigate a possible reason for this, we treated human and murine tumor cells with KRAS inhibitors deltarasin (targeting phosphodiesterase-δ), cysmethynil (targeting isoprenylcysteine carboxylmethyltransferase), and AA12 (targeting KRASG12C ), and silenced/overexpressed mutant KRAS using custom-designed vectors. We showed that KRAS-mutant tumor cells exclusively respond to KRAS blockade in vivo, because the oncogene co-opts host myeloid cells via a C-C-motif chemokine ligand 2 (CCL2)/interleukin-1 beta (IL-1β)-mediated signaling loop for sustained tumorigenicity. Indeed, KRAS-mutant tumors did not respond to deltarasin in C-C motif chemokine receptor 2 (Ccr2) and Il1b gene-deficient mice, but were deltarasin-sensitive in wild-type and Ccr2-deficient mice adoptively transplanted with wild-type murine bone marrow. A KRAS-dependent pro-inflammatory transcriptome was prominent in human cancers with high KRAS mutation prevalence and poor predicted survival. Our findings support that in vitro cellular systems are suboptimal for anti-KRAS drug screens, as these drugs function to suppress interleukin-1 receptor 1 (IL1R1) expression and myeloid IL-1β-delivered pro-growth effects in vivo. Moreover, the findings support that IL-1β blockade might be suitable for therapy for KRAS-mutant cancers. AU - Arendt, K.A.M. AU - Ntaliarda, G.* AU - Armenis, V.* AU - Kati, D.* AU - Henning, C. AU - Giotopoulou, G.A. AU - Pepe, M. AU - Klotz, L.V. AU - Lamort, A.-S. AU - Hatz, R.A.* AU - Kobold, S.* AU - Schamberger, A.C. AU - Stathopoulos, G.T. C1 - 64575 C2 - 52331 TI - An in vivo inflammatory loop potentiates KRAS blockade. JO - Biomedicines VL - 10 IS - 3 PY - 2022 SN - 2227-9059 ER - TY - JOUR AB - While a dramatic increase in obesity and related comorbidities is being witnessed, the underlying mechanisms of their spread remain unresolved. Epigenetic and other non-genetic mechanisms tend to be prominent candidates involved in the establishment and transmission of obesity and associated metabolic disorders to offspring. Here, we review recent findings addressing those candidates, in the context of maternal and paternal influences, and discuss the effectiveness of preventive measures. AU - Comas-Armangue, G. AU - Makharadze, L. AU - Gómez Velázquez, M. AU - Teperino, R. C1 - 66525 C2 - 52890 TI - The legacy of parental obesity: Mechanisms of non-genetic transmission and reversibility. JO - Biomedicines VL - 10 IS - 10 PY - 2022 SN - 2227-9059 ER - TY - JOUR AB - Chronic lung diseases are one of the leading causes of death worldwide. Lung transplantation is currently the only causal therapeutic for lung diseases, which is restricted to end-stage disease and limited by low access to donor lungs. Lung tissue engineering (LTE) is a promising approach to regenerating a replacement for at least a part of the damaged lung tissue. Currently, lung regeneration is limited to a simplified local level (e.g., alveolar-capillary barrier) due to the sophisticated and complex structure and physiology of the lung. Here, we introduce an extracellular matrix (ECM)-integrated scaffold using a cellularization-decellularization-recellularization technique. This ECM-integrated scaffold was developed on our artificial co-polymeric BETA (biphasic elastic thin for air-liquid interface cell culture conditions) scaffold, which were initially populated with human lung fibroblasts (IMR90 cell line), as the main generator of ECM proteins. Due to the interconnected porous structure of the thin (<5 µm) BETA scaffold, the cells can grow on and infiltrate into the scaffold and deposit their own ECM. After a mild decellularization procedure, the ECM proteins remained on the scaffold, which now closely mimicked the cellular microenvironment of pulmonary cells more realistically than the plain artificial scaffolds. We assessed several decellularization methods and found that 20 mM NH4OH and 0.1% Triton X100 with subsequent DNase treatment completely removed the fibroblasts (from the first cellularization) and maintains collagen I and IV as the key ECM proteins on the scaffold. We also showed the repopulation of the primary fibroblast from human (without chronic lung disease (non-CLD) donors) and human bronchial epithelial (16HBE14o-) cells on the ECM-integrated BETA scaffold. With this technique, we developed a biomimetic scaffold that can mimic both the physico-mechanical properties and the native microenvironment of the lung ECM. The results indicate the potential of the presented bioactive scaffold for LTE application. AU - Doryab, A. AU - Schmid, O. C1 - 66038 C2 - 53060 TI - Bioactive cell-derived ECM scaffold forms a unique cellular microenvironment for lung tissue engineering. JO - Biomedicines VL - 10 IS - 8 PY - 2022 SN - 2227-9059 ER - TY - JOUR AB - The transplantation of pancreatic islets can prevent severe long-term complications in diabetes mellitus type 1 patients. With respect to a shortage of donor organs, the transplantation of xenogeneic islets is highly attractive. To avoid rejection, islets can be encapsulated in immuno-protective hydrogel-macrocapsules, whereby 3D bioprinted structures with macropores allow for a high surface-to-volume ratio and reduced diffusion distances. In the present study, we applied 3D bioprinting to encapsulate the potentially clinically applicable neonatal porcine islet-like cell clusters (NICC) in alginate-methylcellulose. The material was additionally supplemented with bovine serum albumin or the human blood plasma derivatives platelet lysate and fresh frozen plasma. NICC were analysed for viability, proliferation, the presence of hormones, and the release of insulin in reaction to glucose stimulation. Bioprinted NICC are homogeneously distributed, remain morphologically intact, and show a comparable viability and proliferation to control NICC. The number of insulin-positive cells is comparable between the groups and over time. The amount of insulin release increases over time and is released in response to glucose stimulation over 4 weeks. In summary, we show the successful bioprinting of NICC and could demonstrate functionality over the long-term in vitro. Supplementation resulted in a trend for higher viability, but no additional benefit on functionality was observed. AU - Duin, S.* AU - Bhandarkar, S.* AU - Lehmann, S. AU - Kemter, E.* AU - Wolf, E.* AU - Gelinsky, M.* AU - Ludwig, B. AU - Lode, A.* C1 - 65533 C2 - 52723 TI - Viability and functionality of neonatal porcine islet-like cell clusters bioprinted in alginate-based bioinks. JO - Biomedicines VL - 10 IS - 6 PY - 2022 SN - 2227-9059 ER - TY - JOUR AB - Glucotoxic metabolites and pathways play a crucial role in diabetic complications, and new treatment options which improve glucotoxicity are highly warranted. In this study, we analyzed bezafibrate (BEZ) treated, streptozotocin (STZ) injected mice, which showed an improved glucose metabolism compared to untreated STZ animals. In order to identify key molecules and pathways which participate in the beneficial effects of BEZ, we studied plasma, skeletal muscle, white adipose tissue (WAT) and liver samples using non-targeted metabolomics (NMR spectroscopy), targeted metabolomics (mass spectrometry), microarrays and mitochondrial enzyme activity measurements, with a particular focus on the liver. The analysis of muscle and WAT demonstrated that STZ treatment elevated inflammatory pathways and reduced insulin signaling and lipid pathways, whereas BEZ decreased inflammatory pathways and increased insulin signaling and lipid pathways, which can partly explain the beneficial effects of BEZ on glucose metabolism. Furthermore, lysophosphatidylcholine levels were lower in the liver and skeletal muscle of STZ mice, which were reverted in BEZ-treated animals. BEZ also improved circulating and hepatic glucose levels as well as lipid profiles. In the liver, BEZ treatment reduced elevated fumarate levels in STZ mice, which was probably due to a decreased expression of urea cycle genes. Since fumarate has been shown to participate in glucotoxic pathways, our data suggests that BEZ treatment attenuates the urea cycle in the liver, decreases fumarate levels and, in turn, ameliorates glucotoxicity and reduces insulin resistance in STZ mice. AU - Frankó, A. AU - Irmler, M. AU - Prehn, C. AU - Heinzmann, S.S. AU - Schmitt-Kopplin, P. AU - Adamski, J. AU - Beckers, J. AU - von Kleist-Retzow, J.C.* AU - Wiesner, R.* AU - Häring, H.-U. AU - Heni, M. AU - Birkenfeld, A.L. AU - Hrabě de Angelis, M. C1 - 64658 C2 - 52006 TI - Bezafibrate reduces elevated hepatic fumarate in insulin-deficient mice. JO - Biomedicines VL - 10 IS - 3 PY - 2022 SN - 2227-9059 ER - TY - JOUR AB - Sepsis is defined by life-threatening organ dysfunction mediated by the host’s response to infection. This can result in septic dyslipidemia, which is involved in the neutralization of pathogen-related lipids. Knowledge of the regulatory mechanisms of septic dyslipidemia is incomplete. The cytokine betatrophin/Angiopoietin-like protein 8 (ANGPTL8) plays a role in the regulation of triacylglyceride metabolism, though its function in septic dyslipidemia remains unknown. Sixty-six patients were enrolled in a cross-sectional study. Circulating concentrations and adipose tissue (AT) mRNA expression of betatrophin/ANGPTL8 were studied in patients suffering from peritoneal sepsis. Insulin-resistant individuals and subjects without metabolic derangement/systemic inflammation were enrolled as controls. All underwent open abdominal surgery. Circulating betatrophin/ANGPTL8 was analyzed by an enzyme-linked immunosorbent assay and AT mRNA expression levels were assessed by real-time PCR. Standard laboratory analyses including lipid electrophoresis were evaluated. Sepsis patients showed pronounced septic dyslipidemia (p < 0.05 for all major lipid classes). Despite comparable betatrophin/ANGPTL8 mRNA expression in AT (p = 0.24), we found significantly increased circulating betatrophin/ANGPTL8 with septic dyslipidemia (p = 0.009). Expression levels of betatrophin/ANGPTL8 in AT correlated with circulating concentrations in both control groups (r = 0.61; p = 0.008 and r = 0.43; p = 0.034), while this association was undetectable in sepsis. After stratification, betatrophin/ANGPTL8 remained associated with hypertriacylglyceridemia (p < 0.05). AU - Horn, P.* AU - Radtke, S.* AU - Metzing, U.B.* AU - Steidl, R.* AU - Sponholz, C.* AU - Sommerfeld, O.* AU - Roth, J.* AU - Claus, R.A.* AU - Birkenfeld, A.L. AU - Settmacher, U.* AU - Rauchfuß, F.* AU - von Loeffelholz, C.* C1 - 67099 C2 - 53469 CY - St Alban-anlage 66, Ch-4052 Basel, Switzerland TI - Associations of betatrophin/ANGPTL8 with septic dyslipidemia in human peritonitis: An explorative analysis. JO - Biomedicines VL - 10 IS - 12 PB - Mdpi PY - 2022 SN - 2227-9059 ER - TY - JOUR AB - CD73 catalyzes the conversion of ATP to adenosine, which is involved in various physiological and pathological processes, including tumor immune escape. Because CD73 expression and activity are particularly high on cancer cells and contribute to the immunosuppressive properties of the tumor environment, it is considered an attractive target molecule for specific cancer therapies. In line, several studies demonstrated that CD73 inhibition has a significant antitumor effect. How-ever, complete blocking of CD73 activity can evoke autoimmune phenomena and adverse side ef-fects. We developed a CD73-specific antibody, 22E6, that specifically inhibits the enzymatic activity of membrane-tethered CD73 present in high concentrations on cancer cells and cancer cell-derived extracellular vesicles but has no inhibitory effect on soluble CD73. Inhibition of CD73 on tumor cells with 22E6 resulted in multiple effects on tumor cells in vitro, including increased apoptosis and interference with chemoresistance. Intriguingly, in a xenograft mouse model of acute lymphocytic leukemia (ALL), 22E6 treatment resulted in an initial tumor growth delay in some animals, followed by a complete loss of CD73 expression on ALL cells in all 22E6 treated animals, indicating tumor immune escape. Taken together, 22E6 shows great potential for cancer therapy, favorably in combination with other drugs. AU - Kellner, M. AU - von Neubeck, B. AU - Czogalla, B.* AU - Feederle, R. AU - Vick, B. AU - Jeremias, I. AU - Zeidler, R. C1 - 64861 C2 - 52521 TI - A novel anti-CD73 antibody that selectively inhibits membrane 2 CD73 shows antitumor activity and induces tumor immune escape. JO - Biomedicines VL - 10 IS - 4 PY - 2022 SN - 2227-9059 ER - TY - JOUR AB - Exercise and physical activity induces physiological responses in organisms, and adaptations in skeletal muscle, which is beneficial for maintaining health and preventing and/or treating most chronic diseases. These adaptations are mainly instigated by transcriptional responses that ensue in reaction to each individual exercise, either resistance or endurance. Consequently, changes in key metabolic, regulatory, and myogenic genes in skeletal muscle occur as both an early and late response to exercise, and these epigenetic modifications, which are influenced by environmental and genetic factors, trigger those alterations in the transcriptional responses. DNA methylation and histone modifications are the most significant epigenetic changes described in gene transcription, linked to the skeletal muscle transcriptional response to exercise, and mediating the exercise adaptations. Nevertheless, other alterations in the epigenetics markers, such as epitranscriptomics, modifications mediated by miRNAs, and lactylation as a novel epigenetic modification, are emerging as key events for gene transcription. Here, we provide an overview and update of the impact of exercise on epigenetic modifications, including the well-described DNA methylations and histone modifications, and the emerging modifications in the skeletal muscle. In addition, we describe the effects of exercise on epigenetic markers in other metabolic tissues; also, we provide information about how systemic metabolism or its metabolites influence epigenetic modifications in the skeletal muscle. AU - Plaza-Díaz, J.* AU - Izquierdo, D.* AU - Torres-Martos, Á.* AU - Baig, A.T.* AU - Aguilera, C.M.* AU - Ruiz Ojeda, F.J. C1 - 64273 C2 - 52163 TI - Impact of physical activity and exercise on the epigenome in skeletal muscle and effects on systemic metabolism. JO - Biomedicines VL - 10 IS - 1 PY - 2022 SN - 2227-9059 ER - TY - JOUR AB - The clinical impact of anti-spike monoclonal antibodies (mAb) in Coronavirus Disease 2019 (COVID-19) breakthrough infections is unclear. We present the results of an observational prospective cohort study assessing and comparing COVID-19 progression in high-risk outpatients receiving mAb according to primary or breakthrough infection. Clinical, serological and virological predictors associated with 28-day COVID-19-related hospitalization were identified using multivariate logistic regression and summarized with odds ratio (aOR) and 95% confidence interval (CI). A total of 847 COVID-19 outpatients were included: 414 with primary and 433 with breakthrough infection. Hospitalization was observed in 42/414 (10.1%) patients with primary and 8/433 (1.8%) patients with breakthrough infection (p < 0.001). aOR for hospitalization was significantly lower for breakthrough infection (aOR 0.12, 95%CI: 0.05–0.27, p < 0.001) and higher for immunocompromised status (aOR:2.35, 95%CI:1.08–5.08, p = 0.003), advanced age (aOR:1.06, 95%CI: 1.03–1.08, p < 0.001), and male gender (aOR:1.97, 95%CI: 1.04–3.73, p = 0.037). Among the breakthrough infection group, the median SARS-CoV-2 anti-spike IgGs was lower (p < 0.001) in immunocompromised and elderly patients >75 years compared with that in the immunocompetent patients. Our findings suggest that, among mAb patients, those with breakthrough infection have significantly lower hospitalization risk compared with patients with primary infection. Prognostic algorithms combining clinical and immune-virological characteristics are needed to ensure appropriate and up-to-date clinical protocols targeting high-risk categories. AU - Savoldi, A.* AU - Morra, M.* AU - Castelli, A.* AU - Mirandola, M.* AU - Berkell, M.* AU - Smet, M.* AU - Konnova, A.* AU - Rossi, E.* AU - Cataudella, S.* AU - De Nardo, P.* AU - Gentilotti, E.* AU - Gupta, A.* AU - Fasan, D.* AU - Gibbin, E.* AU - Puviani, F.C.* AU - Hasenauer, J. AU - Gusinow, R. AU - Tami, A.* AU - Kumar-Singh, S.* AU - Malhotra-Kumar, S.* AU - Tacconelli, E.* C1 - 66291 C2 - 53128 TI - Clinical impact of monoclonal antibodies in the treatment of high-risk patients with SARS-CoV-2 breakthrough infections: The ORCHESTRA prospective cohort study. JO - Biomedicines VL - 10 IS - 9 PY - 2022 SN - 2227-9059 ER - TY - JOUR AB - Chimeric antigen receptor (CAR) T cell therapy has achieved remarkable response rates and revolutionized the treatment of patients suffering from defined hematological malignancies. However, many patients still do not respond to this therapy or relapse after an initial remission, underscoring the need for improved efficacy. Insufficient in vivo activity, persistence, trafficking, and tumor infiltration of CAR T cells, as well as antigen escape and treatment‐associated adverse events, limit the therapeutic success. Multiple strategies and approaches have been investigated to further improve CAR T cell therapy. Besides genetic modification of the CAR itself, the combination with other treatment modalities has the potential to improve this approach. In particular, combining CAR T cells with clinically approved compounds such as monoclonal antibodies and small molecule inhibitors might be a promising strategy. Combination partners could already be applied during the production process to influence the cellular composition and immunophenotype of the final CAR T cell product. Alternatively, simultaneous administration of clinically approved compounds with CAR T cells would be another feasible avenue. In this review, we will discuss current strategies to combine CAR T cells with compounds to overcome recent limitations and further enhance this promising cancer therapy, potentially broadening its application beyond hematology. AU - Stock, S.* AU - Kluever, A.K.* AU - Endres, S. AU - Kobold, S. C1 - 64201 C2 - 52104 CY - St Alban-anlage 66, Ch-4052 Basel, Switzerland TI - Enhanced chimeric antigen receptor T cell therapy through co‐application of synergistic combination partners. JO - Biomedicines VL - 10 IS - 2 PB - Mdpi PY - 2022 SN - 2227-9059 ER - TY - JOUR AB - Radiation-induced cardiovascular disease is associated with metabolic remodeling in the heart, mainly due to the inactivation of the transcription factor peroxisome proliferator-activated receptor alpha (PPARα), thereby inhibiting lipid metabolic enzymes. The objective of the present study was to investigate the potential protective effect of fenofibrate, a known agonist of PPARα on radiation-induced cardiac toxicity. To this end, we compared, for the first time, the cardiac proteome of fenofibrate- and placebo-treated mice 20 weeks after local heart irradiation (16 Gy) using label-free proteomics. The observations were further validated using immunoblotting, enzyme activity assays, and ELISA. The analysis showed that fenofibrate restored signalling pathways that were negatively affected by irradiation, including lipid metabolism, mitochondrial respiratory chain, redox response, tissue homeostasis, endothelial NO signalling and the inflammatory status. The results presented here indicate that PPARα activation by fenofibrate attenuates the cardiac proteome alterations induced by irradiation. These findings suggest a potential benefit of fenofibrate administration in the prevention of cardiovascular diseases, following radiation exposure. AU - Azimzadeh, O. AU - Subramanian, V. AU - Sievert, W.* AU - Merl-Pham, J. AU - Oleksenko, K. AU - Rosemann, M. AU - Multhoff, G.* AU - Atkinson, M.J. AU - Tapio, S. C1 - 63879 C2 - 51778 CY - St Alban-anlage 66, Ch-4052 Basel, Switzerland TI - Activation of PPARα by fenofibrate attenuates the effect of local heart high dose irradiation on the mouse cardiac proteome. JO - Biomedicines VL - 9 IS - 12 PB - Mdpi PY - 2021 SN - 2227-9059 ER - TY - JOUR AB - Fibroblast growth factor 21 (FGF21) is a regulator of addictive behavior. Increasing evidence suggests an impact of FGF21 on eating behavior, food and drug cravings and on other adipokines like insulin-like growth factor 1 (IGF-1) or adiponectin. We investigated the association of serum FGF21 and genetic variants with aspects of food and drug craving and obesity related metabolic parameters including serum adipokine levels. Standardized questionnaires, blood samples and anthropometric data of the Sorbs cohort (n = 1046) were analyzed using SPSS. For genetic analyses, the FGF21-locus ±10 kb was genotyped and analyzed using PLINK. Validation was conducted in a second independent cohort (n = 704). FGF21 was significantly associated with alcohol and coffee consumption, smoking and eating behavior (disinhibition). We confirmed correlations of FGF21 serum levels with IGF-1, adiponectin, pro-enkephalin, adipocyte fatty-acid-binding protein, chemerin and progranulin. FGF21 genetic variants were associated with anthropometric and metabolic parameters, adipokines, food and drug craving while strongest evidence was seen with low-density lipoprotein cholesterol (LDL-C). We highlight the potential role of FGF21 in food and drug cravings and provide new insights regarding the link of FGF21 with other adipokines as well as with metabolic traits, in particular those related to lipid metabolism (LDL-C). AU - Epperlein, S.* AU - Gebhardt, C. AU - Rohde-Zimmermann, K. AU - Chakaroun, R.* AU - Patt, M.* AU - Schamarek, I.* AU - Kralisch, S.* AU - Heiker, J.T. AU - Scholz, M.* AU - Stumvoll, M. AU - Kovacs, P.* AU - Breitfeld, J.* AU - Tönjes, A.* C1 - 61741 C2 - 50440 CY - St Alban-anlage 66, Ch-4052 Basel, Switzerland TI - The effect of FGF21 and its genetic variants on food and drug cravings, adipokines and metabolic traits. JO - Biomedicines VL - 9 IS - 4 PB - Mdpi PY - 2021 SN - 2227-9059 ER - TY - JOUR AB - Breast cancer is a complex tumor type involving many biological processes. Most chemotherapeutic agents exert their antitumoral effects by rapid induction of apoptosis. Another main feature of breast cancer is hypoxia, which may drive malignant progression and confer resistance to various forms of therapy. Thus, multi-aspect imaging of both tumor apoptosis and oxygenation in vivo would be of enormous value for the effective evaluation of therapy response. Herein, we demonstrate the capability of a hybrid imaging modality known as multispectral optoacoustic tomography (MSOT) to provide high-resolution, simultaneous imaging of tumor apoptosis and oxygenation, based on both the exogenous contrast of an apoptosis-targeting dye and the endogenous contrast of hemoglobin. MSOT imaging was applied on mice bearing orthotopic 4T1 breast tumors before and following treatment with doxorubicin. Apoptosis was monitored over time by imaging the distribution of xPLORE-APOFL750©, a highly sensitive poly-caspase binding apoptotic probe, within the tumors. Oxygenation was monitored by tracking the distribution of oxy- and deoxygenated hemoglobin within the same tumor areas. Doxorubicin treatment induced an increase in apoptosis-depending optoacoustic signal of xPLORE-APOFL750© at 24 h after treatment. Furthermore, our results showed spatial correspondence between xPLORE-APO750© and deoxygenated hemoglobin. In vivo apoptotic status of the tumor tissue was independently verified by ex vivo fluorescence analysis. Overall, our results provide a rationale for the use of MSOT as an effective tool for simultaneously investigating various aspects of tumor pathophysiology and potential effects of therapeutic regimes based on both endogenous and exogenous molecular contrasts. AU - Karlas, A. AU - Nunes, A. AU - Driessen, W.* AU - Liapis, E. AU - Reber, J. C1 - 63623 C2 - 51635 CY - St Alban-anlage 66, Ch-4052 Basel, Switzerland TI - Multi-aspect optoacoustic imaging of breast tumors under chemotherapy with exogenous and endogenous contrasts: Focus on apoptosis and hypoxia. JO - Biomedicines VL - 9 IS - 11 PB - Mdpi PY - 2021 SN - 2227-9059 ER - TY - JOUR AB - Increased plasma and adipose tissue protease activity is observed in patients with type 2 diabetes and obesity. It has been proposed that specific proteases contribute to the link between obesity, adipose tissue inflammation and metabolic diseases. We have recently shown that ablation of the serine protease kallikrein-related peptidase 7 (Klk7) specifically in adipose tissue preserves systemic insulin sensitivity and protects mice from obesity-related AT inflammation. Here, we investigated whether whole body Klk7 knockout (Klk7-/-) mice develop a phenotype distinct from that caused by reduced Klk7 expression in adipose tissue. Compared to littermate controls, Klk7-/- mice gain less body weight and fat mass both under chow and high fat diet (HFD) feeding, are hyper-responsive to exogenous insulin and exhibit preserved adipose tissue function due to adipocyte hyperplasia and lower inflammation. Klk7-/- mice exhibit increased adipose tissue thermogenesis, which is not related to altered thyroid function. These data strengthen our recently proposed role of Klk7 in the regulation of body weight, energy metabolism, and obesity-associated adipose tissue dysfunction. The protective effects of Klk7 deficiency in obesity are likely linked to a significant limitation of adipocyte hypertrophy. In conclusion, our data indicate potential application of specific KLK7 inhibitors to regulate KLK7 activity in the development of obesity and counteract obesity-associated inflammation and metabolic diseases. AU - Kunath, A.* AU - Weiner, J.* AU - Krause, K.* AU - Rehders, M.* AU - Pejkovska, A.* AU - Gericke, M.* AU - Biniossek, M.L.* AU - Dommel, S.* AU - Kern, M.* AU - Ribas-Latre, A. AU - Schilling, O.* AU - Brix, K.* AU - Stumvoll, M. AU - Klöting, N. AU - Heiker, J.T. AU - Blüher, M. C1 - 61312 C2 - 50147 CY - St Alban-anlage 66, Ch-4052 Basel, Switzerland TI - Role of kallikrein 7 in body weight and fat mass regulation. JO - Biomedicines VL - 9 IS - 2 PB - Mdpi PY - 2021 SN - 2227-9059 ER - TY - JOUR AB - Sedentary behavior constitutes a pandemic health threat contributing to the pathophysiology of obesity and type 2 diabetes (T2D). Sedentarism is further associated with liver disease and particularly with nonalcoholic/metabolic dysfunction associated fatty liver disease (NAFLD/MAFLD). Insulin resistance (IR) represents an early pathophysiologic key element of NAFLD/MAFLD, prediabetes and T2D. Current treatment guidelines recommend regular physical activity. There is evidence, that physical exercise has impact on a variety of molecular pathways, such as AMP-activated protein kinase and insulin signaling as well as glucose transporter 4 translocation, modulating insulin action, cellular substrate flow and in particular ectopic lipid and glycogen storage in a positive manner. Therefore, physical exercise can lead to substantial clinical benefit in persons with diabetes and/or NAFLD/MAFLD. However, experience from long term observational studies shows that the patients' motivation to exercise regularly appears to be a major limitation. Strategies to integrate everyday physical activity (i.e., nonexercise activity thermogenesis) in lifestyle treatment schedules might be a promising approach. This review aggregates evidence on the impact of regular physical activity on selected molecular mechanisms as well as clinical outcomes of patients suffering from IR and NAFLD/MAFLD. AU - Loeffelholz, C.V.* AU - Roth, J.* AU - Coldewey, S.M.* AU - Birkenfeld, A.L. C1 - 63878 C2 - 51777 CY - St Alban-anlage 66, Ch-4052 Basel, Switzerland TI - The role of physical activity in nonalcoholic and metabolic dysfunction associated fatty liver disease. JO - Biomedicines VL - 9 IS - 12 PB - Mdpi PY - 2021 SN - 2227-9059 ER - TY - JOUR AB - Glycosylphosphatidylinositol (GPI)-anchored proteins (GPI-APs), which are anchored at the surface of mammalian cultured and tissue cells through a carboxy-terminal GPI glycolipid, are susceptible to release into incubation medium and (rat and human) blood, respectively, in response to metabolic stress and ageing. Those GPI-APs with the complete GPI still attached form micelle-like complexes together with (lyso)phospholipids and cholesterol and are prone to degradation by serum GPI-specific phospholipase D (GPLD1), as well as translocation to the surface of acceptor cells in vitro. In this study, the interaction of GPI-APs with GPLD1 or other serum proteins derived from metabolically deranged rat and humans and their translocation were measured by microfluidic chip-and surface acoustic wave-based sensing of micelle-like complexes reconstituted with model GPI-APs. The effect of GPI-AP translocation on the integrity of the acceptor cell surface was studied as lactate dehydrogenase release. For both rats and humans, the dependence of serum GPLD1 activity on the hyperglycemic/hyperinsulinemic state was found to be primarily based on upregulation of the interaction of GPLD1 with micelle-like GPI-AP complexes, rather than on its amount. In addition to GPLD1, other serum proteins were found to interact with the GPI phosphoinositolglycan of full-length GPI-APs. Upon incubation of rat adipocytes with full-length GPI-APs, their translocation from the micelle-like complexes (and also with lower efficacy from reconstituted high-density lipoproteins and liposomes) to acceptor cells was observed, accompanied by upregulation of their lysis. Both GPI-AP translocation and adipocyte lysis became reduced in the presence of serum proteins, including (inhibited) GPLD1. The reduction was higher with serum from hyperglycemic/hyperinsulinemic rats and diabetic humans compared to healthy ones. These findings suggest that the deleterious effects of full-length GPI-APs following spontaneous release into the circulation of metabolically deranged rats and humans are counterbalanced by upregulated interaction of their GPI anchor with GPLD1 and other serum proteins. Thereby, translocation of GPI-APs to blood and tissue cells and their lysis are prevented. The identification of GPI-APs and serum proteins interacting within micelle-like complexes may facilitate the prediction and stratification of diseases that are associated with impaired cell-surface anchorage of GPI-APs, such as obesity and diabetes. AU - Müller, G. AU - Lechner, A. AU - Tschöp, M.H. AU - Müller, T.D. C1 - 61658 C2 - 50369 CY - St Alban-anlage 66, Ch-4052 Basel, Switzerland TI - Interaction of full-length glycosylphosphatidylinositol-anchored proteins with serum proteins and their translocation to cells in vitro depend on the (Pre-)diabetic state in rats and humans. JO - Biomedicines VL - 9 IS - 3 PB - Mdpi PY - 2021 SN - 2227-9059 ER - TY - JOUR AB - Glycosylphosphatidylinositol (GPI)-anchored proteins (GPI-APs) are anchored at the surface of mammalian blood and tissue cells through a carboxy-terminal GPI glycolipid. Eventually, they are released into incubation medium in vitro and blood in vivo and subsequently inserted into neighboring cells, potentially leading to inappropriate surface expression or lysis. To obtain first insight into the potential (patho)physiological relevance of intercellular GPI-AP transfer and its biochemical characterization, a cell-free chip-and microfluidic channel-based sensing system was introduced. For this, rat or human adipocyte or erythrocyte plasma membranes (PM) were covalently captured by the TiO2 chip surface operating as the acceptor PM. To measure transfer between PM, donor erythrocyte or adipocyte PM were injected into the channels of a flow chamber, incubated, and washed out, and the type and amount of proteins which had been transferred to acceptor PM evaluated with specific antibodies. Antibody binding was detected as phase shift of horizontal surface acoustic waves propagating over the chip surface. Time-and temperature-dependent transfer, which did not rely on fusion of donor and acceptor PM, was detected for GPI-APs, but not typical transmembrane proteins. Transfer of GPI-APs was found to be prevented by α-toxin, which binds to the glycan core of GPI anchors, and serum proteins in concentration-dependent fashion. Blockade of transfer, which was restored by synthetic phosphoinositolglycans mimicking the glycan core of GPI anchors, led to accumulation in the chip channels of full-length GPI-APs in association with phospholipids and cholesterol in non-membrane structures. Strikingly, efficacy of transfer between adipocytes and erythrocytes was determined by the metabolic state (genotype and feeding state) of the rats, which were used as source for the PM and sera, with upregulation in obese and diabetic rats and counterbalance by serum proteins. The novel chip-based sensing system for GPI-AP transfer may be useful for the prediction and stratification of metabolic diseases as well as elucidation of the putative role of intercellular transfer of cell surface proteins, such as GPI-APs, in (patho)physi-ological mechanisms. AU - Müller, G. AU - Tschöp, M.H. AU - Müller, T.D. C1 - 63357 C2 - 51488 CY - St Alban-anlage 66, Ch-4052 Basel, Switzerland TI - Chip-based sensing of the intercellular transfer of cell surface proteins: Regulation by the metabolic state. JO - Biomedicines VL - 9 IS - 10 PB - Mdpi PY - 2021 SN - 2227-9059 ER - TY - JOUR AB - Developmental genes are important regulators of fat distribution and adipose tissue (AT) function. In humans, the expression of homeobox c9 (HOXC9) is significantly higher in subcutaneous compared to omental AT and correlates with body fat mass. To gain more mechanistic insights into the role of Hoxc9in AT, we generated Fabp4-Cre-mediated Hoxc9 knockout mice (ATHoxc9(-/-)). Male and female AT Hoxc9(-/-)mice were studied together with littermate controls both under chow diet (CD) and high-fat diet (HFD) conditions. Under HFD, only male ATHoxc9(-/-)mice gained less body weight and exhibited improved glucose tolerance. In both male and female mice, body weight, as well as the parameters of glucose metabolism and AT function were not significantly different between ATHoxc9(-/-) and littermate control CD fed mice. We found that crossing Hoxc9 floxed mice with Fabp4-Cre mice did not produce a biologically relevant ablation of Hoxc9in AT. However, we hypothesized that even subtle reductions of the generally low AT Hoxc9 expression may cause the leaner and metabolically healthier phenotype of male HFD-challenged AT Hoxc9(-/-)mice. Different models of in vitro adipogenesis revealed that Hoxc9 expression precedes the expression of Fabp4, suggesting that ablation of Hoxc9 expression in AT needs to be achieved by targeting earlier stages of AT development. AU - Dommel, S.* AU - Berger, C.* AU - Kunath, A.* AU - Kern, M.* AU - Gericke, M.* AU - Kovacs, P.* AU - Guiu-Jurado, E.* AU - Klöting, N. AU - Blüher, M. C1 - 59579 C2 - 48855 CY - St Alban-anlage 66, Ch-4052 Basel, Switzerland TI - The Fabp4-Cre-model is insufficient to study Hoxc9 function in adipose tissue. JO - Biomedicines VL - 8 IS - 7 PB - Mdpi PY - 2020 SN - 2227-9059 ER - TY - JOUR AB - Type 2 diabetes (T2D) is associated with worse prognosis of prostate cancer (PCa). The molecular mechanisms behind this association are still not fully understood. The aim of this study was to identify key factors, which contribute to the more aggressive PCa phenotype in patients with concurrent T2D. Therefore, we investigated benign and PCa tissue of PCa patients with and without diabetes using real time qPCR. Compared to patients without diabetes, patients with T2D showed a decreased E‐cadherin/N‐cadherin (CDH1/CDH2) ratio in prostate tissue, indicating a switch of epithelial‐mesenchymal transition (EMT), which is a pivotal process in carcinogenesis. In addition, the gene expression levels of matrix metalloproteinases (MMPs) and CC chemokine ligands (CCLs) were higher in prostate samples of T2D patients. Next, prostate adenocarcinoma PC3 cells were treated with increasing glucose concentrations to replicate hyperglycemia in vitro. In these cells, high glucose induced expressions of MMPs and CCLs, which showed significant positive associations with the proliferation marker proliferating cell nuclear antigen (PCNA). These results indicate that in prostate tissue of men with T2D, hyperglycemia may induce EMT, increase MMP and CCL gene expressions, which in turn activate invasion and inflammatory processes accelerating the progression of PCa. AU - Frankó, A. AU - Berti, L. AU - Hennenlotter, J.* AU - Rausch, S.* AU - Scharpf, M.O.* AU - Hrabě de Angelis, M. AU - Stenzl, A.* AU - Peter, A. AU - Birkenfeld, A.L. AU - Lutz, S.Z. AU - Häring, H.-U. AU - Heni, M. C1 - 60575 C2 - 49413 CY - St Alban-anlage 66, Ch-4052 Basel, Switzerland TI - Increased expressions of matrix metalloproteinases (MMPs) in prostate cancer tissues of men with type 2 diabetes. JO - Biomedicines VL - 8 IS - 11 PB - Mdpi PY - 2020 SN - 2227-9059 ER -