TY - JOUR A1 - Jonas, Wenke A1 - Kluth, Oliver A1 - Helms, Anett A1 - Voss, Sarah A1 - Jahnert, Markus A1 - Gottmann, Pascal A1 - Speckmann, Thilo A1 - Knebel, Birgit A1 - Chadt, Alexandra A1 - Al-Hasani, Hadi A1 - Schürmann, Annette A1 - Vogel, Heike T1 - Identification of novel genes involved in hyperglycemia in mice JF - International journal of molecular sciences N2 - Current attempts to prevent and manage type 2 diabetes have been moderately effective, and a better understanding of the molecular roots of this complex disease is important to develop more successful and precise treatment options. Recently, we initiated the collective diabetes cross, where four mouse inbred strains differing in their diabetes susceptibility were crossed with the obese and diabetes-prone NZO strain and identified the quantitative trait loci (QTL) Nidd13/NZO, a genomic region on chromosome 13 that correlates with hyperglycemia in NZO allele carriers compared to B6 controls. Subsequent analysis of the critical region, harboring 644 genes, included expression studies in pancreatic islets of congenic Nidd13/NZO mice, integration of single-cell data from parental NZO and B6 islets as well as haplotype analysis. Finally, of the five genes (Acot12, S100z, Ankrd55, Rnf180, and Iqgap2) within the polymorphic haplotype block that are differently expressed in islets of B6 compared to NZO mice, we identified the calcium-binding protein S100z gene to affect islet cell proliferation as well as apoptosis when overexpressed in MINE cells. In summary, we define S100z as the most striking gene to be causal for the diabetes QTL Nidd13/NZO by affecting beta-cell proliferation and apoptosis. Thus, S100z is an entirely novel diabetes gene regulating islet cell function. KW - beta-cell KW - diabetes KW - proliferation KW - apoptosis KW - QTL Y1 - 2022 U6 - https://doi.org/10.3390/ijms23063205 SN - 1661-6596 SN - 1422-0067 VL - 23 IS - 6 PB - MDPI CY - Basel ER - TY - JOUR A1 - Delfan, Maryam A1 - Juybari, Raheleh Amadeh A1 - Gorgani-Firuzjaee, Sattar A1 - Nielsen, Jens Høiriis A1 - Delfan, Neda A1 - Laher, Ismail A1 - Saeidi, Ayoub A1 - Granacher, Urs A1 - Zouhal, Hassane T1 - High-Intensity Interval Training Improves Cardiac Function by miR-206 Dependent HSP60 Induction in Diabetic Rats JF - Frontiers in Cardiovascular Medicine N2 - Objective: A role for microRNAs is implicated in several biological and pathological processes. We investigated the effects of high-intensity interval training (HIIT) and moderate-intensity continuous training (MICT) on molecular markers of diabetic cardiomyopathy in rats. Methods: Eighteen male Wistar rats (260 ± 10 g; aged 8 weeks) with streptozotocin (STZ)-induced type 1 diabetes mellitus (55 mg/kg, IP) were randomly allocated to three groups: control, MICT, and HIIT. The two different training protocols were performed 5 days each week for 5 weeks. Cardiac performance (end-systolic and end-diastolic dimensions, ejection fraction), the expression of miR-206, HSP60, and markers of apoptosis (cleaved PARP and cytochrome C) were determined at the end of the exercise interventions. Results: Both exercise interventions (HIIT and MICT) decreased blood glucose levels and improved cardiac performance, with greater changes in the HIIT group (p < 0.001, η2: 0.909). While the expressions of miR-206 and apoptotic markers decreased in both training protocols (p < 0.001, η2: 0.967), HIIT caused greater reductions in apoptotic markers and produced a 20% greater reduction in miR-206 compared with the MICT protocol (p < 0.001). Furthermore, both training protocols enhanced the expression of HSP60 (p < 0.001, η2: 0.976), with a nearly 50% greater increase in the HIIT group compared with MICT. Conclusions: Our results indicate that both exercise protocols, HIIT and MICT, have the potential to reduce diabetic cardiomyopathy by modifying the expression of miR-206 and its downstream targets of apoptosis. It seems however that HIIT is even more effective than MICT to modulate these molecular markers. KW - diabetes KW - apoptosis KW - miRNAs KW - exercise KW - cardiomyopathy Y1 - 2022 U6 - https://doi.org/10.3389/fcvm.2022.927956 SN - 2297-055X VL - 9 SP - 1 EP - 11 PB - Frontiers CY - Lausanne, Schweiz ER - TY - JOUR A1 - Zhivkova, Veselina A1 - Kiecker, Felix A1 - Langer, Peter A1 - Eberle, Jürgen T1 - Crucial role of reactive oxygen species (ROS) for the proapoptotic effects of indirubin derivative DKP-073 in melanoma cells JF - Molecular carcinogenesis N2 - Melanoma represents a prime example demonstrating the success of targeted therapy in cancer. Nevertheless, it remained a deadly disease until now, and the identification of new, independent strategies as well as the understanding of their molecular mechanisms may help to finally overcome the high mortality. Both indirubins and TNF-related apoptosis-inducing ligand (TRAIL) represent promising candidates. Here, the indirubin derivative DKP-073 is shown to trigger apoptosis in melanoma cells, which is enhanced by the combination with TRAIL and is accompanied by complete loss of cell viability. Addressing the signaling cascade, characteristic molecular steps were identified as caspase-3 activation, downregulation of XIAP, upregulation of p53 and TRAIL receptor 2, loss of mitochondrial membrane potential, and STAT-3 dephosphorylation. The decisive step, however, turned out to be the early production of ROS already at 1 h. This was proven by antioxidant pretreatment, which completely abolished apoptosis induction and loss of cell viability as well as abrogated all signaling effects listed above. Thus, ROS appeared as upstream of all proapoptotic signaling. The data indicate a dominant role of ROS in apoptosis regulation, and the new pathway may expose a possible Achilles heel of melanoma. KW - apoptosis KW - kinase pathway KW - melanoma KW - stat 3 Y1 - 2018 U6 - https://doi.org/10.1002/mc.22924 SN - 0899-1987 SN - 1098-2744 VL - 58 IS - 2 SP - 258 EP - 269 PB - Wiley CY - Hoboken ER -