Development of a peptide drug restoring AMPK and adipose tissue functionality in cancer cachexia

Cancer cachexia is a severe systemic wasting disease that negatively affects quality of life and survival in patients with cancer. To date, treating cancer cachexia is still a major unmet clinical need. We recently discovered the destabilization of the AMP-activated protein kinase (AMPK) complex in adipose tissue as a key event in cachexia-related adipose tissue dysfunction and developed an adeno-associated virus (AAV)-based approach to prevent AMPK degradation and prolong cachexia-free survival. Here, we show the development and optimization of a prototypic peptide, Pen-X-ACIP, where the AMPK-stabilizing peptide ACIP is fused to the cell-penetrating peptide moiety penetratin via a propargylic glycine linker to enable late-stage functionalization using click chemistry. Pen-X-ACIP was efficiently taken up by adipocytes, inhibited lipolysis, and restored AMPK signaling. Tissue uptake assays showed a favorable uptake profile into adipose tissue upon intraperitoneal injection. Systemic delivery of Pen-X-ACIP into tumor-bearing animals prevented the progression of cancer cachexia without affecting tumor growth and preserved body weight and adipose tissue mass with no discernable side effects in other peripheral organs, thereby achieving proof of concept. As Pen-X-ACIP also exerted its anti-lipolytic activity in human adipocytes, it now provides a promising platform for further (pre)clinical development toward a novel, first-in-class approach against cancer cachexia

Mesoporous Electrodes and Polymer supported Electrolytes for Efficiency of Electrochemical Energy Storage Devices

Previous studies displayed that the supercapacitor electrodes possessing high surface area and rich surface chemistry contribute to energy densities and charge rapidly. New mesoporous films which are a combination of graphene, CNT and carbon complexes preferably in core-shell architectures introduce superior capacitive charge-storage properties. Moreover, the electrolytes also play an important role for the increase of the potential window but must be compatible with the electrode materials as well as sustaining environmental retention and being durable under exceptional conditions such as these at space. Low-Orbit satellites require energy harvesting systems and the rapid charging, peak power storage devices for their long-term self-sufficient decentral operation. This work describes the fabrication and performance of the cells made of mesoporous carbon-based electrodes which are either embedded as composites or nano-structured and polymeric solid electrolytes containing integrated salts and ionic liquids. The electrode layers are deposited by doctor-blade technique or by vacuum deposition techniques and combined with polymer based electrolytes in pouch cells. For comparison of the specific and areal capacitance values, discharge capacitance retention and charge-discharge performances, the pouch cells consisted of carbon black electrodes and ionic liquid and LiClO4 based polymer electrolytes are manufactured and tested. The electrochemical performances, energy and power densities are calculated and compared. The cyclic charge and discharge behavior are considered in terms of discharge capacitance fading. The role of specific electrolyte and the effect of mesoporous electrode materials and conducting polymers are determined and the beneficial factors are demonstrated by means of Nyquist plots

POLYMERIC IONIC ELECTROLYTES VS. LIQUID IONIC ELECTROLYTES IN THIN-FILM SUPERCAPACITORS INTEGRATED IN HIGHLY COMPLEX AEROSPACE STRUCTURES

Abstract The latest fear of energy shortage drives the research of highly efficient energy storage and applications with the lowest possible consumption. A lot of research is currently done to develop more powerful and efficient batteries. However, due to the chemical storage processes their lifetime is limited to less than 30000 cycles. In contrast, supercapacitors, as a second way of energy storage, use reversable physical processes for energy storage, allowing more than 1 million cycles. Therefore, they can be considered as maintenance-free and are ideal candidates for being integrated within composite structures. In this publication, semi-finished thin-film supercapacitors are integrated into fiber reinforced plastics composites by autoclave processing. The supercapacitors are manufactured using aluminum collectors with activated carbon. As standard ionic liquid 1-ethyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide is used on the one hand as liquid and on the other hand as part of a polymeric electrolyte. Intensive electro-mechanical characterizations of the multifunctional composites are carried out. The reduction of parasitic masses and reproducible results are aims of this screening. It can be shown that the electrical conductivity of the supercapacitor and the ionic conductivity between the electrodes play decisive roles. Furthermore, the exact processing of the polymeric electrolyte avoiding leakage into the composite is especially challenging

Diabetes-induced alterations in tissue collagen and carboxymethyllsine in rat kidneys: Association with increased collagent-degrading proteinases and amelioration by Cu(II)-slective chelation

AbstractAdvanced glycation end-products (AGEs) comprise a group of non-enzymatic post-translational modifications of proteins and are elevated in diabetic tissues. AGE-modification impairs the digestibility of collagen in vitro but little is known about its relation to collagen-degrading proteinases in vivo. Nε-carboxymethyllysine (CML) is a stable AGE that forms on lysyl side-chains in the presence of glucose, probably via a transition metal-catalysed mechanism.Here, rats with streptozotocin-induced diabetes and non-diabetic controls were treated for 8weeks with placebo or the Cu(II)-selective chelator, triethylenetetramine (TETA), commencing 8weeks after disease induction. Actions of diabetes and drug treatment were measured on collagen and collagen-degrading proteinases in kidney tissue.The digestibility and CML content of collagen, and corresponding levels of mRNAs and collagen, were related to changes in collagen-degrading-proteinases. Collagen-degrading proteinases, cathepsin L (CTSL) and matrix metalloproteinase-2 (MMP-2) were increased in diabetic rats. CTSL-levels correlated strongly and positively with increased collagen-CML levels and inversely with decreased collagen digestibility in diabetes. The collagen-rich mesangium displayed a strong increase of CTSL in diabetes. TETA treatment normalised kidney collagen content and partially normalised levels of CML and CTSL.These data provide evidence for an adaptive proteinase response in diabetic kidneys, affected by excessive collagen-CML formation and decreased collagen digestibility. The normalisation of collagen and partial normalisation of CML- and CTSL-levels by TETA treatment supports the involvement of Cu(II) in CML formation and altered collagen metabolism in diabetic kidneys. Cu(II)-chelation by TETA may represent a treatment option to rectify collagen metabolism in diabetes independent of alterations in blood glucose levels

Projekt-Abschlussbericht DLR-FB-2019-33 DLR-FuE-Projekt Peak Power Platform Programm: GigaStore

Die Aufgabenstellung des Projektes Peak Power Platform war für eine konkrete Anwendung, ne-ben Grundlagenbetrachtungen zur Technologie, einen sogenannten strukturintegrierten Energie-speicher mit einem speziellen elektrischen Energieeinspeisungs- und -rückspeisesystem zu definieren und als Demonstrator aufzubauen. Dabei soll die Technologie durch eine Weltraum-Qualifizierung und elektrochemische Charakterisierung überprüft und als System modelliert bzw. nach den folgenden Parametern bewertet werden: Optimiertes Leistung/Gewichts-Verhältnis ( Leistungsdichte ) Qualifikation des Systems (Radiation, Thermal, Vibration, Pyro-Shock, EMV) Hohe Zyklen-Festigkeit, Langzeitstabilität ( Degradation ) Integrationsfähigkeit in Satellitenstrukturen Kaskadierbarkeit in Kondensatorbänken mit hoher Zuverlässigkeit der Zellen Hybridisierbarkeit mit Standard-Batteriesystemen kurzfristig (innerhalb 3 Jahren) Erreichung eines anwendbaren Technologielevels (TRL5

Transport limits in defect-engineered LaAlO 3_{3} /SrTiO 3_{3} bilayers

The electrical properties of the metallic interface in LaAlO3/SrTiO3 (LAO/STO) bilayers are investigated with focus on the role of cationic defects in thin film STO. Systematic growth-control of the STO thin film cation stoichiometry (defect-engineering) yields a relation between cationic defects in the STO layer and electronic properties of the bilayer-interface. Hall measurements reveal a stoichiometry-effect primarily on the electron mobility. The results indicate an enhancement of scattering processes in as-grown non-stoichiometric samples indicating an increased density of defects. Furthermore, we discuss the thermodynamic processes and defect-exchange reactions at the LAO/STO-bilayer interface determined in high temperature equilibrium. By quenching defined defect states from high temperature equilibrium, we finally connect equilibrium thermodynamics with room temperature transport. The results are consistent with the defect-chemistry model suggested for LAO/STO interfaces. Moreover, they reveal an additional healing process of extended defects in thin film STO