In keeping with recent developments in basic research; the importance of the Cathepsins as targets in cancer therapy have taken on increasing importance and given rise to a number of key areas of interest in the clinical setting. In keeping with driving basic research in this area in a translational direction; recent findings have given rise to a number of exciting developments in the areas of cancer diagnosis; prognosis and therapeutic development. As a fast-moving area of research; the focus of this review brings together the latest findings and highlights the translational significance of these developments.
The recent developments in Cathepsin protease research have unveiled a number of key observations which are fundamental to further our understanding of normal cellular homeostasis and disease. By far, the most interesting and promising area of Cathepsin biology stems from how these proteins are linked to the fate of living cells through the phenomenon of Lysosomal Leakage and Lysosomal Membrane Permeabilisation. While extracellular Cathepsins are generally believed to be of central importance in tumour progression, through their ability to modulate the architecture of the Extracellular Matrix, intracellular Cathepsins have been established as being of extreme significance in mediating cell death through Apoptosis. With these two juxtaposed key research areas in mind, the focus of this review highlights recent advancements in how this fastpaced area of Cathepsin research has recently evolved in the context of their mechanistic regulation in cancer research.
Heart failure (HF) is the ending of practically all cardiovascular diseases and the reason for hospitalization of 49% of patients in a cardiological hospital. Available instrumental diagnostic methods and biomarkers not always allow verification of HF, particularly in patients with preserved left ventricular ejection fraction. Prediction of chronic HF in patients with risk factors faces great difficulties. Currently, natriuretic peptides (NUP) are widely used for the diagnosis, prognosis and management of patients with HF and are included in clinical guidelines for diagnosis and treatment of HF. Following multiple studies, the understanding of NUP significance has changed. This resulted in a need for new biomarkers to improve the insight into the process of HF and to personalize the treatment by better individual phenotyping. In addition, current technologies, such as transcriptomic, proteomic and metabolomic analyses, provide identification of new biomarkers and better understanding of features of the HF pathogenesis. The aim of this study was to discuss recent reports on NUP and novel, most promising biomarkers in respect of their possible use in clinical practice.
Taken with the growing importance of cathepsin-mediated substrate proteolysis in tumor biology and progression, the focus and emphasis placed on therapeutic design and development is coming into fruition. Underpinning this approach is the invariable progression from the direction of fully characterizing cathepsin protease members and their substrate targets, towards targeting such an interaction with tangible therapeutics. The two groups of such substrates that have gained much attention over the years are the pro- and anti- apoptotic protein intermediates from the extrinsic and intrinsic signaling arms of the apoptosis pathway. As proteins that are central to determining cellular fate, some of them present themselves as very favorable candidates for therapeutic targeting. However, considering that both anti- and pro- apoptotic signaling intermediates have been reported to be downstream substrates for certain activated cathepsin proteases, therapeutic targeting approaches based on greater selectivity do need to be given greater consideration. Herein, we review the relationships shared by the cathepsin proteases and the Bcl-2 homology domain proteins, in the context of how the topical approach of adopting ‘BH3-mimetics’ can be explored further in modulating the relationship between the anti- and pro- apoptotic signaling intermediates from the intrinsic apoptosis pathway and their upstream cathepsin protease regulators. Based on this, we highlight important future considerations for improved therapeutic design.
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