Maintenance of proteostasis is crucial in cell survival, whereas its violation underlies numerous pathologies. 70 kDa heat shock proteins (Hsp70) are known actors of proteostasis, although their effects can vary greatly between in vivo and in vitro studies, as well as between different isoforms. Depending on the type of interaction and localization of HSP70 with other components of PQC, it can both counteract and promote the progression of pathological processes. Here, we review Hsp70 role in proteostasis with respect to these differences. The structural arrangement of the Hsp70 molecule dictates its mode of binding to target proteins (also referred to as client proteins) and to its partners, such as co-chaperones and other members of the Hsp family. Depending on certain isoform and on these partners, Hsp70 can act in two ways, directing client proteins either into refolding or degradation via ubiquitin-proteasome system or autophagy. In disease, different isoforms of Hsp70 play an essential role in the progression of pathology. We briefly summarize key findings about Hsp70 involvement into neurodegeneration, ischemic injury, diabetes mellitus, viral infections and skin diseases. Potential clinical application of Hsp70 modulators depends on both with a need for selectivity for certain isoforms and a proper extrapolation between pools of data from in vitro and in vivo studies.
Adoptive cell therapy has been revolutionized by chimeric antigen receptor (CAR)-based immunotherapy, but its applications are still mainly limited to T and natural killer (NK) cells. The FDA-approved seven CAR-T products in less than ten years, demonstrating the high capacity of this approach. However, given the limitations of CAR-T cell therapy, such as low tumor infiltration and clinical efficacy in solid tumors, there has been significant interest in recent years to engineer other immune cell types, including neutrophils, with CARs because they provide special advantages for cancer therapy, such as rapid infiltration into tumor sites, strong cytotoxic functions, and the ability to modify the tumor microenvironment (TME). However, the main barriers to the practical translation of CAR-neutrophils are their short lifespan, restricted ex vivo proliferation, and inherent resistance to genetic alterations, which calls for the availability of an infinite source for the ongoing supply of CAR-neutrophil therapy. These obstacles may be overcome by developments in induced pluripotent stem cell (iPSC) technology, which offers a consistent, renewable, and genetically changeable source of CAR-neutrophils (CAR-Neuts). The goal of this study is to present a comprehensive analysis of the state, gaps, and potential future directions of this recently developed topic.
The beneficial effects of statins for cardiovascular system were widely described in various pathologies. However, much less is known about the effects of statins in healthy organism, especially in systemic resistance arteries. We aimed to evaluate the effect of chronic administration of atorvastatin, one of the most prescribed drugs, on the arterial functioning in various organs (brain, small intestine, skeletal muscle) of mice, including the procontractile influence of NADPH oxidase derived reactive oxygen species (ROS) as well as Rho-kinase. Mature male outbred ICR(CD-1) mice were administered with atorvastatin during 4 weeks (daily dose ⁓ 7 mg/kg), control animals drank water with its solvent DMSO (0.3
