Cellular senescence inhibits renal regeneration after injury in mice, with senolytic treatment promoting repair.

The ability of the kidney to regenerate successfully after injury is lost with advancing age, chronic kidney disease, and after irradiation. The factors responsible for this reduced regenerative capacity remain incompletely understood, with increasing interest in a potential role for cellular senescence in determining outcomes after injury. Here, we demonstrated correlations between senescent cell load and functional loss in human aging and chronic kidney diseases including radiation nephropathy. We dissected the causative role of senescence in the augmented fibrosis occurring after injury in aged and irradiated murine kidneys. In vitro studies on human proximal tubular epithelial cells and in vivo mouse studies demonstrated that senescent renal epithelial cells produced multiple components of the senescence-associated secretory phenotype including transforming growth factor ß1, induced fibrosis, and inhibited tubular proliferative capacity after injury. Treatment of aged and irradiated mice with the B cell lymphoma 2/w/xL inhibitor ABT-263 reduced senescent cell numbers and restored a regenerative phenotype in the kidneys with increased tubular proliferation, improved function, and reduced fibrosis after subsequent ischemia-reperfusion injury. Senescent cells are key determinants of renal regenerative capacity in mice and represent emerging treatment targets to protect aging and vulnerable kidneys in man.

Biopolymeric Coacervate Microvectors for the Delivery of Functional Proteins to Cells.

The extent to which biologic payloads can be effectively delivered to cells is a limiting factor in the development of new therapies. Limitations arise from the lack of pharmacokinetic stability of biologics in vivo. Encapsulating biologics in a protective delivery vector has the potential to improve delivery profile and enhance performance. Coacervate microdroplets are developed as cell-mimetic materials with established potential for the stabilization of biological molecules, such as proteins and nucleic acids. Here, the development of biodegradable coacervate microvectors (comprising synthetically modified amylose polymers) is presented, for the delivery of biologic payloads to cells. Amylose-based coacervate microdroplets are stable under physiological conditions (e.g., temperature and ionic strength), are noncytotoxic owing to their biopolymeric structure, spontaneously interacted with the cell membrane, and are able to deliver and release proteinaceous payloads beyond the plasma membrane. In particular, myoglobin, an oxygen storage and antioxidant protein, is successfully delivered into human mesenchymal stem cells (hMSCs) within 24 h. Furthermore, coacervate microvectors are implemented for the delivery of human bone morphogenetic protein 2 growth factor, inducing differentiation of hMSCs into osteoprogenitor cells. This study demonstrates the potential of coacervate microdroplets as delivery microvectors for biomedical research and the development of new therapies.

Elemental copper nanoparticle toxicity to anaerobic ammonium oxidation and the influence of ethylene diamine-tetra acetic acid (EDTA) on copper toxicity.

Soluble ions released by elemental copper nanoparticles (Cu0 NP) are toxic to key microorganisms of wastewater treatment processes. However, their toxicity to anaerobic ammonium oxidation (anammox) has not yet been studied. Chelating agents occurring in wastewater may decrease copper ions (Cu2+) concentration and consequently, decrease copper toxicity. This study evaluated Cu0 NP and CuCl2 toxicity to anammox and the influence of ethylene diamine-tetra acetic acid (EDTA) on copper toxicity. Bioassays were supplemented with Cu0 NP or CuCl2 with and without EDTA. Anammox activities were used to calculate inhibition constants (Ki). Results showed that Cu0 NP are toxic to anammox. Ki constants with respect to added copper were 1.8- and 2.81-fold larger (less toxic) in EDTA-containing assays for Cu0 NP and CuCl2, respectively, compared to EDTA-free assays. Additionally, Ki constants calculated in EDTA-free assays with respect the measured dissolved copper concentration were 0.023 mM Cu0 NP and 0.014 mM CuCl2. The similarity of these Ki constants indicates that Cu0 NP toxicity to anammox is caused by the release of Cu2+. Finally, severe toxicity caused by 0.315 mM and Cu0 NP 0.118 mM CuCl2 was attenuated by 88-100% when 0.14 mM EDTA was supplied. Toxicity attenuation likely occurred because EDTA complexed Cu2+ ions, thus, decreasing their bioavailability. Overall, this study indicates that Cu0 NP and CuCl2 are toxic to anammox, and furthermore, that EDTA attenuates Cu0 NP and CuCl2 toxicity to anammox by complexing Cu2+ ions.