Apoptosis as Driver of Therapy-Induced Cancer Repopulation and Acquired Cell-Resistance (CRAC): A Simple In Vitro Model of Phoenix Rising in Prostate Cancer.

Apoptotic cells stimulate compensatory proliferation through the caspase-3-cPLA-2-COX-2-PGE-2-STAT3 Phoenix Rising pathway as a healing process in normal tissues. Phoenix Rising is however usurped in cancer, potentially nullifying pro-apoptotic therapies. Cytotoxic therapies also promote cancer cell plasticity through epigenetic reprogramming, leading to epithelial-to-mesenchymal-transition (EMT), chemo-resistance and tumor progression. We explored the relationship between such scenarios, setting-up an innovative, straightforward one-pot in vitro model of therapy-induced prostate cancer repopulation. Cancer (castration-resistant PC3 and androgen-sensitive LNCaP), or normal (RWPE-1) prostate cells, are treated with etoposide and left recovering for 18 days. After a robust apoptotic phase, PC3 setup a coordinate tissue-like response, repopulating and acquiring EMT and chemo-resistance; repopulation occurs via Phoenix Rising, being dependent on high PGE-2 levels achieved through caspase-3-promoted signaling; epigenetic inhibitors interrupt Phoenix Rising after PGE-2, preventing repopulation. Instead, RWPE-1 repopulate via Phoenix Rising without reprogramming, EMT or chemo-resistance, indicating that only cancer cells require reprogramming to complete Phoenix Rising. Intriguingly, LNCaP stop Phoenix-Rising after PGE-2, failing repopulating, suggesting that the propensity to engage/complete Phoenix Rising may influence the outcome of pro-apoptotic therapies. Concluding, we established a reliable system where to study prostate cancer repopulation, showing that epigenetic reprogramming assists Phoenix Rising to promote post-therapy cancer repopulation and acquired cell-resistance (CRAC).

Tailoring the Cathode-Electrolyte Interface with Nanoparticles for Boosting the Solid Oxide Fuel Cell Performance of Chemically Stable Proton-Conducting Electrolytes.

Solid oxide fuel cells (SOFCs) represent the most efficient devices for producing electrical power from fuels. The limit in their application is due to the high operation temperature of conventional SOFC materials. Progress is made toward lower operating temperatures using alternative oxygen-ion conducting electrolytes, but problems of stability and electronic conductivity still remain. A promising alternative is the use of chemically stable proton-conducting Y-doped BaZrO3 (BZY) electrolytes, but their practical applications are limited by the BZY's relatively low performance. Herein, it is reported that deposition by impregnation of cathode nanoparticles on BZY backbones provides a powerful strategy to improve the BZY-based SOFC performance below 600 °C, allowing an outstanding power output for this chemically stable electrolyte. Moreover, it is demonstrated that keeping the nanostructure is more important than keeping the desired chemical composition. The proposed scalable processing method can make BZY a competitive electrolyte for SOFC applications.

Slow release of etoposide from dextran conjugation shifts etoposide activity from cytotoxicity to differentiation: A promising tool for dosage control in anticancer metronomic therapy.

Drug conjugation, improving drug stability, solubility and body permanence, allows achieving impressive results in tumor control. Here, we show that conjugation may provide a straightforward method to administer drugs by the emerging anticancer metronomic approach, presently consisting of low, repeated doses of cytotoxic drugs used in traditional chemotherapy, thus reducing toxicity without reducing efficiency; however, low dose maintenance in tumor sites is difficult. We show that conjugating the antitumor drug etoposide to dextran via pH-sensitive bond produces slow releasing, apoptosis-proficient conjugates rapidly internalized into acidic lysosomes; importantly, release of active etoposide requires cell internalization and acidic pH. Conjugation, without impairing etoposide-induced complete elimination of tumor cells, shifted the mode of apoptosis from cytotoxicity- to differentiation-related; interestingly, high conjugate doses acted as low doses of free etoposide, thus mimicking the effect of metronomic therapy. This indicates slow release as a promising novel strategy for stabilizing low drug levels in metronomic regimens.

Probing the bulk ionic conductivity by thin film hetero-epitaxial engineering.

Highly textured thin films with small grain boundary regions can be used as model systems to directly measure the bulk conductivity of oxygen ion conducting oxides. Ionic conducting thin films and epitaxial heterostructures are also widely used to probe the effect of strain on the oxygen ion migration in oxide materials. For the purpose of these investigations a good lattice matching between the film and the substrate is required to promote the ordered film growth. Moreover, the substrate should be a good electrical insulator at high temperature to allow a reliable electrical characterization of the deposited film. Here we report the fabrication of an epitaxial heterostructure made with a double buffer layer of BaZrO3 and SrTiO3 grown on MgO substrates that fulfills both requirements. Based on such template platform, highly ordered (001) epitaxially oriented thin films of 15% Sm-doped CeO2 and 8 mol% Y2O3 stabilized ZrO2 are grown. Bulk conductivities as well as activation energies are measured for both materials, confirming the success of the approach. The reported insulating template platform promises potential application also for the electrical characterization of other novel electrolyte materials that still need a thorough understanding of their ionic conductivity.

Steam electrolysis by solid oxide electrolysis cells (SOECs) with proton-conducting oxides.

Energy crisis and environmental problems caused by the conventional combustion of fossil fuels boost the development of renewable and sustainable energies. H2 is regarded as a clean fuel for many applications and it also serves as an energy carrier for many renewable energy sources, such as solar and wind power. Among all the technologies for H2 production, steam electrolysis by solid oxide electrolysis cells (SOECs) has attracted much attention due to its high efficiency and low environmental impact, provided that the needed electrical power is generated from renewable sources. However, the deployment of SOECs based on conventional oxygen-ion conductors is limited by several issues, such as high operating temperature, hydrogen purification from water, and electrode stability. To avoid these problems, proton-conducting oxides are proposed as electrolyte materials for SOECs. This review paper provides a broad overview of the research progresses made for proton-conducting SOECs, summarizing the past work and finding the problems for the development of proton-conducting SOECs, as well as pointing out potential development directions.

The Impressive Anti-Inflammatory Activity of Cerium Oxide Nanoparticles: More than Redox?

Cerium oxide nanoparticles (CNPs) are biocompatible nanozymes exerting multifunctional biomimetic activities, including superoxide dismutase (SOD), catalase, glutathione peroxidase, photolyase, and phosphatase. SOD- and catalase-mimesis depend on Ce3+/Ce4+ redox switch on nanoparticle surface, which allows scavenging the most noxious reactive oxygen species in a self-regenerating, energy-free manner. As oxidative stress plays pivotal roles in the pathogenesis of inflammatory disorders, CNPs have recently attracted attention as potential anti-inflammatory agents. A careful survey of the literature reveals that CNPs, alone or as constituents of implants and scaffolds, strongly contrast chronic inflammation (including neurodegenerative and autoimmune diseases, liver steatosis, gastrointestinal disorders), infections, and trauma, thereby ameliorating/restoring organ function. By general consensus, CNPs inhibit inflammation cues while boosting the pro-resolving anti-inflammatory signaling pathways. The mechanism of CNPs' anti-inflammatory effects has hardly been investigated, being rather deductively attributed to CNP-induced ROS scavenging. However, CNPs are multi-functional nanozymes that exert additional bioactivities independent from the Ce3+/Ce4+ redox switch, such as phosphatase activity, which could conceivably mediate some of the anti-inflammatory effects reported, suggesting that CNPs fight inflammation via pleiotropic actions. Since CNP anti-inflammatory activity is potentially a pharmacological breakthrough, it is important to precisely attribute the described effects to one or another of their nanozyme functions, thus achieving therapeutic credibility.

Safe-Shields: Basal and Anti-UV Protection of Human Keratinocytes by Redox-Active Cerium Oxide Nanoparticles Prevents UVB-Induced Mutagenesis.

Cerium oxide nanoparticles (nanoceria), biocompatible multifunctional nanozymes exerting unique biomimetic activities, mimic superoxide-dismutase and catalase through a self-regenerating, energy-free redox cycle driven by Ce3+/4+ valence switch. Additional redox-independent UV-filter properties render nanoceria ideal multitask solar screens, shielding from UV exposure, simultaneously protecting tissues from UV-oxidative damage. Here, we report that nanoceria favour basal proliferation of primary normal keratinocytes, and protects them from UVB-induced DNA damage, mutagenesis, and apoptosis, minimizing cell loss and accelerating recovery with flawless cells. Similar cell-protective effects were found on irradiated noncancerous, but immortalized, p53-null HaCaT keratinocytes, with the notable exception that here, nanoceria do not accelerate basal HaCaT proliferation. Notably, nanoceria protect HaCaT from oxidative stress induced by irradiated titanium dioxide nanoparticles, a major active principle of commercial UV-shielding lotions, thus neutralizing their most critical side effects. The intriguing combination of nanoceria multiple beneficial properties opens the way for smart and safer containment measures of UV-induced skin damage and carcinogenesis.

Human cardiac progenitor cell grafts as unrestricted source of supernumerary cardiac cells in healthy murine hearts.

Human heart harbors a population of resident progenitor cells that can be isolated by stem cell antigen-1 antibody and expanded in culture. These cells can differentiate into cardiomyocytes in vitro and contribute to cardiac regeneration in vivo. However, when directly injected as single cell suspension, less than 1%-5% survive and differentiate. Among the major causes of this failure are the distressing protocols used to culture in vitro and implant progenitor cells into damaged hearts. Human cardiac progenitors obtained from the auricles of patients were cultured as scaffoldless engineered tissues fabricated using temperature-responsive surfaces. In the engineered tissue, progenitor cells established proper three-dimensional intercellular relationships and were embedded in self-produced extracellular matrix preserving their phenotype and multipotency in the absence of significant apoptosis. After engineered tissues were leant on visceral pericardium, a number of cells migrated into the murine myocardium and in the vascular walls, where they integrated in the respective textures. The study demonstrates the suitability of such an approach to deliver stem cells to the myocardium. Interestingly, the successful delivery of cells in murine healthy hearts suggests that myocardium displays a continued cell cupidity that is strictly regulated by the limited release of progenitor cells by the adopted source. When an unregulated cell source is added to the system, cells are delivered to the myocardium. The exploitation of this novel concept may pave the way to the setup of new protocols in cardiac cell therapy.

Substrate stiffness affects skeletal myoblast differentiation in vitro.

To maximize the therapeutic efficacy of cardiac muscle constructs produced by stem cells and tissue engineering protocols, suitable scaffolds should be designed to recapitulate all the characteristics of native muscle and mimic the microenvironment encountered by cells in vivo. Moreover, so not to interfere with cardiac contractility, the scaffold should be deformable enough to withstand muscle contraction. Recently, it was suggested that the mechanical properties of scaffolds can interfere with stem/progenitor cell functions, and thus careful consideration is required when choosing polymers for targeted applications. In this study, cross-linked poly-ε-caprolactone membranes having similar chemical composition and controlled stiffness in a supra-physiological range were challenged with two sources of myoblasts to evaluate the suitability of substrates with different stiffness for cell adhesion, proliferation and differentiation. Furthermore, muscle-specific and non-related feeder layers were prepared on stiff surfaces to reveal the contribution of biological and mechanical cues to skeletal muscle progenitor differentiation. We demonstrated that substrate stiffness does affect myogenic differentiation, meaning that softer substrates can promote differentiation and that a muscle-specific feeder layer can improve the degree of maturation in skeletal muscle stem cells.

High proton conduction in grain-boundary-free yttrium-doped barium zirconate films grown by pulsed laser deposition.

Reducing the operating temperature in the 500-750 °C range is needed for widespread use of solid oxide fuel cells (SOFCs). Proton-conducting oxides are gaining wide interest as electrolyte materials for this aim. We report the fabrication of BaZr(0.8)Y(0.2)O(3-δ) (BZY) proton-conducting electrolyte thin films by pulsed laser deposition on different single-crystalline substrates. Highly textured, epitaxially oriented BZY films were obtained on (100)-oriented MgO substrates, showing the largest proton conductivity ever reported for BZY samples, being 0.11 S cm(-1) at 500 °C. The excellent crystalline quality of BZY films allowed for the first time the experimental measurement of the large BZY bulk conductivity above 300 °C, expected in the absence of blocking grain boundaries. The measured proton conductivity is also significantly larger than the conductivity values of oxygen-ion conductors in the same temperature range, opening new potential for the development of miniaturized SOFCs for portable power supply.

Cerium oxide nanoparticles: a promise for applications in therapy.

In the last years, increasing biological interest is emerging for nanotechnology that can improve pharmacological treatments, by using nanomaterials. In particular, cerium oxide nanoparticles, considered one of the most interesting nanomaterials for their catalytic properties, show a promise for application in therapy. Due to the presence of oxygen vacancies on its surface and autoregenerative cycle of its two oxidation states, Ce3+ and Ce4+, nanoceria can be used as an antioxidant agent. Because many disorders are associated with oxidative stress and inflammation, cerium oxide nanoparticles may be a tool for the treatment of these pathologies. In this review we analyze the opinions, sometimes conflicting, of the scientific community about nanoceria, together with its capability to protect from various damages that induce cells to death, and to reduce oxidative stress, associated with a consequent reduction of inflammation.

Lowering grain boundary resistance of BaZr(0.8)Y(0.2)O(3-δ) with LiNO3 sintering-aid improves proton conductivity for fuel cell operation.

A novel sintering additive based on LiNO(3) was used to overcome the drawbacks of poor sinterability and low grain boundary conductivity in BaZr(0.8)Y(0.2)O(3-δ) (BZY20) protonic conductors. The Li-additive totally evaporated during the sintering process at 1600 °C for 6 h, which led to highly dense BZY20 pellets (96.5% of the theoretical value). The proton conductivity values of BZY20 with Li sintering-aid were significantly larger than the values reported for BZY sintered with other metal oxides, due to the fast proton transport in the "clean" grain boundaries and grain interior. The total conductivity of BZY20-Li in wet Ar was 4.45 × 10(-3) S cm(-1) at 600 °C. Based on the improved sinterability, anode-supported fuel cells with 25 µm-thick BZY20-Li electrolyte membranes were fabricated by a co-firing technique. The peak power density obtained at 700 °C for a BZY-Ni/BZY20-Li/La(0.6)Sr(0.4)Co(0.2)Fe(0.8)O(3-δ) (LSCF)-BZY cell was 53 mW cm(-2), which is significantly larger than the values reported for fuel cells using electrolytes made of BZY sintered with the addition of ZnO and CuO, confirming the advantage of using Li as a sintering aid.

Materials challenges toward proton-conducting oxide fuel cells: a critical review.

The increasing world population and the need to improve quality of life for a large percentage of human beings are the driving forces for the search for sustainable energy production systems, alternative to fossil fuel combustion. Among the various types of alternative energy production technologies, solid oxide fuel cells (SOFCs) operating at intermediate temperatures (400-700 °C) show the advantage of possible use both for stationary and mobile energy production. To reach the goal of reducing the SOFC operating temperature, proton-conducting oxides are gaining wide interest as electrolyte materials. This critical review provides a broad overview of the most recent progresses obtained tailoring the properties of proton-conducting oxides for fuel cell applications, analyzing and comparing the different strategies proposed to match high-proton conductivity with good chemical stability (170 references).

Defect Engineering for Tuning the Photoresponse of Ceria-Based Solid Oxide Photoelectrochemical Cells.

Solid oxide photoelectrochemical cells (SOPECs) with inorganic ion-conducting electrolytes provide an alternative solution for light harvesting and conversion. Exploring potential photoelectrodes for SOPECs and understanding their operation mechanisms are crucial for continuously developing this technology. Here, ceria-based thin films were newly explored as photoelectrodes for SOPEC applications. It was found that the photoresponse of ceria-based thin films can be tuned both by Sm-doping-induced defects and by the heating temperature of SOPECs. The whole process was found to depend on the surface electrochemical redox reactions synergistically with the bulk photoelectric effect. Samarium doping level can selectively switch the open-circuit voltages polarity of SOPECs under illumination, thus shifting the potential of photoelectrodes and changing their photoresponse. The role of defect chemistry engineering in determining such a photoelectrochemical process was discussed. Transient absorption and X-ray photoemission spectroscopies, together with the state-of-the-art in operando X-ray absorption spectroscopy, allowed us to provide a compelling explanation of the experimentally observed switching behavior on the basis of the surface reactions and successive charge balance in the bulk.

Monodisperse Cu Cluster-Loaded Defective ZrO2 Nanofibers for Ambient N2 Fixation to NH3.

Electrocatalytic nitrogen reduction to ammonia has attracted increasing attention as it is more energy-saving and eco-friendly. For this endeavor, the development of high-efficiency electrocatalysts with excellent selectivity and stability is indispensable to break up the stable covalent triple bond in nitrogen. In this study, we report monodisperse Cu clusters loaded on defective ZrO2 nanofibers for nitrogen reduction under mild conditions. Such an electrocatalyst achieves an NH3 yield rate of 12.13 µg h-1 mgcat.-1 and an optimal Faradaic efficiency of 13.4% at -0.6 V versus the reversible hydrogen electrode in 0.1 M Na2SO4. Density functional theory calculations reveal that the N2 molecule was reduced to NH3 at the Cu active site with an ideal overpotential. Meanwhile, the interaction between bonding and antibonding of the Cu-N bond promotes activation of N2 and maintains a low desorption barrier.

Iron-Doped MoO3 Nanosheets for Boosting Nitrogen Fixation to Ammonia at Ambient Conditions.

Nitrogen can be electrochemically reduced to produce ammonia, which supplies an energy-saving and environmental-benign route at room temperature, but high-efficiency catalysts are sought to reduce the reaction barrier. Here, iron-doped α-MoO3 nanosheets are thus designed and proposed as potential catalysts for fixing N2 to NH3. The α-MoO3 band structure is intentionally modulated by the iron doping, which narrows the band gap of α-MoO3 and turns the semiconductor into a metal-like catalyst. Oxygen vacancies, generated by substituting Mo6+ for Fe3+ anions, are beneficial for nitrogen adsorption at the active sites. In 0.1 M Na2SO4, the Fe-doped MoO3 catalyst reached a high faradaic efficiency of 13.3% and an excellent NH3 yield rate of 28.52 µg h-1 mgcat-1 at -0.7 V versus reversible hydrogen electrode, superior to most of the other metal-based catalysts. Theoretical calculations confirmed that the N2 reduction reaction at the Fe-MoO3 surface followed the distal reaction path.

Superhard nanobuttons: constraining crystal plasticity and dealing with extrinsic effects at the nanoscale.

The compressive plastic strength of nanosized single-crystal metallic pillars is known to depend on their diameter D. Herein, the role of pillar height h is analyzed instead, and the suppression of the generalized crystal plasticity below a critical value h(CR) is observed. Novel in situ compression tests on regular pillars as well as nanobuttons, that is, pillars with h < h(CR), show that the latter are much harder, withstanding stresses >2 GPa. A statistical model that holds for both pillars and buttons is formulated. Owing to their superhard nature, the nanobuttons examined here underline with unprecedented resolution the extrinsic effects-often overlooked-that naturally arise during testing when the Saint-Venant assumption ceases to be accurate. The bias related to such effects is identified in the test data and removed when possible. Finally, continuous hardening is observed to occur under increasing stress level, in analogy to reports on nanoparticles. From a metrological standpoint the results expose some difficulties in nanoscale testing related to current methodology and technology. The implications of the analysis of extrinsic effects go beyond nanobuttons and extend to nano-/microelectromechanical system design and nanomechanics in general.

Electrode materials: a challenge for the exploitation of protonic solid oxide fuel cells.

High temperature proton conductor (HTPC) oxides are attracting extensive attention as electrolyte materials alternative to oxygen-ion conductors for use in solid oxide fuel cells (SOFCs) operating at intermediate temperatures (400-700 °C). The need to lower the operating temperature is dictated by cost reduction for SOFC pervasive use. The major stake for the deployment of this technology is the availability of electrodes able to limit polarization losses at the reduced operation temperature. This review aims to comprehensively describe the state-of-the-art anode and cathode materials that have so far been tested with HTPC oxide electrolytes, offering guidelines and possible strategies to speed up the development of protonic SOFCs.

Ionic conductivity in oxide heterostructures: the role of interfaces.

Rapidly growing attention is being directed to the investigation of ionic conductivity in oxide film heterostructures. The main reason for this interest arises from interfacial phenomena in these heterostructures and their applications. Recent results revealed that heterophase interfaces have faster ionic conduction pathways than the bulk or homophase interfaces. This finding can open attractive opportunities in the field of micro-ionic devices. The influence of the interfaces on the conduction properties of heterostructures is becoming increasingly important with the miniaturization of solid-state devices, which leads to an enhanced interface density at the expense of the bulk. This review aims to describe the main evidence of interfacial phenomena in ion-conducting film heterostructures, highlighting the fundamental and technological relevance and offering guidelines to understanding the interface conduction mechanisms in these structures.

Biofabrication of Hepatic Constructs by 3D Bioprinting of a Cell-Laden Thermogel: An Effective Tool to Assess Drug-Induced Hepatotoxic Response.

A thermoresponsive Pluronic/alginate semisynthetic hydrogel is used to bioprint 3D hepatic constructs, with the aim to investigate liver-specific metabolic activity of the 3D constructs compared to traditional 2D adherent cultures. The bioprinting method relies on a bioinert hydrogel and is characterized by high-shape fidelity, mild depositing conditions and easily controllable gelation mechanism. Furthermore, the dissolution of the sacrificial Pluronic templating agent significantly ameliorates the diffusive properties of the printed hydrogel. The present findings demonstrate high viability and liver-specific metabolic activity, as assessed by synthesis of urea, albumin, and expression levels of the detoxifying CYP1A2 enzyme of cells embedded in the 3D hydrogel system. A markedly increased sensitivity to a well-known hepatotoxic drug (acetaminophen) is observed for cells in 3D constructs compared to 2D cultures. Therefore, the 3D model developed herein may represent an in vitro alternative to animal models for investigating drug-induced hepatotoxicity.