The cytotoxicity of zinc oxide nanoparticles to 3D brain organoids results from excessive intracellular zinc ions and defective autophagy.

Although the neurotoxicity of ZnO nanoparticles (NPs) has been evaluated in animal and nerve cell culture models, these models cannot accurately mimic human brains. Three-dimensional (3D) brain organoids based on human-induced pluripotent stem cells have been developed to study the human brains, but this model has rarely been used to evaluate NP neurotoxicity. We used 3D brain organoids that express cortical layer proteins to investigate the mechanisms of ZnO NP-induced neurotoxicity. Cytotoxicity caused by high levels of ZnO NPs (64 µg/mL) correlated with high intracellular Zn ion levels but not superoxide levels. Exposure to a non-cytotoxic concentration of ZnO NPs (16 µg/mL) increased the autophagy-marker proteins LC3B-II/I but decreased p62 accumulation, whereas a cytotoxic concentration of ZnO NPs (64 µg/mL) decreased LC3B-II/I proteins but did not affect p62 accumulation. Fluorescence micro-optical sectioning tomography revealed that 64 µg/mL ZnO NPs led to decreases in LC3B proteins that were more obvious at the outer layers of the organoids, which were directly exposed to the ZnO NPs. In addition to reducing LC3B proteins in the outer layers, ZnO NPs increased the number of micronuclei in the outer layers but not the inner layers (where LC3B proteins were still expressed). Adding the autophagy flux inhibitor bafilomycin A1 to ZnO NPs increased cytotoxicity and intracellular Zn ion levels, but adding the autophagy inducer rapamycin only slightly decreased cellular Zn ion levels. We conclude that high concentrations of ZnO NPs are cytotoxic to 3D brain organoids via defective autophagy and intracellular accumulation of Zn ions.

Comparison of cytotoxicity of Ag/ZnO and Ag@ZnO nanocomplexes to human umbilical vein endothelial cells in vitro.

Novel metal and metal oxide-based nanocomplexes are being developed due to their superior properties compared with nanoparticles (NPs) based on single composition. In this study, we synthesized Ag-coated ZnO (Ag/ZnO) and Ag-doped ZnO (Ag@ZnO) NPs. The cytotoxicity and mechanisms associated with the synthesized NPs were investigated to understand the influence of Ag positions on biocompatibility of the NPs. After exposure to human umbilical vein endothelial cells (HUVECs), Ag/ZnO, Ag@ZnO, and ZnO NPs all significantly induced cytotoxicity, but the cytotoxic effects of Ag/ZnO and Ag@ZnO NPs were more modest in comparison with ZnO NPs. At cytotoxic concentrations, all NPs significantly induced intracellular Zn ions, which suggested a role of excessive Zn ions on cytotoxicity of NPs. All types of NPs significantly induced the expression of endoplasmic reticulum (ER) stress genes including DNA damage-inducible transcript 3 (DDIT3), X-box binding protein 1 (XBP-1), and ER to nucleus signaling 1 (ERN1), but Ag/ZnO and Ag@ZnO NPs were less effective to induce DDIT3 and XBP-1 expression compared with ZnO NPs. Not surprisingly, only ZnO NPs significantly induced the expression of caspase 3. Combined, the results from this study showed that Ag/ZnO and Ag@ZnO NPs were less cytotoxic and less potent to induce ER stress gene expression compared with ZnO NPs, but there were no significant differences between Ag/ZnO and Ag@ZnO NPs. Our results may provide novel understanding about the biocompatibility of Ag-ZnO nanocomplexes.

In Situ Two-Step Activation Strategy Boosting Hierarchical Porous Carbon Cathode for an Aqueous Zn-Based Hybrid Energy Storage Device with High Capacity and Ultra-Long Cycling Life.

Aqueous Zn-based hybrid energy storage devices (HESDs) exhibit great potential for large-scale energy storage applications for the merits of environmental friendliness, low redox potential, and high theoretical capacity of Zn anode. However, they are still subjected to low specific capacities since adsorption-type cathodes (i.e., activated carbon, hard carbon) have limited capability to accommodate active ions. Herein, a hierarchical porous activated carbon cathode (HPAC) is prepared via an in situ two-step activation strategy, different from the typical one-step/postmortem activation of fully carbonized precursors. The strategy endows the HPAC with a high specific surface area and a large mesoporous volume, and thus provides abundant active sites and fast kinetics for accommodating active ions. Consequently, pairing the HPAC with Zn anode yields an aqueous Zn-based HESD, which delivers a high specific capacity of 231 mAh g-1 at 0.5 A g-1 and excellent rate performance with a retained capacity of 119 mAh g-1 at 20 A g-1 , the best result among previously reported lithium-free HESDs based on carbon cathodes. Further, the aqueous Zn-based HESD shows ultra-long cycling stability with a capacity retention of ≈70% after 18 000 cycles at 10 A g-1 , indicating great potential for environmentally friendly, low-cost, and high-safety energy storage applications.

Great Enhancement of Carbon Energy Storage through Narrow Pores and Hydrogen-Containing Functional Groups for Aqueous Zn-Ion Hybrid Supercapacitor.

The proton transfer mechanism on the carbon cathode surface has been considered as an effective way to boost the electrochemical performance of Zn-ion hybrid supercapacitors (SCs) with both ionic liquid and organic electrolytes. However, cheaper, potentially safer, and more environmental friendly supercapacitor can be achieved by using aqueous electrolyte. Herein, we introduce the proton transfer mechanism into a Zn-ion hybrid supercapacitor with the ZnSO4 aqueous electrolyte and functionalized activated carbon cathode materials (FACs). We reveal both experimentally and theoretically an enhanced performance by controlling the micropores structure and hydrogen-containing functional groups (-OH and -NH functions) of the activated carbon materials. The Zn-ion SCs with FACs exhibit a high capacitance of 435 F g-1 and good stability with 89% capacity retention over 10,000 cycles. Moreover, the proton transfer effect can be further enhanced by introducing extra hydrogen ions in the electrolyte with low pH value. The highest capacitance of 544 F g-1 is obtained at pH = 3. The proton transfer process tends to take place preferentially on the hydroxyl-groups based on the density functional theory (DFT) calculation. The results would help to develop carbon materials for cheaper and safer Zn-ion hybrid SCs with higher energy.

Contributions of Zn Ions to ZnO Nanoparticle Toxicity on Microcystis aeruginosa During Chronic Exposure.

In this work, we assessed the toxic effects of ZnO nanoparticles (NPs; 1, 10, and 50 mg L-1) and the corresponding dissoluble Zn ions (0.71, 8.66, and 35.59 mg L-1) on Microcystis aeruginosa. After chronic exposure (28 days), significantly higher growth inhibition was observed under ZnO NPs at 1 mg L-1 (47%) than under Zn ions at 0.71 mg L-1 (-15%). The opposite effect pattern was observed for ZnO NPs at 10 (71% vs. 80%) and 50 mg L-1 (73% vs. 95%) compared to Zn ions at the corresponding concentrations. After 7 days of exposure, ZnO NPs at 10 and 50 mg L-1 led to an increase of 83 and 53% in malondialdehyde content, as well as an increase of 106 and 61% in superoxide dismutase activity, respectively. However, Zn ions at the corresponding concentrations showed negligible impacts on the two parameters. The different results indicate that the insoluble NPs during the initial exposure mostly account for lipid peroxidation, which further lead to microalgal antioxidant response. During the subsequent exposure, the contributors of ZnO NP toxicity shift with the concentration and exposure time of ZnO NPs. In conclusion, the study presents new insights into the different contributions of insoluble NPs and dissoluble metallic ions to metallic NP toxicity.

In vitro α-glucosidase, docking and density functional theory studies on novel azide metal complexes.

Aim: The goal of this study is to synthesize new metal complexes containing N-methyl-1-(pyridin-2-yl)methanimine and azide ligands as α-glucosidase inhibitors for Type 2 diabetes. Materials & methods: The target complexes (12-16) were synthesized by reacting N-methyl-1-(pyridin-2-yl)methanimine (L1) with sodium azide in the presence of corresponding metal salts. The investigation of target protein interactions, vibrational, electronic and nonlinear optical properties for these complexes was performed by molecular docking and density functional theory studies. Results: Among these complexes, complex 13 (IC50 = 0.2802 ± 0.62 µM) containing Hg ion showed the highest α-glucosidase inhibitory property. On the other hand, significant results were detected for complexes containing Cu and Ag ions. Conclusion: Complex 13 may be an alternate anti-diabetic inhibitor according to in vitro/docking results.

[Box: see text].

Building microcracked structure fibrous cathode coated by Poly(3,4-ethylenedioxythiophene):poly(styrene sulfonate) for ultra-stable fiber-shaped aqueous zinc ions batteries.

Attributing to the advantages of intrinsic safety, high energy density, and good omnidirectional flexibility, fiber-shaped aqueous zinc ions batteries (FAZIBs), serving as energy supply devices, have multitude applications in flexible and wearable electronic devices. However, the detachment of active materials caused by bending stress generated during flexing process limits their practical application severely. To address the above issue, an effective integrated strategy employing microcracked activated cobalt hydroxide [A-Co(OH)2] cathode with protective coating of poly(3,4-ethylenedioxythiophene)poly(styrenesulfonate) (PEDOT:PSS) was proposed in this work to enhance the cyclic and bending performances of FAZIBs. The microcracked A-Co(OH)2 cathode relieves stress concentration under bending conditions, while the PEDOT:PSS coating is responsible to maintain the structural integrity and prevents the detachment of A-Co(OH)2. The FAZIBs based on a gel electrolyte achieved a high energy density (173.5 Wh·kg-1) at a power density 90 W·kg-1 and a bending durability (94.4 % capacity retention after 500 cycles) as a consequence of the synergistic effect of microcracked A-Co(OH)2 cathode and the PEDOT:PSS coating. This work will offer a new approach for devising high-performance FAZIBs and promote the development of highly flexible and stable fiber-shaped batteries.

Sodium alginate-derived porous carbon: Self-template carbonization mechanism and application in capacitive energy storage.

Sodium alginate (SA) is an environment-friendly and low-cost polysaccharide carbohydrate extracted from seaweed. As a carbon precursor, sodium alginate has the advantages of clear molecular structure, small molecular weight, and easy controls of the structure and composition of the product, but there have been few studies for the mechanism for SA carbonization. In this work, the carbon skeleton cross-linking mode, heteroatom doping and defect generation mechanism in the process of SA pyrolysis are clarified. Subsequently, based on the understanding of the carbonization mechanism of SA-derived carbon, we have prepared a stable SA-derived interconnected porous carbon by self-template method. The materials prepared by this method possess high oxygen content (17.6 at%) and high specific surface area (384.4 m2 g-1). Zn-ion hybrid capacitors (ZICs) device assembled with SA-derived porous carbon performs superior energy densities (based on cathode mass) of 78.35 and 35.56 Wh kg-1 at the power densities of 160 and 5120 W kg-1, respectively. This work deeply explained the carbonization mechanism of sodium alginate and evaluated the application prospects of SA-based carbon in ZICs comprehensively.

Zirconia-incorporated zinc oxide eugenol has improved mechanical properties and cytocompatibility with human dental pulp stem cells.

OBJECTIVE: Zinc oxide eugenol (ZOE) is widely used as a therapeutic dental restorative material. However, ZOE has poor mechanical properties and high cytotoxicity toward human dental pulp stem cells (hDPSCs) due to the release of Zn ions. In this study, zirconia-incorporated ZOE (ZZrOE) was developed to reduce the cytotoxicity and improve the mechanical properties of ZOE with sustained therapeutic effects on inflamed hDPSCs in terms of inflammatory gene expression levels compared with those of the original material. METHODS: After the setting time and mechanical properties of ZZrOE incorporating varying amounts of zirconia (0, 5, 10, and 20wt% in powder) were characterized, the surface morphology and composition of the resulting ZZrOE materials were investigated. The ions and chemicals released into the cell culture medium from ZOE and ZZrOE (3cm2/mL) were measured by inductively coupled plasma atomic emission spectroscopy and gas chromatography, respectively. After testing cytotoxicity against hDPSCs using the above extracts, the therapeutic effects on lipopolysaccharide-inflamed hDPSCs in terms of compromising the upregulation of inflammatory response-related mRNA expression were tested using real-time PCR. RESULTS: ZZrOE 20% exhibited increased compressive strength (∼45%), 3-point flexural strength (∼150%) and hardness (∼75%), as well as a similar setting time (∼90%), compared with those of ZOE. After the rough surface of ZZrOE was observed, significantly fewer released Zn ions and eugenol (∼40% of that from ZOE) were detected in ZZrOE 20%. ZZrOE showed less cytotoxicity because of the lower amount of Zn ions released from ZOE while showing sustained inhibition of inflammatory marker (e.g., interleukin 1ß, 6 and 8) mRNA levels. SIGNIFICANCE: The improved mechanical properties and cytocompatibility, as well as the sustained therapeutic effects on inflamed hDPSCs, were investigated in ZZrOE compared with those of ZOE. Therefore, ZZrOE has the potential to be used as an alternative to ZOE as a dental restorative material.

New biochemical insight of conserved water molecules at catalytic and structural Zn2+ ions in human matrix metalloproteinase-I: a study by MD-simulation.

Human matrix metalloproteinase (MMP)-1 or collagenase-1 plays a significant role in embryonic development, tissue remodeling, and is also involved in several diseases like arthritis, metastasis, etc. Molecular dynamics simulation studies on hMMP-1 X-ray structures (PDB Id. 1CGE, 1CGF, 1CGL, 1HFC, and 2TCL) suggest that the three conserved water molecules (WH/1, WI, WS) are coordinated with catalytic zinc (ZnC), and one water molecule (W) is associated at structural zinc ion (ZnS). Transition of the coordination geometry around ZnC from tetrahedral to octahedral and tetrahedral to trigonal bipyramidal at ZnS are also observed during the dynamics. Recognition of two zinc ions through water mediated bridges (ZnC - WH (W1)…W2….H183 - ZnS) and stabilization of secondary coordination zone around the metal ions indicates the possibility of ZnC…ZnS coupled catalytic mechanism in hMMP-I. This study not only reveals a functionally important role of conserved water molecules in hMMP-I but also highlights the involvement of other non catalytic residues, such as S172 and D170 in the catalytic mechanism. The results obtained in this study could be relevant for importance of conserved water mediated recognition site of the sequence residue id. 202(RWTNNFREY)210, interaction of W(tryptophan)203 to zinc bound histidine, their influence on the water molecules that are involved in bridging between ZnC and ZnS, and structure-based design of specific hMMP inhibitors. Graphical abstract Water mediated recognition of structural and catalytic zinc ions of hMMP-1 structure (MD simulatated conformation).

Growth of a Novel Nanostructured ZnO Urchin: Control of Cytotoxicity and Dissolution of the ZnO Urchin.

The applications of zinc oxide (ZnO) nanowires (NWs) in implantable wireless devices, such as diagnostic nanobiosensors and nanobiogenerators, have recently attracted enormous attention due to their unique properties. However, for these implantable nanodevices, the biocompatibility and the ability to control the behaviour of cells in contact with ZnO NWs are demanded for the success of these implantable devices, but to date, only a few contrasting results from their biocompatibility can be found. There is a need for more research about the biocompatibility of ZnO nanostructures and the adhesion and viability of cells on the surface of ZnO nanostructures. Here, we introduce synthesis of a new nature-inspired nanostructured ZnO urchin, with the dimensions of the ZnO urchin's acicula being controllable. To examine the biocompatibility and behaviour of cells in contact with the ZnO urchin, the Madin-Darby canine kidney (MDCK) epithelial cell line was chosen as an in vitro experimental model. The results of the viability assay indicated that, compared to control, the number of viable cells attached to the surface of the ZnO urchin and its surrounding area were reduced. The measurements of the Zn contents of cell media confirmed ZnO dissolution, which suggests that the ZnO dissolution in cell culture medium could lead to cytotoxicity. A purposeful reduction of ZnO cytotoxicity was achieved by surface coating of the ZnO urchin with poly(vinylidene fluorid-co-hexafluoropropylene) (PVDF-HFP), which changed the material matrix to slow the Zn ion release and consequently reduce the cytotoxicity of the ZnO urchin without reducing its functionality.

Insight towards the conserved water mediated recognition of catalytic and structural Zn(+2) ions in human Matrix Metalloproteinase-8 enzyme: A study by MD-simulation methods.

Human matrix metalloproteinase-8 (hMMP-8) plays a important role in the progression of colorectal cancer, metastasis, multiple sclerosis and rheumetoid arthritis. Extensive MD-simulation of the PDB and solvated structures of hMMP-8 has revealed the presence of few conserved water molecules around the catalytic and structural zinc (ZnC and ZnS) ions. The coordination of two conserved water molecules (W and WS) to ZnS and the H-bonding interaction of WS to S151 have indicated the plausible involvement of that metal ion in the catalytic process. Beside this the coupling of ZnC and ZnS metal ions (ZnC - W(H) (W(1))…..W(2) ….H(162) - ZnS) through two conserved hydrophilic centers (occupied by water molecules) may also provide some rational on the recognition of two zinc ions which were separated by ~13 Å in their X-ray structures. This unique recognition of both the Zn(+2) ions in the enzyme through conserved water molecules may be implemented/ exploited for the design of antiproteolytic agent using water mimic drug design protocol.