Abstract The new ternary CM2A8 (CaMg2Al16O27) and C2M2A14 (Ca2Mg2Al28O46) pure and dense ceramics were first prepared by a hot-press sintering technique, and their physical and mechanical properties were investigated. The purity of obtained CM2A8 and C2M2A14 ceramics reaches 98.1 wt% and 97.5 wt%, respectively. Their microstructure is dense with few observable pores, and their grain size is about a few dozen microns. For their physical properties, the average apparent porosity of CM2A8 and C2M2A14 ceramics is 0.18% and 0.13%, and their average bulk density is 3.66 g/cm3 and 3.71 g/cm3, respectively. The relative density of CM2A8 ceramic is 98.12% and that of C2M2A14 ceramic is 98.67%. The thermal expansivity (50–1400 °C) of CM2A8 and C2M2A14 ceramics is 9.24×10–6 K–1 and 8.92×10–6 K–1, respectively. The thermal conductivity of CM2A8 and C2M2A14 ceramic is 21.32 W/(m·K) and 23.25 W/(m·K) at 25 °C and 18.76 W/(m·K) and 19.42 W/(m·K) as temperature rises to 350 °C, respectively. In addition, the mechanical properties are also achieved. For CM2A8 ceramic, the flexural strength is 248 MPa, the fracture toughness is 2.17 MPa·m1/2, and the Vickers hardness is 12.26 GPa. For C2M2A14 ceramic, the flexural strength is 262 MPa, the fracture toughness is 2.23 MPa·m1/2, and the Vickers hardness is 12.95 GPa.

Significance We demonstrate that Candidatus Nanohaloarchaeum antarcticus requires Halorubrum lacusprofundi for growth, illustrating that Nanohaloarchaeota require a host rather than being free living as previously proposed. Developing the means of cultivating Nanohaloarchaeota in the laboratory provides the capacity to advance understanding of how archaea interact and the factors that control their symbiotic relationship (e.g. mutualism, commensalism, antagonism). Our findings amplify the view that Antarctic lakes are a treasure trove for the discovery of microbes with previously unknown properties.

VAMP4 is a molecular rheostat that adjusts neurotransmitter release to both the activity and degradative status of neurons.

ObjectivesRecent investigations in humans and mouse models with lupus have revealed evidence of mitochondrial dysfunction and production of mitochondrial reactive oxygen species (mROS) in T cells and neutrophils. This can provoke numerous cellular changes including oxidation of nucleic acids, proteins, lipids and even induction of cell death. We have previously observed that in T cells from patients with lupus, the increased mROS is capable of provoking oligomerisation of mitochondrial antiviral stimulator (MAVS) and production of type I interferon (IFN-I). mROS in SLE neutrophils also promotes the formation of neutrophil extracellular traps (NETs), which are increased in lupus and implicated in renal damage. As a result, in addition to traditional immunosuppression, more comprehensive treatments for lupus may also include non-immune therapy, such as antioxidants.MethodsLupus-prone MRL-lpr mice were treated from weaning for 11 weeks with the mitochondria-targeted antioxidant, MitoQ (200 µM) in drinking water. Mice were then assessed for ROS production in neutrophils, NET formation, MAVS oligomerisation, serum IFN-I, autoantibody production and renal function.ResultsMitoQ-treated mice manifested reduced neutrophil ROS and NET formation, decreased MAVS oligomerisation and serum IFN-I, and reduced immune complex formation in kidneys, despite no change in serum autoantibody .ConclusionsThese findings reveal the potential utility of targeting mROS in addition to traditional immunosuppressive therapy for lupus.

Cetuximab, an epidermal growth factor receptor inhibitor (EI), is currently the only targeted molecular therapy used in combination with radiotherapy for head and neck squamous cell carcinoma (HNSCC). Gold nanoparticles (AuNPs) are expected to enhance radiotherapy effects in cancers. To investigate whether AuNPs combined with AG1478, an EI, enhanced irradiation effects on HNSCC cells, we first examined AG1478 adsorption on AuNP surfaces, using surface-enhanced Raman scattering, which indicated an adsorption equilibrium of AG1478 to AuNPs. We then used transmission electron microscopy to find internalization rates of AuNP alone and AuNP+AG1478; we found that intracellular uptake of AuNP alone and AuNP+AG1478 did not significantly differ. We compared cell numbers, proliferation, apoptosis, and migration between control cells and those treated with or without 60 nm AuNP (1.0 nM), AG1478 (0.5 μM), and irradiation (4 Gy). We found that AuNP+AG1478 inhibited proliferation more than AG1478 alone; the combination of irradiation+AuNP+AG1478 significantly reduced total cell numbers compared with the combination of irradiation+AuNP; AuNP+AG1478 increased apoptotic reaction to irradiation; the combinations of AuNP+AG1478 and irradiation+AuNP induced more apoptosis than AG1478+irradiation. Whereas AuNP+AG1478 enhanced cytotoxicity in human HNSCC cells by inhibiting proliferation, irradiation+AuNP enhanced cytotoxicity by inducing apoptosis.

Methicillin-resistant Staphylococcus aureus (MRSA) can cause a wide range of infections from mild to life-threatening conditions. Its enhanced antibiotic resistance often leads to therapeutic failures and therefore alternative eradication methods must be considered. Potential candidates to control MRSA infections are bacteriophages and their lytic enzymes, lysins. In this study, we isolated a bacteriophage against a nosocomial MRSA strain belonging to the ST45 epidemiologic group. The phage belonging to Caudovirales, Siphoviridae, showed a narrow host range and stable lytic activity without the emergence of resistant MRSA clones. Phylogenetic analysis showed that the newly isolated Staphylococcus phage R4 belongs to the Triavirus genus in Siphoviridae family. Genetic analysis of the 45 kb sequence of R4 revealed 69 ORFs. No remnants of mobile genetic elements and traces of truncated genes were observed. We have localized the lysin (N-acetylmuramoyl-L-alanine amidase) gene of the new phage that was amplified, cloned, expressed, and purified. Its activity was verified by zymogram analysis. Our findings could potentially be used to develop specific anti-MRSA bacteriophage- and phage lysin-based therapeutic strategies against major clonal lineages and serotypes.

We prepared silver nanoparticles (AgNP) embedded in SiO2 using a green polyol approach by conducting the synthesis at ambient temperature and pH. Glycerol solutions of SiO2 and silver nitrate were stirred overnight at room temperature. UV-vis spectra and TEM images of the reaction dispersion and XRD patterns of the centrifuged solid confirmed formation of AgNP (6 ± 2 nm) were embedded in SiO2. AAS showed that, about 50% of initial silver was deposited on SiO2. The presence of SiO2 enhanced the formation of AgNP and the stability of Ag/SiO2 in glycerol. The reason for these findings was probably the ultrasonic-probe dispersion of SiO2 in glycerol, which caused chemical interactions between glycerol and SiO2. Compared to bare AgNP, the AgNP/SiO2 demonstrated higher catalytic activity toward 4-nitrophenol reduction by NaBH4. The highest apparent rate constant was approximately 1.1 ∗ 10−4 s−1, comparable with Ag/SiO2 catalysts prepared using other methods. This study proposes a greener polyol method to synthesize SiO2-supported AgNP catalyst that does not require heating or regulating pH of the reaction mixture. This nanocomposite can be used in catalytic, antimicrobial, sensing, and other applications that are using AgNP/SiO2 synthesized by conventional methods.

In this study, CuO-ZnO composite was synthesized via the sol-gel method using oxalic acid to form the medium complex and its applications in antibacterial have been conducted with B. cereus, E. coli, S. aureus, Salmonella, and P. aeruginosa. Then, nanopowder of CuO-ZnO was coated on shoe insoles and their antibacterial effect with S. aureus was tested. The nanocomposite products were characterized by XRD, XPS, SEM, TEM, and UV-Vis. The results showed that the CuO-ZnO composite has the average particle size in a range of 20-50 nm, the point of zero charge of 7.8, and the bandgap of 1.7 eV. XPS result shows the composite structure with Cu2+ in the product. The minimum inhibitory concentration (MIC) of CuO-ZnO nanocomposite was 0.313 mg·mL-1 for S. aureus and Samonella, 0.625 mg·mL-1 for E. coli, and 5 mg·mL-1 for B. cereus and P. aeruginosa. The shoe insoles coated with 0.35 wt.% of CuO-ZnO nanocomposite also had high antibacterial activity against S. aureus, and this antibacterial nanocomposite was implanted durably on the surface of the shoe insoles.

In the present work, a dual-drug-loaded soy lecithin liposomal system was developed by coencapsulation of Letrozole (LET) with Paclitaxel (PTX) to improve the efficacy in breast cancer therapy. Liposomes were synthesized by the thin film layer hydration. To sufficiently evaluate the characteristics of these liposomes, the particle size, zeta potential, morphology, drug encapsulation, in vitro drug release, and cytotoxicity were ascertained. Results showed promisingly anticancer potentials, as the following parameters indicated: nanosize diameter (around 193 nm) and negative surface charge. Data collected from the coloaded drug liposomes showed suitable encapsulation efficiency (50.56% for PTX and 31.13% for LET). Controlled and sustained releases were achieved up to 72 h for both the loaded drugs following the diffusion mechanism. In addition, the in vitro cytotoxicity study on the human breast cancer cell line (MCF-7) given the dual-drug-loaded liposome showed greater inhibition of cell growth than the single drug. Consequently, LET and PTX coloaded liposomes made from soy lecithin are expected to be an ingenious drug-delivery system for combination chemotherapy.

Diabetic retinopathy (DR) is a kind of severe retinal neurodegeneration. The advanced glycation end products (AGEs) affect autophagy, and mitochondrial function is involved in DR. Adenosine-activated protein kinase (AMPK) is an important metabolic sensor that can regulate energy homeostasis in cells. However, the effect of AMPK in DR is still not fully understood. In this study, we investigated the effect of AMPK on diabetes-induced photoreceptor cell degeneration. In vivo, a diabetic mouse model was established by streptozotocin (STZ) injection. Haematoxylin-eosin (HE) staining was used to observe retinal morphology and measure the thicknesses of different layers in the retina. Electroretinogram (ERG) was used to evaluate retinal function. In vitro, 661w cells were treated with AGEs with/without an AMPK agonist (metformin) or AMPK inhibitor (compound C). Flow cytometry and CCK-8 assays were used to analyse apoptosis. Mitochondrial membrane potential was analysed by JC-1. Western blotting and qRT-PCR were used to examine the expression of related proteins and genes, respectively. The wave amplitude and the thickness of the outer nuclear layer were decreased in diabetic mice. The expression of rhodopsin and opsin was also decreased in diabetic mice. In vitro, the percentage of apoptotic cells was increased, the expression of the apoptosis-related protein Bax was increased, and Bcl-2 was decreased after AGE treatment in 661w cells. The expression of the autophagy-related protein LC3 was decreased, and p62 was increased. The mitochondrial-related gene expression and membrane potential were decreased, and mitochondrial morphology was abnormal, as observed by TEM. However, AMPK stimulation ameliorated this effect. These results indicate that AMPK stimulation can delay diabetes-induced photoreceptor degeneration by regulating autophagy and mitochondrial function.

Endometrial cancer (EC) is a common gynecological malignancy worldwide whose therapy mainly depends on chemotherapy. In past years, an increasing number of studies indicate that hollow MnO2 could serve as a nanoplatform in the drug delivery system. The Brucea javanica oil emulsion (BJOE) has been illustrated to play a vital role in cancers. However, knowledge about the combined effect of H-MnO2-PEG/BJOE in endometrial cancer remains ambiguous up to now. In the present work, we prepared a drug-delivery vector H-MnO2-PEG by chemical synthesis and found that H-MnO2-PEG significantly inhibited cell proliferation in endometrial cancer cells. Moreover, the combination of H-MnO2-PEG/BJOE could repress cell proliferation more efficiently and promote cell apoptosis. Mechanistically, we found that BJOE exerted its role as a promoter of endometrial apoptosis by regulating relative protein expressions. In general, the present study demonstrates that H-MnO2-PEG functions as a critical vector in the tumor microenvironment of endometrial cancer and the significant effect of H-MnO2-PEG/BJOE on cancer cells, suggesting a new paradigm for the treatment of endometrial cancer.

Chromolaena odorata is a medicinal herb with prominent pharmacological properties. The therapeutic efficiency of Chromolaena odorata extracts and its ingredients have, however, been limited by various factors, including the lack of targeting capacity and poor bioavailability. To approach this drawback, ethyl acetate fraction extract of Chromolaena odorata- (EA.ChO-) encapsulated pluronic-based nanocarriers was disclosed herein. The most common pluronic triblock copolymer micelles (pluronic F127) was used for the nanosized formulation of Chromolaena odorata extract. The obtained results show that EA.ChO-encapsulated nanoparticles have a spherical morphology with a designed hydrodynamic size was about 183.7 nm and zeta potential -39.5 mV. The EA.ChO nanoparticles are stable in different aqueous solutions (water, PBS 2.8, and PBS 7.4). The lyophilized form of the EA.ChO nanoparticles exhibited excellent stability for long-term storage. Notably, the EA.ChO nanoparticles were 1.3-1.4 fold more effective in the growth of fibroblast than the free EA.ChO, verifying the potential of pluronic F127 nanoparticles to the increased function of EA.ChO in the proliferation of fibroblast cell. In addition, bleeding stopped within $55\pm 6$  s which was 20 s faster than that of free EA.ChO and 38-44 s faster than that of negative control treatments. The EA.ChO nanoencapsulation processed a rapid blood clot formation compared to control, free EA.ChO, pluronic F127, and water, suggesting the excellent bioavailability of EA.ChO nanoencapsulation. The obtained results thus provided a promising prospect for raising the activity Chromolaena odorata extract in wound healing application.

In this work, silver nanoparticle- (AgNP-) embedded graphene oxide- (GO-) TiO2 nanotube (TNT) nanocomposite (labelled GAT) was successfully synthesized by gamma ray radiolysis. The influence of irradiation process, including one-step and two-step assistances and at different irradiation doses (5, 10, 15, 20, and 25 kGy), on the GAT’s physicochemical properties was achieved. Structure and properties of irradiated materials were analyzed by Fourier-transformed infrared (FT-IR), ultraviolet-visible absorption (UV-Vis), and Raman spectroscopies; X-ray diffraction (XRD); and scanning electron (SEM) and transmission electron (TEM) microscopies. In addition, selective scavengers of e-aq and ⋅OH radicals were used to investigate the radiolytic synthesis of GAT nanocomposite. It was revealed that gamma ray irradiation could strongly support the relation of the composite synthesis. Furthermore, the synthesized GAT nanocomposites showed a significant effect for Rhodamine B (RhB) photodecomposition after 60 minutes of natural sunlight exposure and evaluation by UV-Vis absorption spectroscopy. Briefly, the obtained results highlighted the potential of gamma irradiation as a “clean” and controllable way for synthesizing beneficial nanocomposite materials for wastewater purification and other environmental aspects.

An atomic implantation method was used to modify diatomite with CuCl. The CuCl/diatomite samples were characterized by different techniques, including FTIR, XRD, BET, SEM-TEM, EDX, and CO-TPR. Characterization results revealed the formation of CuCl particles of 50–60 nm highly dispersed on diatomite surface. CO adsorption measurements showed that 2CuCl/diatomite exhibits the highest CO adsorption capacity among all CuCl-modified samples with diatomite. Its CO adsorption capacity of 2.96 mmol/g at 30°C is 10 times higher than that of unmodified diatomite (0.29 mmol/g). The CO adsorption on CuCl-modified diatomites was found to fit well with the Langmuir–Freundlich model.

Abstract Background: The skin is both a target and a potential conduit for the delivery of drugs, but its cornified cell layer resists penetration by most molecules. This study investigated the potential of superparamagnetic iron oxide nanoparticles to facilitate the transdermal delivery of anti-cancer agents. Results: Chemotherapeutic cancer drugs were applied with or without nanoparticles to the skin of hairless mice, and their ability to penetrate the skin was assessed using fluorescence microscopy and tumor growth. Nanoparticles enhanced the penetration of the skin by doxorubicin and 5-fluorouracil as determined by fluorescence microscopy and growth retardation of experimental melanoma in immunocompetent, syngeneic mice. This drug enhancement did not require conjugation or encapsulation of the drugs by the nanoparticles – simple co-administration sufficed. Nanoparticles applied topically to melanomas increased the cytotoxicity and immune cell infiltration induced by co-administered 5-fluorouracil, and also reduced vascularization of the tumors independently of 5-fluorouracil. Conclusion: Correctly formulated superparamagnetic iron oxide nanoparticles can facilitate the chemotherapeutic effectiveness of cytotoxic drugs on skin tumors by both increasing their transdermal penetration and ameliorating host-tumor interactions. This enhancement of skin penetration occurs without the need for conjugation or encapsulation of the co-administered drugs and so will likely be applicable to other drugs, also.

Abstract Background: A range of neurodegenerative and related aging diseases, such as Alzheimer’s disease, Parkinson’s disease, and type 2 diabetes, are linked to toxic protein aggregation. Yet the mechanisms of protein aggregation inhibition by small molecule inhibitors remain poorly understood, in part because most protein targets of aggregation assembly are partially unfolded or intrinsically disordered, which hinders detailed structural characterization of protein-inhibitor complexes and structural-based mechanistic elucidation. Methods: Herein we employed a small molecule screening approach to identify inhibitors against three prototype amyloidogenic proteins in neurodegeneration and related proteinopathies: amylin, Ab and tau. We further systematically investigated selected class of inhibitors under aerobic and anaerobic conditions to uncover a key determinant of the inhibitory activities.Results: One remarkable class of inhibitors identified from all three parallel screenings against different amyloidogenic proteins was catechol-containing compounds and redox-related quinones/anthraquinones. Further mechanistic studies determined that the redox state of the broad class of catechol-containing compounds is a key determinant of the amyloid inhibitor activities. Conclusion: Our small molecule library screening platform was able to identify a broad class of amyloid inhibitors. Redox was found to be a key factor not only regulating the inhibitory activities but also involving the mechanism of inhibition. The molecular insights we gained not only explain why a large number of catechol-containing natural compounds, often enriched in healthy diet, have anti-neurodegeneration and anti-aging activities, but also could guide the rational design of therapeutic or nutraceutical strategies to target a broad range of neurodegenerative and related aging diseases.

Abstract Background: The aim of this work was to develop a novel and feasible modification strategy by utilizing the supramolecular effect of 2-hydroxypropyl-beta-cyclodexrin (2-HP-β-CD) for enhancing the biological transport efficiency of paclitaxel (PTX)-loaded poly(lactide-co-glycolide)(PLGA) nanoparticles.Methods: PTX-loaded 2-HP-β-CD-modified PLGA nanoparticles (2-HP-β-CD/PLGA NPs) were prepared using the modified emulsion method. Nano-characteristics, drug release behavior, in vitro cytotoxicity, cellular uptake profiles and in vivo bio-behavior of the nanoparticles were then characterized. Results: Compared with the plain PLGA NPs, 2-HP-β-CD/PLGA NPs exhibited smaller particle sizes (151.03±1.36 nm), increased entrapment efficiency (~49.12% increase) and sustained drug release. When added to A549 human lung cancer cells, compared with PLGA NPs, 2-HP-β-CD/PLGA NPs exhibited higher cytotoxicity in MTT assays and improved cellular uptake efficiency. Pharmacokinetic analysis showed that the AUC value of 2-HP-β-CD/PLGA NPs was 2.4-fold higher than commercial Taxol® and 1.7-fold higher than plain PLGA NPs. In biodistribution assays, 2-HP-β-CD/PLGA NPs exhibited excellent stability in the circulation.Conclusions: The results of this study suggest that formulation contains 2-HP-β-CD can prolong PTX release, enhance drug transpot efficiency and serve as a potential tumor targeting system for PTX.

Abstract The authors have withdrawn this preprint due to erroneous posting.

Abstract Metal-organic frameworks (MOFs) have proven to be a promising class of drug carriers due to their high porosity, crystalline properties with defined structure information, and their potential for further functionalization. However, to date, no extensive research has been conducted on MOF-based drug carriers with stimuli-responsive, dual-drug delivery, and tumor targeting functions. Here, we demonstrate the strategy of constructing a redox responsive and tumor-targeted MOF, as dual-drug carrier, by anchoring functional disulfide anhydride and folic acid (FA) molecules to the organic links of MOFs, respectively. The MOF composites show the controlled release of loaded 5-fluorouracil (5-FU) entrapped within UiO-66-NH2 nanostructures modified by dichloroacetic acid (DCA). Moreover, the MOF building block DCA acts as a synergistical drug to 5-FU in cancer cells inhibition. Through disulfide bonds, the gated MOF has redox-responsive drugs release. The confocal laser scanning microscopy further proved that conjugation of folic acid to the MOF surface can significantly enhance the targeting ability to cancer cells and the cancer cell uptake of FA-MOFs. The synthesis of redox-responsive dual-drug delivery MOF hybrids paves the way to assemble of other MOF hybrids that respond to other triggering factors such as light, temperature, pH, or biomarkers. The properties and functions of such materials are expected to influence the development of sensors, new catalysts, photonic devices, and drug delivery carriers.

In mammalian skin, ninein localizes to the centrosomes of progenitor cells and relocates to the cell cortex upon differentiation of keratinocytes, where cortical arrays of microtubules are formed. To examine the function of ninein in skin development, we use epidermis-specific and constitutive ninein-knockout mice to demonstrate that ninein is necessary for maintaining regular protein levels of the differentiation markers filaggrin and involucrin, for the formation of desmosomes, for the secretion of lamellar bodies, and for the formation of the epidermal barrier. Ninein-deficient mice are viable but develop a thinner skin with partly impaired epidermal barrier. We propose two underlying mechanisms: first, ninein contributes to spindle orientation during the division of progenitor cells, whereas its absence leads to misoriented cell divisions, altering the pool of progenitor cells. Second, ninein is required for the cortical organization of microtubules in differentiating keratinocytes, and for the cortical re-localization of microtubule-organizing proteins, and may thus affect any mechanisms that depend on localized microtubule-dependent transport.