Osteogenic effect of magnesium oxychloride cement modified with phytic acid and loaded with strontium ranelate.

BACKGROUND: Magnesium oxychloride cement has good mechanical properties, but poor water resistance. METHODS: Phytic acid, which can form chelate with Mg2+, was used to modify magnesium oxychloride cement, and the effects of phytic acid on the strength, in vitro degradation and biological activity of magnesium oxychloride cement were studied. Based on the preparation of phytic acid modified magnesium oxychloride cement with good water resistance and biological activity, osteoporosis treatment strontium ranelate was loaded on phytic acid- magnesium oxychloride cement, strontium ranelate/phytic acid-magnesium oxychloride cement was prepared. RESULTS: It was found that the compressive strength of 1.25 wt% phytic acid-magnesium oxychloride cement after soaking in SBF for 28 d could reach 40.5 ± 2.0 MPa, 13.33% higher than that of the control group (when phytic acid was 0 wt%), and the mass loss rate of all ages was lower than that of the control group. The water resistance of magnesium oxychloride cement was effectively improved by phytic acid. After loading with strontium ranelate, the water resistance of 1.25 wt% phytic acid-magnesium oxychloride cement was improved. Cell experiments showed that strontium ranelate could effectively promote cell proliferation and improve the expression of osteoblast-related proteins. When strontium ranelate/phytic acid-magnesium oxychloride cement samples were implanted subcutaneously in rats for 4 w, no obvious inflammatory response was observed, and the material was tightly bound to the surrounding tissues. When bone cement was implanted into rat femur for 4 w, the bone cement was gradually wrapped and absorbed by new bone tissue, which grew from the outside to the inside, indicating that the bone cement containing strontium ranelate/phytic acid-magnesium oxychloride cement had excellent bone-forming ability. CONCLUSIONS: In conclusion, the results indicated that strontium ranelate/phytic acid-magnesium oxychloride cement composite bone cement had a potential application prospect in clinical bone repair.

Correlation Between Chronotypes and Depressive Symptoms Mediated by Sleep Quality Among Chinese College Students During the COVID-19 Pandemic.

Purpose: The COVID-19 pandemic has adversely impacted the mental health of the population. The current study aimed to determine the prevalence of depressive symptoms and sleep disturbances among Chinese college students during the COVID-19 pandemic and investigate the correlations between chronotypes, sleep quality, and depressive symptoms. Participants and Methods: In the current study, 2526 college students responded anonymously to an online questionnaire survey from 26 May 2020 to 20 July 2020. The participants' chronotypes, sleep quality, and depressive symptoms were evaluated using the Chinese version of the Morning and Evening Questionnaire-5 (MEQ-5), Pittsburgh Sleep Quality Index (PSQI), and Patient Health Questionnaire-9 (PHQ-9). Sociodemographic information of the participants was also acquired. Statistical analyses were performed using Statistical Package for Social Sciences (SPSS) 19.0 software, with the mediating effect assessed by Hayes' PROCESS Macro. Results: During the COVID-19 pandemic, the prevalence of depressive symptoms and sleep disturbances among Chinese college students surveyed was 54.95% and 48.18%, respectively. From absolute evening chronotype to absolute morning chronotype, the surveyed college students' chronotypes were negatively correlated with their depressive symptoms. Moreover, the mediation analysis showed that the correlation between chronotypes and depressive symptoms was fully mediated by sleep quality. Eveningness college students with poorer sleep quality were more likely to report higher levels of depressive symptoms. Conclusion: Our findings suggest that during the COVID-19 pandemic, delayed circadian preference (ie, eveningness) may be linked to worse depressive symptoms among Chinese college students, and call for more attention to the sleep quality of Chinese college students as sleep quality fully mediated the correlation between chronotypes and depressive symptoms among them. Reasonable adjustment in bedtime/circadian preference and improvement in sleep quality may help to reduce the prevalence and severity of depressive symptoms among Chinese college students.

Strontium hydroxyapatite/magnesium oxychloride cement with high strength and high osteogenic activity for bone defect repair.

Strontium is a kind of element which can promote the increase of bone density and benefit the growth of bone tissue. This study combined strontium hydroxyapatite (Sr-HAp) with magnesium oxychloride cement (MOC) to prepare a bioactive material with good osteogenic activity and degradability. The results revealed that the incorporation of 10 wt.% Sr-HAp densified the structure of MOC, slowed down the degradation rate of hydration product phase 5 in water, and enhanced the water resistance of MOC. After soaking for 28 days, the compressive strength of Sr-HAp/MOC decreased by 53%, which was lower than that of MOC (93%) and HAp/MOC (61%) without adding Sr-HAp. During the degradation processin vitro, Sr-HAp/MOC continuously released Sr2+and the cumulative concentration of Sr2+releasedin vitroafter seven days of immersion was 1.27 ± 0.15 ppm. When Sr-HAp/MOC was soaking in simulated body fluid, Sr-HAp induced the growth and deposition of bone-like component hydroxyapatite crystals on MOC's surface, improving MOC's bioactivity. After implantation of femur defect in rats, the new bone tissue grew from outside to inside around Sr-HAp/MOC, which showed Sr-HAp/MOC had better osteogenic activity. MOC was containing 10 wt.% Sr-HAp can not only provide strong support for bone defects but also have the potential to promote bone regeneration.

NIR-excited upconversion nanoparticles used for targeted inhibition of Aß42 monomers and disassembly of Aß42 fibrils.

Much attention has been paid to oxidising amyloid-ß peptides (Aß) for inhibiting their aggregation using photosensitive materials. However, the low penetration of ultraviolet/visible light into biological tissues and low targeting properties of the materials hinder their application. Here, we constructed a novel platform for attenuating the neurotoxicity of Aß through functional upconversion nanoparticles (UCNPs@SiO2-ThS). UCNPs@SiO2-ThS can not only inhibit the aggregation of Aß42 monomers, but also disassemble Aß42 fibrils by its selective photooxidative capacity under the irradiation of near-infrared (NIR) light. Moreover, based on the enhancement of ThS fluorescence after attaching to Aß42 fibrils, only Aß42 fibrils exposed to both UCNPs@SiO2-ThS and light can be oxidized rather than other normal proteins. To further enhance Aß-target photooxygenation, we introduced the Aß-target peptide (KLVFF) on the surface. Compared to traditional chemotherapies and radiotherapies, this novel PDT strategy shows remarkably reduced side effects and improved targeting.

Chain structure and ß conformation of poly(9,9-dioctylfluorene) (PFO) with different molecular weights delivering from the solution to the film in a drop-casting process.

Over the last decade, considerable attention has been paid to the formation mechanism of the ordered ß conformation for PFO both in the solution and film to prepare high-efficiency optoelectronic devices. However, the process of solvent evaporation and aggregates transferred from the solution to the film also play key roles in forming ordered structures, which have been neglected. In this study, the influence of molecular weight on the above process was systematically studied using techniques such as SLS/DLS, UV-Vis, PL, and TEM. Five samples with different Mw ranging from 25 100 Da to 117 000 Da were obtained by the precipitation fractionation method. In dilute THF solution, the molecular chains were in α conformation without aggregates. In films, as the molecular weight increased, the content of ß conformation and ordered structure increased first and then decreased. By studying the solvent evaporation process, for the first time, we propose a possible mechanism for the transformation process of chain structure and ß conformation from the solution to the film, which involves three stages. This study reveals the transformation process of the chain structure and ß conformation of PFO from the solution to the film and its relationship with the molecular weight, which provides theoretical and practical versions for in-depth understanding and control of the formation of the ordered structure in high-efficiency films.

Aß aggregation behavior at interfaces with switchable wettability: a bioinspired perspective to understand amyloid formation.

An amphiphilic taurocholic acid (TCA) doped polypyrrole (PPy) film (PPy/TCA) was used as a dynamic mimic membrane model to explore how switchable surface wettability influences amyloid aggregation. Our results indicate that the hydrophobic surface, not the hydrophilic surface, plays important roles in Aß40 adsorption and aggregation.

Wireless near-infrared electrical stimulation of neurite outgrowth.

Herein, through using electropolymerized pyrrole (PPy) to coat near-infrared upconversion nanoparticles (UCNPs) on an indium tin oxide (ITO) electrode, the as-prepared PPy/UCNPs photoelectrode could generate an interfacial electric field, release rare earth ions and induce reactive oxygen species (ROS) in PC12 cells under NIR irradiation, which could realize wireless neurite development and outgrowth.

Chirality-Selected Chemical Modulation of Amyloid Aggregation.

Due to the composed α-helical/ß-strand structures, ß-amyloid peptide (Aß) is sensitive to chiral environments. The orientation and chirality of the Aß strand strongly influence its aggregation. Aß-formed fibrils have a cascade of chirality. Therefore, for selectively targeting amyloid aggregates, chirality preference can be one key issue. Inspired by the natural stereoselectivity and the ß-sheet structure, herein, we synthesized a series of d- and l-amino acid-modified polyoxometalate (POM) derivatives, including positively charged amino acids (d-His and l-His) and negatively charged (d-Glu and l-Glu) and hydrophobic amino acids (d-Leu, l-Leu, d-Phe, and l-Phe), to modulate Aß aggregation. Intriguingly, Phe-modified POMs showed a stronger inhibition effect than other amino acid-modified POMs, as evidenced by multiple biophysical and spectral assays, including fluorescence, circular dichroism, NMR, molecular dynamic simulations, and isothermal titration calorimetry. More importantly, d-Phe-modified POM had an 8-fold stronger inhibition effect than l-Phe-modified POM, indicating high enantioselectivity. Furthermore, in vivo studies demonstrated that the chiral POM derivatives crossed the blood-brain barrier, extended the life span of AD transgenic Caenorhabditis elegans CL2006 strain, and had low cytotoxicity, even at a high dosage.

Metal-Organic Frameworks Harness Cu Chelating and Photooxidation Against Amyloid ß Aggregation in Vivo.

Recently, photooxygenation of amyloidâ€…ß (Aß) has emerged as an effective way to inhibit Aß aggregation in Alzheimer's disease (AD) treatment. However, their further application has been highly obstructed by self-aggregation, no metal chelating ability, and poor protein-enrichment capacity. Herein, porphyrinic metal-organic frameworks (PMOFs) are utilized as a superior CuII chelating and photooxidation agent for inhibiting Aß aggregation. We selected only four classical kinds of POMFs (Zr-MOF, Al-MOF, Ni-MOF, Hf-MOF) for further investigation in our study, which are stable in physiological conditions and exhibit excellent biocompatibility. Among them, Hf-MOF was the most efficient Aß photooxidant. A possible explanation about the difference in capacity of 1 O2 generation of these four PMOFs has been provided according to the experimental results and DFT calculations. Furthermore, Hf-MOFs are modified with Aß-targeting peptide, LPFFD. This can not only enhance Hf-MOFs targeting cellular Aß to decrease Aß-induced cytotoxicity, but also improve Aß photooxidation in the complicated living environment. More intriguingly, in vivo studies indicate that the well-designed LPFFD modified Hf-MOFs can decrease Aß-induced neurotoxicity and extend the longevity of the commonly used transgenic AD model Caenorhabditis elegans CL2006. Our work may open a new avenue for using MOFs as neurotoxic-metal-chelating and photo-therapeutic agents for AD treatment.

Stereochemistry and amyloid inhibition: Asymmetric triplex metallohelices enantioselectively bind to Aß peptide.

Stereochemistry is vital for pharmaceutical development and can determine drug efficacy. Herein, 10 pairs of asymmetric triplex metallohelix enantiomers as a library were used to screen inhibitors of amyloid ß (Aß) aggregation via a fluorescent cell-based high-throughput method. Intriguingly, Λ enantiomers show a stronger inhibition effect than Δ enantiomers. In addition, the metallohelices with aromatic substituents are more effective than those without, revealing that these groups play a key role in the Aß interaction. Fluorescence stopped-flow kinetic studies indicate that binding of the Λ enantiomer to Aß is much faster than that of the Δ enantiomer. Furthermore, studies in enzyme digestion, isothermal titration calorimetry, nuclear magnetic resonance, and computational docking demonstrate that the enantiomers bind to the central hydrophobic α-helical region of Aß13-23, although with different modes for the Λ and Δ enantiomers. Finally, an in vivo study showed that these metallohelices extend the life span of the Caenorhabditis elegans CL2006 strain by attenuating Aß-induced toxicity. Our work will shed light on the design and screening of a metal complex as an amyloid inhibitor against Alzheimer's disease.

Manganese Dioxide Nanozymes as Responsive Cytoprotective Shells for Individual Living Cell Encapsulation.

A powerful individual living cell encapsulation strategy for long-term cytoprotection and manipulation is reported. It uses manganese dioxide (MnO2 ) nanozymes as intelligent shells. As expected, yeast cells can be directly coated with continuous MnO2 shells via bio-friendly Mn-based mineralization. Significantly, the durable nanozyme shells not only can enhance the cellular tolerance against severe physical stressors including dehydration and lytic enzyme, but also enable the survival of cells upon contact with high levels of toxic chemicals for prolonged periods. More importantly, these encased cells after shell removal via a facile biomolecule stimulus can fully resume growth and functions. This strategy is applicable to a broad range of living cells.

Using Multifunctional Peptide Conjugated Au Nanorods for Monitoring ß-amyloid Aggregation and Chemo-Photothermal Treatment of Alzheimer's Disease.

Development of sensitive detectors of Aß aggregates and effective inhibitors of Aß aggregation are of diagnostic importance and therapeutic implications for Alzheimer's disease (AD) treatment. Herein, a novel strategy has been presented by self-assembly of peptide conjugated Au nanorods (AuP) as multifunctional Aß fibrillization detectors and inhibitors. Our design combines the unique high NIR absorption property of AuNRs with two known Aß inhibitors, Aß15-20 and polyoxometalates (POMs). The synthesized AuP can effectively inhibit Aß aggregation and dissociate amyloid deposits with NIR irradiation both in buffer and in mice cerebrospinal fluid (CSF), and protect cells from Aß-related toxicity upon NIR irradiation. In addition, with the shape and size-dependent optical properties, the nanorods can also act as effective diagnostic probes to sensitively detect the Aß aggregates. This is the first report to integrate 3 segments, an Aß-targeting element, a reporter and inhibitors, in one drug delivery system for AD treatment.

Light-Mediated Reversible Modulation of ROS Level in Living Cells by Using an Activity-Controllable Nanozyme.

Nanozymes have shown great potential in bioapplications owing to their low cost, high stability, multiple activity, and biocompatibility. However, most of the known nanozymes are always at turn-on state, hindering their further applications. Herein, a simple and versatile method for constructing activity-controllable nanozymes is presented. To the best of our knowledge, this is the first report to utilize the light-driven isomerization of azobenzene (Azo) and host-guest interaction to reversibly photoregulating the activity of nanozyme. Gold nanoparticles as a typical catalase-mimic nanozyme are used in this design. The expanded Azo-modified mesoporous silica is employed as supported material to encapsulate and disperse Au nanoparticles, which further combines with cyclodextrin (CD). The catalytic activity of the nanozyme is blocked by CD and can be activated or inhibited reversibly by UV or visible light. The results indicated that the nanozyme can reversibly regulate reactive oxygen species (ROS) level in extracellular and intracellular environment for multiple cycles and change cell viability by simply changing the irradiated light. This is a general method and can be adapted to construct various smart nanozymes with highly spatiotemporal resolution.

Rationally Designed CeNP@MnMoS4 Core-Shell Nanoparticles for Modulating Multiple Facets of Alzheimer's Disease.

Alzheimer's disease (AD) is a complicated multifactorial syndrome. Lessons have been learned through failed clinical trials that targeting multiple key pathways of the AD pathogenesis is necessary to halt the disease progression. Here, we construct core-shell nanoparticles (CeNP@MnMoS4 ) targeting multiple key pathways of the AD pathogenesis, including elimination of toxic metal ions, decrease of oxidative stress, and promotion of neurite outgrowth. The SOD activity and copper removal capacity of CeNP@MnMoS4 -n (n represents the number of layers of MnMoS4 , n=1-5) was investigated in vitro. We found that CeNP@MnMoS4 -3 made an excellent balance between SOD activity and copper removal capacity. The effect of CeNP@MnMoS4 -3 on Cu(2+) -induced Aß aggregation was studied by gel electrophoresis, transmission electron microscope (TEM), and atomic force microscopy (AFM). Compared with MnMoS4 or CeNP alone, a synergistic effect was observed. Moreover, CeNP@MnMoS4 -3 promoted neurite outgrowth in a dose-dependent manner. Taken together, the results reported in this work show the potential of new multifunctional core-shell nanoparticles as AD therapeutics.

Ceria/POMs hybrid nanoparticles as a mimicking metallopeptidase for treatment of neurotoxicity of amyloid-ß peptide.

Protein misfolding to amyloid aggregates is the hallmark for neurodegenerative disease. While much attention has been paid to screen natural proteases that can degrade amyloid-ß peptides (Aß), it is difficult to apply them in the clinics with the intractable problem of immunogenicity in living organisms. Herein, we rationally designed an artificial nanozyme, Ceria/Polyoxometalates hybrid (CeONP@POMs) with both proteolytic and superoxide dismutase (SOD) activities. Our results indicated that CeONP@POMs could efficiently degrade Aß aggregates and reduce intracellular reactive oxygen species (ROS). More importantly, CeONP@POMD could not only promote PC12 cell proliferation and can cross blood-brain barrier (BBB), but also inhibit Aß-induced BV2 microglial cell activation which was demonstrated by immunoluorescence assay and flow cytometry measurements. In vivo studies further indicated that CeONP@POMD as nanozyme possessed good biocompatibility, evidenced by a detailed study of their biodistribution, body weight change, and in vivo toxicology. Therefore, our results pave the way for design of multifunctional artificial nanozyme for treatment of neurotoxicity of amyloid-ß peptide.

An ultrathin graphitic carbon nitride nanosheet: a novel inhibitor of metal-induced amyloid aggregation associated with Alzheimer's disease.

Herein we report that a g-C3N4 nanosheet can act as a nanochelator to inhibit Cu2+ induced Aß aggregation and disassemble the preformed Aß-Cu2+ aggregates.

Synthesis of fluorinated and nonfluorinated graphene quantum dots through a new top-down strategy for long-time cellular imaging.

Herein, a new strategy has been developed through combining a microwave-assisted technique with hydrothermal treatment to reduce graphene waste and improve production yield of graphene quantum dots (GQDs) prepared by top-down methods. By using fluorinated graphene oxide (FGO) as a raw material, fluorinated GQDs and nonfluorinated GQDs can be synthesized. Additionally, in the fluorinated GQDs, the protective shell supplied by fluorine improves the pH stability of photoluminescence and the strong electron-withdrawing group, -F, reduces the π-electron density of the aromatic structure; thus inhibiting reactivity toward singlet oxygen produced during irradiation and improving the photostability. Therefore, the as-prepared fluorinated GQDs with excellent photo- and pH stability are suitable for long-term cellular imaging.

Highly stable and reusable imprinted artificial antibody used for in situ detection and disinfection of pathogens.

Sandwich ELISA methods have been widely used for biomarker and pathogen detection because of their high specificity and sensitivity. However, the main drawbacks of this assay are the cost, the time-consuming procedure for the isolation of antibodies and their poor stability. To overcome these restrictions, we herein fabricated artificial antibodies based on imprinting technology and developed a sandwich ELISA for pathogen detection. Both the capture and detection antibodies were obtained via an in situ method, with simplicity, rapidity and low cost. The peroxidase mimics, the CeO2 nanoparticles, as signal generators were integrated with the detection antibody. The fabricated artificial antibodies exhibited not only natural antibody-like binding affinities and selectivities, but also superior stability and reusability. The detection limit was about 500 CFU mL-1, which is much lower than that of traditional ELISA methods (104 to 105 CFU mL-1). Furthermore, the capture antibody can disinfect pathogens in situ.

A fluorescent probe for detection of an intracellular prognostic indicator in early-stage cancer.

Cyclin A2 is a promising cancer prognostic indicator, but its intracellular in situ imaging is still a challenging task. This work designs an "off-on" fluorescent probe, which can fluorescently detect intracellular cyclin A2 and distinguish cancer cells. In addition, this work sheds light on the development of future protein biosensors.

NIR-responsive upconversion nanoparticles stimulate neurite outgrowth in PC12 cells.

Nerve regeneration is of diagnostic importance in neuroscience in regards to the treatment of degenerative disease. Owing to the ability to release rare-earth ions and produce ROS during upconversion process, upconversion nanoparticles are first reported for promoting neurite outgrowth. Different charged coating materials which play a critical role in cell attachment, can further lead to different effects on cell differentiation.