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Effectively activating macrophages that can engulf cancer cells is a promising immunotherapeutic strategy but remains a major challenge due to the expression of "self" signals (e.g., CD47 molecules) by tumor cells to prevent phagocytosis. Herein, we explored a siRNA-assisted assembly strategy for the simultaneous delivery of siRNA and mitoxantrone hydrochloride (MTO·2HCl) via PLGA-based nanoparticles. The siRNA suppressed a "self" signal by silencing the CD47 gene, while the MTO induced surface exposure of calreticulin (CRT) to provide an "eat-me" signal. The siRNA-assisted assembly strategy synergistically increased the phagocytosis of tumor cells by macrophages, promoted effective antigen presentation, and initiated T cell-mediated immune responses in two aggressive tumor animal models of melanoma and colon cancer, eventually achieving significantly improved antitumor activity. This study provides a straightforward codelivery strategy to simultaneously suppress "self" and upregulate "eat-me" signals to potentiate macrophage-mediated immunotherapy.

Trauma hemorrhage (TH) and subsequent sepsis are well known to frequently result in severe organ damage. Although macrophage-activating lipopeptide-2 (MALP-2) has been described to exert beneficial effects on organ damage, and further clinical course after both isolated trauma and sepsis, little is known about the impact of MALP-2 in a clinically realistic two-hit scenario of TH and subsequent sepsis. As the liver represents a key organ for the posttraumatic immune response and development of complications, the effects of MALP-2 on the posttraumatic hepatic immunologic response and tissue damage were investigated in a murine “two-hit” model. In C57BL/6 mice, blood pressure-controlled (35 ± 5 mm Hg) TH was induced. Cecal ligation and puncture (CLP) was performed 48 h after TH. Mice were divided into two control groups (control 1, TH and laparotomy without CLP; control 2, TH and CLP) and three experimental groups (TH + CLP) treated with MALP-2 at different timepoints (ETH, end of TH; ECLP, end of CLP; 6CLP, 6 h after CLP). The observation time lasted for 168 h after induction of TH. Kupffer cells (KC) were isolated and cultured, and MPO activity was analyzed. Cell culture supernatants were taken for cytokine analysis (TNF-α, IL-6, MCP-1, GM-CSF, IL-10). Histological analysis was performed using the Hepatic Injury Severity Scoring (HISS). Statistical evaluation was carried out using SPSS (version 24.0.0; IBM, Armonk, NY, USA). MPO activity of control 1 group was lowest compared with all the other groups (p

Pulmonary complications after severe trauma and sepsis remain to be the main cause for adverse outcome. MALP-2 has been described to exert beneficial effects on organ damage and the further course after isolated trauma and sepsis. However, the impact of MALP-2 on a clinically realistic two-hit scenario of trauma and subsequent sepsis remains unknown. We, therefore, investigated if the systemic inflammatory response and pulmonary immune response and damage are beneficially modulated by MALP-2 in a murine two-hit model. Blood pressure-controlled trauma-hemorrhage (TH) and cecal ligation and puncture (CLP) were induced in C57/BL6 mice. Mice were divided into 2 control groups (control 1: TH without CLP; control 2: TH and CLP) and 3 experimental groups treated with MALP-2 at different time points (ETH, end of TH; ECLP, end of CLP; and 6CLP 6 h after CLP). Survival rates were assessed over the observation period of 168 h after the induction of TH. Concentrations of plasma inflammatory cytokines and chemokines (TNF-α, IL-6, MIP-1α, IFN-γ, and IL-10) were assessed, and bacterial clearance of the lungs was determined. Furthermore, pulmonary MPO activity assay to evaluate the infiltration of polymorphonuclear neutrophils (PMN) and histological evaluation were performed. Survival rates were evaluated. Compared with control group 1, the level of TNF-α in the ECLP group showed a significant increase (ECLP, 2.27 pg./ml ± 1.39 vs. control 1: 0.16 pg./ml ± 0.11, p = 0.021). In contrast, levels of IFN-γ were significantly reduced in groups ETH and 6CLP compared with control group 1 (control 1: 8.92 pg./ml ± 4.38 vs. ETH: 1.77 pg./ml ± 4.34, p = 0.026 resp. vs. 6CLP: 1.83 pg./ml ± 4.49, p = 0.014). While systemic concentrations of inflammatory mediators were not affected by MALP-2 treatment, the lung tissue presented with significant alterations. Reduced MPO activity was lowest in group ECLP (ECLP 11,196.77 ± 547.81 vs. ETH 12,773.94 ± 1011.76; p = 0.023 resp. vs. 6CLP 13,155.19 ± 423.99, p = 0.016) in experimental groups. Also, histological damage after MALP-2 application was lowest in ECLP animals (ECLP 0.50 ± 0.08 vs. ETH 0.71 ± 0.05, p = 0.034 resp. vs. 6CLP 0.64 ± 0.08, p = 0.021). Furthermore, MALP-2 treatment was associated with a trend towards improved survival in the ECLP group (ECLP 83.3% vs. ETH 66.7 and 6CLP 58.3%, p > 0.05). Based on our results, MALP-2 might have beneficial effects on the clinical course after hemorrhage and sepsis by reducing pulmonary damage and PMN infiltration. This might also affect survival. According to our data, MALP-2 should be given at the earliest possible time point after the onset of sepsis. However, the optimal dosage and confirmation of our results in larger cohorts need to be the focus of further research.

To investigate the beneficial effects of oridonin, a diterpenoid compound isolated from Rabdosia rubescens, on the inflammatory response in TNBS-induced post-inflammatory irritable bowel syndrome (PI-IBS) model and the underlying mechanism. Using the PI-IBS rat model and Caco-2 cell lines, we found that intestinal barrier function reflected by lactulose/mannitol (L/M) ratio and tight junction protein level was significantly ameliorated by oridonin. We also demonstrated that oridonin abrogated inflammation through inhibiting the phosphorylation of NF-κBp65 as well as its downstream gene (iNOS, COX-2, IL-1β, and IL-6) level. Molecular docking studies confirmed the good binding activity between oridonin and PXR. In Caco-2 cell lines, oridonin markedly inhibited LPS-induced NF-κB activation in a PXR-dependent manner. Meanwhile, PXR and its target genes CYP3A4 and P-gp were induced by oridonin, which was associated with the decreased expression of NF-κB and the recovery of intestinal barrier. This study indicated that the therapeutic effect of oridonin on experimental PI-IBS through repairing intestinal barrier function may be closely associated with the regulatory role of PXR/NF-κB signaling pathway. Oridonin may serve as a PXR ligand for the development of drugs in the therapy for PI-IBS.

Inflammation 43(5), 1611-1619 (2020). doi:10.1007/s10753-020-01236-7, Published by Springer Science + Business Media B.V., New York, NY [u.a.]

Resistance development to one chemotherapeutic reagent leads frequently to acquired tolerance to other compounds, limiting the therapeutic options for cancer treatment. Herein, we find that overexpression of Rac1 is associated with multi-drug resistance to the neoadjuvant chemotherapy (NAC). Mechanistically, Rac1 activates aldolase A and ERK signaling which up-regulates glycolysis and especially the non-oxidative pentose phosphate pathway (PPP). This leads to increased nucleotides metabolism which protects breast cancer cells from chemotherapeutic-induced DNA damage. To translate this finding, we develop endosomal pH-responsive nanoparticles (NPs) which deliver Rac1-targeting siRNA together with cisplatin and effectively reverses NAC-chemoresistance in PDXs from NAC-resistant breast cancer patients. Altogether, our findings demonstrate that targeting Rac1 is a potential strategy to overcome acquired chemoresistance in breast cancer., Acquired resistance to chemotherapy can lead to multi-drug resistance and poor prognosis in cancer. Here, the authors show that Rac1 increases glycolysis and non-oxidative pentose phosphate pathway activity leading to neoadjuvant chemotherapy (NAC) resistance, thus its inhibition sensitizes resistant breast cancer PDXs to NAC.

Structural morphology is the key parameter for efficacy of nanomedicine. To date, lipid-based nanomaterial has been the most widely used material in nanomedicine and many other biomedical applications. However, to the best of our knowledge, there has not been an in-depth or systematic investigation of the structure-function relationship of lipid-based nanostructures. In this report, we investigated the formulation of novel lipid-based nanostructures via simple tuning of lipid combinations. To prove this concept, we used a combination of various ratios of simple and common phospholipids with different chain lengths (14-carbon chain DMPC: 6-carbon chain DHPC) to find out whether a myriad of novel lipid nanostructures could be obtained. Interestingly, many combinations resulted in distinct lipid nanostructures. Drug encapsulation tests confirmed that they are able to load large amounts of drugs for biological application. In vivo anti-tumor efficacy revealed that certain lipid nanostructures possessed superior tumor retardation effects.

S100A12, an EF-hand calcium-binding protein, can be secreted by a variety of cell types and plays proinflammatory roles in a number of pathological conditions. Although S100A12 has been shown to interact with heparan sulfate (HS), the molecular detail of the interaction remains unclear. Here we investigate the structural basis of S100A12–HS interaction and how the interaction is regulated by the availability of divalent cations and the oligomeric states of S100A12. We discovered that S100A12–HS interaction requires calcium, while zinc can further enhance binding by inducing S100A12 hexamerization. In contrast, the apo form and zinc-induced tetramer form were unable to bind HS. Guided by the crystal structures of S100A12, we have identified the HS-binding site of S100A12 by site-directed mutagenesis. Characterization of the HS-binding site of S100A12 allowed us to convert the non-HS-binding apo and tetramer forms of S100A12 into a high affinity HS-binding variant by engineering a single-point mutation. Using a HS oligosaccharide microarray, we demonstrated that the N43K mutant displayed markedly enhanced selectivity toward longer HS oligosaccharides compared to the WT S100A12, likely due to the expanded dimension of the reengineered HS-binding site in the mutant. This unexpected finding strongly suggests that HS-binding sites of proteins might be amenable for engineering.

In this work, polymer chains of different molecular weights are grafted onto a zero-dimensional filler. The effects of molecular weight and filler size on the confined crystallization of grafted polymer systems are systematically studied using Monte Carlo simulations. It is found that when the molecular weight is higher, the restriction effect is weaker. The crystallization ability and the ultimate crystallinity are enhanced. The simulation results also found that as the chain length increases, the average segment density of the interface region increases and the mobility of the molecular chain is enhanced. This leads to the increase of supercooling and the decrease of critical nucleation free energy barrier. During isothermal crystallization kinetics processes, the nucleation mode is homogeneous nucleation. The effects of the filler size of grafted polymer systems were also investigated. When the number of segments was fixed, the crystallization ability can be improved by reducing the filler size. However, when the distribution of grafting points is the same, the crystallization ability becomes stronger with the increase of filler size. The simulations reproduce the experimental results and vividly present the evolution process of microstructures, which cannot be observed experimentally at present. These findings are helpful in understanding the microscopic mechanism of crystallization behavior of polymer composites and the corresponding reinforcement mechanism.

Heparan sulfate (HS) is a sulfated polysaccharide presenting on the animal cell surface and in the extracellular matrix that plays a critical role in a range of different biological processes. The receptor for advanced glycation end-products (RAGE), as a major receptor linked to numerous diseases, can interact with HS to activate signaling of RAGE ligands in the disease process. We herein report a concise chemoenzymatic approach for the synthesis of HS-mimetic glycopolymers as RAGE antagonists. Glycopolymer with GlcA units was chemically synthesized and subsequently modified by enzymatic elongation and chemical sulfation. Six HS-mimetic glycopolymers with pendant sulfated di-, tri-, or tetrasaccharides were successfully prepared for evaluation of their interaction with RAGE. Upon evaluation, the HS-mimetic glycopolymer decorated with overall sulfated trisaccharides was determined to have the highest binding affinity with RAGE. These findings would promote the further exploration of HS-RAGE interactions and the development of RAGE antagonists.

AIM: To preliminarily test proteomics in aqueous humor in patients with dry age-related macular degeneration (AMD) by using the proteomic technology. METHODS: Aqueous humor samples were collected from patients with or without dry AMD, who underwent cataract surgery. The aqueous samples were analyzed with isobaric tags for relative and absolute quantification (iTRAQ) combined with liquid chromatography tandem mass spectrometry (LC-MS/MS) technology. The differential expressed proteins were analyzed with gene ontology (GO) enrichment, Kyoto Encyclopedia of Genes and Genomes (KEGG) and protein-protein interaction (PPI) network analysis. The data were partly validated by ELISA and Western blot. False discovery rate (FDR) was used for statistical analysis. RESULTS: A total of 244 proteins were detected, in which 38 proteins were up-regulated and 51 were down-regulated significantly in patients with dry AMD compared with that in control groups (FDR value

Selective amplification of reactive oxygen species (ROS) generation in tumor cells has been recognized as an effective strategy for cancer therapy. However, an abnormal tumor metabolism, especially the mitochondrial glutaminolysis, could promote tumor cells to generate high levels of antioxidants (e.g., glutathione) to evade ROS-induced damage. Here, we developed a tumor-targeted nanoparticle (NP) platform for effective breast cancer therapy via combining inhibition of mitochondrial glutaminolysis and chemodynamic therapy (CDT). This NP platform is composed of bovine serum albumin (BSA), ferrocene, and purpurin. After surface decoration with a tumor-targeting aptamer and then intravenous administration, this NP platform could target tumor cells and release ferrocene to catalyze hydrogen peroxide (H2O2) into the hydroxyl radical (·OH) for CDT. More importantly, purpurin could inhibit mitochondrial glutaminolysis to concurrently prevent the nutrient supply for tumor cells and disrupt intracellular redox homeostasis for enhanced CDT, ultimately leading to the combinational inhibition of tumor growth.

Most therapeutic peptides available on the market today are naturally occurring hormones or protein fragments that were serendipitously discovered to possess therapeutic effects. However, the limited repertoire of available natural resources presents difficulties for the development of new peptide drug candidates. Traditional peptides possess several shortcomings that must be addressed for biomedical applications, including relatively low affinity or specificity toward biological targets compared to antibody- and protein scaffold-based affinity molecules, poor in vivo stability owing to rapid enzymatic degradation, and rapid clearance from circulation owing to their small size. Going forward, it will be increasingly important for scientists to develop novel classes of high-affinity and -specificity peptides against desired targets that mitigate these limitations while remaining compatible with pharmaceutical manufacturing processes. Recently, several highly constrained, artificial cyclic peptides have emerged as platforms capable of generating high-affinity peptide binders against various disease-associated protein targets by combining with phage or mRNA display method, some of which have entered clinical trials. In contrast, although linear peptides are relatively easy to synthesize cost-effectively and modify site-specifically at either N- or C-termini compared to cyclic peptides, there have been few linear peptide-based platforms that can provide high-affinity and -specificity peptide binders.In this Account, we describe the creation and development of a novel class of high-affinity peptides, termed "aptide"-from the Latin word "aptus" meaning "to fit" and "peptide"-and summarize their biomedical applications. In the first part, we consider the design and creation of aptides, with a focus on their unique structural features and binding mode, and address screening and identification of target protein-specific aptides. We also discuss advantages of the aptide platform over ordinary linear peptides lacking preorganized structures in terms of the affinity and specificity of identified peptide binders against target molecules. In the second part, we describe the potential biomedical applications of various target-specific aptides, ranging from imaging and therapy to theranostics, according to the types of aptides and diseases. We show that certain aptides can not only bind to a target protein but also inhibit its biological function, thereby showing potential as therapeutics per se. Further, aptides specific for cancer-associated protein antigens can be used as escort molecules or targeting ligands for delivery of chemotherapeutics, cytokine proteins, and nanomedicines, such as liposomes and magnetic particles, to tumors, thereby substantially improving therapeutic effects. Finally, we present a strategy capable of overcoming the critical issue of short blood circulation time associated with most peptides by constructing a hybrid system between an aptide and a hapten cotinine-specific antibody.

Interlayer spacing is expected to influence the properties of multilayer two-dimensional (2D) materials. However, the ability to non-destructively regulate the interlayer spacing bidirectionally and reversibly is challenging. Here we report the preparation of 2D materials with tunable interlayer spacing by introducing active sites (Ce ions) in 2D materials to capture and immobilize Pt single atoms. The strong chemical interaction between active sites and Pt atoms contributes to the intercalation behavior of Pt atoms in the interlayer of 2D materials and further promotes the formation of chemical bonding between Pt atom and host materials. Taking cerium-embedded molybdenum disulfide (MoS2) as an example, intercalation of Pt atoms enables interlayer distance tuning via an electrochemical protocol, leading to interlayer spacing reversible and linear compression and expansion from 6.546 ± 0.039 Å to 5.792 ± 0.038 Å (~11 %). The electronic property evolution with the interlayer spacing variation is demonstrated by the photoluminescence (PL) spectra, delivering that the well-defined barrier between the multilayer and monolayer layered materials can be artificially designed., Modifying the interlayer spacing in two-dimensional materials is an effective approach to tune their chemical and physical properties. Here the authors report that intercalation of Pt atoms into cerium-doped MoS2 enables adjusting the interlayer spacing bidirectionally and reversibly.

RAGE, a druggable inflammatory receptor, is known to function as an oligomer but the exact oligomerization mechanism remains poorly understood. Previously we have shown that heparan sulfate (HS) plays an active role in RAGE oligomerization. To understand the physiological significance of HS-induced RAGE oligomerization in vivo, we generated RAGE knock-in mice (RageAHA/AHA) by introducing point mutations to specifically disrupt HS–RAGE interaction. The RAGE mutant demonstrated normal ligand-binding but impaired capacity of HS-binding and oligomerization. Remarkably, RageAHA/AHA mice phenocopied Rage−/− mice in two different pathophysiological processes, namely bone remodeling and neutrophil-mediated liver injury, which demonstrates that HS-induced RAGE oligomerization is essential for RAGE signaling. Our findings suggest that it should be possible to block RAGE signaling by inhibiting HS-RAGE interaction. To test this, we generated a monoclonal antibody that targets the HS-binding site of RAGE. This antibody blocks RAGE signaling in vitro and in vivo, recapitulating the phenotype of RageAHA/AHA mice. By inhibiting HS-RAGE interaction genetically and pharmacologically, our work validated an alternative strategy to antagonize RAGE. Finally, we have performed RNA-seq analysis of neutrophils and lungs and found that while Rage−/− mice had a broad alteration of transcriptome in both tissues compared to wild-type mice, the changes of transcriptome in RageAHA/AHA mice were much more restricted. This unexpected finding suggests that by preserving the expression of RAGE protein (in a dominant-negative form), RageAHA/AHA mouse might represent a cleaner genetic model to study physiological roles of RAGE in vivo compared to Rage−/− mice.

Significance Sepsis is a condition wherein a microbial infection leads to life-threatening systemic hyperactivation of innate immunity. Blood pH is normally maintained tightly between 7.35 and 7.45, and lactic acidosis with a pH, Blood pH is tightly maintained between 7.35 and 7.45, and acidosis (pH

A simple and sensitive liquid chromatography with tandem mass spectrometry method was developed for simultaneous quantification of paeoniflorin, albiflorin, oxypaeoniflorin, liquiritin, liquiritigenin, glycyrrhetinic acid, and glycyrrhizin in rat plasma after oral administration of Shaoyao-Gancao decoction, which is traditionally used in the treatment of polycystic ovary syndrome. The plasma samples were pretreated with methanol as precipitant. The method exhibited good linearity (correlation coefficient (R2 ) > 0.99) with lower quantification limits of 0.595-4.69 ng/mL for all analytes. Intra- and interbatch precision, accuracy, recovery, and stability of the method were all within accepted criteria. The results showed that the pharmacokinetic behaviors of the seven compounds were altered in the pathological status of polycystic ovary syndrome. Furthermore, a total of 36 metabolites were structurally identified based on their accurate masses and fragment ions. The major metabolic pathway involves phase I metabolic reactions (such as hydroxylation), phase II metabolic reactions (such as sulfation and glucuronidation conjugation) as well as the combined multiple-step metabolism. This study is the first report on the pharmacokinetic and metabolic information of Shaoyao-Gancao decoction in both normal and model rats, which would provide scientific evidences for the bioactive chemical basis of herbal medicines and also promote the clinical application of Shaoyao-Gancao decoction for treating polycystic ovary syndrome.

Crystallisation of polymer chains grafted onto a nanoparticle and the effects of grafting density and polymer–nanoparticle interaction were investigated by Monte Carlo simulations. The increase of ...

The crystallization behaviors of five polymer chain systems grafted on a nanorod and the corresponding effect of grafting density were investigated by dynamic Monte Carlo simulations. The segment density near the interfacial regions, the number of crystallites, and the mean square radius of gyration () increase with increasing grafting density, which are beneficial to the enhancement of crystallizability. Meanwhile, the crystalline morphology is greatly influenced by grafting density and polymer-nanorod interaction. For the grafted system with 52 chains, a nanohybrid shish-kebab (NHSK) structure is formed, when the polymer-nanorod interaction (Eb/Ec) is -0.4. For the system with 128 chains, a NHSK structure is formed, when Eb/Ec is -1.0. For the system with 252 chains, NHSK structure cannot be formed. The findings in this work can supply important theoretical reference for the design, preparation, and application of polymer nanocomposites.

The intrinsic limits of conventional cancer therapies prompt the development of a new technology for a more effective and safer cancer treatment. The bioresponsive delivery technique has recently emerged as an innovative strategy to overcome multiple barriers in the systemic delivery of nanoparticle (NP)-based therapeutics. However, some issues especially the tumor penetration-retention balance have not been completely solved, which may induce the suboptimal therapeutic effect. Herein, we developed a new multifunctional sharp pH-responsive NP platform for targeted drug delivery and effective cancer therapy. This NP platform is made of the sharp pH-responsive poly(2-(diisopropylamino)ethylmethacrylate) (PDPA) polymer as the inner core, amphiphilic lipid-poly(ethylene glycol) (lipid-PEG) as the outer shell, and the internalizing RGD (iRGD) peptide encoded on the surface. After anticancer drug loading and then systemic administration, the resulting NP platform shows the following features in one nanostructure: (i) the PEG shell to prolong blood circulation; (ii) the iRGD peptide to enhance tumor targeting and penetration; (iii) a larger particle size (∼80 nm) than that of free drug to ensure long tumor retention; (iv) the sharp endosomal pH response of the PDPA polymer to induce fast intracellular drug release and thus efficient inhibition of tumor growth. Together with facile polymer synthesis and robust NP formulation to enable easy scale-up, the multifunctional NP platform reported herein shows great potential as a new generation nanomedicine for effective cancer treatment.

Vibrio parahaemolyticus causes not only various diseases in aquaculture animals but also seafood-borne illness in humans. Outer membrane proteins (OMPs) are species-specific proteins found in bilayer membranes of gram-negative bacteria. Egg yolk immunoglobulin (IgY) has been reported to serve as oral administration of antibodies against bacteria and virus. RESULTS The present research extracted and identified OMPs from V. parahaemolyticus, and then the extracted OMPs were used to immunize hens to obtain specific IgY. The efficacy of IgY against V. parahaemolyticus were investigated in vitro and in vivo. The specific IgY effectively inhibited the growth of V. parahaemolyticus in liquid medium rather than Escherichia coli and Staphylococcus aureus. Specific IgY antibodies were incorporated into extruded food pellets and fed to bacteria-challenged white pacific shrimp to observe the anti-bacterial effect in vivo. The bacterial loads in muscles of V. parahaemolyticus infected shrimp fed with specific IgY-included diets were significantly fewer than those fed with non-specific IgY-included diets. The superoxide dismutase activities in muscles of infected shrimp fed with specific IgY-included diets were significantly higher than the control group. CONCLUSION The results suggested that the specific IgY effectively inhibited the growth of V. parahaemolyticus and introduced passive immunity to shrimp. ? 2018 Society of Chemical Industry

The crystallization behaviors of polymers can be changed by grafting them onto the surface of fillers. In this work, the effect of molecular weight of polymers grafted in two-dimensional filler on the isothermal crystallization behaviors was studied by the dynamic Monte Carlo simulation. The result shows that the grafted polymer system can shorten the nucleation induction period compared with ungrafted polymer systems, but its ultimate crystallinity is reduced. With increasing molecular weight, the nucleation induction period becomes shorter and the final crystallinity becomes higher. The polymer system with low molecular weight shows the intermolecular nucleation, while it exhibits the intramolecular nucleation for the one with high molecular weight. In addition, at lower molecular weights, the crystalline bonds tend to perpendicular to the filler. As the molecular weight increases, the crystalline bonds progressively inclined to deviate from the Z direction and return to the direction parallel to the Z axis ultimately. These simulation results can illustrate the micro-mechanism of the effect of molecular weight on crystallization behaviors of polymer composites from a microscopic perspective, which can provide important theoretical basis for improving the properties of polymer composites.

Previous structural studies of osteoprotegerin (OPG), a crucial negative regulator of bone remodeling and osteoclastogenesis, were mostly limited to the N-terminal ligand-binding domains. It is now known that the three C-terminal domains of OPG also play essential roles in its function by mediating OPG dimerization, OPG–heparan sulfate (HS) interactions, and formation of the OPG–HS–receptor activator of nuclear factor κB ligand (RANKL) ternary complex. Employing hydrogen–deuterium exchange MS methods, here we investigated the structure of full-length OPG in complex with HS or RANKL in solution. Our data revealed two noteworthy aspects of the OPG structure. First, we found that the interconnection between the N- and C-terminal domains is much more rigid than previously thought, possibly because of hydrophobic interactions between the fourth cysteine-rich domain and the first death domain. Second, we observed that two hydrophobic clusters located in two separate C-terminal domains directly contribute to OPG dimerization, likely by forming a hydrophobic dimerization interface. Aided by site-directed mutagenesis, we further demonstrated that an intact dimerization interface is essential for the biological activity of OPG. Our study represents an important step toward deciphering the structure–function relationship of the full-length OPG protein.

Selenium oxyanion reduction is an effective detoxification or/and assimilation processes in organisms, but little is known the mechanisms in aerobic bacteria. Aerobic Comamonas testosteroni S44 reduces Se(VI)/Se(IV) to less-toxic elemental selenium nanoparticles (SeNPs). For Se(VI) reduction, sulfate and Se(VI) reduction displayed a competitive relationship. When essential sulfate reducing genes were respectively disrupted, Se(VI) was not reduced to red-colored SeNPs. Consequently, Se(VI) reduction was catalyzed by enzymes of the sulfate reducing pathway. For Se(IV) reduction, one of the potential periplasm molybdenum oxidoreductase named SerT was screened and further used to analyze Se(IV) reduction. Compared to the wild type and the complemented mutant strain, the ability of Se(IV) reduction was reduced 75% in the deletion mutant ΔserT. Moreover, the Se(IV) reduction rate was significantly enhanced when the gene serT was overexpressed in Escherichia coli W3110. In addition, Se(IV) was reduced to SeNPs by the purified SerT with the presence of NADPH as the electron donor in vitro, showing a Vmax of 61 nmol/min·mg and a Km of 180 μmol/L. A model of Se(VI)/Se(IV) reduction was generated in aerobic C. testosteroni S44. This work provides new insights into the molecular mechanisms of Se(VI)/Se(IV) reduction activities in aerobic bacteria.

Cystatin C (Cst-3) is a potent inhibitor of cysteine proteases with diverse biological functions. As a secreted protein, the potential interaction between Cst-3 and extracellular matrix components has not been well studied. Here we investigated the interaction between Cst-3 and heparan sulfate (HS), a major component of extracellular matrix. We discovered that Cst-3 is a HS-binding protein only at acidic pH. By NMR and site-directed mutagenesis, we identified two HS binding regions in Cst-3: the highly dynamic N-terminal segment and a flexible region located between residue 70-94. The composition of the HS-binding site by two highly dynamic halves is unique in known HS-binding proteins. We further discovered that HS-binding severely impairs the inhibitory activity of Cst-3 towards papain, suggesting the interaction could actively regulate Cst-3 activity. Using murine bone tissues, we showed that Cst-3 interacts with bone matrix HS at low pH, again highlighting the physiological relevance of our discovery., Zhang et al. identify Cystatin C as a new heparan sulfate (HS) binding protein, however only at acidic pH (≤6.5). They further identify two isolated HS binding motifs on Cystatin C that are required to come together to form a complete HS-binding site, which is a unique property among known HS binding proteins.

To evaluate the effect of resveratrol in rats with chronic prostatitis, 24 rats were randomly divided into the negative control, vehicle-treated and resveratrol groups. The rats in the vehicle-treated group and the resveratrol group were injected subcutaneously with 17-β-oestradiol (0.25 mg/kg) daily for 6 weeks while the rats in the control group were injected with equivalent normal saline. From the 45th day, the rats in the resveratrol group were given resveratrol (10 mg/kg) by gavage per day while the rest rats were given normal saline. After 55 days, all the rats were sacrificed and the prostatic tissue was removed. Morphological changes were examined by light microscope after H&E staining. The expressions of IL-6, IL-8 and TNF-α were determined through ELISA and immunohistochemical staining. As a result, significant inflammatory cell infiltration and fibroblastic hyperplasia were observed in prostatic stroma in the vehicle-treated group compared with the negative control group, as well as the high expression of IL-6, IL-8 and TNF-α. After resveratrol treatment, inflammatory cell infiltration and fibroblastic hyperplasia were shown prominently reduced. Meanwhile, the expression of IL-6, IL-8 and TNF-α was significantly suppressed. For conclusion, resveratrol could attenuate the prostatic inflammation and downregulate the expression of IL-6, IL-8 and TNF-α in rat with oestradiol-induced chronic prostatitis.

Aims: Retinal microvasculature shares prominent similarities with the brain vasculature. We aimed to assess the association between retinal microvasculature and subtypes of ischemic stroke.Method: We consecutively enrolled ischemic stroke patients within 7 days of onset, who met the criteria of subtype of atherothrombosis (AT), small artery disease (SAD), or cardioembolism (CE) according to a modified version of the Trial of Org 10172 in Acute Stroke Treatment (NEW-TOAST). Digital fundus photographs were taken within 72 h of hospital admission using a digital camera (Topcon TRC-50DX), and fundus photographs were semi-automatically measured by software (Canvus 14 and NeuroLucida) for retinal vasculature parameters.Results: A total of 141 patients were enrolled, including 72 with AT, 54 with SAD, and 15 with CE. AT subtype patients had the widest mean venular diameter within 0.5–1.0 disk diameter (MVD0.5−1.0DD) followed by SAD and CE subtypes (86.37 ± 13.49 vs. 83.55 ± 11.54 vs. 77.90 ± 8.50, respectively, P = 0.047); CE subtype patients had the highest mean arteriovenous ratio within 0.5–1.0 disk diameter (MAVR0.5−1.0DD) followed by the AT and SAD subtype groups (0.97 ± 0.03 vs. 0.89 ± 0.99 vs. 0.89 ± 0.11, respectively, P = 0.010); SAD subtype patients were found with the highest mean venular tortuosity within 0.0–2.0 disk diameter (MVT0.0−2.0DD) followed by the AT and CE subtypes (1.0294 ± 0.0081 vs. 1.0259 ± 0.0084 vs. 1.0243 ± 0.0066, respectively, P = 0.024). After adjusting for clinic characteristics, MVD0.5−1.0DD was significantly different among AT, SAD, and CE subtypes (P = 0.033). By receiver operating characteristic curve analysis, MVD0.5−1.0DD predicted the AT subtype (area 0.690, 95% confidence interval, 0.566–0.815), with a cutoff value of 82.23 μm (sensitivity 61.1%, specificity 73.3%).Conclusion: Retinal MVD0.5−1.0DD (>82.23 μm) might be associated with the AT stroke subtype; however, we need large-scale prospective studies in future to explore the underlying mechanism and causal explanation for this finding.

Bacteria are the most common pathogens to cause infection of surgical sites, which usually induce severe postoperative morbidity and more healthcare costs. Inhibition of bacteria adhesion and colonization is an effective strategy to prevent the spread of infection at the surgical sites. Hydrogels have been widely used as promising antibacterial materials, due to their unique porous structure that could accommodate various antibacterial agents (e.g., antibiotics and cationic polymers with inherent antibacterial activity). Herein, inspired by the natural protein self-assembly, an amphiphilic peptide comprised of a hydrophobic naphthyl (Nap) acetyl tail and a hydrophilic peptide backbone was employed to construct supramolecular hydrogel for sustained release of the antibiotic polymyxin B. At neutral pH, the negatively charged amphiphilic peptide could form electrostatic attraction interaction with the positively charged polymyxin B, which could thus drive the ionized peptide molecules to get close to each other and subsequently trigger the self-assembly of the amphiphilic peptide into supramolecular hydrogel via intermolecular hydrogen bonding interaction among the peptide backbones and π-stacking of the hydrophobic Nap tails. More importantly, the electrostatic attraction interaction between polymyxin B and the amphiphilic peptide could ensure the sustained release of polymyxin B from the supramolecular hydrogel, leading to an effective inhibition of Gram-negative bacteria Escherichia coli growth. Combining the good biocompatibility of the amphiphilic peptide, the supramolecular hydrogel developed in this work shows a great potential for the surgical site infection application.

Pancreatic cancer (PAC) is one of the most lethal malignant neoplasms with poor prognosis and high mortality. Emerging evidence has revealed that abnormal tumor lipid metabolism and tumor-associated macrophages (TAMs) significantly contribute to PAC development and progression. Therefore, concurrently reprogramming tumor lipid metabolism and regulating TAMs function could be a promising strategy for effective PAC therapy. Herein, we identified an important enzyme catabolizing lipids (monoacylglycerol lipase, MGLL) and a key receptor regulating macrophage phenotype (endocannabinoid receptor-2, CB-2) that are over-expressed in PAC cells and on TAMs, respectively. Based on this finding, we developed a reduction-responsive poly (disulfide amide) (PDSA)-based nanoplatform for systemic co-delivery of MGLL siRNA (siMGLL) and CB-2 siRNA (siCB-2). This nanoplatform could utilize its reduction-responsive characteristic to rapidly release siRNA for efficient silencing of MGLL and CB-2, inducing concurrent suppression of free fatty acids (FFAs) generation in PAC cells and repolarization of TAMs into tumor-inhibiting M1-like phenotype. With this suppressed FFAs generation to inhibit nutrient supply for tumor cells and repolarized TAMs to secrete tumoricidal cytokines such as TNF-α and IL-12, a combinational anticancer effect could be achieved in both xenograft and orthotopic PAC tumor models.

The ability of energy carriers to move within and between atoms and molecules underlies virtually all material function. Understanding and controlling energy flow requires observing it on ultrasmall and ultrafast spatiotemporal scales, where energetic and structural roadblocks dictate the fate of energy carriers. I will describe a new optical ultrafast microscope based on stroboscopic elastic scattering that allows direct visualization of energy carrier transport in 3D with few-nm spatial precision and picosecond temporal resolution. I will demonstrate the wide applicability of the method for watching all forms of energy carriers – free charges, excitons, phonons and ions – move in materials ranging from silicon to conjugated polymers via 2D transition metal dichalcogenides and metal halide perovskites. Beyond quantifying carrier mobilities, our approach directly correlates material resistivities to local morphology, shedding light on how disorder affects transport pathways in 3D.

Histatin 5 (Hst 5) is an antimicrobial peptide produced in human saliva with antifungal activity for opportunistic pathogen Candida albicans. Hst 5 binds to multiple cations including dimerization-inducing zinc (Zn2+), although the function of this capability is incompletely understood. Hst 5 is taken up by C. albicans and acts on intracellular targets under metal-free conditions, however, Zn2+ is abundant in saliva and may functionally affect Hst 5. We hypothesized that Zn2+ binding would induce membrane-disrupting pores through dimerization. Through the use of Hst 5 and two derivatives, P113 (AA 4-15 of Hst 5) and Hst 5&Delta, MB (AA 1-3 and 15-19 mutated to Glu), we determined that Zn2+ significantly increases killing activity of Hst 5 and P113 for both C. albicans and Candida glabrata. Cell association assays determined that Zn2+ did not impact initial surface binding by the peptides, but Zn2+ did decrease cell association due to active peptide uptake. ATP efflux assays with Zn2+ suggested rapid membrane permeabilization by Hst 5 and P113 and that Zn2+ affinity correlates to higher membrane disruption ability. High-performance liquid chromatography (HPLC) showed that the higher relative Zn2+ affinity of Hst 5 likely promotes dimerization. Together, these results suggest peptide assembly into fungicidal pore structures in the presence of Zn2+, representing a novel mechanism of action that has exciting potential to expand the list of Hst 5-susceptible pathogens.

Blood pH is tightly regulated between 7.35-7.45, with values below 7.3 during sepsis being associated with lactic acidosis, low serum zinc, and release of proinflammatory HMGB1 from activated and/or necrotic cells. Using an ex vivo whole blood system to model lactic acidosis, we show that while HMGB1 does not engage leukocyte receptors at physiological pH, lowering pH with lactic acid facilitates binding. At normal pH, micromolar zinc supports plasma sialoglycoprotein binding by HMGB1, which is markedly reduced when pH is adjusted with lactic acid to sepsis levels. Glycan array studies confirmed zinc and pH-dependent HMGB1 binding to sialoglycans typical of plasma glycoproteins. Thus, proinflammatory effects of HMGB1 are suppressed via plasma sialoglycoproteins until drops in pH and zinc release HMGB1 to trigger downstream immune activation.Significance StatementHMGB1 sequestered by plasma sialoglycoproteins at physiological pH is released when pH and zinc concentrations fall in sepsis.

Osteoprotegerin (OPG), a secreted decoy receptor for receptor activator of nuclear factor B ligand (RANKL), plays an essential role in regulating bone resorption. While much is known about the function of the N-terminal domains of OPG, which is responsible for binding to RANKL, the exact biological functions of the three C-terminal domains of OPG remain uncertain. We have previously shown that one likely function of the C-terminal domains of OPG is to bind cell surface heparan sulfate (HS), but the in vivo evidence was lacking. To investigate the biological significance of OPG–HS interaction in bone remodeling, we created OPG knock-in mice (opg(AAA)). The mutated OPG is incapable of binding to HS but binds RANKL normally. Surprisingly, opg(AAA/AAA) mice displayed a severe osteoporotic phenotype that is very similar to opg-null mice, suggesting that the antiresorption activity of OPG requires HS. Mechanistically, we propose that the HS immobilizes secreted OPG at the surface of osteoblasts lineage cells, which facilitates binding of OPG to membrane-anchored RANKL. To further support this model, we altered the structure of osteoblast HS genetically to make it incapable of binding to OPG. Interestingly, osteocalcin-Cre;Hs2st(f/f) mice also displayed osteoporotic phenotype with similar severity to opg(AAA/AAA) mice. Combined, our data provide strong genetic evidence that OPG–HS interaction is indispensable for normal bone homeostasis.

Animal cells express heparan sulfate proteoglycans that perform many important cellular functions by way of heparan sulfate-protein interactions. The identification of membrane heparan sulfate-binding proteins is challenging because of their low abundance and the need for extensive enrichment. Here, we report a proteomics workflow for the identification and characterization of membrane-anchored and extracellular proteins that bind heparan sulfate. The technique is based on limited proteolysis of live cells in the absence of denaturation and fixation, heparin-affinity chromatography, and high-resolution LC-MS/MS, and we designate it LPHAMS. Application of LPHAMS to U937 monocytic and primary murine and human endothelial cells identified 55 plasma membrane, extracellular matrix, and soluble secreted proteins, including many previously unidentified heparin-binding proteins. The method also facilitated the mapping of the heparin-binding domains, making it possible to predict the location of the heparin-binding site. To validate the discovery feature of LPHAMS, we characterized one of the newly-discovered heparin-binding proteins, C-type lectin 14a (CLEC14A), a member of the C-type lectin family that modulates angiogenesis. We found that the C-type lectin domain of CLEC14A binds one-to-one to heparin with nanomolar affinity, and using molecular modeling and mutagenesis, we mapped its heparin-binding site. CLEC14A physically interacted with other glycosaminoglycans, including endothelial heparan sulfate and chondroitin sulfate E, but not with neutral or sialylated oligosaccharides. The LPHAMS technique should be applicable to other cells and glycans and provides a way to expand the repertoire of glycan-binding proteins for further study.

Osteoclasts are bone-resorbing cells differentiated from macrophage/monocyte precursors in response to macrophage colony-stimulating factor (M-CSF) and receptor activator of NF-κB ligand (RANKL). In vitro models are principally based on primary bone marrow macrophages (BMMs), but RAW 264.7 cells are frequently used because they are widely available, easy to culture, and more amenable to genetic manipulation than primary cells. Increasing evidence, however, has shown that the vastly different origins of these two cell types may have important effects on cell behavior. In particular, M-CSF is a prerequisite for the differentiation of BMMs, by promoting survival and proliferation and priming the cells for RANKL induction. RAW 264.7 cells readily form osteoclasts in the presence of RANKL, but M-CSF is not required. Based on these key differences, we sought to understand their functional implications and how it might affect osteoclast differentiation and related signaling pathways. Using a robust and high-throughput proteomics strategy, we quantified the global protein changes in osteoclasts derived from BMMs and RAW 264.7 cells at 1, 3, and 5 days of differentiation. Data are available via ProteomeXchange with the identifier PXD009610. Correlation analysis of the proteomes demonstrated low concordance between the two cell types (R2 ≈ 0.13). Bioinformatics analysis indicate that RANKL-dependent signaling was intact in RAW 264.7 cells, but biological processes known to be dependent on M-CSF were significantly different, including cell cycle control, cytoskeletal organization, and apoptosis. RAW 264.7 cells exhibited constitutive activation of Erk and Akt that was dependent on the activity of Abelson tyrosine kinase, and the timing of Erk and Akt activation was significantly different between BMMs and RAW 264.7 cells. Our findings provide the first evidence for major discrepancies between BMMs and RAW 264.7 cells, indicating that careful consideration is needed when using the RAW 264.7 cell line for studying M-CSF-dependent signaling and functions. © 2018 American Society for Bone and Mineral Research. © 2018 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

Heparan sulfate (HS) is widely present on the animal cell surface and in the extracellular matrix. HS achieves its biological functions by interacting with proteins to change proteins’ conformation, oligomerization state and cellular location. The challenging question to study HS is how to dissect the relationship between the structures of HS and the biological activities. In the past several years, crucial techniques have been developed to overcome this challenge. A novel chemoenzymatic method to synthesize structurally defined HS oligosaccharides has offered a key access to this class of sulfated carbohydrate molecules. Recent rapid progress of HS microarray technology allows screening of the interaction of a target protein with a large number of HS oligosaccharides. The improved availability of HS oligosaccharides and HS microarray analysis will undoubtedly accelerate the investigation of the contribution of the specific sulfated carbohydrate structures of HS in a wide range of biological contexts.

Clinical success of cancer radiotherapy is usually impeded by a combination of two factors, i.e., insufficient DNA damage and rapid DNA repair during and after treatment, respectively. Existing strategies for optimizing the radiotherapeutic efficacy often focus on only one facet of the issue, which may fail to function in the long term trials. Herein, we report a DNA-dual-targeting approach for enhanced cancer radiotherapy using a hierarchical multiplexing nanodroplet, which can simultaneously promote DNA lesion formation and prevent subsequent DNA damage repair. Specifically, the ultrasmall gold nanoparticles encapsulated in the liquid nanodroplets can concentrate the radiation energy and induce dramatic DNA damage as evidenced by the enhanced formation of γ-H2AX foci as well as in vivo tumor growth inhibition. Additionally, the ultrasound-triggered burst release of oxygen may relieve tumor hypoxia and fix the DNA radical intermediates produced by ionizing radiation, prevent DNA repair, and eventually result in cancer death. Finally, the nanodroplet platform is compatible with fluorescence, ultrasound, and magnetic resonance imaging techniques, allowing for real-time in vivo imaging-guided precision radiotherapy in an EMT-6 tumor model with significantly enhanced treatment efficacy. Our DNA-dual-targeting design of simultaneously enhancing DNA damage and preventing DNA repair presents an innovative strategy to effective cancer radiotherapy.

The periodontal pathogen Tannerella forsythia has the unique ability to produce methylglyoxal (MGO), an electrophilic compound which can covalently modify amino acid side chains and generate inflammatory adducts known as advanced glycation endproducts (AGEs). In periodontitis, concentrations of MGO in gingival-crevicular fluid are increased and are correlated with the T. forsythia load. However, the source of MGO and the extent to which MGO may contribute to periodontal inflammation has not been fully explored. In this study we identified a functional homolog of the enzyme methylglyoxal synthase (MgsA) involved in the production of MGO in T. forsythia. While wild-type T.forsythia produced a significant amount of MGO in the medium, a mutant lacking this homolog produced little to no MGO. Furthermore, compared with the spent medium of the T. forsythia parental strain, the spent medium of the T. forsythia mgsA-deletion strain induced significantly lower nuclear factor-kappa B activity as well as proinflammogenic and pro-osteoclastogenic cytokines from THP-1 monocytes. The ability of T. forsythia to induce protein glycation endproducts via MGO was confirmed by an electrophoresis-based collagen chain mobility shift assay. Together these data demonstrated that T. forsythia produces MGO, which may contribute to inflammation via the generation of AGEs and thus act as a potential virulence factor of the bacterium.

Emerging two-dimensional (2D) nanomaterials, such as transition-metal dichalcogenide (TMD) nanosheets (NSs), have shown tremendous potential for use in a wide variety of fields including cancer nanomedicine. The interaction of nanomaterials with biosystems is of critical importance for their safe and efficient application. However, a cellular-level understanding of the nano-bio interactions of these emerging 2D nanomaterials (i.e., intracellular mechanisms) remains elusive. Here we chose molybdenum disulfide (MoS2) NSs as representative 2D nanomaterials to gain a better understanding of their intracellular mechanisms of action in cancer cells, which play a significant role in both their fate and efficacy. MoS2 NSs were found to be internalized through three pathways: clathrin → early endosomes → lysosomes, caveolae → early endosomes → lysosomes, and macropinocytosis → late endosomes → lysosomes. We also observed autophagy-mediated accumulation in the lysosomes and exocytosis-induced efflux of MoS2 NSs. Ba...

Extra domain B of fibronectin (FN-EDB) is upregulated in the extracellular matrix during tissue remodeling and has been postulated as a potential biomarker for atherosclerosis, yet no systematic test for FN-EDB in plaques has been reported. We hypothesized that FN-EDB expression would intensify in advanced plaques. Furthermore, engineering of FN-EDB-targeted nanoparticles (NPs) could enable imaging/diagnosis and local delivery of payloads to plaques. Methods: The amount of FN-EDB in human atherosclerotic and normal arteries (ages: 40 to 85 years) was assessed by histological staining and quantification using an FN-EDB-specific aptide (APTFN-EDB). FN-EDB-specific NPs that could serve as MRI beacons were constructed by immobilizing APTFN-EDB on the NP surface containing DTPA[Gd]. MRI visualized APTFN-EDB-[Gd]NPs administered to atherosclerotic apolipoprotein E-deficient mice in the brachiocephalic arteries. Analysis of the ascending-to-descending thoracic aortas and the aortic roots of the mice permitted quantitation of Gd, FN-EDB, and APTFN-EDB-[Gd]NPs. Cyanine, a model small molecule drug, was used to study the biodistribution and pharmacokinetics of APTFN-EDB-NPs to evaluate their utility for drug delivery. Results: Atherosclerotic tissues had significantly greater FN-EDB-positive areas than normal arteries (P < 0.001). This signal pertained particularly to Type III (P < 0.01), IV (P < 0.01), and V lesions (P < 0.001) rather than Type I and II lesions (AHA classification). FN-EDB expression was positively correlated with macrophage accumulation and neoangiogenesis. Quantitative analysis of T1-weighted images of atherosclerotic mice revealed substantial APTFN-EDB-[Gd]NPs accumulation in plaques compared to control NPs, conventional MRI contrast agent (Gd-DTPA) or accumulation in wild-type C57BL/6J mice. Additionally, the APTFN-EDB-NPs significantly prolonged the blood-circulation time (t1/2: ~ 6 h) of a model drug and increased its accumulation in plaques (6.9-fold higher accumulation vs. free drug). Conclusions: Our findings demonstrate augmented FN-EDB expression in Type III, IV, and V atheromata and that APTFN-EDB-NPs could serve as a platform for identifying and/or delivering agents locally to a subset of atherosclerotic plaques.

Nanocomposites for integrating imaging and therapy have attracted tremendous attention for biomedical applications. Herein, Fe@Bi2S3 nanocomposites modified with polyethylene glycol (PEG) molecules are fabricated for synergistic thermoradiotherapy. For such nanocomposites, Bi2S3 exhibits a strong absorbance in the near-infrared (NIR) region, which allows Bi2S3 to convert energy from light into heat for effective photothermal therapy (PTT), whereas Bi can also significantly enhance radio-mediated cell death induction as a radiotherapy sensitizer due to its high atomic number (high-Z). Most importantly, it is found that the combination of PTT and radiation therapy (RT), using PEGylated Fe@Bi2S3 nanocomposites, can bring a strong synergistic effect for the tumor treatment in in vitro and in vivo experiments. Besides, the magnetic Fe core and the Bi2S3 shell components endow this nanocomposite with an ability to serve as both a magnetic resonance imaging (MRI) and computed tomography (CT) contrast agent. Therefore, our work presents a new type of multifunctional nanocomposite with the potential for synergistic thermoradiotherapy and simultaneously MRI/CT imaging.

In this study, two new coordination polymers (CPs) containing Co(II) ions as nodes were successfully prepared via hydrothermal synthesis employing 3′-nitro-biphenyl-2,4,4′-tricarboxylic acid (H3nbtc) and different N-donor co-ligand as the building blocks, and their chemical formulae are {[Co3(μ4-nbtc)2(μ-4,4′-bipy)2.5(μ-H2O)(H2O)3]•4H2O}n (1) and {[Co2(μ5-nbtc)(μ3 OH)(μ-4,4′-bipy)]•4,4′-bipy•H2O}n (2). Their application values in bone healing were evaluated, and their corresponding mechanism was explored. Real-time reverse transcription-polymerase chain reaction was implemented to measure the inflammatory response levels in mesenchymal stem cells after treatment with the compound. Afterward, enzyme-linked immunosorbent assay was conducted, and the TNF-α and IL-1β contents released by the mesenchymal stem cells were measured. Next, the levels of osteogenic differentiation were assessed via Western blot analysis by measuring alkaline phosphatase expression. Finally, the percentage of the Runx2 positive mesenchymal stem cells after compound treatment was determined by flow cytometry.

Lanthanide (Ln) group elements have been attracting considerable attention owing to the distinct optical properties. The crystal-field surroundings of Ln ions in the host materials can determine their energy level splitting, which is of vital importance to tailor their optical properties. 2D MoS2 single crystals were utilized as the host material to embed Eu3+ and energy-level splitting was achieved for tuning its photoluminescence (PL). The high anisotropy of the 2D host materials makes them distort the degenerate orbitals of the Ln ions more efficiently than the symmetrical bulk host materials. A significant red-shift of the PL peak for Eu3+ was observed. The strategy for tailoring the energy level splitting of Ln ions by the highly designable 2D material crystal field provides a new method to extend their optical properties.

Background To evaluate wide-field laser ophthalmoscopy (Optomap 200Tx) for screening retinal lesions before myopic refractive surgery. Methods Seventy-eight eyes of 78 consecutive refractive surgery candidates were included in this study. All subjects underwent Optomap 200Tx, mydriatic slit-lamp lens examination and the Goldmann three-mirror contact lens examination, which was considered as the reference method for determining retinal lesions. Results Forty of 78 eyes had retinal lesions (51.28%) and three eyes had retinal breaks (3.85%), which were diagnosed by the Goldmann three-mirror contact lens examination. Compared to the Goldmann three-mirror contact lens examination, the detection rate with the Optomap 200Tx was 91.73%% for retinal lesions, while the detection rate of mydriatic slit-lamp lens exams was 81.20%. There were no statistically significant differences among the three methods used for the diagnoses of myopic conus, tessellation and retinal breaks(all p > 0.05). For peripheral retinal lesions, the detection rate of the Optomap 200Tx examinations were similar to the Goldmann three-mirror contact lens exams (all p > 0.05), but were higher than the results of slit-lamp lens examinations (all p

Reduced Cu/ZnO catalyst was synthesized through solid phase grinding of the mixture of oxalic acid, copper nitrate and zinc nitrate, followed by subsequent calcination in N2 atmosphere without further H2 reduction. The catalysts were characterized by various techniques, such as XRD, TG-DTA, TPR and N2O chemisorption. Characterization results suggested that during the calcination in N2, as-ground precursor (oxalate complexes) decomposed to CuO and ZnO, releasing considerable amount of CO, which could be used for in situ reduction of CuO to Cuo. The in situ reduced O/I-Cu/ZnO catalyst was evaluated in CO2 hydrogenation to methanol, which exhibited superior catalytic performance to its counterpart O/H-Cu/ZnO catalyst obtained through conventional H2 reduction. The decomposition of precursor and reduction of CuO happened simultaneously during the calcination in N2, preventing the growth of active Cu0 species and aggregation of catalyst particles, which was inevitable during conventional H2 reduction process. This method is simple and solvent-free, opening a new route to prepare metallic catalysts without further reduction.

A Gram-stain-positive, rod-shaped, non-spore-forming bacterium, designated as x-2T, was isolated from lakeside soil of Sayram in the Xinjiang Uygur Autonomous Region, PR China. On the basis of 16S rRNA gene sequences, strain x-2T belongs to the genus Nocardioides in the family Nocardioidaceae , being most closely related to Nocardioides panacisoli Gsoil 346T (97.36 % 16S rRNA gene sequence similarity). Strain x-2T was characterized chemotaxonomically and found to have ll-diaminopimelic acid in the cell-wall peptidoglycan, phosphatidylglycerol, diphosphatidylglycerol, glycolipids and another three unknown phospholipids as the major polar lipids, MK-8(H4) as the predominant menaquinone and C18 : 1ω9c, iso-C16 : 0, C17 : 1ω8c and C16 : 0 as the major fatty acids. The genomic DNA G+C content of the novel strain was 71.1 mol%. The level of DNA–DNA relatedness between strain x-2T and N. panacisoli KCTC 19470T (=Gsoil 346T) was 29.8 %. These chemotaxonomic characters support the position of strain x-2T within the genus Nocardioides . The results of physiological and biochemical tests, as well as phylogenetic analysis, suggest that strain x-2T represents a novel species of the genus Nocardioides , for which the name Nocardioides litorisoli sp. nov. is proposed. The type strain is x-2T (=KCTC 39845T=CCTCCAB 2016255T).

We report a new peptidyl boronic acid-based fluorescent probe with an aggregation-induced emission (AIE) characteristic. Through specific recognition between the boronic acid group and the cancer-associated sialic acid (SA), this fluorescent probe shows an ability for targeted labelling and imaging of cancer cells.

Synergistic therapy involving two or more therapeutic agents with different anticancer mechanisms represents a promising approach to eradicate chemotherapy-refractory cancers. However, the preparation of a synergistic therapy platform generally involves complicated procedures to encapsulate different therapeutic agents and thereby increases the purification difficulty. In this work, we reported a simple but robust strategy to prepare a highly controllable drug delivery system (DDS) for synergistic cancer therapy. To construct this robust DDS, mesoporous silica nanoparticles (MSNs) were employed as a nanoplatform to encapsulate anticancer drug doxorubicin (DOX). After using a tumor-targeting cellular membrane-penetrating peptide (TCPP) and a mitochondria-targeting therapeutic peptide (TPP) to seal the surface pores via disulfide bonds, these newly developed MSNs can target cancer cells, penetrate cell membrane and rapidly release anticancer drug and mitochondria-targeted peptide in cytoplasm, inducing a remarkable synergistic anticancer effect. The new design concept reported here will promote the development of targeted and smart DDSs for synergistic cancer therapy.