Building Ion-Conductive Supramolecular Elastomeric Protective Layer via Dynamic Hard Domain Design for Stable Zinc Metal Anodes.

The instability of zinc metal anode caused by zinc dendrite growth and severe parasitic reactions has significantly restricted the extensive application of rechargeable aqueous zinc-ion batteries (RAZBs). Herein, based on the strategy of dynamic hard domains, we develop an ion-conductive supramolecular elastomer consisting of Zn salts and the polyurethane-urea-polypropylene glycol polymer skeleton. This elastomer combines high mechanical strength, high ionic conductivity, decent hydrophobicity, and high adhesion to stabilize the electrode-electrolyte interface. In the elastomer system, this elastomer can dynamically adapt to the volume changes of Zn anodes during repeated zinc plating/stripping processes through the reversible dissociation/reassociation of hierarchical hydrogen bonds (H-bonds) formed by the polar groups of urea and urethane moieties. Meanwhile, the coordination of Zn2+ with soft polypropylene glycol (PPG) segments contributes to fast ion transport. This hydrophobic elastomer can also effectively inhibit water-induced corrosion by shielding the active Zn metal from the aqueous electrolyte. Based on the above synergies, the surface-modified anode shows excellent cycling stability above 550 h at a high current density of 5 mA cm-2 and a capacity of 2.5 mAh cm-2. Moreover, the assembled Zn//MnO2 full cell also displayed an enhanced electrochemical performance. This work provides inspiration for the design of solid electrolyte interphase (SEI) layers in aqueous battery chemistry to accelerate the application of RAZBs.

Encapsulation of tea polyphenols into high amylose corn starch composite nanofibrous film for active antimicrobial packaging.

Starch-based composite nanofibrous films loaded with tea polyphenols (TP) were successfully fabricated through electrospinning high amylose corn starch (HACS) with aid of polyvinyl alcohol (PVA), referred as HACS/PVA@TP. With the addition of 15 % TP, HACS/PVA@TP nanofibrous films exhibited enhanced mechanical properties and water vapor barrier capability, and their hydrogen bonding interactions were further evidenced. TP was slowly released from the nanofibrous film and followed Fickian diffusion mechanism, which achieved the controlled sustained release of TP. Interesting, HACS/PVA@TP nanofibrous films effectively improved antimicrobial activities against Staphylococcus aureus (S. aureus) and prolonged the shelf life of strawberry. HACS/PVA@TP nanofibrous films showed superior antibacterial function by by destroying cell wall and cytomembrane, and degrading existing DNA fragments, stimulating excessive intracellular reactive oxygen species (ROS) generation. Our study demonstrated that the functional electrospun Starch-based nanofibrous films with enhanced mechanical properties and superior antimicrobial activities were potential for the application in active food packaging and relative areas.

Prognostic Value of Immunotyping Combined with Targeted Therapy in Patients with Non-Small-Cell Lung Cancer and Establishment of Nomogram Model.

Objective: Bioinformatics methods were used to analyze non-small-cell lung cancer gene chip data, screen differentially expressed genes (DEGs), explore biomarkers related to NSCLC prognosis, provide new targets for the treatment of NSCLC, and build immunotyping and line-map model. Methods: NSCLC-related gene chip data were downloaded from the GEO database, and the common DEGs of the two datasets were screened by using the GEO2R tool and FunRich 3.1.3 software. DAVID database was used for GO analysis and KEGG analysis of DEGs, and protein-protein interaction (PPI) network was constructed by STRING database and Cytoscape 3.8.0 software, and the top 20 hub genes were analyzed and screened out. The expression of pivot genes and their relationship with prognosis were verified by multiple external databases. Results: 159 common DEGs were screened from the two datasets. PPI network was constructed and analyzed, and the genes with the top 20 connectivity were selected as the pivotal genes of this study. The results of survival analysis and the patients' survival curve was reflected in the line graph model of NSCLC. Conclusion: Through the screening and identification of the VIM-AS1 gene, as well as the analysis of immune infiltration and immune typing, the successful establishment of the rosette model has a certain guiding value for the molecular targeted therapy of patients with non-small-cell lung cancer.

Copenhagen index (CPH-I) is more favorable than CA125, HE4, and risk of ovarian malignancy algorithm (ROMA): Nomogram prediction models with clinical-ultrasonographic feature for diagnosing ovarian neoplasms.

Background: We aimed to analyze the benign and malignant identification efficiency of CA125, HE4, risk of ovarian malignancy algorithm (ROMA), Copenhagen Index (CPH-I) in ovarian neoplasms and establish a nomogram to improve the preoperative evaluation value of ovarian neoplasms. Methods: A total of 3,042 patients with ovarian neoplasms were retrospectively classified according to postoperative pathological diagnosis [benign, n = 2389; epithelial ovarian cancer (EOC), n = 653]. The patients were randomly divided into training and test cohorts at a ratio of 7:3. Using CA125, HE4, ROMA, and CPH-I, Receiver operating characteristic (ROC) curves corresponding to different truncation values were calculated and compared, and optimal truncation values were selected. Clinical and imaging risk factors were calculated using univariate regression, and significant variables were selected for multivariate regression analysis combined with ROMA and CPH-I. Nomograms were constructed to predict the occurrence of EOC, and the accuracy was assessed by external validation. Results: When the cutoff value of CA125, HE4, ROMA, and CPH-I was 100 U/ml, 70 pmol/L, 12.5/14.4% (premenopausal/postmenopausal) and 5%, respectively, the AUC was 0.674, 0.721, 0.750 and 0.769, respectively. From univariate regression, the clinical risk factors were older age, menopausal status, higher birth rate, hypertension, and diabetes; imaging risk factors were multilocular tumors, solid nodules, bilateral tumors, larger tumor diameter, and ascites. The AUC of the nomogram containing ROMA and CPH-I was 0.8914 and 0.9114, respectively, which was better than the prediction accuracies of CA125, HE4, ROMA, and CPH-I alone. The nomogram with CPH-I was significantly better than that with ROMA (P < 0.001), and a nomogram decision curve analysis (DCA) containing CPH-I seemed to have better clinical benefits than ROMA. For external validation of this nomogram containing ROMA and CPH-I, the C-indices were 0.889 and 0.900, and the calibration curves were close to 45°, showing good agreement with the predicted values. Conclusion: We conclude that CPH-I and ROMA have higher diagnostic values in the preoperative diagnosis of EOC than other single tumor markers like CA125 or HE4. A nomogram based on CPH-I and ROMA with clinical and ultrasonic indicators had a better diagnostic value, and the CPH-I nomogram had the highest diagnostic efficacy.

TNFAIP3 Interacting Protein 3 Is an Activator of Hippo-YAP Signaling Protecting Against Hepatic Ischemia/Reperfusion Injury.

BACKGROUND AND AIMS: Hepatic ischemia/reperfusion (I/R) injury, a common clinical problem that occurs during liver surgical procedures, causes a large proportion of early graft failure and organ rejection cases. The identification of key regulators of hepatic I/R injury may provide potential strategies to clinically improve the prognosis of liver surgery. Here, we aimed to identify the role of tumor necrosis factor alpha-induced protein 3-interacting protein 3 (TNIP3) in hepatic I/R injury and further reveal its immanent mechanisms. APPROACH AND RESULTS: In the present study, we found that hepatocyte TNIP3 was markedly up-regulated in livers of both persons and mice subjected to I/R surgery. Hepatocyte-specific Tnip3 overexpression effectively attenuated I/R-induced liver necrosis and inflammation, but improved cell proliferation in mice, whereas TNIP3 ablation largely aggravated liver injury. This inhibitory effect of TNIP3 on hepatic I/R injury was found to be dependent on significant activation of the Hippo-YAP signaling pathway. Mechanistically, TNIP3 was found to directly interact with large tumor suppressor 2 (LATS2) and promote neuronal precursor cell-expressed developmentally down-regulated 4-mediated LATS2 ubiquitination, leading to decreased Yes-associated protein (YAP) phosphorylation at serine 112 and the activated transcription of factors downstream of YAP. Notably, adeno-associated virus delivered TNIP3 expression in the liver substantially blocked I/R injury in mice. CONCLUSIONS: TNIP3 is a regulator of hepatic I/R injury that alleviates cell death and inflammation by assisting ubiquitination and degradation of LATS2 and the resultant YAP activation.TNIP3 represents a promising therapeutic target for hepatic I/R injury to improve the prognosis of liver surgery.

Low-Dose Sorafenib Acts as a Mitochondrial Uncoupler and Ameliorates Nonalcoholic Steatohepatitis.

Nonalcoholic steatohepatitis (NASH) is becoming one of the leading causes of hepatocellular carcinoma (HCC). Sorafenib is the only first-line therapy for advanced HCC despite its serious adverse effects. Here, we report that at an equivalent of approximately one-tenth the clinical dose for HCC, sorafenib treatment effectively prevents the progression of NASH in both mice and monkeys without any observed significant adverse events. Mechanistically, sorafenib's benefit in NASH is independent of its canonical kinase targets in HCC, but involves the induction of mild mitochondrial uncoupling and subsequent activation of AMP-activated protein kinase (AMPK). Collectively, our findings demonstrate a previously unappreciated therapeutic effect and signaling mechanism of low-dose sorafenib treatment in NASH. We envision that this new therapeutic strategy for NASH has the potential to translate into a beneficial anti-NASH therapy with fewer adverse events than is observed in the drug's current use in HCC.

UV-light cross-linked and pH de-cross-linked coumarin-decorated cationic copolymer grafted mesoporous silica nanoparticles for drug and gene co-delivery in vitro.

The chemotherapy combined with gene therapy has emerged as a promising strategy for cancer therapy because of enhanced anticancer efficacy. To this end, we constructed a novel UV-light cross-linked and pH de-cross-linked coumarin-decorated cationic copolymer functionalized mesoporous silica nanoparticles (MSN) for co-delivery of chemotherapeutic agent 5-FU and tumor suppresser p53 gene. The multifunctional MSN were modified with poly(glycidyl methacrylate)-b-poly(2-(dimethylamino)ethyl methacrylate) (PGMA-b-PDMAEMA) via two sequential surface-initiated atom transfer radical polymerization (ATRP), followed by ring-opening of epoxy groups with ethanediamine and covalent conjugation with coumarin moieties via acid-liable cis-aconityl bonds. The in vitro drug release results indicated that the premature release was negligible at physiological pH when coumarin moieties on the MSN-g-PCAAMC-b-PDMAEMA surface underwent UV-light induced photo-dimerization (cross-linking), while the release of embedded drugs was accelerated under acidic conditions, which was attributed to the hydrolytic cleavage of cis-aconityl bonds (de-crosslinking). In addition to small-molecule drug, the established MSN-g-PCAAMC-b-PDMAEMA also could carry p53 gene in outer cationic copolymers, and the formed complex exhibited good gene transfection activity. Interestingly, coumarin moieties themselves could emit blue fluorescence, which was used to track the cellular uptake of the nanocarriers without the need of additional fluorescence probes. Importantly, the cytotoxicity and cell apoptosis assays confirmed that co-delivery of 5-FU and p53 gene by the cross-linked MSN-g-PCAAMC-b-PDMAEMA@5-FU/p53 induced enhanced chemotherapeutic efficacy as compared to 5-FU delivery alone. In conclusion, these results suggested that the constructed stimuli-responsive co-delivery system may hold the promise for cancer therapeutic application.

Hepatocyte TNF Receptor-Associated Factor 6 Aggravates Hepatic Inflammation and Fibrosis by Promoting Lysine 6-Linked Polyubiquitination of Apoptosis Signal-Regulating Kinase 1.

Activation of apoptosis signal-regulating kinase 1 (ASK1) is a key driving force of the progression of nonalcoholic steatohepatitis (NASH) and represents an attractive therapeutic target for NASH treatment. However, the molecular and cellular mechanisms underlying ASK1 activation in the pathogenesis of NASH remain incompletely understood. In this study, our data unequivocally indicated that hyperactivated ASK1 in hepatocytes is a potent inducer of hepatic stellate cell (HSC) activation by promoting the production of hepatocyte-derived factors. Our previous serial studies have shown that the ubiquitination system plays a key role in regulating ASK1 activity during NASH progression. Here, we further demonstrated that tumor necrosis factor receptor-associated factor 6 (TRAF6) promotes lysine 6 (Lys6)-linked polyubiquitination and subsequent activation of ASK1 to trigger the release of robust proinflammatory and profibrotic factors in hepatocytes, which, in turn, drive HSC activation and hepatic fibrosis. Consistent with the in vitro findings, diet-induced liver inflammation and fibrosis were substantially attenuated in Traf6+/- mice, whereas hepatic TRAF6 overexpression exacerbated these abnormalities. Mechanistically, Lys6-linked ubiquitination of ASK1 by TRAF6 facilitates the dissociation of thioredoxin from ASK1 and N-terminal dimerization of ASK1, resulting in the boosted activation of ASK1-c-Jun N-terminal kinase 1/2 (JNK1/2)-mitogen-activated protein kinase 14(p38) signaling cascade in hepatocytes. Conclusion: These results suggest that Lys6-linked polyubiquitination of ASK1 by TRAF6 represents a mechanism underlying ASK1 activation in hepatocytes and a key driving force of proinflammatory and profibrogenic responses in NASH. Thus, inhibiting Lys6-linked polyubiquitination of ASK1 may serve as a potential therapeutic target for NASH treatment.

Triple-Stimuli-Responsive Smart Nanocontainers Enhanced Self-Healing Anticorrosion Coatings for Protection of Aluminum Alloy.

Novel acid/alkali/corrosion potential triple-stimuli-responsive smart nanocontainers (TSR-SNs) were successfully assembled to regulate the release of an encapsulated corrosion inhibitor, benzotriazole (BTA), by installing specially structured bistable pseudorotaxanes as supramolecular nanovalves onto orifices of mesoporous silica nanoparticles. In normal conditions, BTA molecules were sealed in the mesopores. Upon any stimulus of acid, alkali, or corrosion potential, BTA molecules were quickly released because of the open states of the supramolecular nanovalves. TSR-SNs as smart nanocontainers were added into the SiO2-ZrO2 sol-gel coating to fabricate a stimuli-feedback, corrosion-compensating self-healing anticorrosion coating (SF-SHAC). Compared with the conventional pH-responsive smart nanocontainers synthesized for the SHAC, TSR-SNs not only respond to the pH changes occurring on corrosive microregions but also, and more importantly, feel the corrosion potential of aluminum alloys and give quick feedback. This design avoids wasting smart nanocontainers because of the local-dependent, gradient pH stimulus intensities and obviously enhances the response sensitivity of the SF-SHAC. Electrochemical impedance spectroscopy and salt spray tests prove the excellent physical barrier of the SF-SHAC. Through scanning vibrating electrode technique measurements, the SF-SHAC doped with TSR-SNs demonstrates inhibiting rates for corrosive microcathodic/anodic current densities that are faster than other control SHACs. The new incorporated corrosion potential-responsive function ensures the efficient working efficiency of TSR-SNs and makes full use of the preloaded corrosion inhibitors as repair factors.

Supramolecular Valves Functionalized Rattle-Structured UCNPs@hm-SiO2 Nanoparticles with Controlled Drug Release Triggered by Quintuple Stimuli and Dual-Modality Imaging Functions: A Potential Theranostic Nanomedicine.

Integrating multimodality bioimaging and multiple stimuli-responsive controlled drug release properties into one single nanosystem for therapeutic application is highly desirable but still remains a challenge. Herein, we coated a hollow mesoporous silica shell on to upconversion nanoparticles (UCNPs) and conjugated pillarene-based supramolecular valves on to surface of UCNPs@hm-SiO2 using amine-coumarin phototriggers to obtain the multifunctional nanoparticles, UCNPs@hm-SiO2-Cou-Cys-DOX/WP[5]. Benefiting from the core-shell structured UCNPs, the UCNPs@hm-SiO2-Cou-Cys-DOX/WP[5] can serve as efficient contrast agents for upconversion luminescence and T1-weighted magnetic resonance imaging in vitro/in vivo. More importantly, depending on exquisitely designed supramolecular valves, UCNPs@hm-SiO2-Cou-Cys-DOX/WP[5] can realize zero-premature release under normal physiological conditions (pH 7.4), which produces minimal damage to normal tissue, whereas this nanosystem can respond to several disease-related signals, including acid (most cancers), alkali (metabolic alkalosis), and Zn2+ (Alzheimer's disease), along with two external stimuli, including near-infrared (NIR) light and reductive electrical potential, via altering the spatial structure of pseudorotaxanes, disassembling the molecular stalks, or undergoing photochemical reactions, ultimately resulting in opening of the gatekeepers and release of encapsulated drugs. The multifunctional UCNP-based nanoparticles were endowed with such quintuple stimuli-responsive controlled release characteristics. Specifically, in anticancer application, the rational utilization of the two of them, acid and NIR light, could regulate the release amount and rate of DOX from UCNPs@hm-SiO2-Cou-Cys-DOX/WP[5], accelerate the accumulation of DOX in cell nuclei, and thereby promote the cancer cell apoptosis, indicating that the nanomaterials have promising application in cancer treatment. This study provides a novel design strategy for constructing multifunctional UCNP-based nanoparticles with multiple stimuli-responsive drug release features, which have great potential in diagnosis and therapy of relevant diseases as theranostic nanomedicines.

Recent Advances in Stimuli-Responsive Release Function Drug Delivery Systems for Tumor Treatment.

Benefiting from the development of nanotechnology, drug delivery systems (DDSs) with stimuli-responsive controlled release function show great potential in clinical anti-tumor applications. By using a DDS, the harsh side effects of traditional anti-cancer drug treatments and damage to normal tissues and organs can be avoided to the greatest extent. An ideal DDS must firstly meet bio-safety standards and secondarily the efficiency-related demands of a large drug payload and controlled release function. This review highlights recent research progress on DDSs with stimuli-responsive characteristics. The first section briefly reviews the nanoscale scaffolds of DDSs, including mesoporous nanoparticles, polymers, metal-organic frameworks (MOFs), quantum dots (QDs) and carbon nanotubes (CNTs). The second section presents the main types of stimuli-responsive mechanisms and classifies these into two categories: intrinsic (pH, redox state, biomolecules) and extrinsic (temperature, light irradiation, magnetic field and ultrasound) ones. Clinical applications of DDS, future challenges and perspectives are also mentioned.

Dual pH-Mediated Mechanized Hollow Zirconia Nanospheres.

We demonstrate for the first time how to assemble mechanized hollow zirconia nanospheres (MHzNs), consisting of hollow mesoporous zirconia nanospheres (HMZNs) as nanoscaffolds and supramolecular switches anchored on the exterior surface of HMZNs. The remarkable advantage of substitution of HMZNs for conventional mesoporous silica nanoscaffolds is that HMZNs can suffer the hot alkaline reaction environment, which provides a novel strategy for functionalization and thus achieve dual pH-mediated controlled release functions by simple and practicable assembly procedure. Under neutral solution, cucurbituril[7] (CB[7]) macrocycles complexed with propanone bis(2-aminoethyl)ketal (PBAEK) to form [2]pseudorotaxanes as supramolecular switches, blocking the pore orifices and preventing the undesirable leakage of cargoes. When solution pH was adjusted to alkaline range, CB[7] macrocycles, acting as caps, disassociated from PBAEK stalks and opened the switches due to the dramatic decrease of ion-dipole interactions. While under acidic conditions, PBAEK stalks were broken on account of the cleavage of ketal groups, resulting in the collapse of supramolecular switches and subsequent release of encapsulated cargoes. MHzNs owning dual pH-mediated controlled release characteristic are expected to apply in many fields. In this work, the feasibility of doxorubicin (DOX)-loaded MHzNs as targeted drug delivery systems was evaluated. In vitro cellular studies demonstrate that DOX-loaded MHzNs can be easily taken up by SMMC-7721 cells, can rapidly release DOX intracellularly, and can enhance cytotoxicity against tumor cells, proving their potential for chemotherapy.

Voltage/pH-Driven Mechanized Silica Nanoparticles for the Multimodal Controlled Release of Drugs.

The major challenges of current drug delivery systems for combination chemotherapy focus on how to efficiently transport drugs to target sites and release multiple drugs in a programmed manner. Herein, we report a novel multidrug delivery system, MSNPs 1, based on mechanized silica nanoparticles, which were constructed through functionalization of mesoporous silica nanoparticles with the acid-cleavable intermediate linkages and the monoferrocene functionalized ß-cyclodextrin (Fc-ß-CD) as supramolecular nanovalves. MSNPs 1 achieved zero premature release in the physiological pH solution and realized two different release modalities. In modality 1, MSNPs 1 released the encapsulated drugs gemcitabine (GEM) and doxorubicin (DOX) in sequence when they were successively applied to voltage and acid stimuli. The release time and dosage of GEM were precisely controlled via external voltage. The subsequent acid-triggered release of DOX was attributed to breakage of the intermediate linkages containing ketal groups. Modality 2 is the concurrent release of these two drugs directly upon acid exposure. Furthermore, the cell viability experiments demonstrated that MSNPs 1 had an improved cytotoxicity to MCF7 cells in comparison with single DOX- or GEM-loaded mechanized silica nanoparticles. We envisage that MSNPs 1 will play an important role in research and development for a new generation of controlled-release drug delivery system.

[Determination of twenty free amino acids in flue-cured tobacco leaves using ultra performance liquid chromatography-single quadruple mass spectrometry and pre-column derivatization].

Free amino acids in flue-cured tobacco leaves were investigated using the ultra performance liquid chromatography-single quadruple mass spectrometry detection and pre-column derivatization method. The validation results showed that the method could meet the analytical requirements. A total of 138 tobacco leaf samples were collected from 14 provinces in China in 2011 in which the free amino acids were determined. The relative standard deviations (RSDs) of the contents of free amino acids in different growing regions ranged from 28.50%-94.20%, and those of asparagine and glutamine were over 80%. The RSDs of the contents of free amino acids in full aroma tobacco leaves were larger than those in fresh aroma and medium aroma tobacco leaves. The principal component analysis (PCA) and non-parameter Mann-Whitney U test were used for data analysis. The free amino acids of the same aroma type grown in different regions or different aroma types in the same province showed great variation. The contents of free amino acids of full aroma tobacco grown in Southeast region were much lower than those in Huanghuai region. The contents of free amino acids in Hunan province were much lower than the average contents. The results showed that free amino acids in flue-cured tobacco leaves were affected by the growing region.

Study on cerium-doped nano-TiO2 coatings for corrosion protection of 316 L stainless steel.

Many methods have been reported on improving the photogenerated cathodic protection of nano-TiO2 coatings for metals. In this work, nano-TiO2 coatings doped with cerium nitrate have been developed by sol-gel method for corrosion protection of 316 L stainless steel. Surface morphology, structure, and properties of the prepared coatings were investigated by X-ray diffraction, X-ray photoelectron spectroscopy, scanning electron microscopy and energy dispersive X-ray spectroscopy. The corrosion protection performance of the prepared coatings was evaluated in 3 wt% NaCl solution by using electrochemical techniques in the presence and absence of simulated sunlight illumination. The results indicated that the 1.2% Ce-TiO2 coating with three layers exhibited an excellent photogenerated cathodic protection under illumination attributed to the higher separation efficiency of electron-hole pairs and higher photoelectric conversion efficiency. The results also showed that after doping with an appropriate concentration of cerium nitrate, the anti-corrosion performance of the TiO2 coating was improved even without irradiation due to the self-healing property of cerium ions.