Mechanically Adaptive Polymers Constructed from Dynamic Coordination Equilibria.

Designing materials capable of adapting their mechanical properties in response to external stimuli is the key to preventing failure and extending their service life. However, existing mechanically adaptive polymers are hindered by limitations such as inadequate load-bearing capacity, difficulty in achieving reversible changes, high cost, and a lack of multiple responsiveness. Herein, we address these challenges using dynamic coordination bonds. A new type of mechanically adaptive material with both rate- and temperature-responsiveness was developed. Owing to the stimuli-responsiveness of the coordination equilibria, the prepared polymers, PBMBD-Fe and PBMBD-Co, exhibit mechanically adaptive properties, including temperature-sensitive strength modulation and rate-dependent impact hardening. Benefitting from the dynamic nature of the coordination bonds, the polymers exhibited impressive energy dissipation, damping capacity (loss factors of 1.15 and 2.09 at 1.0 Hz), self-healing, and 3D printing abilities, offering durable and customizable impact resistance and protective performance. The development of impact-resistant materials with comprehensive properties has potential applications in the sustainable and intelligent protection fields.

Effect of tandem repeats of antimicrobial peptide CC34 on production of target proteins and activity of Pichia pastoris.

Antimicrobial peptides (AMPs) are attracting attention in the fields of medicine, food, and agriculture because of their broad-spectrum antibacterial properties, low resistance, and low-residue in the body. However, the low yield and instability of the prepared AMP drugs limit their application. In this study, we designed a tetramer of the AMP CC34, constructed and transfected two recombinant expression vectors with pGAPZαA containing a haploid CC34 and tetraploid CC34 (CC34-4js) into Pichia pastoris to explore the effect of biosynthesized peptides. The results showed that CC34 and CC34-4js expression levels were 648.2 and 1105.3 mg/L, respectively, in the fermentation supernatant of P. pastoris. The CC34-4js tetramer showed no antibacterial activity, could be cleaved to the monomer using formic acid, and the hemolytic rate of the polyploid was slightly lower than that of monomeric CC34. The average daily gain, average daily feed intake, feed conversion ratio and immune organ index of rats fed CC34 and CC34-4js showed no differences. In conclusion, CC34-4js exhibited a higher yield and lower hemolysis in P. pastoris than those of CC34. Finally, CC34 and CC34-4js enterokinase lysates showed similar antibacterial activity and both expressed peptides potentially improved the growth performance and organ indices of rats.

Tough, Reprocessable, and Recyclable Dynamic Covalent Polymers with Ultrastable Long-Lived Room-Temperature Phosphorescence.

Room-temperature phosphorescence (RTP) polymers, whose emission can persist for a long period after photoexcitation, are of great importance for practical applications. Herein, dynamic covalent boronic ester linkages with internal B-N coordination are incorporated into a commercial epoxy matrix. The reversible dissociation of B-N bonds upon loading provides an efficient energy dissipation pathway for the epoxy network, while the rigid epoxy matrix can inhibit the quenching of triplet excitons in boronic esters. The obtained polymers exhibit enhanced mechanical toughness (12.26 MJ m-3 ), ultralong RTP (τ=540.4 ms), and shape memory behavior. Notably, there is no apparent decrease in the RTP property upon prolonged immersion in various solvents because the networks are robust. Moreover, the dynamic bonds endow the polymers with superior reprocessablity and recyclability. These novel properties have led to their potential application for information encryption and anti-counterfeiting.

Erratum: Lentinan-functionalized Selenium Nanoparticles target Tumor Cell Mitochondria via TLR4/TRAF3/MFN1 pathway: Erratum.

[This corrects the article DOI: 10.7150/thno.46467.].

Genomic Analysis Uncovers the Prognostic and Immunogenetic Feature of Pyroptosis in Gastric Carcinoma: Indication for Immunotherapy.

Crosstalk between pyroptosis and tumor immune microenvironment (TIME) in cancer has yet to be elucidated. Herein, we aimed to explore the role of pyroptosis and its association with TIME in gastric cancer. Unsupervised clustering was performed to identify the pyroptosis-related clusters. Pyroptosis risk score was constructed using LASSO Cox regression. Clinicopathological and genetic data of pyroptosis clusters and pyroptosis risk scores were explored. Reproducibility of pyroptosis risk score in predicting response to immunotherapy and screening potential antitumor drugs was also investigated. Three pyroptosis clusters with distinct prognosis, immune cell fractions and signatures, were constructed. A low-pyroptosis risk score was characterized by increased activated T-cell subtype and M1 macrophage, decreased M2 macrophage, higher MSI status, and TMB. Meanwhile, low-score significantly correlated with PD-L1 expression, antigen presentation markers, and IFN-γ signature. The 5-year AUCs of PRS were 0.67, 0.62, 0.65, 0.67, and 0.67 in the TCGA, three external public and one real-world validation (SYSUCC) cohorts. Multivariable analyses further validated the prognostic performance of the pyroptosis risk scoring system, with HRs of 2.43, 1.83, 1.78, 2.35, and 2.67 (all p < 0.05) in the five cohorts. GSEA indicated significant enrichment of DNA damage repair pathways in the low-score group. Finally, the pyroptosis risk scoring system was demonstrated to be useful in predicting response to immunotherapy, and in screening potential antitumor drugs. Our study highlights the crucial role of interaction between pyroptosis and TIME in gastric cancer. The pyroptosis risk scoring system can be used independently to predict the survival of individuals and their response to immunotherapy.

Leonurus japonicus Houtt. (Motherwort): Systematic research through chemical profiling, stability under controlled conditions and pharmacokinetic analysis on screening Q-markers for quality control.

Leonurus japonicus Houtt. (Motherwort) is the fresh or dried aerial part of Leonurus japonicus Houtt. (Labiaceae), which is widely used in clinical practice and daily life, used to treat gynecological diseases. However, the differences between different parts, single index component in Pharmacopoeias and the less stability of active ingredients affect its clinical efficacy. This study aimed to find the multi-active compounds between different parts of Motherwort to ensure its clinical efficacy, which related to stability and had pharmacokinetic behavior. Firstly, HPLC-Q-TOF-MS/MS was used to analyze the components in vitro and in vivo, as well as multivariate statistical analysis and network pharmacology analysis was conducted to find the significant different components related to activity. Secondly, the content determination methods were established to study the stability of effective components during storage in order to establish the content limit for quality control of Motherwort. Thirdly, UFLC-MS/MS was used to analyze the pharmacokinetic behavior of active components in Motherwort. The results showed that a total of 131 chemical constituents were identified in vitro and 21 prototype absorption compounds and 72 metabolites were found in vivo. Meantime, multivariate statistical analysis and network pharmacology analysis was combined to find that leonurine, stachydrine and trigonelline were activity-related substance, which could be used as active components related to pharmacodynamics in different parts. Then the stability variation trend and content limit of three alkaloids were found, which could be used for the quality control of Motherwort. Furthermore, the results showed that three alkaloids had pharmacokinetic behavior in vivo. 3 alkaloids were screened, which could be used as active components most closely related to pharmacodynamics among different parts. The stable stage, assay tolerance and pharmacokinetic characteristics were studied by the active substances, which could provide a basis for quality control and clinical medication of Motherwort.

Universal Self-Healing Poly(dimethylsiloxane) Polymer Crosslinked Predominantly by Physical Entanglements.

Harsh conditions are inevitable for long-term use of self-healing polymers. However, the majority of reported self-healing materials cannot remain stable under harsh conditions due to the presence of vulnerable dynamic crosslinking sites. Herein, a universal self-healing poly(dimethylsiloxane) (PDMS) polymer is reported. In our design, the PDMS polymer chains are crosslinked predominantly through physical entanglements. Owing to the invulnerable nature of the entanglement junctions and high mobility of polymer chains, the as-synthesized polymer exhibits autonomous self-healing capabilities not only under ambient conditions but also in a variety of harsh environments, including aqueous solutions, organic solvents, and extreme conditions (strong acid/alkali, redox agents, freezing temperature). Moreover, this polymer can be easily integrated with a eutectic gallium-indium (EGaIn) alloy to achieve layer-by-layer self-healing electronic skin sensors, which realize the combination of excellent electrical conductivity, long-term sensing stability, and universal self-healing capability.

[Main chemical constituents in aerial parts of Glycyrrhiza uralensis by UPLC-Q-Exactive Orbitrap-MS].

Chemical constituents from aerial parts of Glycyrrhiza uralensis were analyzed and identified using ultra-high performance liquid chromatography coupled with hybrid quadrupole-orbitrap mass spectrometry(UPLC-Q-Exactive Orbitrap-MS). The chromatographic column of Waters Acquity UPLC BEH-C_(18)(2.1 mm×100 mm, 1.7 µm) was adopted, with acetonitrile-water(0.5% formic acid) as mobile phase at a flow rate of 0.2 mL·min~(-1). Data was collected in positive and negative modes of electrospray ionization(ESI). A total of 55 compounds, including 42 flavonoids, 9 stilbenes, 2 coumarins, 1 lignin and 1 phenolic acid, which were characterized in the aerial parts of G. uralensis based on accurate molecular mass information of molecular and product ions provided by UPLC-Q-Exactive Orbitrap-MS based on comparison with standard substances and references. It is an effective and accurate method to provide chemical information of constituents in aerial parts of G. uralensis, and can provide a reference for further study on pharmacodynamic material basis and resources development and utilization.

Lentinan-functionalized Selenium Nanoparticles target Tumor Cell Mitochondria via TLR4/TRAF3/MFN1 pathway.

Rationale: Malignant ascites caused by cancer cells results in poor prognosis and short average survival time. No effective treatment is currently available for malignant ascites. In this study, the effects of lentinan (LNT)-functionalized selenium nanoparticles (Selene) on malignant ascites were evaluated. Furthermore, the mechanism of Selene targeting mitochondria of tumor cells were also investigated. Methods: Selene were synthesized and characterized by TEM, AFM and particle size analysis. The OVCAR-3 and EAC cells induced ascites models were used to evaluate the effects of Selene on malignant ascites. Proteomic analysis, immunofluorescence, TEM and ICP-MS were used to determine the location of Selene in tumor cells. Mitochondrial membrane potential, ROS, ATP content, and caspase-1/3 activity were detected to evaluate the effect of Selene on mitochondrial function and cell apoptosis. Immunofluorescence, Co-IP, pull-down, duolink, Western blot, and FPLC were used to investigate the pathway of Selene targeting mitochondria. Results: Selene could effectively inhibit ascites induced by OVCAR-3 and EAC cells. Selene was mainly located in the mitochondria of tumor cells and induced apoptosis of tumor cells. The LNT in Selene was involved in caveolae-mediated endocytosis through the interaction between toll-like receptor-4 (TLR4) and caveolin 1 (CAV1). Furthermore, the Selene in the endocytic vesicles could enter the mitochondria via the mitochondrial membrane fusion pathway, which was mediated by TLR4/TNF receptor associated factor 3 (TRAF3)/mitofusin-1 (MFN1) protein complex. Conclusion: Selene is a candidate anticancer drug for the treatment of malignant ascites. And TLR4/TRAF3/MFN1 may be a specific nano-drug delivery pathway that could target the mitochondria.

Inhibition of lncRNA PART1 Chemosensitizes Wild Type but Not KRAS Mutant NSCLC Cells.

BACKGROUND: Lung cancer has the highest incidence among solid tumors in men and is the third most common cancer in women. Despite improved understanding of genomic and mutational landscape in non-small cell lung cancer (NSCLC), the five-year survival in these patients has remained stagnant at a dismal 15%. The first line of treatment commonly adapted for NSCLC patients with somatic mutation in EGFR is tyrosine kinase inhibitor gefitinib or erlotinib. EGFR mutant cells seem to be intrinsically sensitive to tyrosine kinase inhibitors; however, the remaining 20-30% patients are resistant to tyrosine kinase inhibitor. MATERIALS AND METHODS: Here we show, using in vitro normal and NSCLS cell lines, that the lncRNA Prostate androgen-regulated transcript 1 (PART1) is expressed at higher levels in NSCLC cells compared to normal lung epithelial cell line, corroborating two earlier studies. RESULTS: We additionally show that these cells are resistant to erlotinib which is reversed in some, but not all, cell lines following suppression of PART1 expression. The differential response to erlotinib following siRNA-mediated knockdown of PART1 was found to be related to the mutational status of KRAS. Only in cells with wild-type KRAS suppression of PART1 sensitized them to erlotinib. Knockdown of mutant KRAS did not sensitize those cell lines to erlotinib. But knockdown of mutant KRAS along with suppression of PART1 sensitized the cells to treatment with erlotinib. The results from the study reveal a yet undefined and important role of lncRNA PART1 in defining sensitivity to erlotinib. This action is mediated by mutation status of KRAS. CONCLUSION: Even though preliminary, our results indicate PART1 might be a potential candidate for targeted therapy or used as a predictor of chemosensitivity in patients with NSCLC.

Protopanaxadiol inhibits epithelial-mesenchymal transition of hepatocellular carcinoma by targeting STAT3 pathway.

Diol-type ginsenosides, such as protopanaxadiol (PPD), exhibit antioxidation, anti-inflammation, and antitumor effects. However, the antitumor effect of these ginsenosides and the mechanism of PPD remain unclear. In this work, the antitumor effects of several derivatives, including PPD, Rg5, Rg3, Rh2, and Rh3, were evaluated in five different cancer cell lines. PPD demonstrated the best inhibitory effects on the proliferation and migration of the five cancer cell lines, especially the hepatocellular carcinoma (HCC) cell lines. Therefore, the mechanism of action of PPD in HCC cells was elucidated. PPD inhibited the proliferation, migration, and invasion ability of HepG2 and PLC/PRF/5 cells in a dose-dependent manner. Western blot and immunofluorescence assay showed that PPD can alter the expression of epithelial-mesenchymal transition markers, increase E-cadherin expression, and decrease vimentin expression. Docking and biacore experiments revealed that STAT3 is the target protein of PPD, which formed hydrogen bonds with Gly583/Leu608/Tyr674 at the SH2 domain of STAT3. PPD inhibited the phosphorylation of STAT3 and its translocation from the cytosol to the nucleus, thereby inhibiting the expression of Twist1. PPD also inhibited tumor volume and tumor lung metastasis in PLC/PRF/5 xenograft model. In conclusion, PPD can inhibit the proliferation and metastasis of HCC cells through the STAT3/Twist1 pathway.