Bithiophene-Functionalized Infrared Two-Photon Absorption Metal Complexes as Single-Molecule Platforms for Synergistic Photodynamic, Photothermal, and Chemotherapy.

A planar conjugated ligand functionalized with bithiophene and its Ru(II), Os(II), and Ir(III) complexes have been constructed as single-molecule platform for synergistic photodynamic, photothermal, and chemotherapy. The complexes have significant two-photon absorption at 808 nm and remarkable singlet oxygen and superoxide anion production in aqueous solution and cells when exposed to 808 nm infrared irradiation. The most potent Ru(II) complex Ru7 enters tumor cells via the rare macropinocytosis, locates in both nuclei and mitochondria, and regulates DNA-related chemotherapeutic mechanisms intranuclearly including DNA topoisomerase and RNA polymerase inhibition and their synergistic effects with photoactivated apoptosis, ferroptosis and DNA cleavage. Ru7 exhibits high efficacy in vivo for malignant melanoma and cisplatin-resistant non-small cell lung cancer tumors, with a 100 % survival rate of mice, low toxicity to normal cells and low residual rate. Such an infrared two-photon activatable metal complex may contribute to a new generation of single-molecule-based integrated diagnosis and treatment platform to address drug resistance in clinical practice and phototherapy for large, deeply located solid tumors.

Marine ecological security shelter in China: Concept, policy framework, mechanism and implementation obstacles.

Building a marine ecological security shelter (MESS) has become the main strategy to adapt marine ecological threats in China. As China's marine policy lacks a robust framework document, it is necessary to consider whether the policy system can effectively support the construction of MESS. However, the linkage between the construction measures of MESS and related policies is not clear. Therefore, the purpose of this paper is to clarify the concept of MESS and its connection with policy, by adopting the policy content analysis method to analyze the evolution process of MESS-related policy system. The legislative shortcomings and implementation obstacles of the MESS-related policy system are then summarized and discussed. The results show that from 1981 to 2021 the MESS-related policy system has been continuously improved. However, the policy system's support and guarantee capacity for building MESS still needs to be improved. (1) Due to the lack of basic laws and special laws, the coordination among governance subjects and among policies lacks legislative guarantee. (2) The construction of MESS continues the inter-regional and inter-department administrative barriers in collaborative governance of marine environment. To establish an effective collaborative governance model, it is essential to improve the governance structure and mechanism. (3) The government-led governance pattern faces the problem of mechanism failure. The command and control instrument accounts for more than 82%, and the public and enterprises lack strong policy guarantees to participate in marine governance. (4) The policy system's adaptability to emerging threats must be improved. Marine policies rarely involve emerging threats such as climate change and new pollutants. Meanwhile, the real-time supervision and monitoring mechanism is weak. The real-time supervision is only accounting for about 10%. Generally speaking, as a complex and long-term system engineering, the construction of MESS will inevitably encounter contradictions in politics, culture, and economy. China should deepen the construction of marine ecological civilization and form a governance concept based on ecosystems. Overall, this paper helps to understand the internal connection between MESS and policy comprehensively and provides a new perspective for improving China's marine governance capacity.

Magnetic nanoagent assisted deciphering of heterogeneous glycans in extracellular vesicles of varied cellular origins.

Extracellular vesicles bear a rich glycome that presents versatile functions in diverse biological processes. Leverage polydopamine modified magnetic particles to serve as nanosized agents for rapid and robust EV capture and manipulation, we here integrated the easy magnetic actuation with specific lectin-glycan binding and enzyme-mediated fluorescence amplification and thus proposed a facile approach to efficiently decipher a broad spectrum of glycans in EVs. Termed magnetic nanoagent assisted extracellular vesicle glycan deciphering (MAEG), the developed assay utilized a magnet as the assistant operation tool and realized fast (∼1 h) and sensitive (a limit of detection of ∼0.7 µg/mL vesicles) EV glycan analysis in a simple low-cost (around 2.27 Chinese Yuan for one test) manner without requirement of any sophisticated platforms. With robust performance for different sample species, the assay achieved to depict the comprehensive glycosylation landscapes for varied EVs derived from eight cell lines focusing on non-small-cell lung cancer. Systematic analyses clearly revealed the high heterogeneity in glycan features of EVs of varied cellular origins. Using an established difference network method, unique glycan features in different EVs were sifted out and further compiled to construct lectin-denoted patterns as dedicated glycosylation fingerprints, potentially expanding EV-based clinical applications.

Neuroprotective Effect of Hydrogen Sulfide Subchronic Treatment Against TBI-Induced Ferroptosis and Cognitive Deficits Mediated Through Wnt Signaling Pathway.

Emerging evidence shows that targeting ferroptosis may be a potential therapeutic strategy for treating traumatic brain injury (TBI). Hydrogen sulfide (H2S) has been proven to play a neuroprotective role in TBI, but little is known about the effects of H2S on TBI-induced ferroptosis. In addition, it is reported that the Wnt signaling pathway can also actively regulate ferroptosis. However, whether H2S inhibits ferroptosis via the Wnt signaling pathway after TBI remains unclear. In this study, we first found that in addition to alleviating neuronal damage and cognitive impairments, H2S remarkably attenuated abnormal iron accumulation, decreased lipid peroxidation, and improved the expression of glutathione peroxidase 4, demonstrating the potent anti-ferroptosis action of H2S after TBI. Moreover, Wnt3a or liproxstatin-1 treatment obtained similar results, suggesting that activation of the Wnt signaling pathway can render the cells less susceptible to ferroptosis post-TBI. More importantly, XAV939, an inhibitor of the Wnt signaling pathway, almost inversed ferroptosis inactivation and reduction of neuronal loss caused by H2S treatment, substantiating the involvement of the Wnt signaling pathway in anti-ferroptosis effects of H2S. In conclusion, the Wnt signaling pathway might be the critical mechanism in realizing the anti-ferroptosis effects of H2S against TBI. TBI induces ferroptosis-related changes characterized by iron overload, impaired antioxidant system, and lipid peroxidation at the chronic phase after TBI. However, NaHS subchronic treatment reduces the susceptibility to TBI-induced ferroptosis, at least partly by activating the Wnt signaling pathway.

Vascularized polypeptide hydrogel modulates macrophage polarization for wound healing.

Wound repair involves a sophisticated process that includes angiogenesis, immunoregulation and collagen deposition. However, weak revascularization performance and the lack of biochemical cues to trigger immunomodulatory function currently limit biomaterial applications for skin regeneration and tissue engineering. Herein, we fabricate a new bioactive polypeptide hydrogel (QK-SF) constituted by silk fibroin (SF) and a vascular endothelial growth factor mimetic peptide KLTWQELYQLKYKGI (QK) for tissue regeneration by simultaneously promoting vascularization and macrophage polarization. Our results showed that this QK-SF hydrogel can be prepared via an easy manufacturing process, and exhibited good gel stability and low cytotoxicity to cultured human umbilical vein endothelial cells (HUVECs) via both live/dead and cell counting kit-8 assays. Importantly, this QK-SF hydrogel triggered macrophage polarization from M1 into M2, as exemplified by the enhanced expression of the M2 marker and decreased expression of the M1 marker in RAW264.7 cells. Furthermore, the QK-SF hydrogel showed high capacity for inducing endothelial growth, migration and angiogenesis, which were proved by increased expression of angiogenesis-related genes in HUVECs. Consistent with in vitro findings, in vivo data show that the QK-SF hydrogel promoted M2 polarization, keratinocyte differentiation, and collagen deposition in the mouse skin wound model in immunohistochemistry assay. Furthermore, this QK-SF hydrogel can reduce inflammation, induce angiogenesis and promote wound healing as exemplified by the increased vessel formation and decreased wound area in the mouse skin wound model. Altogether, these results indicate that the bioactive QK-SF hydrogel plays dual functional roles in promoting angiogenesis and immunoregulation for tissue regeneration. STATEMENT OF SIGNIFICANCE: The QK-SF hydrogel plays dual functional roles in promoting angiogenesis and immunoregulation for tissue repair and wound healing. The QK-SF hydrogel can be prepared via an easy manufacturing process, and exhibited good gel stability and low cytotoxicity to cultured HUVECs. The QK-SF hydrogel triggered macrophage polarization from M1 into M2. The QK-SF hydrogel showed high capacity for inducing endothelial growth, migration and angiogenesis. The QK-SF hydrogel promoted M2 polarization, keratinocyte differentiation, and collagen deposition.

The relationship between student interaction with generative artificial intelligence and learning achievement: serial mediating roles of self-efficacy and cognitive engagement.

Generative artificial intelligence (GAI) shocked the world with its unprecedented ability and raised significant tensions in the education field. Educators inevitably transition to an educational future that embraces GAI rather than shuns it. Understanding the mechanism between students interacting with GAI tools and their achievement is important for educators and schools, but relevant empirical evidence is relatively lacking. Due to the characteristics of personalization and real-time interactivity of GAI tools, we propose that the students-GAI interaction would affect their learning achievement through serial mediators of self-efficacy and cognitive engagement. Based on questionnaire surveys that include 389 participants as the objective, this study finds that: (1) in total, there is a significantly positive relationship between student-GAI interaction and learning achievement. (2) This positive relationship is mediated by self-efficacy, with a significant mediation effect value of 0.015. (3) Cognitive engagement also acts as a mediator in the mechanism between the student-GAI interaction and learning achievement, evidenced by a significant and relatively strong mediating effect value of 0.046. (4) Self-efficacy and cognitive engagement in series mediate this positive association, with a serial mediating effect value of 0.011, which is relatively small in comparison but also shows significance. In addition, the propensity score matching (PSM) method is applied to alleviate self-selection bias, reinforcing the validity of the results. The findings offer empirical evidence for the incorporation of GAI in teaching and learning.

Construction of Active Protein Materials: Manipulation on Morphology of Salmon Calcitonin Assemblies with Enhanced Bone Regeneration Effect.

The effect of protein drugs is always limited by their relatively low stability and fast degradation property; thus, various elegant efforts have been made to improve the bioactivity and biocompatibility of the protein drugs. Here, an alternative way is proposed to solve this problem. By simply adding a limited amount of small-molecular regulator, which tunes the subtle balance of protein-protein interactions (PPIs) and disulfide bond formation, the self-assembly property of the protein drug can be regulated, forming an "active protein material" itself. This means that, the resulting biomaterial is dominated by the protein drug and water, with significantly enhanced bone regeneration effect compared to the virgin protein in vitro and in vivo, through multivalent effect between the protein and receptor and the retarded degradation of the assembled proteins. In this active protein material, the protein drug is not only the active drug, but also the drug carrier, which greatly increases the drug-loading efficiency of the biomaterial, indicating the advantages of the easy preparation, high efficiency, and low cost of the active protein material with a bright future in biomedical applications.

Notch-activated mesenchymal stromal/stem cells enhance the protective effect against acetaminophen-induced acute liver injury by activating AMPK/SIRT1 pathway.

BACKGROUND: Notch signaling plays important roles in regulating innate immunity. However, little is known about the role of Notch in mesenchymal stromal/stem cell (MSC)-mediated immunomodulation during liver inflammatory response. METHODS: Notch activation in human umbilical cord-derived MSCs was performed by a tissue culture plate coated with Notch ligand, recombinant human Jagged1 (JAG1). Mice were given intravenous injection of Notch-activated MSCs after acetaminophen (APAP)-induced acute liver injury. Liver tissues were collected and analyzed by histology and immunohistochemistry. RESULTS: MSC administration reduced APAP-induced hepatocellular damage, as manifested by decreased serum ALT levels, intrahepatic macrophage/neutrophil infiltration, hepatocellular apoptosis and proinflammatory mediators. The anti-inflammatory activity and therapeutic effects of MSCs were greatly enhanced by Notch activation via its ligand JAG1. However, Notch2 disruption in MSCs markedly diminished the protective effect of MSCs against APAP-induced acute liver injury, even in the presence of JAG1 pretreatment. Strikingly, Notch-activated MSCs promoted AMP-activated protein kinase (AMPKα) phosphorylation, increased the sirtuins 1 (SIRT1) deacetylase expression, but downregulated spliced X-box-binding protein 1 (XBP1s) expression and consequently reduced NLR family pyrin domain-containing 3 (NLRP3) inflammasome activation. Furthermore, SIRT1 disruption or XBP1s overexpression in macrophages exacerbated APAP-triggered liver inflammation and augmented NLRP3/caspase-1 activity in MSC-administrated mice. Mechanistic studies further demonstrated that JAG1-pretreated MSCs activated Notch2/COX2/PGE2 signaling, which in turn induced macrophage AMPK/SIRT1 activation, leading to XBP1s deacetylation and inhibition of NLRP3 activity. CONCLUSIONS: Activation of Notch2 is required for the ability of MSCs to reduce the severity of APAP-induced liver damage in mice. Our findings underscore a novel molecular insights into MSCs-mediated immunomodulation by activating Notch2/COX2/AMPK/SIRT1 pathway and thus provide a new strategy for the treatment of liver inflammatory diseases.

Self-Assembled Nanospheres with Enhanced Interfacial Lubrication for the Treatment of Osteoarthritis.

Osteoarthritis is associated with an increase in mechanical friction of the joint, which causes irreversible damage to articular cartilage. Consequently, it is crucial to restore joint lubrication for effectively treating osteoarthritis. In the present study, hyaluronic acid (HA)-based zwitterionic nanospheres with phosphocholine groups on the surface were synthesized, which achieved excellent lubrication behavior due to the hydration lubrication mechanism. Specifically, HA was initially thiolated and modified with hexadecylamine based on an amidation reaction, then it was grafted with 2-methacryloyloxyethyl phosphocholine (MPC) by the thiol-ene click reaction, and finally self-assembled into nanospheres (HA-MPC) by hydrophobic interaction and cross-linking of the thiol group. The lubrication test demonstrated that the HA-MPC nanospheres improved lubrication under shear force, with a 40% reduction in the friction coefficient compared with HA. The in vitro experiment indicated that the HA-MPC nanospheres had excellent biocompatibility, and they upregulated the cartilage anabolic gene and downregulated cartilage catabolic proteases as well as the pain-related gene. The in vivo test showed that the injection of HA-MPC nanospheres to the joint cavity could inhibit the development of osteoarthritis, which was examined based on histological staining and also morphological evaluation. In conclusion, the new self-assembled zwitterionic HA-MPC nanospheres may be intra-articularly injected for the effective treatment of osteoarthritis by restoring joint lubrication.

How Does Social Currency Influence Prosocial Behavior? The Role of Collective Self-Esteem and Communication Network Heterogeneity.

The social currency, the existing potential resource in the social networks and communities of an individual, has become more significant in the era of information technology. Meanwhile, the rapid development of Internet service, especially its application on mobile devices, brings many new contents of prosocial behaviors (PBs), which benefits both individuals and communities. Specifically, social currency plays a positive role in promoting PB, forming positive personalities, promoting positive social adaptation, and contributing to human survival and social development. However, the theoretical research in this field still lags far behind the development of practice, and the research on the impact of social currency on PB remains exceedingly scarce. Grounded in the social exchange theory (SET), the present study collects a total of 497 WeChat user questionnaires, constructs a model for the influence mechanism of social currency on PB, and tests the hypothesis through hierarchical regression. According to the results obtained, it was found that the social currency is positively associated with PB, and users with a more social currency are more likely to act prosocially on their own. The PB of an individual is then influenced by the social currency generated through collective self-esteem (CS) so that the perception of CS can be considered as a mediating variable. Moreover, the communication network heterogeneity (CNH) moderates the above relationship, and the degree of heterogeneity will have different effects on the relationship of CS. The obtained conclusions enrich the previous theoretical results of PB and provided new insights for social managers to enhance the prosocial-related behaviors for the group, organization, and society.

The Antecedents of Thriving at Work: A Meta-Analytic Review.

In this study, a systematic and comprehensive meta-analysis of the relationship between thriving at work and its antecedents is conducted. The antecedents in terms of the characteristics of unit contextual features, the resources produced at work, agentic work behaviors, and personality traits are illustrated according to the socially embedded model of thriving described by Spreitzer and research. Additionally, we examine possible cultural influence on the relationship between thriving and its antecedents at different levels of individualistic culture. According to 67 independent samples (N = 28,097), our findings reveal the correlations between thriving at work and the antecedents such as those in the form of unit contextual features, the resources produced at work, agentic work behaviors, and personality traits. Furthermore, we find that individualism moderate the relationships between certain antecedents and thriving at work. Finally, we discuss the theoretical and practical implications of this study as well as the directions for future research.

Extra- and Intra-Cellular Mechanisms of Hepatic Stellate Cell Activation.

Hepatic fibrosis is characterized by the pathological accumulation of extracellular matrix (ECM) in the liver resulting from the persistent liver injury and wound-healing reaction induced by various insults. Although hepatic fibrosis is considered reversible after eliminating the cause of injury, chronic injury left unchecked can progress to cirrhosis and liver cancer. A better understanding of the cellular and molecular mechanisms controlling the fibrotic response is needed to develop novel clinical strategies. It is well documented that activated hepatic stellate cells (HSCs) is the most principal cellular players promoting synthesis and deposition of ECM components. In the current review, we discuss pathways of HSC activation, emphasizing emerging extra- and intra-cellular signals that drive this important cellular response to hepatic fibrosis. A number of cell types and external stimuli converge upon HSCs to promote their activation, including hepatocytes, liver sinusoidal endothelial cells, macrophages, cytokines, altered ECM, hepatitis viral infection, enteric dysbiosis, lipid metabolism disorder, exosomes, microRNAs, alcohol, drugs and parasites. We also discuss the emerging signaling pathways and intracellular events that individually or synergistically drive HSC activation, including TGFß/Smad, Notch, Wnt/ß-catenin, Hedgehog and Hippo signaling pathways. These findings will provide novel potential therapeutic targets to arrest or reverse fibrosis and cirrhosis.

Effects of posterior tibial slope on the mid-term results of medial unicompartmental knee arthroplasty.

OBJECTIVE: To evaluate the effect of medial posterior tibial slope (PTS) on mid-term postoperative range of motion (ROM) and functional improvement of the knee after medial unicompartmental knee arthroplasty (UKA). METHODS: Medical records of 113 patients who had undergone 124 medial UKAs between April 2009 through April 2014 were reviewed retrospectively. The mean follow-up lasted 7.6 years (range, 6.2-11.2 years). Collected were demographic data, including gender, age, height, weight of the patients. Anteroposterior (AP) and lateral knee radiographs of the operated knees were available in all patients. The knee function was evaluated during office follow-up or hospital stay. Meanwhile, postoperative PTS, ROM, maximal knee flexion and Hospital for Special Surgery (HSS) knee score (pre-/postoperative) of the operated side were measured and assessed. According to the size of the PTS, patients were divided into 3 groups: group 1 (<4°), group 2 (4° ~ 7°) and group 3 (>7°). The association between PTS and the knee function was investigated. RESULTS: In our cohort, the average PTS was 2.7° ± 0.6° in group 1, 5.6° ± 0.9° in group 2 and 8.7° ± 1.2° in group 3. Pairwise comparisons showed significant differences among them (p < 0.01). The average maximal flexion range of postoperative knees in each group was 112.4° ± 5.6°, 116.4° ± 7.2°, and 117.5° ± 6.1°, respectively, with significant difference found between group 1 and group 2 (p < 0.05), and between group 1 and group 3 (p < 0.05). However, the gender, age, and body mass index (BMI) did not differ between three groups and there was no significant difference between groups in terms of pre-/postoperative HSS scores or postoperative knee ROM. CONCLUSION: A mid-term follow-up showed that an appropriate PTS (4° ~ 7°) can help improve the postoperative flexion of knee. On the other hand, too small a PTS could lead to limited postoperative knee flexion. Therefore, the PTS less than 4° should be avoided during medial UKA.

The impact of online reviews in the presence of customer returns.

We develop a duopoly model to examine how online reviews influence the decisions of two competing online sellers who sell products of differentiated quality under different returns policies. We derive the competing sellers' optimal decisions on price and returns policy with and without online reviews, and we find that online reviews have greater impact on the high-quality seller than on the low-quality seller. If the salvage value of the product is relatively low, the seller has less opportunity to benefit from online reviews when it offers an MBG, as compared to a no-refund policy. The impact of online reviews on the competition between the two sellers has a "symmetric effect area," where reviews may either weaken or intensify the price competition between the two sellers when they both offer a no-refund policy, but always intensify the competition if they both offer an MBG. We have identified the conditions under which online reviews lead to a win-win, or benefit one seller, or present a prisoner's dilemma for the two online sellers. We also show that MBGs at both sellers help mitigate the prisoner's dilemma if the net salvage value at both sellers is sufficiently high.

High Mineralization Capacity of IDG-SW3 Cells in 3D Collagen Hydrogel for Bone Healing in Estrogen-Deficient Mice.

Tissue engineering with 3D scaffold is a simple and effective method for bone healing after large-scale bone loss. So far, bone marrow-derived mesenchymal stem cells (BMSCs) are mostly used in the treatment of bone healing in animal models due to their self-renewal capability and osteogenic potential. Due to the fact that the main functional cells in promoting osteoid mineralization and bone remodeling were osteocytes, we chose an osteoblast-to-osteocyte transition cell line, IDG-SW3, which are not proliferative under physiological conditions, and compared the healing capability of these cells to that of BMSCs in bone defect. In vitro, IDG-SW3 cells revealed a stronger mineralization capacity when grown in 3D collagen gel, compared to that of BMSCs. Although both BMSC and IDG-SW3 can generate stable calcium-phosphate crystal similar to hydroxyapatite (HA), the content was much more enriched in IDG-SW3-mixed collagen gel. Moreover, the osteoclasts co-cultured with IDG-SW3-mixed collagen gel were easier to be activated, indicating that the IDG-SW3 grafting could promote the bone remodeling more efficiently in vivo. Last, in order to reduce the self-healing capability, we assessed the healing capability between the IDG-SW3 cells and BMSCs in osteoporotic mice. We found that the collagen hydrogel mixed with IDG-SW3 cells has a better healing pattern than what was seen in hydrogel mixed with BMSCs. Therefore, these results demonstrated that by promoting osteoblast-to-osteocyte transition, the therapeutic effect of BMSCs in bone defect repair could be improved.

Consecutive dephosphorylation by alkaline phosphatase-directed in situ formation of porous hydrogels of SF with nanocrystalline calcium phosphate ceramics for bone regeneration.

Alkaline phosphatase, as an enzyme involved in the process of bone mineralization and regeneration, was incorporated into a solution of SF to induce its gelation and mineralization through consecutive dephosphorylation actions on different substrates. In these processes, alkaline phosphatase firstly worked on a small peptide of NapGFFYp by removing its hydrophilic phosphate group. The resulted NapGFFY performed supramolecular assembly in the solution of SF and synergistically induced the conformation transition of SF from random coil to ß-sheet structures, leading to the formation of a stable SF hydrogel under physiological conditions. And then, the entrapped ALP within the SF-NY gel network retained its catalytic activity, released phosphate ions from glycerophosphate, and catalysed the formation of calcium phosphate minerals within the porous gel. Because of the mild conditions of these processes and good biocompatibility of the scaffold, the mineralized SF gel can work as a biomimetic scaffold to promote the osteogenic differentiation of rBMSCs and stimulate femoral defect regeneration in a rat model.

Cartilage matrix-inspired biomimetic superlubricated nanospheres for treatment of osteoarthritis.

The superlubrication of natural joint has been attributed to hydration lubrication of articular cartilage. Here, inspired by the structure of phosphatidylcholine lipid (a typical cartilage matrix) with the presence of zwitterionic charges, we developed superlubricated nanospheres, namely poly (2-methacryloyloxyethyl phosphorylcholine)-grafted mesoporous silica nanospheres (MSNs-NH2@PMPC), via photopolymerization. The biomimetic nanospheres could enhance lubrication due to the formation of a tenacious hydration layer surrounding the zwitterionic charges of polymer brushes (PMPC), and achieve local delivery of an anti-inflammatory drug employing the nanocarriers (MSNs). The tribological and drug release tests showed improved lubrication and sustained drug release of the nanospheres. Additionally, the in vitro and in vivo tests revealed that the superlubricated drug-loaded nanospheres inhibited the development of osteoarthritis by up-regulating cartilage anabolic components and down-regulating catabolic proteases and pain-related gene. The nanospheres, with an integrated feature of both enhanced lubrication and sustained drug delivery, can be an efficient intra-articular nanomedicine for the treatment of osteoarthritis.

O-Mannosylation Affords a Glycopeptide Hydrogel with Inherent Antibacterial Activities against E. coli via Multivalent Interactions between Lectins and Supramolecular Assemblies.

Multivalent carbohydrate-lectin interactions play a crucial role in bacterial infection. Biomimicry of multivalent glycosystems represents a major strategy in the repression of bacterial growth. In this study, a new kind of glycopeptide (Naphthyl-Phe-Phe-Ser-Tyr, NMY) scaffold with mannose modification is designed and synthesized, which is able to perform supramolecular self-assembly with the assistance of catalytic enzyme, and present multiple mannose ligands on its self-assembled structure to target mannose-binding proteins. Relying on multivalent carbohydrate-lectin interactions, the glycopeptide hydrogel is able to bind Escherichia coli (E. coli) in high specificity, and result in bacterial adhesion, membrane disruption and subsequent cell death. In vivo wound healing assays reveal that this glycopeptide hydrogel exhibits considerable potentials for promoting wound healing and preventing E. coli infection in a full-thickness skin defect mouse model. Therefore, through a specific mannose-lectin interaction, a biocompatible hydrogel with inherent antibacterial activity against E. coli is achieved without the need to resort to antibiotic or antimicrobial agent treatment, highlighting the potential role of sugar-coated nanomaterials in wound healing and control of bacterial pathogenesis.

Glucosamine sulphate-loaded distearoyl phosphocholine liposomes for osteoarthritis treatment: combination of sustained drug release and improved lubrication.

Osteoarthritis (OA) is a chronic joint disease resulting from joint inflammation and damage. In this study, we employed a boundary lubricant known as a 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC) liposome for loading of an anti-inflammatory drug d-glucosamine sulphate (GAS) to construct a treatment strategy allowing for sustained anti-inflammation and reduced damage. This kind of drug-loaded nanocarrier integrates the anti-inflammatory effect of the GAS and the lubrication ability of DSPC liposomes without the involvement of complex synthesis processes leading to easier popularization. Our experimental results indicated that the GAS-loaded DSPC liposomes could release GAS in a sustained manner while providing good lubrication in pure water (H2O) and phosphate buffered saline (PBS). Moreover, the GAS-loaded DSPC liposomes prepared at a 2 : 8 molar ratio in PBS exhibited a greater entrapment efficiency, lower GAS release rate and smaller friction coefficient as compared to those prepared in H2O. The superiority of the drug release and lubrication ability achieved with the GAS-loaded DSPC liposomes in PBS were elucidated on the basis of salt-induced enhancement in liposomal stability and hydration lubrication by the hydrated salt ions. Such GAS release accelerated the viability and proliferation of primary mouse chondrocytes while also providing the anti-inflammatory and chondroprotective potential for tumor necrosis factor (TNF-α) induced chondrocyte degeneration through the down-regulation of pro-inflammatory cytokines, pain related gene and catabolic proteases, as well as the up-regulation of anabolic components. We envision that the GAS-loaded DSPC liposomes could represent a promising new strategy for clinical treatment of OA in the future.

TRAF6 neddylation drives inflammatory arthritis by increasing NF-κB activation.

Neddylation is a process similar to ubiquitination, and is critical in various inflammatory diseases; however, its importance in the pathogenesis of inflammatory arthritis is not well understood. Here, we investigated the role of neddylation in collagen-induced arthritis (CIA) and its clinical relevance. We showed that neddylation-related genes, including NEDD8 and CULLIN-1, were significantly upregulated in inflamed arthritic synovia. Functionally, neddylation activation was crucial for synovitis of CIA, as the inhibition of neddylation by MLN4924 significantly suppressed synovial cell proliferation and inflammatory responses. Mechanistically, neddylation mediated inflammatory arthritis by regulating NF-κB activation in fibroblast-like synovial cells (FLSs). Furthermore, TNF receptor-associated factor 6 (TRAF6) neddylation at Lys124 was essential for IL-17A-induced NF-κB activation. Replacing the Lys-124 residue with Arg (K124R) resulted in significantly impaired conjugation of NEDD8 to TRAF6, as well as markedly attenuated IL-17A-induced NF-κB activity. Therefore, the pathogenic role of neddylation in CIA as well as its mechanism of action demonstrated here provides a new insight into understanding the role of post-transcriptional modifications in the arthritis inflammatory response.