Sialic Acid-Functionalized Pyroptosis Nanotuner for Epigenetic Regulation and Enhanced Cancer Immunotherapy.

The efficacy of immune checkpoint blockade (ICB) in promoting an immune response against tumors still encounters challenges such as low response rates and off-target effects. Pyroptosis, an immunogenic cell death (ICD) mechanism, holds the potential to overcome the limitations of ICB by activating and recruiting immune cells. However, the expression of the pyroptosis-related protein Gasdermin-E(GSDME) in some tumors is limited due to mRNA methylation. To overcome this obstacle, sialic acid-functionalized liposomes coloaded with decitabine, a demethylation drug, and triclabendazole, a pyroptosis-inducing drug are developed. This nanosystem primarily accumulates at tumor sites via sialic acid and the Siglec receptor, elevating liposome accumulation in tumors up to 3.84-fold at 24 h and leading to the upregulation of pyroptosis-related proteins and caspase-3/GSDME-dependent pyroptosis. Consequently, it facilitates the infiltration of CD8+ T cells into the tumor microenvironment and enhances the efficacy of ICB therapy. The tumor inhibition rate of the treatment group is 89.1% at 21 days. This study highlights the potential of sialic acid-functionalized pyroptosis nanotuners as a promising approach for improving the efficacy of ICB therapy in tumors with low GSDME expression through epigenetic alteration and ICD.

Glutamine promotes the proliferation of epithelial cells via mTOR/S6 pathway in oral lichen planus.

BACKGROUND: Although abnormal cell proliferation and apoptosis are associated with the pathogenesis of oral lichen planus (OLP), the exactly mechanism of which is not yet known. It has been reported that glutamine (Gln) can promote cell proliferation and inhibit apoptosis of various tumor cells. This study aims to evaluate the effect of Gln metabolism on the balance of proliferation and apoptosis in epithelial cells of OLP. METHODS: Thirty human OLP specimens and 11 normal controls were stained by immunohistochemistry to detect the levels of proliferation and Gln metabolism related proteins. Then, the critical role of Gln in cell proliferation and apoptosis was determined by Gln deprivation or treatment with glutaminase inhibitor (CB-839) to intervene Gln metabolism in human gingival epithelial cells. Cell proliferation was detected using CCK8, p-mTOR and p-S6 proteins were detected using Western Blot, cell apoptosis and cell cycle were detected using flow cytometry, and cell stress was detected using immunofluorescence. RESULTS: Compared with normal controls, OLP specimens showed higher levels of Ki-67 and Gln metabolism-related proteins, including Gln transporter (ASCT2), glutaminase (GLS), and pathway proteins (p-mTOR and p-S6). In vitro, Gln promoted cell proliferation and simultaneously upregulated the activity of mTOR/S6 pathway. Moreover, rapamycin, an mTOR pathway inhibitor, could effectively block the Gln-induced cell proliferation. MHY1485, an mTOR pathway agonist, could effectively reverse the decline of cell proliferation under Gln deprivation. In addition, inhibiting Gln metabolism caused the accumulation of intracellular radical oxygen species (ROS) and induced cell apoptosis. However, N-acetylcysteine reversed this state and then decreased cell apoptosis by eliminating intracellular ROS. CONCLUSION: Gln metabolism is essential to maintain the balance of proliferation and apoptosis in oral epithelial cells, and inhibition of Gln metabolism may have a beneficial effect on OLP treatment.

ZnO nanoparticles embedded in hollow carbon fiber membrane for electrochemical H2O2 production by two-electron water oxidation reaction.

Electrochemical two-electron water oxidation reaction (2e-WOR) provides a promising alternative route for hydrogen peroxide (H2O2) production, where the design of earth abundant and environmentally friendly electrocatalysts with both high selectivity and production rate is crucial. Here we report the synthesis of ZnO nanoparticles embedded in hollow carbon fiber membrane as efficient 2e-WOR electrocatalyst by a metal-organic framework engaged electrospinning-pyrolysis method. The resultant ZnO@carbon composite fiber exhibits a foam-like hierarchical structure composed of interconnected hollow carbon nanocubes encapsulated with oxygen vacancy rich ZnO nanocrystals. Owing to the improved selectivity of ZnO, excellent conductivity of carbon fiber, promoted active site exposure and mass transfer of hollow structure, the free-standing membrane electrode shows superior 2e-WOR performances with high selectivity (83.8% at 2.8 V vs. RHE), H2O2 generation rate (19.7 µmol cm-2 min-1) and robust stability.

An injectable thermosensitive hyaluronic acid/pluronic F-127 hydrogel for deep penetration and combination therapy of frozen shoulder.

Frozen shoulder (FS) is a common and progressive shoulder disorder that causes glenohumeral joint stiffness, characterized by inflammation and fibrosis. The treatment options are quite limited, and the therapeutic response is hindered by the fibrous membrane formed by excessive collagen and the rapid removal by synovial fluid. To address these challenges, we designed a hyaluronic acid/Pluronic F-127 (HP)-based injectable thermosensitive hydrogel as a drug carrier loaded with dexamethasone and collagenase (HPDC). We screened for an optimal HP hydrogel that can sustain drug release for approximately 10 days both in vitro and in vivo. In the meanwhile, we found that HP hydrogel could inhibit the proliferation and diminish the adhesion capacity of rat synovial cells induced by transforming growth factor-ß1. Furthermore, using an established immobilization rat model of FS, intra-articular injection of HPDC significantly improved joint range of motion compared to medication alone. Relying on sustained drug release, the accumulated collagen fibers were degraded by collagenase to promote the deep delivery of dexamethasone. These findings showed a positive combined treatment effect of HPDC, providing a novel idea for the comprehensive treatment of FS.

MicroRNA-146a-loaded magnesium silicate nanospheres promote bone regeneration in an inflammatory microenvironment.

Reconstruction of irregular oral-maxillofacial bone defects with an inflammatory microenvironment remains a challenge, as chronic local inflammation can largely impair bone healing. Here, we used magnesium silicate nanospheres (MSNs) to load microRNA-146a-5p (miR-146a) to fabricate a nanobiomaterial, MSN+miR-146a, which showed synergistic promoting effects on the osteogenic differentiation of human dental pulp stem cells (hDPSCs). In addition, miR-146a exhibited an anti-inflammatory effect on mouse bone marrow-derived macrophages (BMMs) under lipopolysaccharide (LPS) stimulation by inhibiting the NF-κB pathway via targeting tumor necrosis factor receptor-associated factor 6 (TRAF6), and MSNs could simultaneously promote M2 polarization of BMMs. MiR-146a was also found to inhibit osteoclast formation. Finally, the dual osteogenic-promoting and immunoregulatory effects of MSN+miR-146a were further validated in a stimulated infected mouse mandibular bone defect model via delivery by a photocuring hydrogel. Collectively, the MSN+miR-146a complex revealed good potential in treating inflammatory irregular oral-maxillofacial bone defects.

Upregulation of IL-37 in epithelial cells: A potential new mechanism of T cell inhibition induced by tacrolimus.

Oral lichen planus (OLP) is a chronic T cell-mediated mucocutaneous disease characterized by T cell infiltration at the connective tissue-epithelium interface. Traditionally, topical corticosteroids are used as the first-line drugs to treat OLP. However, long-term use of corticosteroids may lead to drug tolerance, secondary candidiasis, and autoimmune adrenal insufficiency. Although topical tacrolimus has often been recommended for short-term use in corticosteroid-refractory OLP, the precise role of tacrolimus in epithelial cells remains elusive. This study showed that tacrolimus could directly upregulate the expression of IL-37 in human gingival epithelial cells by promoting the TGF-ßRI/Smad3 pathway independently of calcineurin inhibition and MAPKs. In contrast, dexamethasone, one of the corticosteroids, did not have the same effect. Moreover, IL-37 could inhibit the proliferation of activated T cells and the secretion of effector cytokines and alleviate epithelial cell apoptosis and death caused by activated T cells ina co-culturesystem. Furthermore, compared with healthy controls, IL-37 and p-Smad3 levels significantly increased in the oral mucosa affected by OLP, especially in the epithelium. IL-37 might have mediated a negative feedback mechanism to curb excessive inflammation in OLP. However, the expression of IL-37 was not associated with the infiltration of CD8+ T cells and Tregs in OLP, implying that IL-37 might mostly affect T cell activation rather than T cell differentiation and migration. Overall, this study discovered a potential novel mechanism by which tacrolimus might indirectly inhibit T cell-mediated immune damage by upregulating IL-37 in human gingival epithelial cells.

ASCT2-mediated glutamine uptake of epithelial cells facilitates CCL5-induced T cell infiltration via ROS-STAT3 pathway in oral lichen planus.

BACKGROUND: Oral lichen planus (OLP) is a chronic inflammatory disease characterized by T cell infiltration at lesion sites. T cell migration is greatly facilitated by chemokines produced by epithelial cells. Studies have noted the potential role of glutamine uptake in OLP and other inflammatory diseases. Here, we investigated the effect of altered glutamine uptake of epithelial cells on T cell infiltration and its underlying mechanisms in OLP. METHODS: Immunohistochemistry was used to identify the expressions of glutamine transporter alanine-serine-cysteine transporter 2 (ASCT2) and C-C motif chemokine ligand 5 (CCL5) in oral tissues of OLP and healthy controls. Human gingival epithelial cells (HGECs) were treated with glutamine deprivation and ASCT2 inhibiter GPNA respectively to detect the expressions of CCL5 and its related signaling molecules. Additionally, we had determined the impact of epithelial cell-derived CCL5 on T-cell migration using a co-culture system in vitro. RESULTS: ASCT2 and CCL5 expressions in OLP were significantly higher than healthy controls and positively correlated with the density of inflammatory infiltrations. Glutamine supplement significantly increased CCL5 production in HGECs, which was effectively inhibited by GPNA. Besides, glutamine could inhibit reactive oxygen species (ROS) production to activate the signal transducer and activator of transcription 3 (STAT3) causing higher expression level of CCL5 in HGECs. Simultaneously, T cell migration could be blocked by anti-CCL5 neutralizing antibody and STAT3 inhibitor stattic in the co-culture system. CONCLUSION: The upregulated ASCT2-mediated glutamine uptake in epithelial cells promotes CCL5 production via ROS-STAT3 signaling, which boosts the T-cell infiltration in OLP lesion.

Functionalizing Ti3C2Tx for enhancing fire resistance and reducing toxic gases of flexible polyurethane foam composites with reinforced mechanical properties.

Flexible polyurethane foam (FPUF) is the most used polyurethane, but the highly flammable characteristic limits its widespread usage. In this work, ZIF-8@Ti3C2Txwas synthesized to reduce the heat and toxic gases of FPUF. Flame-retardant FPUF was characterized by cone calorimeter (Cone), thermogravimetric analysis/fourier-transform infrared spectroscopy (TG-FTIR), tensileand compression tests. Compared with pure FPUF, these results showed that the peak of heat release rate (PHRR), total heat release (THR), CO and HCN of FPUF6 decreased by 46%, 69%, 27% and 43.5%, respectively. Moreover, the tensile and compression strength of FPUF6 demonstrated a 52% and 130% increment, respectively. The superior dual metal catalytical charring-forming effect and physical barrier effect of ZIF-8@Ti3C2Tx were achieved. In summary, a simple and reliable strategy for preparing flame-retardant FPUF with reinforced mechanical and fire safety properties was provided.

Design of copper salt@graphene nanohybrids to accomplish excellent resilience and superior fire safety for flexible polyurethane foam.

Flexible polyurethane foam (FPUF) is the most commonly used polyurethane, but its highly flammable characteristics makes it ignite easily and release a lot of heat and toxic gases. Here, the effect of different forms of copper salt modified graphene (rGO@CuO, rGO@Cu2O and rGO@CSOH) on improving the fire protection efficiency and mechanical property of FPUF is explored. Hybrid FPUF is characterized by thermogravimetric analysis (TGA), cone calorimeter, thermogravimetric analysis/Fourier transform infrared spectroscopy (TG-IR), tension, compression, and falling ball rebound testing. Compared with pure FPUF, the FPUF/rGO@CSOH show a significant decreasement in reducing the heat release of FPUF, the PHRR and THR are reduced by 36.9% and 29.4%, respectively. While the FPUF/rGO@Cu2O demonstrate excellent smoke and toxic gases suppression in FPUF, the PSPR and TSR are reduced by 24.6% and 51.9%, and the COP and COY are also reduced by 51.9% and 55.3%, respectively. After adding the copper salt hybrid, the buffering performance of FPUF did not change. Fortunately, the tensile and compressive strength increase obviously. The flame retardant and smoke suppression mechanism of hybrid FPUF has also been studied. This article gives a effective strategy for the preparation of FPUF with outstanding mechanical property, flame retardant and smoke suppression properties.

Sharing on Facebook and Face-to-Face What Others Do or Approve: Word-of-Mouth Driven by Social Norms.

Information sharing on social media [i.e., electronic word-of-mouth, (eWOM) and face-to-face word-of-mouth (fWOM)] plays an important role in message dissemination. This study investigates the effectiveness of group norms in motivating eWOM and fWOM. Drawing upon the psychological distance and construal level literature, this study tests the impact of group norms, the interaction effect of norms type (descriptive vs. injunctive norms), and the group distance on eWOMand fWOM. Based on one field study and three laboratory experiments, this study finds that normative cues in messages are impactful in driving WOM and the impact becomes especially stronger when the psychological distance of the social group is congruent with that of norms type tied to the group. Specifically, an interaction effect emerges, such as distant (close) group injunctive (descriptive) norms, are more impactful in driving WOM than close (distant) group injunctive (descriptive) norms. Contrary to the conventional wisdom that a close group has greater impacts than distant groups in terms of social influence, this study shows that messages with distant groups are more (or at least equally) likely to be shared than with a close group when tied with injunctive norms. The findings suggest that group norms are perceived to be more relevant when there is a match between the psychological distance of the social group and the norms type tied to the group.

Anti-inflammatory effect of IL-1ra-loaded dextran/PLGA microspheres on Porphyromonas gingivalis lipopolysaccharide-stimulated macrophages in vitro and in vivo in a rat model of periodontitis.

Periodontitis is a multifactorial chronic infectious disease leading to a host immune response involving inflammatory cytokines, especially IL-1ß, which is the main reason for further developing this disease. IL-1 receptor antagonist (IL-1ra) binds IL-1 receptor, inhibiting IL-1ß signaling and reducing the levels of other cytokines closely related to periodontitis, such as IL-6 and TNF-α. Therefore, the use of IL-1ra to inhibit periodontitis development in a system, ensuring its sustained release, might be an effective way to combat this disease. Hence, in this study, a novel IL-1ra-loaded dextran/PLGA microsphere was developed to allow the sustained release of IL-1ra and enhance the anti-inflammatory properties. Therefore, this study's purposes were to develop a novel periodontal treatment for inhibition and treatment of periodontitis and evaluate the sustained-release effect and anti-inflammatory properties of IL-1ra-loaded dextran/PLGA microspheres in vitro by cell experiments and in vivo by animal experiments. The results showed that IL-1ra-loaded dextran/PLGA microspheres were non-toxic both in vitro and in vivo and could be used as a safe and effective treatment. In addition, these microspheres could significantly prolong the half-life of IL-1ra drug, exerting a useful anti-inflammatory effect in macrophages stimulated with P. gingivalis lipopolysaccharide and in rats with periodontitis. In conclusion, IL-1ra-loaded dextran/PLGA microsphere might be a useful tool to combat periodontal disease.

A facile strategy for lightweight, anti-dripping, flexible polyurethane foam with low smoke emission tendency and superior electromagnetic wave blocking.

Flexible polyurethane foam (FPUF) has been considered as an excellent material in many fields, such as furniture and electromagnetic interference (EMI) shielding products due to its lightweight and flexibility. However, there is a severe fire hazard problem for FPUF that makes it unsuitable to be used in practical. Herein, a facile method was to prepare anti-dripping FPUF via electroless plating at ambient temperature. The silver nanoparticles (SNPs) were in-situ grown on the surface along with the polydopamine (PDA) as an adhesive and template (SNP@PDA@FPUF). As a result, these FPUFs show outstanding fire safety and anti-dripping capacity, and the heat release rate reduced 80.92%. Furthermore, the amounts of carbon oxide (CO) and carbon dioxide (CO2) decreased 75.01% and 22.4%, respectively. Above all, the EMI shielding effectiveness (SE) accomplished almost 120 dB as the increasing electroless time with a low density of 0.051 g/cm3. Furthermore, the specific EMI SE (SSE) and the absolute EMI SE (SSE/t) accomplished 2630.98 dB·cm3/g and 2434 dB·cm2/g, respectively, which was far beyond the commercial request. Therefore, this work may provide a facile way to prepare low density and EMI shielding products with high fire safety for next generation electronic products.

Preparation and Evaluation of IL-1ra-Loaded Dextran/PLGA Microspheres for Inhibiting Periodontal Inflammation In Vitro.

Periodontitis is a chronic infectious disease, the course and progression of which are determined by the interaction between microorganisms and the host. Interleukin 1ß plays an important role in the destruction of periodontal tissues. Interleukin 1 receptor antagonist (IL-1ra) can inhibit the biological activity of IL-1ß without triggering any intracellular signaling. This study aimed to prepare IL-1ra-loaded dextran/PLGA microspheres and evaluate the physical and chemical characteristics and anti-inflammatory properties. Results suggested that the microspheres can be easily prepared into a drug carrier with good biocompatibility and can effectively inhibit the gene expression of pro-inflammatory factors induced by IL-1ß in human gingival fibroblasts. Hence, the microspheres are excellent candidate for periodontitis treatment.