Impact of different types of temporomandibular disorders on jaw functional limitation and psychological distress in orthodontic patients.

BACKGROUND: Some orthodontic patients are associated with temporomandibular joint disorders (TMDs), and the differences between jaw function and psychological states in orthodontic patients with different types of TMDs remain unknown. OBJECTIVE: This cross-sectional study aimed to investigate the prevalence of different types of TMDs in orthodontic patients and to evaluate the relationship between different types of TMDs and jaw functional limitation and psychological distress in orthodontic patients. METHODS: A questionnaire was sent to patients willing to participate in this survey, which included questions about the demographic characteristics of the participants, the five TMD symptoms (5Ts) of the Diagnostic Criteria for TMDs, the Jaw Functional Limitation Scale-8 (JFLS-8) and the Patient Health Questionnaire for Depression and Anxiety (PHQ-4). The subjects were divided into three groups: painful TMDs (PT), non-painful TMDs (NPT), and TMD-free according to whether they had TMDs and its subtypes. RESULTS: A total of 670 valid questionnaires were collected from 182 males and 488 females. The prevalence of TMDs was 35.4%, of which the prevalence of PT was 11.8% and the prevalence of NPT was 23.6%. The median JLFS-8 score of TMD patients was significantly higher than TMD-free, and PT patients were significantly higher than NPT (p = .026). After adjusting for confounding factors, the jaw function and psychological states of PT patients and NPT patients were worse than those of the TMD-free group. CONCLUSIONS: Among the orthodontic patients surveyed, more than one-third had TMDs and the prevalence of PT was lower than NPT. Having TMDs is associated with more severe jaw functional limitation, and PT patients were more serious than NPT patients. At the same time, the psychological states of TMDs patients were also worse.

Niche partitioning among three snail-eating snakes revealed by dentition asymmetry and prey specialisation.

The level of dentition asymmetry in snail-eating snakes may reflect their prey choice and feeding efficiency on asymmetric land snails. The three species of Pareas snakes (Squamata: Pareidae) in Taiwan, which form partially sympatric distribution on the island, provide a potential case to test the hypothesis of niche partitioning and character displacement with regard to dentition asymmetry and specialisation in feeding behaviour. In this study, behavioural experiments confirmed that P. formosensis feeds exclusively on slugs, whereas P. atayal and P. komaii consumed both. However, P. atayal more efficiently preys on land snails than P. komaii, exhibiting a shorter handling time and fewer mandibular retractions. Micro-CT and ancestral character reconstruction demonstrated the lowest asymmetry in P. formosensis (the slug specialist), the highest dentition asymmetry in P. atayal (the land snail specialist) and flexibility in P. komaii (the niche switcher): increased dentition asymmetry when sympatrically distributed with the slug eater (character displacement), and decreased asymmetry when living alone (ecological niche release). Ecological niche modelling showed that the distribution of P. formosensis is associated with the presence of slugs, while that of P. atayal could be explained by the land snails. Combining the results from morphology, phylogeny, behavioural experiments and ecological niche modelling, we showed that competition in the sympatric region might have facilitated character displacement among congeners, while the absence of competition in allopatric region has led to ecological niche release.

Chitosan cross-linked with poly(ethylene glycol)dialdehyde via reductive amination as effective controlled release carriers for oral protein drug delivery.

The covalently cross-linked chitosan-poly(ethylene glycol)1540 derivatives have been developed as a controlled release system with potential for the delivery of protein drug. The swelling characteristics of the hydrogels based on these derivatives as the function of different PEG content and the release profiles of a model protein (bovine serum albumin, BSA) from the hydrogels were evaluated in simulated gastric fluid with or without enzyme in order to simulate the gastrointestinal tract conditions. The derivatives cross-linked with difunctional PEG1540-dialdehyde via reductive amination can swell in alkaline pH and remain insoluble in acidic medium. The cumulative release amount of BSA was relatively low in the initial 2h and increased significantly at pH 7.4 with intestinal lysozyme for additional 12h. The results proved that the release-and-hold behavior of the cross-linked CS-PEG1540H-CS hydrogel provided a swell and intestinal enzyme controlled release carrier system, which is suitable for oral protein drug delivery.

Preparation of a Two-Dimensional Ion-Imprinted Polymer Based on a Graphene Oxide/SiO2 Composite for the Selective Adsorption of Nickel Ions.

In the present work, a novel two-dimensional (2D) nickel ion-imprinted polymer (RAFT-IIP) has been successfully synthesized based on the graphene oxide/SiO2 composite by reversible addition-fragmentation chain-transfer (RAFT) polymerization. The imprinted materials obtained are characterized by Fourier transmission infrared spectrometry (FT-IR), scanning electron microscopy (SEM), transmission electron microscopy (TEM), X-ray diffraction (XRD), and thermogravimetric analysis (TGA). The results show that the thermal stability of the graphene oxide/SiO2 composite is obviously higher than that of graphene oxide. RAFT-IIP possesses an excellent 2D homogeneous imprinted polymer layer, which is a well-preserved unique structure of graphene oxide/SiO2. Owing to the intrinsic advantages of RAFT polymerization and 2D imprinted material, RAFT-IIP demonstrate a superior specific adsorption capacity (81.73 mg/g) and faster adsorption kinetics (30 min) for Ni(II) in comparison to the ion-imprinted polymer prepared by traditional radical polymerization and based on the common carbon material. Furthermore, the adsorption isotherm and selectivity toward Ni(II) onto RAFT-IIP and nonimprinted polymer (NIP) are investigated, indicating that RAFT-IIP has splendid recognizing ability and a nearly 3 times larger adsorption capacity than that of NIP (30.94 mg/g). Moreover, a three-level Box-Behnken experimental design with three factors combining the response surface method is utilized to optimize the desorption process. The optimal conditions for the desorption of Ni(II) from RAFT-IIP are as follows: an HCl-type eluent, an eluent concentration of 2.0 mol/L, and an eluent volume of 10 mL.

Hidden dangers: High levels of organic pollutants in hadal trenches.

The "V"-shaped structure of hadal trenches acts as a natural collector of organic pollutants, drawing attention to the need for extensive research in these areas. Our review identifies significant concentrations of organic pollutants, including persistent organic pollutants, black carbon, antibiotic-resistant genes, and plastics, which often match those in industrialized regions. They may trace back to both human activities and natural sources, underscoring the trenches' critical role in ocean biogeochemical cycles. We highlight the complex lateral and vertical transport mechanisms within these zones. Advanced methodologies, including stable isotope analysis, biomarker identification, and chiral analysis within isotope-based mixing models, are crucial for discerning the origins and pathways of these pollutants. In forthcoming studies, we aim to explore advanced methods for precise pollutant tracing, develop predictive models to forecast the future distribution and impacts of pollutants in hadal zones and on the Earth's larger ecological systems.

Emergence, circulation, and spatiotemporal phylogenetic analysis of coxsackievirus a6- and coxsackievirus a10-associated hand, foot, and mouth disease infections from 2008 to 2012 in Shenzhen, China.

Sporadic hand, foot, and mouth disease (HFMD) outbreaks and other infectious diseases in recent years have frequently been associated with certain human enterovirus (HEV) serotypes. This study explored the prevalences and genetic characteristics of non-HEV71 and non-coxsackievirus A16 (CV-A16) human enterovirus-associated HFMD infections in Shenzhen, China. A total of 2,411 clinical stool specimens were collected from hospital-based surveillance for HFMD from 2008 to 2012. The detection of HEV was performed by real-time reverse transcription-PCR (RT-PCR) and RT-seminested PCR, and spatiotemporal phylogenetic analysis was performed based on the VP1 genes. A total of 1,803 (74.8%) strains comprising 28 different serotypes were detected. In the past 5 years, the predominant serotypes were HEV71 (60.0%), followed by CV-A16 (21.2%) and two uncommon serotypes, CV-A6 (13.0%) and CV-A10 (3.3%). However, CV-A6 replaced CV-A16 as the second most common serotype between 2010 and 2012. As an emerging pathogen, CV-A6 became as common a causative agent of HFMD as HEV71 in Shenzhen in 2012. Phylogenetic analysis revealed that little variation occurred in the Chinese HEV71 and CV-A16 strains. The genetic characteristics of the Chinese CV-A6 and CV-A10 strains displayed geographic differences. The CV-A6 and CV-A10 strains circulating in Shenzhen likely originated in Europe. It was found that human enteroviruses have a high mutation rate due to evolutionary pressure and frequent recombination (3.2 × 10(-3) to 6.4 ×10(-3) substitutions per site per year for HEV71, CV-A6, CV-A16, and CV-A10). Since certain serotypes are potential threats to the public health, this study provides further insights into the significance of the epidemiological surveillance of HFMD.

Isolation of mono-caffeoylquinic acids from tobacco waste using continuous resin-based pre-separation and preparative HPLC.

Three isomers of mono-caffeoylquinic acid, specifically, 3-O-caffeoylquinic acid, 4-O-caffeoylquinic acid and 5-O-caffeoylquinic acid, were successfully isolated from a crude extract of tobacco (Nicotiana tobaccum L.) wastes using continuous resin-based pre-separation and preparative high-performance liquid chromatography (HPLC). The extract of tobacco wastes was continuously pre-separated by resin-based columns packed with D101 and XAD-4, yielding total mono-caffeoylquinic acids with a purity of 67.71% and a recovery rate of 90.06%. Variables affecting resolution and productivity of three mono-caffeoylquinic acid isomers in preparative HPLC (i.e. mobile-phase composition, pH, flow rate and loading amount) were studied. The optimum chromatographic conditions were determined to be a mobile phase consisting of 15% (v/v) methanol and aqueous acetic acid with a pH of 4.5, a flow rate of 4.0 mL/min, a loading amount of 4 mL and a detection wavelength of 360 nm. From 300 mg of loading sample, 56.3 mg of 3-O-caffeoylquinic acid, 92.8 mg of 5-O-caffeoylquinic acid and 73.1 mg of 4-O-caffeoylquinic acid were obtained in a single run, each with a purity of over 98% by HPLC. The structures of the isolated compounds were elucidated by ESI-MS, (1) H-NMR and (13) C-NMR spectral data.

Tripterin liposome relieves severe acute respiratory syndrome as a potent COVID-19 treatment.

For coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), 15-30% of patients are likely to develop COVID-19-related acute respiratory distress syndrome (ARDS). There are still few effective and well-understood therapies available. Novel variants and short-lasting immunity are posing challenges to vaccine efficacy, so finding antiviral and antiinflammatory treatments remains crucial. Here, tripterin (TP), a traditional Chinese medicine, was encapsulated into liposome (TP lipo) to investigate its antiviral and antiinflammatory effects in severe COVID-19. By using two severe COVID-19 models in human ACE2-transgenic (hACE2) mice, an analysis of TP lipo's effects on pulmonary immune responses was conducted. Pulmonary pathological alterations and viral burden were reduced by TP lipo treatment. TP lipo inhibits SARS-CoV-2 replication and hyperinflammation in infected cells and mice, two crucial events in severe COVID-19 pathophysiology, it is a promising drug candidate to treat SARS-CoV-2-induced ARDS.

Repair of exposed hydroxyapatite orbital implants by subconjunctival tissue flaps.

PURPOSE: The purpose of the study was to determine the feasibility of the use of subconjunctival tissue flaps to repair exposed hydroxyapatite (HA) orbital implants. METHODS: One hundred thirty-eight consecutive patients underwent repair of exposed HA orbital implants via a procedure that involved the creation of subconjunctival tissue flaps. After the superior and inferior subconjunctival flaps were created, they were sutured together in the tension-free state to seal the exposure. During follow-up examinations, complications were assessed. RESULTS: Twelve patients were lost after the 3-month follow-up, leaving 126 patients who were followed from 12 to 60 months (average, 24 months). Problems occurred in 22 patients (17.5%), including recurrence of exposure in 4 patients (3.2%), ptosis in 12 patients (9.5%), pyogenic granulomas in 1 patient (0.8%), a conjunctival cyst in 1 patient (0.8%), implant infection in 1 patient (0.8%), and poor transfer of movement in 3 patients (2.4%). CONCLUSIONS: The use of the subconjunctival tissue flaps for repairing exposed HA orbital implants is a promising alternative for the management of implant exposure. Although this novel technique is associated with some complications, these problems can be minimized by careful case selection and careful surgery.

Lignocellulose-based free-standing hybrid electrode with natural vessels-retained, hierarchically pores-constructed and active materials-loaded for high-performance hybrid oxide supercapacitor.

Lignocellulose including cellulose, lignin, and hemicellulose could be extracted from wood, and has been used to prepare carbon electrode. However, complicated extraction greatly increases preparation cost. To achieve maximum utilization of lignocellulose and avoid complicated extraction, wood with porous structure and good mechanical strength is used as carbon precursor. Additionally, chemical activation is commonly used to create micropores to provide high capacitance, but it brings in natural structure destruction, and generation of wastewater during pickling. Moreover, to achieve desirable energy density, multi-step strategy with long duration is required for loading active materials on carbonized lignocellulose (CL). Herein, a one-step method is developed to prepare a free-standing hybrid CL electrode (CLE) by using Lewis acid in three aspects: (1) as structure protection agent, (2) as activating agent, (3) as active materials donor, which bypasses pickling and further avoids the generation of wastewater. Additionally, natural vessels in wood can not only provide large space for active materials loading, but also act as rapid ions diffusion way, simultaneously confining active materials detachment. Benefiting from the synergistic effect of porous structure and Lewis acid, this work not only makes full utilization of lignocellulose, but also makes CLE exhibit excellent performance in hybrid oxide supercapacitor.

Salivary KLK5 and uPA are potential biomarkers for malignant transformation of OLK and OLP.

BACKGROUND: Oral squamous cell carcinoma (OSCC) usually originates from oral potentially malignant disorders (OPMD), such as oral leukoplakia (OLK) and oral lichen planus (OLP). Identifying biomarkers for the early diagnosis and evaluation of malignant transformation in OPMD could improve the survival rate of OSCC patients. OBJECTIVE: The present study aimed to screen for potential salivary biomarkers for evaluating the malignant transformation of OPMD. METHODS: Salivary proteases from OLK and OSCC patients or healthy donors and proteases in cultural medium from DOK and Cal-27 cells were detected with a human protease array kit. The concentrations of the salivary Kallikrein 5 (KLK5) and urokinase-type plasminogen activator (uPA) proteases were measured by ELISA. Receiver operating characteristics (ROC) to determine the potential value of these proteases in clinical diagnosis were calculated using SPSS software. Immunohistochemistry was used to detect the KLK5 and uPA expression in the oral organizations. RESULTS: The salivary protease spectrum was different among patients with OLK and OSCC and healthy donors. KLK5 and uPA levels in saliva tended to increase as the disease progressed (healthy < OPMD [OLK and OLP] < OSCC). ROC curves showed the optimum diagnostic cutoffs for KLK5 as a biomarker for OLK, OLP, and OSCC were 5.97, 6.03, and 9.45 pg/mL, respectively, while the cutoffs for uPA were 17.19, 17.26, and 20.96 pg/mL. Their combined analysis showed a higher sensitivity for the differential diagnosis of disease. Furthermore, higher levels of KLK5 and uPA were observed in OSCC tissues than in OLK and OLP. CONCLUSIONS: Salivary KLK5 and uPA are potential biomarkers for evaluating OLK and OLP malignant transformation and early diagnosis of OSCC.

One-pot synthesis of multi-functional cellulose-based ionic conductive organohydrogel with low-temperature strain sensitivity.

The advent of high-performance conductive organohydrogels, which are sustainable in extremely cold environment, has attracted immersing interest in biosensors. In this work, a highly stretchable, self-healable, adhesive and antibacterial cellulose-based ionic conductive organohydrogel with low-temperature strain sensitivity was developed, using in-situ polymerization of acrylamide in glycerol-water with poly (vinyl alcohol), chitosan, FeCl3 and 2,2,6,6-Tetramethylpiperidine-1-oxyl oxidized cellulose nanofibril (TCNF). Owing to their chemically cross-linked structures and multiple H-bonding networks, the organohydrogel exhibits excellent mechanical properties, such as high stretchability (540 %), high compression strength (0.44 MPa), nearly 87 % self-healing efficiency and adhesive to various substrates. Also, good antibacterial property was confirmed by the diameter of inhibition zone (∼5.1 mm) against Salmonella enteritidis. Notably, the organohydrogels remained high conductivity and flexibility even below -20 °C, which can be applied as low-temperature strain sensor for real-time. Therefore, it has promising applications in artificial intelligence and personal healthcare under cold environment.

Thermal-sensitive lipid nanoparticles potentiate anti-PD therapy through enhancing drug penetration and T lymphocytes infiltration in metastatic tumor.

The response rate of anti-PD therapy in most cancer patients remains low. Therapeutic drug and tumor-infiltrating lymphocytes (TILs) are usually obstructed by the stromal region within tumor microenvironment (TME) rather than distributed around tumor cells, thus unable to induce the immune response of cytotoxic T cells. Here, we constructed the cationic thermosensitive lipid nanoparticles IR780/DPPC/BMS by introducing cationic NIR photosensitizer IR-780 iodide (IR780) modified lipid components, thermosensitive lipid DPPC and PD-1/PD-L1 inhibitor BMS202 (BMS). Upon laser irradiation, IR780/DPPC/BMS penetrated into deep tumor, and reduced cancer-associated fibroblasts (CAFs) around tumor cells to remodel the spatial distribution of TILs in TME. Interestingly, the cationic IR780/DPPC/BMS could capture released tumor-associated antigens (TAAs), thereby enhancing the antigen-presenting ability of DCs to activate cytotoxic T lymphocytes. Moreover, IR780/DPPC/BMS initiated gel-liquid crystal phase transition under laser irradiation, accelerating the disintegration of lipid bilayer structure and leading to the responsive release of BMS, which would reverse the tumor immunosuppression state by blocking PD-1/PD-L1 pathway for a long term. This combination treatment can synergistically exert the antitumor immune response and inhibit the tumor growth and metastasis.

Prolonged activation of innate immune pathways by a polyvalent STING agonist.

The stimulator of interferon genes (STING) is an endoplasmic reticulum transmembrane protein that is a target of therapeutics for infectious diseases and cancer. However, early-phase clinical trials of small-molecule STING agonists have shown limited antitumour efficacy and dose-limiting toxicity. Here, we show that a polyvalent STING agonist-a pH-sensitive polymer bearing a seven-membered ring with a tertiary amine (PC7A)-activates innate-immunity pathways through the polymer-induced formation of STING-PC7A condensates. In contrast to the natural STING ligand 2',3'-cyclic-GMP-AMP (cGAMP), PC7A stimulates the prolonged production of pro-inflammatory cytokines by binding to a non-competitive STING surface site that is distinct from the cGAMP binding pocket. PC7A induces antitumour responses that are dependent on STING expression and CD8+ T-cell activity, and the combination of PC7A and cGAMP led to synergistic therapeutic outcomes (including the activation of cGAMP-resistant STING variants) in mice bearing subcutaneous tumours and in resected human tumours and lymph nodes. The activation of the STING pathway through polymer-induced STING condensation may offer new therapeutic opportunities.

Fast oxygen, nitrogen co-functionalization on electrospun lignin-based carbon nanofibers membrane via air plasma for energy storage application.

The conventional method of thermal post-modification for introducing heteroatom into carbon nanofiber (CNF) generally suffered from some drawbacks in high-cost preparation and requirement of extra chemical agents. Herein, a more cost-efficient method based on air plasma was applied to introduce oxygen/nitrogen into lignin-based carbon nanofiber (LCNF). Massive free radicals (N, O+ 2, O+, O- 2, O-) generating from air plasma contributed to a high content of oxygen (15.24 wt%) and nitrogen (11.48 wt%) within the plasma-modified LCNF (P-LCNF). Furthermore, air plasma also resulted in rough surface of the P-LCNF. Benefiting from the synergistic effect of oxygen/nitrogen co-doped and rough surface, the water contact angle of the P-LCNF was reduced by 64%. In a 6.0 mol/L KOH electrolyte, the P-LCNF electrode exhibited excellent specific capacitance (344.6 F/g at 1.0 A/g), good rate capability (68.5% capacitance retention), low internal resistance (0.34 Ω), as well as high capacitance retention of 102.4% after 2000 cycles.

Targeting folate receptor ß positive tumor-associated macrophages in lung cancer with a folate-modified liposomal complex.

Tumor-associated macrophages (TAMs) facilitate cancer progression by promoting tumor invasion, angiogenesis, metastasis, inflammatory responses, and immunosuppression. Folate receptor ß (FRß) is overexpressed in TAMs. However, the clinical significance of FRß-positive macrophages in lung cancer remains poorly understood. In this study, we verified that FRß overexpression in lung cancer TAMs was associated with poor prognosis. We utilized a folate-modified lipoplex comprising a folate-modified liposome (F-PLP) delivering a BIM-S plasmid to target both lung cancer cells and FRß-positive macrophages in the tumor microenvironment. Transfection of LL/2 cells and MH-S cells with F-PLP/pBIM induced cell apoptosis. Injection of F-PLP/pBIM into LL/2 and A549 lung cancer models significantly depleted FRß-positive macrophages and reduced tumor growth. Treatment of tumor-bearing mice with F-PLP/pBIM significantly inhibited tumor growth in vivo by inducing tumor cell and macrophage apoptosis, reducing tumor proliferation, and inhibiting tumor angiogenesis. In addition, a preliminary safety evaluation demonstrated a good safety profile of F-PLP/pBIM as a gene therapy administered intravenously. This work describes a novel application of lipoplexes in lung cancer targeted therapy that influences the tumor microenvironment by targeting TAMs.

Fast one-pot microwave preparation and plasma modification of porous carbon from waste lignin for energy storage application.

Because the commonly used two-step approach (carbonization followed by activation) usually produces microporous carbons and requires a long production duration, obtaining a low-cost porous-carbon-based supercapacitor with both high energy density and rate capability is a challenge. Herein, a more cost-effective one-pot approach via microwave heating in humidified N2 combined with water vapor plasma modification is proposed to obtain lignin-based porous carbon with a hierarchical and oxygen-enriched structure. Humidified microwave heating can produce hierarchical porous carbon with a high specific surface area (SBET) of 2866 m2 g-1 and high mesopore content of 68.16%. Water vapor plasma modification not only results in a further development of the porosity with an increase in SBET by 11.6% but also results in the doping of oxygen (up to 33.43%). These characteristics ensure a high energy storage capacity and an excellent rate capability for the prepared supercapacitor, which exhibits the highest specific capacitance of 254.6 F g-1 at 0.5 A g-1 with a retention rate of 75.6% at 10 A g-1. The results of this study confirm the good feasibility of the one-pot preparation approach combined with plasma modification for the effective use of waste lignin for advanced energy storage applications.

Mussel-inspired injectable hydrogel and its counterpart for actuating proliferation and neuronal differentiation of retinal progenitor cells.

Biomaterials-mediated retinal progenitor cell (RPC)-based transplantation therapy has shown substantial potential for retinal degeneration (RD), but it is limited by the poor RPC survival, proliferation and differentiation. Herein, the gelatin-hyaluronic acid (Gel-HA)-based hydrogels formed via moderate Michael-type addition reaction with or without the introduction of mussel-inspired polydopamine (PDA), i.e. Gel-HA-PDA and its counterpart Gel-HA hydrogels are developed, and their effects on the biological behaviour of RPCs, including adhesion, survival, proliferation, differentiation, delivery and migration are investigated. The hybrid hydrogels can adopt the intricate structure of the retina with suitable mechanical strength, degradation rate and biological activity to support cellular adhesion, survival and delivery. Meanwhile, Gel-HA hydrogel can remarkably promote RPC proliferation with much larger cell clusters, while Gel-HA-PDA hydrogel significantly enhances RPC adhesion and migration, and directs RPCs to preferentially differentiate toward retinal neurons such as photoreceptors (the most crucial cell-type for RD treatment), which is mainly induced by the activation of integrin α5ß1-phosphatidylinositol-3-kinase (PI3K) pathway. This study demonstrates that Gel-HA hydrogel possesses great potential for RPC proliferation, while mussel-inspired PDA-modified Gel-HA hydrogel with superior biocompatibility can significantly promote RPC neuronal differentiation, providing new insights for developing biomedical materials applied for RPC-based transplantation therapy.

Construction and optimization of pH-sensitive nanoparticle delivery system containing PLGA and UCCs-2 for targeted treatment of Helicobacter pylori.

The acidic environment of the stomach is a threat to the curative effect of antimicrobial drugs for the eradication of Helicobacter pylori (H. pylori) in the infected area. The conventional clinical formulations of antibiotics have low specificity to H. pylori, which disrupts the normal balance of intestinal microbiomes. Therefore, oral drug delivery system with better stability at low pH as well as higher specificity to target H. pylori would provide more effective strategy to eradicate H. pylori and reduce the side effect of antibiotics. Based on the construction of UreI-mediated targeted drug delivery system developed by our group, in this work, using urea-modified UCCs-2 as targeting moiety to the UreI channel protein which is specifically expressed on H. pylori, pH-sensitive amoxicillin-loaded AMX-PLGA/UCCs-2 nanoparticles produced by UCCs-2 and PLGA for targeted treatment of H. pylori infection were established. The nanoparticles were prepared by double emulsion-solvent evaporation method. To achieve a promising drug delivery system with favorable pH-sensitive properties, we adopted an orthogonal design to obtain the optimal formulation. The results showed that the optimized AMX-PLGA/UCCs-2 nanoparticles were in a favorable pH sensitive manner and exhibited low cytotoxicity, higher specificity and better anti-H. pylori efficiency than amoxicillin and non-targeting AMX-PLGA/Cs nanoparticle both in vitro and in vivo, which can protect the antimicrobial drugs against acidic environment and deliver them to targeted eradicate H. pylori in the infected location. The cellular uptake mechanism showed that AMX-PLGA/UCCs-2 nanoparticles are an effective UreI-mediated targeted drug delivery system for anti-H. pylori treatment, which can also be used as promising nanocarriers for oral delivery of other therapeutic drugs to targeted treat H. pylori.

Negative regulation of cationic nanoparticle-induced inflammatory toxicity through the increased production of prostaglandin E2 via mitochondrial DNA-activated Ly6C+ monocytes.

Rationale: Cationic nanocarriers present with well-known toxicities, including inflammatory toxicity, which limit their clinical application. How the cationic nanocarrier-induced inflammatory response is negatively regulated is unknown. Herein, we found that following a sublethal dose of cationic nanocarriers, the induced inflammatory response is characterized by early neutrophil infiltration and spontaneous resolution within 1 week. Methods: C57BL/6 mice were intravenously injected with a dosage of 1-100 mg/kg cationic DOTAP liposomes as well as other cationic materials. Cell necrosis was detected by flow cytometry. Release of mitochondrial DNA was quantified by qPCR via Taqman probes. Signal proteins were detected by Western blotting. PGE2 production in the supernatant was quantitated using an enzyme immunoassay (EIA). The infiltrated inflammatory cells were observed in WT mice, Ccr2-/- mice, Sting-/- mice and Tlr9-/- mice. Results: The early stage (24-48 h) inflammatory neutrophil infiltration was followed by an increasing percentage of monocytes; and, compared with WT mice, Ccr2-/- mice presented with more severe pulmonary inflammation. A previously uncharacterized population of regulatory monocytes expressing both inflammatory and immunosuppressive cytokines was identified in this model. The alteration in monocyte phenotype was directly induced by mtDNA release from cationic nanocarrier-induced necrotic cells via a STING- or TLR9-dependent pathway. Neutrophil activation was specifically inhibited by PGE2 from Ly6C+ inflammatory monocytes, and intravenous injections of dual-phenotype monocytes beneficially modified the immune response; this inhibitory effect was abolished after treatment with indomethacin. Moreover, we provide clear evidence that mitochondrial DNA activated Ly6C+ monocytes and increased PGE2 production through TLR9- or STING-mediated MAPK-NF-κB-COX2 pathways. Conclusion: Our findings suggest that Ly6C+ monocytes and mtDNA-induced Ly6C+ monocyte PGE2 production may be part of a feedback mechanism that contributes to the resolution of cationic nanocarrier-induced inflammatory toxicity and may have important implications for understanding nanoparticle biocompatibility and designing better, safer drug delivery systems.