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Ultrasmall Pd4 clusters form in the micropores of FER zeolite during low-temperature treatment (100 °C) in the presence of humid CO gas. They effectively catalyze CO oxidation below 100 °C, whereas Pd nanoparticles are not active as they are poisoned by CO. Using catalytic measurements, infrared (IR) spectroscopy, X-ray absorption spectroscopy (EXAFS), microscopy, and density functional theory calculations, we provide the molecular-level insight into this previously unreported phenomenon. Pd nanoparticles get covered with CO at low temperatures, which effectively blocks O2 activation until CO desorption occurs. Small Pd clusters in zeolites, in contrast, demonstrate fluxional behavior in the presence of CO, which significantly increases the affinity for binding O2. Our study provides a pathway to achieve low-temperature CO oxidation activity on the basis of a well-defined Pd/zeolite system.
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Research interest in single-atom catalysts (SACs) has been continuously increasing. However, the lack of understanding of the dynamic behaviors of SACs during applications hinders catalyst development and mechanistic understanding. Herein, we report on the evolution of active sites over Pd/TiO2-anatase SAC (Pd1/TiO2) in the reverse water-gas shift (rWGS) reaction. Combining kinetics, in situ characterization, and theory, we show that at T ≥ 350 °C, the reduction of TiO2 by H2 alters the coordination environment of Pd, creating Pd sites with partially cleaved Pd-O interfacial bonds and a unique electronic structure that exhibit high intrinsic rWGS activity through the carboxyl pathway. The activation by H2 is accompanied by the partial sintering of single Pd atoms (Pd1) into disordered, flat, â¼1 nm diameter clusters (Pdn). The highly active Pd sites in the new coordination environment under H2 are eliminated by oxidation, which, when performed at a high temperature, also redisperses Pdn and facilitates the reduction of TiO2. In contrast, Pd1 sinters into crystalline, â¼5 nm particles (PdNP) during CO treatment, deactivating Pd1/TiO2. During the rWGS reaction, the two Pd evolution pathways coexist. The activation by H2 dominates, leading to the increasing rate with time-on-stream, and steady-state Pd active sites similar to the ones formed under H2. This work demonstrates how the coordination environment and nuclearity of metal sites on a SAC evolve during catalysis and pretreatments and how their activity is modulated by these behaviors. These insights on SAC dynamics and the structure-function relationship are valuable to mechanistic understanding and catalyst design.
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Atom trapping leads to catalysts with atomically dispersed Ru1O5 sites on (100) facets of ceria, as identified by spectroscopy and DFT calculations. This is a new class of ceria-based materials with Ru properties drastically different from the known M/ceria materials. They show excellent activity in catalytic NO oxidation, a critical step that requires use of large loadings of expensive noble metals in diesel aftertreatment systems. Ru1/CeO2 is stable during continuous cycling, ramping, and cooling as well as the presence of moisture. Furthermore, Ru1/CeO2 shows very high NOx storage properties due to formation of stable Ru-NO complexes as well as a high spill-over rate of NOx onto CeO2. Only â¼0.05 wt % of Ru is required for excellent NOx storage. Ru1O5 sites exhibit much higher stability during calcination in air/steam up to 750 °C in contrast to RuO2 nanoparticles. We clarify the location of Ru(II) ions on the ceria surface and experimentally identify the mechanism of NO storage and oxidation using DFT calculations and in situ DRIFTS/mass spectroscopy. Moreover, we show excellent reactivity of Ru1/CeO2 for NO reduction by CO at low temperatures: only 0.1-0.5 wt % of Ru is sufficient to achieve high activity. Modulation-excitation in situ infrared and XPS measurements reveal the individual elementary steps of NO reduction by CO on an atomically dispersed Ru ceria catalyst, highlighting unique properties of Ru1/CeO2 and its propensity to form oxygen vacancies/Ce+3 sites that are critical for NO reduction, even at low Ru loadings. Our study highlights the applicability of novel ceria-based single-atom catalysts to NO and CO abatement.
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In Chen and Turunen (Commun Math Phys 374(3):1577-1643, 2020), we have studied the Boltzmann random triangulation of the disk coupled to an Ising model on its faces with Dobrushin boundary condition at its critical temperature. In this paper, we investigate the phase transition of this model by extending our previous results to arbitrary temperature: We compute the partition function of the model at all temperatures, and derive several critical exponents associated with the infinite perimeter limit. We show that the model has a local limit at any temperature, whose properties depend drastically on the temperature. At high temperatures, the local limit is reminiscent of the uniform infinite half-planar triangulation decorated with a subcritical percolation. At low temperatures, the local limit develops a bottleneck of finite width due to the energy cost of the main Ising interface between the two spin clusters imposed by the Dobrushin boundary condition. This change can be summarized by a novel order parameter with a nice geometric meaning. In addition to the phase transition, we also generalize our construction of the local limit from the two-step asymptotic regime used in Chen and Turunen (2020) to a more natural diagonal asymptotic regime. We obtain in this regime a scaling limit related to the length of the main Ising interface, which coincides with predictions from the continuum theory of quantum surfaces (a.k.a. Liouville quantum gravity).
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BACKGROUND: Opioid prescription for inflammatory bowel disease (IBD)-related pain is on the rise. However, the use of strong opioids can result in severe complications, and even death, in IBD patients. This study aimed to define the role of fentanyl and morphine, two representative strong opioids, in the pathogenesis of dextran sodium sulfate (DSS)- and 2,4,6-trinitrobenzenesulfonic acid solution (TNBS)-induced colitis. METHOD: DSS and TNBS models were induced in C57BL/6J and Balb/c mice, respectively. Disease activity index (DAI), histopathology, enzyme-linked immunosorbent assay (ELISA), multiplex ELISA, and flow cytometry were performed to evaluate the effects of fentanyl and morphine. RESULT: Fentanyl exacerbated DSS- and TNBS-induced colitis, while morphine exhibited no significant immunomodulatory effect. Fentanyl and morphine had no obvious effects on the serum levels of adrenocorticotropic hormone (ACTH), glucocorticoid (GC), and prostaglandin E2 (PGE-2) in DSS and TNBS models. Fentanyl elevated the proportions of Th1 cells, µ-opioid receptor (MOR) + Th1 cells, and MOR + macrophages in the colonic mucosa of DSS-treated mice, and enhanced the proportions of Th1 cells, macrophages, MOR + Th1 cells, and MOR + macrophages in the colonic mucosa of TNBS-treated mice. We found that fentanyl upregulated the levels of inflammatory cytokines/chemokines in MOR + macrophages of the colonic lamina propria mononuclear cells (LPMCs) from DSS-treated mice, whereas it had no effect on the expression of most inflammatory cytokines/chemokines in MOR + macrophages in the colonic LPMCs from TNBS-treated mice. CONCLUSION: Our findings suggest that fentanyl exacerbates murine colitis via Th1 cell- and macrophage-mediated mechanisms, while morphine exhibits no significant immunomodulatory effect.
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Fentanila , Morfina , Camundongos , Animais , Ácido Trinitrobenzenossulfônico/toxicidade , Fentanila/farmacologia , Camundongos Endogâmicos C57BL , Morfina/farmacologiaRESUMO
Single-atom catalysts (SACs) often exhibit dynamic responses to the reaction and pretreatment environment that affect their activity. The lack of understanding of these behaviors hinders the development of effective, stable SACs, and makes their investigations rather difficult. Here we report a reduction-oxidation cycle that induces nearly 5-fold activity enhancement on Pt/TiO2 SACs for the reverse water-gas shift (rWGS) reaction. We combine microscopy (STEM) and spectroscopy (XAS and IR) studies with kinetic measurements, to convincingly show that the low activity on the fresh SAC is a result of limited accessibility of Pt single atoms (Pt1) due to high Pt-O coordination. The reduction step mobilizes Pt1, forming small, amorphous, and unstable Pt aggregates. The reoxidation step redisperses Pt into Pt1, but in a new, less O-coordinated chemical environment that makes the single metal atoms more accessible and, consequently, more active. After the cycle, the SAC exhibits superior rWGS activity to nonatomically dispersed Pt/TiO2. During the rWGS, the activated Pt1 experience slow deactivation, but can be reactivated by mild oxidation. This work demonstrates a clear picture of how the structural evolution of Pt/TiO2 SACs leads to ultimate catalytic efficiency, offering desired understanding on the rarely explored dynamic chemical environment of supported single metal atoms and its catalytic consequences.
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Invited for this month's cover is the group of Steven Tait at Indiana University. The image shows single metal atoms stabilized by small molecules on a titanium dioxide powder support that are active in catalyzing ethylene hydrogenation. The Full Paper itself is available at 10.1002/cssc.202100208.
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Ligand-coordinated supported catalysts (LCSCs) are of growing interest for heterogeneous single-atom catalysis. Here, the effect of the choice of organic ligand on the activity and stability of TiO2 -supported single-atom Pt-ligand catalysts was investigated for ethylene hydrogenation. The activity of these catalysts showed a significant dependence on the choice of ligand and also correlated with coordination number for Pt-ligand and Pt-Cl- . Of the three ligands examined in this study, the one with the lowest Pt coordination number, 1,10-phenanthroline-5,6-dione (PDO), showed the lowest reaction temperature and highest reaction rate, likely due to those metal sites being more accessible to reactant adsorption. In-situ X-ray absorption spectroscopy (XAS) experiments showed that the activity also correlated with good heterolytic dissociation of hydrogen, which was supported by OH/OD exchange experiments and was the rate-determining step of the hydrogenation reaction. In these in-situ XAS experiments up to 190 °C, the supported Pt-ligand catalyst showed excellent stability against structural and chemical change. Instead of Pt, the PDO ligand could be coordinated with Ir on TiO2 to form Ir LCSCs that showed slow activation by loss of Ir-Cl bonds, then excellent stability in the hydrogenation of ethylene. These results provide the chance to engineer ligand-coordinated supported catalysts at the single-atom catalyst level by the choice of ligand and enable new applications at relatively high temperature.
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Traditional Chinese medicine (TCM) has been practiced for thousands of years for treating human diseases. In comparison to modern medicine, one of the advantages of TCM is the principle of herb compatibility, known as TCM formulae. A TCM formula usually consists of multiple herbs to achieve the maximum treatment effects, where their interactions are believed to elicit the therapeutic effects. Despite being a fundamental component of TCM, the rationale of combining specific herb combinations remains unclear. In this study, we proposed a network-based method to quantify the interactions in herb pairs. We constructed a protein-protein interaction network for a given herb pair by retrieving the associated ingredients and protein targets, and determined multiple network-based distances including the closest, shortest, center, kernel, and separation, both at the ingredient and at the target levels. We found that the frequently used herb pairs tend to have shorter distances compared to random herb pairs, suggesting that a therapeutic herb pair is more likely to affect neighboring proteins in the human interactome. Furthermore, we found that the center distance determined at the ingredient level improves the discrimination of top-frequent herb pairs from random herb pairs, suggesting the rationale of considering the topologically important ingredients for inferring the mechanisms of action of TCM. Taken together, we have provided a network pharmacology framework to quantify the degree of herb interactions, which shall help explore the space of herb combinations more effectively to identify the synergistic compound interactions based on network topology.
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Algoritmos , Medicamentos de Ervas Chinesas/farmacologia , Medicina Tradicional Chinesa/métodos , Modelos Biológicos , Mapas de Interação de Proteínas/efeitos dos fármacos , Astragalus propinquus/química , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/uso terapêutico , Glycyrrhiza uralensis/química , Humanos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Cirrose Hepática/metabolismo , Cirrose Hepática/prevenção & controle , Raízes de Plantas/químicaRESUMO
Heat stress is a major growth-limiting factor for most crops over the world. Chitin elicitor receptor kinase 1 (CERK1) is a chitin/chitooligosaccharides receptor, and ERECTA (ER) plays a crucial role in plant resistance to heat stress. In the present study, a chitooligosaccharides-induced CERK1n-ERc fusion gene was designed and synthesized, in which the extracellular domain and transmembrane domain of CERK1 gene is connected with the response region of ER gene. We successfully constructed the CERK1n-ERc fusion gene by Overlap PCR and introduced it into Arabidopsis by Agrobacterium-medicated infection. Genetically modified (GM) plants had a greater germination rate and germination index, as well as a shorter mean germination time, indicating that they had a better thermotolerance compared with the wild-type (WT) lines under heat stress. Moreover, the GM lines showed a lower level of hydrogen peroxide (H2O2) and relative electrolyte leakage (REL), suggesting that they were in better state compared with the WT plants when exposed to high temperature. UPLC-MS/MS was employed to assess the phytohormone level, suggesting that the GM lines acquired a better thermotolerance via jasmonic acid (JA) signaling pathways. In general, we constructed a COS-induced fusion gene to enhance the thermotolerance of Arabidopsis during seed germination and postgermination growth.
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Proteínas de Arabidopsis/genética , Arabidopsis/genética , Arabidopsis/fisiologia , Quitina/análogos & derivados , Proteínas Serina-Treonina Quinases/genética , Receptores de Superfície Celular/genética , Proteínas Recombinantes de Fusão/genética , Termotolerância/fisiologia , Ácido Abscísico/metabolismo , Arabidopsis/efeitos dos fármacos , Proteínas de Arabidopsis/metabolismo , Quitina/farmacologia , Quitosana , Ciclopentanos/metabolismo , Eletrólitos/metabolismo , Germinação/efeitos dos fármacos , Proteínas de Fluorescência Verde/metabolismo , Resposta ao Choque Térmico/efeitos dos fármacos , Peróxido de Hidrogênio/metabolismo , Hipocótilo/anatomia & histologia , Hipocótilo/efeitos dos fármacos , Oligossacarídeos , Oxilipinas/metabolismo , Plantas Geneticamente Modificadas , Plasmídeos/genética , Proteínas Serina-Treonina Quinases/metabolismo , Receptores de Superfície Celular/metabolismo , Proteínas Recombinantes de Fusão/metabolismo , Ácido Salicílico/metabolismo , Frações Subcelulares/metabolismo , Termotolerância/efeitos dos fármacos , Termotolerância/genéticaRESUMO
BACKGROUND: A high prevalence of osteoblastic bone metastases is characteristic of prostate cancer. Prostate-specific antigen (PSA) is a serine protease uniquely produced by prostate cancer cells and is an important serological marker for prostate cancer. However, whether PSA modulates the osteogenic process remains largely unknown. In this study, we explored the effect of PSA on modulating the osteoblastic differentiation of mesenchymal stem cells (MSCs). In this study, we used flow cytometry, CCK-8 assay, Alizarin red S (ARS) staining and quantification, alkaline phosphatase (ALP) activity and staining, Western blotting, and quantitative real-time PCR (qRT-PCR) to explore the effect of PSA on osteogenic differentiation of MSCs. RESULTS: We first demonstrated that although PSA did not affect the proliferation, morphology, or phenotype of MSCs, it significantly promoted the osteogenic differentiation of MSCs in a concentration-dependent manner. Furthermore, we demonstrated that PSA promoted the osteogenic differentiation of MSCs by elevating the expression of Cadherin 11 in MSCs and, thus, activating the Akt signaling pathway. CONCLUSIONS: In conclusion, we demonstrated that PSA could promote the osteogenesis of MSCs through Akt signaling pathway activation by elevating the expression of cadherin-11 in MSCs. These findings imply a possible role of PSA in osteoblastic bone metastases in prostate cancer.
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The application of single-atom catalysts (SACs) to high-temperature hydrogenation requires materials that thermodynamically favor metal atom isolation over cluster formation. We demonstrate that Pd can be predominantly dispersed as isolated atoms onto TiO2 during the reverse water-gas shift (rWGS) reaction at 400 °C. Achieving atomic dispersion requires an artificial increase of the absolute TiO2 surface area by an order of magnitude and can be accomplished by physically mixing a precatalyst (Pd/TiO2 ) with neat TiO2 prior to the rWGS reaction. The inâ situ dispersion of Pd was reflected through a continuous increase of rWGS activity over 92â h and supported by kinetic analysis, infrared and X-ray absorption spectroscopies and scanning transmission electron microscopy. The thermodynamic stability of Pd under high-temperature rWGS conditions is associated with Pd-Ti coordination, which manifests upon O-vacancy formation, and the artificial increase in TiO2 surface area.
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Anesthetics are thought to be involved in immunomodulation. Avertin is one of the safest and most commonly used intravenous anesthetics in rodent experiments; it is also widely used in euthanasia of inflammatory bowel disease (IBD) models. This study aimed to define the role and mechanism of action of Avertin on murine colitis. We assessed the effects of a single Avertin injection on colitis using the disease activity index (DAI), pathology, enzyme-linked immunosorbent assay (ELISA), multiplex-ELISA, flow cytometry, and routine blood examination in wild-type (WT) and dextran sodium sulphate (DSS)-treated mice. Although Avertin caused acute cecitis in WT mice after 24 h and aggravated inflammation in the medium term, it alleviated inflammation in the late stage of DSS-induced colitis according to the DAI. Avertin upregulated MPO production and induced the accumulation of neutrophils and macrophages in intestinal mucosa of both WT and DSS-treated mice; the altered MPO might indicate a change in respiratory burst. However, it exhibited a more effective suppression of inflammatory factors secreted by macrophages as the colitis progressed. Avertin led to an increase in neutrophils and decrease in monocytes in both WT and DSS-treated mice blood. Our findings suggest that Avertin aggravates inflammation in the early and medium terms, but alleviates inflammation in the late stage of colitis by regulating neutrophils and macrophages.
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Anestésicos/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Colite/tratamento farmacológico , Etanol/análogos & derivados , Macrófagos/efeitos dos fármacos , Neutrófilos/efeitos dos fármacos , Animais , Ceco/efeitos dos fármacos , Ceco/patologia , Colite/induzido quimicamente , Colite/imunologia , Colite/patologia , Colo/efeitos dos fármacos , Colo/imunologia , Sulfato de Dextrana , Etanol/uso terapêutico , Feminino , Contagem de Leucócitos , Macrófagos/imunologia , Masculino , Camundongos Endogâmicos C57BL , Neutrófilos/imunologiaRESUMO
In this present study, the structure and immunomodulatory activity of a novel polysaccharide (WSRP-1b) from Kushui rose (Rosa setate x Rosa rugosa) waste were investigated. Structure characterization demonstrated that WSRP-1b had a weight-average molecular weight of 1.11 × 104 Da and consisted of glucose (42.6 %), mannose (21.4 %), arabinose (9.9 %), xylose (2.2 %), and galactose (23.9 %). Its backbone was composed of 1, 4-linked α-Glcp, 1, 4-linked ß-Glcp, and 1, 4-linked ß-Manp, with branches of 1, 4-linked α-Glcp and 1, 4-linked ß-Manp substituted at C-6 by 1, 6-linked ß-Galp. The branches mainly contained 1, 5-linked Araf, terminal arabinose and terminal glucose. Bioactivity assays showed that WSRP-1b had immunomodulatory activity by enhancing phagocytosis of macrophages, increasing production of ROS, NO, cytokines (IL-6, TNF-α), and activating NF-κB signaling pathway. These results suggested that it could be developed as a potential and safe immunomodulatory agent in fields of pharmacological or functional foods.
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Fatores Imunológicos/farmacologia , Macrófagos/efeitos dos fármacos , Polissacarídeos/farmacologia , Rosa/química , Configuração de Carboidratos , Citocinas/biossíntese , Humanos , Fatores Imunológicos/química , Macrófagos/metabolismo , NF-kappa B/imunologia , Óxido Nítrico/biossíntese , Polissacarídeos/química , Espécies Reativas de Oxigênio/metabolismoRESUMO
Chitosan and its derivatives are widely used in medical, cosmetic and food fields. In this study, chitosan-N-arginine (CSA) was synthesized and characterized by Fourier-transform infrared (FT-IR), 1H NMR, gel permeation chromatography (GPC), thermogravimetric analysis (TGA) and scanning electron microscopy (SEM). A novel antibacterial composite film consisting of CSA, hydroxypropyl methylcellose (HPMC) and glycerol was then prepared. The transparent and homogeneous film presented good compatibility between CSA and HPMC, confirmed by SEM. The thickness of the film was about 44.8 µm and its moisture content was 23.0%. Antimicrobial evaluation of CSA/HPMC film showed 9.0 mm bacteriostatic diameter zone against E. coli and 10.5 mm one against S. aureus. The film exhibited cell biocompatibility and promoted proliferation with L929 cell cytotoxicity test. Both antibacterial and cytotoxic results showed that the CSA/HPMC film was a promising material for medication, cosmetics and food preservation applications.
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Antibacterianos/química , Arginina/química , Quitosana/química , Derivados da Hipromelose/química , Antibacterianos/farmacologia , Materiais Biocompatíveis/química , Proliferação de Células/efeitos dos fármacos , Escherichia coli/efeitos dos fármacos , Espectroscopia de Ressonância Magnética/métodos , Microscopia Eletrônica de Varredura/métodos , Espectroscopia de Infravermelho com Transformada de Fourier/métodos , Staphylococcus aureus/efeitos dos fármacosRESUMO
The bacterial outer membrane (OM) is a barrier containing membrane proteins and liposaccharides that fulfill crucial functions for Gram-negative bacteria. With the advent of drug-resistant bacteria, it is necessary to understand the functional role of this membrane and its constituents to enable novel drug designs. Here we report a simple method to form an OM-like supported bilayer (OM-SB), which incorporates native lipids and membrane proteins of gram-negative bacteria from outer membrane vesicles (OMVs). We characterize the formation of OM-SBs using quartz crystal microbalance with dissipation (QCM-D) and fluorescence microscopy. We show that the orientation of proteins in the OM-SB matches the native bacterial membrane, preserving the characteristic asymmetry of these membranes. As a demonstration of the utility of the OM-SB platform, we quantitatively measure antibiotic interactions between OM-SBs and polymyxin B, a cationic peptide used to treat Gram-negative infections. This data enriches understanding of the antibacterial mechanism of polymyxin B, including disruption kinetics and changes in membrane mechanical properties. Combining OM-SBs with microfluidics will enable higher throughput screening of antibiotics. With a broader view, we envision that a molecularly complete membrane-scaffold could be useful for cell-free applications employing engineered membrane proteins in bacterial membranes for myriad technological purposes.
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Proteínas da Membrana Bacteriana Externa/metabolismo , Cinética , Lipossomos , Microscopia de Fluorescência , Técnicas de Microbalança de Cristal de QuartzoRESUMO
The O-antigen polysaccharide (O-PS) component of lipopolysaccharides on the surface of gram-negative bacteria is both a virulence factor and a B-cell antigen. Antibodies elicited by O-PS often confer protection against infection; therefore, O-PS glycoconjugate vaccines have proven useful against a number of different pathogenic bacteria. However, conventional methods for natural extraction or chemical synthesis of O-PS are technically demanding, inefficient, and expensive. Here, we describe an alternative methodology for producing glycoconjugate vaccines whereby recombinant O-PS biosynthesis is coordinated with vesiculation in laboratory strains of Escherichia coli to yield glycosylated outer membrane vesicles (glycOMVs) decorated with pathogen-mimetic glycotopes. Using this approach, glycOMVs corresponding to eight different pathogenic bacteria were generated. For example, expression of a 17-kb O-PS gene cluster from the highly virulent Francisella tularensis subsp. tularensis (type A) strain Schu S4 in hypervesiculating E. coli cells yielded glycOMVs that displayed F. tularensis O-PS. Immunization of BALB/c mice with glycOMVs elicited significant titers of O-PS-specific serum IgG antibodies as well as vaginal and bronchoalveolar IgA antibodies. Importantly, glycOMVs significantly prolonged survival upon subsequent challenge with F. tularensis Schu S4 and provided complete protection against challenge with two different F. tularensis subsp. holarctica (type B) live vaccine strains, thereby demonstrating the vaccine potential of glycOMVs. Given the ease with which recombinant glycotopes can be expressed on OMVs, the strategy described here could be readily adapted for developing vaccines against many other bacterial pathogens.
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Anticorpos Antibacterianos/imunologia , Vacinas Bacterianas/imunologia , Francisella tularensis/imunologia , Vesículas Transportadoras/metabolismo , Tularemia/imunologia , Animais , Vacinas Bacterianas/genética , Vacinas Bacterianas/metabolismo , Escherichia coli/genética , Escherichia coli/metabolismo , Feminino , Francisella tularensis/genética , Francisella tularensis/metabolismo , Glicosilação , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Antígenos O/imunologia , Vesículas Transportadoras/genética , Tularemia/microbiologia , Tularemia/prevenção & controle , VacinaçãoRESUMO
The development of antibodies against specific glycan epitopes poses a significant challenge due to difficulties obtaining desired glycans at sufficient quantity and purity, and the fact that glycans are usually weakly immunogenic. To address this challenge, we leveraged the potent immunostimulatory activity of bacterial outer membrane vesicles (OMVs) to deliver designer glycan epitopes to the immune system. This approach involved heterologous expression of two clinically important glycans, namely polysialic acid (PSA) and Thomsen-Friedenreich antigen (T antigen) in hypervesiculating strains of non-pathogenic Escherichia coli. The resulting glycOMVs displayed structural mimics of PSA or T antigen on their surfaces, and induced high titers of glycan-specific IgG antibodies following immunization in mice. In the case of PSA glycOMVs, serum antibodies potently killed Neisseria meningitidis serogroup B (MenB), whose outer capsule is PSA, in a serum bactericidal assay. These findings demonstrate the potential of glycOMVs for inducing class-switched, humoral immune responses against glycan antigens.
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Anticorpos Antibacterianos/imunologia , Antígenos de Bactérias/imunologia , Proteínas da Membrana Bacteriana Externa/imunologia , Epitopos/imunologia , Switching de Imunoglobulina , Neisseria meningitidis Sorogrupo B/imunologia , Polissacarídeos/imunologia , Animais , Reações Antígeno-Anticorpo , Epitopos/química , Feminino , Imunização , Camundongos , Camundongos Endogâmicos BALB C , Polissacarídeos/químicaRESUMO
Vaccine adjuvants are an essential component of vaccine design, helping to generate immunity to pathogen antigens in the absence of infection. Recent advances in nanoscale engineering have created a new class of particulate bionanotechnology that uses biomimicry to better integrate adjuvant and antigen. These pathogen-like particles, or PLPs, can come from a variety of sources, ranging from fully synthetic platforms to biologically derived, self-assembling systems. By employing molecularly engineered targeting and stimulation of key immune cells, recent studies utilizing PLPs as vaccine delivery platforms have shown great promise against high-impact, unsolved vaccine targets ranging from bacterial and viral pathogens to cancer and addiction.
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Portadores de Fármacos/química , Nanopartículas/química , Vacinas de Partículas Semelhantes a Vírus/imunologia , Vacinas/imunologia , Adjuvantes Imunológicos , Materiais Biocompatíveis/química , Materiais Biocompatíveis/metabolismo , Biomimética , Vacinas Sintéticas/imunologia , Vacinas de Partículas Semelhantes a Vírus/administração & dosagemRESUMO
Outer membrane vesicles (OMVs) are nanoscale proteoliposomes that are ubiquitously secreted by Gram-negative bacteria. Interest in these bioparticles has escalated over the years, leading to discoveries regarding their composition, production, and vaccine potential. Given that many steps in vesicle biogenesis are 'engineerable,' it is now possible to tailor OMVs for specific applications. Such tailoring involves modifying the OMV-producing bacterium through protein, pathway, or genome engineering in a manner that specifically alters the final OMV product. For example, targeted deletion or upregulation of genes associated with the cell envelope can modulate vesicle production or remodel the composition of vesicle components such as lipopolysaccharide. Likewise, bacteria can be reprogrammed to incorporate heterologously expressed proteins into either the membrane or lumenal compartment of OMVs. We anticipate that further research in the field of OMV engineering will enable continued design and biosynthesis of specialized vesicles for numerous biotechnological purposes ranging from the delivery of vaccines to the deconstruction of cellulosic substrates.