RESUMO
Fluoride has strong electronegativity and exposes diversely in nature. Water fluoridation is the most pervasive form of occurrence, representing a significant threat to human health. In this study, we investigate the morphometric and physiological alterations triggered by fluoride stimulation during the embryogenesis of zebrafish and reveal its putative effects of stage- and/or dose-dependent. Fluoride exhibits potent biological activity and can be extensively absorbed by the yolk sac, exerting significant effects on the development of multiple organs. This is primarily manifested as restricted nutrient utilization and elevated levels of lipid peroxidation, further leading to the accumulation of superoxide in the yolk sac, liver, and intestines. Moreover, pericardial edema exerts pressure on the brain and eye development, resulting in spinal curvature and reduced body length. Besides, acute fluoride exposure with varying concentrations has led to diverse teratogenic outcomes. A low dose of water fluoridation tends to induce abnormal development of the embryonic yolk sac, while vascular malformation is widely observed in all fluoride-treated groups. The effect of fluoride exposure on blood circulation is universally present, even in zebrafish larvae that do not exhibit obvious deformities. Their swimming behavior is also affected by water fluoridation, resulting in reduced activity and delayed reactions. In conclusion, this study provides valuable insights into the monitoring of environmental quality related to water fluoridation and disease prevention.
Assuntos
Poluentes Químicos da Água , Peixe-Zebra , Animais , Humanos , Fluoretos/toxicidade , Fluoretação , Desenvolvimento Embrionário , Saco Vitelino , Embrião não Mamífero , Poluentes Químicos da Água/toxicidadeRESUMO
OBJECTIVES: This study aims to investigate longitudinally the activation of Toll-like receptor-4 (TLR-4) by subgingival biofilm samples before and after nonsurgical periodontal therapy (NSPT). MATERIALS AND METHODS: Forty periodontitis patients received NSPT and were reviewed 3 and 6 months post-treatment. Subgingival biofilm was sampled from 4 teeth per patient, at baseline and each follow-up time point. TLR-4 activation was determined using the HEK-BLUE™/hTLR4 system. Changes in TLR-4 activation and probing pocket depths (PPDs) were evaluated using generalised linear models, and the association between TLR-4 activation and pocket reduction (defined as 6-month PPDs ≤ 3mm) was determined using generalised estimating equations. RESULTS: At 6 months, the mean TLR-4 activation by subgingival biofilm samples was significantly reduced from 11.2AU (95%CI 7.1AU, 15.4AU) to 3.6AU (95%CI 2.3AU, 4.8AU, p < 0.001), paralleling significant reductions in mean PPDs at sampled sites. The response to NSPT was associated with longitudinal TLR-4 activation profiles, with significantly higher TLR-4 activation by subgingival biofilm obtained from sites that did not achieve pocket reduction, compared to sites at which pocket reduction was achieved. CONCLUSIONS: The activation of TLR-4 by subgingival biofilm samples was reduced after NSPT, and this reduction was significantly associated with the clinical improvements (PPD reductions) at sampled sites. CLINICAL RELEVANCE: This study demonstrated an association between the longitudinal profile of TLR-4 activation by subgingival biofilm and periodontal treatment response. Longitudinal monitoring of TLR-4 activation by subgingival biofilm may potentially identify non-responsive sites, enabling targeted additional treatment.
Assuntos
Periodontite , Receptor 4 Toll-Like , Humanos , Bolsa Periodontal/terapia , Periodontite/tratamento farmacológicoRESUMO
One new polyacetylene glycoside eprostrata â (1), together with seven known compounds (2-8), were isolated from Eclipta prostrata. Their structures were elucidated on the basis of spectroscopic and physico-chemical analyses. All the isolates were evaluated inhibitory activity on DGAT in an in vitro assay. Compounds 1-8 were found to exhibit inhibitory activity of DGAT1 with IC50 values ranging from 74.4 ± 1.3 to 101.1 ± 1.1 µM.
Assuntos
Diacilglicerol O-Aciltransferase/antagonistas & inibidores , Eclipta/química , Polímero Poliacetilênico/química , Polímero Poliacetilênico/farmacologia , Animais , Configuração de Carboidratos , Concentração Inibidora 50 , Fígado/efeitos dos fármacos , Fígado/enzimologia , Espectroscopia de Ressonância Magnética , Caules de Planta/química , RatosRESUMO
Mg-5.6Zn-0.5Zr alloy (ZK60) tends to degrade too rapid for orthopedic application, in spite of its natural degradation, suitable strength and good biocompatibility. In this study, Nd was alloyed with ZK60 via laser melting method to enhance its corrosion resistance. The microstructure features, mechanical properties and corrosion behaviors of ZK60-xNd (x = 0, 1.8, 3.6, 5.4 wt.%) were investigated. Results showed that laser melted ZK60-xNd were composed of fine É-Mg grains and intermetallic phases along grain boundaries. And the precipitated intermetallic phases experienced successive changes: divorced island-like MgZn phase â honeycomb-like T phase â coarsened and agglomerated W phase with Nd increasing. It was worth noting that ZK60-3.6Nd with honeycomb-like T phase exhibited an optimal corrosion behavior with a corrosion rate of 1.56 mm year-1. The improved corrosion behavior was ascribed to: (I) dense surface film caused by the formation of Nd2O3 hindered the invasion of immersion solution; (II) the three-dimensional honeycomb structure of intermetallic phases formed a tight barrier to restrain the propagation of corrosion. Moreover, ZK60-3.6Nd exhibited good biocompatibility. It was suggested that ZK60-3.6Nd was a preferable candidate for biodegradable bone implant.
Assuntos
Ligas , Interface Osso-Implante , Neodímio/química , Implantes Absorvíveis , Animais , Osso e Ossos , Linhagem Celular Tumoral , Corrosão , Humanos , Teste de Materiais , Fenômenos Mecânicos , Osteossarcoma , Propriedades de Superfície , ZircônioRESUMO
The rapid degradation rate of Magnesium (Mg) alloy limits its biomedical application even though it possesses outstanding biological performance and biomechanical compatibility. In this study, a combined method of laser rapid melting and alloying Zinc (Zn) was proposed to decrease the degradation rate of Mg-Sn alloy. The microstructure, degradation behaviors and mechanical properties of the laser-melted Mg-5Sn-xZn (x = 0, 2, 4, 6 and 8 wt.%) alloys were investigated. The results indicated that the grain size of the alloys decreased with increasing Zn content, due to the increased number of nucleation particles formed in the process of solidification. Moreover, the laser-melted Mg-Sn alloys possessed finer grains compared with traditional as-cast and as-rolled Mg-Sn alloys. The degradation rate of the alloys decreased with increasing Zn content (0-4 wt.%), which was ascribed to the grain refinement and the formation of Zn(OH)2 protective layer. However, the degradation rate increased as the Zn content further increased (4-8 wt.%), which was caused by the galvanic corrosion between the Mg matrix and the generated Mg7Zn3 phase. Besides, Zn also increased the hardness of the alloys owing to the grain refinement strengthening and solid solution strengthening.
Assuntos
Ligas/química , Magnésio/química , Estanho/química , Zinco/química , Implantes Absorvíveis , Materiais Biocompatíveis/química , Fenômenos Biomecânicos , Corrosão , Cristalização , Cristalografia por Raios X , Dureza , Humanos , Lasers , Teste de Materiais/métodos , Pós , Soluções , Estresse MecânicoRESUMO
Chronic periodontitis has a polymicrobial biofilm aetiology. Polymicrobial biofilms are complex, dynamic microbial communities formed by two or more bacterial species that are important for the persistence and proliferation of participating microbes in the environment. Interspecies adherence, which often involves bacterial surface-associated molecules, and communications are essential in the spatial and temporal development of a polymicrobial biofilm, which in turn is necessary for the overall fitness of a well-organized multispecies biofilm community. In the oral cavity, interactions between key oral bacterial species, including Porphyromonas gingivalis, Treponema denticola and Tannerella forsythia, are essential for the progression of chronic periodontitis. In vivo, P. gingivalis and T. denticola are frequently found to co-exist in deep periodontal pockets and have been co-localized to the superficial layers of subgingival plaque as microcolony blooms adjacent to the pocket epithelium, suggesting possible interbacterial interactions that contribute towards disease. The motility and chemotactic ability of T. denticola, although not considered as classic virulence factors, are likely to be important in the synergistic biofilm formation with P. gingivalis. In vitro, P. gingivalis and T. denticola display a symbiotic relationship in nutrient utilization and growth promotion. Together these data suggest there is an intimate relationship between these two species that has evolved to enhance their survival and virulence.
Assuntos
Placa Dentária/microbiologia , Gengiva/microbiologia , Porphyromonas gingivalis/fisiologia , Tannerella forsythia/crescimento & desenvolvimento , Treponema denticola/fisiologia , Adesinas Bacterianas/fisiologia , Biofilmes/crescimento & desenvolvimento , Quimiotaxia/fisiologia , Periodontite Crônica/microbiologia , Contagem de Colônia Microbiana , Humanos , Interações Microbianas , Bolsa Periodontal/microbiologia , Simbiose , VirulênciaRESUMO
A simple, accurate, and highly sensitive analytical method was developed in this study for the determination of nine ß-agonists in milk. In this method, a new magnetic adsorbent of molecularly imprinted polymers/magnetic nanoparticles prepared by simple physical blending was adopted, which enabled magnetic solid-phase extraction. Thus, the resultant material can be separated from the solvent rapidly and conveniently by a magnet. Two kinds of molecularly imprinted polymer/magnetic nanoparticles materials were fabricated, and the characteristics of materials such as the ratio, pH, amount, desorption, and regeneration were investigated. The analytes were quantified by ultra high performance liquid chromatography coupled to an electrospray ionization tandem mass spectrometer operating in multiple reaction monitoring modes. The detection limit of the method was 0.003-0.3 µg/L, and the detection capability was 0.01-0.3 µg/L. The recoveries of these compounds were 65.7-114% at three spiked levels. Reproducibility represented by relative standard deviation was 11.2% or less. The method was successfully applied to the screening of real samples obtained from local markets and confirmation of the suspected target analytes.
Assuntos
Agonistas Adrenérgicos beta/análise , Agonistas Adrenérgicos beta/isolamento & purificação , Magnetismo/métodos , Polímeros/química , Extração em Fase Sólida/métodos , Adsorção , Animais , Bovinos , Cromatografia Líquida de Alta Pressão , Contaminação de Alimentos/análise , Limite de Detecção , Magnetismo/instrumentação , Impressão Molecular , Polímeros/síntese química , Extração em Fase Sólida/instrumentaçãoRESUMO
Facial features are important sources of information about perceived trustworthiness. Masks and protective clothing diminish the visibility of facial cues by either partially concealing the mouth and nose or covering the entire face. During the pandemic, the use of personal protective equipment affected and redefined who trusts whom in society. This study used the classical investment game of interpersonal trust with Chinese participants to explore the impact of occlusion on interpersonal trust. Faces with moderate initial trustworthiness were occluded by a mask or protective clothing in Experiment 1 and were digitally occluded by a square in Experiment 2, and faces with three levels of initial trustworthiness were occluded by a mask in Experiment 3. Results showed that both undergraduates (Experiment 1a) and non-student adults (Experiment 1b) perceived the faces with protective clothing as more trustworthy than faces wearing standard masks and faces not wearing masks. Faces with the top halves showing were perceived as trustworthy as full faces, while faces with the bottom halves showing were perceived as less trustworthy. The effect of masks is weak and complex. Masks reduced participants' trust in faces with high initial trustworthiness, had no effect on faces with low and moderate initial trustworthiness, and only slightly increased the trust of undergraduates in faces with moderate initial trustworthiness. Our findings indicate that the lack of information caused by occlusion and the social significance associated with occlusion collectively affect people's trust behavior in Chinese society. We believe the findings of this study will be useful in elucidating the effects of personal protective equipment usage on perceptions of trustworthiness.
Assuntos
Reconhecimento Facial , Máscaras , Roupa de Proteção , Percepção Social , Confiança , Humanos , Masculino , Feminino , Adulto Jovem , Adulto , China , Reconhecimento Facial/fisiologia , Roupa de Proteção/normas , Adolescente , Jogos Experimentais , COVID-19/prevenção & controle , População do Leste AsiáticoRESUMO
Despite numerous advantages of liposomes in treating rheumatoid arthritis (RA), the in vivo stability remains a critical issue. Current strategies for improving liposomal stability often compromise their original properties. Herein, we designed an alginate nanogel-embedded liposome aiming at retaining those inherent advantages while enhancing their in vivo stability. The introduction of alginate network within the liposome core can provide mechanical support and controlled drug release without affecting the surface properties. Results showed the cross-linking of alginate network within the inner core of liposomes elevated the particle rigidity to 3 times, allowing for improved stability and decreased drug leakage. Moreover, this nanogel-embedded liposome with optimized elasticity obviously facilitated cellular uptake in inflammatory macrophages. When entering blood circulation, increased rigidity altered the composition of protein corona on the particle surface, resulting in 2-fold increase in circulation time and improved drug accumulation in arthritic joints. When anti-inflammatory chlorogenic acid (CA) was encapsulated into the nanogel network, this CA-loaded nanogel-embedded liposome significantly inhibited ROS production and inflammatory response, ultimately achieved superior therapeutic outcome in arthritic rats. Results demonstrated that this nanogel-embedded liposomes can essentially retain the inherent advantages and overcome the drawbacks of liposomes, thereby improving the drug delivery efficiency.
Assuntos
Alginatos , Portadores de Fármacos , Lipossomos , Nanogéis , Alginatos/química , Animais , Lipossomos/química , Portadores de Fármacos/química , Ratos , Nanogéis/química , Camundongos , Liberação Controlada de Fármacos , Sistemas de Liberação de Medicamentos , Células RAW 264.7 , Masculino , Polietilenoglicóis/química , Artrite Experimental/tratamento farmacológicoRESUMO
The diversity-invasibility hypothesis predicts that native plant communities with high biodiversity should be more resistant to invasion than low biodiversity communities. However, observational studies have found that there is often a positive relationship between native community diversity and invasibility. Pollutants were not tested for their potential to cause this positive relationship. Here, we established native communities with three levels of diversity (1, 2 and 4 species) and introduced an invasive plant [Symphyotrichum subulatum (Michx.) G. L. Nesom] to test the effects of different pollutant treatments (i.e., unpolluted control, microplastics (MPs) alone, cadmium (Cd) alone, and their combination) on the relationship between native community diversity and community invasibility. Our results indicate that different MPs and Cd treatments altered the invasibility of native communities, but this effect may depend on the type of pollutant. MPs single treatment reduced invasion success, and the degree of reduction increased with increasing native community diversity (Diversity 2: - 14.1 %; Diversity 4: - 63.1 %). Cd single treatment increased the aboveground biomass of invasive plants (+ 40.2 %) and invasion success. The presence of MPs inhibited the contribution of Cd to invasion success. Furthermore, we found that the complementarity and selection effects of the native community were negatively correlated with invasion success, and their relative contributions to invasion success also depended on the pollutant type. We found new evidence of how pollutants affect the relationship between native community diversity and habitat invasibility, which provides new perspectives for understanding and managing biological invasions in the context of environmental pollution. This may contribute to promoting the conservation of biodiversity, especially in ecologically sensitive and polluted areas.
Assuntos
Cádmio , Poluentes Ambientais , Cádmio/toxicidade , Microplásticos , Plásticos , Ecossistema , Biodiversidade , Plantas , Espécies IntroduzidasRESUMO
Hypomyelinating leukodystrophy (HLD) is a rare genetic heterogeneous disease that can affect myelin development in the central nervous system. This study aims to analyze the clinical phenotype and genetic function of a family with HLD-7 caused by POLR3A mutation. The proband (IV6) in this family mainly showed progressive cognitive decline, dentin dysplasia, and hypogonadotropic hypogonadism. Her three old brothers (IV1, IV2, and IV4) also had different degrees of ataxia, dystonia, or dysarthria besides the aforementioned manifestations. Their brain magnetic resonance imaging showed bilateral periventricular white matter atrophy, brain atrophy, and corpus callosum atrophy and thinning. The proband and her two living brothers (IV2 and IV4) were detected to carry a homozygous mutation of the POLR3A (NM_007055.4) gene c. 2300G > T (p.Cys767Phe), and her consanguineous married parents (III1 and III2) were p.Cys767Phe heterozygous carriers. In the constructed POLR3A wild-type and p.Cys767Phe mutant cells, it was seen that overexpression of wild-type POLR3A protein significantly enhanced Pol III transcription of 5S rRNA and tRNA Leu-CAA. However, although the mutant POLR3A protein overexpression was increased compared to the wild-type protein overexpression, it did not show the expected further enhancement of Pol III function. On the contrary, Pol III transcription function was frustrated (POLR3A, BC200, and tRNA Leu-CAA expression decreased), and MBP and 18S rRNA expressions were decreased. This study indicates that the POLR3A p.Cys767Phe variant caused increased expression of mutated POLR3A protein and abnormal expression of Pol III transcripts, and the mutant POLR3A protein function was abnormal.
Assuntos
Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central , Masculino , Feminino , Humanos , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/genética , Mutação , Fenótipo , Atrofia , RNA de Transferência , RNA Polimerase III/genética , RNA Polimerase III/metabolismoRESUMO
Polyethylene glycol conjugation (PEGylation) is the most successful strategy to promote the stability, pharmacokinetics, and efficacy of therapeutics; however, anti-PEG antibodies induced by repeated treatments raise serious concerns about the future of PEGylated therapeutics. In order to solve the "PEG dilemma", polymers with excellent water solubility and biocompatibility are urgently desired to attenuate the generation of anti-PEG antibodies. Here, poly(ethyl ethylene phosphate) (PEEP) with excellent degradability and stealth effects is used as an alternative to PEG to overcome the "PEG dilemma". PEEPylated liposomes exhibit lower immunogenicity and generate negligible anti-PEEP antibodies (IgM and IgG) after repeated treatments. In vivo studies confirm that PEEPylated liposomes loaded with oxaliplatin (PEEPlipo@OxPt) show better pharmacokinetics compared to PEGlipo@OxPt, and they exhibit potent antitumor performances, which can be further promoted with checkpoint blockade immunotherapy. In addition, PEEPylated lipid nanoparticle is also used to develop an mRNA vaccine with the ability to evoke a potent antigen-specific T cell response and achieve excellent antitumor efficacy. PEEP shows promising potentials in the development of next-generation nanomedicines and vaccines with higher safety and efficacy.
Assuntos
Neoplasias , Polietilenoglicóis , Humanos , Polietilenoglicóis/farmacocinética , Lipossomos , Neoplasias/tratamento farmacológico , Imunoterapia , Vacinação , EtilenosRESUMO
Microplastics exposure is a new human health crisis. Although progress in understanding health effects of microplastic exposure has been made, microplastic impacts on absorption of co-exposure toxic pollutants such as arsenic (As), i.e., oral bioavailability, remain unclear. Microplastic ingestion may interfere As biotransformation, gut microbiota, and/or gut metabolites, thereby affecting As oral bioavailability. Here, mice were exposed to arsenate (6 µg As g-1) alone and in combination with polyethylene particles of 30 and 200 µm (PE-30 and PE-200 having surface area of 2.17 × 103 and 3.23 × 102 cm2 g-1) in diet (2, 20, and 200 µg PE g-1) to determine the influence of microplastic co-ingestion on arsenic (As) oral bioavailability. By determining the percentage of cumulative As consumption recovered in urine of mice, As oral bioavailability increased significantly (P < 0.05) from 72.0 ± 5.41% to 89.7 ± 6.33% with PE-30 at 200 µg PE g-1 rather than with PE-200 at 2, 20, and 200 µg PE g-1 (58.5 ± 19.0%, 72.3 ± 6.28%, and 69.2 ± 17.8%). Both PE-30 and PE-200 exerted limited effects on pre- and post-absorption As biotransformation in intestinal content, intestine tissue, feces, and urine. They affected gut microbiota dose-dependently, with lower exposure concentrations having more pronounced effects. Consistent with the PE-30-specific As oral bioavailability increase, PE exposure significantly up-regulated gut metabolite expression, and PE-30 exerted greater effects than PE-200, suggesting that gut metabolite changes may contribute to As oral bioavailability increase. This was supported by 1.58-4.07-fold higher As solubility in the presence of up-regulated metabolites (e.g., amino acid derivatives, organic acids, and pyrimidines and purines) in the intestinal tract assessed by an in vitro assay. Our results suggested that microplastic exposure especially smaller particles may exacerbate the oral bioavailability of As, providing a new angle to understand health effects of microplastics.
Assuntos
Arsênio , Microbioma Gastrointestinal , Humanos , Animais , Camundongos , Microplásticos/química , Plásticos/toxicidade , Disponibilidade Biológica , Arsênio/toxicidade , Compostos Orgânicos , Polietileno/farmacologiaRESUMO
OBJECTIVE: Obstructive sleep apnoea (OSA) is a common cause of secondary hypertension. This network meta-analysis (NMA) assessed the effect of different OSA treatments on lowering blood pressure. METHODS: PubMed, EMBASE, Web of Science, and Cochrane Library databases were searched for relevant randomized controlled trials. The search strategies included the concepts of OSA, blood pressure, hypertension, and blood pressure-reducing treatments without language or data restriction (from inception to 1 June 2021). The outcomes included office SBP, office DBP, daytime SBP (dSBP) and DBP (dDBP), and night-time SBP (nSBP) and DBP (nDBP). A Bayesian network meta-analysis was performed, and mean differences with 95% credibility intervals were calculated. RESULTS: We reviewed 49 randomized controlled trials involving 4893 patients and the following interventions: continuous positive-airway pressure (CPAP), mandibular advancement devices, nocturnal supplemental oxygen, surgery, ß-blocker, angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin receptor blockers (ARBs), renal sympathetic denervation (RDN), mineralocorticoid receptor antagonists (MRAs), calcium channel blockers. MRAs were significantly associated with blood pressure reduction followed by ACEI/ARB. RDN could reduce office SBP, office DBP, 24-h SBP, 24-h DBP, dSBP, and dDBP. CPAP also demonstrated modest blood pressure lowering. CONCLUSION: MRAs and ACEIs/ARBs can reduce blood pressure effectively in patients with OSA. RDN is a novel hypertension treatment that lowered blood pressure in such patients. CPAP was associated with mild but stable blood pressure reduction, and it might be helpful as an adjunctive therapy in OSA patients with hypertension. REVIEW REGISTRATION: This systematic review and meta-analysis was registered in PROSPERO: CRD42021240891.
Assuntos
Pressão Sanguínea , Hipertensão , Apneia Obstrutiva do Sono , Antagonistas de Receptores de Angiotensina/farmacologia , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Teorema de Bayes , Pressão Positiva Contínua nas Vias Aéreas , Humanos , Hipertensão/complicações , Hipertensão/terapia , Metanálise em Rede , Ensaios Clínicos Controlados Aleatórios como Assunto , Apneia Obstrutiva do Sono/complicações , Apneia Obstrutiva do Sono/terapiaRESUMO
Three-dimensional (3D) cell culture system, as an alternative approach for traditional cell culture, attracts great attention because of physiological relevance and great microenvironment similarity to human conditions. Herein, a facile paper-polylactic (PLA) platform that was fabricated by wax printing and 3D printing, coupled with electrochemical sensor, was designed for the construction and intervention of 3D cell damage model. Pheochromocytoma cells (PC12) and bone marrow mesenchymal stem cells (BMSCs) were seeded on the paper-PLA 3D platforms and displayed the features of uniform distribution, good adhesion and perfect proliferation, as well as decreased circularity when compared to those grown on the two-dimensional (2D) interfaces. The electrochemical sensors revealed cell viability by monitoring dopamine released by cell models, ascertaining the applicability of the paper-PLA platform to a long-term 3D cell culture and drug assessment. Additionally, the results revealed that donepezil and BMSCs-secreted active molecules exhibited stronger cytoprotective effect against amyloid-beta oligomers-induced cell damage on the paper-PLA 3D printed platforms, indicating the cell damage model and the cell intervention model were achieved successfully in the simulated in vivo physiological microenvironment. Thus, the proposed paper-PLA platform may serve as a promising candidate for efficient drug screening and toxicity evaluation due to its simple structure, low cost, and convenient integration of 3D cell culture and activity evaluation.
Assuntos
Técnicas de Cultura de Células em Três Dimensões , Preparações Farmacêuticas , Animais , Humanos , Células PC12 , Poliésteres , Impressão Tridimensional , RatosRESUMO
Rationale: Messenger RNA (mRNA) vaccine outperforms other kinds of cancer immunotherapy due to its high response rates, easy preparation, and wide applicability, which is considered as one of the most promising forms of next-generation cancer therapies. However, the inherent instability and insufficient protein expression duration of mRNA limit the efficacy and widespread application of the vaccine. Methods: Here, we first tested the possibility of a novel circular RNA (circRNA) platform for protein expression and compare its duration with linear RNA. Then, we developed a lipid nanoparticle (LNP) system for circRNA delivery in vitro and in vivo. Next, the innate and adaptive immune response of circRNA-LNP complex was evaluated in vivo. The anti-tumor efficacy of circRNA-LNP was further confirmed in three tumor models. Finally, the possibility of combination therapy with circRNA-LNP and adoptive cell transfer therapy was further investigated in a late-stage tumor model. Results: We successfully increased the stability of the RNA vaccine by circularizing the linear RNA molecules to form highly stable circRNA molecules which exhibited durable protein expression ability. By encapsulating the antigen-coding circRNA in LNP enabling in vivo expression, we established a novel circRNA vaccine platform, which was capable of triggering robust innate and adaptive immune activation and showed superior anti-tumor efficacy in multiple mouse tumor models. Conclusions: Overall, our circRNA vaccine platform provides a novel prospect for the development of cancer RNA vaccines in a wide range of hard-to-treat malignancies.
Assuntos
Vacinas Anticâncer , Nanopartículas , Neoplasias , Animais , Lipossomos , Camundongos , Neoplasias/terapia , RNA/genética , RNA Circular/genética , RNA Mensageiro/genética , Vacinas Sintéticas , Vacinas de mRNARESUMO
Mammalian tooth development relies heavily on the reciprocal and sequential interactions between cranial neural crest-derived mesenchymal cells and stomadial epithelium. During mouse tooth development, odontogenic potential, that is, the capability to direct an adjacent tissue to form a tooth, resides in dental epithelium initially, and shifts subsequently to dental mesenchyme. Recent studies have shown that mouse embryonic dental epithelium possessing odontogenic potential is able to induce the formation of a bioengineered tooth crown when confronted with postnatal mesenchymal stem cells of various sources. Despite many attempts, however, postnatal stem cells have not been used successfully as the epithelial component in the generation of a bioengineered tooth. We show here that epithelial sheets of cultured human keratinocytes, when recombined with mouse embryonic dental mesenchyme, are able to support tooth formation. Most significantly, human keratinocytes, recombined with mouse embryonic dental mesenchyme in the presence of exogenous FGF8, are induced to express the dental epithelial marker PITX2 and differentiate into enamel-secreting ameloblasts that develop a human-mouse chimeric whole tooth crown. We conclude that in the presence of appropriate odontogenic signals, human keratinocytes can be induced to become odontogenic competent; and that these are capable of participating in tooth crown morphogenesis and differentiating into ameloblasts. Our studies identify human keratinocytes as a potential cell source for in vitro generation of bioengineered teeth that may be used in replacement therapy.
Assuntos
Morfogênese/fisiologia , Odontogênese , Dente/embriologia , Ameloblastos/metabolismo , Animais , Bioengenharia , Diferenciação Celular , Criança , Pré-Escolar , Esmalte Dentário/metabolismo , Epitélio/embriologia , Fator 8 de Crescimento de Fibroblasto , Humanos , Queratinócitos , Masculino , Mesoderma , Camundongos , Transdução de Sinais , Células-Tronco , Coroa do DenteRESUMO
Interest in xylan-rich hemicelluloses (XH) film is growing, and efforts have been made to prepare XH films with improved mechanical properties. This work described an effective approach to produce nanocomposite films with enhanced mechanical properties by incorporation of cellulose nanofibers (CNFs) into XH. Aqueous dispersions of XH (64-75 wt %), sorbitol (16-25 wt %), and CNF (0-20 wt %) were cast at a temperature of 23 °C and 50% relative humidity. The surface morphology of the films was revealed by scanning electron microscopy (SEM) and atomic force microscopy (AFM). The thermal properties and crystal structure of the films were evaluated by thermal analysis (TG) and X-ray diffraction (XRD). The surface of XH films with and without CNF was composed primarily of nanonodules, and CNFs were embedded in the XH matrix. Freeze-dried XH powder was amorphous, whereas the films with and without CNF showed a distinct peak at around 2θ = 18°, which suggested that XH molecules aggregated or reordered in the casting solution or during water evaporation. Furthermore, the nanocomposite films had improved thermal stability. XH film with 25 wt % plasticizer (sorbitol, based on dry XH weight) showed poor mechanical properties, whereas incorporation of CNF (5-20 wt %, based on the total dry mixture) into the film resulted in enhanced mechanical properties due to the high aspect ratio and mechanical strength of CNF and strong interactions between CNF and XH matrix. This effective method makes it possible to produce hemicellulose-based biomaterials of high quality.
Assuntos
Materiais Biocompatíveis/síntese química , Nanocompostos/química , Nanofibras/química , Polissacarídeos/química , Engenharia Tecidual/métodos , Xilanos/química , Materiais Biocompatíveis/análise , Celulose/química , Quitosana/química , Cristalografia por Raios X , Liofilização , Microscopia de Força Atômica , Microscopia Eletrônica de Varredura , Nanocompostos/análise , Nanocompostos/ultraestrutura , Nanofibras/análise , Nanofibras/ultraestrutura , Plastificantes/química , Soluções , Sorbitol , TemperaturaRESUMO
PURPOSE: To explore pro-angiogenic miRNAs differentially expressed in dental tissue-derived stem cells under hypoxia. METHODS: Stem cells from apical papilla, dental pulp stem cells and periodontal ligament stem cells were obtained from 3 patients, and treated with nomoxia or hypoxia for 1, 3, 5 d, respectively. Real-time PCR was performed to evaluate the expression of 9 specifically identified pro-angiogenic miRNAs and HIF-1α. SPSS 19.0 software package was used for statistical analysis. RESULTS: At the fifth day of hypoxic condition, as for SCAPs, the expression of miR-126 was relatively increased while miR-20a, miR-20b, miR-21, miR-130a, miR-132, miR-210 and miR-503 deceased. As for DPSCs, the expression of miR-21, miR-130a, miR-126 and miR-210 were relatively increased while miR-132 decreased. As for PDLSCs, the expression of miR-126, miR-21 and miR-296 were relatively increased. Finally, the expression of HIF-1α was relatively upregulated in all three type of cells. CONCLUSIONS: Pro-angiogenic miRNAs in dental tissue-derived stem cells under hypoxia exists specific expression profile.
Assuntos
Polpa Dentária , MicroRNAs , Hipóxia Celular , Células Cultivadas , Polpa Dentária/metabolismo , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , Ligamento Periodontal , Reação em Cadeia da Polimerase em Tempo Real , Células-Tronco/metabolismoRESUMO
The serious problem of pharmaceutical and personal care product pollution places great pressure on aquatic environments and human health. Herein, a novel coating photocatalyst was synthesized by adhering Ag-AgCl/WO3/g-C3N4 (AWC) nanoparticles on a polydopamine (PDA)-modified melamine sponge (MS) through a facile layer-by-layer assembly method to degrade trimethoprim (TMP). The formed PDA coating was used for the anchoring of nanoparticles, photothermal conversion, and hydrophilic modification. TMP (99.9%; 4 mg/L) was removed in 90 min by the photocatalyst coating (AWC/PDA/MS) under visible light via a synergistic photocatalytic-photothermal performance route. The stability and reusability of the AWC/PDA/MS have been proved by cyclic experiments, in which the removal efficiency of TMP was still more than 90% after five consecutive cycles with a very little mass loss. Quantitative structure-activity relationship analysis revealed that the ecotoxicities of the generated intermediates were lower than those of TMP. Furthermore, the solution matrix effects on the photocatalytic removal efficiency were investigated, and the results revealed that the AWC/PDA/MS still maintained excellent photocatalytic degradation efficiency in several actual water and simulated water matrices. This work develops recyclable photocatalysts for the potential application in the field of water remediation.