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Human health can be affected by materials indirectly through exposure to the environment or directly through close contact and uptake. With the ever-growing use of 2D materials in many applications such as electronics, medical therapeutics, molecular sensing, and energy storage, it has become more pertinent to investigate their impact on the immune system. Dendritic cells (DCs) are highly important, considering their role as the main link between the innate and the adaptive immune system. By using primary human DCs, it is shown that hexagonal boron nitride (hBN), graphene oxide (GO) and molybdenum disulphide have minimal effects on viability. In particular, it is evidenced that hBN and GO increase DC maturation, while GO leads to the release of reactive oxygen species and pro-inflammatory cytokines. hBN and MoS2 increase T cell proliferation with and without the presence of DCs. hBN in particular does not show any sign of downstream T cell polarization. The study allows ranking of the three materials in terms of inherent toxicity, providing the following trend: GO > hBN ≈ MoS2 , with GO the most cytotoxic.
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Células Dendríticas , Molibdeno , Humanos , Molibdeno/toxicidadRESUMEN
Polymer micelles with distinct morphologies and unique microphase separation microstructures can exhibit different properties and functions, holding great promise for a range of biomedical applications. In the current work, the topological effects of grafted triblock copolymers on the morphologies and microphase separation microstructures of micelles, including block arrangements and grafting arrangements of hydrophobic side chains, are systematically studied. Using common copolymer components of typical drug carriers, micelles with interesting geometries are achieved, such as raspberry, multicompartment, ellipsoidal and dumbbell shapes, in which the relationship between micelle morphology and copolymer topology is verified. With further exploration of the grafting position and amount of hydrophobic side chains, the microstructure influencing mechanism of copolymer micelles in self-assembly is discussed. The block arrangements of hydrophobic side chains determine the configurations of copolymers (zigzag/bridge) inside micelles, which in turn affect the morphological transitions (from spherical to ringed short-rods and then to cylinders) and the size of the hydrophobic ring, which further gradually change into hydrophobic cage. This study provides insight into the microstructure of hydrophobic side chain grafted copolymer micelles and further helps to understand the mechanism of controlling the morphology of micelles, which might be useful to guide the molecular design and experimental preparation of micelles with controllable morphology for drug encapsulation and delivery.
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Micelas , Polímeros , Portadores de Fármacos/química , Interacciones Hidrofóbicas e Hidrofílicas , Polímeros/químicaRESUMEN
Multi-geometry nanostructures with high-order, complex, and controllable geometries have attracted extensive attention in the development of functional nanomaterials. A simple and versatile strategy is proposed to construct various anisotropic nanostructures through the directed self-assembly (DSA) of patchy microgels. A general criterion for interaction parameters is developed by the variance analysis method to achieve the formation of 1D nanorods by the single directional DSA process, and 2D or 3D polymorphs including V/T/h/cross shapes, multiple arms, multi-directional bending, single/multiple rings, nanocages, etc., by the multi-directional DSA process of binary microgel blends. At the optimum interaction parameters, the nanorods exhibit the quickest formation process and the most thermodynamically stable geometry, while the various 2D or 3D assemblies exhibit controlled jointing behaviors for versatile assembly geometries. The number of recognition sites on the patchy microgel surface guides the aggregation modes of microgels during the DSA process. These assemblies can bear large curvature variance with the increase of shear rates due to the high flexibility and the ability of adjusting orientation spontaneously. The DSA behavior of patchy microgels differs from the traditional self-assembly process of block copolymers, which may open a new route for guiding the formation of controllable nanoparticle architectures.
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Microgeles/química , Nanoestructuras/química , Anisotropía , Interacciones Hidrofóbicas e Hidrofílicas , Simulación de Dinámica Molecular , Nanotubos/química , TermodinámicaRESUMEN
Dissipative particle dynamics (DPD) simulation is used to study the effect of pH on the morphological transition in micelles assembled from dirhamnolipids (diRLs), and analyze the pH-driven mechanism and influence factors of micellar surface patterns. At pH < 4.0, various multilayer structures with homogeneous surface patterns are observed, whereas diRLs can self-assemble into novel anisotropic morphologies with phase-separated surface patterns at pH > 7.4, such as patchy spherical micelles, rod-like micelles with helical surface patterns and a lamellar phase with anisotropic surface patterns. The change in a surface pattern results from the diverse molecular arrangement in the course of assembly due to the deprotonation of carboxyl groups. Further studies show that influence factors, such as molecular structure, solvent selectivity and intramolecular interaction, are closely associated with the changes in surface patterns and topological structures. In detail, decreasing the critical packing parameter of rhamnolipids, increasing the solution polarity and weakening the compatibility between rhamnose rings and alkyl chains are all beneficial to the formation of phase-separated surface patterns. Remarkably, a wider variety of surface patterns (randomly anisotropic surface patterns) can be further obtained with the different factors mentioned above. This work is expected to extend the applications of diRLs to advanced functional materials like drug delivery, optoelectronics and nanofiltration membranes.
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In Arabidopsis, the miR171-GRAS module has been clarified as key player in meristem maintenance. However, the knowledge about its role in fruit crops like tomato (Solanum lycopersicum) remains scarce. We previously identified tomato SlGRAS24 as a target gene of Sly-miR171. To study the role of this probable transcription factor, we generated transgenic tomato plants underexpressing SlGRAS24, overexpressing SlGRAS24, overexpressing Sly-miR171 and expressing ß-glucuronidase (GUS) under the SlGRAS24 promoter (proSlGRAS24-GUS). Plants overexpressing SlGRAS24 (SlGRAS24-OE) had pleiotropic phenotypes associated with multiple agronomical traits including plant height, flowering time, leaf architecture, lateral branch number, root length, fruit set and development. Many GA/auxin-related genes were down-regulated and altered responsiveness to exogenous IAA/NAA or GA3 application was observed in SlGRAS24-OE seedlings. Moreover, compromised fruit set and development in SlGRAS24-OE was also observed. These newly identified phenotypes for SlGRAS24 homologs in tomato were later proved to be caused by impaired pollen sacs and fewer viable pollen grains. At anthesis, the comparative transcriptome results showed altered expression of genes involved in pollen development and hormone signalling. Taken together, our data demonstrate that SlGRAS24 participates in a series of developmental processes through modulating gibberellin and auxin signalling, which sheds new light on the involvement of hormone crosstalk in tomato development.
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Giberelinas/metabolismo , Ácidos Indolacéticos/metabolismo , MicroARNs/genética , Solanum lycopersicum/metabolismo , Regulación del Desarrollo de la Expresión Génica/genética , Regulación de la Expresión Génica de las Plantas/genética , Glucuronidasa/genética , Glucuronidasa/metabolismo , Solanum lycopersicum/genética , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Plantas Modificadas Genéticamente/genética , Plantas Modificadas Genéticamente/metabolismoRESUMEN
Previous reports showed that the large linear plasmid SCP1 of Streptomyces coelicolor A3(2) contains a 5.4 kb centrally located replication locus. We report here that SCP1 actually contains three internal replication loci. Subcloning of the 5.4 kb sequence identified a 3.2 kb minimal locus (rep1A/repB/iteron) that determined propagation in Streptomyces lividans. The two newly identified replication genes, rep2A and rep3A, resembled the rep gene of Streptomyces circular plasmid pZL12. Transcription start points of the three replication genes were determined. The three replication loci could independently determine propagation in linear mode in S. lividans. Individual and sequential deletions of the rep1A and rep3A genes were successful. The SCP1-derived linear plasmids with deletions of the rep1A and/or rep3A genes still propagated in similar copy numbers, were inherited largely stable and were transferred efficiently by conjugation in S. coelicolor. Interestingly, SCP1 can be artificially circularized to yield a 280 kb circular plasmid, circular SCP-1 (C-SCP1), which contains the three replication loci. Strikingly, the copy numbers, inheritance and transfer of C-SCP1 resembled that of the linear SCP1 plasmids. Transcripts of the rep1A, rep2A and rep3A genes in linear or artificially circularized SCP1 were detected at all the time points of strain growth.
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Plásmidos , Origen de Réplica , Streptomyces coelicolor/genética , Clonación Molecular , Replicación del ADN , Inestabilidad Genómica , Replicón , Streptomyces lividans/genética , Sitio de Iniciación de la TranscripciónRESUMEN
OBJECTIVES: This study aimed to investigate how naringenin (Nar) affected the anti-inflammatory, vascula-rization, and osteogenesis differentiation of human periodontal ligament stem cells (hPDLSCs) stimulated by lipopolysaccharide (LPS) and to preliminarily explore the underlying mechanism. METHODS: Cell-counting kit-8 (CCK8), cell scratch test, and Transwell assay were used to investigate the proliferation and migratory capabilities of hPDLSCs. Alkaline phosphatase (ALP) staining, alizarin red staining, lumen-formation assay, enzyme-linked immunosorbent assay, quantitative timed polymerase chain reaction, and Western blot were used to measure the expression of osteopontin (OPN), Runt-related transcription factor 2 (RUNX2), vascular endothlial growth factor (VEGF), basic fibroblast growth factor (bFGF), von Willebrand factor (vWF), tumor necrosis factor-α (TNF-α), and interleukin (IL)-6. RESULTS: We observed that 10 µmol/L Nar could attenuate the inflammatory response of hPDLSCs stimulated by 10 µg/mL LPS and promoted their proliferation, migration, and vascularization differentiation. Furthermore, 0.1 µmol/L Nar could effectively restore the osteogenic differentiation of inflammatory hPDLSCs. The effects of Nar's anti-inflammatory and promotion of osteogenic differentiation significantly decreased and inflammatory vascularization differentiation increased after adding AMD3100 (a specific CXCR4 inhibitor). CONCLUSIONS: Nar demonstrated the ability to promote the anti-inflammatory, vascularization, and osteogenic effects of hPDLSCs stimulated by LPS, and the ability was associated with the stromal cell-derived factor/C-X-C motif chemokine receptor 4 signaling axis.
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Lipopolisacáridos , Ligamento Periodontal , Humanos , Antiinflamatorios/metabolismo , Antiinflamatorios/farmacología , Diferenciación Celular , Proliferación Celular , Células Cultivadas , Quimiocina CXCL12 , Lipopolisacáridos/metabolismo , Lipopolisacáridos/farmacología , Osteogénesis , Ligamento Periodontal/metabolismo , Receptores de Quimiocina/metabolismo , Células Madre , Interleucina-8/metabolismoRESUMEN
Pulmonary exposure to some engineered nanomaterials can cause chronic lesions as a result of unresolved inflammation. Among 2D nanomaterials and graphene, MoS2 has received tremendous attention in optoelectronics and nanomedicine. Here an integrated approach is proposed to follow up the transformation of MoS2 nanosheets at the nanoscale and assesss their impact on lung inflammation status over 1 month after a single inhalation in mice. Analysis of immune cells, alveolar macrophages, extracellular vesicles, and cytokine profiling in bronchoalveolar lavage fluid (BALF) shows that MoS2 nanosheets induced initiation of lung inflammation. However, the inflammation is rapidly resolved despite the persistence of various biotransformed molybdenum-based nanostructures in the alveolar macrophages and the extracellular vesicles for up to 1 month. Using in situ liquid phase transmission electron microscopy experiments, the dynamics of MoS2 nanosheets transformation triggered by reactive oxygen species could be evidenced. Three main transformation mechanisms are observed directly at the nanoscale level: 1) scrolling of the dispersed sheets leading to the formation of nanoscrolls and folded patches, 2) etching releasing soluble MoO4 - , and 3) oxidation generating oxidized sheet fragments. Extracellular vesicles released in BALF are also identified as a potential shuttle of MoS2 nanostructures and their degradation products and more importantly as mediators of inflammation resolution.
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Vesículas Extracelulares , Neumonía , Animales , Ratones , Molibdeno/química , Disulfuros/química , Inflamación/inducido químicamenteRESUMEN
Bladder cancer (BLCA) is the most common malignancy whose early diagnosis can ensure a better prognosis. However, the predictive accuracy of commonly used predictors, including patients' general condition, histological grade, and pathological stage, is insufficient to identify the patients who need invasive treatment. Autophagy is regarded as a vital factor in maintaining mitochondrial function and energy homeostasis in cancer cells. Whether autophagy-related genes (ARGs) can predict the prognosis of BLCA patients deserves to be investigated. Based on BLCA data retrieved from the Cancer Genome Atlas and ARGs list obtained from the Human Autophagy Database website, we identified prognosis-related differentially expressed ARGs (PDEARGs) through Wilcox text and constructed a PDEARGs-based prognostic model through multivariate Cox regression analysis. The predictive accuracy, independent forecasting capability, and the correlation between present model and clinical variables or tumor microenvironment were evaluated through R software. Enrichment analysis of PDEARGs was performed to explore the underlying mechanism, and a systematic prognostic signature with nomogram was constructed by integrating clinical variables and the aforementioned PDEARGs-based model. We found that the risk score generated by PDEARGs-based model could effectively reflect deteriorated clinical variables and tumor-promoting microenvironment. Additionally, several immune-related gene ontology terms were significantly enriched by PDEARGs, which might provide insights for present model and propose potential therapeutic targets for BLCA patients. Finally, a systematic prognostic signature with promoted clinical utility and predictive accuracy was constructed to assist clinician decision. PDEARGs are valuable prognostic predictors and potential therapeutic targets for BLCA patients.
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Autofagia/genética , Neoplasias de la Vejiga Urinaria/diagnóstico , Neoplasias de la Vejiga Urinaria/genética , Biomarcadores de Tumor/genética , Correlación de Datos , Bases de Datos Genéticas , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Estimación de Kaplan-Meier , Masculino , Análisis Multivariante , Nomogramas , Pronóstico , Factores de Riesgo , Microambiente Tumoral/genéticaRESUMEN
Background: Bladder cancer patients have a high recurrence and poor survival rates worldwide. Early diagnosis and intervention are the cornerstones for favorable prognosis. However, commonly used predictive tools cannot meet clinical needs because of their insufficient accuracy. Methods: We have developed an enhancer RNA (eRNA)-based signature to improve the prediction for bladder cancer prognosis. First, we analyzed differentially expressed eRNAs in gene expression profiles and clinical data for bladder cancer from The Cancer Genome Atlas database. Then, we constructed a risk model for prognosis of bladder cancer patients, and analyzed the correlation between this model and tumor microenvironment (TME). Finally, regulatory network of downstream genes of eRNA in the model was constructed by WGCNA and enrichment analysis, then Real-time quantitative PCR verified the differentiation of related genes between tumor and adjacent tissue. Results: We first constructed a risk model composed of eight eRNAs, and found the risk model could be an independent risk factor to predict the prognosis of bladder cancer. Then, the log-rank test and time-dependent ROC curve analysis shown the model has a favorable ability to predict prognosis. The eight risk eRNAs may participate in disease progression by regulating cell adhesion and invasion, and up-regulating immune checkpoints to suppress the immunity in TME. mRNA level change in related genes further validated regulatory roles of eRNAs in bladder cancer. In summary, we constructed an eRNA-based risk model and confirmed that the model could predict the prognosis of bladder cancer patients.
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The genus of Nocardiopsis is a new source of antibiotics, chemicals, and enzymes. Here we reported the development of a vector and host system in moderately halophilic Nocardiopsis via an oriT-mediated conjugation. By screening about 80 Nocardiopsis strains, 6 of them harbored 8 plasmids (18-80 kb). The complete nucleotide sequence of pSQ10 consisted of 18,219 bp, with 71.9% G + C content, encoding 17 open reading frames, 5 of them resembled those of Streptomyces plasmids. A rep locus (iteron within the gene) was identified for replication in Nocardiopsis sp. YIM 90083, and rep protein bound to its iteron sequence. This system may be useful for gene cloning and expression in Nocardiopsis.
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Actinomycetales/genética , Replicación del ADN , Vectores Genéticos/genética , Plásmidos/genética , Actinomycetales/clasificación , Actinomycetales/metabolismo , Antibacterianos/farmacología , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Composición de Base/genética , Secuencia de Bases , ADN Bacteriano/química , ADN Bacteriano/genética , ADN Bacteriano/metabolismo , Farmacorresistencia Bacteriana , Escherichia coli/genética , Datos de Secuencia Molecular , Sistemas de Lectura Abierta/genética , Filogenia , Unión Proteica , Origen de Réplica/genética , Análisis de Secuencia de ADN , Especificidad de la Especie , Tioestreptona/farmacología , Transformación BacterianaRESUMEN
Based on the tumor microenvironment with weak acidic characteristics, a nano-drug delivery system that achieves controlled release of drugs through the pH response has been a popular strategy to improve the effectiveness of tumor therapy and reduce toxic side effects, and combining photothermal therapy (PTT) on this basis can help improve the antitumor effect. In this study, mesoporous silica nanoparticles (MSNs) were surface-modified with polymer poly(PEGMA-co-HEMA) via surface-initiated atom transfer radical polymerization, and a multifunctional nanoplatform MSN@poly(PEGMA-co-HEMA-g-doxorubicin (DOX)/indocyanine green (ICG) was designed for effective photothermal/chemotherapy combination therapy. The anticancer drug DOX was anchored to the polymer on the surface of MSN by reversible covalent bond cis-aconitic anhydride with a drug loading of 10%. Meanwhile, the small-molecule dye was loaded into the pores of MSN, and PTT mediated by near-infrared (NIR) radiation could further kill cancer cells. Under low-pH stimulation, the cis-aconitic anhydride bond breaks and DOX is released, with a 65% increase in cumulative drug release over 50 h compared to that at pH 7.4 (normal physiological environment). The high temperature induced by photothermal conversion accelerated the reversible covalent bond breakage, and the cumulative drug release at pH 5.0 for 3 h at elevated temperature up to 50 °C increased by 24.3% compared with that under normal physiological conditions (T = 37 °C), demonstrating that increasing the temperature can reduce the time required to reach blood drug concentration. In vitro cytotoxicity results revealed that the prodrug delivery system showed stronger cytotoxicity under NIR light irradiation compared with free DOX, with more than 90% of tumor cells killed after 48 h. Therefore, MSN@poly(PEGMA-co-HEMA-g-DOX)/ICG enhanced the synergistic effect of chemotherapy through photothermal action and accelerated reversible chemical bond cleavage, which has great potential in the combined therapy of cancer.
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Hipertermia Inducida , Dióxido de Silicio , Doxorrubicina/farmacología , Hipertermia Inducida/métodos , Verde de Indocianina/química , Fototerapia/métodos , Terapia Fototérmica , Polímeros , Dióxido de Silicio/químicaRESUMEN
Intervertebral disk degeneration (IDD) is a severe health problem that results in lower back pain and disability. Previous evidence has indicated that excessive apoptosis of nucleus pulposus (NP) cell is involved in the occurrence and development of IDD. However, the underlying mechanisms regulating NP cell apoptosis are unclear. The present study aimed to investigate the function of a novel long non-coding RNA RP11-81H3.2 in modulating NP cell apoptosis and the potential underlying mechanisms. The results demonstrated that the RP11-81H3.2 expression levels were significantly decreased in NP tissues from patients with IDD compared with those from healthy controls, and that lower expression levels were associated with higher-grade disk degeneration. Functionally, RP11-81H3.2 silencing promoted apoptosis and decreased the viability of NP cells derived from tissue samples of patients with IDD, whereas RP11-81H3.2 overexpression induced opposite effects. Bioinformatics analysis, luciferase assays and reverse transcription-quantitative PCR revealed that microRNA (miR)-1539 was a direct target of RP11-81H3.2. A mechanistic analysis demonstrated that RP11-81H3.2 functioned as an RNA sink to downregulate miR-1539, which led to the upregulation of collagen type 2 α 1 chain (COL2A1), a target of miR-1539. Collectively, the present results suggested that lower RP11-81H3.2 expression levels were associated with higher-grade IDD, and that RP11-81H3.2 inhibited NP cell apoptosis by decreasing the levels of miR-1539 to increase COL2A1 expression levels. The present study identified a beneficial role of RP11-81H3.2 against NP cell apoptosis.
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Previous reports showed that Streptomyces linear plasmids usually contain one internal replication locus. Here, we identified two new replication loci on pFRL1, one (rep1A-ncs1) next to a telomere and another (rep2A-ncs2) approximately 10 kb from it. The rep1A-ncs1 locus was able to direct replication independently in both linear and circular modes, whereas rep2A-ncs2 required an additional locus, rlrA-rorA, in order to direct propagation in linear mode. Rep1A protein bound to ncs1 in vitro. By quantitative reverse transcription-PCR and Northern hybridization, we showed that transcription of rep1A and rep2A varied during development and that each dominated at different time points. pFRL1-derived linear plasmids were inherited through spores more stably than circular plasmids and were more stable with pSLA2 telomeres than with pFRL1 telomeres in Streptomyces lividans.
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Replicación del ADN , ADN Bacteriano/genética , ADN Bacteriano/metabolismo , Plásmidos , Origen de Réplica , Streptomyces lividans/genética , ADN Circular/genética , ADN Circular/metabolismoRESUMEN
Good stability and controlled drug release are important properties of polymeric micelles for drug delivery. A good candidate for drug delivery must have outstanding stability in a normal physiological environment, followed with low drug leakage and side effects. Moreover, the chemotherapeutic drug in the micellar core should also be quickly and "on-demand" released in the intracellular microenvironment at the tumor site, which is in favor of overcoming multidrug resistance (MDR) effects of tumor cells. In this work, a mixed micelle was prepared by the simple mix of two amphiphilic copolymers, namely PCL-SS-P(PEGMA-co-MAEBA) and PCL-SS-PDMAEMA, in aqueous solution. In the mixed micelle's core-shell structure, PCL blocks were used as the hydrophobic core, while the micellar hydrophilic shell consisted of two blocks, namely P(PEGMA-co-MAEBA) and PDMAEMA. In the micellar shell, PEGMA provided hydrophilicity and stability, while MAEBA introduced the aldehyde sites for reversible crosslinking. Meanwhile, the PDMAEMA blocks were also introduced in the micellar shell for pH-responding protonation and swelling of the micelle. The disulfide bonds between the hydrophobic core and hydrophilic shell had redox sensitive properties. Reversible cross-linked micelles (RCLMs) were obtained by crosslinking the micellar shell with an imine structure. RCLMs showed good stability and excellent ability against extensive dilution by aqueous solution. In addition, the stability in different conditions with various pH values and glutathione (GSH) concentrations was studied. Then, the anticancer drug doxorubicin (DOX) was selected as the model drug to evaluate drug entrapment and release capacity of mixed micelles. The in vitro release profiles indicated that this RCLM had controlled drug release. In the simulated normal physiological environment (pH 7.4), the drug release of the RCLMs was restrained obviously, and the cumulative drug release content was only 25.7 during 72 h. When it came to acidic conditions (pH 5.0), de-crosslinking of the micelles occurred, as well as protonation of PDMAEMA blocks and micellar swelling at the same time, which enhanced the drug release to a large extent (81.4%, 72 h). Moreover, the drug release content was promoted further in the presence of the reductant GSH. In the condition of pH 5.0 with 10 mM GSH, disulfide bonds broke-up between the micelle core and shell, followed by shedding of the shell from the inner core. Then, the micellar disassembly (degradation) happened based on the de-crosslinking and swelling, and the drug release was as high as 95.3%. The MTT assay indicated that the CLSMs showed low cytotoxicity and good biocompatibility against the HepG2 cells. In contrast, the DOX-loaded CLSMs could efficiently restrain the proliferation of tumor cells, and the cell viability after 48 h incubation was just 13.2%, which was close to that of free DOX. This reversible cross-linked mixed micelle with pH/redox responsive behaviors is a potential nanocarrier for chemotherapy.
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The SARS-Cov-2 pandemic has spread worldwide during 2020, setting up an uncertain start of this decade. The measures to contain infection taken by many governments have been extremely severe by imposing home lockdown and industrial production shutdown, making this the biggest crisis since the second world war. Additionally, the continuous colonization of wild natural lands may touch unknown virus reservoirs, causing the spread of epidemics. Apart from SARS-Cov-2, the recent history has seen the spread of several viral pandemics such as H2N2 and H3N3 flu, HIV, and SARS, while MERS and Ebola viruses are considered still in a prepandemic phase. Hard nanomaterials (HNMs) have been recently used as antimicrobial agents, potentially being next-generation drugs to fight viral infections. HNMs can block infection at early (disinfection, entrance inhibition) and middle (inside the host cells) stages and are also able to mitigate the immune response. This review is focused on the application of HNMs as antiviral agents. In particular, mechanisms of actions, biological outputs, and limitations for each HNM will be systematically presented and analyzed from a material chemistry point-of-view. The antiviral activity will be discussed in the context of the different pandemic viruses. We acknowledge that HNM antiviral research is still at its early stage, however, we believe that this field will rapidly blossom in the next period.
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Antivirales/uso terapéutico , Betacoronavirus , Infecciones por Coronavirus/terapia , Nanoestructuras/uso terapéutico , Pandemias , Neumonía Viral/terapia , Inmunidad Adaptativa , Betacoronavirus/efectos de los fármacos , Betacoronavirus/fisiología , Betacoronavirus/ultraestructura , COVID-19 , Infecciones por Coronavirus/epidemiología , Infecciones por Coronavirus/virología , Sistemas de Liberación de Medicamentos , Fulerenos/uso terapéutico , Interacciones Microbiota-Huesped/efectos de los fármacos , Humanos , Inmunidad Innata , Nanopartículas del Metal/uso terapéutico , Modelos Biológicos , Nanotecnología , Neumonía Viral/epidemiología , Neumonía Viral/virología , Especies Reactivas de Oxígeno/uso terapéutico , SARS-CoV-2 , Internalización del Virus/efectos de los fármacosRESUMEN
BACKGROUND: Preeclampsia (PE) is a common pregnancy-related syndrome characterized by hypertension and proteinuria, and a major cause of maternal mortality. Therefore, there is an urgent need to identify early biomarkers of PE. The aim of the present study was to identify the functions of miR-576-5p in PE. METHODS: Effects of miR-576-5p and transcription factor AP-2α (TFAP2A) on invasion of human trophoblast HTR8/SVneo cells were investigated. Real-time quantitative polymerase chain reaction (RT-qPCR) and western blotting were used to assess the expression of miR-576-5p, TFAP2A, E-cad, and Vimentin in PE tissues and cells. Additionally, immunofluorescence was used to detect the expression of TFAP2A in PE trophoblastic tissue. Subsequently, constructed miR-576-5p mimics, miR-576-5p inhibitor, and siRNA-TFAP2A plasmids were transfected into HTR8/SVneo cells for further experiments, including a CCK-8 assay for cell proliferation, Transwell assay for cell invasion and the luciferase reporter gene system was employed for target verification. RESULTS: A lower expression of miR-576-5p and a higher expression of TFAP2A were identified in PE rats. E-cadherin was highly expressed while Vimentin was downregulated. Further statistical analysis indicated that cell proliferation of HTR8/SVneo cells decreased in the miR-576-5p inhibitor group and increased in the miR-576-5p mimics and siRNA-TFAP2A groups. miR-576-5p inhibitor suppressed cell invasion, and miR-576-5p mimics and siRNA-TFAP2A improved cell invasion. The analysis of luciferase reporter demonstrated a decreased luciferase activity in miR-576-5p mimics group compared with control group, which indicates that TFAP2A may be a target of miR-576-5p. Interference of TFAP2A could downregulate E-cadherin and upregulate Vimentin expression. CONCLUSION: Overexpression of miR-576-5p and knockdown of TFAP2A may elevate cell proliferation and invasion of human trophoblast cells in vitro. Therefore, miR-576-5p may be used as a notable biomarker for the diagnosis, prevention, and treatment of PE. miR-576-5p targeting TFAP2A deserve further investigation in order to explore their potential role in PE.
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MicroARNs/metabolismo , Preeclampsia/metabolismo , Factor de Transcripción AP-2/genética , Trofoblastos/metabolismo , Animales , Biomarcadores/metabolismo , Cadherinas/genética , Cadherinas/metabolismo , Movimiento Celular , Células Cultivadas , Femenino , Humanos , MicroARNs/genética , Embarazo , Ratas , Ratas Sprague-Dawley , Factor de Transcripción AP-2/metabolismo , Trofoblastos/fisiología , Vimentina/genética , Vimentina/metabolismoRESUMEN
Novel approach has been constructed for preparing the amphiphilic star copolymer pH/reduction stimuli-responsive cross-linked micelles (SCMs) as a smart drug delivery system for the well-controlled anti-tumor drug doxorubicin (DOX) release. The SCMs had a low CMC value of 5.3 mg/L. The blank and DOX-loaded SCMs both had a spherical shape with sizes around 100-180 nm. In addition, the good stability and well pH/reduction-sensitivity of the SCMs were determined by dynamic light scattering (DLS) as well. The SCMs owned a low release of DOX in bloodstream and normal tissues while it had a fast release in tumor higher glutathione (GSH) concentration and/or lower pH value conditions, which demonstrates their pH/reduction dual-responsiveness. Furthermore, we conducted the thermodynamic analysis to study the interactions between the DOX and polymer micelles in the DOX release process. The values of the thermodynamic parameters at pH 7.4 and at pH 5.0 conditions indicated that the DOX release was endothermic and controlled mainly by the forces of an electrostatic interaction. At pH 5.0 with 10 mM GSH condition, electrostatic interaction, chemical bond, and hydrophobic interactions contributed together on DOX release. With the low cytotoxicity of blank SCMs and well cytotoxicity of DOX-loaded SCMs, the results indicated that the SCMs could form a smart cancer microenvironment-responsive drug delivery system. The release kinetic and thermodynamic analysis offer a theoretical foundation for the interaction between drug molecules and polymer matrices, which helps provide a roadmap for the oriented design and control of anti-cancer drug release for cancer therapy.
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This study introduced multistage pH-responsive nanohybrids (MSN-hyd-MOP) based on mesoporous silica nanoparticles (MSNs) modified with polymers with charge-reversal property via an acid-labile hydrazone linker, which were applied as a drug delivery system loaded anticancer drugs. In this study, MSN-hyd-MOP nanohybrids were completely investigated for their synthesis, pH response, drug release behavior, cytotoxicity capability and endocytic behavior. Responding to the acidic extracellular microenvironment of solid tumor (pH 6.5), MSN-hyd-MOP nanohybrids exhibited surface charge-reversal characteristic from negative (-10.2â¯mV, pH 7.4) to positive (16.6â¯mV, pH 6.5). The model drug doxorubicin (Dox) was efficiently loaded within the channels of MSN-hyd-MOP (encapsulation efficiency about 87%). The increased acidity in endo-/lysosome promote Dox-loaded MSN-hyd-MOP (MSN-hyd-MOP@Dox) release Dox quickly. In vitro study revealed the drug delivery system had good biocompatibility and could deliver the payload to tumor cells. Overall, the described nanohybrids can be used as a potential anticancer drug delivery system.
Asunto(s)
Antibióticos Antineoplásicos/farmacología , Doxorrubicina/farmacología , Sistemas de Liberación de Medicamentos , Nanopartículas/química , Dióxido de Silicio/química , Antibióticos Antineoplásicos/química , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Doxorrubicina/química , Portadores de Fármacos/química , Ensayos de Selección de Medicamentos Antitumorales , Células Hep G2 , Humanos , Concentración de Iones de Hidrógeno , Estructura Molecular , Tamaño de la Partícula , Porosidad , Dióxido de Silicio/síntesis química , Propiedades de Superficie , Células Tumorales CultivadasRESUMEN
In this study, Schiff-base copolymer coating and mesoporous silica nanoparticles (Polymer@MSN) were synthesized by ARGET ATRP and sol-gel method respectively. Imine bonds acted as the pH-cleavable linker between copolymer gatekeepers and MSN to promote the controlled-release performance of DOX. The DOX-loaded nanoparticles (Polymer@MSN-DOX) were spherical with a diameter of approximately 150 nm. At pH 5.0 (pH of intracellular environment), the cumulative release of DOX within 72 h was 45% higher than that at pH 7.4 (normal physiological environment) due to the cleavage of imine bonds, showing obvious pH-responsive drug release performance. Confocal microscopy studies and in vitro cytotoxicity results revealed that Polymer@MSN-DOX could smoothly enter HepG2 cells to release DOX and show a high cytotoxicity. Noted specially that molecular dynamics simulations were applied to investigate the microcosmic adsorption/diffusion interaction between drug molecules and MSN. Simulation results showed that the driving force of DOX adsorption in mesoporous channels was originated from hydrogen bonding interaction between the mesoporous wall and DOX molecules and π-π conjugated interaction between benzene rings in addition to concentration differences. The structural design of composite nanocarriers in this research could provide guidance for the application of pH-responsive MSN-based drug delivery system.