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Messenger RNA (mRNA)-based therapeutics are transforming the landscapes of medicine, yet targeted delivery of mRNA to specific cell types while minimizing off-target accumulation remains challenging for mRNA-mediated therapy. In this study, we report an innovative design of a cationic lipid- and hyaluronic acid-based, dual-targeted mRNA nanoformulation that can display the desirable stability and efficiently transfect the targeted proteins into lung tissues. More importantly, the optimized dual-targeted mRNA nanoparticles (NPs) can not only accumulate primarily in lung tumor cells and inflammatory macrophages after inhalation delivery but also efficiently express any desirable proteins (e.g., p53 tumor suppressor for therapy, as well as luciferase and green fluorescence protein for imaging as examples in this study) and achieve efficacious lung tissue transfection in vivo. Overall, our findings provide proof-of-principle evidence for the design and use of dual-targeted mRNA NPs in homing to specific cell types to up-regulate target proteins in lung tissues, which may hold great potential for the future development of mRNA-based inhaled medicines or vaccines in treating various lung-related diseases.
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Nanopartículas , Neoplasias , RNA Mensageiro/genética , Transfecção , Pulmão , MacrófagosRESUMO
Metformin is a synthetic biguanide proven to have beneficial effects against various human diseases. Research has confirmed that metformin exerts its effects by regulating the composition of intestinal microbiota. The composition of intestinal microbiota influences the efficacy of anti-PD-L1 immunotherapy. We assume that the regulation of metformin on intestinal microbiota could enhance the therapeutic efficiency of anti-PD-L1 antibodies. In Lewis lung cancer-bearing C57BL/6J mice, we find that metformin enhances PD-L1 antibody efficacy mainly depending on the existence of gut microbiota, and metformin increases the anti-tumor immunity through modulation of intestinal microbiota and affects the integrity of the intestinal mucosa. Antibiotic depletion of gut microbiota abolished the combination efficacy of PD-L1 antibody and metformin, implying the significance of intestinal microbiota in metformin's antitumor action. Combining anti-PD-L1 antibody with metformin provoked tumor necrosis by causing increased CD8 T-cell infiltration and IFN-γ expression. In conclusion, metformin could be employed as a microecological controller to prompt antitumor immunity and increase the efficacy of anti-PD-L1 antibodies. Our study provided reliable evidence that metformin could be synergistically used with anti-PD-L1 antibody to enhance the anti-cancer effect.
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Microbioma Gastrointestinal , Metformina , Camundongos , Animais , Humanos , Metformina/farmacologia , Metformina/uso terapêutico , Antígeno B7-H1 , Camundongos Endogâmicos C57BL , Linfócitos T CD8-Positivos , Linhagem Celular TumoralRESUMO
Foreign ions as additives are of great significance for realizing excellent control over the morphology of noble metal nanostructures in the state-of-the-art seed-mediated growth method; however, they remain largely unexplored in chiral synthesis. Here, we report on a Cu2+-dominated chiral growth strategy that can direct the growth of concave chiral Au nanoparticles with C3-dominant chiral centers. The introduction of trace amounts of Cu2+ ions in the seed-mediated chiral growth process is found to dominate the chirality transfer from chiral molecules to chiral nanoparticles, leading to the formation of chiral nanoparticles with a concave VC geometry. Both experimental and theoretical results further demonstrate the correlation between the nanoparticle structure and optical chirality for the concave chiral nanoparticle. The Cu2+ ion is found to dominate the chiral growth by selectively activating the deposition of Au atoms along the [110] and [111] directions, facilitating the formation of the concave VC. We further demonstrate that the Cu2+-dominated chiral growth strategy can be employed to generate a variety of concave chiral nanoparticles with enriched geometric chirality and desired chiroptical properties. Concave chiral nanoparticles also exhibit appealing catalytic activity and selectivity toward electrocatalytic oxidation of enantiomers in comparison to helicoidal nanoparticles. The ability to tune the geometric chirality in a controlled manner by simply manipulating the Cu2+ ions as additives opens up a promising strategy for creating chiral nanomaterials with increasing architectural diversity for chirality-dependent optical and catalytic applications.
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Stroke is an acute injury of the central nervous system caused by the disorders of cerebral blood circulation, which has become one of the major causes of disability and death. Hemorrhage, particularly subarachnoid hemorrhage (SAH), is one of the poorest prognostic factors in stroke, which is related to the thrombolytic therapy, and has been considered very dangerous. In this context, the MR angiography with high sensitivity and resolution has been developed based on biocompatible paramagnetic ultrasmall NaGdF4 nanoprobes. Owing to the appropriate hydrodynamic diameter, the nanoprobe can be confined inside the blood vessels and it only extravasates at the vascular injury site when the bleeding occurs. Relying on this property, the three-dimensional (3D) anatomic structures of artery occlusion of stroke rat can be precisely visualized; reperfusion-related SAH has been successfully visualized and identified. Benefiting from the long blood half-life of the nanoprobe, the observation window of MR angiography can last for the whole period of reperfusion, thereby monitoring the probable SAH in real time during thrombolytic therapy. More importantly, through reconstruction of multiparametric MRI, the arterial occlusion, cerebral ischemic region, and SAH can be simultaneously visualized in vivo in a 3D manner for the first time. Therefore, the current study provides a novel approach for both noninvasive 3D vascular visualization and hemorrhage alert, which possesses great prospects for clinical translation.
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AVC Isquêmico , Angiografia por Ressonância Magnética , Hemorragia Subaracnóidea , Animais , Hemorragia Subaracnóidea/diagnóstico por imagem , Ratos , AVC Isquêmico/diagnóstico por imagem , Ratos Sprague-Dawley , Masculino , Gadolínio/química , ReperfusãoRESUMO
Integrating the plasmonic chirality with excellent catalytic activities in plasmonic hybrid nanostructures provides a promising strategy to realize the chiral nanocatalysis toward many chemical reactions. However, the controllable synthesis of catalytically active chiral plasmonic nanoparticles with tailored geometries and compositions remains a significant challenge. Here it is demonstrated that chiral Au-Pd alloy nanorods with tunable optical chirality and catalytically active surfaces can be achieved by a seed-mediated coreduction growth method. Through manipulating the chiral inducers, Au nanorods selectively transform into two different intrinsically chiral Au-Pd alloy nanorods with distinct geometric chirality and tunable optical chirality. By further adjusting several key synthetic parameters, the optical chirality, composition, and geometry of the chiral Au-Pd nanorods are fine-tailored. More importantly, the chiral Au-Pd alloy nanorods exhibit appealing chiral catalytic activities as well as polarization-dependent plasmon-enhanced nanozyme catalytic activity, which has great potential for chiral nanocatalysis and plasmon-induced chiral photochemistry.
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Maize is one of the most important crops for food, cattle feed and energy production. However, maize is frequently attacked by various pathogens and pests, which pose a significant threat to maize yield and quality. Identification of quantitative trait loci and genes for resistance to pests will provide the basis for resistance breeding in maize. Here, a ß-glucosidase ZmBGLU17 was identified as a resistance gene against Pythium aphanidermatum, one of the causal agents of corn stalk rot, by genome-wide association analysis. Genetic analysis showed that both structural variations at the promoter and a single nucleotide polymorphism at the fifth intron distinguish the two ZmBGLU17 alleles. The causative polymorphism near the GT-AG splice site activates cryptic alternative splicing and intron retention of ZmBGLU17 mRNA, leading to the downregulation of functional ZmBGLU17 transcripts. ZmBGLU17 localizes in both the extracellular matrix and vacuole and contribute to the accumulation of two defence metabolites lignin and DIMBOA. Silencing of ZmBGLU17 reduces maize resistance against P. aphanidermatum, while overexpression significantly enhances resistance of maize against both the oomycete pathogen P. aphanidermatum and the Asian corn borer Ostrinia furnacalis. Notably, ZmBGLU17 overexpression lines exhibited normal growth and yield phenotype in the field. Taken together, our findings reveal that the apoplastic and vacuolar localized ZmBGLU17 confers resistance to both pathogens and insect pests in maize without a yield penalty, by fine-tuning the accumulation of lignin and DIMBOA.
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Zea mays , beta-Glucosidase , Animais , Bovinos , Zea mays/genética , Zea mays/química , beta-Glucosidase/genética , Estudo de Associação Genômica Ampla , Lignina , Melhoramento Vegetal , InsetosRESUMO
Transgenerational plasticity (TGP) allows a plant to acclimate to external variable environments and is a potential mechanism that explains the range expansion and invasion success of some exotic plants. Most studies explored the traits of TGP associated with the success of exotic plant invasions by comparison studies among exotic, native, invasive, and noninvasive species. However, studies on the TGP of invasive plants in different resource environments are scarce, and the biological mechanisms involved are not well understood. This study aimed to determine the role of TGP in the invasiveness of Xanthium strumarium in northeast China. We measured the plant morphology of aboveground parts and the growth of three generations of the invader under different environmental conditions. The results showed that the intergenerational plasticity of X. strumarium was stronger under stress conditions. We found that the X. strumarium parent generation (F0) grown under water and/or nutrient deficiency conditions transferred the environmental information to their offspring (F1 and F2). The F1 generation grown under high-resource conditions has greater height with larger crown sizes, thicker basal diameters, and higher biomass. Both water and nutrients can affect the intergenerational transmission of plant plasticity, nutrients play a more important role compared with water. The high morphological intergenerational plasticity of X. strumarium under a pressure environment can help it quickly adapt to the new environment and accelerate the rapid expansion of the population in the short term. The root:shoot ratio and reproductive and nutrient distribution of the X. strumarium F0 and F1 generations showed high stability when the growth environment of the F0 generation differed from that of the F1 generation. The stable resource allocation strategy can ensure that the obtained resources are evenly distributed to each organ to maintain the long-term existence of the community. Therefore, the study of intergenerational transmission plasticity is of great significance for understanding the invasion process, mechanism, and prevention of invasive plants.
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Xanthium , Biomassa , Plantas , Adaptação Fisiológica , ÁguaRESUMO
Three series of N-{[4-([1,2,4]triazolo[1,5-α]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl]methyl}acetamides (14a-d, 15a-n, and 16a-f) were synthesized and evaluated for activin receptor-like kinase 5 (ALK5) inhibitory activities in an enzymatic assay. The target compounds showed high ALK5 inhibitory activity and selectivity. The half maximal inhibitory concentration (IC50) for phosphorylation of ALK5 of 16f (9.1 nM), the most potent compound, was 2.7 times that of the clinical candidate EW-7197 (vactosertib) and 14 times that of the clinical candidate LY-2157299. The selectivity index of 16f against p38α mitogen-activated protein kinase was >109, which was much higher than that of positive controls (EW-7197: >41, and LY-2157299: 4). Furthermore, a molecular docking study provided the interaction modes between the target compounds and ALK5. Compounds 14c, 14d, and 16f effectively inhibited the protein expression of α-smooth muscle actin (α-SMA), collagen I, and tissue inhibitor of metalloproteinase 1 (TIMP-1)/matrix metalloproteinase 13 (MMP-13) in transforming growth factor-ß-induced human umbilical vein endothelial cells. Compounds 14c and 16f showed especially high activity at low concentrations, which suggests that these compounds could inhibit myocardial cell fibrosis. Compounds 14c, 14d, and 16f are potential preclinical candidates for the treatment of cardiac fibrosis.
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Fibrose , Imidazóis , Simulação de Acoplamento Molecular , Receptor do Fator de Crescimento Transformador beta Tipo I , Humanos , Imidazóis/farmacologia , Imidazóis/síntese química , Imidazóis/química , Relação Estrutura-Atividade , Receptor do Fator de Crescimento Transformador beta Tipo I/antagonistas & inibidores , Receptor do Fator de Crescimento Transformador beta Tipo I/metabolismo , Fibrose/tratamento farmacológico , Estrutura Molecular , Receptores de Fatores de Crescimento Transformadores beta/antagonistas & inibidores , Receptores de Fatores de Crescimento Transformadores beta/metabolismo , Antifibróticos/farmacologia , Antifibróticos/síntese química , Antifibróticos/química , Amidas/farmacologia , Amidas/síntese química , Amidas/química , Relação Dose-Resposta a Droga , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/metabolismoRESUMO
Creating customizable metallic nanostructures in a simple and controllable manner has been a long-standing goal in nanoscience. In this study, we use DNA origami as a letterpress printing plate and gold nanoparticles as ink to produce predesigned gold nanostructures. The letterpress plate is reusable, enabling the repetitive production of predesigned gold nanostructures. Furthermore, by modifying the DNA origami letterpress plate on magnetic beads, we can simplify the printing processes. We have successfully printed gold nanoparticle dimers, trimers, straight and quadrilateral tetramers, and other nanostructures. Our approach improves the flexibility and stability of metallic nanostructures, simplifying both their design and their operation. It promises universal applicability in the fabrication of metamaterials, biosensors, and surface plasma nanooptics.
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Nanopartículas Metálicas , Nanoestruturas , Ouro/química , Nanopartículas Metálicas/química , Nanoestruturas/química , DNA/química , Impressão Tridimensional , NanotecnologiaRESUMO
Constructing chiral plexcitonic systems with tunable plasmon-exciton coupling may advance the scientific exploitation of strong light-matter interactions. Because of their intriguing chiroptical properties, chiral plasmonic materials have shown promising applications in photonics, sensing, and biomedicine. However, the strong coupling of chiral plasmonic nanoparticles with excitons remains largely unexplored. Here we demonstrate the construction of a chiral plasmon-exciton system using chiral AuAg nanorods and J aggregates for tuning the plexcitonic optical chirality. Circular dichroism spectroscopy was employed to characterize chiral plasmon-exciton coupling, in which Rabi splitting and anticrossing behaviors were observed, whereas the extinction spectra exhibited less prominent phenomena. By controlling the number of molecular excitons and the energy detuning between plasmons and excitons, we have been able to fine-tune the plexcitonic optical chirality. The ability to fine-tune the plexcitonic optical chirality opens up unique opportunities for exploring chiral light-matter interactions and boosting the development of emerging chiroptical devices.
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Conjugation with the increment of consumption of polypropylene (PP) masks and antidepressants during pandemic, PP microplastics (MPs) and Venlafaxine (VEN) widely co-existed in surface waters. However, their environmental fate and the combined toxicity were unclear. Hence, we investigated the adsorption behaviors, and associated mechanisms of PP MPs for VEN. The impact factors including pH, salinity, and MPs aging were estimated. The results indicated PP MPs could adsorb amount of VEN within 24 h. The pseudo second-order kinetic model (R2 = 0.97) and Dubinin-Radushkevich model (R2 = 0.89) fitted well with the adsorption capacity of PP MPs for VEN, implying that chemical adsorption accompanied by electrostatic interaction might be the predominant mode for the interactions between PP MPs and VEN. Meanwhile, the adsorption capacity of PP MPs declined from pH of 2.5-4.5 and then increased from 4.5 to 9.5. The increased salinity (5-35 ppt) significantly suppressed the adsorption capacity. Aging by sunlight and UV triggered the formation of new functional group (carbonyl) on MPs, and then enhanced the adsorption capacity for VEN. Gaussian Model analysis further evidenced the electrostatic adsorption occurring in PP MPs and VEN. The combined exposure to PP MPs and VEN showed significantly antagonistic toxicity on Daphnia magna. The adsorption of VEN by PP MPs mitigated the lethal effects and behavioral function impairment posed by VEN on animals, implying the potential protective effects on zooplankton by PP MPs. This study for the first time provides perspective for assessing the environmental fate of MPs and antidepressants in aquatic system.
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Plásticos , Poluentes Químicos da Água , Animais , Cloridrato de Venlafaxina , Adsorção , Microplásticos , Polipropilenos , Antidepressivos , Poluentes Químicos da Água/toxicidadeRESUMO
Analyzing and characterizing the differences between networks is a fundamental and challenging problem in network science. Most previous network comparison methods that rely on topological properties have been restricted to measuring differences between two undirected networks. However, many networks, such as biological networks, social networks, and transportation networks, exhibit inherent directionality and higher-order attributes that should not be ignored when comparing networks. Therefore, we propose a motif-based directed network comparison method that captures local, global, and higher-order differences between two directed networks. Specifically, we first construct a motif distribution vector for each node, which captures the information of a node's involvement in different directed motifs. Then, the dissimilarity between two directed networks is defined on the basis of a matrix, which is composed of the motif distribution vector of every node and the Jensen-Shannon divergence. The performance of our method is evaluated via the comparison of six real directed networks with their null models, as well as their perturbed networks based on edge perturbation. Our method is superior to the state-of-the-art baselines and is robust with different parameter settings.
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A series of novel chitosan-based magnetic flocculants FS@CTS-P(AM-DMC) was prepared by molecular structure control. The characterization results showed that FS@CTS-P(AM-DMC) had a uniform size of about 21.46 nm, featuring a typical core-shell structure, and the average coating layer thickness of CTS-P(AM-DMC) was about 5.03 nm. FS@CTS-P(AM-DMC) exhibited excellent flocculation performance for kaolin suspension, achieved 92.54% turbidity removal efficiency under dosage of 150 mg/L, pH 7.0, even at high turbidity (2000 NTU) with a removal efficiency of 96.96%. The flocculation mechanism was revealed to be dominated by charge neutralization under acidic and neutral conditions, while adsorption and bridging effects play an important role in alkaline environments. The properties of magnetic aggregates during flocculation, breakage, and regeneration were studied at different pH levels and dosages. In the process of magnetophoretic, magnetic particles collide and adsorb with kaolin particles continuously due to magnetic and electrostatic attraction, transform into magnetic chain clusters, and then further form three-dimensional network magnetic aggregates that can capture free kaolin particles and other chain clusters. Particle image velocimetry confirmed the formation of eddy current of magnetic flocs and experienced three stages: acceleration, stabilization, and deceleration.
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Quitosana , Purificação da Água , Quitosana/química , Caulim/química , Floculação , Fenômenos Magnéticos , Purificação da Água/métodosRESUMO
This paper aims to study the therapeutic effect of Massa Medicata Fermentata on hyperlipidemia model rats and investigate its mechanism of hypolipidemic effect with the help of non-targeted metabolomics. The mixed hyperlipidemia model rats were constructed by giving high-fat chow. After successful modeling, the rats were divided into the model group, pravastatin sodium group(4.4 mg·kg~(-1)), lipotropic group(0.1 g·kg~(-1)), high-dose group(2.4 g·kg~(-1)), medium-dose group(1.2 g·kg~(-1)), and low-dose group(0.6 g·kg~(-1)) of Massa Medicata Fermentata, and they were administered for four weeks once daily. An equal volume of ultrapure water was given to the blank group and model group. Serum lipid level and liver hematoxylin-eosin(HE) staining were used as indicators to estimate the intervention effect of Massa Medicata Fermentata on mixed hyperlipidemia, and the changes in metabolites in plasma of mixed hyperlipidemia model rats were analyzed by non-targeted metabolomics. The mechanism of the hypolipidemic effect of Massa Medicata Fermentata was analyzed through metabolite pathway enrichment. The results showed that compared with the model group, the Massa Medicata Fermentata administration group, especially the high-dose group, could significantly reduce the content of total cholesterol(TC), triglyceride(TG), and low-density lipoprotein cholesterol(LDL-c)(P<0.05 or P<0.01), and liver HE staining revealed that the number of adipocytes in the high-dose group was reduced to some extent. The potential biomarkers obtained by non-targeted metabolomics screening included glycerol 3-phosphate, sphingomyelin, sphingosine 1-phosphate, and deoxyuridine, which were mainly involved in the sphingolipid metabolism process, glycerophospholipid metabolism process, glycerol ester metabolism pathway, and pyrimidine metabolism pathway, totaling four possible metabolic pathways related to lipid metabolism. This study provides a reference for an in-depth investigation of the hypolipidemic mechanism of Massa Medicata Fermentata, which is of great significance for further promoting the clinical application of Massa Medicata Fermentata and increasing the indications.
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Medicamentos de Ervas Chinesas , Hiperlipidemias , Ratos , Animais , Medicamentos de Ervas Chinesas/farmacologia , Fígado , Hiperlipidemias/tratamento farmacológico , Metabolômica , Colesterol , Dieta Hiperlipídica/efeitos adversosRESUMO
Site-selective chiral growth of anisotropic nanoparticles is of great importance to realize the plasmonic nanostructures with delicate geometry and desired optical chirality; however, it remains largely unexplored. This work demonstrates a controlled site-selective chiral growth system based on the seed-mediated growth of anisotropic Au triangular nanoplates. The site-selective chiral growth involves two distinct underlying pathways, faceted growth and island growth, which are interswitchable upon maneuvering the interplay of chiral molecules, surfactants, and reducing agents. The pathway switch governs the geometric and chirality evolution of Au triangular nanoplates, giving rise to tailorable circular dichroism spectra. The ability to tune the optical chirality in a controlled manner by manipulating the site-selective chiral growth pathway opens up a promising strategy for exploiting chiral metamaterials with increasing architectural complexity in chiroptical applications.
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Metabolism and metabolic processes have long been considered to shape the tumour immunosuppressive microenvironment. Recent research has demonstrated that T regulatory cells (Tregs) display high rates of fatty acid oxidation (FAO) and a relatively low rate of glycolysis. Sphingosine 1-phosphate (S1P), which is a G protein signalling activator involved in immune regulation and FAO modulation, has been implicated in Treg differentiation. However, the precise relation between Treg differentiation and S1P remains unclear. In this study, we isolated naïve CD4+ T cells from the spleens of 6-8-week-old BALB/c mice using magnetic bead sorting, which was used in our study for Treg differentiation. S1P stimulation was performed during Treg differentiation. We examined the oxygen consumption and palmitic acid metabolism of the differentiated Tregs and evaluated the expression levels of various proteins, including Nrf2, CPT1A, Glut1, ACC1 and PPARα, through Western blotting. Our results demonstrate that S1P promotes Treg differentiation and enhances FAO, and that the expression of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and peroxisome proliferator-activated receptor α (PPARα) is upregulated. Furthermore, Nrf2 or PPARα knockdown dampened the Treg differentiation and FAO that were promoted by S1P, confirming that S1P can bind with S1PR4 to promote Treg differentiation through the Nrf2/PPARα signalling pathway, which may be related to FAO facilitation.
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Diferenciação Celular , Lisofosfolipídeos , Camundongos Endogâmicos BALB C , Fator 2 Relacionado a NF-E2 , Oxirredução , PPAR alfa , Esfingosina , Linfócitos T Reguladores , Animais , Lisofosfolipídeos/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Diferenciação Celular/imunologia , Camundongos , PPAR alfa/metabolismo , Esfingosina/análogos & derivados , Esfingosina/metabolismo , Transdução de Sinais , Receptores de Lisoesfingolipídeo/metabolismo , Receptores de Lisoesfingolipídeo/genética , Receptores de Esfingosina-1-Fosfato/metabolismo , Ácidos Graxos/metabolismo , Células CultivadasRESUMO
Malignant tumors have been one of the major reasons for deaths worldwide. Timely and accurate diagnosis as well as effective intervention of tumors play an essential role in the survival of patients. Genomic instability is the important foundation and feature of cancer, hence, in vivo oncogene imaging based on novel probes provides a valuable tool for the diagnosis of cancer at early-stage. However, the in vivo oncogene imaging is confronted with great challenge, due to the extremely low copies of oncogene in tumor cells. By combining with various novel activatable probes, the molecular imaging technologies provide a feasible approach to visualize oncogene in situ, and realize accurate treatment of tumor. This review aims to declare the design of nanoprobes responded to tumor associated DNA or RNA, and summarize their applications in detection and bioimaging for tumors. The significant challenges and prospective of oncogene-targeting nanoprobes towards tumors diagnosis are revealed as well.
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Detecção Precoce de Câncer , Neoplasias , Humanos , Neoplasias/diagnóstico por imagem , Imagem Óptica/métodos , OncogenesRESUMO
BACKGROUND: Although the promising advancements of current therapeutic approaches is available for the squamous cell carcinoma (SCC) patients, the clinical treatment of SCC still faces many difficulties. The surgical irreparable disfigurement and the postoperative wound infection largely hamper the recovery, and the chemo/radiotherapy leads to toxic side effects. RESULTS: Herein, a novel pH/Hyaluronidase (HAase) dual-stimuli triggered smart nanoprobe FeIIITA@HA has been designed through the biomineralization of Fe3+ and polyphenol tannic acid (TA) under the control of hyaluronic acid (HA) matrix. With the HA residues on the outer surface, FeIIITA@HA nanoprobes can specifically target the SCC cells through the over-expressed CD44, and accumulate in the carcinoma region after intravenously administration. The abundant HAase in carcinoma microenvironment will trigger the degradation of HA molecules, thereby exposing the FeIIITA complex. After ingesting by tumor cells via CD44 mediated endocytosis, the acidic lysosomal condition will further trigger the protonation of TA molecules, finally leading to the Fe3+ release of nanoprobe, and inducing a hybrid ferroptosis/apoptosis of tumor cells through peroxidase activity and glutathione depletion. In addition, Owing to the outstanding T1 magnetic resonance imaging (MRI) performance and phototermal conversion efficiency of nanoprobes, the MRI-guided photothermal therapy (PTT) can be also combined to complement the Fe3+-induced cancer therapy. Meanwhile, it was also found that the nanoprobes can promote the recruitment of CD4+ and CD8+ T cells to inhibit the tumor growth through the cytokines secretion. In addition, the FeIIITA@HA nanoprobes can be eliminated from the body and no obvious adverse side effect can be found in histological analysis, which confirmed the biosafety of them. CONCLUSION: The current FeIIITA@HA nanoprobe has huge potential in clinical translation in the field of precise diagnosis and intelligent synergistic therapy of superficial SCC. This strategy will promisingly avoid the surgical defects, and reduce the systemic side effect of traditional chemotherapy, paving a new way for the future SCC treatment.
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Carcinoma de Células Escamosas , Nanopartículas , Neoplasias , Humanos , Linfócitos T CD8-Positivos , Neoplasias/tratamento farmacológico , Fototerapia/métodos , Carcinoma de Células Escamosas/diagnóstico por imagem , Carcinoma de Células Escamosas/tratamento farmacológico , Linhagem Celular Tumoral , Nanopartículas/uso terapêutico , Nanopartículas/química , Microambiente TumoralRESUMO
Enhancing pig reproductive efficiency has the potential to have a significant positive economic impact on the pig business. We collected four reproduction records of 734 Yunong black pigs in this study, including the total number of piglets born (TNB), the number born alive (NBA), the average birth interval of piglets (ABI) and the average birth weight (ABW). A total of 453 Yunong black pigs were genotyped with Porcine 50K SNP BeadChip. Twenty-five SNPs and 35 genomic areas were found to have a substantial impact on the reproductive performance of Yunong black pigs by single-locus GWAS and single-step GWAS (ssGWAS). For the ssGWAS, we found that the two genomic regions (12.67-13.85 and 14.26-15.01 Mb) on Sus scrofa chromosome X were associated with TNB, NBA and ABI. It is worth noting that CNC10110530 and CNC100141254 significantly affected the TNB by both GWAS methods. Finally, we further determined the gene functions by enrichment analysis and a literature search, and identified 28 of them as candidate genes affecting the reproductive performance of Yunong black pigs, including RET, EIF1AX, NELL2, CTPS2, S100G, RBBP7 and PDHA1. This study further promotes understanding of the genetic mechanism of porcine reproductive performance, and also provides more molecular markers for pig breeding.
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Estudo de Associação Genômica Ampla , Reprodução , Suínos , Gravidez , Feminino , Animais , Tamanho da Ninhada de Vivíparos/genética , Fenótipo , Genótipo , Reprodução/genéticaRESUMO
Yunong black pig is an indigenous black pig breed being cultivated that has a pure black whole body. However, some individuals appear with a white spot on the nose. We performed case-control association studies and FST approaches in 76 animals with nose color records (26 white-nosed pigs vs. 50 black-nosed pigs) by Illumina Porcine SNP50 BeadChip data. In total, 76 SNPs, which included 2 genome-wide significant SNPs and 18 chromosome-wide suggestive SNPs, were identified by association study. The top-ranked 0.1% windows of FST results as signals under selection and 24 windows were selected. The lymphoid enhancer binding factor 1 was identified as candidate gene with strong signal in analyses of genome-wide association study and FST in black- and white-nosed pigs. Overall, our findings provide evidence that nose color is a heritable trait influenced by many loci. The results contribute to expand our understanding of pigmentation in pigs and provide SNP markers for skin color and related traits selection in Yunong black pigs. Additional research on the genetic link between nose pigmentation is needed.