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The clinical failure mode of dental crown ceramics involves radial cracking at the interface, driven by the surface tension generated from the flexure of the ceramic layer on the subsurface. This results in a reduced lifespan for most all-ceramic dental crowns. Therefore, investigating optimal material combinations to reduce stress concentration in dental crown materials has become crucial for future successful clinical applications. The anisotropic complex structures of natural materials, such as nacre, could potentially create suitable strong and damage-resistant materials. Their imitation of natural structural optimisation and mechanical functionality at both the macro- and micro-levels minimises weaknesses in dental crowns. This research aims to optimise cost-effective, freeze-casted bioinspired composites for the manufacture of novel, strong, and tough ceramic-based dental crowns. To this end, multilayer alumina (Al2O3) composites with four different polymer phases were tested to evaluate their bending behaviour and determine their flexural strength. A computational model was developed and validated against the experimental results. This model includes Al2O3 layers that undergo gentle compression and distribute stress, while the polymer layers act as stress relievers, undergoing plastic deformation to reduce stress concentration. Based on the experimental data and numerical modelling, it was concluded that these composites exhibit variability in mechanical properties, primarily due to differences in microstructures and their flexural strength. Furthermore, the findings suggest that bioinspired Al2O3-based composites demonstrate promising deformation and strengthening behaviour, indicating potential for application in the dental field.
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Porcine epidemic diarrhea virus (PEDV) is an enteric coronavirus that has been the main cause of diarrhea in piglets since 2010 in China. The aim of this study was to investigate sequence variation and recombination events in the spike (S) gene of PEDV isolates from China. Thirty complete S gene sequences were obtained from PEDV-positive samples collected in six provinces in China from 2020 to 2023. Phylogenetic analysis showed that 10% (3/30) belonged to subtype GII-a, 6.67% (2/30) were categorized as subtype GII-b, 66.67% (20/30) were categorized as subtype GII-c, and 16.66% (5/30) were clustered with the S-INDEL strains. Amino acid sequence alignments showed that, when compared to strains of other subtypes, the GII-c strains had two characteristic amino acid substitutions (N139D and I289M). Five S-INDEL subtype strains had a single amino acid deletion (139N) and four amino acid substitutions (N118G, T137S, A138S, and D141G). Recombination analysis allowed six putative recombination events to be identified, one involving recombination between GII-c strains, two involving GII-c and GII-b strains, two involving GII-c and GI-a strains, and one involving GII-a and GI-b strains. These results suggest that recombination between PEDV strains has been common and complex in recent years and is one of the main reasons for the continuous variation of PEDV strains.
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Infecciones por Coronavirus , Virus de la Diarrea Epidémica Porcina , Recombinación Genética , Glicoproteína de la Espiga del Coronavirus , Enfermedades de los Porcinos , Animales , Secuencia de Aminoácidos , Sustitución de Aminoácidos , China/epidemiología , Infecciones por Coronavirus/virología , Infecciones por Coronavirus/veterinaria , Infecciones por Coronavirus/epidemiología , Diarrea/virología , Diarrea/veterinaria , Diarrea/epidemiología , Variación Genética , Genotipo , Filogenia , Virus de la Diarrea Epidémica Porcina/genética , Virus de la Diarrea Epidémica Porcina/clasificación , Virus de la Diarrea Epidémica Porcina/aislamiento & purificación , Glicoproteína de la Espiga del Coronavirus/genética , Porcinos , Enfermedades de los Porcinos/virología , Enfermedades de los Porcinos/epidemiologíaRESUMEN
Alginate is a linear polysaccharide with a modifiable structure and abundant functional groups, offers immense potential for tailoring diverse alginate-based materials to meet the demands of biomedical applications. Given the advancements in modification techniques, it is significant to analyze and summarize the modification of alginate by physical, chemical and biological methods. These approaches provide plentiful information on the preparation, characterization and application of alginate-based materials. Physical modification generally involves blending and physical crosslinking, while chemical modification relies on chemical reactions, mainly including acylation, sulfation, phosphorylation, carbodiimide coupling, nucleophilic substitution, graft copolymerization, terminal modification, and degradation. Chemical modified alginate contains chemically crosslinked alginate, grafted alginate and oligo-alginate. Biological modification associated with various enzymes to realize the hydrolysis or grafting. These diverse modifications hold great promise in fully harnessing the potential of alginate for its burgeoning biomedical applications in the future. In summary, this review provides a comprehensive discussion and summary of different modification methods applied to improve the properties of alginate while expanding its biomedical potentials.
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Porcine deltacoronavirus (PDCoV), a cross-species transmissible enterovirus, frequently induces severe diarrhea and vomiting symptoms in piglets, which not only pose a significant menace to the global pig industry but also a potential public safety risk. In a previous study, we isolated a vaccine candidate, PDCoV CZ2020-P100, by passaging a parental PDCoV strain in vitro, exhibiting attenuated virulence and enhanced replication. However, the factors underlying these differences between primary and passaged strains remain unknown. In this study, we present the transcriptional landscapes of porcine kidney epithelial cells (LLC-PK1) cells infected with PDCoV CZ2020-P1 strain and P100 strain using the RNA-sequencing. We identified 105 differentially expressed genes (DEGs) in P1-infected cells and 295 DEGs in P100-infected cells. Enrichment analyses indicated that many DEGs showed enrichment in immune and inflammatory responses, with a more and higher upregulation of DEGs enriched in the P100-infected group. Notably, the DEGs were concentrated in the MAPK pathway within the P100-infected group, with significant upregulation in EphA2 and c-Fos. Knockdown of EphA2 and c-Fos reduced PDCoV infection and significantly impaired P100 replication compared to P1, suggesting a novel mechanism in which EphA2 and c-Fos are highly involved in passaged virus replication. Our findings illuminate the resemblances and distinctions in the gene expression patterns of host cells infected with P1 and P100, confirming that EphA2 and c-Fos play key roles in high-passage PDCoV replication. These results enhance our understanding of the changes in virulence and replication capacity during the process of passaging.
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Deltacoronavirus , Receptor EphA2 , Transcriptoma , Replicación Viral , Animales , Porcinos , Deltacoronavirus/genética , Deltacoronavirus/fisiología , Deltacoronavirus/patogenicidad , Receptor EphA2/genética , Enfermedades de los Porcinos/virología , Proteínas Proto-Oncogénicas c-fos/genética , Proteínas Proto-Oncogénicas c-fos/metabolismo , Células LLC-PK1 , Línea Celular , Infecciones por Coronavirus/virología , Infecciones por Coronavirus/veterinariaRESUMEN
The exploration potential within deep-water petroliferous basins holds great promise for oil and gas resources. However, the dearth of geochemical and isotopic data poses a formidable challenge in comprehending the intricate hydrocarbon charging processes, thereby impeding the comprehensive understanding of hydrocarbon accumulation mechanisms and models. Consequently, the establishment of robust source-reservoir relationships in deep-water petroliferous basins represents a pivotal challenge that significantly influences the exploration strategies and the comprehension of hydrocarbon enrichment dynamics within such basins. In this study, we introduce a novel approach, termed the "source-reservoir dynamic evaluation method," tailored to investigate reservoir accumulation models in deep-water petroliferous basins. This method uses basin simulation technology to recover the thermal evolution history and hydrocarbon generation and expulsion history of source rocks, and on this basis delimits the hydrocarbon kitchen range. At the same time, the maturity of source rocks corresponding to crude oil and natural gas in typical reservoirs is calculated. Then, when the thermal evolution degree of source rocks adjacent to the reservoir reaches this maturity, the corresponding geological period is the main charging period of hydrocarbon. As a typical deep-water petroliferous basin, the Santos Basin in Brazil has abundant oil and gas reservoirs under the thick salt rock, but there are still some fundamental problems such as unclear oil-gas accumulation process and model. Therefore, in this paper, the main charging periods of typical hydrocarbon reservoirs are determined based on the internal relationship between the thermal evolution history of the main source rocks and the maturity of crude oil and natural gas, and then the hydrocarbon accumulation process is analyzed and the dynamic accumulation model is established. Finally, the favorable prospecting direction is pointed out. The results show that the oil and gas in the Barra Velha Formation in the Santos basin are mainly derived from the Itapema Formation lacustrine shale source rock, and the source rock is mainly developed in the Eastern Sag of the Central Depression, and its main hydrocarbon generation period is from the deposition period of Florianopolis Formation to the deposition period of Santos Formation. The main hydrocarbon expulsion period was from the deposition period of the Santos Formation to the Early deposition of the Iguape Formation. The oil and gas in the Barra Velha Formation were mainly charged from the Late deposition period of the Santos Formation to the Early deposition period of the Iguape Formation. During this period, the hydrocarbon migrated vertically along the normal fault formed in the rift period to the trap of the adjacent inheritance structural highs and accumulated in the reservoir, which was dominated by the accumulation model of the "lower generation-upper reservoir-salt cap". Since the Barra Velha Formation has the characteristics of near-source accumulation, based on the hydrocarbon expulsion center and hydrocarbon expulsion intensity of the source rock of the Itapema Formation, the distribution ranges of 85% and 50% Pre-salt accumulation probability in the Santos basin were calculated by using the quantitative analysis model of the hydrocarbon distribution threshold. It is suggested that the next oil and gas exploration should be carried out in the paleo-structural highs and slope of Class I favorable area (the hydrocarbon accumulation probability is more than 85%) and Class II favorable area (the hydrocarbon accumulation probability is 85-50%).
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Myricetin, a natural flavonoid found in various foods, was investigated for its antiviral effect against transmissible gastroenteritis virus (TGEV). This α-coronavirus causes significant economic losses in the global swine industry. The study focused on the papain-like protease (PLpro), which plays a crucial role in coronavirus immune evasion by mediating deubiquitination. Targeting PLpro could potentially disrupt viral replication and enhance antiviral responses. The results demonstrated that myricetin effectively inhibited TGEV-induced cytopathic effects in a dose-dependent manner, with an EC50 value of 31.19 µM. Myricetin significantly reduced TGEV viral load within 48 h after an 8-h co-incubation period. Further investigations revealed that myricetin at a concentration of 100 µM directly inactivated TGEV and suppressed its intracellular replication stage. Moreover, pretreatment with 100 µM myricetin conferred a protective effect on PK-15 cells against TGEV infection. Myricetin competitively inhibited PLpro with an IC50 value of 6.563 µM. Molecular docking experiments show that myricetin binds to the Cys102 residue of PLpro through conventional hydrogen bonds, Pi-sulfur, and Pi-alkyl interactions. This binding was confirmed through site-directed mutagenesis experiments, indicating myricetin as a potential candidate for preventing and treating TGEV infection.
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Closed chest drainage is typically necessary following Lobar and Sublobar resections to evacuate gases and fluids from the thoracic cavity, eliminate residual pleural space for lung expansion, and maintain negative pressure. Currently, three conventional closed chest drainage systems are commonly employed: single-chamber, double-chamber, and triple-chamber systems; each system has its own advantages and disadvantages. Despite the emergence of digital drainage systems in recent years, their high cost hinders their widespread adoption. Based on this premise, our research team has achieved a patent for a micro air pump-integrated chest closed drainage bottle, which has been further developed into a novel device integrating a three-chamber system with negative pressure control and power supply capabilities. This device enables patients undergoing perioperative lung procedures to ambulate freely while simultaneously receiving chest suction therapy-a concept that theoretically promotes rapid postoperative recovery. Moreover, this device offers economic benefits and holds potential for clinical implementation (particularly in economically underdeveloped regions). In this article, we modified the thoracic closed drainage device based on our patent and presented this novel thoracic closed drainage device after 3D printing and assembly.
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Drenaje , Diseño de Equipo , Humanos , Drenaje/instrumentación , Drenaje/métodos , Tubos Torácicos , Neumonectomía/instrumentación , Neumonectomía/métodos , Impresión Tridimensional , Succión/instrumentaciónRESUMEN
The purpose of this study was to compare the effects of High-Intensity Interval Training (HIIT) and Moderate-Intensity Continuous Training (MICT) on weight, body composition, blood lipid indicators, and metabolic status in college students living with obesity. The study focused on a sample of 40 college students living with obesity, including 20 males and 20 females, aged between 18 and 25. Participants were randomly assigned to either the HIIT group or the MICT group. Both groups underwent an 8-week intervention, consisting of three sessions per week with alternate-day training. The MICT group's training consisted of continuous aerobic exercise for 35 min at 60-70% of maximum heart rate. The HIIT group engaged in 28 min of alternating high-intensity and low-intensity exercise, where the high-intensity phase was at 85-90% of maximum heart rate for 4 min, followed by a 3-min recovery period at 50-60% of maximum heart rate, repeated four times. Both groups underwent heart rate monitoring before and after the training sessions to ensure the accuracy of the training intensity. Within each group, further distinctions were made based on gender, resulting in the following subgroups: Male HIIT group (n = 10), Female HIIT group (n = 10), Male MICT group (n = 10), and Female MICT group (n = 10). Differences in anthropometric and biochemical indicators among the groups were analyzed, and the different effects of the two intervention strategies on the obese college student population were comprehensively evaluated. Compared to the baseline assessment, the HIIT group showed a more favorable declining trend than the MICT group in terms of body morphology and body composition, particularly in the aspect of body fat percentage (BF%). The male HIIT group, female HIIT group, male MICT group, and female MICT group respectively reduced by - 23.71%, - 26.76%, - 9.81%, - 7.16%. Male and female HIIT group experienced a more pronounced decrease compared to the MICT group, with the female HIIT group reducing an additional 3.75% more than the male HIIT group. Regarding intergroup differences, BF% significant differences were shown between male MICT group and the HIIT group (P < 0.05), and female MICT group and the HIIT group (P < 0.01). In terms of biochemical indicators, the HIIT group also presented a more favorable declining trend compared to the MICT group, with male HIIT participants showing more reduction than female HIIT participants, especially in total cholesterol (TC) (10.64%), low-density lipoprotein cholesterol (LDL-C) (11.73%), alanine aminotransferase (ALT) (11.99%), and uric acid (UA) (11.76%). Regarding triglycerides (TG), significant intergroup differences were observed between male MICT and HIIT groups (P < 0.01) and female MICT and HIIT groups (P < 0.01). Concerning ALT, a significant difference was shown between female MICT and HIIT groups (P < 0.01), while no significant difference was observed among male participants. Overall, for college students living with obesity, both HIIT and MICT have shown positive effects. Among these, HIIT demonstrates greater effectiveness compared to MICT in BF% and biochemical markers.
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Entrenamiento de Intervalos de Alta Intensidad , Obesidad , Estudiantes , Humanos , Masculino , Femenino , Entrenamiento de Intervalos de Alta Intensidad/métodos , Obesidad/terapia , Obesidad/metabolismo , Adulto Joven , Adulto , Adolescente , Composición Corporal , Peso Corporal , Frecuencia Cardíaca , Ejercicio Físico/fisiología , UniversidadesRESUMEN
With the improvement of national health awareness and the popularization of a series of screening methods, the number of patients with early colorectal cancer is gradually increasing, and accurate prediction of lymph node metastasis of T1 colorectal cancer is the key to determining the optimal therapeutic solutions. Whether patients with T1 colorectal cancer undergoing endoscopic resection require additional surgery and regional lymph node dissection is inconclusive in current guidelines. However, we can be sure that in early colorectal cancer without lymph node metastasis, endoscopic resection alone does not affect the prognosis, and it greatly improves the quality of life and reduces the incidence of surgical complications while preserving organ integrity. Therefore, it is vital to discriminate patients without lymph node metastasis in T1 colorectal cancer, and this requires accurate predictors. This paper briefly explains the significance and shortcomings of traditional pathological factors, then extends and states the new pathological factors, clinical test factors, molecular biomarkers, and the risk assessment models of lymph node metastasis based on artificial intelligence.
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Nod-like receptor family pyrin-containing protein 3 (NLRP3) inflammasome plays a pathologic role in metabolic dysfunction-associated steatohepatitis (MASH), but the molecular mechanism regulating the NLRP3 inflammasome activation in hepatocellular lipotoxicity remains largely unknown. Bromodomain-containing protein 4 (BRD4) has emerged as a key epigenetic reader of acetylated lysine residues in enhancer regions that control the transcription of key genes. The aim of this study is to investigate if and how BRD4 regulated the NLRP3 inflammasome activation and pyroptosis in MASH. Using the AML12 and primary mouse hepatocytes stimulated by palmitic acid (PA) as an in vitro model of hepatocellular lipotoxicity, we found that targeting BRD4 by genetic knockdown or a selective BRD4 inhibitor MS417 protected against hepatosteatosis; and this protective effect was attributed to inhibiting the activation of NLRP3 inflammasome and reducing the expression of Caspase-1, gasdermin D (GSDMD), interleukin (IL)-1ß and IL-6. Moreover, BRD4 inhibition limited the voltage-dependent anion channel-1 (VDAC1) expression and oligomerization in PA-treated AML12 hepatocytes, thereby suppressing the NLRP3 inflammasome activation. Additionally, the expression of BRD4 enhanced in MASH livers of humans. Mechanistically, BRD4 was upregulated during hepatocellular lipotoxicity that in turn modulated the active epigenetic mark H3K27ac at the promoter regions of the Vdac and Gsdmd genes, thereby enhancing the expression of VDAC and GSDMD. Altogether, our data provide novel insights into epigenetic mechanisms underlying BRD4 activating the NLRP3 inflammasome and promoting GSDMD-mediated pyroptosis in hepatocellular lipotoxicity. Thus, BRD4 might serve as a novel therapeutic target for the treatment of MASH.
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Hepatocitos , Inflamasomas , Ratones Endogámicos C57BL , Proteína con Dominio Pirina 3 de la Familia NLR , Proteínas de Unión a Fosfato , Piroptosis , Factores de Transcripción , Animales , Humanos , Masculino , Ratones , Proteínas que Contienen Bromodominio , Proteínas de Ciclo Celular , Hígado Graso/metabolismo , Hígado Graso/patología , Furanos , Gasderminas , Hepatocitos/metabolismo , Hepatocitos/efectos de los fármacos , Hepatocitos/patología , Compuestos Heterocíclicos de 4 o más Anillos/farmacología , Indenos/farmacología , Inflamasomas/metabolismo , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Péptidos y Proteínas de Señalización Intracelular/genética , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Proteínas Nucleares , Ácido Palmítico/farmacología , Proteínas de Unión a Fosfato/metabolismo , Proteínas de Unión a Fosfato/genética , Piroptosis/efectos de los fármacos , Sulfonamidas/farmacología , Factores de Transcripción/metabolismo , Factores de Transcripción/genéticaRESUMEN
OBJECTIVES: To investigate the age-related changes of the mandibular third molar root pulp visibility in individuals in East China, and to explore the feasibility of applying this method to determine whether an individual is 18 years or older. METHODS: A total of 1 280 oral panoramic images were collected from the 15-30 years old East China population, and the mandibular third molar root pulp visibility in all oral panoramic images was evaluated using OLZE 0-3 four-stage method, and the age distribution of the samples at each stage was analyzed using descriptive statistics. RESULTS: Stages 0, 1, 2 and 3 first appeared in 16.88, 19.18, 21.91 and 25.44 years for males and in 17.47, 20.91, 22.01 and 26.01 years for females. In all samples, individuals at stages 1 to 3 were over 18 years old. CONCLUSIONS: It is feasible to determine whether an individual in East China is 18 years or older based on the mandibular third molar root pulp visibility on oral panoramic images.
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Determinación de la Edad por los Dientes , Pulpa Dental , Tercer Molar , Radiografía Panorámica , Raíz del Diente , Humanos , Tercer Molar/diagnóstico por imagen , Masculino , Adolescente , Femenino , Adulto , Adulto Joven , China , Raíz del Diente/diagnóstico por imagen , Determinación de la Edad por los Dientes/métodos , Pulpa Dental/diagnóstico por imagen , Mandíbula/diagnóstico por imagen , Odontología Forense/métodos , Factores de EdadRESUMEN
Pullorum disease (PD) is a bacterial infection caused by Salmonella pullorum (S. pullorum) that affects poultry. It is highly infectious and often fatal. Antibiotics are currently the mainstay of prophylactic and therapeutic treatments for PD, but their use can lead to the development of resistance in pathogenic bacteria and disruption of the host's intestinal flora. We added neomycin sulfate and different doses of tannic acid (TA) to the drinking water of chicks at 3 days of age and infected them with PD by intraperitoneal injection of S. pullorum at 9 days of age. We analyzed intestinal histopathological changes and the expression of immune-related genes and proteins by using the plate smear method, histological staining, real-time fluorescence quantitative PCR, ELISA kits, and 16S rRNA Analysis of intestinal flora. The results demonstrate that S. pullorum induces alterations in the immune status and impairs the functionality of the liver and intestinal barrier. We found that tannic acid significantly ameliorated S. pullorum-induced liver and intestinal damage, protected the intestinal physical and chemical barriers, restored the intestinal immune barrier function, and regulated the intestinal flora. Our results showed that TA has good anti-diarrhoeal, growth-promoting, immune-regulating, intestinal barrier-protecting and intestinal flora-balancing effects, and the best effect was achieved at an additive dose of 0.2%.
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Ecosystem services (ESs) and their changes are complex processes driven by multiple factors. Understanding the trade-off and synergy between ESs and their driving factors is essential for achieving effective management of ESs and human well-being. Taking the Yangtze River Economic Belt as the research area, this study analyzed the temporal and spatial variation characteristics of four ESs including water yield, soil conservation, carbon sequestration, and food supply from 2000 to 2020. Correlation analysis and geographically weighted regression were used to identify and quantify the trade-off and synergy between ESs. On this basis, the partial least squares structural equation model was used to explore the impact of natural and human activities on ESs, and then the driving mechanism of ESs relationship change was analyzed via GeoDetector. The results showed that:â During the 20 years, the average annual carbon sequestration increased from 946.14 t·km-2 to 1 202.73 t·km-2, and the average food supply increased from 32.73×104 Yuan·km-2 to 127.22×104 Yuan·km-2. Water yield and soil conservation increased to a lesser degree. â¡ On the whole, carbon sequestration and soil conservation and food supply and water yield showed synergy, and other ESs were trade-offs. The relationship between ESs varied in different regions. ⢠Terrain and climate were important driving factors for ESs and the trade-off and synergy of multiple ESs. Among them, structural equation model results showed that climate had a positive impact on water yield (S=0.73), and terrain had a negative impact on food supply (S=-0.57). GeoDetector results revealed that the main driving factors affecting the spatial relationship between carbon sequestration and water yield were elevation (q=0.38) and precipitation (q=0.19). The results of this study can provide a scientific reference for the sustainable management of ESs in the Yangtze River Economic Belt and the realization of the coordinated development of ecological environment protection and social economy in the region.
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Neoadjuvant tyrosine kinase inhibitor (TKI) therapy is an important treatment option for advanced renal cell carcinoma (RCC). Many RCC patients may fail to respond or be resistant to TKI therapy. We aimed to explore the key mechanisms of neoadjuvant therapy résistance. We obtained tumor samples from matched pre-treatment biopsy and post-treatment surgical samples and performed single-cell RNA sequencing. Sunitinib-resistant ccRCC cell lines were established. Ferroptosis was detected by ferrous ion and lipid peroxidation levels. Tumor growth and resistance to Sunitinib was validated in vitro and vivo. Immunohistochemistry was used to validate the levels key genes and lipid peroxidation. Multi-center cohorts were included, including TCGA, ICGC, Checkmate-025 and IMmotion151 clinical trial. Survival analysis was performed to identify the associated clinical and genomic variables. Intratumoral heterogeneity was first described in the whole neoadjuvant management. The signature of endothelial cells was correlated with drug sensitivity and progression-free survival. Ferroptosis was shown to be the key biological program in malignant cell resistance. We observed tissue lipid peroxidation was negatively correlated with IL6 and tumor response. TKI-resistant cell line was established. SLC7A11 knockdown promoted cell growth and lipid peroxidation, increased the ferroptosis level, and suppressed the growth of tumor xenografts significantly (P < 0.01). IL6 could reverse the ferroptosis and malignant behavior caused by SLC7A11 (-) via JAK2/STAT3 pathway, which was rescued by the ferroptosis inducer Erastin. Our data indicate that ferroptosis is a novel strategy for advanced RCC treatment, which activated by IL6, providing a new idea for resistance to TKIs.
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Sistema de Transporte de Aminoácidos y+ , Carcinoma de Células Renales , Resistencia a Antineoplásicos , Ferroptosis , Neoplasias Renales , Terapia Neoadyuvante , Sunitinib , Carcinoma de Células Renales/tratamiento farmacológico , Carcinoma de Células Renales/patología , Carcinoma de Células Renales/genética , Carcinoma de Células Renales/metabolismo , Ferroptosis/efectos de los fármacos , Ferroptosis/genética , Humanos , Neoplasias Renales/patología , Neoplasias Renales/tratamiento farmacológico , Neoplasias Renales/genética , Neoplasias Renales/metabolismo , Terapia Neoadyuvante/métodos , Sunitinib/farmacología , Animales , Línea Celular Tumoral , Ratones , Sistema de Transporte de Aminoácidos y+/genética , Sistema de Transporte de Aminoácidos y+/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto , Inhibidores de Proteínas Quinasas/farmacología , Peroxidación de Lípido/efectos de los fármacos , Factor de Transcripción STAT3/metabolismo , Factor de Transcripción STAT3/genética , Femenino , Masculino , Terapia Molecular Dirigida , Interleucina-6/metabolismo , Interleucina-6/genética , Progresión de la EnfermedadRESUMEN
BACKGROUND: Kidney renal papillary cell carcinoma (KIRP) is the second most prevalent malignant cancer originating from the renal epithelium. Nowadays, cancer stem cells and stemness-related genes (SRGs) are revealed to play important roles in the carcinogenesis and metastasis of various tumors. Consequently, we aim to investigate the underlying mechanisms of SRGs in KIRP. METHODS: RNA-seq profiles of 141 KIRP samples were downloaded from the TCGA database, based on which we calculated the mRNA expression-based stemness index (mRNAsi). Next, we selected the differentially expressed genes (DEGs) between low- and high-mRNAsi groups. Then, we utilized weighted gene correlation network analysis (WGCNA) and univariate Cox analysis to identify prognostic SRGs. Afterwards, SRGs were included in the multivariate Cox regression analysis to establish a prognostic model. In addition, a regulatory network was constructed by Pearson correlation analysis, incorporating key genes, upstream transcription factors (TFs), and downstream signaling pathways. Finally, we used Connectivity map analysis to identify the potential inhibitors. RESULTS: In total, 1124 genes were characterized as DEGs between low- and high-RNAsi groups. Based on six prognostic SRGs (CCKBR, GPR50, GDNF, SPOCK3, KC877982.1, and MYO15A), a prediction model was established with an area under curve of 0.861. Furthermore, among the TFs, genes, and signaling pathways that had significant correlations, the CBX2-ASPH-Notch signaling pathway was the most significantly correlated. Finally, resveratrol might be a potential inhibitor for KIRP. CONCLUSIONS: We suggested that CBX2 could regulate ASPH through activation of the Notch signaling pathway, which might be correlated with the carcinogenesis, development, and unfavorable prognosis of KIRP.
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Carcinoma de Células Renales , Neoplasias Renales , Células Madre Neoplásicas , Humanos , Pronóstico , Neoplasias Renales/genética , Neoplasias Renales/patología , Carcinoma de Células Renales/genética , Carcinoma de Células Renales/patología , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , Regulación Neoplásica de la Expresión Génica , Redes Reguladoras de Genes , Masculino , Biomarcadores de Tumor/genética , Femenino , Perfilación de la Expresión Génica , Persona de Mediana Edad , Transducción de Señal/genéticaRESUMEN
Targeting "undruggable" targets with intrinsically disordered structures is of great significance for the treatment of disease. The transcription factor c-Myc controls global gene expression and is an attractive therapeutic target for multiple types of cancers. However, due to the lack of defined ligand binding pockets, targeted c-Myc have thus far been unsuccessful. Herein, to address the dilemma of lacking ligands, an efficient and high throughput aptamer screening strategy is established, named polystyrene microwell plate-based systematic evolution of ligands by exponential enrichment (microwell-SELEX), and identify the specific aptamer (MA9C1) against c-Myc. The multifunctional aptamer-based Proteolysis Targeting Chimeras (PROTAC) for proteolysis of the c-Myc (ProMyc) is developed using the aptamer MA9C1 as the ligand. ProMyc not only significantly degrades c-Myc by the ubiquitin-proteasome system, but also reduces the Max protein, synergistically inhibiting c-Myc transcriptional activity. Combination of the artificial cyclization and anti-PD-L1 aptamer (PA1)-based delivery system, circular PA1-ProMyc chimeras achieve tumor regression in the xenograft tumor model, laying a solid foundation for the development of efficacious c-Myc degrader for the clinic. Therefore, this aptamer-based degrader provides an invaluable potential degrader in drug discovery and anti-tumor therapy, offering a promising degrader to overcome the challenge of targeting intractable targets.
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Aptámeros de Nucleótidos , Proteolisis , Proteínas Proto-Oncogénicas c-myc , Proteínas Proto-Oncogénicas c-myc/metabolismo , Proteínas Proto-Oncogénicas c-myc/genética , Humanos , Aptámeros de Nucleótidos/farmacología , Animales , Ratones , Proteolisis/efectos de los fármacos , Línea Celular Tumoral , Modelos Animales de Enfermedad , Técnica SELEX de Producción de Aptámeros/métodos , Antineoplásicos/farmacologíaRESUMEN
Chemotherapy of glioblastoma (GBM) has not yielded success due to inefficient blood-brain barrier (BBB) penetration and poor glioma tissue accumulation. Aerobic glycolysis, as the main mode of energy supply for GBM, safeguards the rapid growth of GBM while affecting the efficacy of radiotherapy and chemotherapy. Therefore, to effectively inhibit aerobic glycolysis, increase drug delivery efficiency and sensitivity, a novel temozolomide (TMZ) nanocapsule (ApoE-MT/siPKM2 NC) is successfully designed and prepared for the combined delivery of pyruvate kinase M2 siRNA (siPKM2) and TMZ. This drug delivery platform uses siPKM2 as the inner core and methacrylate-TMZ (MT) as the shell component to achieve inhibition of glioma energy metabolism while enhancing the killing effect of TMZ. By modifying apolipoprotein E (ApoE), dual targeting of the BBB and GBM is achieved in a "two birds with one stone" style. The glutathione (GSH) responsive crosslinker containing disulfide bonds ensures "directional blasting" cleavage of the nanocapsules to release MT and siPKM2 in the high GSH environment of glioma cells. In addition, in vivo experiments verify that ApoE-MT/siPKM2 NC has good targeting ability and prolongs the survival of tumor-bearing nude mice. In summary, this drug delivery system provides a new strategy for metabolic therapy sensitization chemotherapy.
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Glioblastoma , Glucólisis , Nanocápsulas , Temozolomida , Glioblastoma/tratamiento farmacológico , Glioblastoma/metabolismo , Glioblastoma/patología , Animales , Temozolomida/farmacología , Temozolomida/química , Nanocápsulas/química , Ratones , Línea Celular Tumoral , Glucólisis/efectos de los fármacos , Humanos , Ratones Desnudos , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , ARN Interferente Pequeño/metabolismo , Barrera Hematoencefálica/metabolismo , Glutatión/metabolismo , Glutatión/químicaRESUMEN
Porcine epidemic diarrhea (PED) is a highly contagious swine intestinal disease caused by PED virus (PEDV). Vaccination is a promising strategy to prevent and control PED. Previous studies have confirmed that glycosylation could regulate the immunogenicity of viral antigens. In this study, we constructed three recombinant PEDVs which removed the glycosylation sites in RBD. Viral infection assays revealed that similar replication characteristics between the recombinant viruses and parental PEDV. Although animal challenging study demonstrated that the glycosylation sites in RBD do not affect the pathogenicity of PEDV, we found that removing the glycosylation sites on the RBD regions could promote the IgG and neutralization titer in vivo, suggesting deglycosylation in RBD could enhance the immunogenicity of PEDV. These findings demonstrated that removal of the glycosylation sites in RBD is a promising method to develop PEDV vaccines.
Asunto(s)
Anticuerpos Neutralizantes , Anticuerpos Antivirales , Virus de la Diarrea Epidémica Porcina , Glicoproteína de la Espiga del Coronavirus , Enfermedades de los Porcinos , Animales , Virus de la Diarrea Epidémica Porcina/inmunología , Virus de la Diarrea Epidémica Porcina/genética , Glicosilación , Glicoproteína de la Espiga del Coronavirus/inmunología , Glicoproteína de la Espiga del Coronavirus/genética , Porcinos , Enfermedades de los Porcinos/virología , Enfermedades de los Porcinos/inmunología , Enfermedades de los Porcinos/prevención & control , Anticuerpos Antivirales/inmunología , Anticuerpos Neutralizantes/inmunología , Vacunas Virales/inmunología , Infecciones por Coronavirus/prevención & control , Infecciones por Coronavirus/veterinaria , Infecciones por Coronavirus/inmunología , Infecciones por Coronavirus/virología , Células Vero , Chlorocebus aethiops , Inmunoglobulina G/inmunología , Inmunoglobulina G/sangre , Inmunogenicidad Vacunal , RatonesRESUMEN
Paeoniae Radix alba is used in Traditional Chinese Medicine for the treatment of gastrointestinal disorders, immunomodulatory, cancer, and other diseases. In the current study, the yield of Paeoniae Radix alba polysaccharide (PRP) was significantly increased with optimal ultrasound-assisted extraction compared to hot water extraction. Further, an acidic polysaccharide (PRP-AP) was isolated from PRP after chromatographic separation and was characterized as a typical pectic polysaccharide with side chains of arabinogalactans types I and II. Moreover, it showed antioxidant effects on LPS-induced damage on IPEC-J2 cells determined by qRT-PCR and ELISA, including decreasing the pro-inflammatory factors' expressions and increasing the antioxidant enzymes activities, which was shown to be related to the Nrf2/Keap1 pathway modulated by PRP-AP. The metabolites change (such as itaconate, cholesterol sulfate, etc.) detected by untargeted metabolomic analysis in cells was also shown to be modulated by PRP-AP, and these metabolites were further utilized and protected cells damaged by LPS. These results revealed the cellular active mechanism of the macromolecular PRP-AP on protecting cells, and supported the hypothesis that PRP-AP has strong benefits as an alternative dietary supplement for the prevention of intestinal oxidative stress by modulating cellular metabolism.
Asunto(s)
Antioxidantes , Paeonia , Polisacáridos , Polisacáridos/farmacología , Polisacáridos/química , Polisacáridos/aislamiento & purificación , Antioxidantes/farmacología , Antioxidantes/química , Antioxidantes/aislamiento & purificación , Paeonia/química , Ondas Ultrasónicas , Línea Celular , Animales , Estrés Oxidativo/efectos de los fármacos , Fraccionamiento Químico/métodos , Lipopolisacáridos/farmacologíaRESUMEN
Lead and cadmium are foodborne contaminants that threaten human and animal health. It is well known that lead and cadmium produce hepatotoxicity; however, defense mechanisms against the co-toxic effects of lead and cadmium remain unknown. We investigated the mechanism of autophagy (defense mechanism) against the co-induced toxicity of lead and cadmium in rat hepatocytes (BRL-3A cells). Cultured rat liver BRL-3A cell lines were co-cultured with 10, 20, 40 µM lead and 2.5, 5, 10 µM cadmium alone and in co-culture for 12 h and exposed to 5 mM 3-Methyladenine (3-MA), 10 µM rapamycin (Rapa), and 50 nM Beclin1 siRNA to induce cellular autophagy. Our results show that treatment of BRL-3A cells with lead and cadmium significantly decreased the cell viability, increased intracellular reactive oxygen species levels, decreased mitochondrial membrane potential levels, and induced apoptosis, which are factors leading to liver injury, and cell damage was exacerbated by co-exposure to lead-cadmium. In addition, the results showed that lead and cadmium co-treatment induced autophagy. We further observed that the suppression of autophagy with 3-MA or Beclin1 siRNA promoted lead-cadmium-induced apoptosis, whereas enhancement of autophagy with Rapa suppressed lead-cadmium-induced apoptosis. These results demonstrated that co-treatment with lead and cadmium induces apoptosis in BRL-3A cells. Interestingly, the activation of autophagy provides cells with a self-protective mechanism against induced apoptosis. This study provides insights into the role of autophagy in lead-cadmium-induced apoptosis, which may be beneficial for the treatment of lead-cadmium-induced liver injury.