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Monascus red pigments (MRP) may have benefits against NAFLD with an unclear mechanism. This study aimed to explore the protective effect of MRP supplementation against NAFLD through regulation of gut microbiota and metabolites. The C57BL/6 mice animals were randomly allocated into the normal diet (NC), HFHS diet-induced NAFLD model, and MRP intervention group fed with HFHS diet. Serum lipid profiles and liver function parameters were measured. Liver and colon histopathology analysis was conducted to determine the injury in the liver and colon. 16S rRNA gene sequencing was employed to analyze gut microbial composition from fecal samples. Untargeted metabonomics was performed to analyze changes in metabolites in serum and fecal samples. MRP supplementation significantly improved the HFHS-induced alterations in body weight, lipid profiles, and liver function (p < .01). MRP supplementation decreased the abundance of Akkermansia, Candidatus saccharimonas, Dubosiella, and Oscillibacter, while increasing Lactobacillus, Lachnospiraceae NK4A136 group, and Rikenella in mice fed the HFHS diet. Furthermore, MRP supplementation improved the serum and fecal metabolic profiles induced by the HFHS diet, primarily involving the arachidonic acid metabolism, unsaturated fatty acid biosynthesis, and adipocyte lipolysis pathways. Liver function and lipid profiles were closely associated with the abundance of Lactobacillus, Streptococcus, Oscillibacter, Akkemansia, and Desulfovibrio (p < .01). These findings revealed that MRP supplementation may help restore gut microbiota composition and balance its metabolites, thereby improving NAFLD. This study presents a novel outlook on the potential benefits of MRP supplementation in ameliorating NAFLD and supports the application of MRP as a new functional food.
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Despite the superior efficacy of radiotherapy in esophageal squamous cell carcinoma (ESCC), radioresistance by cancer stem cells (CSCs) leads to recurrence, metastasis, and treatment failure. Therefore, it is necessary to develop CSC-based therapies to enhance radiotherapy. miR-339-5p (miR339) is involved in stem cell division and DNA damage checkpoint signaling pathways based on ESCC cohort. miR339 inhibited ESCC cell stemness and enhanced radiation-induced DNA damage by targeting USP8, suggesting that it acts as a potential CSC regulator and radiosensitizer. Considering the limited circulating periods and poor tumor-targeting ability of miRNA, a multifunctional nanoplatform based on bismuth sulfide nanoflower (Bi@PP) is developed to efficiently deliver miR339 and improve radioresistance. Intriguingly, Bi@PP encapsulates more miR339 owing to their flower-shaped structure, delivering more than 1000-fold miR339 into cells, superior to free miR339 alone. Besides being used as a carrier, Bi@PP is advantageous for dynamically monitoring the distribution of delivered miR339 in vivo while simultaneously inhibiting tumor growth. Additionally, Bi@PP/miR339 can significantly enhance radiotherapy efficacy in patient-derived xenograft models. This multifunctional platform, incorporating higher miRNA loading capacity, pH responsiveness, hypoxia relief, and CT imaging, provides another method to promote radiosensitivity and optimize ESCC treatment.
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Bismuto , Neoplasias Esofágicas , MicroARNs , Células Madre Neoplásicas , Sulfuros , Bismuto/química , Bismuto/farmacología , Humanos , MicroARNs/genética , MicroARNs/metabolismo , Neoplasias Esofágicas/patología , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/tratamiento farmacológico , Sulfuros/química , Sulfuros/farmacología , Animales , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/efectos de los fármacos , Células Madre Neoplásicas/patología , Ratones , Tolerancia a Radiación/efectos de los fármacos , Ubiquitina Tiolesterasa/metabolismo , Ubiquitina Tiolesterasa/antagonistas & inhibidores , Ratones Desnudos , Ratones Endogámicos BALB C , Proliferación Celular/efectos de los fármacos , Línea Celular Tumoral , Carcinoma de Células Escamosas de Esófago/patología , Carcinoma de Células Escamosas de Esófago/metabolismo , Carcinoma de Células Escamosas de Esófago/genéticaRESUMEN
Background: Terbinafine hydrochloride (TEB) is a broad-spectrum antifungal medication commonly used to treat fungal infections of the skin. This study designed a hydrogel patch assisted by an iontophoresis system to enhance the transdermal permeability of TEB, enabling deeper penetration into the skin layers. Methods: The influences of current intensity, pH levels, and drug concentration on the TEB hydrogel patch's permeability were explored using an adaptive ion electroosmosis system. The pharmacokinetic profile, facilitated by iontophoresis for transdermal permeation, was analyzed through the application of microdialysis technology. Scanning electron microscopy and transmission electron microscopy were employed to assess the impact of ion electroosmotic systems on skin integrity. Results: The cumulative drug accumulation within 8 h of the TEB hydrogel patches, assisted by iontophoresis, was 2.9 and 7.9 times higher than without iontophoresis assistance and TEB cream in the control group, respectively. TEB hydrogel patches assisted by iontophoresis can significantly increase the permeability of TEB, and the AUC(0-8 h) was 3.4 and 5.4 times higher, while the Cmax was 4.2 and 7.3 times higher than the TEB hydrogel patches without iontophoresis, respectively. This system has no significant impact on deep-layer cells. Conclusions: This system may offer a safe and effective clinical strategy for the local treatment of deep antifungal infections.
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The downward migration of soil heavy metal(loid)s (HMs) at smelting sites poses a significant risk to groundwater. Therefore, it is requisite for pollution control to determine the pollution characteristics of soil HMs and their migration risks to groundwater. 198 soil samples collected from a Pb-Zn smelting site were classified into 6 clusters by self-organizing map (SOM) and K-means clustering. Cd, Zn, As, and Pb were identified as the characteristic contaminants of the site. The driving factors for the heterogeneous distribution of HMs have been validated through the implementation of K-means clustering and multiple-hits calculation. Using ultrafiltration extraction and microscopic analysis, the soil colloids were identified as crucial carriers facilitating the migration of HMs. Specifically, the colloidal fractions of Cd, Zn, and As, Pb in deep soil (3-4 m) accounted for 91 %, 78 %, 88 %, and 82 %, respectively, consistently surpassing those found in topsoil (0-0.5 m). It was primarily attributed to the strong affinity of HMs toward soil colloids (franklinite, PbS, and kaolinite) and dissolved organic matter (humic acids and protein). The research findings highlight the potential risk of colloidal HMs to groundwater contamination, providing valuable insights for the development of targeted management and remediation strategies.
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BACKGROUND: The 5-year survival rate of oesophageal squamous cell carcinoma (ESCC) is approximately 20%. The prognosis and drug response exhibit substantial heterogeneity in ESCC, impeding progress in survival outcomes. Our goal is to identify a signature for tumour subtype classification, enabling precise clinical treatments. METHODS: Utilising pre-treatment multi-omics data from an ESCC dataset (n = 310), an enhancer methylation-eRNA-target gene regulation network was constructed and validated by in vitro experiments. Four machine learning methods collectively identified core target genes, establishing an Enhancer Demethylation-Regulated Gene Score (EDRGS) model for classification. The molecular function of EDRGS subtyping was explored in scRNA-seq (n = 60) and bulk-seq (n = 310), and the EDRGS's potential to predict treatment response was assessed in datasets of various cancer types. FINDINGS: EDRGS stratified ESCCs into EDRGS-high/low subtypes, with EDRGS-high signifying a less favourable prognosis in ESCC and nine additional cancer types. EDRGS-high exhibited an immune-hot but immune-suppressive phenotype with elevated immune checkpoint expression, increased T cell infiltration, and IFNγ signalling in ESCC, suggesting a better response to immunotherapy. Notably, EDRGS outperformed PD-L1 in predicting anti-PD-1/L1 therapy effectiveness in ESCC (n = 42), kidney renal clear cell carcinoma (KIRC, n = 181), and bladder urothelial carcinoma (BLCA, n = 348) cohorts. EDRGS-low showed a cell cycle-activated phenotype with higher CDK4 and/or CDK6 expression, demonstrating a superior response to the CDK4/6 inhibitor palbociclib, validated in ESCC (n = 26), melanoma (n = 18), prostate cancer (n = 15) cells, and PDX models derived from patients with pancreatic cancer (n = 30). INTERPRETATION: Identification of EDRGS subtypes enlightens ESCC categorisation, offering clinical insights for patient management in immunotherapy (anti-PD-1/L1) and CDK4/6 inhibitor therapy across cancer types. FUNDING: This study was supported by funding from the National Key R&D Program of China (2021YFC2501000, 2020YFA0803300), the National Natural Science Foundation of China (82030089, 82188102), the CAMS Innovation Fund for Medical Sciences (2021-I2M-1-018, 2022-I2M-2-001, 2021-I2M-1-067), the Fundamental Research Funds for the Central Universities (3332021091).
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Biomarcadores de Tumor , Quinasa 4 Dependiente de la Ciclina , Quinasa 6 Dependiente de la Ciclina , Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Regulación Neoplásica de la Expresión Génica , Inmunoterapia , Humanos , Quinasa 6 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 6 Dependiente de la Ciclina/genética , Quinasa 4 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 4 Dependiente de la Ciclina/genética , Carcinoma de Células Escamosas de Esófago/genética , Carcinoma de Células Escamosas de Esófago/tratamiento farmacológico , Carcinoma de Células Escamosas de Esófago/mortalidad , Carcinoma de Células Escamosas de Esófago/terapia , Carcinoma de Células Escamosas de Esófago/inmunología , Carcinoma de Células Escamosas de Esófago/metabolismo , Carcinoma de Células Escamosas de Esófago/patología , Inmunoterapia/métodos , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/tratamiento farmacológico , Neoplasias Esofágicas/terapia , Neoplasias Esofágicas/mortalidad , Neoplasias Esofágicas/metabolismo , Pronóstico , Metilación de ADN , Elementos de Facilitación Genéticos , Perfilación de la Expresión Génica , Biología Computacional/métodos , Línea Celular Tumoral , Inhibidores de Proteínas Quinasas/uso terapéutico , Inhibidores de Proteínas Quinasas/farmacología , Redes Reguladoras de Genes , AnimalesRESUMEN
The occurrence and migration of colloids at smelting sites are crucial for the formation of multi-metal(loid)s pollution in groundwater. In this study, the behavior of natural colloids (1 nm-0.45 µm) at an abandoned smelting site was investigated by analyzing groundwater samples filtered through progressively decreasing pore sizes. Smelting activities in this site had negatively impacted the groundwater quality, leading to elevated concentrations of zinc (Zn), lead (Pb), arsenic (As), and cadmium (Cd). The results showed that heavy metal(loid)-bearing colloids were ubiquitous in the groundwater with the larger colloidal fractions (â¼75 -450 nm) containing higher abundances of pollutants. It was also observed that the predominant colloids consisted of Zn-Al layered double hydroxide (LDH), sphalerite, kaolinite, and hematite. By employing multiple analytical techniques, including leaching experiments, soil colloid characterization, and Pb stable isotope measurements, the origin of groundwater colloids was successfully traced to the topsoil colloids. Most notably, our findings highlighted the increased risk of heavy metal(loid)s migration from polluted soils into adjacent sites through the groundwater because of colloid-mediated transport of contaminants. This field-scale investigation provides valuable insights into the geochemical processes governing heavy metal(loid) behavior as well as offering pollution remediation strategies specifically tailored for contaminated groundwater.
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Heavy metal pollution in soils of smelting sites is an important environmental problem to be solved urgently. Solidification technology has become one of the mainstream technologies for heavy metal remediation in contaminated sites owing to its shorter remediation time, low cost, and high treatment efficiency. On the basis of summarizing the latest research progress on the remediation of heavy metal pollution in sites by solidification in the past 10 years, this study focused on the mechanisms of solidification technology and analyzed the advantages and disadvantages of different mechanisms (mechanism of inorganic materials, mechanism of organic materials, mechanism of mechanical ball milling, and mechanism of microbial-induced carbonate mineralization (MICP)) and their scope of application. Then, according to the research focus and development trend presented by CiteSpace, the application prospects and limiting factors of MICP technology for the solidification and remediation of heavy metal pollution in sites were summarized from three aspects:the application of MICP in multi-metal remediation, the application of MICP composites in contaminated sites, and the influencing factors of MICP technology application. Finally, the prospects and challenges in solidification technology were put forward in order to provide reference for the future development.
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Cancer stem cells (CSCs) are essential for tumor initiation, recurrence, metastasis, and resistance. However, targeting CSCs as a therapeutic approach remains challenging. Here, a stemness signature based on 22-gene is developed to predict prognosis in esophageal squamous cell carcinoma (ESCC). Staurosporine (STS) is identified as a radioresistance suppressor by high-throughput screening of a library of 2131 natural compounds, leading to dramatically improved radiotherapy efficacy in subcutaneous tumor models. Mechanistically, STS inhibits cell proliferation through the mTOR/AKT signaling pathway and suppressed stemness by targeting ATP-binding cassette A1 (ABCA1), which is transcriptionally regulated by liver X receptor alpha (LXRα). STS can selectively bind to the nucleotide-binding domain (NBD) of ABCA1 and compete for ATP, blocking ABCA1-mediated drug efflux and facilitating intracellular accumulation of STS. Considering the cytotoxicity of STS, an extracellular vesicle-encapsulated STS system (EV-STS) is established for effective STS delivery. EV-STS shows remarkable tumor growth inhibition, even at half the dose of STS, with superior safety and efficacy. These findings indicate that ABCA1 may serve as a predictor of response to neoadjuvant chemotherapy and/or radiotherapy in ESCC patients. EV-STS has shown improved antitumor efficacy and low systemic toxicity, offering a promising therapeutic approach for ESCC.
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Transportador 1 de Casete de Unión a ATP , Vesículas Extracelulares , Tolerancia a Radiación , Estaurosporina , Humanos , Transportador 1 de Casete de Unión a ATP/metabolismo , Transportador 1 de Casete de Unión a ATP/genética , Estaurosporina/farmacología , Estaurosporina/análogos & derivados , Animales , Vesículas Extracelulares/metabolismo , Tolerancia a Radiación/efectos de los fármacos , Línea Celular Tumoral , Ratones , Proliferación Celular/efectos de los fármacos , Células Madre Neoplásicas/efectos de los fármacos , Células Madre Neoplásicas/metabolismo , Neoplasias Esofágicas/tratamiento farmacológico , Neoplasias Esofágicas/patología , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/terapia , Ratones Desnudos , Carcinoma de Células Escamosas de Esófago/tratamiento farmacológico , Carcinoma de Células Escamosas de Esófago/patología , Carcinoma de Células Escamosas de Esófago/metabolismo , Ratones Endogámicos BALB CRESUMEN
Radiotherapy, a widely used therapeutic strategy for esophageal squamous cell carcinoma (ESCC), is always limited by radioresistance of tumor tissues and side-effects on normal tissues. Herein, a signature based on four core genes of cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway, is developed to predict prognosis and assess immune cell infiltration, indicating that the cGAS-STING pathway and radiotherapy efficacy are closely intertwined in ESCC. A novel lipid-modified manganese diselenide nanoparticle (MnSe2-lipid) with extraordinarily uniform sphere morphology and tumor microenvironment (TME) responsiveness is developed to simultaneously overcome radioresistance and reduce side-effects of radiation. The uniform MnSe2 encapsulated lipid effectively achieves tumor accumulation. Octadecyl gallate on surface of MnSe2 forming pH-responsive metal-phenolic covalent realizes rapid degradation in TME. The released Mn2+ promotes radiosensitivity by generating reactive oxygen species induced by Fenton-like reaction and activating cGAS-STING pathway. Spontaneously, selenium strengthens immune response by promoting secretion of cytokines and increasing white blood cells, and performs antioxidant activity to reduce side-effects of radiotherapy. Overall, this multifunctional remedy which is responsive to TME is capable of providing radiosensitivity by cGAS-STING pathway-mediated immunostimulation and chemodynamic therapy, and radioprotection of normal tissues, is highlighted here to optimize ESCC treatment.
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Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Nanopartículas , Tolerancia a Radiación , Carcinoma de Células Escamosas de Esófago/tratamiento farmacológico , Carcinoma de Células Escamosas de Esófago/patología , Humanos , Neoplasias Esofágicas/patología , Neoplasias Esofágicas/tratamiento farmacológico , Neoplasias Esofágicas/metabolismo , Tolerancia a Radiación/efectos de los fármacos , Animales , Nanopartículas/química , Línea Celular Tumoral , Ratones , Ácido Gálico/química , Ácido Gálico/farmacología , Ácido Gálico/análogos & derivados , Lípidos/química , Selenio/química , Selenio/farmacología , Microambiente Tumoral/efectos de los fármacos , Protectores contra Radiación/farmacología , Protectores contra Radiación/química , Manganeso/química , Fármacos Sensibilizantes a Radiaciones/química , Fármacos Sensibilizantes a Radiaciones/farmacologíaRESUMEN
Therapy resistance and metastatic progression jointly determine the fatal outcome of cancer, therefore, elucidating their crosstalk may provide new opportunities to improve therapeutic efficacy and prevent recurrence and metastasis in esophageal squamous cell carcinoma (ESCC). Here, we have established radioresistant ESCC cells with the remarkable metastatic capacity, and identified miR-494-3p (miR494) as a radioresistant activator. Mechanistically, we demonstrated that cullin 3 (CUL3) is a direct target of miR494, which is transcriptionally regulated by JunD, and highlighted that JunD-miR494-CUL3 axis promotes radioresistance and metastasis by facilitating epithelial-mesenchymal transition (EMT) and restraining programmed cell death 1 ligand 1 (PD-L1) degradation. In clinical specimens, miR494 is significantly up-regulated and positively associated with T stage and lymph node metastasis in ESCC tissues and serum. Notably, patients with higher serum miR494 expression have poor prognosis, and patients with higher CUL3 expression have more conventional dendritic cells (cDCs) and plasmacytoid DCs (pDCs), less cancer-associated fibroblasts (CAF2/4), and tumor endothelial cells (TEC2/3) infiltration than patients with lower CUL3 expression, suggesting that CUL3 may be involved in tumor microenvironment (TME). Overall, miR494 may serve as a potential prognostic predictor and therapeutic target, providing a promising strategy for ESCC treatment.
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Carcinoma de Células Escamosas , Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , MicroARNs , Humanos , Carcinoma de Células Escamosas de Esófago/genética , Carcinoma de Células Escamosas de Esófago/radioterapia , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/radioterapia , Carcinoma de Células Escamosas/metabolismo , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/radioterapia , Neoplasias Esofágicas/metabolismo , Células Endoteliales/metabolismo , Pronóstico , Transición Epitelial-Mesenquimal , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica , Movimiento Celular , Microambiente Tumoral , Proteínas Proto-Oncogénicas c-jun/metabolismo , Proteínas Cullin/genéticaRESUMEN
Groundwater pollution is a recurrent problem in abandoned non-ferrous metal smelting sites, and its severity is influenced by topsoil contamination, hydrogeological characteristics, and hydrogeochemical conditions. In such unique areas, traditional methods for evaluating groundwater pollution risk are biased, as the long production history of these sites have led to highly polluted and heterogeneous soil and groundwater. Herein, based on a typical lead-zinc smelting site, As, Pb, Zn, Cd, Mn, and Ni were found to be the predominant heavy metal (loid)s in groundwater, with respective exceedance rates of 44.4%, 50.0%, 72.2%, 88.9%, 88.9%, and 61.1%. Combined with the groundwater pollution characteristics, the representative hydrogeochemical factors were screened out to optimize the following aquifer vulnerability evaluation using the AHP-DRASTICH method. A comprehensive evaluation model (DI-NCPI) for groundwater pollution risk was established by combining the DRASTICH index (DI) obtained after optimization and the Nemerow comprehensive contamination index (NCPI) of topsoil. The fit between DI-NCPI and groundwater heavy metal (loid) pollution index reached 0.956, which laterally confirms that the model has some reference value. In terms of distribution, the high-risk and very high-risk zones were mainly concentrated in the zinc smelting system, located in the southeastern and central-western parts of the site. These areas have relatively high levels of topsoil contamination and aquifer vulnerability and require focused attention in site remediation. This research highlights the importance of combining topsoil contamination and aquifer vulnerability to evaluate groundwater pollution risk in smelting areas. It provides a more targeted reference for groundwater remediation strategies in abandoned smelting sites, as well as severely polluted industrial areas.
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Agua Subterránea , Metales Pesados , Contaminantes del Suelo , Zinc/análisis , Contaminantes del Suelo/análisis , Monitoreo del Ambiente/métodos , Medición de Riesgo , Metales Pesados/análisis , Suelo , ChinaRESUMEN
Dysregulated expression of long-stranded non-coding RNAs is strongly associated with carcinogenesis. However, the precise mechanisms underlying their involvement in ovarian cancer pathogenesis remain poorly defined. Here, we found that lncRNA RUNX1-IT1 plays a crucial role in the progression of ovarian cancer. Patients with high RUNX1-IT1 expression had shorter survival and poorer outcomes. Notably, knockdown of RUNX1-IT1 suppressed the proliferation, migration and invasion of ovarian cancer cells in vitro, and reduced the formation of peritoneum metastasis in vivo. Mechanistically, RUNX1-IT1 bound to HDAC1, the core component of the NuRD complex, and STAT1, acting as a molecular scaffold of the STAT1 and NuRD complex to regulate intracellular reactive oxygen homeostasis by altering the histone modification status of downstream targets including GPX1. Consequently, RUNX1-IT1 activated NF-κB signaling and altered the biology of ovarian cancer cells. In conclusion, our findings demonstrate that RUNX1-IT1 promotes ovarian malignancy and suggest that targeting RUNX1-IT1 represents a promising therapeutic strategy for ovarian cancer treatment.
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Neoplasias Ováricas , ARN Largo no Codificante , Humanos , Femenino , Complejo Desacetilasa y Remodelación del Nucleosoma Mi-2/metabolismo , FN-kappa B/genética , FN-kappa B/metabolismo , Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , Subunidad alfa 2 del Factor de Unión al Sitio Principal/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Proliferación Celular/genética , Neoplasias Ováricas/genética , Neoplasias Ováricas/patología , Histona Desacetilasas/genética , ARN Largo no Codificante/genética , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica , Movimiento Celular/genética , Factor de Transcripción STAT1/genética , Factor de Transcripción STAT1/metabolismoRESUMEN
Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are common clinical critical diseases with high morbidity and mortality. Especially since the COVID-19 outbreak, the mortality rates of critically ill patients with ARDS can be as high as 60%. Therefore, this problem has become a matter of concern to respiratory critical care. To date, the main clinical measures for ALI/ARDS are mechanical ventilation and drug therapy. Although ventilation treatment reduces mortality, it increases the risk of hyperxemia, and drug treatment lacks safe and effective delivery methods. Therefore, novel therapeutic strategies for ALI/ARDS are urgently needed. Developments in nanotechnology have allowed the construction of a safe, efficient, precise, and controllable drug delivery system. However, problems still encounter in the treatment of ALI/ARDS, such as the toxicity, poor targeting ability, and immunogenicity of nanomaterials. Cell-derived biomimetic nanodelivery drug systems have the advantages of low toxicity, long circulation, high targeting, and high bioavailability and show great therapeutic promises for ALI/ARDS owing to their acquired cellular biological features and some functions. This paper reviews ALI/ARDS treatments based on cell membrane biomimetic technology and extracellular vesicle biomimetic technology, aiming to achieve a significant breakthrough in ALI/ARDS treatments.
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Lesión Pulmonar Aguda , Nanopartículas , Síndrome de Dificultad Respiratoria , Humanos , Síndrome de Dificultad Respiratoria/tratamiento farmacológico , Nanopartículas/administración & dosificación , Lesión Pulmonar Aguda/tratamiento farmacológico , Materiales Biomiméticos/química , Materiales Biomiméticos/administración & dosificación , Sistemas de Liberación de Medicamentos , COVID-19 , Biomimética , Tratamiento Farmacológico de COVID-19 , AnimalesRESUMEN
The lack of understanding of heavy metal speciation and solubility control mechanisms in smelting soils limits the effective pollution control. In this study smelting soils were investigated by an advanced mineralogical analysis (AMICS), leaching tests and thermodynamic modelling. The aims were to identify the partitioning and release behaviour of Pb, Zn, Cd and As. The integration of multiple techniques was necessary and displayed coherent results. In addition to the residual fraction, Pb and Zn were predominantly associated with reducible fractions, and As primarily existed as the crystalline iron oxide-bound fractions. AMICS quantitative analysis further confirmed that Fe oxyhydroxides were the common dominant phase for As, Cd, Pb and Zn. In addition, a metal arsenate (paulmooreite) was an important mineral host for Pb and As. The pH-stat leaching indicted that the release of Pb, Zn and Cd increased towards low pH values while release of As increased towards high pH values. The separate leaching schemes were associated with the geochemical behaviour under the control of minerals and were confirmed by thermodynamic modelling. PHREEQC calculations suggested that the formation of arsenate minerals (schultenite, mimetite and koritnigite) and the binding to Fe oxyhydroxides synchronously controlled the release of Pb, Zn, Cd and As. Our results emphasized the governing role of Fe oxyhydroxides and secondary insoluble minerals in natural attenuation of heavy metals, which provides a novelty strategy for the stabilization of multi-metals in smelting sites.
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Metales Pesados , Contaminantes del Suelo , Zinc/análisis , Arseniatos , Plomo/análisis , Cadmio/análisis , Suelo/química , Contaminantes del Suelo/análisis , Monitoreo del Ambiente/métodos , Metales Pesados/análisis , Minerales , ChinaRESUMEN
Esophageal squamous cell carcinoma (ESCC) is an aggressive epithelial malignancy with poor prognosis. Interestingly, ESCC is strongly characterized by a male-predominant propensity. Our previous study showed that androgen receptor (AR) orchestrated a transcriptional repression program to promote ESCC growth, but it remains unclear whether AR can also activate oncogenic signaling during ESCC progression. In this study, by analyzing our previous AR cistromes and androgen-regulated transcriptomes, we identified uridine diphosphate glucuronosyltransferase family 2 member B15 (UGT2B15) as a bona fide target gene of AR. Mechanistically, AP-1 cofactors played important and collaborative roles in AR-mediated UGT2B15 upregulation. Functional studies have revealed that UGT2B15 promoted invasiveness in vitro and lymph node metastasis in vivo. UGT2B15 was partially responsible for the AR-induced invasive phenotype in ESCC cells. Importantly, simultaneous blocking of AP-1 and AR resulted in stronger inhibition of cell invasiveness compared to inhibiting AP-1 or AR alone. In conclusion, our study reveals the molecular mechanisms underlying the AR-driven ESCC invasion and suggests that the AR/AP1/UGT2B15 transcriptional axis can be potentially targeted in suppressing metastasis in male ESCC patients.
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BACKGROUND: Despite years of effort to develop an effective vaccine against malaria infection, a vaccine that provides individuals with sufficient protection against malaria illness and death in endemic areas is not yet available. The development of transmission-blocking vaccines (TBVs) is a promising strategy for malaria control. A dual-antigen malaria vaccine targeting both pre- and post-fertilization antigens could effectively improve the transmission-blocking activity of vaccines against the sexual stages of the parasite. METHODS: A chimeric recombinant protein Pb22-Pbg37 (Plasmodium berghei 22-P. berghei G37) composed of 19-218 amino acids (aa) of Pb22 and the N-terminal 26-88 aa of Pbg37 was designed and expressed in the Escherichia coli expression system. The antibody titers of the fusion (Pb22-Pbg37) and mixed (Pb22+Pbg37) antigens, as well as those of Pb22 and Pbg37 single antigens were evaluated by enzyme-linked immunosorbent assay. Immunofluorescence and western blot assays were performed to test the reactivity of the antisera with the native proteins in the parasite. The induction of transmission-blocking activity (TBA) by Pb22-Pbg37 and Pb22+Pbg37 were evaluated by in vitro gametocyte activation, gamete and exflagellation center formation, ookinete conversion, and in the direct mosquito feeding assay. RESULTS: The Pb22-Pbg37 fusion protein was successfully expressed in vitro. Co-administration of Pb22 and Pbg37 as a fusion or mixed protein elicited comparable antibody responses in mice and resulted in responses to both antigens. Most importantly, both the mixed and fusion antigens induced antibodies with significantly higher levels of TBA than did each of the individual antigens when administered alone. In addition, the efficacy of vaccination with the Pb22-Pbg37 fusion protein was equivalent to that of vaccination with the mixed single antigens. CONCLUSIONS: Dual-antigen vaccines, which expand/lengthen the period during which the transmission-blocking antibodies can act during sexual-stage development, can provide a promising higher transmission-reducing activity compared to single antigens.
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Vacunas contra la Malaria , Malaria , Ratones , Animales , Vacunas contra la Malaria/genética , Proteínas Protozoarias/metabolismo , Malaria/parasitología , Vacunación , Proteínas Recombinantes , Anticuerpos Antiprotozoarios , Antígenos de Protozoos/genética , Plasmodium falciparumRESUMEN
Background: The healthiest way to prevent metabolic syndrome (MetS) is through behavioral and nutritional adjustments. We examined the relationship between total flavonoids intake, flavonoid subclasses, and clinically manifest MetS. Methods: A cross-sectional analysis was conducted among 28,719 individuals from the National Health and Nutrition Examination Survey (NHANES) and Food and Nutrient Database for Dietary Studies (FNDDS) 2007-2011 and 2017-2018. Two 24-h reviews were conducted to determine flavonoids intake and subclasses. The link between flavonoids intake and MetS was investigated using a multivariate logistic regression model. Results: Q2 and Q3 of total flavonoids intake were associated with 20 and 19% lower risk of incident MetS after adjusting age and sex. Anthocyanidins and flavanones intake in Q2 and Q3 substantially reduced the MetS risk compared to Q1. MetS risk decreased steadily as the total intake of flavonoids increased to 237.67 mg/d. Flavanones and anthocyanidins also displayed V-shaped relationship curves (34.37 and 23.13 mg/d). Conclusion: MetS was adversely linked with total flavonoids intake, flavanones, and anthocyanidins. Moreover, the most effective doses of total flavonoids, flavanones, and anthocyanidins were 237.67, 34.37, and 23.13 mg/d, respectively, potentially preventing MetS.
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BACKGROUND: Diet may influence biological aging and the discrepancy (∆age) between a subject's biological age (BA) and chronological age (CA). We aimed to investigate the correlation of dietary flavonoids with the ∆age of organs (heart, kidney, liver) and the whole body. METHOD: A total of 3193 United States adults were extracted from the National Health and Nutrition Examination Survey (NHANES) in 2007-2008 and 2017-2018. Dietary flavonoids intake was assessed using 24-h dietary recall method. Multiple linear regression analysis was performed to evaluate the association of dietary flavonoids intake with the ∆age of organs (heart, kidney, liver) and the whole body. BA was computed based on circulating biomarkers, and the resulting ∆age was tested as an outcome in linear regression analysis. RESULTS: The ∆age of the whole body, heart, and liver was inversely associated with higher flavonoids intake (the whole body ∆age ß = - 0.58, cardiovascular ∆age ß = - 0.96, liver ∆age ß = - 3.19) after adjustment for variables. However, higher flavonoids intake positively related to renal ∆age (ß = 0.40) in participants with chronic kidney disease (CKD). Associations were influenced by population characteristics, such as age, health behavior, or chronic diseases. Anthocyanidins, isoflavones and flavones had the strongest inverse associations between the whole body ∆age and cardiovascular ∆age among all the flavonoids subclasses. CONCLUSION: Flavonoids intake positively contributes to delaying the biological aging process, especially in the heart, and liver organ, which may be beneficial for reducing the long-term risk of cardiovascular or liver disease.
Asunto(s)
Flavonoides , Corazón , Adulto , Humanos , Encuestas Nutricionales , Hígado , EnvejecimientoRESUMEN
Heavy metal(loid)s pollution of industrial legacies has become a severe environmental issue worldwide. Linking soil pollution to groundwater contaminant plumes would make invisible pollution features visible across the site, but related studies are lacking and require the convergence of multiple technologies. This study uniformly managed the soil and groundwater data in a 3D visualization model to pellucidly assess the spatial distribution of critical contaminants beyond simple drilling information. The distribution of Pb, Zn, As, and Cd in soil-groundwater system has a strong correlation to historical production, substance type, soil property, and groundwater flow direction. Over 2600 measurements of High-density electrical resistivity tomography (ERT) data were used to guarantee the exactness of soil structures. Hydraulic conductivity showed a strongest correlation (R2 = 0.86), yielding a calibrated model to reveal the anisotropic and contaminant transport in the region, with the consequent minimize the drilling tests. This study provides a template for the description of a verifiable scenario of hydrogeological conditions and pollution characteristics at smelting sites, coupled with traditional exploration and non-invasive techniques. The findings highlight the significance of visualizing the internal state of the soil-groundwater system under consideration, thus providing a basis for targeted control measures against site contamination.
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The widespread application of antiandrogen therapies has aroused a significant increase in the incidence of NEPC, a lethal form of the disease lacking efficient clinical treatments. Here we identified a cell surface receptor neurokinin-1 (NK1R) as a clinically relevant driver of treatment-related NEPC (tNEPC). NK1R expression increased in prostate cancer patients, particularly higher in metastatic prostate cancer and treatment-related NEPC, implying a relation with the progression from primary luminal adenocarcinoma toward NEPC. High NK1R level was clinically correlated with accelerated tumor recurrence and poor survival. Mechanical studies identified a regulatory element in the NK1R gene transcription ending region that was recognized by AR. AR inhibition enhanced the expression of NK1R, which mediated the PKCα-AURKA/N-Myc pathway in prostate cancer cells. Functional assays demonstrated that activation of NK1R promoted the NE transdifferentiation, cell proliferation, invasion, and enzalutamide resistance in prostate cancer cells. Targeting NK1R abrogated the NE transdifferentiation process and tumorigenicity in vitro and in vivo. These findings collectively characterized the role of NK1R in tNEPC progression and suggested NK1R as a potential therapeutic target.