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Epidemiological and animal studies have shown that maternal fine particulate matters (PM2.5) exposure correlates with various adverse pregnancy outcomes such as low birth weight (LBW) of offspring. However, the underlying biological mechanisms have not been fully understood. In this study, female C57Bl/6 J mice were exposed to filtered air (FA) or concentrated ambient PM2.5 (CAP) during pregestational and gestational periods, and metabolomics was performed to analyze the metabolic features in maternal serum and placenta by liquid chromatography-mass spectrometry (LC-MS). The partial least squares discriminate analysis (PLS-DA) displayed evident clustering of FA- and CAP-exposed samples for both maternal serum and placenta. In addition, pathway analysis identified that vitamin digestion and absorption was perturbed in maternal serum, while metabolic pathways including arachidonic acid metabolism, serotonergic synapse, 2-oxocarboxylic acid metabolism and cAMP signaling pathway were perturbed in placenta. Further analysis indicated that CAP exposure influenced the nutrient transportation capacity of placenta, by not only changing the ratios of some critical metabolites in placenta to maternal serum but also significantly altering the expressions of nutrition transporters in placenta. These findings reaffirm the importance of protecting women from PM2.5 exposure, and also advance our understanding of the toxic actions of ambient PM2.5.
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Contaminantes Atmosféricos , Exposición Materna , Embarazo , Humanos , Femenino , Ratones , Animales , Exposición Materna/efectos adversos , Contaminantes Atmosféricos/análisis , Material Particulado/análisis , Placenta/química , Ratones Endogámicos C57BL , HomeostasisRESUMEN
BACKGROUND: Rapid and accurate quantification of the supraspinatus outlet view (SOV) is a clinical challenge. PURPOSE: To quantify the X-ray beam angle of the SOV using the horizontal angle of the subscapular spine line (SSSL) and to further verify the feasibility of this method. MATERIAL AND METHODS: A total of 119 patients who underwent shoulder computed tomography (CT) examination were enrolled in the retrospective study. Three-dimensional (3D) CT reconstruction was performed and manually adjusted to provide the position similar to SOV. The rotation angle of the 3D image along the long axis of the human body (marked as ß) was obtained. The horizontal angle of SSSL (marked as α) was measured on the anteroposterior localizer image of shoulder CT. Pearson correlation and linear regression correlation analysis were performed. In addition, the first-time success rate between the experience-based group and the measurement-based group were compared to verify the novel method. RESULTS: We found a linear correlation between α and ß (r = 0.962; P = 0.000). There was no significant correlation between the experience-based group and the measurement-based group in terms of age (P = 0.500), sex (P = 0.397), and side (P = 0.710), but there was a significant statistical difference in the first success rate between the two validation groups (χ2 = 5.808a, P = 0.016). CONCLUSION: This novel quantitative measurement method for determining the X-ray beam angle of SOV using the horizontal angle of SSSL is feasible.
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Imagenología Tridimensional , Manguito de los Rotadores , Humanos , Imagenología Tridimensional/métodos , Estudios Retrospectivos , Tomografía Computarizada por Rayos X/métodos , Rayos XRESUMEN
BACKGROUND: Flurochloridone (FLC), a selective herbicide used on a global scale, has been reported to have male reproductive toxicity whose evidence is limited, but its mechanism remains unclear. The present study was conducted to systematically explore the male reproductive toxicity of FLC, including sperm quality, spermatogenesis, toxicity targets, and potential mechanisms. METHODS: Male C57BL/6 mice aged 6-7 weeks received gavage administration of FLC (365/730 mg/kg/day) for 28 consecutive days. Then, the tissue and sperm of mice were collected for analysis. We measured the gonadosomatic index and analyzed sperm concentration, motility, malformation rate, and mitochondrial membrane potential (MMP). Spermatocyte immunofluorescence staining was performed to analyze meiosis. We also performed pathological staining on the testis and epididymis tissue and TUNEL staining, immunohistochemical analysis, and ultrastructural observation on the testicular tissue. RESULTS: Results showed that FLC caused testicular weight reduction, dysfunction, and architectural damage in mice, but no significant adverse effect was found in the epididymis. The exposure interfered with spermatogonial proliferation and meiosis, affecting sperm concentration, motility, kinematic parameters, morphology, and MMP, decreasing sperm quality. Furthermore, mitochondrial damage and apoptosis of testicular Sertoli cells were observed in mice treated with FLC. CONCLUSION: We found that FLC has significant adverse effects on spermatogonial proliferation and meiosis. Meanwhile, apoptosis and mitochondrial damage may be the potential mechanism of Sertoli cell damage. Our study demonstrated that FLC could induce testicular Sertoli cell damage, leading to abnormal spermatogenesis, which decreased sperm quality. The data provided references for the toxicity risk and research methods of FLC application in the environment.
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Infertilidad Masculina , Células de Sertoli , Humanos , Masculino , Ratones , Animales , Testículo , Ratones Endogámicos C57BL , Semen , Espermatogénesis , Infertilidad Masculina/patología , EspermatozoidesRESUMEN
BACKGROUND: Ambient fine particles (PM2.5) are known to cause various reproductive and developmental diseases. However, the potential mechanisms of PM2.5 exposure induced female reproductive damage remain unclear. METHODS: Four weeks old female C57BL/6 J mice were exposed to filtered air (FA, n = 10) or concentrated ambient PM2.5 (CAP, n = 10) using a versatile aerosol concentration enrichment system. After 9 weeks of the exposure, mice were sacrificed under sevoflurane anesthesia and tissue samples were collected. Immunohistochemical analysis, enzyme-linked immunosorbent assay, quantitative polymerase chain reaction, and RNA-sequencing were performed to analyze the effects of PM2.5 exposure on follicle development and elucidate its potential mechanisms. RESULTS: Chronic PM2.5 exposure resulted in follicular dysplasia. Compared to the FA-exposed group, follicular atresia in the CAP-exposed mice were significantly increased. Further studies confirmed that CAP induced apoptosis in granulosa cells, accompanied by a distortion of hormone homeostasis. In addition, RNA-sequencing data demonstrated that CAP exposure induced the alteration of ovarian gene expressions and was associated with inflammatory response. CONCLUSIONS: Chronic exposure to CAP can induce follicular atresia, which was associated with hormone modulation and inflammation.
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Contaminantes Atmosféricos , Material Particulado , Aerosoles , Contaminantes Atmosféricos/análisis , Contaminantes Atmosféricos/toxicidad , Animales , Femenino , Atresia Folicular , Ratones , Ratones Endogámicos C57BL , Folículo Ovárico , Material Particulado/toxicidadRESUMEN
BACKGROUND: Maternal exposure to ambient fine particulate matters (PM2.5) is associated with low birth weight (LBW) in offspring, but the underlying biological mechanisms are not yet fully understood. As the bridge that connects mother and fetus, the placenta plays a crucial role in fetal development by providing the fetus with nutrients and oxygen. However, whether PM2.5 exposure would impact the placental development and the related mechanisms are unclear. RESULTS: In the present study, female C57Bl/6j mice were exposed to filtered air (FA) or concentrated ambient PM2.5 (CAP) during pregestational and gestational periods, and the fetal development and placental structure were investigated. Our results showed that maternal exposure to CAP induced fetal growth restriction (FGR) and LBW. The placenta from CAP-exposed mice exhibited abnormal development including significant decrease of surface area, smaller junctional zone and impaired spiral artery remodeling. Meanwhile, CAP exposure altered trophoblast lineage differentiation and disrupted the balance between angiogenic and angiostatic factors in placenta. In addition, the inflammatory cytokines levels in lung, placenta and serum were significantly increased after ambient PM2.5 exposure. CONCLUSION: Our findings indicate that maternal exposure to PM2.5 disrupts normal structure and spiral artery remodeling of placenta and further induces FGR and LBW. This effect may be caused by the placental inflammation response subsequent to the pulmonary and systemic inflammation induced by ambient PM2.5 exposure.
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Retardo del Crecimiento Fetal , Exposición Materna , Animales , Arterias , Femenino , Retardo del Crecimiento Fetal/inducido químicamente , Humanos , Inflamación , Exposición Materna/efectos adversos , Ratones , Ratones Endogámicos C57BL , Material Particulado/toxicidad , Placenta , EmbarazoRESUMEN
Organophosphates (OPs) and pyrethroids (PYRs) are extensively used pesticides and often occur in the form of mixture, whereas little was known about their joint toxicities. We aim to investigate the individual and joint effects of OPs and PYRs exposure on zebrafish embryo by employing chlorpyrifos (CPF) and deltamethrin (DM) as representatives. Zebrafish embryos at 2 hours post fertilization (hpf) were exposed to CPF (4.80, 39.06, and 78.13 µg/L), DM exposure (0.06, 1.60, and 3.19 µg/L), and CPF + DM (4.80 + 0.06, 39.06 + 1.60, and 78.13 + 3.19 µg/L) until 144 hpf. Embryonic development, locomotor activity, and metabolomic changes were recorded and examined. Results displayed that individual exposure to CPF and DM significantly increased the mortality and malformation rate of zebrafish embryos, but decreased hatching rate was only found in CPF + DM co-exposure groups (p < .05). Meanwhile, individual CPF exposure had no detrimental effect on locomotor activity, high dose of individual CPF exposure decreased the swimming speed but had adaptability to the conversion from dark to light, whereas high dose of CPF + DM co-exposure exhibited not only significant decline in swimming speed but also no adaptability to the repeated stimulations, suggesting deficit in learning and memory function. In metabolomic analysis, individual CPF exposure mainly influenced the metabolism of glycerophospholipids and amino acids, individual DM exposure mainly influenced glycerophospholipids, and CPF + DM co-exposure mainly influenced glycerophospholipids and amino acids. Taken together, our findings suggested the embryonic toxicities and neurobehavioral changes caused by CPF and/or DM exposure. The disorder metabolomics of glycerophospholipids and amino acids might be involved in the underlying mechanism of those toxicities.
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Cloropirifos/toxicidad , Embrión no Mamífero/efectos de los fármacos , Desarrollo Embrionario/efectos de los fármacos , Insecticidas/toxicidad , Locomoción/efectos de los fármacos , Metabolómica , Nitrilos/toxicidad , Piretrinas/toxicidad , Pez Cebra , Anomalías Inducidas por Medicamentos/patología , Adaptación Fisiológica/efectos de los fármacos , Aminoácidos/metabolismo , Animales , Femenino , Glicerofosfolípidos/metabolismo , Aprendizaje/efectos de los fármacos , Masculino , Memoria/efectos de los fármacos , NataciónRESUMEN
Exposure to ambient PM2.5 may correlate with the decline of semen quality, and the underlying biological mechanism has not been fully understood. In the present study, mice were intratracheally instilled with diesel exhaust PM2.5 (DEP), and its effects on the spermatogenic process as well as the alterations of testicular gene expression profile were assessed. Our results showed that chronic exposure to DEP impaired the fertility of male mice without influencing their libido. Compared with Vehicle-exposed group, the sperm count and motility from DEP-exposed mice were significantly decreased. In addition, immunohistological staining of γH2AX and DMC1, biomarkers for meiotic double strand breaks (DSBs), demonstrated that chronic exposure to DEP comprised the repair of meiotic DSBs, thus disrupting the spermatogenesis. Deep RNA sequencing test showed altered expressions of testicular genes including the GnRH signaling pathway. In summary, our research demonstrated that chronic exposure to DEP may disrupt spermatogenesis through targeting the meiotic recombination, providing a new perspective for the research on the male reproductive system damage caused by air pollution.
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Contaminantes Atmosféricos/toxicidad , Espermatogénesis/efectos de los fármacos , Emisiones de Vehículos/toxicidad , Animales , Fertilidad , Masculino , Ratones , Material Particulado/toxicidad , Análisis de Semen , Espermatozoides/efectos de los fármacos , TestículoRESUMEN
BACKGROUND: Yunnan and Hainan provinces are the two major endemic regions for Plasmodium falciparum malaria in China. However, few studies have investigated the characteristics of this parasite. Therefore, this study aimed to evaluate the genetic diversity and population structure of P. falciparum to predict the geographic origin of falciparum malaria. METHODS: Thirteen highly polymorphic microsatellite loci were studied to estimate the genetic diversity and population structure of 425 P. falciparum isolates obtained from blood samples collected from Yunnan and Hainan provinces of South China. The isolates were analysed for genetic diversity, linkage disequilibrium, and population structure. The parasite populations were clustered into two subgroups (i.e., Yunnan and Hainan) and a classification algorithm was used to identify molecular markers for classifying the P. falciparum populations. RESULTS: All 13 microsatellite loci were highly polymorphic, with the number of alleles per locus varying from 5 to 20. The mean expected heterozygosity (He) in Yunnan and Hainan was 0.766 ± 0.036 and 0.677 ± 0.039, respectively, revealing a moderate high level of genetic diversity. Significant linkage disequilibrium was found for some regions of Yunnan (Lazan county and Xishuangbanna region) and Hainan (Dongfang city and Sanya city) province. According to the classification algorithm, a combination of three microsatellites could be used as a discriminatory marker to identify the origin of P. falciparum isolates. CONCLUSIONS: The results on the genetic structure of P. falciparum populations from South China provide a basis for developing a genetic marker-based tool to trace the source of the parasite infections and consequently improve malaria control and elimination strategies.
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Variación Genética/genética , Malaria Falciparum/epidemiología , Malaria Falciparum/parasitología , Plasmodium falciparum/genética , Teorema de Bayes , China/epidemiología , ADN Protozoario/sangre , ADN Protozoario/genética , Genética de Población , Humanos , Desequilibrio de Ligamiento , Repeticiones de Microsatélite/genéticaRESUMEN
BACKGROUND: Various chemicals released into the aquatic environment adversely affect the reproductive system of fish, particularly by changing gonad structure and function. 17alpha-ethinylestradiol (EE2) is a potent environmental estrogen that disrupts sexual differentiation and normal reproduction in fish. Previous studies have shown that exposure to endocrine-disrupting chemicals (EDCs) disrupts the migration of primordial germ cells (PGCs) in zebrafish. METHODS: To investigate the effects of EE2 exposure on PGC migration, zebrafish embryos were injected with gfp-nanos mRNA to label PGCs and subsequently exposed to different concentrations of EE2. Typical estrogen receptor antagonist treatment and morpholino knockdown experiments were used to identify functional estrogen receptors that mediate the effects of EE2. RESULTS: The migration of PGCs was disrupted after exposure to high concentrations of EE2 (1 mirog/L). Loss-of-function analyses were performed for estrogen receptor ESR1, ESR2a, and ESR2b, and only loss of ESR2a resulted in a decreased number of ectopic PGCs following exposure to 1 mirog/L EE2. CONCLUSIONS: EE2 exposure disrupts PGC migration and distribution, and this effect is mediated through the estrogen receptor ESR2a.
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Disruptores Endocrinos/toxicidad , Antagonistas del Receptor de Estrógeno/farmacología , Etinilestradiol/toxicidad , Células Germinativas/efectos de los fármacos , Morfolinos/farmacología , Proteínas de Pez Cebra/agonistas , Pez Cebra/embriología , Regiones no Traducidas 5'/efectos de los fármacos , Animales , Movimiento Celular/efectos de los fármacos , Desarrollo Embrionario/efectos de los fármacos , Receptor alfa de Estrógeno/agonistas , Receptor alfa de Estrógeno/antagonistas & inhibidores , Receptor alfa de Estrógeno/genética , Receptor alfa de Estrógeno/metabolismo , Receptor beta de Estrógeno/agonistas , Receptor beta de Estrógeno/antagonistas & inhibidores , Receptor beta de Estrógeno/genética , Receptor beta de Estrógeno/metabolismo , Colorantes Fluorescentes/metabolismo , Genes Reporteros/efectos de los fármacos , Células Germinativas/metabolismo , Proteínas Fluorescentes Verdes/genética , Proteínas Fluorescentes Verdes/metabolismo , Microinyecciones , Receptores de Estrógenos/antagonistas & inhibidores , Receptores de Estrógenos/genética , Receptores de Estrógenos/metabolismo , Desarrollo Sexual/efectos de los fármacos , Contaminantes Químicos del Agua/toxicidad , Pez Cebra/metabolismo , Proteínas de Pez Cebra/antagonistas & inhibidores , Proteínas de Pez Cebra/genética , Proteínas de Pez Cebra/metabolismoRESUMEN
Manganese-based cathodes are competitive candidates for state-of-the-art aqueous zinc-ion batteries (AZIBs) because of their easy preparation method, sufficient nature reserve, and environmental friendliness. However, their poor cycle stability and low rate performance have prevented them from practical applications. In this study, Mn3O4 nanoparticles were formed in situ on the surface and between the interlayers of Ti3C2Tx MXene, which was pretreated by the intercalation of K+ ions. Ti3C2Tx MXene not only provides abundant active sites and high conductivity but also hinders the structural damage of Mn3O4 during charging and discharging. Benefiting from the well-designed K-Ti3C2@Mn3O4 structure, the battery equipped with the K-Ti3C2@Mn3O4 cathode achieved a maximum specific capacity of 312 mAh/g at a current density of 0.3 A/g and carried a specific capacity of approximately 120 mAh/g at a current density of 1 A/g, which remained stable for approximately 500 cycles. The performance surpasses that of most reported Mn3O4-based cathodes. This study pioneers a new approach for building better cathode materials for AZIBs.
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The effect of BHC80 (a component of BRAF-HDAC complex) on development was not well studied, because BHC80 gene knock-out mice died in one day after birth. Interestingly, zebrafish embryos can live, even if their important organs like cardiac system has severe dysfunction, as 25%-40% O2 are supplied through their skin. Therefore, a model of BHC80 gene knock-down zebrafish embryos was established to explore the effect of BHC80 on the early embryonic development. BHC80-morpholino antisense oligonucleotides 2 (BHC80-MO2) was designed and injected into zebrafish embryos to interrupt the correct translation of BHC80 mRNA at one or two cells stage, which was proved by RT-PCR analysis. Two control groups, including non-injection group and control-MO (con-MO) injection group, and four different doses of BHC80-MO2 injection groups, including 4 ng, 6 ng, 8 ng and 10 ng per embryo were set up. The embryonic heart phenotype and cardiac function were monitored, analyzed and compared between con-MO and BHC80-MO2 groups by fluorescence microscope in vmhc:gfp transgenic zebrafish which express green fluorescent protein in ventricle. The results showed that BHC80-MO2 microinjection effectively knocked down the BHC80 gene expression, because the BHC80-MO2 group emerged a new 249 bp band which reduced 51 bp compared to 300 bp band of con-MO group in RT-PCR analysis, and the 51 bp was the extron 10. The abnormal embryo rate rose with the increase of BHC80-MO2 dosage. The proper BHC80-MO2 injection dosage was 8 ng per embryo, as minor embryos had abnormal phenotype in 4 ng and 6 ng per embryo groups and most embryos died in 10 ng per embryo group. BHC80-MO2 embryos exhibited abnormal cardiac phenotype, including imbalance of the proportion of heart ventricle to atrium, incomplete D-loop, even tubular heart, slow heart rates and cardiac dysfunction. The results from a model of BHC80 gene knock-down zebrafish embryos show that the abnormal cardiac phenotype and cardiac dysfunction of BHC80-MO2 embryos may be one of the probable reasons for the BHC80 gene knock-out mice death, which would provide a good research model to clarify the mechanism of cardiac development.
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Desarrollo Embrionario/genética , Técnicas de Silenciamiento del Gen , Corazón/embriología , Histona Desacetilasas/genética , Pez Cebra/embriología , Animales , Regulación del Desarrollo de la Expresión Génica , Ratones Noqueados , Oligonucleótidos Antisentido , ARN Mensajero , Proteínas de Pez Cebra/genéticaRESUMEN
Metacognition monitoring is the ability to evaluate the cognitive process actively. L2 learners with high metacognition monitoring ability can better monitor reading processes and outcomes consciously, thus facilitating self-regulated learning and improving reading efficiency. Previous studies mostly used offline self-reports to examine the metacognition monitoring in static text reading by L2 learners. This study investigated the effects of different indicators of metacognition monitoring on L2 Chinese audiovisual comprehension by online confidence judgment and audiovisual comprehension tasks. Target measures of metacognition monitoring included absolute calibration accuracy based on video or test and relative calibration accuracy measured by Gamma or Spearman correlation coefficient. 38 intermediate-advanced Chinese learners participated in the study. Multiple regression analysis showed three main results. First, absolute calibration accuracy can significantly predict L2 Chinese audiovisual comprehension, while relative calibration accuracy has no significant effect. Second, the predictive effect of video-based absolute calibration accuracy is affected by the video difficulty, that is, the greater the video difficulty, the greater the impact on the performance of audiovisual comprehension. Third, the predictive effect of test-based absolute calibration accuracy is influenced by the language proficiency, specifically, the higher the L2 Chinese proficiency, the stronger the prediction on the performance of audiovisual comprehension. These results support a multidimensional view of metacognition monitoring by specifying how different indicators of metacognition monitoring may predict L2 Chinese audiovisual comprehension. The findings have important pedagogical implications for strategy training of metacognition monitoring and point to the necessity to take task difficulty and individual differences among learners into full consideration.
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Blending biodegradable polymers with plant materials is an effective method to improve the biodegradability of solid carbon sources and save denitrification costs, but the recalcitrant lignin in plant materials hinders the microbial decomposition of available carbon sources. In the present study, corncob pretreated by different methods was used to prepare polybutylene succinate/corncob (PBS/corncob) composites for biological denitrification. The PBS/corncob composite with alkaline pretreatment achieved the optimal NO3--N removal rate (0.13 kg NO3--N m-3 day-1) with less adverse effects. The pretreatment degree, temperature, and their interaction distinctly impacted the nitrogen removal performance and dissolved organic carbon (DOC) release, while the N2O emission was mainly affected by the temperature and the interaction of temperature and pretreatment degree. Microbial community analysis showed that the bacterial community was responsible for both denitrification and lignocellulose degradation, while the fungal community was primarily in charge of lignocellulose degradation. The outcomes of this study provide an effective strategy for improving the denitrification performance of composite carbon sources.
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Colorectal cancer (CRC) remains a primary cause of cancer mortality globally, necessitating precise prognostic indicators for effective clinical management. Our study introduces the Senescence Risk Score (SRRS), based on several senescence-related genes (SRGs), a potent prognostic tool designed to measure cellular senescence in CRC. The higher SRRS predicts a poorer prognosis, providing a novel and efficient approach to patient stratification. Notably, we found that SRRS correlates with methylation and mutation variations, and increased immune infiltration in the tumor microenvironment, thus revealing potential therapeutic targets. We also discovered an inverse relationship between SRRS and cell stemness, which could have significant implications for cancer treatment strategies. Utilizing bioinformatics resources and machine learning, we identified LIMK1 and WRN as key genes associated with SRRS, further enhancing its prognostic value. Importantly, the modulation of these genes significantly impacts cellular senescence, proliferation, and stemness in CRC cells. In summary, our development of SRRS offers a powerful tool for CRC prognosis and paves the way for novel therapeutic strategies, underscoring its potential in transforming CRC patient management.
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Senescencia Celular , Neoplasias Colorrectales , Humanos , Pronóstico , Factores de Riesgo , Inmunidad , Neoplasias Colorrectales/genética , Microambiente Tumoral , Quinasas LimRESUMEN
Colorectal cancer (CRC) is in the forefront of malignancies for its high incidence and mortality. 5-Fluorouracil (5-FU) is one of the most widely used effective drugs for the treatment of CRC. However, there is an urgent need in reducing its systemic side effects and chemoresistance, in order to make 5-FU-based chemotherapy more effective in the treatment of CRC. In this study, engineered CRC cells were established to overexpress miR-323a-3p, which was a tumor suppressor that targeted both EGFR and TYMS. Then miR-323a-3p-loaded exosomes (miR-Exo) were obtained with suitable methods of collection and purification. We found that miR-Exo significantly inhibited CRC cell proliferation and induced apoptosis by the way of targeting EGFR directly in the cells, which eventually led to desirable tumor regression in the cell derived xenograft (CDX) and patient derived xenograft (PDX) tumor mice models. Moreover, we discovered that miR-323a-3p released from miR-Exo directly inhibited the upregulation of thymidylate synthase (TYMS) induced by 5-FU-resistence in CRC cells, resulting in the revival of tumor cytotoxicity from 5-FU. MiR-Exo could effectively induce the CRC cell apoptosis by targeting EGFR and TYMS, and enhance the therapeutic effects of 5-FU on CRC. Our work demonstrates the potency of miR-Exo for advanced CRC biotherapy.
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Neoplasias Colorrectales , Exosomas , MicroARNs , Humanos , Animales , Ratones , MicroARNs/genética , Exosomas/genética , Resistencia a Antineoplásicos , Fluorouracilo/farmacología , Fluorouracilo/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Proliferación Celular , Receptores ErbB/genética , Receptores ErbB/uso terapéutico , Regulación Neoplásica de la Expresión Génica , Línea Celular TumoralRESUMEN
The current COVID-19 pandemic is motivating us to elucidate the molecular mechanism of SARS-CoV-2 invasion and find methods for decreasing its transmissibility. We found that SARS-CoV-2 could increase the protein level of ACE2 in mice. Folic acid and 5-10-methylenetetrahydrofolate reductase (MTHFR) could promote the methylation of the ACE2 promoter and inhibit ACE2 expression. Folic acid treatment decreased the binding ability of Spike protein, pseudovirus and inactivated authentic SARS-CoV-2 to host cells. Thus, folic acid treatment could decrease SARS-CoV-2 invasion and SARS-CoV-2-neutralizing antibody production in mice. These data suggest that increased intake of folic acid may inhibit ACE2 expression and reduce the transmissibility of SARS-CoV-2. Folic acid could play an important role in SARS-CoV-2 infection prevention and control.
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Introduction: The large-scale development of animal husbandry and industrialization lead to more and more serious co-contamination from heavy metals and antibiotics in soils. Ecotoxic effects of residues from antibiotics and heavy metals are of increasing concern. Materials and Methods: In this study, oxytetracycline (OTC) and cadmium (Cd) were selected as target pollutants to evaluate the individual and combined effects on nitrification process using four different soil types sampled from North to South China through a 56-day incubation experiment. Results and Discussion: The results demonstrated that the contaminations of OTC and Cd, especially combined pollution had significant inhibitory effects on net nitrification rates (NNRs) as well as on AOA and AOB abundance. The toxic effects of contaminants were greatly enhanced with increasing OTC concentration. AOB was more sensitive than AOA to exogenous contaminants. And the interaction effects of OTC and Cd on ammonia oxidizers were mainly antagonistic. Furthermore, Cd contaminant (with or without OTC) had indirect effects on nitrification activity via inhibiting mineral N and AOA/AOB, while OTC alone indirectly inhibited nitrification activity by inhibiting ammonia oxidizers. The results could provide theoretical foundation for exploring the eco-environmental risks of antibiotics and heavy metals, as well as their toxic effects on nitrification processes.
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The rapid onset of resistance to epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) limits its clinical utility in colorectal cancer (CRC) patients, and pan-erb-b2 receptor tyrosine kinase (ErbB) treatment strategy may be the alternative solution. The aim of this study was to develop a possible microRNA multi-ErbB treatment strategy to overcome EGFR-TKI resistance. We detect the receptor tyrosine kinase activity in gefitinib-resistant colorectal cancer cells, ErbB3/EGFR is significantly activated and provides a potential multi-ErbB treatment target. MiR-323a-3p, a tumor suppressor, could target both ErbB3 and EGFR directly. Apoptosis is the miR-323a-3p inducing main biological process by functional enrichment analysis, and The EGFR and ErbB signaling are the miR-323a-3p inducing main pathway by KEGG analysis. MiR-323a-3p promotes CRC cells apoptosis by targeting ErbB3-phosphoinositide 3-kinases (PI3K)/PKB protein kinase (Akt)/glycogen synthase kinase 3 beta (GSK3ß)/EGFR-extracellular regulated MAP kinase (Erk1/2) signaling directly. And miR-323a-3p, as a multi-ErbBs inhibitor, increase gefitinib sensitivity of the primary cell culture from combination miR-323a-3p and gefitinib treated subcutaneous tumors. MiR-323a-3p reverses ErbB3/EGFR signaling activation in gefitinib-resistant CRC cell lines and blocks acquired gefitinib resistance.
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Neoplasias Colorrectales , Neoplasias Pulmonares , MicroARNs , Línea Celular Tumoral , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Resistencia a Antineoplásicos/genética , Receptores ErbB/metabolismo , Gefitinib/farmacología , Gefitinib/uso terapéutico , Humanos , Neoplasias Pulmonares/patología , MicroARNs/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Receptor ErbB-2/metabolismo , Receptor ErbB-3/genética , Receptor ErbB-3/metabolismoRESUMEN
Glucopyranosyl-conjugated benzyl derivatives containing a [1,2,3]-triazole linker were synthesized. Benzyl served as an important pharmacophore in anti-cancer compounds. Compound 8d inhibited the proliferation of colorectal cancer cells with the potency comparable to 5-fluorouracil (5-FU) with improved selectivity towards cancer cells. The antiproliferative activity of 8d is achieved through triggering apoptotic cell death.
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BACKGROUND: Dibutyl phthalate (DBP) is an environmental endocrine disruptor detected in water, soil, and other environmental media frequently. Growing concerns regarding DBP exposure focus on toxicity to male reproduction. Reports about the developmental toxicity of paternal DBP exposure are rare. In this study, we investigated the developmental toxicity of paternal exposure to DBP on offspring in zebrafish. METHODS: Adult male zebrafish with normal reproductive function were exposed to 0.2, 0.6, 1.8 mg/L of DBP or acetone solvent control for 30 days, and then mated with females. Thirty embryos per group were randomly selected to be observed, and malformations were recorded and photographed. The mating and observations were repeated three times, for a total of 90 embryos per group. RESULTS: The results showed that the percentage of malformations, such as edema and a bent trunk, was increased in the 0.6 and 1.8 mg/L DBP exposure groups, the heart rate and spontaneous contraction decreased in the 0.6 and 1.8 mg/L DBP exposure groups and migration of primordial germ cells was disrupted in some F1 embryos in all DBP exposure group after paternal exposure. The axial skeleton was affected in some F1 adults in the 1.8 mg/L DBP exposure group. CONCLUSIONS: Our findings demonstrate the developmental toxicity of paternal DBP exposure in zebrafish.