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OBJECTIVE: To compare the outcomes of intelligent first-aid training based on virtual reality (VR) among individuals with different demographic characteristics. METHODS: A total of 50 nonmedical professional volunteers from Nanchang were conveniently sampled in March 2021. All participants underwent intelligent VR first-aid training, and a comparative analysis was conducted by dividing them into different groups based on demographic characteristics. RESULTS: Male participants had a lower chest compression interruption time compared to female participants (7.40 ± 0.50 vs. 8.04 ± 0.56, t = -4.231, p < 0.001). Additionally, male participants had a higher proportion of compressions with correct compression depth (81.33 ± 1.24 vs. 79.78 ± 1.48, t = 4.038, p < 0.001), higher mean ventilation volume (518.11 ± 1.50 vs. 516.61 ± 2.17, t = 2.881, p = 0.006), and higher theoretical knowledge test score (8.74 ± 0.59 vs. 8.00 ± 0.43, t = 4.981, p < 0.001). There were statistically significant differences in the mean chest compression frequency (110.38 ± 5.74 vs. 105.00 ± 4.78 vs. 107.80 ± 5.97, F = 5.187, p = 0.009) among participants with different educational backgrounds. Pairwise comparisons showed that technical degree holders had a higher mean chest compression frequency than bachelor's degree holders, whereas no statistically significant difference was observed between master's degree holders and bachelor's degree holders. CONCLUSION: The outcomes of first-aid training differ among participants of different genders and with different educational backgrounds. With all participants meeting the training qualifications, it is believed that the application of intelligent VR first-aid training platforms can improve the first aid capabilities of the public.
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Lactoferrin (LF), an iron-binding glycoprotein rich in human milk, promotes neurodevelopment and cognition, but whether it acts through the LF receptor (LfR) and its expression profile in the brain remains unknown. We characterized 972 bp of piglet brain LfR cDNA and found LfR mRNA was expressed all brain regions being highest in the frontal lobe, followed by parietal lobe, brainstem, occipital lobe, cingulate gyrus, subventricular zone, olfactory bulb, hippocampus, amygdala, cerebellum, and thalamus. LfR mRNA and protein in different regions of the brain responded to low (155 mg/kg/day) and high (285 mg/kg/day) LF supplementation of piglets from postnatal days 3 to 38. By postnatal day 39, the low LF diet significantly increased LfR protein expression in the occipital lobe compared to controls, but not the high LF diet. LfR protein in the subventricular zone of the high LF group was 42% and 38% higher than that of the low LF group and controls, respectively. There was a trend for a dose-response relationship between LF intervention and LfR protein expression only in the prefrontal and parietal lobes. LF supplementation significantly improved piglet working memory for a difficult task, which was positively correlated with LfR protein in the prefrontal, parietal, and occipital lobes, but no dose response. Brain LfR responds to dietary LF supplementation, a mechanism by which LF can promote learning and working memory through its receptor. LfR is expressed in the whole brain, and its expression level is anatomic region specific.
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Sepsis is a leading cause of mortality among severely ill individuals, primarily due to its potential to induce fatal organ dysfunction. For clinicians, it is vital to have appropriate indicators, including the physiological status and personal experiences of patients with sepsis, to monitor the condition and assess prognosis. This approach aids in preventing the worsening of the illness and reduces mortality. Recent guidelines for sepsis focus on improving patient outcomes through early detection and timely treatment. Nonetheless, identifying severe cases and predicting their prognoses remain challenging. In recent years, there has been considerable interest in utilising the C-reactive protein (CRP)/albumin ratio (CAR) to evaluate the condition and forecast the prognosis of patients with sepsis. This research concentrates on the significance of CAR in the pathological process of sepsis, its association with prognosis, and the latest developments in employing procalcitonin, lactic acid, CRP, and other potential biomarkers. The CAR, with its predictive value for sepsis prognosis and mortality, is increasingly used as a clinical biochemical marker in diagnosing and monitoring patients with sepsis.
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BACKGROUND: Delayed cerebral ischemia (DCI) is a common and serious complication of subarachnoid hemorrhage (SAH). Its pathogenesis is not fully understood. Here, we developed a predictive model based on peripheral blood biomarkers and validated the model using several bioinformatic multi-analysis methods. METHODS: Six datasets were obtained from the GEO database. Characteristic genes were screened using weighted correlation network analysis (WGCNA) and differentially expressed genes. Three machine learning algorithms, elastic networks-LASSO, support vector machines (SVM-RFE) and random forests (RF), were also used to construct diagnostic prediction models for key genes. To further evaluate the performance and predictive value of the diagnostic models, nomogram model were constructed, and the clinical value of the models was assessed using Decision Curve Analysis (DCA), Area Under the Check Curve (AUC), Clinical Impact Curve (CIC), and validated in the mouse single-cell RNA-seq dataset. Mendelian randomization(MR) analysis explored the causal relationship between SAH and stroke, and the intermediate influencing factors. We validated this by retrospectively analyzing the qPCR levels of the most relevant genes in SAH and SAH-DCI patients. This experiment demonstrated a statistically significant difference between SAH and SAH-DCI and normal group controls. Finally, potential small molecule compounds interacting with the selected features were screened from the Comparative Toxicogenomics Database (CTD). RESULTS: The fGSEA results showed that activation of Toll-like receptor signaling and leukocyte transendothelial cell migration pathways were positively correlated with the DCI phenotype, whereas cytokine signaling pathways and natural killer cell-mediated cytotoxicity were negatively correlated. Consensus feature selection of DEG genes using WGCNA and three machine learning algorithms resulted in the identification of six genes (SPOCK2, TRRAP, CIB1, BCL11B, PDZD8 and LAT), which were used to predict DCI diagnosis with high accuracy. Three external datasets and the mouse single-cell dataset showed high accuracy of the diagnostic model, in addition to high performance and predictive value of the diagnostic model in DCA and CIC. MR analysis looked at stroke after SAH independent of SAH, but associated with multiple intermediate factors including Hypertensive diseases, Total triglycerides levels in medium HDL and Platelet count. qPCR confirmed that significant differences in DCI signature genes were observed between the SAH and SAH-DCI groups. Finally, valproic acid became a potential therapeutic agent for DCI based on the results of target prediction and molecular docking of the characterized genes. CONCLUSION: This diagnostic model can identify SAH patients at high risk for DCI and may provide potential mechanisms and therapeutic targets for DCI. Valproic acid may be an important future drug for the treatment of DCI.
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Biomarcadores , Isquemia Encefálica , Ácido Valproico , Humanos , Animais , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/genética , Isquemia Encefálica/sangue , Isquemia Encefálica/imunologia , Ácido Valproico/uso terapêutico , Camundongos , Biomarcadores/sangue , Hemorragia Subaracnóidea/sangue , Hemorragia Subaracnóidea/imunologia , Hemorragia Subaracnóidea/genética , Hemorragia Subaracnóidea/tratamento farmacológico , Biologia Computacional , Bases de Dados Genéticas , Aprendizado de MáquinaRESUMO
Cadmium poses a severe health risk, impacting various bodily systems. Monitoring human exposure is vital. Urine and blood cadmium serve as critical biomarkers. However, current urine and blood cadmium detection methods are expensive and complex. Being cost-effective, user-friendly, and efficient, visual biosensing offers a promising complement to existing techniques. Therefore, we constructed a cadmium whole-cell biosensor using CadR10 and deoxyviolacein pigment in this study. We assessed the sensor for time-dose response, specific response to cadmium, sensitivity response to cadmium, and stability response to cadmium. The results showed that (1) the sensor had a preferred signal-to-noise ratio when the incubation time was 4 h; (2) the sensor showed excellent specificity for cadmium compared to the group 12 metals and lead; (3) the sensor was responsive to cadmium down to 1.53 nM under experimental conditions and had good linearity over a wide range from 1.53 nM to 100 µM with good linearity (R2 = 0.979); and (4) the sensor had good stability. Based on the excellent results of the performance tests, we developed a cost-effective, high-throughput method for detecting urinary and blood cadmium. Specifically, this was realized by adding the blood or urine samples into the culture system in a particular proportion. Then, the whole-cell biosensor was subjected to culture, n-butanol extraction, and microplate reading. The results showed that (1) at 20% urine addition ratio, the sensor had an excellent curvilinear relationship (R2 = 0.986) in the range of 3.05 nM to 100 µM, and the detection limit could reach 3.05 nM. (2) At a 10% blood addition ratio, the sensor had an excellent nonlinear relationship (R2 = 0.978) in the range of 0.097-50 µM, and the detection limit reached 0.195 µM. Overall, we developed a sensitive and wide-range method based on a whole-cell biosensor for the detection of cadmium in blood and urine, which has the advantages of being cost-effective, ease of operation, fast response, and low dependence on instrumentation and has the potential to be applied in the monitoring of cadmium exposure in humans as a complementary to the mainstream detection techniques.
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Técnicas Biossensoriais , Cádmio , Humanos , Cádmio/urina , Cádmio/sangue , Cádmio/análise , Técnicas Biossensoriais/métodos , Limite de DetecçãoRESUMO
OBJECTIVE: Although some studies have linked smoking to mortality after out-of-hospital cardiac arrests (OHCAs), data regarding smoking and mortality after OHCAs have not yet been discussed in a meta-analysis. Thus, this study conducted this systematic review to clarify the association. METHODS: The study searched Medline-PubMed, Web of Science, Embase and Cochrane libraries between January 1972 and July 2022 for studies that evaluated the association between smoking and mortality after OHCAs. Studies that reportedly showed relative risk estimates with 95% confidence intervals (CIs) were included. RESULTS: Incorporating a collective of five studies comprising 2477 participants, the analysis revealed a lower mortality risk among smokers in the aftermath of OHCAs compared with non-smokers (odds ratio: 0.77; 95% CI 0.61-0.96; P < 0.05). Egger's test showed no publication bias in the relationship between smoking and mortality after OHCAs. CONCLUSIONS: After experiencing OHCAs, smokers had lower mortality than non-smokers. However, due to the lack of data, this 'smoker's paradox' still needs other covariate effects and further studies to be considered valid.
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não Fumantes , Parada Cardíaca Extra-Hospitalar , Fumantes , Humanos , Parada Cardíaca Extra-Hospitalar/mortalidade , Parada Cardíaca Extra-Hospitalar/terapia , Fumantes/estatística & dados numéricos , não Fumantes/estatística & dados numéricos , Fumar , Feminino , Masculino , Pessoa de Meia-Idade , IdosoRESUMO
In this study, a series of new formylpiperazine-derived ferroptosis inhibitors were designed and synthesized based on the structure of a known ferroptosis inhibitor, ferrostatin-1 (Fer-1). The anti-ferroptosis activity of these synthetic compounds in human umbilical vein endothelial cells (HUVECs) induced by Erastin was evaluated. It was found that some of the new compounds, especially compound 26, showed potent anti-ferroptosis activity, as evidenced by its ability to restore cell viability, reduce iron accumulation, scavenge reactive oxygen species, maintain mitochondrial membrane potential, increase GSH levels, decrease LPO and MDA content, and upregulate GPX4 expression. Moreover, compound 26 exhibited superior microsomal stability than Fer-1. The present results suggest that compound 26 is a promising lead compound for the development of new ferroptosis inhibitors for the treatment of vascular diseases.
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Sobrevivência Celular , Cicloexilaminas , Desenho de Fármacos , Ferroptose , Células Endoteliais da Veia Umbilical Humana , Piperazinas , Humanos , Ferroptose/efeitos dos fármacos , Piperazinas/farmacologia , Piperazinas/síntese química , Piperazinas/química , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Relação Estrutura-Atividade , Cicloexilaminas/farmacologia , Cicloexilaminas/química , Cicloexilaminas/síntese química , Sobrevivência Celular/efeitos dos fármacos , Estrutura Molecular , Fenilenodiaminas/farmacologia , Fenilenodiaminas/química , Fenilenodiaminas/síntese química , Relação Dose-Resposta a Droga , Espécies Reativas de Oxigênio/metabolismo , Compostos Ferrosos/farmacologia , Compostos Ferrosos/química , Compostos Ferrosos/síntese química , Potencial da Membrana Mitocondrial/efeitos dos fármacosRESUMO
Ferroptosis is a nonapoptotic, iron-catalyzed form of regulated cell death. It has been shown that high glucose (HG) could induce ferroptosis in vascular endothelial cells (VECs), consequently contributing to the development of various diseases. This study synthesized and evaluated a series of novel ferrostatin-1 (Fer-1) derivatives fused with a benzohydrazide moiety to prevent HG-induced VEC ferroptosis. Several promising compounds showed similar or improved inhibitory effects compared to positive control Fer-1. The most effective candidate 12 exhibited better protection against erastin-induced ferroptosis and high glucose-induced ferroptosis in VECs. Mechanistic studies revealed that compound 12 prevented mitochondrial damage, reduced intracellular ROS accumulation, upregulated the expression of GPX4, and decreased the amounts of ferrous ion, LPO and MDA in VECs. However, compound 12 still exhibited undesirable microsomal stability like Fer-1, suggesting the need for further optimization. Overall, the present findings highlight ferroptosis inhibitor 12 as a potential lead compound for treating ferroptosis-associated vascular diseases.
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A farmland area in Zhaotong City was taken as the research objectï¼ and the method of point-to-point collaborative sampling was used to collect farmland soil and vegetables in Zhaotong and test the content of six heavy metalsï¼ namely Asï¼ Pbï¼ Cuï¼ Znï¼ Cdï¼ and Cr. The geo-accumulation index and potential ecological risk index were used to evaluate the heavy metal pollution of soil. The health risk model was used to evaluate the risk to the human body imposed by vegetables. The results showed that Cuï¼ Znï¼ Pbï¼ Cdï¼ and Cr pollution existed in the research area. Compared with the risk screening value of farmlandï¼ the over-standard rates were 34.35%ï¼ 6.87%ï¼ 2.29%ï¼ 80.15%ï¼ and 6.11%ï¼ respectivelyï¼ Pbï¼ Cdï¼ and Cr were found in vegetables. Compared with the pollutant limit in foodï¼ the over-standard rates were 6.87%ï¼ 15.27%ï¼ and 36.64%ï¼ respectively. According to the soil pollution evaluationï¼ Cd in the soil showed a strong ecological riskï¼ and other heavy metals in the soil showed a mild ecological risk. The human health risk evaluation model showed that both non-carcinogenic risk and carcinogenic risk were out of the acceptable range and had a greater influence on children. Correlation analysis showed that As in the soil had an antagonistic effect on Cu and Zn absorption by vegetablesï¼ whereas Cr in the soil could promote Cu and Zn absorption by vegetables.
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Metais Pesados , Poluentes do Solo , Criança , Humanos , Solo , Fazendas , Verduras , Cádmio , Chumbo , Monitoramento Ambiental/métodos , Poluentes do Solo/análise , Metais Pesados/análise , Poluição Ambiental , Medição de Risco , ChinaRESUMO
Objective: To reveal the safety and efficacy of clipping and coiling in patients with ruptured distal anterior cerebral artery aneurysms (DACAA) and to calculate the risk factors affecting the two-year survival rate in follow-up patients. Methods: A retrospective study was conducted on the data of 140 patients (21 were lost to follow-up) with DACAA rupture who were treated by neurosurgery at 12 medical centers over a 2-year period, from January 2017 to December 2020. Univariate analysis was used to examine factors contributing to poor patient prognosis and to compare the prognosis of coiling and clipping treatments. Survival analysis was employed to compare survival rates between coiling and clipping, and risk factors affecting patient survival were analyzed using multivariate Cox regression analysis. Results: Out of 140 patients with ruptured DACAA, 80 (57.1%) were male, and 60 (42.9%) were female. A total of 111 (79.3%) patients were classified under Hunt-Hess scale grades I-III, while 95 (67.9%) were graded I-III according to the WFNs classification. Among them, 63 (45%) were treated with clipping, and 77 (55%) underwent coiling. Within 2 years of discharge from the hospital, 31 (59.6%) patients who underwent clipping and 54 (80.6%) who underwent coiling had a good prognosis. Multivariate Cox regression analysis revealed that only WFNs classification (I-III) was a protective factor influencing the 2-year survival of patients with ruptured DACAA. Conclusion: In the reality of medical practice, neurosurgeons are more likely to choose clipping as the treatment for cases with WFNs classification than or equal to III. There was no difference between clipping and coiling in the two-year prognosis at discharge. High priority should be given to DACAA cases with WFNs grading (I-III), as better outcomes can be achieved. The sample size will continue to be enlarged in the future to obtain more accurate findings. Abstracts for reviews, technical notes, and historical vignettes do not need to be separated into sections. They should begin with a clear statement of the paper's purpose followed by appropriate details that support the authors' conclusion(s).
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The gut-brain axis plays a vital role in Parkinson's disease (PD). The mechanisms of gut-brain transmission mainly focus on α-synuclein deposition, intestinal inflammation and microbiota function. A few studies have shown the trigger of PD pathology in the gut. α-Synuclein is highly conserved in food products, which was able to form ß-folded aggregates and to infect the intestinal mucosa. In this study we investigated whether α-synuclein-preformed fibril (PFF) exposure could modulate the intestinal environment and induce rodent models replicating PD pathology. We first showed that PFF could be internalized into co-cultured Caco-2/HT29/Raji b cells in vitro. Furthermore, we demonstrated that PFF perfusion caused the intestinal inflammation and activation of enteric glial cells in an ex vivo intestinal organ culture and in an in vivo intestinal mouse coloclysis model. Moreover, we found that PFF exposure through regular coloclysis induced PD pathology in wild-type (WT) and A53T α-synuclein transgenic mice with various phenotypes. Particularly in A53T mice, PFF induced significant behavioral disorders, intestinal inflammation, α-synuclein deposition, microbiota dysbiosis, glial activation as well as degeneration of dopaminergic neurons in the substantia nigra. In WT mice, however, the PFF induced only mild behavioral abnormalities, intestinal inflammation, α-synuclein deposition, and glial activation, without significant changes in microbiota and dopaminergic neurons. Our results reveal the possibility of α-synuclein aggregates binding to the intestinal mucosa and modeling PD in mice. This study may shed light on the investigation and early intervention of the gut-origin hypothesis in neurodegenerative diseases.
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Doença de Parkinson , Transtornos Parkinsonianos , Humanos , Camundongos , Animais , alfa-Sinucleína/metabolismo , Células CACO-2 , Transtornos Parkinsonianos/metabolismo , Doença de Parkinson/metabolismo , Camundongos Transgênicos , Neurônios Dopaminérgicos/metabolismo , Inflamação/metabolismoRESUMO
ARHGEF17 encodes the protein RhoGEF17, which is highly expressed in vascular endothelial cells. It is a guanine nucleotide exchange factor (GEF) that accelerates the exchange of GDP with GTP on many small GTPases through its Dbl homology (DH) domain, enabling the activation of Rho-GTPases such as RhoA, RhoB, and RhoC. Rho GTPase-regulated changes in the actin cytoskeleton and cell adhesion kinetics are the main mechanisms mediating many endothelial cell (EC) alterations, including cell morphology, migration, and division changes, which profoundly affect EC barrier function. This review focuses on ARHGEF17 expression, activation and biological functions in ECs, linking its regulation of cellular morphology, migration, mitosis and other cellular behaviors to disease onset and progression. Understanding ARHGEF17 mechanisms of action will contribute to the design of therapeutic approaches targeting RhoGEF17, a potential drug target for the treatment of various endothelium-related diseases, Such as vascular inflammation, carcinogenesis and transendothelial metastasis of tumors.
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Células Endoteliais , Neoplasias , Humanos , Células Endoteliais/metabolismo , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Proteínas rho de Ligação ao GTP/metabolismo , Proteína rhoA de Ligação ao GTP/metabolismo , Neoplasias/tratamento farmacológico , EndotélioRESUMO
Whole-cell biosensors could be helpful for in situ disease diagnosis. However, their use in analyzing biological samples has been hindered by unstable responses, low signal enhancement, and growth inhibition in complex media. Here, we offered a solution by building a visual whole-cell biosensor for urinary mercury determination. With deoxyviolacein as the preferred signal for the mercury biosensor for the first time, it enabled the quantitative detection of urinary mercury with a favorable linear range from 1.57 to 100 nM. The biosensor can accurately diagnose urine mercury levels exceeding the biological exposure index with 95.8% accuracy. Thus, our study provided a biosensing platform with great potential to serve as a stable, user-friendly, and high-throughput alternative for the daily monitoring or estimating of urinary mercury.
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Técnicas Biossensoriais , Mercúrio , Humanos , Ensaios de Triagem em Larga EscalaRESUMO
The concept of sepsis has recently evolved from one of a 'systemic inflammatory response syndrome caused by infection' to a 'severe, potentially fatal organic dysfunction caused by an inadequate or imbalanced host response to infection'. Organ dysfunction is closely related to sepsis. Multiple organ dysfunction syndrome (MODS) is the most serious outcome of sepsis, often leading to a poor prognosis. However, specific drugs for sepsis and MODS caused by sepsis remain undetermined, and the fatality rate is relatively high. Under the guidance of modern medicine, traditional Chinese medicine (TCM) has gained a wealth of experience in the prevention and treatment of sepsis and plays a key role via the effects of its numerous components, pathways and targets. This study used 'Sepsis', 'Organ dysfunction' and 'Traditional Chinese medicine' as strategies for searching the databases of Chinese National Knowledge Infrastructure, Wanfang, PubMed and The Web of Science. This paper presents an overview of the current status of TCM component formulations for preventing and treating sepsis with MODS to provide a theoretical basis for clinical treatment and drug development.
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To explore the safe utilization technology of farmland polluted by the heavy metals cadmium (Cd) and lead (Pb) and to realize the safe production of agricultural products, a pot experiment was conducted to investigate the effects of two soil passivators and five foliar inhibitors on Cd and Cd-accumulation and quality of lettuce with low Pb and Cd accumulation (KCW). The results showed that different control measures had different effects on the soil pH value of lettuce, and the application of 45 g·m-2biochar-based passivator had the most significant difference in improving the soil pH value, which was increased by 0.8 units compared with that in CK. By using 72 g·m-2 of humic acid passivator yielded notable difference in reducing the soil pH value of lettuce. A reduction of 0.25 units was achieved compared with that in CK. Among all the control measures, the application of 45 g·m-2 biocharcoal-based passivation agent had the best effect on reducing soil available Cd content, which was significantly reduced by 53% compared with that in CK, and the application of 135 g·m-2biocharcoal-based passivation agent had the best effect on reducing soil available Pb content, which was significantly reduced by 64% compared with that in CK. Spraying 0.8% FAK-Zn foliar inhibitor not only had the best control effect on reducing Cd and Pb contents in the edible parts of lettuce, which were significantly reduced by 77% and 60%, respectively, compared with that in CK, but it also significantly reduced Cd and Pb enrichment coefficients and transport coefficients from the root to the edible parts of the lettuce. Different control measures had different effects on the nutritional quality of lettuce, and 0.4% FAK-Zn foliar inhibitor had the best effect on soluble protein. The 0.6% FAK-Zn had the best effect on soluble sugar, and the 0.4% FAK-Zn inhibitor had the best effect on vitamin C content. The application of biocarbon-based passivator could effectively repair lettuce soil polluted by Cd and Pb, whereas the application of FAK-Zn leaf surface inhibitor could effectively inhibit the accumulation, absorption, and transfer of Cd and Pb in lettuce; improve the nutritional quality of lettuce; provide a theoretical basis for safe production of vegetables polluted by heavy metals; and promote the recycling of resources and environment.
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Cádmio , Lactuca , Chumbo , Verduras , SoloRESUMO
With the rapid development of synthetic biology, various whole-cell biosensors have been designed as valuable biological devices for the selective and sensitive detection of toxic heavy metals in environmental water. However, most proposed biosensors are based on fluorescent and bioluminescent signals invisible to the naked eye. The development of visible pigment-based biosensors can address this issue. The pbr operon from Klebsiella pneumoniae is selectively induced by bioavailable Pb(II). In the present study, the proviolacein biosynthetic gene cluster was transcriptionally fused to the pbr Pb(II) responsive element and introduced into Escherichia coli. The resultant biosensor responded to Pb(II) in a time- and dose-dependent manner. After a 5-h incubation with Pb(II), the brown pigment was produced, which could be extracted into n-butanol. Extra hydrogen peroxide treatment during n-butanol extract resulted in the generation of a stable green pigment. An increased brown signal was observed upon exposure to lead concentrations above 2.93 nM, and a linear regression was fitted from 2.93 to 3,000 nM. Extra oxidation significantly decreased the difference between parallel groups. The green signal responded to as low as 0.183 nM Pb(II), and a non-linear regression was fitted in a wide concentration range from 0.183 to 3,000 nM. The specific response toward Pb(II) was not interfered with by various metals except for Cd(II) and Hg(II). The PV-based biosensor was validated in monitoring bioaccessible Pb(II) spiked into environmental water. The complex matrices did not influence the regression relationship between spiked Pb(II) and the dual-color signals. Direct reading with the naked eye and colorimetric quantification enable the PV-based biosensor to be a dual-color and low-cost bioindicator for pollutant heavy metal.
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BACKGROUND AND PURPOSE: The scaffold molecule Axin2 is constitutively activated in colorectal cancer (CRC) and functions as a potent promoter of CRC behaviour. Pharmacological targeting of Axin2 may therefore exert a therapeutic effect in patients with CRC. Here, we discovered a potent small-molecule inhibitor of Axin2, based on the mechanism by which Axin2 is regulated post-translationally, and investigated its antitumour effects. EXPERIMENTAL APPROACH: Compound discovery and its inhibitory action on Axin2 protein were revealed by microscale thermophoresis, in vitro kinase assay, quantitative kinetic assay, immunoblotting/immunoprecipitation, RT-qPCR and cycloheximide pulse-chase assay. Compound antitumour effects and the underlying mechanisms were evaluated in multiple cell-based assays and mouse models. KEY RESULTS: We discovered that glycogen synthase kinase 3ß (GSK3ß) phosphorylates Axin2 at two consensus motifs and coupled Axin2 phosphorylation to its ubiquitination (mediated by the E3 ligase ß-Trcp2) and proteasomal degradation. The binding of Axin2 to GSK3ß in CRC cells is faint, which enables most of the Axin2 protein to maintain an unphosphorylated status and thereby permits the cells to preserve high levels of Axin2. Importantly, we identified a small-molecule compound CW85319 that enhances Axin2's interaction with GSK3ß via forming a high affinity for Axin2. Treatment of CRC cells with CW85319 enhanced Axin2 binding with GSK3ß, thereby promoting Axin2 phosphorylation, subsequent ubiquitination, and degradation. Furthermore, we demonstrated that CW85319 efficiently suppressed Axin2-driven CRC growth and metastasis, without eliciting side toxicity. CONCLUSIONS AND IMPLICATIONS: These findings suggest that pharmacological targeting of Axin2 by CW85319 may provide therapeutic benefits against certain human cancers, especially CRC.
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Neoplasias Colorretais , Camundongos , Animais , Humanos , Linhagem Celular Tumoral , Glicogênio Sintase Quinase 3 beta , Modelos Animais de Doenças , Immunoblotting , Neoplasias Colorretais/metabolismo , Proteína Axina/metabolismoRESUMO
Arbuscular mycorrhizal fungi (AMF) play key roles in enhancing plant tolerance to heavy metals, and iron (Fe) compounds can reduce the bioavailability of arsenic (As) in soil, thereby alleviating As toxicity. However, there have been limited studies of the synergistic antioxidant mechanisms of AMF (Funneliformis mosseae) and Fe compounds in the alleviation of As toxicity on leaves of maize (Zea mays L.) with low and moderate As contamination. In this study, a pot experiment was conducted with different concentrations of As (0, 25, 50 mgêkg-1) and Fe (0, 50 mgêkg-1) and AMF treatments. Results showed that under low and moderate As concentrations (As25 and As50), the co-inoculation of AMF and Fe compound significantly increased the biomass of maize stems and roots, phosphorus (P) concentration, and P-to-As uptake ratio. Moreover, the co-inoculation of AMF and Fe compound addition significantly reduced the As concentration in stem and root, malondialdehyde (MDA) content in leaf, and soluble protein and non-protein thiol (NPT) contents in leaf of maize under As25 and As50 treatments. In addition, co-inoculation with AMF and Fe compound addition significantly increased the activities of catalase (CAT), peroxidase (POD), and superoxide dismutase (SOD) in the leaves of maize under As25 treatment. Correlation analysis showed that stem biomass and leaf MDA content were very significantly negatively correlated with stem As content, respectively. In conclusion, the results indicated that the co-inoculation of AMF and Fe compound addition can inhibit As uptake and promote P uptake by maize under low and moderate As contamination, thereby mitigating the lipid peroxidation on maize leaves and reducing As toxicity by enhancing the activities of antioxidant enzymes under low As contamination. These findings provide a theoretical basis for the application of AMF and Fe compounds in the restoration of cropland soil contaminated with low and moderate As.
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Background: Nowadays, with the fast-increasing demand for neuro-endovascular therapy, surgeons in this field are in urgent need. Unfortunately, there is still no formal skill assessment in neuro-endovascular therapy in China. Methods: We used a Delphi method to design a newly objective checklist for standards of cerebrovascular angiography in China and evaluated its validity and reliability. A total of 19 neuro-residents with no interventional experience and 19 neuro-endovascular surgeons from two centers (Guangzhou and Tianjin) were recruited; they were divided into two groups: residents and surgeons. Residents completed a simulation-based cerebrovascular angiography operation training before assessment. Assessments were under live and video record forms with two tools: the existing global rating scale (GRS) of endovascular performance and the new checklist. Results: The average scores of residents were significantly increased after training in two centers (p < 0.05). There is good consistency between GRS and the checklist (p = 0.856). Intra-rater reliability (Spearman's rho) of the checklist was >0.9, and the same result was also observed in raters between different centers and different assessment forms (p < 0.001, rho > 0.9). The reliability of the checklist was higher than that of the GRS (Kendall's harmonious coefficient is 0.849, while GRS is 0.684). Conclusion: The newly developed checklist appears reliable and valid for evaluating the technical performance of cerebral angiography and differentiating between trained and untrained trainees' performance well. For its efficiency, our method has been proven to be a feasible tool for resident angiography examination in certification nationwide.
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PURPOSE: Available evidence indicates that dipyridamole enhances the anti-thrombotic effects of aspirin for the prevention of secondary strokes. Aspirin is a well-known non-steroid anti-inflammatory drug. This anti-inflammatory property has turned aspirin into a potential drug for inflammation-related cancers such as colorectal cancer (CRC). Here, we aimed to explore whether the anti-cancer effect of aspirin against CRC could be improved by combined administration with dipyridamole. METHODS: Population-based clinical data analysis was conducted to assess a possible therapeutic effect of combined dipyridamole and aspirin treatment in inhibiting CRC compared with either monotherapy. This therapeutic effect was further verified in different CRC mouse models, i.e. an orthotopic xenograft mouse model, an AOM/DSS mouse model, an Apcmin/+ mouse model and a patient derived xenograft (PDX) mouse model. The in vitro effects of the drugs on CRC cells were tested using CCK8 and flow cytometry assays. RNA-Seq, Western blotting, qRT-PCR and flow cytometry were used to identify the underlying molecular mechanisms. RESULTS: We found that dipyridamole combined with aspirin had a better inhibitory effect on CRC than either monotherapy alone. The enhanced anti-cancer effect of the combined use of dipyridamole with aspirin was found to rely on the induction of an overwhelmed endoplasmic reticulum (ER) stress and subsequent pro-apoptotic unfolded protein response (UPR), which was different from the anti-platelet effect. CONCLUSIONS: Our data indicate that the anti-cancer effect of aspirin against CRC may be enhanced by combined administration with dipyridamole. In case further clinical studies confirm our findings, these may be repurposed as adjuvant agents.