Temporal variations in absorption and translocation of heavy metal(loid)s in pak choi (Brassica rapa L.) under open-field and greenhouse cultivation.

Elucidating the absorption and translocation of heavy metal(loid)s by common vegetables across different growth environments and stages is crucial for conducting accurate environmental risk assessments and for associated control. This study investigated temporal variations in the absorption and translocation capacities of pak choi (Brassica rapa L.) for As, Cd, Cr, Cu, Pb, and Zn in polluted soils during the plant growth cycle under greenhouse and open-field cultivation modes. Results showed high root metal(loid) bioconcentration factors and root-to-shoot translocation factors for Cd (0.25 and 1.44, respectively) and Zn (0.26 and 1.01), but low values for As (0.06 and 0.88) and Pb (0.06 and 0.87). The Cd concentration in the aerial edible parts peaked during the early slow growth period, whereas other heavy metal(loid)s peaked during the later stable maturity period. Root bioconcentration and root-to-shoot translocation factors did not significantly differ between cultivation modes. However, greenhouse cultivation exhibited lower average Cd and Zn concentrations in the edible parts and cumulative uptake amounts of most metal(loid)s than open-field cultivation during the typical harvest period spanning days 60 and 90. Short-term transitioning from open-field to greenhouse cultivation may reduce health risks associated with heavy metal(loid) intake via pak choi consumption. These findings facilitate sustainable agricultural practices and food safety management.

[Spatiotemporal Response of Ecosystem Service Value to Land Use Change in the Lanzhou-Xining Urban Agglomeration over the Past 20 Years].

With rapid urbanization and human activities exacerbating threats to the degradation of various ecosystem services in modern urban agglomerations, the exploration of the state of ecological security at the scale of urban agglomerations is of great significance. This study considered the Lanzhou-Xining Urban Agglomeration as the research area, based on the land use data in 2000, 2005, 2010, 2015, and 2020. At the same time, the landscape ecological risk index was introduced. The land use change characteristics of the Lanzhou-Xining Urban Agglomeration were analyzed by using the land use transfer matrix, the value per unit area equivalent factor method, and the bivariate spatial autocorrelation analysis method to elucidate the impacts of the changes in the ecological risk index induced by the land use transition on the value of ecosystem services. This study analyzed the land use change characteristics of the Lanzhou-Xining Urban Agglomeration and elucidated the impacts of changes in the ecological risk index on the value of ecosystem services caused by land use transformation. The results showed that:① During the period from 2000 to 2020, the land use types of the Lanzhou-Xining Urban Agglomeration were mainly dominated by grassland, cropland, and forest land. The construction land area had expanded significantly mainly from cropland and grassland, and the six land use types had strong cross-transformation. The total area of land use change was 6 646.05 km2. ② In terms of spatial changes, the spatial pattern of ecosystem service value in the Lanzhou-Xining Urban Agglomeration had not undergone obvious transformation. However, the regional variability was significant, generally showing the distribution characteristics of high in the northwest and low in the southeast. ③From the perspective of temporal change, the value of ecosystem services in the Lanzhou-Xining Urban Agglomeration showed an upward trend, with the total flow of value increasing from 186.459 billion yuan to 192.156 billion yuan, with a total value-added of 5.697 billion yuan. ④ There was a rising trend in the overall ecological risk index of the Lanzhou-Xining Urban Agglomeration over the past 20 years. Low ecological risk areas and lower ecological risk areas dominated the ecological risk areas. There was a significant positive correlation between the value of ecosystem services and the ecological risk index. This study aimed to reveal the understanding of the impacts of land-use practices on ecosystem service values and ecological risks, to provide important references for regional ecological risk management and land-use policy formulation, and thus to promote the high-quality development of the ecological environment in the Yellow River Basin.

CsNYC1a Mediates Chlorophyll Degradation and Albino Trait Formation in the Arbor-Type Tea Plant Camellia nanchuanica.

Albino germplasms are prized tea plant mutants with yellow/white leaves. However, understanding of the albino mechanisms in non-Camellia sinensis tea species remains limited. This study elucidated the albino trait formation in Nanchuan Dachashu (C. nanchuanica), an arbor-type tea species, and its association with tea quality. The yellow-leaved albino individual NH1 exhibited abnormal chloroplast ultrastructure and reduced chlorophyll/carotenoid levels compared to green-leaved NL1. Integrating transcriptomics, metabolomics, yeast one-hybrid, and transgenic approaches identified the chlorophyll b reductase gene CsNYC1a as a key regulator, which was significantly up-regulated in NH1, and its overexpression in Arabidopsis recapitulated the albino phenotype. In yeast, histone CsH1.2 binds to the CsNYC1a promoter. These findings suggest that CsH1.2-CsNYC1a-mediated chlorophyll degradation may be a key mechanism underlying albino formation in Nanchuan Dachashu. In addition, as a germplasm with higher polyphenol-to-amino acid ratio than NL1, NH1 offers more possibilities for breeding and application.

Lathyrane and premyrsinane Euphorbia diterpenes against Alzheimer's disease: Bioinspired synthesis, anti-cholinesterase and neuroprotection bioactivity.

The first systematic acylated diversification of naturally scarce premyrsinane diterpenes, together with their biosynthetic precursors lathyrane diterpene were carried out. Two new series of premyrsinane derivates (1a-32a) and lathyrane derivates (1-32) were synthesized from the naturally abundant lathyrane diterpene Euphorbia factor L3 through a bioinspired approach. The cholinesterase inhibitory and neuroprotective activities of these diterpenes were investigated to explore potential anti-Alzheimer's disease (AD) bioactive lead compounds. In general, the lathyrane diterpenes showed the better acetylcholinesterase (AChE) inhibitory activity than that of premyrsinanes. The lathyrane derivative 17 bearing a 3-dimethylaminobenzoyl moiety showed the best AChE inhibition effect with the IC50 value of 7.1 µM. Molecular docking demonstrated that 17 could bond with AChE well (-8 kal/mol). On the other hand, premyrsinanes showed a better neuroprotection profile against H2O2-induced injury in SH-SY5Y cells. Among them, the premyrsinane diterpene 16a had significant neuroprotective effect with the cell viability rate of 113.5 % at 12.5 µM (the model group with 51.2 %). The immunofluorescence, western blot and reactive oxygen species (ROS) analysis were conducted to demonstrate the mechanism of 16a. Furthermore, a preliminary SAR analysis of the two categories of diterpenes was performed to provide the insights for anti-AD drug development.

Group 1 innate lymphoid cell activation via recognition of NKG2D and liver resident macrophage MULT-1: Collaborated roles in triptolide induced hepatic immunotoxicity in mice.

Triptolide (TP) is the major bioactive component of traditional Chinese medicine Tripterygium wilfordii Hook. F., a traditional Chinese medicinal plant categorized within the Tripterygium genus of the Celastraceae family. It is recognized for its therapeutic potential in addressing a multitude of diseases. Nonetheless, TP is known to exhibit multi-organ toxicity, notably hepatotoxicity, which poses a significant concern for the well-being of patients undergoing treatment. The precise mechanisms responsible for TP-induced hepatotoxicity remain unresolved. In our previous investigation, it was determined that TP induces heightened hepatic responsiveness to exogenous lipopolysaccharide (LPS). Additionally, natural killer (NK) cells were identified as a crucial effector responsible for mediating hepatocellular damage in this context. However, associated activating receptors and the underlying mechanisms governing NK cell represented innate lymphoid cell (ILC) activation remained subjects of inquiry and were not yet investigated. Herein, activating receptor Killer cell lectin like receptor K1 (NKG2D) of group 1 ILCs was specifically upregulated in TP- and LPS-induced acute liver failure (ALF), and in vivo blockade of NKG2D significantly reduced group 1 ILC mediated cytotoxicity and mitigated TP- and LPS-induced ALF. NKG2D ligand UL16-binding protein-like transcript 1 (MULT-1) was found upregulated in liver resident macrophages (LRMs) after TP administration, and LRMs did exhibit NK cell activating effect. Furthermore, M1 polarization of LRMs cells was observed, along with an elevation in intracellular tumor necrosis factor (TNF)-α levels. In vivo neutralization of TNF-α significantly alleviated TP- and LPS-induced ALF. In conclusion, the collaborative role of group 1 ILCs and LRMs in mediating hepatotoxicity was confirmed in TP- and LPS-induced ALF. TP-induced MULT-1 expression in LRMs was the crucial mechanism in the activation of group 1 ILCs via MULT-1-NKG2D signal upon LPS stimulation, emphasizing the importance of infection control after TP administration.

Conductive and Eco-friendly Biomaterials-based Hydrogels for Noninvasive Epidermal Sensors: A Review.

As noninvasive wearable electronic devices, epidermal sensors enable continuous, real-time, and remote monitoring of various human physiological parameters. Conductive biomaterials-based hydrogels as sensor matrix materials have good biocompatibility, biodegradability, and efficient stimulus response capabilities and are widely applied in motion monitoring, healthcare, and human-machine interaction. However, biomass hydrogel-based epidermal sensing devices still need excellent mechanical properties, prolonged stability, multifunctionality, and extensive practicality. Therefore, this paper reviews the common biomass hydrogel materials for epidermal sensing (proteins, polysaccharides, polyphenols, etc.) and the various types of noninvasive sensing devices (strain/pressure sensors, temperature sensors, glucose sensors, electrocardiograms, etc.). Moreover, this review focuses on the strategies of scholars to enhance sensor properties, such as strength, conductivity, stability, adhesion, and self-healing ability. This work will guide the preparation and optimization of high-performance biomaterials-based hydrogel epidermal sensors.

Identification of Clinical Heterogeneity and Construction of Prediction Models for Novel Subtypes in Patients with Abdominal Aortic Aneurysm: An Unsupervised Machine Learning Study.

BACKGROUND: Abdominal aortic aneurysm (AAA) is one of the most common diseases in vascular surgery. Endovascular aneurysm repair (EVAR) can effectively treat AAA. It is essential to accurately classify patients with AAA who need EVAR. METHODS: We enrolled 266 patients with AAA who underwent EVAR. Unsupervised machine learning algorithms (UMLAs) were used to cluster subjects according to similar clinical characteristics. To verify UMLA's accuracy, the operative and postoperative results of the 2 clusters were analyzed. Finally, a prediction model was developed using binary logistic regression analysis. RESULTS: UMLAs could correctly classify patients based on their clinical characteristics. Patients in Cluster 1 were older, had a higher BMI, and were more likely than patients in Cluster 2 to develop pneumonia, chronic obstructive pulmonary disease, and cerebrovascular disease. The aneurysm diameter, neck angulation, diameter and angulation of bilateral common iliac arteries, and incidence of iliac artery aneurysm were significantly higher in cluster 1 patients than in cluster 2. Cluster 1 had a longer operative time, a longer length of stay in the intensive care unit and hospital, a higher medical expense, and a higher incidence of reintervention. A nomogram was established based on the BMI, neck angulation, left common iliac artery (LCIA) diameter and angulation, and right common iliac artery (RCIA) diameter and angulation. The nomogram was evaluated using receiver operating characteristic curve analysis, with an area under the curve of 0.933 (95% confidence interval, 0.902-0.963) and a C-index of 0.927. CONCLUSIONS: Our findings demonstrate that UMLAs can be used to rationally classify a heterogeneous cohort of patients with AAA effectively, and the analysis of postoperative variables also verified the accuracy of UMLAs. We established a prediction model for new subtypes of AAA, which can improve the quality of management of patients with AAA.

Spatio-temporal data prediction of multiple air pollutants in multi-cities based on 4D digraph convolutional neural network.

In response to the problem that current multi-city multi-pollutant prediction methods based on one-dimensional undirected graph neural network models cannot accurately reflect the two-dimensional spatial correlations and directedness, this study proposes a four-dimensional directed graph model that can capture the two-dimensional spatial directed information and node correlation information related to multiple factors, as well as extract temporal correlation information at different times. Firstly, A four-dimensional directed GCN model with directed information graph in two-dimensional space was established based on the geographical location of the city. Secondly, Spectral decomposition and tensor operations were then applied to the two-dimensional directed information graph to obtain the graph Fourier coefficients and graph Fourier basis. Thirdly, the graph filter of the four-dimensional directed GCN model was further improved and optimized. Finally, an LSTM network architecture was introduced to construct the four-dimensional directed GCN-LSTM model for synchronous extraction of spatio-temporal information and prediction of atmospheric pollutant concentrations. The study uses the 2020 atmospheric six-parameter data of the Taihu Lake city cluster and applies canonical correlation analysis to confirm the data's temporal, spatial, and multi-factor correlations. Through experimentation, it is verified that the proposed 4D-DGCN-LSTM model achieves a MAE reduction of 1.12%, 4.91%, 5.62%, and 11.67% compared with the 4D-DGCN, GCN-LSTM, GCN, and LSTM models, respectively, indicating the good performance of the 4D-DGCN-LSTM model in predicting multiple types of atmospheric pollutants in various cities.

Lake eutrophication prediction based on improved MIMO-DD-3Q Learning.

As for the problem that the traditional single depth prediction model has poor strain capacity to the prediction results of time series data when predicting lake eutrophication, this study takes the multi-factor water quality data affecting lake eutrophication as the main research object. A deep reinforcement learning model is proposed, which can realize the mutual conversion of water quality data prediction models at different times, select the optimal prediction strategy of lake eutrophication at the current time according to its own continuous learning, and improve the reinforcement learning algorithm. Firstly, the greedy factor, the fixed parameter of Agent learning training in reinforcement learning, is introduced into an arctangent function and the mean value reward factor is defined. On this basis, three Q estimates are introduced, and the weight parameters are obtained by calculating the realistic value of Q, taking the average value and the minimum value to update the final Q table, so as to get an Improved MIMO-DD-3Q Learning model. The preliminary prediction results of lake eutrophication are obtained, and the errors obtained are used as the secondary input to continue updating the Q table to build the final Improved MIMO-DD-3Q Learning model, so as to achieve the final prediction of water eutrophication. In this study, multi-factor water quality data of Yongding River in Beijing were selected from 0:00 on July 26, 2021 to 0:00 on September 5, 2021. Firstly, data smoothing and principal component analysis were carried out to confirm that there was a certain correlation between all factors in the occurrence of lake eutrophication. Then, the Improved MIMO-DD-3Q Learning prediction model was used for experimental verification. The results show that the Improved MIMO-DD-3Q Learning model has a good effect in the field of lake eutrophication prediction.

Long-term survival and risk analysis of thoracic endovascular aortic repair for type B aortic dissection.

To explore the safety and efficacy of thoracic endovascular aortic repair (TEVAR) in the treatment of patients with type B aortic dissection, and to evaluate the risk factors for long-term mortality. Our study retrospectively evaluated 729 patients with type B aortic dissection, who were divided into the thoracic endovascular aortic repair group and the optimal medical treatment group according to their treatment. In-hospital mortality, death within 30 days, and aortic-related mortality were lower in the thoracic endovascular aortic repair group than in the optimal medical treatment group (p < 0.05). The cumulative overall survival rates for the thoracic endovascular aortic repair group at 1 year, 5 years, and 10 years were 92.5%, 84.1%, and 73.5%, respectively. The Cox analysis found that TEVAR was beneficial in reducing mortality and that a vertical length of the dissection exceeding 150 mm was a risk factor for mortality.

[Temporal and Spatial Distributions of O3 Concentration and Potential Source Area Analysis of Hexi Corridor Based on Satellite and Ground Monitoring].

Based on 2005-2020 O3 column concentration data of OMI remote sensing satellite, combined with air pollutant data from 10 nationally controlled environmental automatic monitoring stations in the Hexi Corridor and global data assimilation system meteorological data, we used Kriging interpolation, correlation analysis, and backward trajectory (HYSPLIT) models to explore the temporal and spatial distribution characteristics, meteorological factors, transmission paths, and potential sources of O3 in the Hexi Corridor. The results showed the following:① in terms of temporal distribution, O3 column concentration showed an upward trend in 2005-2010 and 2014-2020 and downward trend in 2010-2014; the maximum and minimum values were reached in 2010 and 2014 (332.31 DU and 301.00 DU), respectively, and seasonal changes showed that those in spring and winter were significantly higher than those in summer and autumn. ② In terms of spatial distribution, O3 column concentration showed a latitudinal band distribution characteristic of increasing from southwest to northeast; the high-value areas were primarily distributed in urban areas with low terrain, and the median zone was latitudinally striped with the basic alignment of the Qilian foothills. ③ The analysis of meteorological conditions revealed that temperature, wind speed, and sunshine hours were positively correlated with O3, and relative humidity was negatively correlated with O3. ④ By simulating the airflow transportation trajectory of the receiving point in Wuwei City, it was found that the direction of the O3 conveying path was relatively singular; the dominant airflow in each season was primarily in the west and northwest; and the proportions were 71.62%, 66.85%, 61.22%, and 77.78%, respectively. There were certain seasonal differences in the source areas of O3 potential contribution:the high-value areas of O3 potential sources in spring, summer, and autumn were distributed in Baiyin City and Lanzhou City, which were southeast wind sources, and the high-value areas in winter were distributed between the Badain Jaran Desert and the Tengger Desert, which was the north wind source.

Factors Affecting False Lumen Thrombosis In Type B Aortic Dissection. / Fatores que Afetam a Trombose da Falsa Luz na Dissecção Aórtica Tipo B.

BACKGROUND: Complete thrombosis of the false lumen facilitates remodeling of type B aortic dissection (TBAD). Morphological characteristics affect thrombosis in the false lumen. OBJECTIVES: Discuss the factors present before admission that influence false lumen thrombosis in patients with TBAD. METHODS: We studied 282 patients diagnosed with TBAD in our hospital between January 2008 and December 2017. We divided the subjects into a thrombotic group and a non-thrombotic group based on whether any thrombus was detectable in the false lumen. We analyzed the differences between the two groups with respect to clinical data, the vertical length of the dissection, and the diameter of the aorta. P values < 0.05 were considered statistically significantly different. RESULTS: Significant differences between the thrombotic group and non-thrombotic group were found with respect to age (53.92 ± 11.40 vs. 50.36 ± 10.71, p = 0.009) and proportion of patients with renal insufficiency (7.83% vs. 16.38%, p = 0.026). In zones 3-9, the true lumen diameter of the thrombotic group was significantly larger than in the non-thrombotic group (p < 0.05). Binary logistic regression analysis showed that true lumen diameter in zone 5 and renal insufficiency were independent predictors of false lumen thrombosis. CONCLUSIONS: Age and renal function were associated with thrombosis in the false lumen. Potentially, the difference between the diameter of the true lumen diameter and that of the false lumen may influence the thrombosis of the false lumen.

FUNDAMENTO: A trombose completa da falsa luz facilita a remodelação da dissecção aórtica tipo B (DATB). As características morfológicas afetam a trombose na falsa luz. OBJETIVOS: Discutir os fatores pré-admissão presentes, que influenciam a trombose da falsa luz em pacientes com DATB. METODOLOGIA: Ao todo, 282 pacientes diagnosticados com DATB em nosso hospital foram estudados, no período entre janeiro de 2008 e dezembro de 2017. Os indivíduos foram divididos em um grupo trombótico e um grupo não trombótico, com base na detecção de qualquer trombo na falsa luz. Analisamos as diferenças entre os dois grupos com relação aos dados clínicos, o comprimento vertical da dissecção e o diâmetro da aorta. Valores de p < 0,05 foram considerados estatisticamente diferentes de modo significativo. RESULTADOS: Diferenças significativas entre o grupo trombótico e o grupo não trombótico foram encontradas com relação à idade (53,92 ± 11,40 vs. 50,36 ± 10,71, p = 0,009) e proporção de pacientes com insuficiência renal (7,83% vs. 16,38%, p = 0,026). Nas zonas 3­9, o diâmetro da luz verdadeira do grupo trombótico foi significativamente maior do que no grupo não trombótico (p < 0,05). A análise de regressão logística binária mostrou que o diâmetro da luz verdadeira na zona 5 e a insuficiência renal foram preditores independentes de trombose da falsa luz. CONCLUSÕES: A idade e a função renal estiveram associadas à trombose na falsa luz. Potencialmente, a diferença entre o diâmetro da luz verdadeira e o da falsa luz pode influenciar na trombose da falsa luz.

Factors affecting distal false lumen enlargement after thoracic endovascular aortic repair for type B aortic dissection.

Objective: To investigate the factors influencing distal false lumen enlargement after thoracic endovascular aortic repair (TEVAR) for type B aortic dissection. Materials and methods: Data were collected on patients with type B aortic dissection who underwent TEVAR from January 2008 to August 2022. Patients were divided into a distal aortic segmental enlargement (DSAE) group and a non-DSAE group based on whether the distal false lumen was dilated more than 5 mm on computed tomographic angiography (CTA) images. To analyze the independent influences on distal false lumen dilatation after TEVAR, the variables with a P value < 0.05 during univariate analysis were included in the binary logistic regression analysis model. Results: A total of 335 patients were included in this study, with 85 in the DSAE group and 250 in the non-DSAE group. The mean age was 52.40 ± 11.34 years, 289 (86.27%) were male patients, and the median follow-up time was 6.41 (11.99-29.99) months. There were significant differences in Marfan syndrome, chronic obstructive pulmonary disease (COPD), and follow-up time between the two groups. In terms of morphology, there were statistically significant differences in the number of tears, the size of the primary tear, and the length of dissection between the two groups. Binary logistic regression analysis indicated that Marfan syndrome, COPD, and the primary tear size were associated with distal false lumen dilatation. Conclusions: Marfan syndrome, COPD, and the primary tear size influence distal aortic segmental enlargement after TEVAR in type B aortic dissection patients.

CsXDH1 gene promotes caffeine catabolism induced by continuous strong light in tea plant.

Tea plant (Camellia sinensis) is an important cash crop with extensive adaptability in the world. However, complex environmental factors force a large variation of tea quality-related components. Caffeine is essential for the formation of bitter and fresh flavors in tea, and is the main compound of tea that improves human alertness. Continuous strong light stimulation was observed to cause caffeine reduction in tea leaves, but the mechanism is not clear. In this study, the response of tea plant to light intensity was analysed mainly by multi-omics association, antisense oligodeoxynucleotide (asODN) silencing technique, and in vitro enzyme activity assay. The results revealed multiple strategies for light intensity adaptation in tea plant, among which the regulation of chloroplasts, photosynthesis, porphyrin metabolism, and resistance to oxidative stress were prominent. Caffeine catabolism was enhanced in continuous strong light, which may be a light-adapted strategy due to strict regulation by xanthine dehydrogenase (XDH). asODN silencing and enzymatic activity assays confirmed that CsXDH1 is a protein induced by light intensity to catalyze the substrate xanthine. CsXDH1 asODN silencing resulted in significant up-regulation of both caffeine and theobromine in in vitro enzyme activity assay, but not in vivo. CsXDH1 may act as a coordinator in light intensity adaptation, thus disrupting this balance of caffeine catabolism.

Light Intensity Regulates Low-Temperature Adaptability of Tea Plant through ROS Stress and Developmental Programs.

Low-temperature stress limits global tea planting areas and production efficiency. Light is another essential ecological factor that acts in conjunction with temperature in the plant life cycle. However, it is unclear whether the differential light environment affects the low temperature adaptability of tea plant (Camellia sect. Thea). In this study, tea plant materials in three groups of light intensity treatments showed differentiated characteristics for low-temperature adaptability. Strong light (ST, 240 µmol·m-2·s-1) caused the degradation of chlorophyll and a decrease in peroxidase (POD), superoxide dismutase (SOD), catalase (CAT), ascorbate peroxidase (APX), and polyphenol oxidase (PPO) activities, as well as an increase in soluble sugar, soluble protein, malondialdehyde (MDA), and relative conductivity in tea leaves. In contrast, antioxidant enzyme activities, chlorophyll content, and relative conductivity were highest in weak light (WT, 15 µmol·m-2·s-1). Damage was observed in both ST and WT materials relative to moderate light intensity (MT, 160 µmol·m-2·s-1) in a frost resistance test. Chlorophyll degradation in strong light was a behavior that prevented photodamage, and the maximum photosynthetic quantum yield of PS II (Fv/Fm) decreased with increasing light intensity. This suggests that the browning that occurs on the leaf surface of ST materials through frost may have been stressed by the previous increase in reactive oxygen species (ROS). Frost intolerance of WT materials is mainly related to delayed tissue development and tenderness holding. Interestingly, transcriptome sequencing revealed that stronger light favors starch biosynthesis, while cellulose biosynthesis is enhanced in weaker light. It showed that light intensity mediated the form of carbon fixation in tea plant, and this was associated with low-temperature adaptability.

Triptolide leads to hepatic intolerance to exogenous lipopolysaccharide and natural-killer-cell mediated hepatocellular damage by inhibiting MHC class I molecules.

BACKGROUND: Tripterygium wilfordii Hook. F (TWHF) is used as a traditional Chinese medicine, called thunder god vine, based on its efficacy for treating inflammatory diseases. However, its hepatotoxicity has limited its clinical application. Triptolide (TP) is the major active and toxic component of TWHF. Previous studies reported that a toxic pretreatment dose of TP leads to hepatic intolerance to exogenous lipopolysaccharide (LPS) stimulation, and to acute liver failure, in mice, but the immune mechanisms of TP-sensitised hepatocytes and the TP-induced excessive immune response to LPS stimulation are unknown. PURPOSE: To identify both the key immune cell population and mechanism involved in TP-induced hepatic intolerance of exogenous LPS. STUDY DESIGN: In vitro and in vivo experiments were conducted to investigate the inhibitory signal of natural killer (NK) cells maintained in hepatocytes, and the ability of TP to impair that signal. METHODS: Flow cytometry was performed to determine NK cell activity and hepatocyte histocompatibility complex (MHC) class I molecules expression; the severity of liver injury was determined based on blood chemistry values, and drug- or cell-mediated hepatocellular damage, by measuring lactate dehydrogenase (LDH) release. In vivo H-2Kb transduction was carried out using an adeno-associated viral vector. RESULTS: Interferon (IFN)-γ-mediated necroptosis occurred in C57BL/6N mice treated with 500 µg TP/kg and 0.1 mg LPS/kg to induce fulminant hepatitis. Primary hepatocytes pretreated with TP were more prone to necroptosis when exposed to recombinant murine IFN-γ. In mice administered TP and LPS, the intracellular IFN-γ levels of NK cells increased significantly. Subsequent study confirmed that NK cells were activated and resulted in potent hepatocellular toxicity. In vivo and in vitro TP administration significantly inhibited MHC class I molecules in murine hepatocytes. An in vitro analysis demonstrated the susceptibility of TP-pretreated hepatocytes to NK-cell-mediated cytotoxicity, an effect that was significantly attenuated by the induction of hepatocyte MHC-I molecules by IFN-α. In vivo induction or overexpression of hepatocyte MHC-I also protected mouse liver against TP and LPS-induced injury. CONCLUSION: The TP-induced inhibition of hepatocyte MHC-I molecules expression leads to hepatic intolerance to exogenous LPS and NK-cell mediated cytotoxicity against self-hepatocytes. These findings shed light on the toxicity of traditional Chinese medicines administered for their immunomodulatory effects.

Fatores que Afetam a Trombose da Falsa Luz na Dissecção Aórtica Tipo B / Factors Affecting False Lumen Thrombosis In Type B Aortic Dissection

Resumo Fundamento A trombose completa da falsa luz facilita a remodelação da dissecção aórtica tipo B (DATB). As características morfológicas afetam a trombose na falsa luz. Objetivos Discutir os fatores pré-admissão presentes, que influenciam a trombose da falsa luz em pacientes com DATB. Metodologia Ao todo, 282 pacientes diagnosticados com DATB em nosso hospital foram estudados, no período entre janeiro de 2008 e dezembro de 2017. Os indivíduos foram divididos em um grupo trombótico e um grupo não trombótico, com base na detecção de qualquer trombo na falsa luz. Analisamos as diferenças entre os dois grupos com relação aos dados clínicos, o comprimento vertical da dissecção e o diâmetro da aorta. Valores de p < 0,05 foram considerados estatisticamente diferentes de modo significativo. Resultados Diferenças significativas entre o grupo trombótico e o grupo não trombótico foram encontradas com relação à idade (53,92 ± 11,40 vs. 50,36 ± 10,71, p = 0,009) e proporção de pacientes com insuficiência renal (7,83% vs. 16,38%, p = 0,026). Nas zonas 3-9, o diâmetro da luz verdadeira do grupo trombótico foi significativamente maior do que no grupo não trombótico (p < 0,05). A análise de regressão logística binária mostrou que o diâmetro da luz verdadeira na zona 5 e a insuficiência renal foram preditores independentes de trombose da falsa luz. Conclusões A idade e a função renal estiveram associadas à trombose na falsa luz. Potencialmente, a diferença entre o diâmetro da luz verdadeira e o da falsa luz pode influenciar na trombose da falsa luz.

Abstract Background Complete thrombosis of the false lumen facilitates remodeling of type B aortic dissection (TBAD). Morphological characteristics affect thrombosis in the false lumen. Objectives Discuss the factors present before admission that influence false lumen thrombosis in patients with TBAD. Methods We studied 282 patients diagnosed with TBAD in our hospital between January 2008 and December 2017. We divided the subjects into a thrombotic group and a non-thrombotic group based on whether any thrombus was detectable in the false lumen. We analyzed the differences between the two groups with respect to clinical data, the vertical length of the dissection, and the diameter of the aorta. P values < 0.05 were considered statistically significantly different. Results Significant differences between the thrombotic group and non-thrombotic group were found with respect to age (53.92 ± 11.40 vs. 50.36 ± 10.71, p = 0.009) and proportion of patients with renal insufficiency (7.83% vs. 16.38%, p = 0.026). In zones 3-9, the true lumen diameter of the thrombotic group was significantly larger than in the non-thrombotic group (p < 0.05). Binary logistic regression analysis showed that true lumen diameter in zone 5 and renal insufficiency were independent predictors of false lumen thrombosis. Conclusions Age and renal function were associated with thrombosis in the false lumen. Potentially, the difference between the diameter of the true lumen diameter and that of the false lumen may influence the thrombosis of the false lumen.

Triptolide increases resistance to bile duct ligation-induced liver injury and fibrosis in mice by inhibiting RELB.

Cholestasis is a common, chronic liver disease that may cause fibrosis and cirrhosis. Tripterygium wilfordii Hook.f (TWHF) is a species in the Euonymus family that is commonly used as a source of medicine and food in Eastern and Southern China. Triptolide (TP) is an epoxy diterpene lactone of TWHF, as well as the main active ingredient in TWHF. Here, we used a mouse model of common bile duct ligation (BDL) cholestasis, along with cultured human intrahepatic biliary epithelial cells, to explore whether TP can relieve cholestasis. Compared with the control treatment, TP at a dose of 70 or 140 µg/kg reduced the serum levels of the liver enzymes alanine transaminase, aspartate aminotransferase, and alkaline phosphatase in mice; hematoxylin and eosin staining also showed that TP reduced necrosis in tissues. Both in vitro and in vivo analyses revealed that TP inhibited cholangiocyte proliferation by reducing the expression of RelB. Immunohistochemical staining of CK19 and Ki67, as well as measurement of Ck19 mRNA levels in hepatic tissue, revealed that TP inhibited the BDL-induced ductular reaction. Masson 3 and Sirius Red staining for hepatic hydroxyproline showed that TP alleviated BDL-induced hepatic fibrosis. Additionally, TP substantially inhibited BDL-induced hepatic inflammation. In summary, TP inhibited the BDL-induced ductular reaction by reducing the expression of RelB in cholangiocytes, thereby alleviating liver injury, fibrosis, and inflammation.

Obeticholic acid aggravates liver injury by up-regulating the liver expression of osteopontin in obstructive cholestasis.

AIMS: Obeticholic acid (OCA) was approved for the treatment of primary biliary cholangitis (PBC) patients, as it can significantly improve the level of serum alkaline phosphatase. However, OCA-induced liver injury in PBC patients puts them at risk of acute chronic liver failure, thus limiting the clinical application of OCA. Osteopontin (OPN), an extracellular cell matrix molecule, is highly induced in many cholestatic liver diseases. Herein we explored whether liver injury exacerbation by OCA was related to OPN. MAIN METHODS: Bile duct ligation (BDL) mice were treated with OCA (40 mg/kg) to evaluate its effect on liver injury and OPN involvement. Enzyme-linked immunosorbent assay, western blot, immunohistochemistry, and other assays were used to detect OPN levels in serum and liver. Immunohistochemistry, and immunofluorescence, among other assays, were used to evaluate the extent of ductular reaction. The extent of fibrosis was also determined using various assays, such as immunohistochemistry, quantitative real-time PCR (qPCR), and hydroxyproline assays. KEY FINDINGS: OPN was overexpressed in the liver of BDL mice treated with OCA. OCA induced overexpression of OPN exacerbated ductular reaction, fibrosis, and liver inflammation, and reduced hepatocyte proliferation. SIGNIFICANCE: Upon liver injury, OCA upregulates the expression of OPN in the liver and accelerates disease progression. This mechanism helps explain the risk of liver damage associated with OCA.

Th17/Treg imbalance mediates hepatic intolerance to exogenous lipopolysaccharide and exacerbates liver injury in triptolide induced excessive immune response.

ETHNOPHARMACOLOGICAL RELEVANCE: Triptolide (TP) is a major active ingredient and toxic component of Tripterygium wilfordii Hook F (TWHF), which exhibits multiple activities and remarkable hepatotoxicity, the latter of which limits its clinical application due to the risk of liver injury. Previous research has revealed the hepatotoxicity of TP resulting in liver hypersensitivity upon lipopolysaccharide (LPS) stimulation. However, existing research has not elucidated the potential immune mechanism such as Th17/Treg imbalance in TP-induced hepatic excessive immune response to exogenous LPS. AIM OF THE STUDY: To investigate the role of Th17/Treg imbalance in TP-induced hepatic excessive immune response to exogenous LPS. MATERIALS AND METHODS: Mice were administered with TP, LPS, neutralization antibody and small molecule inhibitor respectively. Serum transaminase level was measured to determine the severity of liver injury. Frequencies of liver Th17 and Treg cells were analyzed by flow cytometry. Serum cytokine levels were performed by ELSIA, and mRNA levels of liver cytokine were performed by qPCR. The status of neutrophil infiltration was performed by myeloperoxidase (MPO) IHC measurement. Morphological observation of liver was performed by hematoxylin and eosin (H&E) staining. RESULTS: Mice given a single intragastric dose of TP (500 µg/kg) developed lethal fulminant hepatitis following intraperitoneal injection of LPS (0.1 mg/kg), characterized by low survival rate, severe liver injury, high levels of inflammation and neutrophil infiltration. Hepatic Th17/Treg imbalance emerged together with liver injury in these mice. Neutralization of IL-17A attenuated the liver injury and ameliorated the neutrophil infiltration. The TP-induced alteration of hepatic Th17/Treg balance was closely related to the outcome of immune-mediated acute liver injury triggered by LPS. Pretreatment with the STAT3 inhibitor AG490 effectively restored Th17/Treg balance, significantly reducing the production of IL-17A and finally attenuating the degree of liver injury. CONCLUSION: Hepatic Th17/Treg imbalance not only exacerbates TP- and LPS-induced liver injury, but also serves as an indispensable part in the mechanisms of TP-induced hepatic intolerance to exogenous endotoxin.