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The goal of this contribution is to construct the inter-satellite links (ISLs) between Global Navigation Satellite System (GNSS) and Low Earth Orbit (LEO) satellite to recover the Earth's gravity field based on the concept of Geodesy and Time Reference in Space (GETRIS). Taking the constellation of the Beidou Navigation Satellite System (BDS) as an example, several types of high-low satellite-to-satellite tracking (H-L SST) modes combining BDS and GETRIS are used to research the tracking mode of high orbit satellites and the distribution of LEO satellite constellations to explore the optimal mode for gravity field recovery. The effects of multiple H-L SST modes on the accuracy of gravity field recovery are studied. In addition, the contribution of each error source is also analyzed. Finally, this study varies LEO satellite constellations to show reduced errors in the temporal gravity field solutions for the improved ISLs. The results showed that the Inclined GeoSynchronous Orbit (IGSO) satellite greatly improved the Geosynchronous orbit (GEO) satellite tracking LEO satellite mode in the high latitude regions. Compared with the Medium Earth Orbit (MEO) satellite tracking LEO satellite, the error of gravity field recovered by combining with GEO, IGSO and MEO can be reduced by 16 %. The largest error is the non-tidal signal, followed by the ocean tidal model difference, and the smallest is the instrument error. For a single LEO satellite, the combination model is more sensitive to the satellite orbital altitude, the cumulative error was decreased from 5.08 mm (550 km) to 0.33 mm (250 km). For LEO constellations, adding inclined orbit satellites can improve the accuracy of the solution to some extent. But the optimal solution can be obtained by the constellation composed of polar orbit satellites with different Right Ascension of Ascending Node (RAAN), the cumulative errors are 0.27 mm (two satellites), 0.19 mm (three satellites), and 0.19 mm (four satellites). [ABSTRACT FROM AUTHOR]

Groundwater potential maps are crucial tools for effectively managing water resources, particularly in agriculturally focused countries such as Vietnam. However, creating these maps is a challenging task that requires reliable data and methods. In this study, we integrated the Split‐Point Sampling and Node Attribute Subsampling Classifier (SPAARC) with the Bagging (B), MultiBoostAB (MBAB), and Random Subspace (RSS) ensemble learning techniques and developed three ensemble models: B‐SPAARC, MBAB‐SPAARC, and RSS‐SPAARC. We selected 13 geoenvironmental factors based on their availability, relevance, and association with groundwater potential in the Sesan River basin of Vietnam. We assessed the models' performance using various metrics such as area under the curve (AUC), accuracy, sensitivity, specificity, and RMSE. The findings indicated that the ensemble models performed better than the single SPAARC model in mapping groundwater potential. The MBAB‐SPAARC model demonstrated the highest accuracy with an AUC value of 0.891, followed by B‐SPAARC (AUC = 0.844), RSS‐SPAARC (AUC = 0.871), and the single SPAARC (AUC = 0.853) models. The results also highlighted that elevation, rainfall, land use/cover, and altitude were the most significant factors for mapping groundwater potential in the Sesan River basin. The innovative ensemble models and reliable potential maps developed in this study assist water resource managers in planning water usage based on the benefits and costs for various users and in devising sustainable strategies for using, protecting, and managing groundwater. Key Points: Groundwater potential mapping was carried out at the Central Highlands of VietnamHybrid Machine learning Models based on Naïve Bayes Tree were developed and usedResults showed that the proposal models are potential and accurate tools [ABSTRACT FROM AUTHOR]

The sequential approximate optimization (SAO) method is widely adopted in aircraft optimization design, whose further improvement in efficacy and efficiency has encountered bottlenecks. In this paper, a collaboratively iterative sequential approximate optimization (CISAO) method with field metamodel (FM) accelerating computational fluid dynamics (CFD) is proposed for aerodynamic optimization problems to enhance the coupling between metamodels and CFD high-fidelity models (HFMs). In this method, the field metamodel is used to predict the flow field distributions with respect to the design variables to accelerate the numerical solution of CFD HFMs. Two benchmark aerodynamic optimization cases are performed to validate the proposed method. The time costs for single CFD HFMs in the two test cases are shortened by 37.76% and 12.11%, respectively, and the total time costs of the two test cases are shrunk by 64.11% and 44.47% compared with the conventional SAO method. The optimization results indicate that the proposed method significantly reduces the time costs and improves the optimization efficiency. The proposed method shows a promising prospect in aircraft optimization design. [ABSTRACT FROM AUTHOR]

Weighted average temperature (Tm) plays a crucial role in global navigation satellite system (GNSS) precipitable water vapor (PWV) retrieval. Aiming at the poor applicability of the existing Tm models in Europe, in the article, we used observations from 48 radiosonde stations over Europe from 2014 to 2020 to establish a weighted average temperature model in Europe (ETm) by the nonlinear least squares estimation method. The ETm model takes into account factors such as ground temperature, water vapor pressure, latitude, and their annual variation, semiannual variation and diurnal variation. Taking the Tm obtained from the radiosonde data by the integration method in 2021 as the reference value, the accuracy of the ETm model was evaluated and compared with the commonly used Bevis model, ETmPoly model, and GPT2w model. The results of the 48 modeled stations showed that the mean bias and root mean square (RMS) values of the ETm model were 0.06 and 2.85 K, respectively, which were 21.7%, 11.5%, and 31.8% higher than the Bevis, ETmPoly, and GPT2w-1 (1° × 1° resolution) models, respectively. In addition, the radiosonde data of 12 non-modeling stations over Europe in 2021 were selected to participate in the model accuracy validation. The mean bias and RMS values of the ETm model were –0.07 and 2.87 K, respectively. Compared with the Bevis, ETmPoly, and GPT2w-1 models, the accuracy (in terms of RMS values) increased by 20.5%, 10.6%, and 35.2%, respectively. Finally, to further verify the superiority of the ETm model, the ETm model, and other Tm models were applied to the GNSS PWV calculation. The ETm model had mean RMSPWV and RMSPWV/PWV values of 0.17 mm and 1.03%, respectively, which were less than other Tm models. Therefore, the ETm model has essential applications in GNSS PWV over Europe. [ABSTRACT FROM AUTHOR]

Geodetic networks are important for most engineering projects. Generally, a geodetic network is designed according to precision, reliability, and cost criteria. This paper provides a new criterion considering the distances between the Net Points (NPs) and the Project Border (PB) in terms of Neighboring (N). Optimization based on the N criterion seeks to relocate the NPs as close as possible to PB, which leads to creating shorter distances between NPs or those distances linking NPs with Target Points (TPs) to be measured inside PB. These short distances can improve the precision of NPs and increase the accuracy of observations and transportation costs between NPs themselves or between NPs and TPs (in real applications). Three normalized N objective functions based on L1, L2, and L∞‒norms were formulated to build the corresponding N optimization models, NL1; NL2; and NL∞ and to determine the best solution. Each model is subjected to safety, precision, reliability, and cost constraints. The feasibility of the N criterion is demonstrated by a simulated example. The results showed the ability of NL∞ to determine the safest positions for the NPs near PB. These new positions led to improving the precision of the network and preserving the initial reliability and observations cost, due to contradiction problems. Also, N results created by all N models demonstrate their theoretical feasibility in improving the accuracy of the observations and transportation cost between points. It is recommended to use multi-objective optimization models to overcome the contradiction problem and consider the real application to generalize the benefits of N models in designing the networks. [ABSTRACT FROM AUTHOR]

The Qinghai–Tibet Plateau region has significant altitude fluctuations and complex climate changes. However, the current global weighted average temperature (Tm) model does not fully consider the impact of meteorological and elevation factors on it, resulting in existing models being unable to accurately predict the Tm in the region. Therefore, this study constructed a weighted average temperature refinement model (XTm) related to surface temperature, water vapor pressure, geopotential height, annual variation, and semi-annual variation based on measured data from 13 radiosonde stations in the Qinghai–Tibet Plateau region from 2008 to 2017. Using the Tm calculated via the numerical integration method of radiosonde observations in the Qinghai–Tibet Plateau region from 2018 to 2019 as a reference value, the quality of the XTm model was tested and compared with the Bevis model and GPT2w (global pressure and temperature 2 wet) model. The results show that for 13 modeling stations, the bias and root-mean-square (RMS) values of the XTm model were −0.02 K and 2.83 K, respectively; compared with the Bevis, GPT2-1, and GPT2w-5 models, the quality of XTm was increased by 47%, 38%, and 47%, respectively. For the four non-modeling stations, the average bias and RMS values of the XTm model were 0.58 K and 2.78 K, respectively; compared with the other three Tm models, the RMS values and the mean bias were both minimal. In addition, the XTm model was also used to calculate the global navigation satellite system (GNSS) precipitable water vapor (PWV), and its average values for the theoretical RMSPWV and RMSPWV/PWV generated by water vapor calculation were 0.11 mm and 1.03%, respectively. Therefore, in the Qinghai–Tibet Plateau region, the XTm model could predict more accurate Tm values, which, in turn, is important for water vapor monitoring. [ABSTRACT FROM AUTHOR]

• A data-mechanism-driven method for assessing the peak shaving potential of VPP users. • The multidimensional uncertainty of the peak shaving capacity is considered using LSTM and MDN. • Risk preference of decision-makers is considered using chance constraint theory and relevant chance constraint theory. There is a consensus regarding the need to realize the transformation of renewable energy by enhancing demand-side regulating ability. This paper proposes a peak shaving potential assessment model based on the price elasticity mechanism and consumer psychology, focusing on the adjustable user load in virtual power plants. The values of deterministic parameters and the distribution of the uncertain parameter of the model are obtained through the long short-term memory network (LSTM) and mixture density network (MDN). Then, the refined distribution of peak shaving potential considering external conditions, incentive inputs, and spatial and temporal scales is obtained. Based on the evaluation results, a peak shaving decision-making model for virtual power plants is constructed using a scenario scheme. Differentiated schemes for traditional, risk-averse, and risk-seeking virtual power plant decision-makers are considered. Case studies using the data of a virtual power plant pilot area show that the proposed model can better characterize the features of virtual power plant users, and a refined control strategy with better economic benefits can be obtained. [ABSTRACT FROM AUTHOR]

Using total electron content (TEC) data over one and a half solar cycles (1999–2015) provided by the Center for Orbit Determination in Europe (CODE), this paper proposes a new empirical TEC model for northeast China (40–50N, 120–130E). The model, called TECM-NEC, involves the multiplication of four separable components, including diurnal variation, seasonal variation, geomagnetic field dependency, and solar dependency. Diurnal variation is composed of three parts: the typical daily variation of TEC; corrections of Mid-latitude Summer Nighttime Anomaly (MSNA) that depend on geographic location, season, and local time; and corrections of day-to-night ratio under different seasons and solar activities. Four sub-harmonics of the year with annual, semiannual, four-, and three-month periods are used to describe seasonal variations. For geomagnetic variation, geomagnetic latitude is based on the latest International Geomagnetic Reference Field (IGRF12) model. Compared with similar empirical models, the solar proxy index F10.7P = (F10.7 + F10.7A)/2, where F10.7A is the 81-day running mean of daily F10.7, is chosen as having linear relationship with TEC for the model. This model has 43 coefficients, which are determined by nonlinear least squares fitting (NLSF) technique. The TECM-NEC model fits with the TEC/CODE input data with a bias of 0.03TECU and a RMS deviation of 2.76TECU. The proposed TECM-NEC model can reproduce the MSNA and nighttime TEC enhancements phenomenon over northeast China. [ABSTRACT FROM AUTHOR]

The height of the peak electron density (hmF2) and the critical frequency of the F2 layer (foF2) are very important in the research of ionospheric electrodynamics and high frequency (HF) wireless communication. In the article, we validated the hmF2/foF2 model values of the latest version of the International Reference Ionosphere (IRI-2016) with observations from three ionosonde stations which belong to low, middle, and high latitudes (i.e., Sanya, Beijing and Mohe) over China during a high solar activity year (2014, F10.7 = 145.9 sfu) and a low solar activity year (2016, F10.7 = 88.7 sfu). Among them, foF2 model values can be obtained through the International Radio Consulting Committee (CCIR) model or the International Union of Radio Science (URSI) model, both of which have the "F-peak storm model" on or 'off' options; hmF2 model values can be obtained through Bilitza-Sheikh-Eyfrig (BSE-1979), Altadill-Magdaleno-Torta-Blanch (AMTB-2013), or SHUbin (SHU-2015) model. The IRI-2016 hmF2/foF2 model values were evaluated by root mean square (RMS) values and mean absolute relative error (MARE). The results show that for the foF2 parameter, the performance of IRI-2016 can be improved by choosing "F-peak storm model" on option in geomagnetic-disturbed days. Whether in high or low solar activity years, for foF2, the IRI-2016 options of CCIR have better prediction ability than IRI-2016 options of URSI in low and high latitudes over China, and the IRI-2016 options of URSI have better prediction ability than IRI-2016 options of URSI in middle latitudes. For hmF2, the IRI-2016 option of SHU-2015 has better prediction ability than the IRI-2016 options of AMTB-2013 and BSE-1949 in high latitudes over China, the IRI-2016 options of SHU-2015 and BSE-1979 have better prediction ability than IRI-2016 options of AMTB-2013 in mid and low latitudes over China. [ABSTRACT FROM AUTHOR]

Viral DNA and RNA polymerases are two kinds of very important enzymes that synthesize the genetic materials of the virus itself, and they have become extremely favorable targets for the development of antiviral drugs because of their relatively conserved characteristics. There are many similarities in the structure and function of different viral polymerases, so inhibitors designed for a certain viral polymerase have acted as effective universal inhibitors on other types of viruses. The present review describes the development of classical antiviral drugs targeting polymerases, summarizes a variety of viral polymerase inhibitors from the perspective of chemically synthesized drugs and natural product drugs, describes novel approaches, and proposes promising development strategies for antiviral drugs. [ABSTRACT FROM AUTHOR]

Stromal cell-derived factor (SDF-1) is a CXC chemokine that selectively activates the CXCR4 chemokine receptor. Fibronectin is an intracellular matrix component that binds integrin and mediates cell-matrix adhesion. Activation of the integrin receptor can occur in two ways: by ligand binding (outside-in signaling), and in response to intracellular events (inside-out signaling). In the current study we showed that SDF-1α inhibited adhesion of T lymphocyte Jurkat cells resulting from binding high concentrations of fibronectin as well as that of THP-1 monocytes. The effect of SDF-1α on fibronectin-mediated adhesion was partly reversed by the CXCR4 receptor antagonist T140. Our results suggest that an SDF-1/ CXCR4 signal pathway modulates fibronectin-mediated lymphocytes adhesion. [ABSTRACT FROM AUTHOR]

The Gravity Recovery and Climate Experiment (GRACE) satellite provides time-varying gravity field models that can detect total water storage change (TWSC) from April 2002 to June 2017, and its second-generation satellite, GRACE Follow-On (GRACE-FO), provides models from June 2018, so there is a one year gap. Swarm satellites are equipped with Global Positioning System (GPS) receivers, which can be used to recover the Earth's time-varying gravitational field. Swarm's time-varying gravitational field models (from December 2013 to June 2018) were solved by the International Combination Service for Time-variable Gravity Field Solutions (COST-G) and the Astronomical Institute of the Czech Academy of Sciences (ASI). On a timely scale, Swarm has the potential to fill the gap between the two generations of GRACE satellites. In this paper, using 26 global watersheds as the study area, first, we explored the optimal data processing strategy for Swarm and then obtained the Swarm-TWSC of each watershed based on the optimal results. Second, we evaluated Swarm's accuracy in detecting regional water storage variations, analyzed the reasons for its superior and inferior performance in different regions, and systematically explored its potential in detecting terrestrial water storage changes in land areas. Finally, we constructed the time series of terrestrial water storage changes from 2002 to 2019 by combining GRACE, Swarm, and GRACE-FO for the Amazon, Volga, and Zambezi Basins. The results show that the optimal data processing strategy of Swarm is different from that of GRACE. The optimal results of Swarm-TWSC were explored in 26 watersheds worldwide; its accuracy is related to the area size, runoff volume, total annual mass change, and instantaneous mass change of the watershed itself, among which the latter is the main factor affecting Swarm-TWSC. Knowledge of the Swarm-TWSC of 26 basins constructed in this paper is important to study long-term water storage changes in basins. [ABSTRACT FROM AUTHOR]

The Gravity Recovery and Climate Experiment (GRACE) mission has measured total water storage change (TWSC) and interpreted drought patterns in an unparalleled way since 2002. Nevertheless, there are few sources that can be used to understand drought patterns prior to the GRACE era. In this study, we extended the gridded GRACE TWSC to 1993 by combining principal component analysis (PCA), least square (LS) fitting, and multiple linear regression (MLR) methods using climate variables as input drivers. We used the extended (climate-driven) TWSC to interpret drought patterns (1993–2019) over the Amazon basin. Results showed that, in the Amazon area with the resolution of 0.5°, GRACE, GRACE follow on, and Swarm had correlation coefficients of 0.95, 0.92, and 0.77 compared with climate-driven TWSCS, respectively. The drought patterns assessed by the climate-driven TWSC were consistent with those interpreted by the Palmer Drought Severity Index and GRACE TWSC. We also found that the 1998 and 2016 drought events in the Amazon, both induced by strong El Niño events, showed similar drought patterns. This study provides a new perspective for interpreting long-term drought patterns prior to the GRACE period. [ABSTRACT FROM AUTHOR]

Groundwater depletion is adversely affecting Beijing's ecology and environment. However, the effective execution of the South-to-North Water Diversion Project's middle route (SNDWP-MR) is anticipated to mitigate Beijing's groundwater depletion. Here, we propose a robust hybrid statistical downscaling method aimed at enhancing the capability of the Gravity Recovery and Climate Experiment (GRACE) to detect the small-scale groundwater storage anomaly (GWSA) in Beijing. We used three deep learning (DL) methods to reconstruct the 0.5° × 0.5° terrestrial water storage anomaly (TWSA) between 2004 and 2021. Moreover, multiple processing strategies were used to downscale the GWSA to 0.25° from 2004 to 2021 by integrating wells and GRACE/GRACE follow-on data from the optimal DL model. Additionally, we analyzed the spatiotemporal evolution trends of GW in Beijing before and after the implementation of the SNDWP-MR. The results show that the long short-term memory model delivers optimal performance in the TWSA reconstruction of Beijing, with the correlation coefficient (CC), Nash–Sutcliffe coefficient (NSE), and root mean square error (RMSE) being 0.98, 0.96, and 10.19 mm, respectively. The GWSA before and after downscaling is basically consistent with wells data, but the CC and RMSE of downscaling the GWSA from 2004 to 2021 are improving by 34% and 31%, respectively. Before the SNDWP-MR (2004–2014), the trend of GWSA in Beijing was − 17.68 ± 4.46 mm/y, with a human contribution of 69.30%. After SNDWP-MR (2015–2021), GWSA gradually increased by 10.00 mm per year, with the SNDWP-MR accounting for 18.30%. This study delivers a technical innovation reference for dynamically monitoring a small-scale GWSA from GRACE/GRACE-FO data. [ABSTRACT FROM AUTHOR]

• Modular co-culture engineering for the production of natural products. • Advantages of modular co-culture engineering in the field of biosynthesis. • Designs and strategies for engineering microbial co-cultures. • Novel approaches are helping to improve properties of modular co-culture system. The microbial production of natural products has been traditionally accomplished in a single organism engineered to accommodate target biosynthetic pathways. Often times, such approaches result in large metabolic burdens as key cofactors, precursor metabolites and energy are channeled to pathways of structurally complex chemicals. Recently, modular co-culture engineering has emerged as a new approach to efficiently conduct heterologous biosynthesis and greatly enhance the production of natural products. This review highlights recent advances that leverage Escherichia coli -based modular co-culture engineering for making natural products. Potential future perspectives for studies in this promising field are addressed as well. [ABSTRACT FROM AUTHOR]

Septic shock is defined as a subset of sepsis, which is associated with a considerably high mortality risk. The caspase-11 non-canonical inflammasome is sensed and activated by intracellular lipopolysaccharide (LPS) leading to pyroptosis, it plays a critical role in septic shock. However, there are few known drugs that can control caspase-11 non-canonical inflammasome activation. We report here that goitrin, an alkaloid from Radix Isatidis, shows protective effects in LPS-induced septic shock and significant inhibitory effect in caspase-11 non-canonical inflammasome pathway. Male C57BL/6J were injected intraperitoneally with LPS (20 mg/kg) to induce experimental septic shock. The results demonstrated that the survival rates of mice pretreated with goitrin or Toll-like receptor 4 (TLR4) inhibitor TKA-242 increased, and LPS-induced hypothermia and lung damage improved by inhibiting inflammatory response. Elucidating the detailed mechanism, we surprisingly found goitrin is really different from TAK-242, it independent of the TLR4 signal activation, but significantly inhibited the activation of caspase-11 non-canonical inflammasome, including cleaved caspase-11 and N-terminal fragment of gasdermin D (GSDMD-NT). Furthermore, with a nonlethal dose of the TLR3 agonist poly(I:C)-primed and subsequently challenged with LPS to induce caspase-11-mediated lethal septic shock, the efficacy of goitrin had been verified. Those results revealed the effect of goitrin in protective against LPS-induced septic shock via inhibiting caspase-11 non-canonical inflammasome, which provided a new therapeutic strategy for clinical treatment of septic shock. [ABSTRACT FROM AUTHOR]

Gentiana crassicaulis and G. straminea are alpine plants of Gentiana with important medicinal value and complex genetic backgrounds. In this study, the mitochondrial genomes (mtDNAs) of these two species were sequenced. The mtDNAs of G. crassicaulis and G. straminea are 368,808 and 410,086 bp long, respectively, 52 and 49 unique genes are annotated in the two species, and the gene arrangement varies widely. Compared to G. crassicaulis, G. straminea loses three effective genes, namely atp6, trnG-GCC and trnV-GAC. As a pseudogene, the atp6 gene of G. straminea is incomplete, which is rare in higher plants. We detected 1696 and 1858 pairs of long repeats and 213 SSRs and 250 SSs in the mtDNAs of G. crassicaulis and G. straminea, respectively. There are 392 SNPs and 18 InDels between the two genomes, and syntenic sequence and structural variation analysis show low collinearity between the two genomes. Chloroplast DNA transferring to mtDNA is observed in both species, and 46,511 and 55,043 bp transferred segments containing three tRNA genes are identified, respectively. Comparative analysis of mtDNAs of G. crassicaulis, G. straminea and four species of Gentianales determined 18 core genes, and there is no specific gene in G. crassicaulis and G. straminea. The phylogenetic tree based on mtDNAs places Gentianaceae in a branch of Gentianales. This study is the first to analyze the mtDNAs of Gentianaceae, which could provide information for analysis of the structure of mtDNAs of higher plants and phylogenetic research of Gentianaceae and Gentianales. [ABSTRACT FROM AUTHOR]

Background: Long noncoding RNAs (lncRNAs) are emerging as critical regulators of gene expression and play fundamental roles in various types of cancer. Current developments in transcriptome analyses unveiled the existence of lncRNAs; however, their functional characterization remains a challenge. Methods: A bioinformatics screen was performed by integration of multiple omics data in hepatocellular carcinoma (HCC) prioritizing a novel oncogenic lncRNA, LINC01132. Expression of LINC01132 in HCC and control tissues was validated by qRT-PCR. Cell viability and migration activity was examined by MTT and transwell assays. Finally, our results were confirmed in vivo mouse model and ex vivo patient derived tumor xenograft experiments to determine the mechanism of action and explore LINC01132-targeted immunotherapy. Results: Systematic investigation of lncRNAs genome-wide expression patterns revealed LINC01132 as an oncogene in HCC. LINC01132 is significantly overexpressed in tumor and associated with poor overall survival of HCC patients, which is mainly driven by copy number amplification. Functionally, LINC01132 overexpression promoted cell growth, proliferation, invasion and metastasis in vitro and in vivo. Mechanistically, LINC01132 acts as an oncogenic driver by physically interacting with NRF and enhancing the expression of DPP4. Notably, LINC01132 silencing triggers CD8+ T cells infiltration, and LINC01132 knockdown combined with anti-PDL1 treatment improves antitumor immunity, which may prove a new combination therapy in HCC. Conclusions: LINC01132 functions as an oncogenic driver that induces HCC development via the NRF1/DPP4 axis. Silencing LINC01132 may enhance the efficacy of anti-PDL1 immunotherapy in HCC patients. [ABSTRACT FROM AUTHOR]

The extraction of active constituents from natural sources in a green and efficient manner is considered an important field in the pharmaceutical industry. In recent years, deep eutectic solvents (DESs), a new type of green solvent, have attracted increasing attention. Therefore, we aimed to establish a green and high-efficiency extraction method for ginsenosides based on DESs. This study takes Panax ginseng as a model sample. Eighteen different DESs were produced to extract polar ginsenosides. Ultrasound-assisted extraction (UAE) was applied for simplicity and efficiency. A binary DES synthesized using choline chloride and urea at a proportion of 1:2 prepared by a heating stirring method is proven to be more effective than other solvents, such as the widely used 70% ethanol for the extraction of ginsenosides. Three variables that might affect the extraction, including the DES content in the extraction solvent, liquid/solid ratio, and ultrasound extraction time, were evaluated for optimization. The optimum extraction conditions for ginsenosides were determined as follows: DES water content of 20 wt%, liquid/solid ratio of 15 mL g−1, and an ultrasonic extraction time of 15 min. The extraction yield for the optimized method is found to be 31% higher than that for 70% ethanol, which achieves efficient extraction. This study shows that DESs are available to extract ginsenosides for use in traditional Chinese medicine. The discovery also contributes to further research into the green extraction of ginsenosides. [ABSTRACT FROM AUTHOR]

The current severe situation of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has not been reversed and posed great threats to global health. Therefore, there is an urgent need to find out effective antiviral drugs. The 3-chymotrypsin-like protease (3CLpro) in SARS-CoV-2 serve as a promising anti-virus target due to its essential role in the regulation of virus reproduction. Here, we report an improved integrated approach to identify effective 3CLpro inhibitors from effective Chinese herbal formulas. With this approach, we identified the 5 natural products (NPs) including narcissoside, kaempferol-3-O-gentiobioside, rutin, vicenin-2 and isoschaftoside as potential anti-SARS-CoV-2 candidates. Subsequent molecular dynamics simulation additionally revealed that these molecules can be tightly bound to 3CLpro and confirmed effectiveness against COVID-19. Moreover, kaempferol-3-o-gentiobioside, vicenin-2 and isoschaftoside were first reported to have SARS-CoV-2 3CLpro inhibitory activity. In summary, this optimized integrated strategy for drug screening can be utilized in the discovery of antiviral drugs to achieve rapid acquisition of drugs with specific effects on antiviral targets. [ABSTRACT FROM AUTHOR]

Abstract: In this study, we investigated the protective effects of S-adenosyl-l-methionine (SAM), which is a precursor of cellular reduced glutathione (GSH), against the hepatotoxicity of pyrrolizidine alkaloid clivorine. MTT assay showed that SAM (5μM) prevented the cytotoxicity of clivorine on human normal liver L-02 cells. DNA fragmentation assay showed that SAM (5μM) improved clivorine-induced L-02 cell apoptosis, and the results of Western blot showed that SAM (5μM) decreased clivorine-induced caspase-3 activation. Cellular GSH analysis showed that when L-02 cells were exposed to different concentrations (0, 3, 10, 30, 50 and 100μM) of clivorine for 48h, cellular GSH was decreased in a concentration-dependent manner, while SAM (5μM) enhanced 50μM clivorine decreased cellular GSH. Further MTT assay showed that 5mM GSH and 5mM N-acetyl-l-cysteine (NAC) both had protective effects against clivorine-induced hepatotoxicity. Our results suggest that SAM has protective effects against the hepatotoxicity of clivorine possibly by enhancing cellular GSH level and increasing cellular defensive ability against clivorine-induced cytotoxicity. [Copyright &y& Elsevier]

The majority of cancer-associated deaths are caused by cancer metastasis, the first step of which is the acquisition of migratory ability by cancer cells. Therefore, the suppression of cancer cell migration represents a potential efficient strategy to inhibit cancer metastasis. Inflammation induces cancer cell migration through the activation of nuclear factor-κB (NF-κB), which is a transcription factor that serves a central role in inflammatory signaling. Recent studies have demonstrated that the phosphorylation of the receptor tyrosine kinase erythropoietin-producing hepatocellular receptor A2 (EphA2) at S897 promotes cancer cell migration. Therefore, a compound with the ability to abolish these two factors may suppress cancer metastasis. In the present study, ginseng saponin ginsenoside Rg5 was found to inhibit the phosphorylation of NF-κB and EphA2. Therefore, this study aimed to elucidate the molecular mechanisms of ginsenoside Rg5 and determine whether it inhibited cancer cell migration. The results demonstrated that ginsenoside Rg5 inhibited the activation of NF-κB by suppressing its upstream kinase transforming growth factor β-activated kinase 1 in TNF-α treated HeLa or A549 cells compared with that in the untreated control group. Furthermore, ginsenoside Rg5 attenuated the expression of EphA2 by lysosomal degradation, which inhibited its phosphorylation. In addition, ginsenoside Rg5 suppressed inflammatory cytokine-induced cancer cell migration. In conclusion, the results of the present study provided a scientific basis for the development of ginsenoside Rg5 as a potential antimetastatic drug. [ABSTRACT FROM AUTHOR]

The Gravity Recovery and Climate Experiment (GRACE) mission has monitored global total water storage anomalies (TWSA) with an unprecedented accuracy since 2002. Yet, many applications require a longer record, that is, extending prior to the GRACE period. Here, we present a new global reconstruction of long‐term (1979–2020) TWSA fields by combining machine learning with time series decomposition and statistical decomposition techniques. We find that the long‐term TWSA reconstructed from GRACE fits well with the GRACE‐FO observation over most grids (0.5° resolution) of the global land and successfully reproduces the strong El Niño signal. Comparisons to Satellite Laser Ranging solutions and to observed global mean sea level change suggest our reconstruction (doi: https://doi.org/10.5061/dryad.z612jm6bt) is more reliable than previously published products. This study provides a viable approach for both reconstructing past TWSA and filling the GRACE data gap at the global scale. Plain Language Summary: Since 2002, temporal changes of vertically integrated water storage have been detected globally with unprecedented accuracy via satellite gravimetry, as first implemented with the Gravity Recovery and Climate Experiment (GRACE) satellites. However, no similar observation system has been in place before 2002, that could have used to measure the total water storage anomalies (TWSA) with an accuracy comparable to GRACE. Several approaches, such as machine learning, have been proposed in previous studies to reconstruct past TWSA based on their empirical relationships with the climatic/hydrological drivers (e.g., precipitation and soil moisture). Different from traditional approaches, we here combine machine learning with statistical decomposition techniques to reconstruct GRACE‐like TWSA (0.5° resolution) for the period 1979–2020 over the global land. We find that the reconstructed TWSA shows strong abnormal signals during El Niño years. In addition, we compare our reconstruction to recent TWSA data obtained using Satellite Laser Ranging analysis to five satellites, that is, Lageos‐1, Lageos‐2, Ajisai, Stella, and Starlette, in the period since 1993, and to the observed global mean sea level change as validations. The comparison suggests that our reconstruction is more accurate than previously published products. We suggest our method provides a viable alternative for reconstructing long‐term TWSA. Key Points: We reconstruct Gravity Recovery and Climate Experiment‐like (GRACE) total water storage anomaly (TWSA) fields over the global land surface for the period 1979–2020TWSA reconstructed from GRACE fit well with GRACE Follow‐On data and correctly reproduce strong El Niño signalsOutside the GRACE period, our reconstruction fits better with satellite laser ranging solutions and global mean sea level than previous reconstruction [ABSTRACT FROM AUTHOR]

Obacunone, a limonoid abundantly found in Citrus fruits, exhibits a variety of bioactivities. To investigate the effects of obacunone on a colorectal cancer (CRC) mouse model, and clarify its potential molecular mechanisms. The male Balb/c mice were induced with azoxymethane and dextran sulfate sodium for 12 weeks. Obacunone (50 mg/kg) was administered via oral gavage three times every week until the end of the experiment. Disease indexes including body weight, spleen weight, bloody diarrhea, colon length, histopathological score, and tumor size were measured. The anti-proliferation activities of obacunone were analyzed by MTT or flow cytometry. The expression of protein and mRNA related to cell proliferation or inflammatory cytokines was determined by Western blot, q-PCR and IHC. Obacunone significantly alleviated bloody diarrhea, colon shortening (7.35 ± 0.2128 vs. 8.275 ± 0.2169 cm), splenomegaly, histological score (9 ± 0.5774 vs. 6 ± 0.5774) and reduced tumor size (4.25 ± 0.6196 vs. 2 ± 0.5669). Meanwhile, the expression of protein and mRNA related to cell proliferation or inflammatory cytokines was remarkably decreased in tumor tissue. Obacunone inhibited the proliferation activities of colorectal cancer cells. Moreover, obacunone induced colorectal cancer cells G1 and G2 phases arrest, and suppressed the expression of cell cycle genes. Obacunone could alleviate CRC via inhibiting inflammatory response and tumor cells proliferation. The results may contribute to the effective utilization of obacunone or its derivatives in the treatment of human CRC. [ABSTRACT FROM AUTHOR]

Background: High fat diet impact transcription of hepatic genes responsible for drug metabolism and pharmacokinetics. Until now, researches just focused on a couple specific genes without a global profile showing. Age-dependent manner was also not noted well. This study aims to investigate the high fat diet effect on transcriptome of drug metabolism and pharmacokinetic system in mouse livers and show the age-dependent evidence. Methods: C57BL/6 male mice were used in this experiment. High fat diet was used to treat mice for 16 and 38 weeks. Serum total cholesterol, low density lipoprotein cholesterol, aspartate transaminase, and alanine transaminaselevels were measured. Meanwhile, Histology, RNA-Seq, RT-PCR analysis and fourteen major hepatic bile acids quantification were performed for the liver tissues. Data was mined at levels of genes, drug metabolism and pharmacokinetic sysem, and genome wide. Results: Treatment with high fat diet for 38 weeks significantly increased levels of serum lipids as well as aspartate transaminase, and alanine transaminase. Meanwhile, lipid accumulation in livers was observed. At week 38 of the experiment, the profile of 612 genes involved in drug metabolism and pharmacokinetics was significantly changed, indicated by a heatmap visulization and a principal component analysis. In total 210 genes were significantly regulated. Cyp3a11, Cyp4a10, and Cyp4a14 were down-regulated by 10–35 folds, while these three genes also were highly expressed in the liver. High fat diet regulated 11% of genome-wide gene while 30% of genes involved in the hepatic drug metabolism and pharmacokinetic system. Genes, including Adh4, Aldh1b1, Cyp3a11, Cyp4a10, Cyp8b1, Fmo2, Gsta3, Nat8f1, Slc22a7, Slco1a4, Sult5a1, and Ugt1a9, were regulated by high fat diet as an aging-dependent manner. Bile acids homeostasis, in which many genes related to metabolism and transportation were enriched, was also changed by high fat diet with an aging-dependet manner. Expression of genes in drug metabolism and disposition system significantly correlated to serum lipid profiles, and frequently correlated with each other. Conclusions: High fat diet changed the global transcription profile of hepatic drug metabolism and pharmacokinetic system with a age-dependent manner. [ABSTRACT FROM AUTHOR]

Progesterone is the representative progestogens in five major classes of steroid hormones and plays important roles in mammalian pregnancy and animal growth and development. Conventional available analytical methods for progesterone involve immunoassay, gas chromatography-mass spectrometry (GC-MS), and high-performance liquid chromatography-mass spectrometry (HPLC-MS), which lack specificity or usually require sophisticated operations and relatively long time. Herein, we developed a novel strategy for rapid analysis of progesterone via direct analysis in real time mass spectrometry (DART-MS) combined with solid-phase extraction (SPE) using an amino functionalized metal-organic frameworks (MOFs). Under optimized conditions, a wide linear range of 0.5–500 ng mL−1 was achieved, with a satisfactory correlation coefficient (R2 = 0.9992). The relative standard deviations (RSDs) were in the range from 2.4 to 8.4%, demonstrating good precision. The applicability was then confirmed by analyzing spiked lake water and synthetic urine samples, and recoveries are between 92.0 and 117.8% in all three spiked levels (5, 25, and 100 ng mL−1). The sensitivity was notably improved compared with solely DART-MS and obtained detection limit decreased by about 50 times. This research provided a rapid, simple, highly sensitive, and efficient approach for analysis of hormones through combination of advantages of ambient mass spectrometry and porous nanomaterials. [ABSTRACT FROM AUTHOR]

The 5α-reductase converts testosterone to dihydrotestosterone (DHT), and excess DHT could cause androgen-related diseases such as androgenetic alopecia and benign prostatic hyperplasia (BPH). To discover new 5α-reductase inhibitors, effective drug screening method with high throughput is thus essential. In this study, fully automated chip-based nanoelectrospray ionization-mass spectrometry (nano-ESI-MS) was innovatively utilized as a screening tool for 5α-reductase inhibitory assay in direct infusion mode, which simplified sample pretreatment and greatly improved experimental efficiency. The preliminary data indicated that curcumin, a natural anti-inflammatory compound, exhibited notably 5α-reductase inhibition activity. Moreover, the obtained results of the chip-based nano-ESI-MS were well consistent with those of HPLC-MS, which suggested that the chip-based nano-ESI-MS could be treated as a rapid and high-throughput drugs screening strategy in pharmaceutical development. [ABSTRACT FROM AUTHOR]

Background: Quality evaluation of multi-species resourced herb medicine (MSRHM) is a main problem for quality control of herb medicine. Current quality evaluation methodology lost consideration of species discrepancy. New quality evaluation strategy for MSRHM is in urgent need. Qinjiao, a representative MSRHM, originated from Gentiana macrophylla Pall., Gentiana straminea Maxim., Gentiana crassicaulis Duthie ex Burk. or Gentiana dahurica Fisch., has been used as an important herb medicine over 2000 years for expelling wind-dampness and relieving impediment pain. However, quality evaluation among species has never been revealed. The current work proposes an integrated quality evaluation strategy for MSRHM of Qinjiao, which may promote innovation of quality control of MSRHM. Methods: In this work, 58 batches of Qinjiao covering 4 species were collected. Genetic comparative analysis based on ITS2 sequence was conducted. Metabolomics analysis based on TOF–MS and NMR spectrum were carried out. Compounds underlying species differences were identified and their discrepancies among species were investigated by ANOVA analysis and multivariate analysis. Results: Four species of Qinjiao can be authenticated by ITS2 sequence comparation. Metabolomics analysis by TOF/MS and NMR revealed chemical discrepancies among species of Qinjiao. Maximum discrepancy was present between Gentiana crassicaulis Duthie ex Burk. and Gentiana dahurica Fisch. Chemical difference among species were tentative explored. For TOF–MS profiling, 28 constituents were tentative identified, 17 of which were further confirmed by standards. For 1H-NMR profiling, signals from 5 compounds were assigned. Contents discrepancies were investigated by ANOVA analysis. It seems that (seco)iridoids like loganic acid, gentiopicroside or swertiamarin were richer in specie of Gentiana crassicaulis Duthie ex Burk., while flavonoid (morroniside) and triterpenoids (roburic aicd, ursolic acid, oleanolic acid, β-sitosterone) were richer in specie of Gentiana dahurica Fisch. The current research demonstrates that metabolite profiling based on both UPLC/Q-TOF MS and 1H-NMR coupled with ITS2 sequence comparation can be a powerful tool for quality investigation of MSRHM of Qinjiao. Conclusions: A comprehensive quality evaluation strategy for MSRHM was proposed by integrating UPLC-Q-TOF–MS, NMR based metabolic analysis and ITS2 sequence genetic comparation. The proposed quality evaluation strategy shall promote innovation of quality control of traditional Chinese medicine. [ABSTRACT FROM AUTHOR]

Endotoxic shock exhibits a considerably high mortality risk. It is defined as a systemic inflammatory response syndrome caused by a microbial infection. Radix Isatidis has anti-inflammatory, antiviral, and antipyretic effects and is used worldwide. This study investigated the antiendotoxin sepsis effects of an aqueous R. Isatidis extract (RIE) and explored the possible pharmacological molecular mechanisms. Male C57BL/6J mice were intravenously injected with 15 mg/kg lipopolysaccharide (LPS) to induce endotoxic shock. The results demonstrated that the survival rate of mice pretreated with RIE increased, and LPS-induced liver and lung damage were reduced by inhibiting inflammation. For elucidating detailed molecular mechanisms, we focused on LPS-induced transcription factors: nuclear factor-κB (NF-κB) and interferon regulatory factor 3 (IRF3). Our results demonstrated that the protective effects of RIE were strongly dependent on IRF3-induced interferon-β, not on NF-κB-induced tumor necrosis factor-α and interleukin-1β. In addition, RIE suppressed the phosphorylation of IRF3, not NF-κB. In conclusion, this study revealed the antiendotoxic properties of RIE on LPS-induced sepsis and provided mechanistic evidence for the beneficial effects of RIE. [ABSTRACT FROM AUTHOR]

[Display omitted] • A novel design of 1D serpentine stretchable conductor with a sheath-core structure. • A novel strategy to achieve thickness-controllable wrapping of the elastic sheath. • This serpentine stretchable conductor has distinctive strain-insensitive behavior. • Many advantages to adapt to various harsh circumstances. Stretchable conductors (SCs) have shown promising potential in the field of stretchable electronic devices for their lightweight, high flexibility, stable performance, and easy integration. However, the conductivity of most reported stretchable conductive composites is sensitive to deformation, and it is still unsatisfactory due to their poor recoverability and low reliability under large strain. In this paper, we have fabricated a serpentine stretchable conductor (SSC) with high conductivity, stretchability, and ultra-stability by spontaneously wrapping elastic waterborne polyurethane (WPU) sheath on the surface of the multi-walled carbon nanotube (MWCNT)/WPU nanocomposite conductive yarn, which was prepared by a simple wet-spinning method. The WPU elastic sheath endows SSC with long-term tensile durability and recoverability. Remarkably, benefiting from the sharing effect of the serpentine structure on the tensile strain energy, SSC shows distinctive strain-insensitive behavior (ΔR/R 0 less than 1.6%) up to 100% strain and ultra-high quality factor (Q = 105) at 80% strain. Furthermore, SSC also has temperature resistance, waterproof ability, and self-healing capability, making it capable of being used in harsh circumstances. The combination of high conductivity, stretchability, and super reliability renders many potential applications for SSC, such as stretchable interconnects and wearable heaters. Such serpentine stretchable device with distinctive strain-insensitive behavior provides a novel design idea for stretchy electronics. [ABSTRACT FROM AUTHOR]

Pyrrolizidine alkaloids (PAs) are naturally occurring hepatotoxins, and herbs containing PAs are of high concern. PAs are normally found in tertiary amines and N -oxide forms (PA N -oxides), yet the latter are less evaluated for their toxicokinetics. As a continuation of our investigation into the safety assessment of PA-containing herbal medicines, the toxicity and toxicokinetic characteristics of senecionine N -oxide (a representative toxic PA N -oxide) were investigated by using the UDP-glucuronosyltransferase 1A4 humanized mouse model (hUGT1A4 mouse model) and compared with those in wild-type mice simultaneously. Results show that the toxicity caused by senecionine N -oxide exposure was evidently decreased in hUGT1A4 mice as approved by pathology and biochemistry assays. In addition, a N -glucuronidation conjugate was exclusively found in hUGT1A4 mice but not in wild-type (WT) mice. In vitro studies proved that senecionine N -oxide initially reduced to the corresponding tertiary amine alkaloid (senecionine) and then underwent N -glucuronidation via human UGT1A4. The variation in toxicokinetic characteristics was also observed between hUGT1A4 mice and WT mice with a notably enhanced clearance of senecionine N -oxide and senecionine, and accordingly less formation of pyrrole–protein adducts in hUGT1A4 mice, which finally led to the detoxification of senecionine N -oxide exposure in hUGT1A4 mice. Our results provided the first in vivo toxicity data and toxicokinetic characteristics of senecionine N -oxide in a humanized animal model and revealed that human UGT1A4 plays an important role in the detoxification of senecionine N -oxide. [Display omitted] • Species difference of organisms in UGT1A4 misleads the safety assessment of senecionine N -oxide. • hUGT1A4 mice are more tolerant to senecionine N -oxide toxication than WT mice. • Senecionine N -oxide is initially reduced to senecionine before the occurrence of UGT1A4-catalyzed N -glucuronidation. • N -glucuronidation is a promising detoxification pathway of senecionine N -oxide. [ABSTRACT FROM AUTHOR]

Background and Purpose: Sleep deprivation compromises learning and memory in both humans and animals, and can be reversed by administration of modafinil, a drug promoting wakefulness. Dysfunctional autophagy increases activation of apoptotic cascades, ultimately leading to increased neuronal death, which can be alleviated by autophagy inhibitors. This study aimed to investigate the alleviative effect and mechanism of modafinil on the excessive autophagy occurring in the hippocampus of mice with deficiency of learning and memory induced by sleep deprivation.Experimental Approach: The Morris water maze was used to assess the effects of modafinil on male C57BL/6Slac mice after 48-hr sleep deprivation. The HT-22 hippocampal neuronal cell line was also used. Nissl staining, transmission electron microscope, immunofluorescence, Western blot, transient transfection, and autophagy inducer were used to study the effect and mechanism of modafinil on hippocampal neurons with excessive autophagy and apoptosis.Key Results: Modafinil improved learning and memory in sleep-deprived mice, associated with the inhibition of excessive autophage and apoptosis and an enhanced activation of the PI3K/Akt/mTOR/P70S6K signalling pathway in hippocampal neurons. These effects of modafinil were abolished by rapamycin. In addition, modafinil suppressed the aberrant autophagy and apoptosis induced by rapamycin and reactivated PI3K/Akt/mTOR/P70S6K signals in HT-22 cells.Conclusions and Implications: These results suggested that modafinil alleviated impaired learning and memory of sleep-deprived mice potentially by suppressing excessive autophagy and apoptosis of hippocampal neurons. This novel mechanism may add to our knowledge of modafinil in the clinical treatment of impaired memory caused by sleep loss. [ABSTRACT FROM AUTHOR]

Abstract Airpotato yam is a traditional Chinese medicine used for treating thyroid disease and cancer in China. Diosbulbin B (DB) is reported to be the main hepatotoxic compound isolated from Airpotato yam. A variety of reports have shown the acute liver injury induced by DB in vivo. However, whether long-term administration of DB will cause liver fibrosis in mice is unknown. This study aims to investigate the liver fibrosis induced by long-term DB treatment in mice. C57BL/6 mice were orally given with DB (25, 50 mg/kg) for 1 or 2 month, respectively. Liver hydroxyproline content, hepatic collagen deposition and immune cells infiltration were increased in mice treated with DB (50 mg/kg) for 2 months. Serum amounts of hyaluronic acid and laminin were increased in mice treated with DB for 1 or 2 months. DB (50 mg/kg) induced hepatic stellate cells (HSCs) activation when mice were treated with DB for 2 months. Liver mRNA expression of Col1a1, Col1a2, Col3a1, fibronectin (Fn1), vimentin (Vim) and fibroblast-specific protein 1 (FSP1) were all increased in DB-treated mice. Hepatic protein expression of Vim, FSP1 and collagen 1 (COL1) were increased in DB-treated mice. Additionally, DB induced nuclear factor κB (NFκB) activation and increased the expression of pro-inflammatory molecules including tumor necrosis factor (TNF)-α, interleukin (IL)-6, intercellular cell adhesion molecule-1 (ICAM-1) and inducible nitric oxide synthase (iNOS) in mice. In conclusion, long-term administration of DB induced liver fibrosis in mice. HSCs activation, epithelial-mesenchymal transition (EMT) and liver inflammation contributed to DB-induced liver fibrosis in mice. Highlights • DB induced hepatic collagen disposition in vivo. • DB induced HSCs activation in vivo. • DB induced hepatic EMT in vivo. • DB induced liver inflammation in vivo. [ABSTRACT FROM AUTHOR]

A practical TLC-direct bioassay method was established for screening and evaluating antioxidant activity. The method was based on series of reactions. Irradiation of linoleic acid with UV 254 nm produced lipid peroxides. Upon heating, the peroxides were converted into malondialdehyde, which combined with thiobarbituric acid to a red pigment with a maximum absorption at 535 nm. Following a TLC separation, substance with anti-lipid peroxidation activity showed white spots/zones against red background on the TLC plate. The proposed method was established by the dot blot test, and validated with respect to selectivity, sensitivity, linearity, precision, and recovery after optimizing key experimental parameters. In an exemplary screening for antioxidant constituents from Perilla fruits, two active zones were discovered and tentatively characterized as salviaflaside and rosmarinic acid by TLC-interface-ESI-MS, respectively. Further verification by HPTLC-bioassay-guided-isolation was carried out and in addition to salviaflaside and rosmarinic acid, also luteolin 5- O -β- d -glucopyranoside and 3′-dehydroxyl-rosmarinic acid-3- O -β-D-glucoside were discovered to show prominent anti-lipid peroxidation activity. [Display omitted] • A practical TLC-bioassay method was established based on anti-lipid peroxidation. • A combined technique TLC-bioassay with TLC-MS was used to quickly identify antioxidants. • Four compounds with anti-lipid peroxidation were discovered and isolated from Perilla fruits. [ABSTRACT FROM AUTHOR]

Gypenosides extracted from Gynostemma pentaphyllum (Thunb.) Makino have significant role in reducing serum lipid level and treating fatty liver diseases, however, without clear mechanism. As gypenosides share the similar core structures with bile acids (the endogenous ligands of nuclear receptor FXR), we hypothesize that gypenosides may improve hypercholesterolemia via FXR-mediated bile acids signaling. The present study was designed to validate the role of gypenosides in reducing levels of serum total cholesterol (TC) and low density lipoprotein cholesterol (LDL-C), as well as in regulating bile acids homeostasis and related gene expression levels. The C57BL/6 male mice were divided into four groups. Mice in groups ND and HFD were fed with normal diet and high fat diet for 38 weeks, respectively. In groups HFD+GP and HFD+ST, mice were fed with high fat diet for 38 weeks and treated with gypenosides and simvastatin (positive control) from weeks 16 to 38, respectively. Serum TC and LDL-C levels were assayed by commercially available kits. Expression levels of genes were tested by the quantitative real-time PCR. The LC-MS/MS was applied to quantify major bile acids in mice livers. Our results showed that gypenosides significantly decreased serum TC and LDL-C levels. The gene expression level of Shp was downregulated while the levels of Cyp7a1, Cyp8b1, Fxr, Lrh1, Jnk1/2, and Erk1/2 were upregulated by gypenosides. Indicated by LC-MS/MS technology, gypenosides increased the hepatic levels of several free bile acids and most taurine-conjugated bile acids while decreasing glycine-conjugated bile acids levels. In addition, gypenosides decreased the CA/CDCA ratio. Gypenosides may improve the abnormal lipid profile of HFD-fed mice via two pathways: (1) enhancing the bile acids biosynthesis from cholesterol; (2) decreasing the CA/CDCA ratio which is positively related to cholesterol absorption. [ABSTRACT FROM AUTHOR]

[Display omitted] • Crataegi Fructus -derived carbon dots (CFCDs) were synthesized by pyrolysis method. • CFCDs can be used for pH sensing under extremely acidic conditions. • CFCDs serve as low-cost fluorescent probes for live cell imaging of various cells. • CFCDs exhibit good hemostatic effect after oral administration. Multifunctional carbon dots with intrinsic biological activity and fluorescent properties exhibit tremendous potential for applications in various fields, especially in the biomedical field. This paper reports a green and facile method for the synthesis of multifunctional carbon dots (CFCDs) via pyrolysis using the herbal medicine Crataegi Fructus as a precursor, and the fluorescent properties and biological activities of CFCDs are investigated, while the corresponding mechanisms are explored. The obtained CFCDs present a graphitic structure with an average particle size of 2.35 nm, abundant functional groups on their surface, and possess high aqueous solubility and excellent stability. Furthermore, under acidic conditions, these CFCDs have pH-dependent fluorescence properties based on protonation and deprotonation, showing a high linear correlation with pH values ranging from 0.5 to 4.5. The low cytotoxicity of CFCDs and their efficient internalization by cells make them ideal for cell imaging. More importantly, CFCDs exert good hemostatic effects through the extrinsic and common pathway and promote platelet aggregation. In conclusion, CFCDs can simultaneously realize pH sensing, cell imaging, and hemorrhagic disease treatment and, thus, have potential for wide application in medical domain. [ABSTRACT FROM AUTHOR]

Bear bile powder is a precious medicinal material. It is characterized by high content of tauroursodeoxycholic acid (TUDCA) at a ratio of 1.0-1.5 to taurochenodeoxycholic acid (TCDCA). Here, we reported the biotransformation of tauroursodeoxycholic acid (TUDCA) through Escherichia coli engineered with a two-step mimic biosynthetic pathway of TUDCA from taurochenodeoxycholic acid (TCDCA). Two 7α-hydroxysteroid dehydrogenase (7α-HSDH) and two 7β-hydroxysteroid dehydrogenase (7β-HSDH) genes (named as α, α, β, and β) were selected and synthesized to create four pathway variants using ePathBrick. All could convert TCDCA to TUDCA and the one harboring α and β (pαβ) showed the strongest capability. Utilizing the oxidative and reductive properties of 7α- and 7β-HSDH, an ideal balance between TUDCA and TCDCA was established by optimizing the fermentation conditions. By applying the optimal condition, E. coli containing pαβ (BL-pαβ) produced up to 1.61 ± 0.13 g/L of TUDCA from 3.23 g/L of TCDCA at a ratio of 1.3 to TCDCA. This study provides a potential approach for bear bile substitute production from cheap and readily available chicken bile. [ABSTRACT FROM AUTHOR]

Caffeic acid (CA) is a natural compound abundant in fruits, coffee and plants. This study aims to investigate the involved mechanism of the therapeutic detoxification of CA against acetaminophen (APAP)-induced hepatotoxicity. CA (10, 30 mg/kg) was orally given to mice at 1 h after mice were pre-administrated with APAP (300 mg/kg). The therapeutic detoxification of CA against APAP-induced hepatotoxicity was observed by detecting serum aminotransferases, liver malondialdehyde (MDA) amount and liver histological evaluation in vivo . CA reduced APAP-induced increase in the mRNA expression of early growth response 1 (Egr1) in hepatocytes, and inhibited APAP-induced Egr1 transcriptional activation in vitro and in vivo . CA reduced the increased expression of growth arrest and DNA-damage-inducible protein (Gadd45)α induced by APAP in hepatocytes. Moreover, Egr1 siRNA reduced Gadd45α expression and reversed APAP-induced cytotoxicity in hepatocytes. Further results showed that CA blocked APAP-induced activation of extracellular-regulated protein kinase (ERK1/2) signaling cascade in vivo and in vitro . In addition, the application of ERK1/2 inhibitors (PD98059 and U0126) abrogated the nuclear translocation of Egr1 induced by APAP in hepatocytes. In conclusion, this study demonstrated the therapeutic detoxification of CA against APAP-induced liver injury, and the inhibition of CA on ERK1/2-mediated Egr1 transcriptional activation was involved in this process. [ABSTRACT FROM AUTHOR]

Vasicine (VAS), a potential natural cholinesterase inhibitor, exhibited promising anticholinesterase activity in preclinical models and has been in development for treatment of Alzheimer’s disease. This study systematically investigated the in vitro and in vivo metabolism of VAS in rat using ultra performance liquid chromatography combined with electrospray ionization quadrupole time-of-flight mass spectrometry. A total of 72 metabolites were found based on a detailed analysis of their 1H- NMR and 13C NMR data. Six key metabolites were isolated from rat urine and elucidated as vasicinone, vasicinol, vasicinolone, 1,2,3,9-tetrahydropyrrolo [2,1-b] quinazolin-3-yl hydrogen sulfate, 9-oxo-1,2,3,9-tetrahydropyrrolo [2,1-b] quinazolin-3-yl hydrogen sulfate, and 1,2,3,9-tetrahydropyrrolo [2,1-b] quinazolin-3-β-D-glucuronide. The metabolic pathway of VAS in vivo and in vitro mainly involved monohydroxylation, dihydroxylation, trihydroxylation, oxidation, desaturation, sulfation, and glucuronidation. The main metabolic soft spots in the chemical structure of VAS were the 3-hydroxyl group and the C-9 site. All 72 metabolites were found in the urine sample, and 15, 25, 45, 18, and 11 metabolites were identified from rat feces, plasma, bile, rat liver microsomes, and rat primary hepatocyte incubations, respectively. Results indicated that renal clearance was the major excretion pathway of VAS. The acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activities of VAS and its main metabolites were also evaluated. The results indicated that although most metabolites maintained potential inhibitory activity against AChE and BChE, but weaker than that of VAS. VAS undergoes metabolic inactivation process in vivo in respect to cholinesterase inhibitory activity. [ABSTRACT FROM AUTHOR]

Alpha-glucosidase inhibitors currently form an important basis for developing novel drugs for diabetes treatment. In our preliminary tests, the ethyl acetate fraction of Phlomis tuberosa extracts showed significant α-glucosidase inhibitory activity (IC₅₀ = 100 μg/mL). In the present study, a combined method using Sepbox chromatography and thin-layer chromatography (TLC) bioautography was developed to probe α-glucosidase inhibitors further. The ethyl acetate fraction of P. tuberosa extracts was separated into 150 individual subfractions within 20 h using Sepbox chromatography. Then, under the guidance of TLC bioautography, 20 compounds were successfully isolated from these fractions, including four new diterpenoids [14-hydroxyabieta-8,11,13-triene-11-carbaldehyde-18-oic-12-carboxy-13-(1-hydroxy-1-methylethyl)-lactone (1), 14-hydroxyabieta-8,11,13-triene-17-oic-12-carboxy-13-(1-hydroxy-1-methylethyl)-lactone (2), 14,16-dihydroxyabieta-8,11,13-triene-15,17-dioic acid (3), and phlomisol (15,16-eposy-8,13(16),14-labdatrien-19-ol) (4)], and 16 known compounds. Activity estimation indicated that 15 compounds showed more potent α-glucosidase inhibitory effects (with IC50 values in the range 0.067–1.203 mM) than the positive control, acarbose (IC50 = 3.72 ± 0.113 mM). This is the first report of separation of α-glucosidase inhibitors from P. tuberosa. [ABSTRACT FROM AUTHOR]

Diabetic retinopathy (DR) is a serious complication of diabetes mellitus. This study aimed to observe the alleviation of the ethanol extract of Dendrobium chrysotoxum Lindl. (DC), a traditional Chinese herbal medicine, on DR and its engaged mechanism. After DC (30 or 300 mg/kg) was orally administrated, the breakdown of blood retinal barrier (BRB) in streptozotocin- (STZ-) induced diabetic rats was attenuated by DC. Decreased retinal mRNA expression of tight junction proteins (including occludin and claudin-1) in diabetic rats was also reversed by DC. Western blot analysis and retinal immunofluorescence staining results further confirmed that DC reversed the decreased expression of occludin and claudin-1 proteins in diabetic rats. DC reduced the increased retinal mRNA expressions of intercellular adhesion molecule-1 (ICAM-1), tumor necrosis factor α (TNFα), interleukin- (IL-) 6, and IL-1β in diabetic rats. In addition, DC alleviated the increased 1 and phosphorylated p65, IκB, and IκB kinase (IKK) in diabetic rats. DC also reduced the increased serum levels of TNFα, interferon-γ (IFN-γ), IL-6, IL-1β, IL-8, IL-12, IL-2, IL-3, and IL-10 in diabetic rats. Therefore, DC can alleviate DR by inhibiting retinal inflammation and preventing the decrease of tight junction proteins, such as occludin and claudin-1. [ABSTRACT FROM AUTHOR]

Quercetin is a plant-derived flavonoid that is widely distributed in nature. The present study is designed to analyze the underlying mechanism in the protection of quercetin against pyrrolizidine alkaloid clivorine-induced acute liver injury in vivo. Serum transaminases, total bilirubin analysis, and liver histological evaluation demonstrated the protection of quercetin against clivorine-induced liver injury. Terminal dUTP nick end-labeling assay demonstrated that quercetin reduced the increased amount of liver apoptotic cells induced by clivorine. Western-blot analysis of caspase-3 showed that quercetin inhibited the cleaved activation of caspase-3 induced by clivorine. Results also showed that quercetin reduced the increase in liver glutathione and lipid peroxidative product malondialdehyde induced by clivorine. Quercetin reduced the enhanced liver immunohistochemical staining for 4-hydroxynonenal induced by clivorine. Results of the Mouse Stress and Toxicity PathwayFinder RT2 Profiler PCR Array demonstrated that the expression of genes related with oxidative or metabolic stress and heat shock was obviously altered after quercetin treatment. Some of the alterations were confirmed by real-time PCR. Our results demonstrated that quercetin prevents clivorine-induced acute liver injury in vivo by inhibiting apoptotic cell death and ameliorating oxidative stress injury. This protection may be caused by the elevation of the body defense capacity induced by quercetin. [ABSTRACT FROM AUTHOR]

The migration of endothelial cells has been regarded as a potential target for the treatment of angiogenesis-related diseases. Previously, we demonstrated that norisoboldine (NOR), an alkaloid compound isolated from Radix Linderae, can significantly suppress synovial angiogenesis by selectively inhibiting endothelial cell migration. In this study, we evaluated the importance of various pathways in VEGF-induced endothelial cell migration using specific inhibitor. VEGF-induced endothelial cell migration and sprouting were significantly inhibited by H-89 (an inhibitor of protein kinase A (PKA)) but not by inhibitors of other pathways. NOR markedly suppressed VEGF-induced intracytoplasmic cAMP production and PKA activation and thereby down-regulated the activation of downstream components of the PKA pathway, including enzymes (src, VASP and eNOS) and the transcription factor NF-κB. Moreover, the transcription activation potential of NF-κB, which is related to IκBα phosphorylation and the disruption of the p65/IκBα complex, was reduced by NOR. Meanwhile, NOR selectively inhibited the expression of p-p65 (ser276) but not p-p65 (ser536) or PKAc, indicating that PKAc participates in the regulation of NF-κB by NOR. Co-immunoprecipitation and immunofluorescence assays confirmed that NOR inhibited the formation of the PKAc/p65 complex and thereby decreased p65 (ser276) phosphorylation to prevent p65 binding to DNA. Docking models indicated that the affinity of NOR for PKA was higher than that of the original PKA ligand. Moreover, the fact that H-89 improved Notch1 activation, but DAPT (an inhibitor of Notch) failed to affect PKA activation, suggested that PKA may act on upstream of Notch1. In conclusion, the inhibitory effects of NOR on endothelial cell migration can be attributed to its modulation of the PKA pathway, especially on the processes of p65/IκBα complex disruption and PKAc/p65 complex formation. These results suggest that NOR inhibit VEGF-induced endothelial cell migration via a cAMP-PKA-NF-κB/Notch1 signaling pathway. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is a chronic autoimmune neuroinflammatory disease found mostly in young adults in the western world. Oxidative stress induced neuronal apoptosis plays an important role in the pathogenesis of MS. In current study, astragaloside IV (ASI), a natural saponin molecule isolated from Astragalus membranceus, given at 20 mg/kg daily attenuated the severity of experimental autoimmune encephalomyelitis (EAE) in mice significantly. Further studies disclosed that ASI treatment inhibited the increase of ROS and pro-inflammatory cytokine levels, down-regulation of SOD and GSH-Px activities, and elevation of iNOS, p53 and phosphorylated tau in central nervous system (CNS) as well as the leakage of BBB of EAE mice. Meanwhile, the decreased ratio of Bcl-2/Bax was reversed by ASI. Moreover, ASI regulated T-cell differentiation and infiltration into CNS. In neuroblast SH-SY5Y cells, ASI dose-dependently reduced cellular ROS level and phosphorylation of tau in response to hydrogen peroxide challenge by modulation of Bcl-2/Bax ratio. ASI also inhibited activation of microglia both in vivo and in vitro. iNOS up-regulation induced by IFNγ stimulation was abolished by ASI dose-dependently in BV-2 cells. In summary, ASI prevented the severity of EAE progression possibly by counterbalancing oxidative stress and its effects via reduction of cellular ROS level, enhancement of antioxidant defense system, increase of anti-apoptotic and anti-inflammatory pathways, as well as modulation of T-cell differentiation and infiltration into CNS. The study suggested ASI may be effective for clinical therapy/prevention of MS. [ABSTRACT FROM AUTHOR]

Toosendanin (TSN) and isotoosendanin (ITSN) are two natural triterpenoids isolated from Fructus Meliae Toosendan or Cortex Meliae. This study aims to observe the inhibition of TSN and ITSN on the growth of triple-negative breast cancer (TNBC) and the preliminary engaged mechanism. Cell viability assay showed that both TSN and ITSN had obvious cytotoxicity in a variety of tumor cells, and they had the best inhibitory effect on TNBC cells including MDA-MB-231, BT549 and 4T1. Propidium iodide (PI) staining results showed the increased number of necrotic MDA-MB-231 and 4T1 cells induced by TSN (20 nM) and ITSN (2.5 μM). Annexin V-FITC and PI double-staining results showed that TSN (20 nM) and ITSN (2.5 μM) induced cell apoptosis in both MDA-MB-231 and 4T1 cells. Moreover, TSN (20 nM) and ITSN (2.5 μM) induced the cleavage of pro-caspase-3 and pro-caspase-9, and decreased the expression of anti-apoptotic Bcl-xL in both MDA-MB-231 and 4T1 cells. Results from scanning electron microscope observation and detecting the expression of microtubule-associated protein 1 light chain 3B (LC3B) and Beclin 1 evidenced that TSN (20 nM) and ITSN (2.5 μM) induced autophagy in both MDA-MB-231 and 4T1 cells. TSN and ITSN decreased 4T1 xenograft tumor growth without inflicting toxicity on vital organs in mice. Collectively, this study shows that natural compound TSN and ITSN suppress TNBC growth via inducing necrosis, apoptosis and autophagy. TSN and ITSN could be promising drugs for TNBC treatment. [Display omitted] • TSN and ITSN suppress TNBC growth both in vivo and in vitro. • TSN and ITSN induce TNBC necrotic death. • TSN and ITSN induce TNBC apoptosis. • TSN and ITSN induce TNBC autophagy. [ABSTRACT FROM AUTHOR]

An agaran-type polysaccharide, GFP08, isolated from Grateloupia filicina (C. Agardh) Lamouroux, was mainly composed of 1,3-linked β-d-galactose partially sulfated at position O-2 and 1,4-linked α-l-galactose O-2, O-3-disulfate, α-l-galactose O-6-sulfate and 3,6-anhydro-α-l-galactose. Small quantities of xylose, 4,6-O-(1′-carboxyethylidene) and 6-O-methyl-β-d-galactose were also present. In mice bearing sarcoma-180 cells, GFP08 decreased tumor weight in a dose-dependent manner. The antiangiogenic activity of GFP08 was evaluated using the chicken chorioallantoic membrane assay, and the results showed that GFP08 dose-dependently reduced new vessel formation. Meanwhile, GFP08 inhibited the differentiation of human umbilical vein endothelial cells (HUVECs) into capillary-like structures in vitro and reduced the number of migrated cells. However, there was no observed cytotoxicity of GFP08 toward HUVECs. Further study revealed that GFP08 decreased tissue factor (TF) expression without affecting the activities of matrix metalloproteinase-2 and -9. All those data indicated that GFP08 had an antitumor effect that might be associated in part with its antiangiogenic effect through down-regulating the expression of TF protein. [ABSTRACT FROM PUBLISHER]

Abstract: Pyrrolizidine alkaloids (PAs) are well-known natural hepatotoxins distributed widely in thousands of plants in the world. Adonifoline (Adon), senecionine (Sene) and monocrotaline (Mono) are retronecine-type PAs, and the present study is designed to observe the effects of intracellular glutathione on toxicity of these three PAs in human normal liver L-02 cells. The ratio of cellular reduced glutathione (GSH) and oxidized glutathione (GSSG) was assayed after L-02 cells were incubated with these three PAs for various times. Results showed that Adon, Sene and Mono all significantly decreased the ratio of GSH/GSSG in L-02 cells in the time- and concentration-dependent manner. The results of 3-(4,5-dimethylthiazol-2-yl) 2,5-diphenyltetrazolium bromide (MTT) and trypan blue staining assay showed that these three PAs all significantly decreased cell viability in L-02 cells when pretreated with 10μM BSO (L-Buthionine-S-R-Sulfoximine) for 24h to deplete intracellular GSH. Further results showed that anti-oxidant compounds such as NAC (N-Acetyl-Cysteine) and GSH could rescue the cytotoxicity caused by these three PAs with BSO pretreatment. Taken together, those results suggest that intracellular GSH plays important roles in regulating the cytotoxicity induced by PAs. [Copyright &y& Elsevier]

Abstract: Radix Linderae, the dry roots of Lindera aggregata (Sims) Kosterm (L. strychnifolia Vill), has been long-term used in traditional Chinese medicine for treating various diseases, and alkaloids are believed to be the main active components. Previously, we reported that the total alkaloids from Radix Linderae (TARL) could effectively alleviate inflammation and protect joints from destruction in mouse collagen-induced arthritis, an animal model of human rheumatoid arthritis (RA). To get insight into the underlying mechanisms of TARL, the present study was performed to investigate the effects of TARL on the activation of macrophages and resultant production of inflammatory mediators. In vitro, TARL concentration-dependently prevented the production of nitric oxide, interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α), as well as the expressions of iNOS, IL-1β and TNF-α mRNA in RAW 264.7 cells stimulated by lipopolysaccharid (LPS). However, it showed little effect on the production of interleukin-6 (IL-6) and the expression of IL-6 mRNA. Signal transduction studies showed that TARL significantly down-regulated the phosphorylation of extracellular signal-regulated kinase (ERK) and p38 MAP kinase rather than c-jun NH2-terminal kinase (JNK). Additionally, TARL prominently decreased LPS-induced activation of IKKα and phosphorylation of p65 on serine 276, but had little impact on the phosphorylation and degradation of IκBα. In summary, our results demonstrate that TARL exhibits inhibitory effects on the production of inflammatory mediators from macrophages via blocking NF-κB and MAPKs signaling pathways. The findings provide a plausible explanation for the therapeutic efficiency of TARL on the inflammation and joint destruction in RA. [Copyright &y& Elsevier]

Alantolactone (ALA) is a sesquiterpene lactone with potent anti-inflammatory activity. However, the effect of ALA on intestinal inflammation remains largely unknown. The present study demonstrated that ALA significantly ameliorated the clinical symptoms of dextran sulfate sodium (DSS)-induced mice colitis as determined by body weight loss, diarrhea, colon shortening, inflammatory infiltration and histological injury. In mice exposed to DSS, ALA treatment significantly lowered pro-inflammatory mediators, including nuclear factor-kappa B (NF-κB) activation. In vitro, ALA inhibited NF-κB nuclear translocation and dose-dependently activated human/mouse pregnane X receptor (PXR), a key regulator gene in inflammatory bowel disease (IBD) pathogenesis. However, the pocket occluding mutants of the ligand-binding domain (LBD) of hPXR, abrogated ALA-mediated activation of the receptor. Overexpression of hPXR inhibited NF-κB-reporter activity and in this setting, ALA further enhanced the hPXR-mediated inhibition of NF-κB-reporter activity. Furthermore, silencing hPXR gene demonstrated the necessity for hPXR in downregulation of NF-κB activation by ALA. Finally, molecular docking studies confirmed the binding affinity between hPXR-LBD and ALA. Collectively, the current study indicates a beneficial effect of ALA on experimental IBD possibly via PXR-mediated suppression of the NF-κB inflammatory signaling. [ABSTRACT FROM AUTHOR]