A Novel Synthetic Analog of 5, 8-Disubstituted Quinazolines Blocks Mitosis and Induces Apoptosis of Tumor Cells by Inhibiting Microtubule Polymerization

Many mitosis inhibitors are powerful anticancer drugs. Tremendous efforts have been made to identify new anti-mitosis compounds for developing more effective and less toxic anti-cancer drugs. We have identified LJK-11, a synthetic analog of 5, 8-disubstituted quinazolines, as a novel mitotic blocker. LJK-11 inhibited growth and induced apoptosis of many different types of tumor cells. It prevented mitotic spindle formation and arrested cells at early phase of mitosis. Detailed in vitro analysis demonstrated that LJK-11 inhibited microtubule polymerization. In addition, LJK-11 had synergistic effect with another microtubule inhibitor colchicine on blocking mitosis, but not with vinblastine or nocodazole. Therefore, LJK-11 represents a novel anti-microtubule structure. Understanding the function and mechanism of LJK-11 will help us to better understand the action of anti-microtubule agents and to design better anti-cancer drugs

Grape seed proanthocyanidin extract targets p66Shc to regulate mitochondrial biogenesis and dynamics in diabetic kidney disease

Mitochondrial biogenesis and dynamics are associated with renal mitochondrial dysfunction and the pathophysiological development of diabetic kidney disease (DKD). Decreased p66Shc expression prevents DKD progression by significantly regulating mitochondrial function. Grape seed proanthocyanidin extract (GSPE) is a potential therapeutic medicine for multiple kinds of diseases. The effect of GSPE on the mitochondrial function and p66Shc in DKD has not been elucidated. Hence, we decided to identify p66Shc as a therapeutic target candidate to probe whether GSPE has a renal protective effect in DKD and explored the underlying mechanisms. Methods. In vivo, rats were intraperitoneally injected with streptozotocin (STZ) and treated with GSPE. Biochemical changes, mitochondrial morphology, the ultrastructure of nephrons, and protein expression of mitochondrial biogenesis (SIRT1, PGC-1α, NRF1, TFAM) and dynamics (DRP1, MFN1) were determined. In vitro, HK-2 cells were transfected with p66Shc and treated with GSPE to evaluate changes in cell apoptosis, reactive oxygen species (ROS), mitochondrial quality, the protein expression. Results. In vivo, GSPE significantly improved the renal function of rats, with less proteinuria and a lower apoptosis rate in the injured renal tissue. Besides, GSPE treatment increased SIRT1, PGC-1α, NRF1, TFAM, and MFN1 expression, decreased p66Shc and DRP1 expression. In vitro, overexpression of p66Shc decreased the resistance of HK-2 cells to high glucose toxicity, as shown by increased apoptosis and ROS production, decreased mitochondrial quality and mitochondrial biogenesis, and disturbed mitochondrial dynamic homeostasis, ultimately leading to mitochondrial dysfunction. While GSPE treatment reduced p66Shc expression and reversed these changes. Conclusion. GSPE can maintain the balance between mitochondrial biogenesis and dynamics by negatively regulating p66Shc expression

Integrated transcriptomic and metabolomic analysis reveals the metabolic programming of GM-CSF- and M-CSF- differentiated mouse macrophages

Macrophages play a critical role in the inflammatory response and tumor development. Macrophages are primarily divided into pro-inflammatory M1-like and anti-inflammatory M2-like macrophages based on their activation status and functions. In vitro macrophage models could be derived from mouse bone marrow cells stimulated with two types of differentiation factors: GM-CSF (GM-BMDMs) and M-CSF (M-BMDMs), to represent M1- and M2-like macrophages, respectively. Since macrophage differentiation requires coordinated metabolic reprogramming and transcriptional rewiring in order to fulfill their distinct roles, we combined both transcriptome and metabolome analysis, coupled with experimental validation, to gain insight into the metabolic status of GM- and M-BMDMs. The data revealed higher levels of the tricarboxylic acid cycle (TCA cycle), oxidative phosphorylation (OXPHOS), fatty acid oxidation (FAO), and urea and ornithine production from arginine in GM-BMDMs, and a preference for glycolysis, fatty acid storage, bile acid metabolism, and citrulline and nitric oxide (NO) production from arginine in M-BMDMs. Correlation analysis with the proteomic data showed high consistency in the mRNA and protein levels of metabolic genes. Similar results were also obtained when compared to RNA-seq data of human monocyte derived macrophages from the GEO database. Furthermore, canonical macrophage functions such as inflammatory response and phagocytosis were tightly associated with the representative metabolic pathways. In the current study, we identified the core metabolites, metabolic genes, and functional terms of the two distinct mouse macrophage populations. We also distinguished the metabolic influences of the differentiation factors GM-CSF and M-CSF, and wish to provide valuable information for in vitro macrophage studies

Drivers of provincial SO2 emissions in China – Based on multi-regional input-output analysis

Studying the driving factors of pollutant emissions is of great significance for China in the formulation of pollution control strategies. Existing studies mainly focus on the causes of national aggregate emission changes. However, considering the large differences among provinces in China and their close economic linkages, it is necessary to develop a provincial-level analysis to shape provincial policies for emission reduction. Using the multi-regional input-output (MRIO) tables of 30 provinces in China and adopting structural decomposition analysis, we analyze how changes in the end-of-pipe treatment, cleaner production, economic production structure, domestic final use, domestic exports and international exports drive national and provincial SO2 emissions. Decomposition results show that during 2002–2010 the absolute value of each effect based on the MRIO model is higher than that based on the national aggregate input-output model, which indicates that the existing studies adopting the national average data conceal the variation in the driving factors and underestimate their contributions to SO2 emission changes. The decomposition results based on MRIO model further show that the end-of-pipe treatment and cleaner production are the major emission reduction factors for all provinces, and the effect of the former has noticeably increased during 2007–2010. For the eastern provinces, interestingly, the economic production structure becomes a major emission reduction factor during the period of 2007–2010. Changes in domestic final demand, domestic exports and international exports exhibit significantly different contributions among provinces. The increased final demand in eastern provinces largely drive SO2 emissions for all provinces. Based on the above findings, policy implications that address the SO2 emission reduction issues are proposed

Does the traditional Chinese medicine theory of five circuits and six qi improve treatment effectiveness? A systematic review of randomized controlled trials

Objective: To evaluate whether the traditional Chinese medicine (TCM) theory of five circuits and six qi (FCSQ) is beneficial in terms of improving clinical effectiveness. Methods: Randomized controlled trials (RCTs) evaluating the clinical value of FCSQ theory were reviewed. Multiple databases (China Network Knowledge Infrastructure, Chinese Scientific Journals Database, Wanfang Data, SinoMed, Cochrane Library, PubMed, and Embase) were systematically searched from inception to June 12, 2018. Two authors independently extracted the data and performed a methodological quality assessment of the RCTs. RevMan 5.3 software was used for the data analysis. The effect sizes for the primary outcome measures were expressed as relative risks or mean differences with 95% confidence intervals. Results: A total of 13 RCTs were selected, involving 12 types of diseases and 4695 patients. The methodological quality of the RCTs was generally low. Five studies compared the effectiveness of TCM treatments guided by FCSQ theory with conventional TCM therapies, and the remaining eight studies compared the effectiveness of TCM treatments guided by FCSQ theory with biomedical treatments. All of the RCTs reported that the effectiveness of the treatment intervention was better than that of the intervention in the control group. Conclusion: Because of many methodological problems in existing clinical studies, it remains impossible to definitively conclude that FCSQ theory can improve clinical effectiveness. It is difficult to unify the clinical application of FCSQ theory. The feasibility and repeatability of FCSQ as an intervention should be given more attention in future clinical research. Future work should also follow international norms for clinical research implementation and reporting to provide high-quality evidence for evaluating the clinical value of FCSQ theory. Keywords: Five circuits and six qi, Randomized controlled trial, Effectiveness, Evaluatio

tarting Control of Free Piston Stirling Linear Generator System Based on FOC

Aiming at the problem of poor system dynamic performance caused by low parameter matching in the coordinated control of Stirling engine and linear generator in the starting stage control of free piston Stirling linear generator system, a joint control method of free piston Stirling permanent magnet synchronous linear generator system based on field orientation control is proposed, based on the theoretical derivation of the mathematical model of the system and the principle of controller parameters setting, the simulation experiments of the system starting stage under several Stirling engine working conditions are carried out under simulation. The experimental results show that the stability and rapidity of the system are improved, and the dynamic response speed of generator parameters under different working conditions is accelerated, what fully verifies the correctness and effectiveness of the method. It provides an effective way to improve the control performance of the system and stabilize the power generation operation

Effects of Residual Composition and Distribution on the Structural Characteristics of the Protein

The effect of ratio and consecutive number of hydrophobic residues in the repeating unit of protein chains was investigated by MD simulation. The modified off-lattice HNP model was applied in this study. The protein chains constituted by different HNP ratios or different numbers of consecutively hydrophobic residues with the same chain length were simulated under a broad temperature range. We concluded that the proteins with higher ratio or larger number of sequentially hydrophobic residues present more orientated and compact structure under a certain low temperature. It is attributed to the lower non-bonded potential energy between H-H residual pairs, especially more hydrophobic residues in a procession among the protein chain. Considering the microscopic structure of the protein, more residue contacts are achieved with the proteins with higher ratios and sequential H residues under the low temperature. Meanwhile, with the ratio and consecutive number of H residues increasing, the distribution of stem length showed a transition from exponential decline to unimodal and even multiple peaks, indicating the specific ordered structure formed. These results provide an insight into 3D structural properties of proteins from their residue sequences, which has a primary structure at molecular level and, ultimately, a practical possibility of applying in biotechnological applications

Nonlinear Dynamic Response of a CC-RCC Combined Dam Structure under Oblique Incidence of Near-Fault Ground Motions

The velocity pulse contained in near-fault ground motions have a tremendous impact on dam safety. Previous studies have mainly focused on the response of dams under near-fault seismic records without considering the obliquely incident seismic waves. In this study, the structure–soil interaction (SSI) is taken into consideration, and the nonlinear behavior of a conventional concrete roller-compacted concrete (CC-RCC) gravity dam under near-fault pulse records and non-pulse records is investigated with consideration of the obliquely incident P waves. On the basis of the dam site conditions, three groups of near-fault pulse records are chosen, and three corresponding non-pulse records are fitted by their acceleration response spectra. Combining with the viscous-spring artificial boundary, the wave input method is proposed to transform the near-fault seismic records into the equivalent nodal forces at the boundary of the foundation. The concrete damaged plasticity model is used for the nonlinear analysis. The results show that the pulse ground motions are more destructive than the non-pulse motions. The nonlinear behavior of the dam varies with the incidence angle of P waves and generally reaches a maximum at 60° and 75°, the worst damage occurs at the interface between different materials of the dam, and the spatial variation of its damage is very obvious under near-fault seismic records with various incidence angles. Therefore, the effect of the angle of obliquely incident seismic waves and near-fault pulse effect should be considered comprehensively in the seismic analysis of dams

Boosting CO2 methanation activity on Ru/TiO2 catalysts by exposing (001) facets of anatase TiO2

Catalytic reduction of CO2 to methane has been recognized as one of the most important strategic reactions to produce highly valuable chemicals and for storage of renewable energy (power-to-gas). This study demonstrates a crystal facet-dependent catalytic reduction of CO2 to CH4 on ruthenium nanoparticles deposited over TiO2 nanocrystal with exposed (001) and (101) facets. Compared with TiO2 (101) nanocrystal with the same Ru loading, Ru nanoparticles supported by TiO2 (001) exhibited a highly enhanced CO2 conversion rate and significantly improved methanation reactivity, along with a considerable durability. The physicochemical properties of the samples were characterized by HR-TEM, XRD, BET, FT-IR, UV-vis, Raman, ICP, and temperature-programmed reaction with CO2, and CO2 + H2. In view of the difference in catalytic activity and the physicochemical properties of the supported Ru/TiO2 catalysts, the results uncovered that the nature of the catalyst support of Ru/TiO2 strongly affected the dispersion of Ru species and the synergistic effect between Ru and underlying TiO2 supporting materials due to the strong metal-support interaction, and thus affected their capability to activate CO2 and determined the catalytic activity for CO2 methanation. Our work demonstrated the important role of the exposed crystal facets of the underlying support and the resulting Ru particle which had a large effect on CO2 methanation

Virtual Screening Guided Design, Synthesis and Bioactivity Study of Benzisoselenazolones (BISAs) on Inhibition of c-Met and Its Downstream Signalling Pathways

c-Met is a transmembrane receptor tyrosine kinase and an important therapeutic target for anticancer drugs. In this study, we designed a small library containing 300 BISAs molecules that consisted of carbohydrates, amino acids, isothiourea, tetramethylthiourea, guanidine and heterocyclic groups and screened c-Met targeting compounds using docking and MM/GBSA. Guided by virtual screening, we synthesised a series of novel compounds and their activity on inhibition of the autophosphorylation of c-Met and its downstream signalling pathway proteins were evaluated. We found a panel of benzisoselenazolones (BISAs) obtained by introducing isothiourea, tetramethylthiourea and heterocyclic groups into the C-ring of Ebselen, including 7a, 7b, 8a, 8b and 12c (with IC50 values of less than 20 μM in MET gene amplified lung cancer cell line EBC-1), exhibited more potent antitumour activity than Ebselen by cell growth assay combined with in vitro biochemical assays. In addition, we also tested the antitumour activity of three cancer cell lines without MET gene amplification/activation, including DLD1, MDA-MB-231 and A549. The neuroblastoma SK-N-SH cells with HGF overexpression which activates MET signalling are sensitive to MET inhibitors. The results reveal that our compounds may be nonspecific multitarget kinase inhibitors, just like type-II small molecule inhibitors. Western blot analysis showed that these inhibitors inhibited autophosphorylation of c-MET, and its downstream signalling pathways, such as PI3K/AKT and MARK/ERK. Results suggest that bensoisoselenones can be used as a scaffold for the design of c-Met inhibiting drug leads, and this study opens up new possibilities for future antitumour drug design