Structural Investigation of the Interaction Mechanism between Chlorogenic Acid and AMPA Receptor via In Silico Approaches

Chlorogenic acid (CGA), an important metabolite in natural plant medicines such as honeysuckle and eucommia, has been shown to have potent antinociceptive effects. Nevertheless, the mechanism by which CGA relieves chronic pain remains unclear. α-amino-3-hydroxy-5-methyl-4-isooxazolpropionic acid receptor (AMPAR) is a major ionotropic glutamate receptor that mediates rapid excitatory synaptic transmission and its glutamate ionotropic receptor AMPA type subunit 1 (GluA1) plays a key role in nociceptive transmission. In this study, we used Western blot, surface plasmon resonance (SPR) assay, and the molecular simulation technologies to investigate the mechanism of interaction between CGA and AMPAR to relieve chronic pain. Our results indicate that the protein expression level of GluA1 showed a dependent decrease as the concentration of CGA increased (0, 50, 100, and 200 μM). The SPR assay demonstrates that CGA can directly bind to GluA1 (K_D = 496 μM). Furthermore, CGA forms a stable binding interaction with GluA1, which is validated by molecular dynamics (MD) simulation. The binding free energy between CGA and GluA1 is −39.803 ± 14.772 kJ/mol, where van der Waals interaction and electrostatic interaction are the major contributors to the GluA1–CGA binding, and the key residues are identified (Val-32, Glu-33, Ala-36, Glu-37, Leu-48), which play a crucial role in the binding interaction. This study first reveals the structural basis of the stable interaction between CGA and GluA1 to form a binding complex for the relief of chronic pain. The research provides the structural basis to understand the treatment of chronic pain and is valuable to the design of novel drug molecules in the future.     

Superconvergence of local discontinuous Galerkin methods with generalized alternating fluxes for 1D linear convection-diffusion equations

This paper investigates superconvergence properties of the local discontinuous Galerkin methods with generalized alternating fluxes for one-dimensional linear convection-diffusion equations. By the technique of constructing some special correction functions, we prove the(2k + 1)-th-order superconvergence for the cell averages, and the numerical traces in the discrete L~2 norm. In addition, superconvergence of orders k + 2 and k + 1 is obtained for the error and its derivative at generalized Radau points. All the theoretical findings are confirmed by numerical experiments.     

Facile Synthesis of Porous Ag Crystals as SERS Sensor for Detection of Five Methamphetamine Analogs

Porous noble metal nanomaterials have attracted extensive attention due to their high specific surface area and surface plasmon resonance effect. However, it is difficult to form porous structures due to the high mobility and low reduction potential of noble metal precursors. In this article, we developed a facile method for preparing porous Ag with a controllable structure at room temperature. Two kinds of Ag crystals with different porous structures were successfully prepared by using AgCl cubes as sacrificial templates. Through the galvanic replacement reaction of Zn and AgCl, Ag crystals with a sponge-like porous structure were successfully prepared. Additionally, using NaBH₄ as the reducing agent, we prepared granular porous Ag cubes by optimizing the amount of reducing agent. Both the sponge-like and granular porous Ag cubes have clean and accessible surfaces. In addition, we used the prepared two porous Ag cubes as substrate materials for SERS detection of five kinds of methamphetamine analogs. The experimental results show that the enhancement effect of granular porous Ag is better than that of sponge-like porous Ag. Furthermore, we probed the hot spot distribution of granular porous Ag by Raman mapping. By using granular porous Ag as the substrate material, we have achieved trace detection of 5 kinds of methamphetamine analogs including Ephedrine, Amphetamine, N-Methyl-1-(benzofuran-5-yl)propan-2-amine (5-MAPB), N-Methyl-1-(4-methoxyphenyl)propan-2-amine (PMMA) and N-Methyl-1-(4-fluorophenyl)propan-2-amine (4-FMA). Furthermore, to achieve qualitative differentiation of analogs with similar structures we performed density functional theoretical (DFT) calculations on the Raman spectra of the above analogs. The DFT calculations provided the vibrational frequencies, Raman activities, and normal mode assignment for each analog, enabling the qualitative differentiation of the above analogs.     

Effect of Thermal Processing on the Metabolic Components of Black Beans on Ultra-High-Performance Liquid Chromatography Coupled with High-Field Quadrupole-Orbitrap High-Resolution Mass Spectrometry

An ultra-high-performance liquid chromatography coupled with high-field quadrupole-orbitrap mass spectrometry (UHPLC-QE-MS) histological platform was used to analyze the effects of two thermal processing methods (cooking and steaming) on the nutritional metabolic components of black beans. Black beans had the most amino acids, followed by lipids and polyphenols, and more sugars. Multivariate statistical analysis indicated that heat processing significantly affected the metabolic component content in black beans, with effects varying among different components. Polyphenols, especially flavonoids and isoflavones, were highly susceptible. A total of 197 and 210 differential metabolites were identified in both raw black beans and cooked and steamed black beans, respectively. Cooking reduced the cumulative content of amino acids, lipids, polyphenols, sugars, and nucleosides, whereas steaming reduced amino acid and lipid content, slightly increased polyphenol content, and significantly increased sugar and nucleoside content. Our results indicated that metabolic components were better retained during steaming than cooking. Heat treatment had the greatest impact on amino acids, followed by polyphenols, fatty acids, sugars, and vitamins, indicating that cooking promotes the transformation of most substances and the synthesis of a few. The results of this study provide a basis for further research and development of nutritional products using black beans.     

DNA Interaction,DNA Photocleavage,Photocytotoxicity In Vitro,and Molecular Docking of Naphthyl-Appended Ruthenium Complexes

With the development of metal-based drugs, Ru(II) compounds present potential applications of PDT (photodynamic therapy) and anticancer reagents. We herein synthesized two naphthyl-appended ruthenium complexes by the combination of the ligand with naphthyl and bipyridyl. The DNA affinities, photocleavage abilities, and photocytotoxicity were studied by various spectral methods, viscosity measurement, theoretical computation method, gel electrophoresis, and MTT method. Two complexes exhibited strong interaction with calf thymus DNA by intercalation. Production of singlet oxygen (¹O₂) led to obvious DNA photocleavage activities of two complexes under 365 nm light. Furthermore, two complexes displayed obvious photocytotoxicity and low dark cytotoxicity towards Hela, A549, and A375 cells.     

Detoxified pneumolysin derivative ΔA146Ply inhibits autophagy and induces apoptosis in acute myeloid leukemia cells by activating mTOR signaling

Leukemia is caused by the malignant clonal expansion of hematopoietic stem cells, and in adults, the most common type of leukemia is acute myeloid leukemia (AML). Autophagy inhibitors are often used in preclinical and clinical models in leukemia therapy. However, clinically available autophagy inhibitors and their efficacy are very limited. More effective and safer autophagy inhibitors are urgently needed for leukemia therapy. In a previous study, we showed that ΔA146Ply, a mutant of pneumolysin that lacks hemolytic activity, inhibited autophagy of triple-negative breast cancer cells by activating mannose receptor (MR) and toll-like receptor 4 (TLR4) and that tumor-bearing mice tolerated ΔA146Ply well. Whether this agent affects AML cells expressing TLR4 and MR and the related mechanisms remain to be determined. In this study, we found that ΔA146Ply inhibited autophagy and induced apoptosis in AML cells. A mechanistic study showed that ΔA146Ply inhibited autophagy by activating mammalian target of rapamycin signaling and induced apoptosis by inhibiting autophagy. ΔA146Ply also inhibited autophagy and induced apoptosis in a mouse model of AML. Furthermore, the combination of ΔA146Ply and chloroquine synergistically inhibited autophagy and induced apoptosis in vitro and in vivo. Overall, this study provides an alternative effective autophagy inhibitor that may be used for leukemia therapy.Subject terms: Translational research, Acute myeloid leukaemia     

Synthesis and Anti-Neuroinflammatory Activity of 1,7-diphenyl-1,4-heptadien-3-ones in LPS-Stimulated BV2 Microglia Via Inhibiting NF-κB/MAPK Signaling Pathways

A series of 1,7-diphenyl-1,4-heptadien-3-ones with various substituents (HO-, CH₃O-, CH₃-, Cl-) on the phenyl rings were synthesized and evaluated for anti-neuroinflammatory effects in LPS-stimulated BV2 microglia. The pharmacological results showed that the target compounds bearing methoxy groups greatly inhibited LPS-induced NO release, and that the active compounds CU-19 and CU-21 reduced the level of NO, TNF-α, IL-6 and PGE-2, downregulated the expression of COX-2 and iNOS in LPS-stimulated BV2 cells. A study of the mechanism of action revealed that CU-19 and CU-21 inhibited the nuclear translocation of NF-κB and phosphorylation of MAPKs (ERK, JNK, and p38). A preliminary pharmacokinetic study in rats revealed that the pharmacokinetic properties of CU-19 and CU-21 were dramatically ameliorated in comparison with the pharmacokinetic properties of curcumin.     

Synthesis,Characterization and Application of Amine-Functionalized Hierarchically Micro-Mesoporous Silicon Composites for CO2 Capture in Flue Gas

An efficient CO₂ adsorbent with a hierarchically micro-mesoporous structure and a large number of amine groups was fabricated by a two-step synthesis technique. Its structural properties, surface groups, thermal stability and CO₂ adsorption performance were fully investigated. The analysis results show that the prepared CO₂ adsorbent has a specific hierarchically micro-mesoporous structure and highly uniformly dispersed amine groups that are favorable for the adsorption of CO₂. At the same time, the CO₂ adsorption capacity of the prepared adsorbent can reach a maximum of 3.32 mmol-CO₂/g-adsorbent in the actual flue gas temperature range of 303–343 K. In addition, the kinetic analysis results indicate that both the adsorption process and the desorption process have rapid adsorption/desorption rates. Finally, the fitting of the CO₂ adsorption/desorption experimental data by Avrami’s fractional kinetic model shows that the CO₂ adsorption rate is mainly controlled by the intra-particle diffusion rate, and the temperature has little effect on the adsorption rate.     

Application of Two Novel Acoustic Emission Parameters on Identifying the Instability of Granite

The issue of monitoring and early warning of rock instability has received increasing critical attention in the study of rock engineering. To investigate the damage evolution process of granite under triaxial compression tests, acoustic emission (AE) tests were performed simultaneously. This study firstly introduced two novel parameters, i.e., the coefficient of variation (CoV) of the information entropy and correlation dimension of the amplitude data from the AE tests, to identify the precursor of the failure of granite. Then the relationship between the changes in these parameters and the stress-time curve was compared and analyzed. The results of this study show that: (1) There is a strong correlation between the CoV of the information entropy and the failure process of granite. The granite failed when the CoV curve raised to a plateau, which could be used as an indicator of rock instability. (2) The fluctuation of the correlation dimension indicates the different stages during the loading process, i.e., the initial compaction stage, the linear elastic stage, the yield stage, and the failure stage. Each stage contains a descending and a rising process in the correlation dimension curve, and the exhibited starting point or the bottom point at the correlation dimension curve could be selected as the indicator point for the rock instability. (3) The combined analysis of the Information entropy and Correlation dimension can improve the accuracy of rock instability prediction. This study provides new insights into the prediction of rock instability, which has theoretical implications for the stability of subsurface engineering rock masses.     

A List-Ranking Framework Based on Linear and Non-Linear Fusion for Recommendation from Implicit Feedback

Although most list-ranking frameworks are based on multilayer perceptrons (MLP), they still face limitations within the method itself in the field of recommender systems in two respects: (1) MLP suffer from overfitting when dealing with sparse vectors. At the same time, the model itself tends to learn in-depth features of user–item interaction behavior but ignores some low-rank and shallow information present in the matrix. (2) Existing ranking methods cannot effectively deal with the problem of ranking between items with the same rating value and the problem of inconsistent independence in reality. We propose a list ranking framework based on linear and non-linear fusion for recommendation from implicit feedback, named RBLF. First, the model uses dense vectors to represent users and items through one-hot encoding and embedding. Second, to jointly learn shallow and deep user–item interaction, we use the interaction grabbing layer to capture the user–item interaction behavior through dense vectors of users and items. Finally, RBLF uses the Bayesian collaborative ranking to better fit the characteristics of implicit feedback. Eventually, the experiments show that the performance of RBLF obtains a significant improvement.