Role of Natural Compounds and Target Enzymes in the Treatment of Alzheimer’s Disease

Alzheimer’s disease (AD) is a progressive neurological condition. The rising prevalence of AD necessitates the rapid development of efficient therapy options. Despite substantial study, only a few medications are capable of delaying the disease. Several substances with pharmacological activity, derived from plants, have been shown to have positive benefits for the treatment of AD by targeting various enzymes, such as acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), β-secretase, γ-secretase, and monoamine oxidases (MAOs), which are discussed as potential targets. Medicinal plants have already contributed a number of lead molecules to medicine development, with many of them currently undergoing clinical trials. A variety of medicinal plants have been shown to diminish the degenerative symptoms associated with AD, either in their raw form or as isolated compounds. The aim of this review was to provide a brief summary of AD and its current therapies, followed by a discussion of the natural compounds examined as therapeutic agents and the processes underlying the positive effects, particularly the management of AD.     

Single-Stage Extraction and Separation of Co2+ from Ni2+ Using Ionic Liquid of [C4H9NH3][Cyanex 272]

The purpose of this study was to optimize the extraction conditions for separating Co²⁺ from Ni²⁺ using N-butylamine phosphinate ionic liquid of [C₄H₉NH₃][Cyanex 272]. A Box–Behnken design of response surface methodology was used to analyze the effects of the initial pH, extraction time, and extraction temperature on the separation factor of Co²⁺ from sulfuric acid solution containing Ni²⁺. The concentrations of Co²⁺ and Ni²⁺ in an aqueous solution were determined using inductively coupled plasma-optical emission spectrometry. The optimized extraction conditions were as follows: an initial pH of 3.7, an extraction time of 55.8 min, and an extraction temperature of 330.4 K. The separation factor of Co²⁺ from Ni²⁺ under optimized extraction conditions was 66.1, which was very close to the predicted value of 67.2, and the error was 1.7%. The equation for single-stage extraction with high reliability can be used for optimizing the multi-stage extraction process of Co²⁺ from Ni²⁺. The stoichiometry of chemical reaction for ion-exchange extraction was also investigated using the slope method.     

The Relationship between Procyanidin Structure and Their Protective Effect in a Parkinson’s Disease Model

This study evaluated the effect of grape seed-derived monomer, dimeric, and trimeric procyanidins on rat pheochromocytoma cell line (PC12) cells and in a zebrafish Parkinson’s disease (PD) model. PC12 cells were cultured with grape seed-derived procyanidins or deprenyl for 24 h and then exposed to 1.5 mm 1-methyl-4-phenylpyridinium (MPP⁺) for 24 h. Zebrafish larvae (AB strain) 3 days post-fertilization were incubated with deprenyl or grape seed-derived procyanidins in 400 µM 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) for 4 days. The results showed that the procyanidin dimers procyanidin B1 (B1), procyanidin B2 (B2), procyanidin B3 (B3), procyanidin B4 (B4), procyanidin B1-3-O-gallate (B1-G), procyanidin B2-3-O-gallate (B2-G), and the procyanidin trimer procyanidin C1 (C1) had a protective effect on PC12 cells, decreasing the damaged dopaminergic neurons and motor impairment in zebrafish. In PC12 cells and the zebrafish PD model, procyanidin (B1, B2, B3, B4, B1-G, B2-G, C1) treatment decreased the content of reactive oxygen species (ROS) and malondialdehyde (MDA), increased the activity of antioxidant enzymes glutathione peroxidase (GSH-Px), catalase (CAT), and superoxide dismutase (SOD), and upregulated the expression of nuclear factor-erythroid 2-related factor (Nrf2), NAD(P)H: quinone oxidoreductase 1 (NQO1), and heme oxygenase-1 (HO-1). These results suggest that in PC12 cells and the zebrafish PD model, the neuroprotective effects of the procyanidins were positively correlated with their degree of polymerization.     

An Exploration of the Effect of the Kleier Model and Carrier-Mediated Theory to Design Phloem-Mobile Pesticides Based on Researching the N-Alkylated Derivatives of Phenazine-1-Carboxylic Acid-Glycine

The Kleier model and Carrier-mediated theory are effective for molecularly designing pesticides with phloem mobility. However, the single Kleier model or Carrier-mediated theory cannot achieve a reliable explanation of the phloem mobility of all exogenous substances. A detailed investigation of the two models and the scope of their applications can provide a more accurate and highly efficient basis for the guidance of the design and development of phloem-mobile pesticides. In the present paper, a strategy using active ingredient-amino acid conjugates as mode compounds is developed based on Carrier-mediated theory. An N-alkylated amino acid is used to improve the pesticide’s physicochemical properties following the Kleier model, thus allowing the conjugates to fall on the predicted and more accessible transportation region of phloem. Moreover, the influence of this movement on phloem is inspected by the Kleier model and Carrier-mediated theory. To verify this strategy, a series of N-alkylated phenazine-1-carboxylic acid-glycine compounds (PCA-Gly) were designed and synthesized. The results related to the castor bean seeds (R. communis L.) indicated that all the target compounds (4a–4f) had phloem mobility. The capacity for phloem mobility shows that N-alkylated glycine containing small substituents can significantly improve PCA phloem mobility, such as 4c(i-C₃H₇-N) > 4a(CH₃-N) ≈ 4b(C₂H₅-N) > 4d (t-C₄H₉-N) > PCA-Gly > 4e(C₆H₅-N) > 4f(CH₂COOH-N), with an oil–water partition coefficient between 1.2~2.5. In particular, compounds 4a(CH₃-N), 4b(C₂H₅-N), and 4c(i-C₃H₇-N) present better phloem mobility, with the average concentrations in phloem sap of 14.62 μΜ, 13.98 μΜ, and 17.63 μΜ in the first 5 h, which are 8 to 10 times higher than PCA-Gly (1.71 μΜ). The results reveal that the Kleier model and Carrier-mediated theory play a guiding role in the design of phloem-mobile pesticides. However, the single Kleier model or Carrier-mediated theory are not entirely accurate. Still, there is a synergism between Carrier-mediated theory and the Kleier model for promoting the phloem transport of exogenous compounds. Therefore, we suggest the introduction of endogenous plant compounds as a promoiety to improve the phloem mobility of pesticides through Carrier-mediated theory. It is necessary to consider the improvement of physicochemical properties according to the Kleier model, which can contribute to a scientific theory for developing phloem-mobile pesticides.     

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.     

Dynamic Deformation of Frozen Soil at a High Strain Rate:Experiments and Damage-Coupled Constitutive Model

The dynamic compressive deformation of frozen soil was investigated by conduct-ing the split-Hopkinson pressure bar (SHPB) experiments at three temperatures and...     

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     

手性大孔磷酸镓Hit-5的水热合成与晶体结构

本文采用水热合成法制备了一个三维手性大孔开放骨架磷酸镓Ga16P16O75·4[1,6-C6H18N2]·[C2H10N2]·2H2O(简称Hit-5).反应起始原料摩尔配比为:1 GaOOH:15 H3PO4:7.5 H2N(CH2)6NH2:0.5 C2H8N2:555 H2O.Hit-5属正交晶系,P21212空间群,晶胞参数:a=0.8671(1)nm,b=1.7945(1)nm,c=0.9101(1)nm,β=108.33(1)°,V=1.3443(2)nm3,Z=4.Hit-5的骨架是由Ga3P3六聚体和Ga4P4八聚体两个不同的二级结构单元通过共顶点联接构成三维纳米孔结构,在[001]方向呈现16-元环孔道.     

钾明矾蓄热性能的研究与改善

钾明矾(KAl(SO4)2·12H2O)有较高的潜热和良好的导热性(熔化热232.4kJ/kg,导热系数为0.55W/m·K),熔点为91℃,是中低温相变材料中较有开发价值的一种.但是它的过冷度高达19.8℃,并且由于相变过程伴随着结晶水的蒸发使无机盐的使用寿命大大降低.本文通过冷指法及添加成核剂的方法对硫酸铝钾的过冷现象进行了研究,结果表明成核剂NiSO4·6H2O、MgCl2·6H2O能较好的改善过冷现象,当MgCl2·6H2O的添加量为2;时可使过冷度降为零,且能保持钾明矾的相变温度而不使其降低.利用MgCl2·6H2O具有很强的吸湿性,可以补充相变过程中损失的水分,使相变材料的使用寿命大大提高.     

An unexpected all-metal aromatic tetranuclear silver cluster in human copper chaperone Atox1

Metal clusters, such as iron–sulfur clusters, play key roles in sustaining life and are intimately involved in the functions of metalloproteins. Herein we report the formation and crystal structure of a planar square tetranuclear silver cluster when silver ions were mixed with human copper chaperone Atox1. Quantum chemical studies reveal that two Ag 5s¹ electrons in the tetranuclear silver cluster fully occupy the one bonding molecular orbital, with the assumption that this Ag₄ cluster is Ag₄²⁺, leading to extensive electron delocalization over the planar square and significant stabilization. This bonding pattern of the tetranuclear silver cluster represents an aromatic all-metal structure that follows a 4n + 2 electron counting rule (n = 0). This is the first time an all-metal aromatic silver cluster was observed in a protein.

Metal clusters, such as iron–sulfur clusters, play key roles in sustaining life and are intimately involved in the functions of metalloproteins.