除草剂的作用靶标与作用模式

综述了除草剂的作用靶标与作用模式,并对除草剂按作用靶标进行分类.全面了解除草剂的作用靶标与作用模式,对指导正确的使用除草剂、对抑制或延缓杂草抗性的产生以及抗性杂草的防除都有着重要的意义.同时,对新的除草剂的研究开发也具有积极的指导作用.     

结构新颖的微生物源除草化合物及其作用特点

介绍了近期国内外引人注目的微生物源除草化合物。这些化合物具有新颖的化学结构、新奇的作用机理以及良好的除草活性。     

农用杀菌剂的作用方式与分类

农用杀菌剂品种逐渐增多,按照其作用方式进行分类,不仅有利于新化合物的合成与筛选,而且有助于了解其抗药性以及科学使用。收集了常用杀菌剂（杀真菌剂和杀细菌剂）共181种,分属12种不同的作用方式和75种不同的化合物类别。     

溴虫腈的杀虫活性及作用方式研究

室内测定研究了溴虫腈的生物活性和作用方式。结果表明,溴虫腈对多种农业害虫和害螨具有优异的毒杀活性,作用方式以胃毒活性为主,兼有触杀和杀卵活性,但无明显的根内吸活性。     

In Silico Identification of Small Molecules as New Cdc25 Inhibitors through the Correlation between Chemosensitivity and Protein Expression Pattern

The cell division cycle 25 (Cdc25) protein family plays a crucial role in controlling cell proliferation, making it an excellent target for cancer therapy. In this work, a set of small molecules were identified as Cdc25 modulators by applying a mixed ligand-structure-based approach and taking advantage of the correlation between the chemosensitivity of selected structures and the protein expression pattern of the proposed target. In the first step of the in silico protocol, a set of molecules acting as Cdc25 inhibitors were identified through a new ligand-based protocol and the evaluation of a large database of molecular structures. Subsequently, induced-fit docking (IFD) studies allowed us to further reduce the number of compounds biologically screened. In vitro antiproliferative and enzymatic inhibition assays on the selected compounds led to the identification of new structurally heterogeneous inhibitors of Cdc25 proteins. Among them, J3955, the most active inhibitor, showed concentration-dependent antiproliferative activity against HepG2 cells, with GI₅₀ in the low micromolar range. When J3955 was tested in cell-cycle perturbation experiments, it caused mitotic failure by G2/M-phase cell-cycle arrest. Finally, Western blotting analysis showed an increment of phosphorylated Cdk1 levels in cells exposed to J3955, indicating its specific influence in cellular pathways involving Cdc25 proteins.     

PLATO: A Predictive Drug Discovery Web Platform for Efficient Target Fishing and Bioactivity Profiling of Small Molecules

PLATO (Polypharmacology pLATform predictiOn) is an easy-to-use drug discovery web platform, which has been designed with a two-fold objective: to fish putative protein drug targets and to compute bioactivity values of small molecules. Predictions are based on the similarity principle, through a reverse ligand-based screening, based on a collection of 632,119 compounds known to be experimentally active on 6004 protein targets. An efficient backend implementation allows to speed-up the process that returns results for query in less than 20 s. The graphical user interface is intuitive to give practitioners easy input and transparent output, which is available as a standard report in portable document format. PLATO has been validated on thousands of external data, with performances better than those of other parallel approaches. PLATO is available free of charge (http://plato.uniba.it/ accessed on 13 April 2022).     

鱼尼丁受体抑制剂及其作用机制研究进展

近年来,以鱼尼丁受体(ryanodine receptor,Ry R)为靶标的杀虫剂研发取得了突破性进展。介绍了Ry R结构和功能,以及Ry R为靶标的杀虫剂的创制历程,作用机制的研究进展。该类杀虫剂靶标新颖,作用机理独特、高效,对非靶标生物安全(如哺乳动物等)以及与传统农药无交互抗性,具有很好的发展前景。     

Plant Growth Inhibitory Activity of L-Canavanine and Its Mode of Action

L-Canavanine is a nonprotein amino acid contained in jack bean [Canavalia ensiformis (L.) DC] and shows a plant inhibitory effect. The inhibitory effect was determined by an immersion test and a microdrop test that employed rice seedlings. L-Canavanine inhibited elongation of the second leaf sheath of rice seedlings more than other natural bioactive substances, such as salicylic acid and cinnamic acid. The modified microdrop test revealed that the mode of action of L-canavanine had no relation to gibberellin synthesis. In the microdrop test, the inhibitory effect of L-canavanine was decreased by simultaneous addition of L-arginine, an analog of L-canavanine. Free amino acid analysis of rice shoots clearly showed that L-canavanine induced an unusual accumulation of L-arginine. However, accumulation of L-arginine did not cause the inhibitory effect on plant growth. These results suggest that the mechanism of inhibition of L-canavanine is closely related to the inhibition of arginine metabolism.     

酸类化合物对南方根结线虫的作用方式

[方法]采用室内离体测定方法,测定3种酸类化合物对南方根结线虫2龄幼虫毒力、死亡时间、运动行为、个体发育及体液外渗作用方式影响。[结果]3种化合物对2龄幼虫毒力大小为甲酸>乙二酸>柠檬酸,死亡时间长短为甲酸<乙二酸<柠檬酸,3种化合物均可抑制2龄幼虫运动行为和个体发育,并导致2龄幼虫体液外渗。[结论]供试化合物通过抑制线虫的运动、发育、促进线虫体液外渗等作用,破坏其正常生理代谢功能,致使线虫死亡。     

D-松醇原药及其水剂对黄瓜白粉病的作用方式

[目的]通过室内试验,验证D-松醇原药及其水剂对黄瓜白粉病的作用方式,为D-松醇的田间应用提供理论支持.[方法]配制不同质量浓度的D-松醇原药及其水剂,在不同时间采用温室喷雾法对黄瓜白粉病进行防治试验,调查其防治效果.[结果]试验表明:接种后第3天,原药和水剂分别处理的防效均优于各接种前5、2 d和接种后1 d处理的效果.原药质量浓度梯度实验显示2000 mg/L时,接菌后7d防效达64.52％,其他处理方式的防效均低于50％.20％(质量分数)水剂稀释至3.3％,接菌后7d,防效为93.07％,同比防效最好.[结论]研究表明:D-松醇对黄瓜白粉病有治疗效果,治疗3d的防效效果最好.原药2000mg/L时防效最好,20％的水剂稀释至3.3％防效最好.水剂在减少D-松醇原药用量的基础上,进一步减轻了黄瓜白粉病发病程度,为D-松醇水剂的开发提供了可行性依据.此外,D-松醇原药及其水剂对黄瓜白粉病作用方式的确定为深入研究D-松醇对黄瓜白粉病菌的作用机制提供了依据.     

Primary Mode of Action of the Novel Sulfonamide Fungicide against Botrytis cinerea and Field Control Effect on Tomato Gray Mold

Botrytis cinerea is considered an important plant pathogen and is responsible for significant crop yield losses. With the frequent application of commercial fungicides, B. cinerea has developed resistance to many frequently used fungicides. Therefore, it is necessary to develop new kinds of fungicides with high activity and new modes of action to solve the increasingly serious problem of resistance. During our screening of fungicide candidates, one novel sulfonamide compound, N-(2-trifluoromethyl-4-chlorphenyl)-2-oxocyclohexyl sulfonamide (L13), has been found to exhibit good fungicidal activity against B. cinerea. In this work, the mode of action of L13 against B. cinerea and the field control effect on tomato gray mold was studied. L13 had good control against B. cinerea resistant to carbendazim, diethofencarb, and iprodione commercial fungicides in the pot culture experiments. SEM and TEM observations revealed that L13 could cause obvious morphological and cytological changes to B. cinerea, including excessive branching, irregular ramification or abnormal configuration, and the decomposition of cell wall and vacuole. L13 induced more significant electrolyte leakage from hyphae than procymidone as a positive control. L13 had only a minor effect on the oxygen consumption of intact mycelia, with 2.15% inhibition at 50 μg/mL. In two locations over 2 years, the field control effect of L13 against tomato gray mold reached 83% at a rate of 450 g ai ha⁻¹, better than the commercial fungicide of iprodione. Moreover, toxicological tests demonstrated the low toxicological effect of L13. This research seeks to provide technical support and theoretical guidance for L13 to become a real commercial fungicide.     

Characteristics of MSCs in Synovial Fluid and Mode of Action of Intra-Articular Injections of Synovial MSCs in Knee Osteoarthritis

We have been studying mesenchymal stem cells (MSCs) in synovial fluid and the intra-articular injection of synovial MSCs in osteoarthritis (OA) knees. Here, mainly based on our own findings, we overview the characteristics of endogenous MSCs in the synovial fluid of OA knees and their mode of action when injected exogenously into OA knees. Many MSCs similar to synovial MSCs were detected in the synovial fluid of human OA knees, and their number correlated with the radiological OA grade. Our suspended synovium culture model demonstrated the release of MSCs from the synovium through a medium into a non-contacting culture dish. In OA knees, endogenous MSCs possibly mobilize in a similar manner from the synovium through the synovial fluid and act protectively. However, the number of mobilized MSCs is limited; therefore, OA progresses in its natural course. Synovial MSC injections inhibited the progression of cartilage degeneration in a rat OA model. Injected synovial MSCs migrated into the synovium, maintained their MSC properties, and increased the gene expressions of TSG-6, PRG-4, and BMP-2. Exogenous synovial MSCs can promote anti-inflammation, lubrication, and cartilage matrix synthesis in OA knees. Based on our findings, we have initiated a human clinical study of synovial MSC injections in OA knees.     

AC‐Impedance Investigation of Different MEA Configurations for Passive‐Mode DMFC Mini‐Stack Applications

Membrane‐electrode assemblies (MEAs) characterised by different hydrophobic–hydrophilic properties were investigated in a passive Direct methanol fuel cell (DMFC) monopolar mini‐stack at room temperature. These properties were modulated by varying the amount of Nafion or replacing the ionomer in the catalytic layer with polytetrafluoroethylene (PTFE). Impedance spectroscopy provided valuable information with respect to the limiting processes occurring during fuel cell operation. Methanol crossover, especially in the presence of high methanol concentration, played a major role in determining the overall performance. The development of a methanol impermeable membrane appears crucial for increasing the performance of DMFC devices for portable applications.     

Chemical Validation of DegS As a Target for the Development of Antibiotics with a Novel Mode of Action

Despite the availability of hundreds of antibiotic drugs, infectious diseases continue to remain one of the most notorious health issues. In addition, the disparity between the spread of multidrug-resistant pathogens and the development of novel classes of antibiotics exemplify an important unmet medical need that can only be addressed by identifying novel targets. Herein we demonstrate, by the development of the first in vivo active DegS inhibitors based on a pyrazolo[1,5-a]-1,3,5-triazine scaffold, that the serine protease DegS and the cell envelope stress-response pathway σE represent a target for generating antibiotics with a novel mode of action. Moreover, DegS inhibition is synergistic with well-established membrane-perturbing antibiotics, thereby opening promising avenues for rational antibiotic drug design.     

Lipidation of Temporin-1CEb Derivatives as a Tool for Activity Improvement,Pros and Cons of the Approach

The alarming raise of multi-drug resistance among human microbial pathogens makes the development of novel therapeutics a priority task. In contrast to conventional antibiotics, antimicrobial peptides (AMPs), besides evoking a broad spectrum of activity against microorganisms, could offer additional benefits, such as the ability to neutralize toxins, modulate inflammatory response, eradicate bacterial and fungal biofilms or prevent their development. The latter properties are of special interest, as most antibiotics available on the market have limited ability to diffuse through rigid structures of biofilms. Lipidation of AMPs is considered as an effective approach for enhancement of their antimicrobial potential and in vivo stability; however, it could also have undesired impact on selectivity, solubility or the aggregation state of the modified peptides. In the present work, we describe the results of structural modifications of compounds designed based on cationic antimicrobial peptides DK5 and CAR-PEG-DK5, derivatized at their N-terminal part with fatty acids with different lengths of carbon chain. The proposed modifications substantially improved antimicrobial properties of the final compounds and their effectiveness in inhibition of biofilm development as well as eradication of pre-formed 24 h old biofilms of Candida albicans and Staphylococcus aureus. The most active compounds (C5-DK5, C12-DK5 and C12-CAR-PEG-DK5) were also potent against multi-drug resistant Staphylococcus aureus USA300 strain and clinical isolates of Pseudomonas aeruginosa. Both experimental and in silico methods revealed strong correlation between the length of fatty acid attached to the peptides and their final membranolytic properties, tendency to self-assemble and cytotoxicity.     

Determination of the Velocity Difference between Jet Fragments for a Range of Copper Liners with Different Small Grain Sizes

A range of small calibre shaped charge copper liners were manufactured experimentally by the electro‐deposition technique. The average grain size of the produced copper liners was determined using the SEM technique. The specific breakup time, which represents the velocity difference between the particulated jet neighboring fragments (V_PL), was determined for the range of copper liners of different grain sizes using Zerelli‐Armstrong constitutive model. The specific breakup time and the total number of the jet fragments were studied over the range of grain size and the predicted jet temperature.     

EphB4 as a Novel Target for the EGFR-Independent Suppressive Effects of Osimertinib on Cell Cycle Progression in Non-Small Cell Lung Cancer

Osimertinib is the latest generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor used for patients with EGFR-mutated non-small cell lung cancer (NSCLC). We aimed to explore the novel mechanisms of osimertinib by particularly focusing on EGFR-independent effects, which have not been well characterized. We explored the EGFR-independent effects of osimertinib on cell proliferation using NSCLC cell lines, an antibody array analysis, and the association between the action of osimertinib and the ephrin receptor B4 (EphB4). We also studied the clinicopathological significance of EphB4 in 84 lung adenocarcinoma patients. Osimertinib exerted significant inhibitory effects on cell growth and cell cycle progression by promoting the phosphorylation of p53 and p21 and decreasing cyclin D1 expression independently of EGFR. EphB4 was significantly suppressed by osimertinib and promoted cell growth and sensitivity to osimertinib. The EphB4 status in carcinoma cells was positively correlated with tumor size, T factor, and Ki-67 labeling index in all patients and was associated with poor relapse-free survival in EGFR mutation-positive patients. EphB4 is associated with the EGFR-independent suppressive effects of osimertinib on cell cycle and with a poor clinical outcome. Osimertinib can exert significant growth inhibitory effects in EGFR-mutated NSCLC patients with a high EphB4 status.     

Experimentation of a new mode of batch culture for lactic acid bacteria: cell reuse with an initial period of cell reactivation at acidic pH

Cell reuse was compared with conventional batch culture for lactic acid fermentation, the objective was to simplify the batch process and to alleviate the need for added nitrogen. At high levels of nitrogen supplementation to the culture medium (20 g dm^?3 yeast extract and 5 g dm^?3 each of tryptic and pancreatic casein peptones), similar mean production rates were obtained with partial cell reuse and the conventional batch process, without any additional gain when cells were initially reactivated at acidic pH. On the other hand, cell reuse with an initial period without pH control appeared particularly effective for low levels of nitrogen supplementation (5 g dm^?3 yeast extract): a 57% increase in the mean production rate with regard to the conventional batch process was obtained. © 2001 Society of Chemical Industry     

Review about Powerful Combinations of Advanced and Hyphenated Sample Introduction Techniques with Inductively Coupled Plasma-Mass Spectrometry (ICP-MS) for Elucidating Trace Element Species in Pathologic Conditions on a Molecular Level

Element analysis in clinical or biological samples is important due to the essential role in clinical diagnostics, drug development, and drug-effect monitoring. Particularly, the specific forms of element binding, actual redox state, or their spatial distribution in tissue or in single cells are of interest in medical research. This review summarized exciting combinations of sophisticated sample delivery systems hyphenated to inductively coupled plasma-mass spectrometry (ICP-MS), enabling a broadening of information beyond the well-established outstanding detection capability. Deeper insights into pathological disease processes or intracellular distribution of active substances were provided, enabling a better understanding of biological processes and their dynamics. Examples were presented from spatial elemental mapping in tissue, cells, or spheroids, also considering elemental tagging. The use of natural or artificial tags for drug monitoring was shown. In the context of oxidative stress and ferroptosis iron, redox speciation gained importance. Quantification methods for Fe²⁺, Fe³⁺, and ferritin-bound iron were introduced. In Wilson’s disease, free and exchangeable copper play decisive roles; the respective paragraph provided information about hyphenated Cu speciation techniques, which provide their fast and reliable quantification. Finally, single cell ICP-MS provides highly valuable information on cell-to-cell variance, insights into uptake of metal-containing drugs, and their accumulation and release on the single-cell level.     

Analysis of Enzyme Activity and Cellular Function for the N80S and S480F Asparagine Synthetase Variants Expressed in a Child with Asparagine Synthetase Deficiency

Asparagine Synthetase Deficiency (ASNSD) is a disease caused by mutations in asparagine synthetase (ASNS). Newborns exhibit microcephaly, intractable epileptic-like seizures, progressive brain atrophy, and axial hypotonia. ASNSD results in global developmental delays and premature death. The present report describes a 9-year-old child who is a compound heterozygote with ASNS mutations c.1439C > T and c.239A > G leading to variants p.S480F and p.N80S, respectively. When grown in a complete culture medium, primary fibroblasts from the child contained ASNS mRNA and protein levels similar to an unrelated wild-type fibroblast cell line. When the child’s fibroblasts were cultured for up to 72 h in a medium lacking asparagine, proliferation was reduced by about 50%. Purification of ASNS proteins harboring either the S480F or the N80S substitution had reduced enzymatic activity by 80% and 50%, respectively. Ectopic expression of either variant in ASNS-null Jensen rat sarcoma (JRS) cells did not support proliferation in the absence of medium-supplied asparagine, whereas expression of wild-type enzyme completely restored growth. These studies add to the list of pathogenic ASNS variants and use enzyme activity and protein expression in ASNS-null cells to expand our knowledge of the biological impact of mutations in the ASNS gene.