Synthesis of Pyrroles and Condensed Pyrroles as Anti-Inflammatory Agents with Multiple Activities and Their Molecular Docking Study

We herein disclose a series of novel pyrrole derivatives as well as fused pyrrolopyridines 6a,b and 7a,b, pyrrolopyrazoles 8a, b, pyrrolo[2,3-d]pyrimidine derivatives 10a-d, 12a,b, 14a,b, 18a,b, 20a,b, 21a,b, 22a,b, 23a,b, 24a,b, 31a,b, 36a,b, 40a,b, pyrrolo[1,2,6]thiadiazine derivatives 19a,b, pyrrolotriazolopyrimidines 25a,b, 26a,b, 27a,b and 28a,b, pyrrolo[2,3-d][1,2,3]triazine derivatives 32a,b and pyrrolo[2,3-d][1,3]oxazine derivatives 39a,b as novel compounds. All compounds were evaluated for their anti-inflammatory, analgesic (compared to the reference drug Indomethacin) and antimicrobial activities (compared to the reference drug Ampicillin and Fluconazole). Compounds 4d, 5b-d, 6a,b, 9c,d, 10d, 12ab, 13b, 19a,b, 21b, 23b, 31a,b, 38b and 40a were found to be the most active anti-inflammatory drugs exhibiting potency ranging from 1 - 1.01 compared to the reference drug indomethacin. In addition to docking study of these highly active twenty compounds against the active site of cyclooxygenase-2 enzyme (COX-2), among the tested compounds, compounds 5d, 9d, 11b, 12a, 13b and 32a showed multiple activities;anti-inflammatory, analgesic and anti-bacterial activities.

New innovation of moisturizers containing non-steroidal anti-inflammatory agents for atopic dermatitis

Atopic dermatitis is a chronic, relapsing and extremely pruritic eczematous disease which commonly affects children. The standard management consists of a combination of anti-inflammatory drugs in adjunctive with skin care management particular moisturizer application. A concern for the side effects associated with long term use of corticosteroids has also been considered. There has been an emerging interest in moisturizer containing non-steroidal anti-inflammatory agents such as herbal extracts, vitamins, mineral and lipids. The in vitro and the in vivo studies of each agent were reviewed. The clinical study on the efficacy of moisturizers containing these agents were also demonstrated including the author's studies and clinicalexperience. These moisturizers might be considered as an alternative treatment in acute flare of mild to moderate atopic dermatitis.

Progress in the Use of Glucocorticoids and Biological Agents in Non-Infectious Uveitis

One of the main immune-mediated diseases that lead to avoidable blindness is non-infectious uveitis. Glucocorticoids are the first-line therapy choice for noninfectious uveitis;however, biologics are also showing promise in the management of this condition. The description of glucocorticoid and biologic usage in non-infectious uveitis is the main topic of this paper.

Near-Infrared Fluorescence Imaging Contrast Agents for Clinical Research: Limitations and Alternatives

Introduction: Near-infrared fluorescence imaging is a technique that will establish itself in the short term at the international level because it is recognized for its potential to improve the performance of surgical interventions, its moderate investment and operating costs and its portability. Although the technology is now mature, there is currently the problem of the availability of contrast agents to be injected IV. The aim of this methodology article is to propose an alternative solution to the need for contrast agents for clinical research, particularly in oncology. Methodology: They consist of coupling a fluorescent marker in the form of an NHS derivative, such as IR DYE manufactured in compliance with GMP, with therapeutic monoclonal antibodies having marketing authorization for molecular imaging. For a given antibody, the marking procedure must be the subject of a validation file on the final preparation filtered on a sterilizing membrane at 0.22 μm. Once the procedure has been validated, it would be unnecessary to repeat the tests before each clinical research examination. A check of the marking by thin-layer chromatography (TLC) and place it in a sample bank at +4˚C for 1 month of each injected formulation would be sufficient for additional tests if necessary. Conclusion: Molecular near-infrared fluorescence imaging is experiencing development, the process of which could be accelerated by greater availability of clinical contrast agents. Alternative solutions are therefore necessary to promote clinical research in this area. These methods must be shared to make it easier for researchers.

Effects of virtual agents on interaction efficiency and environmental immersion in MR environments

Background Physical entity interactions in mixed reality(MR)environments aim to harness human capabilities in manipulating physical objects,thereby enhancing virtual environment(VEs)functionality.In MR,a common strategy is to use virtual agents as substitutes for physical entities,balancing interaction efficiency with environmental immersion.However,the impact of virtual agent size and form on interaction performance remains unclear.Methods Two experiments were conducted to explore how virtual agent size and form affect interaction performance,immersion,and preference in MR environments.The first experiment assessed five virtual agent sizes(25%,50%,75%,100%,and 125%of physical size).The second experiment tested four types of frames(no frame,consistent frame,half frame,and surrounding frame)across all agent sizes.Participants,utilizing a head mounted display,performed tasks involving moving cups,typing words,and using a mouse.They completed questionnaires assessing aspects such as the virtual environment effects,interaction effects,collision concerns,and preferences.Results Results from the first experiment revealed that agents matching physical object size produced the best overall performance.The second experiment demonstrated that consistent framing notably enhances interaction accuracy and speed but reduces immersion.To balance efficiency and immersion,frameless agents matching physical object sizes were deemed optimal.Conclusions Virtual agents matching physical entity sizes enhance user experience and interaction performance.Conversely,familiar frames from 2D interfaces detrimentally affect interaction and immersion in virtual spaces.This study provides valuable insights for the future development of MR systems.

Effects of Water-retaining Agents on Growth, Development, Yield and Quality of Soybean under Drought Stress

[Objectives]The paper was to explore the effects of different doses of water-retaining agent on the growth and development indicators,yield and quality of soybean plants subjected to drought stress.[Methods]The effects of drought stress(MDS)and drought stress with low(MDS-L),medium(MDS-M)and high doses(MDS-H)of the water-retaining agent on the growth and development indicators,root activity,MDA content,antioxidant enzyme activity,yield and quality of soybean were studied by field plot test,with the normal water supply serving as the control(CK).[Results]In response to drought stress,the plant height,stem diameter,and yield of soybean exhibited a notable decline.Additionally,the contents of protein,fat,linoleic acid,and linolenic acid in seeds demonstrated a significant reduction.Conversely,the root activity and antioxidant enzyme activity exhibited a noticeable decline,while the MDA content exhibited an increase.The application of varying doses of the water-retaining agent was found to significantly enhance soybean growth,stimulate root activity,and elevate antioxidant enzyme activity,while concurrently reducing MDA content.The observed effects were found to be dose-dependent,with the greatest effects observed at the highest dose.In comparison to MDS,the yields of soybean in the MDS-L,MDS-M,and MDS-H treatments exhibited a 18.38%,25.58%,and 46.26%increase,respectively.Additionally,the content of protein,fat,linoleic acid,and linolenic acid in seeds demonstrated a notable enhancement.[Conclusions]The application of the water-retaining agent has been demonstrated to significantly promote the growth of soybean plants under conditions of drought stress,resulting in an improvement in both the yield and the quality of the soybean crop.The recommended dosage of the water-retaining agent is 3.3 kg/667 m 2.

Optimizing Grey Wolf Optimization: A Novel Agents’ Positions Updating Technique for Enhanced Efficiency and Performance

Grey Wolf Optimization (GWO) is a nature-inspired metaheuristic algorithm that has gained popularity for solving optimization problems. In GWO, the success of the algorithm heavily relies on the efficient updating of the agents’ positions relative to the leader wolves. In this paper, we provide a brief overview of the Grey Wolf Optimization technique and its significance in solving complex optimization problems. Building upon the foundation of GWO, we introduce a novel technique for updating agents’ positions, which aims to enhance the algorithm’s effectiveness and efficiency. To evaluate the performance of our proposed approach, we conduct comprehensive experiments and compare the results with the original Grey Wolf Optimization technique. Our comparative analysis demonstrates that the proposed technique achieves superior optimization outcomes. These findings underscore the potential of our approach in addressing optimization challenges effectively and efficiently, making it a valuable contribution to the field of optimization algorithms.

Factors Influencing Compliance with Safe Handling Requirements of Anticancer Agents by Nurses in a Tertiary Hospital-A Secondary Publication

Purpose:This research aimed to identify leading factors that affect nurses’compliance with the safe handling of anticancer agents.Methods:Data were collected from 114 nurses working in the university hospital and were analyzed through independent t-test,one-way ANOVA,Pearson’s correlation coefficient,and multiple regression analysis using SPSS25.0.Results:The average level of compliance with the safe handling of anticancer agents was 3.73±0.33 out of 5 points.Workplace safety culture(β=0.40,P<0.001)and knowledge of safe handling(β=0.18,P=0.030)had significant influences on nurses’compliance with the safe handling of anticancer agents.The explained variance for compliance was 28.3%.Conclusion:To enhance the implementation of safety management for anticancer agents,each institution should strive to support human and material resources and enhance specialization in the workplace safety culture through system improvement.Based on the results of this study,we suggest research for the development of a training program for anticancer agent safety management.

Anti-Cancer Agents Associated Diarrhea:Current Status and Prospects

Cancer stands as one of the major threats to human life.Ensuring the safety of drugs is paramount,and the impact of adverse reactions on patients’quality of life and prognosis should not be underestimated.Diarrhea is a common clinical adverse event,and despite the absence of specific anti-diarrhea drugs,there is a pressing need for improvement.This article aims to provide a valuable reference for researchers in clinical drug use and scientific tumor treatment.It summarizes recent advancements in drug mechanisms and adverse reactions,whether in preclinical research or clinical diagnosis and therapy.

基于免疫Agent的电力电缆线路故障检测系统

为区别故障信号、非故障信号,实现对电缆线路故障的准确检测,设计了基于免疫Agent的电力电缆线路故障检测系统。利用前端检测电路为故障分析模块、测距方式切换模块提供电量传输信号,完成系统前端检测装置的连接。按照免疫Agent检测原理提取电力电缆线路故障信号的特征,联合已获取信号对象,求解检测插值指标的具体数值。结合各级硬件设备结构,完成系统设计。实验结果表明,该系统可同时检测波频为10~20 Hz、40~50 Hz、60~70 Hz的故障信号与波频为20~30 Hz、30~40 Hz、50~60 Hz的非故障信号,可以在精准辨别故障与非故障信号的同时,实现对电力电缆线路故障的准确检测。

基于Agent人工智能的异构网络多重覆盖节点入侵检测系统设计

异构网络具有结构复杂、多重覆盖面积大等特征,使得网络入侵检测较为隐蔽,威胁网络运行的安全性;为此,对基于Agent人工智能的异构网络多重覆盖节点入侵检测系统进行了研究;通过检测Agent和通信Agent装设主机Agent,以Cisco Stealthwatch流量传感器作为异构网络传感器检测攻击行为,采用STM32L151RDT664位微控制器传输批量数据,由MAX3232芯片实现系统电平转化,实现硬件系统设计;软件部分设计入侵检测标准,采用传感器设备捕获网络实时数据,通过Agent技术解析异构网络协议并提取数据运行特征,综合考虑协议解析结果及与检测标准匹配度,实现异构网络多重覆盖节点入侵检测;经实验测试表明,基于Agent人工智能的异构网络多重覆盖节点入侵检测系统入侵行为的漏检率和入侵类型误检率的平均值仅为6%和5%,能够有效提高检测精度,减小检测误差。

基于Multi-Agent的无人机集群体系自主作战系统设计

针对无人集群自主作战体系设计中的关键问题,提出基于Multi-Agent的无人集群自主作战系统设计方法。建立无人集群各节点的Agent模型及其推演规则;对于仿真系统模块化和通用化的需求,设计系统互操作式接口和无人集群自主作战的交互关系;开展无人集群系统仿真推演验证。仿真结果表明,所提设计方案不仅能够有效开展并完成自主作战网络生成-集群演化-效能评估的全过程动态演示验证,而且能够通过重复随机试验进一步评估无人集群的协同作战效能,最后总结了集群协同作战的策略和经验。

基于多Agent传动关系的股市趋势预测

股市趋势预测是机器学习领域中一个具有挑战性的任务。由于一些因素对于股市的影响是动态且不确定的,导致股市趋势难以预测。针对已有方法在股市预测时存在的灵敏性差、适应力弱等问题,从快变量和慢变量的传动关系出发,利用Agent技术对股市中的快周期和慢周期进行联合建模,提出一种多Agent传动影响图(MATID)股市趋势预测方法。给出股市中快周期和慢周期的划分标准,并引入周期能量的概念;通过对相关趋势指标的特征融合,给出周期能量的量化计算方法;通过分析快周期和慢周期的动态作用过程,给出传动因子的表示方法;将快周期和慢周期分别对应成不同的Agent,利用多Agent影响图模型建模快周期和慢周期的传动过程;利用股市振子模型表示快Agent和慢Agent之间的传动效用,利用联合树的自动推理技术对股市趋势进行预测。在不同样本数量和不同股市趋势下进行实验,结果表明,与门控循环单元、S-LSTM和Hybrid-RNN预测方法相比,MATID方法预测精确率提升1.5%~7.0%,召回率提升5.4%~6.7%,F1值提升3.7%~6.2%,具有良好的灵敏性和适应力。

Influence ofβ-nucleating Compound Agents on the Mechanical Properties and Crystallization Behavior of Polypropylene Random Copolymer

A novel polypropylene random(PPR)composite materials with optimized properties was developed by addingβ-nucleating compound agents(rare earth complex WBG-2 and aryl amide derivative TMB-5)and ternary compound modifier(TPE/WBG-2/CaCO_(3)).The effects of differentβ-nucleating agents and ternary compound modifier on the mechanical properties and crystallization behavior of PPR were analyzed.The results show that,compared with pure PPR materials,both WBG-2 and TMB-5 could significantly improve the impact strength of PPR.The crystallization temperature of PPR increased with the addition ofβ-nucleating agent.The modified PPR prepared with ternary compound modifier showed the most excellent comprehensive properties.

Novel coumarin–benzimidazole derivatives as antioxidants and safer anti-inflammatory agents

Inspired from occurrence of anti-inflammatory activity of 3-substituted coumarins and antiulcer activity of various 2-substituted benzimidazoles,novel compounds have been designed by coupling coumarin derivatives at 3-position directly or through amide linkage with benzimidazole nucleus at 2-position.The resultant compounds are expected to exhibit both anti-inflammatory and antioxidant activities along with less gastric toxicity profile.Two series of coumarin–benzimidazole derivatives(4a–e and 5a–e)were synthesized and evaluated for anti-inflammatory activity and antioxidant activity.Compounds 4c,4d and 5a displayed good anti-inflammatory(45.45%,46.75%and 42.85%inhibition,respectively,versus 54.54% inhibition by indomethacin)and antioxidant(IC_(50) of 19.7,13.9 and 1.2 mmol/L,respectively,versus 23.4 mmol/L for butylatedhydroxytoluene)activities.Evaluation of ulcer index and in vivo biochemical estimations for oxidative stress revealed that compounds 4d and 5a remain safe on gastric mucosa and did not induce oxidative stress in tissues.Calculation of various molecular properties suggests the compounds to be sufficiently bioavailable.

Synthesis, in vitro and in vivo biological evaluation of novel lappaconitine derivatives as potential anti-inflammatory agents

Lappaconitine(LA),a natural compound with a novel C18-diterpenoid alkaloid skeleton,displayed extensive biological profile.Recent research on LA is focused mainly on its anti-tumor and analgesic effects,and therefore we aimed to investigate its anti-inflammatory potential.A series of novel LA derivatives with various substituents on the 20-N position was designed and synthesized.In the initial screening of LA derivatives against NO production,all the target compounds,except compound E2,exhibited excellent inhibitory ability relative to that of LA.Particularly,compound A4 exhibited the most potent inhibition with IC50 of 12.91 mmol/L.The elementary structureeactivity relationships(SARs)of NO inhibitory activity indicated that replacement of the benzene ring with an electron donating group could improve the anti-inflammatory efficacy.Furthermore,compound A4 shows an anti-inflammatory mechanism by inhibiting NO,PGE2,and TNF-a generation via the suppression of NF-kB and MAPK signaling pathways.Notably,compound A4 could exert a significant therapeutic effect on LPS-induced acute lung injury(ALI)in vivo.Based on the above research,we further investigated the preliminary pharmacokinetic property of A4 in rats.Therefore,compound A4 could be a promising candidate for the development of anti-inflammatory agents in the future.

竞争与合作视角下的多Agent强化学习研究进展

随着深度学习和强化学习研究取得长足的进展,多Agent强化学习已成为解决大规模复杂序贯决策问题的通用方法。为了推动该领域的发展,从竞争与合作的视角收集并总结近期相关的研究成果。该文介绍单Agent强化学习;分别介绍多Agent强化学习的基本理论框架——马尔可夫博弈以及扩展式博弈,并重点阐述了其在竞争、合作和混合三种场景下经典算法及其近期研究进展;讨论多Agent强化学习面临的核心挑战——环境的不稳定性,并通过一个例子对其解决思路进行总结与展望。

Synthesis,characterization and pharmacological evaluation of pyrazolyl urea derivatives as potential anti-inflammatory agents

p38α mitogen activated protein kinase(MAPK) inhibitors provide a novel approach for the treatment of inflammatory disorders.A series of fifteen pyrazolyl urea derivatives(3a-o) were synthesized and evaluated for their p38α MAPK inhibition and antioxidant potential.Compounds 3a-e,3g and 3h showed low micromolar range potency(IC_(50) values ranging from 0.037 ±1.56 to 0.069± 0.07μmol/L)compared to the standard inhibitor SB 203580(IC_(50) = 0.043 + 3.62μmol/L) when evaluated for p38αMAPK inhibition by an immunosorbent-based assay.Antioxidant activity was measured by a 2,2'-diphenyl-1-picryl hydrazyl radical(DPPH) free radical scavenging method and one of the compounds,3c,showed better percentage antioxidant activity(75.06%) compared to butylated hydroxy anisole(71.53%)at 1 mmol/L concentration.Compounds 3a-e,3g and 3h showed promising in vivo anti-inflammatory activity(ranging from 62.25%to 80.93%) in comparison to diclofenac sodium(81.62%).The ulcerogenic liability and lipid peroxidation activity of these compounds were observed to be less in comparison to diclofenac sodium.These compounds also potently inhibited the lipopolysaccharide(LPS)-induced TNF-αrelease in mice(ID_(50) of 3a-c = 19.98,11.32 and 9.67 mg/kg,respectively).Among the screened compounds,derivative 3c was found to be the most potent and its binding mode within the p38α MAPK is also reported.

Cardiac Manifestations with Chemotherapeutic Agents: 5 Fluorouracil-Induced Coronary Artery Vasospasm

5-fluorouracil (5-FU) is a fluorinated, pyrimidine analog, antineoplastic agent that is used in the treatment of several solid organ cancers. Cardiotoxicity is uncommon but life-threatening manifestations such as myocardial infarction may manifest owing to 5-FU-induced coronary artery spasm. Administering smaller doses of the drug, more frequently than not, decreases the risk of cardiotoxicity compared to large doses or with continuous infusions. We present a case of ST-segment elevation in a patient without known coronary artery disease who had presented following continuous 5-FU infusion. Coronary angiogram confirmed absence of coronary artery disease and intravenous calcium channel blockers administration was commensurate with the patient’s improvement in symptoms. We discuss the literature on 5-FU and its association with coronary artery spasm, and also briefly review chemotherapy-induced cardiotoxicities to help better prepare internists and other primary health care providers to face similar challenges, particularly of the uncommon but potentially life-threatening manifestations.

Synthesis and pharmacological properties of naturally occurring prenylated and pyranochalcones as potent anti-inflammatory agents

An efficient approach has been developed for the synthesis of naturally occurring prenylated chalcones viz. kanzonol C （1）, stipulin （2）, crotaorixin （3）, medicagenin （4）, licoagrochalcone A （5） and abyssinone D （6） along with the pyranochalcones paratocarpin C （7）, anthyllisone （8） and 3-O-methylabyssinone A （9）. The key step of the synthesis is a Claisen-Schmidt condensation. Subsequently, their anti-inflammatory effects were investigated in lipopolysaccharides （LPSs）-induced RAW-264.7 macrophages. Of the synthesized chalcones, compounds 5 （IC50= 10.41 μmol[L）, 6 （IC50= 9.65 μmol/L） and 8 （IC50= 15.34 μmol/L） show remarkable activity with no cytotoxicity. Compound 9 （IC50 = 4.5 μmol/L） exhibits maximum （83.6%） nitric oxide （NO） inhibition, but shows slight cytotoxicity. The results reveal that the chalcones bearing the prenyl group at 3- and/or 5-position on ring A （acetophenone moiety）, i.e., 1-4 and 7 show weak, or no inhibition activity, whereas chalcones having the prenyl group only on ring B （aldehyde part）, i.e., 5, 6 and 8 show significant activity on the production of inflammatory mediated NO with no cytotoxicity.