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.

Injectable body temperature responsive hydrogel for encephalitis treatment via sustained release of nano-anti-inflammatory agents

Skull defects are common in the clinical practice of neurosurgery,and they are easily complicated by encephalitis,which seriously threatens the life and health safety of patients.The treatment of encephalitis is not only to save the patient but also to benefit the society.Based on the advantages of injectable hydrogels such as minimally invasive surgery,self-adaptation to irregularly shaped defects,and easy loading and delivery of nanomedicines,an injectable hydrogel that can be crosslinked in situ at the ambient temperature of the brain for the treatment of encephalitis caused by cranial defects is developed.The hydrogel is uniformly loaded with nanodrugs formed by cationic liposomes and small molecule drugs dexmedetomidine hydrochloride(DEX-HCl),which can directly act on the meninges to achieve sustained release delivery of anti-inflammatory nanodrug preparations and achieve the goal of long-term anti-inflammation at cranial defects.This is the first time that DEX-HCl has been applied within this therapeutic system,which is innovative.Furthermore,this study is expected to alleviate the long-term suffering of patients,improve the clinical medication strategies for anti-inflammatory treatment,promote the development of new materials for cranial defect repair,and expedite the translation of research outcomes into clinical practice.

General anesthetic agents induce neurotoxicity through oligodendrocytes in the developing brain

General anesthetic agents can impact brain function through interactions with neurons and their effects on glial cells.Oligodendrocytes perform essential roles in the central nervous system,including myelin sheath formation,axonal metabolism,and neuroplasticity regulation.They are particularly vulnerable to the effects of general anesthetic agents resulting in impaired proliferation,differentiation,and apoptosis.Neurologists are increasingly interested in the effects of general anesthetic agents on oligodendrocytes.These agents not only act on the surface receptors of oligodendrocytes to elicit neuroinflammation through modulation of signaling pathways,but also disrupt metabolic processes and alter the expression of genes involved in oligodendrocyte development and function.In this review,we summarize the effects of general anesthetic agents on oligodendrocytes.We anticipate that future research will continue to explore these effects and develop strategies to decrease the incidence of adverse reactions associated with the use of general anesthetic agents.

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.

General anesthetic agents induce neurotoxicity through astrocytes

Neuroscientists have recognized the importance of astrocytes in regulating neurological function and their influence on the release of glial transmitters.Few studies,however,have focused on the effects of general anesthetic agents on neuroglia or astrocytes.Astrocytes can also be an important target of general anesthetic agents as they exert not only sedative,analgesic,and amnesic effects but also mediate general anesthetic-induced neurotoxicity and postoperative cognitive dysfunction.Here,we analyzed recent advances in understanding the mechanism of general anesthetic agents on astrocytes,and found that exposure to general anesthetic agents will destroy the morphology and proliferation of astrocytes,in addition to acting on the receptors on their surface,which not only affect Ca^(2+)signaling,inhibit the release of brain-derived neurotrophic factor and lactate from astrocytes,but are even involved in the regulation of the pro-and anti-inflammatory processes of astrocytes.These would obviously affect the communication between astrocytes as well as between astrocytes and neighboring neurons,other neuroglia,and vascular cells.In this review,we summarize how general anesthetic agents act on neurons via astrocytes,and explore potential mechanisms of action of general anesthetic agents on the nervous system.We hope that this review will provide a new direction for mitigating the neurotoxicity of general anesthetic agents.

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.

Non-steroidal anti-inflammatory drugs-induced small intestinal injury and probiotic agents

Intestinal bacteria play a role in the development of non-steroidal anti-inflammatory drugs （NSAID）-induced small intestinal injury. Agents such as probiotics, able to modi~ the gut ecology, might theoretically be useful in preventing small intestinal damage induced by NSAIDs. The clinical studies available so far do suggest that some probiotic agents can be effective in this respect.

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.

Improvement Mechanism of Adhesion Performance of Anti-stripping Agents and Coupling Agents on Asphalt-Aggregate Interface Based on Molecular Dynamics

This study examined the mechanisms for improving the adhesion performance of the asphalt-aggregate interface with two anti-stripping agents and two coupling agents.The investigation of contact behavior between various asphalt-aggregate surfaces was conducted using molecular dynamics(MD)simulations.The interaction energy and the relative concentration distribution were employed as the parameters to analyze the enhancement mechanisms of anti-stripping agents and coupling agents on the asphalt-aggregate interface.Results indicated that the adhesion at the asphalt-aggregate interface could be strengthened by both anti-stripping agents and coupling agents.Anti-stripping agents primarily improve adhesion through the reinforcement of electrostatic attraction,while coupling agents primarily upgrade adhesion by strengthening the van der Waals.Hence,the molecular dynamics modeling and calculation techniques presented in this study can be utilized to elucidate the development mechanism of the asphalt-aggregate interface through the use of anti-stripping agents and coupling agents.

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.

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.

Pharmacological effects of bioactive agents in earthworm extract:A comprehensive review

This review compiles information from the literature on the chemical composition,pharmacological effects,and molecular mechanisms of earthworm extract(EE)and suggests possibilities for clinical translation of EE.We also consider future trends and concerns in this domain.We summarize the bioactive components of EE,including G-90,lysenin,lumbrokinase,antimicrobial peptides,earthworm serine protease(ESP),and polyphenols,and detail the antitumor,antithrombotic,antiviral,antibacterial,anti-i nflammatory,analgesic,antioxidant,wound-healing,antifibrotic,and hypoglycemic activities and mechanisms of action of EE based on existing in vitro and in vivo studies.We further propose the potential of EE for clinical translation in anticancer and lipid-modifying therapies,and its promise as source of a novel agent for wound healing and resistance to antibiotic tolerance.The earthworm enzyme lumbrokinase embodies highly effective anticoagulant and thrombolytic properties and has the advantage of not causing bleeding phenomena due to hyperfibrinolysis.Its antifibrotic properties can reduce the excessive accumulation of extracellular matrix.The glycolipoprotein extract G-90 can effectively scavenge reactive oxygen groups and protect cellular tissues from oxidative damage.Earthworms have evolved a well-developed defense mechanism to fight against microbial infections,and the bioactive agents in EE have shown good antibacterial,fungal,and viral properties in in vitro and in vivo experiments and can alleviate inflammatory responses caused by infections,effectively reducing pain.Recent studies have also highlighted the role of EE in lowering blood glucose.EE shows high medicinal value and is expected to be a source of many bioactive compounds.

Design and Synthesis of Some Enaminonitrile Derivatives of Antipyrine as Potential Novel Anti-Inflammatory and Analgesic Agents

The starting (1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)carbon-hydrazonoyl dicyanide (2) was used as a key intermediate for the syntheses of novel acyclic enaminonitriles 3-10. The newly synthesized compounds were characterized by elemental analyses and spectral data (IR, 1H NMR, 13C NMR and mass spectra). The anti-inflammatory activity data indicated that many of tested compounds protected rats from carrageenan-induced inflammation, and tested compounds 3, 4, 9 and 10 were the most potent among tested compounds. The analgesic activity was determined by the hot plate test (central analgesic activity) and acetic acid induced writhing assay. The results revealed that compounds 3, 4, 9, and 10 exhibited significant activity. However, compound 10 proved to have better or equivalent activities in comparison to the reference drug.

Can soil remediation agents synergistically mitigate rice Cd content and CH_(4)emission from karst paddies?

Rice(Oryza sativa L.)paddies are increasingly threatened by cadmium(Cd)pollution,and potentially serve as CH_(4)emitters to the atmosphere.Remediation agents widely mitigate Cd pollution in paddy soil,however,we know little about their regulations on CH_(4)emission.Here,via adding biochar(B),sulfhydryl-modified palygorskite(SMP),and selenium foliar fertilizer(SFF),we conducted a pot experiment to investigate soil and rice Cd contents together with in-situ CH_(4)f luxes.Compared to CK,the addition of SMP,SFF,and B-SMP reduced Cd in brown rice by 25%to 50%,25%,and 50%to 75%,respectively.Agents 7%B,7%B-0.01%SMP,and SFF reduced CH_(4)emissions by 8.46%,5.30%,and 4.11%,respectively.CH_(4)emission increased gradually along the growing season,with the cumulative CH_(4)fluxes ranging between 338.82 and 619.13 kg hm^(-2).Our results highlight that mixed 7%B-0.01%SMP and SFF showed collaborative eff ects on Cd remediation and CH_(4)emission.This study reveals the feasibility of reducing Cd pollution and CH_(4)emission in karst rice paddies,which hopes to supplement the knowledge of collaborative controls on soil remediation and carbon emission.

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.

Travel Agents Around the World Praising the Trip to China

Foreign tourists'trips to China recently reached a new height,both online and offline.Travel agents around the world also made trips to China,generating more thoughts for the development of new routes and the design of innovative tourist products,and contributing to the development of China's inbound tourism.

Effectiveness of Chromated Copper Arsenate against Deteriorating Agents of Eucalyptus Poles and Posts in Four Eco-Regions in Kenya

Previous studies done elsewhere have shown that Eucalyptus poles treated with chromated copper arsenate (CCA) can last over 30 years. Kenya is exceptional because in some eco-regions, the Eucalyptus poles’ life span has greatly reduced to 5 years. The current study was designed to evaluate wood deteriorating agents of CCA-treated Eucalyptus poles and variability in four eco-regions of Kenya, namely, dryland, coastal, highland and humid lake. A total of 360 Eucalyptus pole samples were used for this experiment. Three CCA treatments were used to treat transmission poles at 20 kg/cm3 fencing posts samples at 6 kg/cm3, and a control group. Results indicated that termites and wood-decay fungi attacks caused wood deterioration in the four eco-regions. The proportion of power transmission pole degradation by wood deteriorating agents varied across eco-regions, between treatments and control and between time after treatments. Dryland eco-regions had the highest termite-related degradation (41.82%) while wood-decay fungi attack was highest in the highland eco-regions (9.20%). Samples treated with 6 kg/cm3 recorded the lowest level of wood deterioration, manifested by minimal superficial termite and wood-decay fungi attack. Samples treated with 20 kg/cm3 were characterized by moderate termite and wood-decay fungi attacks observed around the heartwood region, unlike sapwood. This study concluded that the deterioration of Eucalyptus CCA-treated poles is a question of climatic variability and hence, to increase the poles’ lifespan, CCA treatment should be tailored according to the characteristics of the ecoregion of use. Further investigations will inform the diversity of termites and decay-fungi across different eco-regions.

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.