Potent Anti-inflammatory Compound Research Articles

Total Synthesis and Anti-inflammatory Activity of Stemoamide-Type Alkaloids Including Totally Substituted Butenolides and Pyrroles

AbstractTotally substituted butenolide including two tetrasubstituted olefins is a distinct structural motif seen in Stemona alkaloids, but efficient methods for its synthesis are not well developed. As an ongoing program aimed at the collective total synthesis of the stemoamide group, we report a stereodivergent method to give either (E)- or (Z)-totally substituted butenolide from the same intermediate. While AgOTf­-mediated elimination via an E1-type mechanism results in the formation of the kinetic (Z)-tetrasubstituted olefin, subsequent TfOH-mediated isomerization gives the thermodynamic (E)-tetrasubstituted olefin. The pyrrole ring is another important structure found in Stemona alkaloids. The direct oxidation of pyrrolidine rings with MnO2 and careful purification gives the pyrrole groups without isomerization of the stereocenter in the lactone group. These two methods enabled us to synthesize a series of stemoamide-type alkaloids including tricyclic, tetracyclic, and pentacyclic frameworks. The anti-inflammatory activities by inhibition of iNOS expression in macrophage cell line RAW264.7 indicate that the most potent anti-inflammatory compounds without cytotoxicity are protostemonines, which consist of pentacyclic frameworks including the totally substituted butenolide.

Synthesis, analgesic, anti-inflammatory, ulcerogenic evaluation, and docking study of (benzoylphenoxy)-N-{5-[2-methylphenyl-6-chlorobenzoxazole]} acetamides as COX/5-LOX inhibitor

The COX and 5-LOX inhibitors with analgesic and anti-inflammatory effectiveness and very less gastrointestinal toxicity have been recognized as constructive and sustainable agents for inflammatory treatment. In this approach, a series of titled compounds (10a-j) were developed, synthesized, and evaluated in terms of in-vitro COX and LOX enzyme inhibition followed by analgesic, anti-inflammatory, and the ulcerogenic activity. The anti-inflammatory evaluation was conducted on those compounds 10a-c, 10e, and 10g-10i that displayed potential analgesic activity and later, validated for the ulcerogenic effect of potent anti-inflammatory compounds. The compound 10b with ortho substitution of methyl and para substitution of chloro groups on the phenyl ring and meta substitution of chloro group on benzoyl ring of benzophenone appended to benzoxazole was observed to have good inhibitory potency. Furthermore, Autodock tools docking software was used to carry out the in silico studies.

Flavonols and Flavones as Potential anti-Inflammatory, Antioxidant, and Antibacterial Compounds.

Plant preparations have been used to treat various diseases and discussed for centuries. Research has advanced to discover and identify the plant components with beneficial effects and reveal their underlying mechanisms. Flavonoids are phytoconstituents with anti-inflammatory, antimutagenic, anticarcinogenic, and antimicrobial properties. Herein, we listed and contextualized various aspects of the protective effects of the flavonols quercetin, isoquercetin, kaempferol, and myricetin and the flavones luteolin, apigenin, 3′,4′-dihydroxyflavone, baicalein, scutellarein, lucenin-2, vicenin-2, diosmetin, nobiletin, tangeretin, and 5-O-methyl-scutellarein. We presented their structural characteristics and subclasses, importance, occurrence, and food sources. The bioactive compounds present in our diet, such as fruits and vegetables, may affect the health and disease state. Therefore, we discussed the role of these compounds in inflammation, oxidative mechanisms, and bacterial metabolism; moreover, we discussed their synergism with antibiotics for better disease outcomes. Indiscriminate use of antibiotics allows the emergence of multidrug-resistant bacterial strains; thus, bioactive compounds may be used for adjuvant treatment of infectious diseases caused by resistant and opportunistic bacteria via direct and indirect mechanisms. We also focused on the reported mechanisms and intracellular targets of flavonols and flavones, which support their therapeutic role in inflammatory and infectious diseases.

Exploring potential antidiabetic and anti-inflammatory flavonoids from Euphorbia humifusa with an integrated strategy.

E. humifusa Willd, a monoecious annual plant, native to Eastern Asia, has been traditionally attributed to the treatment and prevention of miscellaneous diseases, including diabetes mellitus and its associated complications. Earlier studies have supported this species’ pharmacological efficacies including its antibacterial, antidiabetic, and anti-inflammatory properties. Even so, the underlying bioactive components with their mechanisms of action associated with its antidiabetic and anti-inflammatory effects remain elusive. The preamble in vitro assessments of the crude extract and its different fractions revealed that the n-butanol fraction (EHNB) exhibited the best activity, which was subsequently subjected to a rapid screening of candidate ligands through bio-affinity ultrafiltration with the two enzyme targets: α-glucosidase (α-Glu) and cycloxygenase-2 (COX-2) combined with UPLC/QTOF-MS. As a result, 7 compounds were identified from EHNB, among them, vitexin and astragalin were screened out as the most active ligand compounds. Vitexin showed great specific binding (SB) affinity values of 1.26 toward α-Glu and 1.32 toward COX-2, while astragalin showed 1.32 and 1.36, respectively. The docking simulation results exhibited strong interactions of vitexin and astragalin with the key residues of the enzyme targets, suggesting their possible mechanisms of action. The in vitro antidiabetic validation revealed noticeable half-maximal inhibitory effects (IC50) of 36.38 ± 3.06 µM for vitexin and 42.47 ± 4.13 µM for astragalin, much better than that of the positive drug acarbose (109.54 ± 14.23 µM). Similarly, these two compounds showed the inhibitory activity against COX-2 with the half-maximal inhibitory effects (IC50) at 27.91 ± 1.74 µM and 49.05 ± 1.49 µM, respectively. Therefore, these two flavonoid compounds (vitexin and astragalin) were speculated as potential antidiabetic and anti-inflammatory compounds from E. humifusa. Taken together, the integrated strategy applied to E. humifusa led to the fast identification of two potential double-acting flavonoids and enlightened its antidiabetic and anti-inflammatory uses. Besides these findings, the integrated strategy in this study could also be used to facilitate the rapid discovery and development of active candidates from other traditional herbal medicines against multi-drug targets and to aid in revealing their mechanisms of action for their traditional uses.

Plant Bioactives in the Treatment of Inflammation of Skeletal Muscles: A Molecular Perspective.

Skeletal muscle mass responds rapidly to growth stimuli, precipitating hypertrophies (increased protein synthesis) and hyperplasia (activation of the myogenic program). For ages, muscle degeneration has been attributed to changes in the intracellular myofiber pathways. These pathways are tightly regulated by hormones and lymphokines that ultimately pave the way to decreased anabolism and accelerated protein breakdown. Despite the lacunae in our understanding of specific pathways, growing bodies of evidence suggest that the changes in the myogenic/regenerative program are the major contributing factor in the development and progression of muscle wasting. In addition, inflammation plays a key role in the pathophysiology of diseases linked to the failure of skeletal muscles. Chronic inflammation with elevated levels of inflammatory mediators has been observed in a spectrum of diseases, such as inflammatory myopathies and chronic obstructive pulmonary disease (COPD). Although the pathophysiology of these diseases varies greatly, they all demonstrate sarcopenia and dysregulated skeletal muscle physiology as common symptoms. Medicinal plants harbor potential novel chemical moieties for a plenitude of illnesses, and inflammation is no exception. However, despite the vast number of potential antiinflammatory compounds found in plant extracts and isolated components, the research on medicinal plants is highly daunting. This review aims to explore the various phytoconstituents employed in the treatment of inflammatory responses in skeletal muscles, while providing an in-depth molecular insight into the latter.

Synthesis of Isoindoline-1,3-Dione Derivatives as Cyclooxygenase (Cox) S Inhibitors

Inflammation is the vital part of the immune system's response to injury and infection. It is the body's way of signaling the immune system to heal and repair damaged tissue. The objective of this paper is to design and synthesize a new isoindoline 1,3-dinoe derivative and investigate their selective anti inflammatory activity to COXs. As a potential anti-inflammatory compound, Isoindoline-1,3-dione derivatives were synthesized from the addition reaction of phthalimide, formaldehyde, catalytic amount of potassium hydroxide and cyclic amine in ethanol yielded the desired Isoindoline-1,3-dione compounds (ZJ1-ZJ6. 1H- NMR, ¹³C-NMR, FT-IR and elemental analysis were consistent with the assigned structures. Isoindoline-1,3-dione derivatives exhibited good inhibitory activity against the COX enzymes. To explain the result of our investigation to COX-1 and COX-2 and the selectivity of our compounds to either COX-1 or COX-2, the rationalization in COX-1, the amino group participate more effectively in binding with the ligand while in COX-2, the aryl group is more effective in binding to the ligand. The amino acetylenic compounds behave differently toward COXs from our compound. ZJ4 have shown some selective COX-1 ligand efficiency while ZJ1 promised a potent blockage and ligand efficiency toward the COX-2 enzyme which was found to be higher than the marketed drug Indomethacin and near potency score of Celecoxib. For the first time, this indicates the requirement of investigating the removal of acetylenic group in this study showed that it might be a different binding site in COXs which may result in effective compounds.

Structure and Anti-Inflammatory Activity Relationship of Ergostanes and Lanostanes in Antrodia cinnamomea.

Antrodia cinnamomea is a precious edible mushroom originating from Taiwan that has been popularly used for adjuvant hepatoprotection and anti-inflammation; however, the chemical principle for its anti-inflammatory activity has not been elucidated, which prevents the quality control of related products. Using the RAW264.7 model for the anti-inflammatory activity assay as a guide, we reported the isolation and structural elucidation of three potent anti-inflammatory compounds from isolated ergostanes (16) and lanostanes (6). Their structures were elucidated on the basis of spectroscopic data analysis including NMR and HR-QTOF-MS. Particularly, the absolute configurations of (25R)-antcin K, (25R)-antcin A, versisponic acid D, and (25R)-antcin C were determined by single crystal X-ray diffraction (XRD). The representative and most promising compound antcin A was shown to suppress pro-inflammatory biomolecule release via the down-regulation of iNOS and COX-2 expression through the NF-κB pathway while the mRNA levels of IL-1β, TNF-α and IL-6 were also decreased. The high dependency on structural variation and activity suggests that there might be special biological targets for antcin A. Our work makes it possible to develop evidence-based dietary supplements from Antrodia cinnamomea based on anti-inflammatory constituents.

Autoxidation-Resistant, ROS-Scavenging, and Anti-Inflammatory Micellar Nanoparticles Self-Assembled from Poly(acrylic acid)-Green Tea Catechin Conjugates.

(-)-Epigallocatechin-3-O-gallate (EGCG), the most bioactive catechin in green tea, has drawn significant interest as a potent antioxidant and anti-inflammatory compound. However, the application of EGCG has been limited by its rapid autoxidation at physiological pH, which generates cytotoxic levels of reactive oxygen species (ROS). Herein, we report the synthesis of poly(acrylic acid)-EGCG conjugates with tunable degrees of substitution and their spontaneous self-assembly into micellar nanoparticles with enhanced resistance against autoxidation. These nanoparticles not only exhibited superior oxidative stability and cytocompatibility over native EGCG, but also showed excellent ROS-scavenging and anti-inflammatory effects. This work presents a potential strategy to overcome the stability and cytotoxicity issues of EGCG, making it one step closer toward its widespread application.

Screening and Isolation of Potential Anti-Inflammatory Compounds from Saxifraga atrata via Affinity Ultrafiltration-HPLC and Multi-Target Molecular Docking Analyses.

In this study, a 100 g sample of Saxifraga atrata was processed to separate 1.3 g of 11-O-(4′-O-methylgalloyl)-bergenin (Fr1) after 1 cycle of MCI GEL® CHP20P medium pressure liquid chromatography using methanol/water. Subsequently, COX-2 affinity ultrafiltration coupled with reversed-phase liquid chromatography was successfully used to screen for potential COX-2 ligands in this target fraction (Fr1). After 20 reversed-phase liquid chromatography runs, 74.1 mg of >99% pure 11-O-(4′-O-methylgalloyl)-bergenin (Fr11) was obtained. In addition, the anti-inflammatory activity of 11-O-(4′-O-methylgalloyl)-bergenin was further validated through molecular docking analyses which suggested it was capable of binding strongly to ALOX15, iNOS, ERBB2, SELE, and NF-κB. As such, the AA metabolism, MAPK, and NF-κB signaling pathways were hypothesized to be the main pathways through which 11-O-(4′-O-methylgalloyl)-bergenin regulates inflammatory responses, potentially functioning by reducing pro-inflammatory cytokine production, blocking pro-inflammatory factor binding to cognate receptors and inhibiting the expression of key proteins. In summary, affinity ultrafiltration-HPLC coupling technology can rapidly screen for multi-target bioactive components and when combined with molecular docking analyses, this approach can further elucidate the pharmacological mechanisms of action for these compounds, providing valuable information to guide the further development of new multi-target drugs derived from natural products.

Structural characterization and antagonistic effect against P-selectin-mediated function of SFF-32, a fucoidan fraction from Sargassum fusiforme

Ethnopharmacological relevanceSargassum fusiforme (Harvey) Setchell, or Haizao, has been used in traditional Chinese medicine (TCM) since at least the eighth century a.d. S. fusiforme is an essential component of several Chinese formulas, including Haizao Yuhu Decoction, used to treat goiter, and Neixiao Lei Li Wan used to treat scrofuloderma. The pharmacological efficacy of S. fusiforme may be related to its anti-inflammatory effect. Aim of the studyTo determine the structural characteristics of SFF-32, a fucoidan fraction from S. fusiforme, and its antagonistic effect against P-selectin mediated function. Materials and methodsThe primary structure of SFF-32 was determined using methylation/GC–MS and NMR analysis. Surface morphology and solution conformation of SFF-32 were determined by scanning electron microscopy (SEM), Congo red test, and circular dichroic (CD) chromatography, respectively. The inhibitory effects of SFF-32 against the binding of P-selectin to HL-60 cells were evaluated using flow cytometry, static adhesion assay, and parallel-plate flow chamber assay. Furthermore, the blocking effect of SFF-32 on the interaction between P-selectin and PSGL-1 was evaluated using an in vitro protein binding assay. ResultsThe main linkage types of SFF-32 were proven to →[3)-α-l-Fucp-(1→3,4)-α-l-Fucp-(1]2→[4)-β-d-Manp-(1→3)-d-GlcAp-(1]2→4)-β-d-Manp-(1→3)-β-d-Glcp-(1→4)-β-d-Manp-(1→2,3)-β-d-Galp-(1→4)-β-d-Manp-(1→[4)-α-l-Rhap-(1]3→. The sulfated unit or terminal xylose residues were attached to the backbone through the C-3 of some fucose residues and terminal xylose residues were attached to C-3 of galactose residues. Moreover, SFF-32 disrupted P-selectin-mediated cell adhesion and rolling as well as blocked the interaction between P-selectin and its physiological ligand PSGL-1 in a dose-dependent manner. ConclusionsBlocking the binding between P-selectin and PSGL-1 is the possible underlying mechanism by which SFF-32 inhibits P-selectin-mediated function, which demonstrated that SFF-32 may be a potential anti-inflammatory lead compound.

Bioactivity Study of Tricyclic and Tetracyclic Genipin Derivatives as Anti-inflammatory Agents

A series of genipin derivatives included tricyclic cyclopentaimidazopyridine, cyclopentapyridopyrimidine, octahydrocyclopentapyridodiazepine, and tetracyclic decahydrobenzoimidazocyclopentapyridine were synthesized and developed as anti-inflammatory agents. All of them were tested against NO production in LPS-induced RAW264.7 cells. Based on IC50 data and the SAR study, we found that tricyclic cyclopentaimidazopyridines 3d–f and 7–9 presented the better inhibitory activities (≦ 28.1 μM) in comparison with the reference standard Indomethacin (166 μM). On the other hand, all of them showed inactivity for in vitro cyclooxygenase COX-2 inhibition assays and compounds 8 and 9 possessed the cell toxity. To explore the further anti-inflammatory mechanism, Western blot analysis was carried out. Furthermore, compound 3d shown better bioactivity than Indomethacin. The suppression of NF-κB signal pathway by compound 3d was also determined. To sum-up, compound 3d would be the potential anti-inflammatory lead compound.

Differential Regulation of Inflammatory Responses Following 5‐HT2 Receptor Activation in Pulmonary Tissues

IntroductionThe concept of functional selectivity and psychedelics is often regarded as the ability of different 5‐HT2A receptor agonist compounds to exert varying degrees of psychoactivity in the central nervous system. However, the distribution and expression of the 5‐HT2A receptor, the primary pharmacological target for psychedelics, in peripheral and immune‐related tissue suggests selective signaling may occur here as well. Using an ovalbumin (OVA)‐induced model of rodent acute asthma, our lab has previously shown that subtle changes to the 2,5‐dimethoxy‐phenethylamine pharmacophore structure can profoundly impact the ability of these compounds to prevent asthmatic exacerbations. Here, through both in vitroand in vivoassays, we interrogate elements of functional selectivity in peripheral tissues following exposure to the 5‐HT2 receptor selective agonists (R)‐2,5‐dimethoxy‐4‐iodoamphetamine [(R)‐DOI] and 2,5‐dimethoxy‐4‐trifluoromethylamphetamine (DOTFM). (R)‐DOI is a full and potent anti‐inflammatory compound, whereas DOTFM has no measurable anti‐inflammatory activity. We find that elements of selective signaling combined with modulation to overall chromatin structure and downstream protein expression provide mechanistic clues regarding how psychedelics may elicit their long‐lasting, therapeutic effects.ObjectiveTo elucidate mechanistic variations between anti‐inflammatory and non‐anti‐inflammatory 5‐HT2 receptor agonists.MethodsWe utilized fluorescence recovery after photobleaching (FRAP) to probe the kinetics of the linker histone H1c transiently transfected into a HEK293 cell line stably expressing the human 5‐HT2A receptor, and calcium mobilization assays in the same cell line to determine differences in signaling between (R)‐DOI and DOTFM. For in vivoassays we measured enhanced pause (PenH) values for BALB/c mice challenged with OVA and treated with either (R)‐DOI or DOTFM, using PenH values as a proxy measure for pulmonary inflammation. Lungs were removed en bloc,processed, and analyzed by qPCR and quantitative proteomics using tandem tag mass spectrometry (TMT).ResultsIn vitro assays indicate modest differences irrespective of phenethylamine compound, whereas whole‐body plethysmography (WBP), qPRC, and proteomic analysis reveal significant differential regulation of proteins relevant for both asthmatic initiation and chromatin compaction dependent upon 5‐HT2A agonist.ConclusionAs 5‐HT2‐mediated expression of asthma‐relevant proteins are differentially regulated by either (R)‐DOI and DOTFM, the downregulation of inflammatory pathways via activation of the 5‐HT2 receptor likely requires an accessible, non‐sterically hindered subunit at the 4‐position of the standard 2,5‐dimethoxy‐ampetamine structure to maximally induce anti‐inflammatory effects. Changes to both linker histone mobility and the expression of proteins relevant to chromatin architecture suggest that modulation to the overall chromatin structure combined with downstream epigenetic regulation is a potential mechanism by which certain 5‐HT2A agonists can exert their therapeutic effects.

A New Topical Candidate in Acne Treatment: Characterization of the Meclozine Hydrochloride as an Anti-Inflammatory Compound from In Vitro to a Preliminary Clinical Study.

Acne is a chronic inflammatory multifactorial disease involving the anaerobic bacterium Cutibacterium acnes (C. acnes). Current acne treatments are associated with adverse effects, limiting treatment compliance and use. We showed that meclozine, an anti-histaminic H1 compound, has anti-inflammatory properties. In Vitro, meclozine reduced the production of CXCL8/IL-8 and IL-1β mRNA and protein by C. acnes-stimulated human keratinocytes and monocytes. No cell toxicity was observed at the IC50. Meclozine prevented the phosphorylation of ERK and JNK. In Vivo, 1% meclozine gel significantly decreased C. acnes-mouse ear induced inflammation by 26.7% (p = 0.021). Ex vivo experiments on human skin explants showed that meclozine decreased the production of GM-CSF, IL-1β and TNF-α at transcriptional and translational levels. In a randomized, double-blind, placebo-controlled proof-of-concept clinical trial on 60 volunteers, 2% meclozine pharmaceutical gel decreased by 20.1% (p < 0.001) the ASI score in the treated group after 12 weeks of treatment. No adverse event was reported. Together, these results indicate that meclozine is a potent topical anti-inflammatory compound of potential value for acne treatment.

Spectrum-Effect Relationship Analysis of Bioactive Compounds in Zanthoxylum nitidum (Roxb.) DC. by Ultra-High Performance Liquid Chromatography Mass Spectrometry Coupled With Comprehensive Filtering Approaches.

Zanthoxylum nitidum (Roxb.) DC. (ZN), with strong effects of anti-inflammation and antioxidant activities is treated as a core herb in traditional Chinese medicine (TCM) preparation for treating stomachache, toothache, and rheumatoid arthritis. However, the active ingredients of ZN are not fully clarified due to its chemical complexity. In the present study, a double spectrum–effect analysis strategy was developed and applied to explore the bioactive components in herbs, and ZN was used as an example. Here, the chemical components in ZN were rapidly and comprehensively profiled based on the mass defect filtering-based structure classification (MDFSC) and diagnostic fragment-ion-based extension approaches. Furthermore, the fingerprints of 20 batches of ZN samples were analyzed by high-performance liquid chromatography, and the anti-inflammatory and antioxidant activities of the 20 batches of ZN samples were studied. Finally, the partial least squares regression (PLSR), gray relational analysis models, and Spearman’s rank correlation coefficient (SRCC) were applied to discover the bioactive compounds in ZN. As a result, a total of 48 compounds were identified or tentatively characterized in ZN, including 35 alkaloids, seven coumarins, three phenolic acids, two flavonoids, and one lignan. The results achieved by three prediction models indicated that peaks 4, 12, and 17 were the potential anti-inflammatory compounds in ZN, whereas peaks 3, 5, 7, 12, and 13 were involved in the antioxidant activity. Among them, peaks 4, 5, 7, and 12 were identified as nitidine, chelerythrine, hesperidin, and oxynitidine by comparison with the standards and other references. The data in the current study achieved by double spectrum–effect analysis strategy had great importance to improve the quality standardization of ZN, and the method might be an efficiency tool for the discovery of active components in a complex system, such as TCMs.

Khasianine ameliorates psoriasis-like skin inflammation and represses TNF-α/NF-κB axis mediated transactivation of IL-17A and IL-33 in keratinocytes

Ethno-pharmacological relevanceKhasianine is recently identified as a bioactive compound from Solanum nigrum L. (SNL) which is a traditional Chinese herb (named LongKui in China) and has been clinically applied for treating psoriasis in China but with limited knowledge about the active ingredients. Aim of the studyThis study tried to explore the bioactivity of Khasianine and showed that Khasianine possessed highly anti-inflammatory bioactivity which rapidly alleviated psoriasis-like mice skin inflammation. Materials and methodsImiquimod induced psoriasis-like mouse model, and human keratinocytes were employed in this study. In vivo, immunohistochemistry and immunofluorescence were performed to evaluate the pathological improvement in psoriatic lesions after Khasianine treatment. In vitro, tumor necrosis factor α (TNF-α) treated HaCaT cells with or without Khasianine, were used to analyze the expression and cellular location of NF-κB p65, the expression of IL-17A and IL-33, and the binding intensity of NF-κB p65 on the promoter of IL-17A and IL-33 to understand the molecular mechanism of Khasianine mediated anti-inflammatory effect. ResultsKhasianine reduced infiltration of CD4+ T helper cells (Th cells) and macrophages in mice psoriatic lesions. Immunohistochemistry analysis revealed that Khasianine reduced TNF-α levels in lesions and suppressed NF-κB p65 activation as well as expression of IL-17A and IL-33 in mice epidermal keratinocytes. Further studies in human keratinocytes demonstrated that Khasianine inhibited TNF-α-induced transcriptional activation (transactivation) of NF-κB p65 such as evicting NF-κB p65 binding from the promoter regions of IL-17A and IL-33 and preventing NF-κB nuclear translocation. ConclusionsOur results suggested that Khasianine is a potent anti-inflammatory compound with the bioactivity of NF-κB inhibition and is a promising candidate for psoriasis topical therapy.

Molecular modeling and structural analysis of some tetrahydroindazole and cyclopentanepyrazole derivatives as COX-2 inhibitors

In an attempt to rationalize the search for new potential anti-inflammatory compounds on the COX-2 enzyme, we carried out an in silico protocol that successfully combines the prediction of physicochemical and pharmacokinetic properties, molecular docking, molecular dynamic simulation, and free energy calculation. Starting from a small library of compounds synthesized previously, it was found that 70% of the compounds analyzed satisfy with the associated values to physicochemical principles as key evaluation parameters for the drug-likeness; all the compounds presented good gastrointestinal absorption and cerebral permeability and they showed an interaction with the Arg 106 residue of the COX-2 isoenzyme. Finally, it was obtained that compound 3ab has a binding mode, binding energy, and stability in the active site of COX-2 like the reference drug celecoxib, suggesting that this compound could become a powerful candidate in the inhibition of the COX-2 enzyme. In addition, we realized the crystallographic analysis of compounds 3j, 3r, and 3t defining the crystal parameters and the Packing interactions.

Antioxidant and Anti-Inflammatory Activities of Phytochemicals from Ruellia tuberosa

In Vietnam, the aerial parts of Ruellia tuberosa L. are used to treat stress oxidation and inflammatory symptoms in diabetes mellitus. The present study was designed to determine the antioxidant and inflammatory inhibition activities of Ruellia tuberosa L. extract (RTE) and those of the isolated compounds by column chromatography. The crude ethanol extract and ethyl acetate fraction exhibited potent antioxidant activity in the 2,2-diphenyl-1-picryl-hydrazyl-hydrate (DPPH) and 2,2-azinobis-(3-ethylbenzothiazoline-6-sulfonate) (ABTS) assays with an IC50 of 25.18 and 14.71 (DPPH test) and 18.22 and 15.27 µg/ml (ABTS test), respectively. The RTE contained high concentrations of polyphenols (308.21 mg GAE/g) and moderate concentrations of flavonoids (97.80 mg QE/g). In the anti-inflammatory screening assay, the crude ethanol extract, ethyl acetate, and methanol fractions suppressed the release of IL-6 and nitric oxide production, but the production of IL-10 was not enhanced in LPS-induced RAW 264.7 cells. Three potential anti-inflammatory compounds as hispidulin (6), physalin E (7), and physalin D (8) along with five other compounds named myricitrin (1), afzelin (2), apigenin (3), taraxerol (4), and lupeol (5) were isolated and identified from the ethyl acetate fraction. Physalin D (8) exhibited a strong, dose-dependent anti-inflammatory activity by inhibiting the production of IL-6 proinflammatory cytokines; however, the IL-10 expression was independent of its concentration in macrophages at noncytotoxic concentrations ranging from 5 to 40 μg/mL. Based on the data obtained, compounds 6–8 sourced from Ruellia tuberosa L are potentially bioactive compounds for the treatment of inflammation symptoms in type 2 diabetes mellitus.

Ginkgolide B inactivates the NLRP3 inflammasome by promoting autophagic degradation to improve learning and memory impairment in Alzheimer's disease.

The NLR family, pyrin domain containing 3 (NLRP3) inflammasome drives the progression of Alzheimer's disease (AD). Ginkgolide B (GB) is a potential anti-inflammatory compound that controls neuro-inflammation. The aim of this study was to evaluate the effect of GB on the NLRP3 inflammasome in AD. The effect of GB on the conversion between the M1 and M2 microglial phenotype was examined using quantitative real-time PCR and immunostaining. Western blotting assays and ELISA were used to detect changes in neuro-inflammation following GB treatment, including the NLRP3 inflammasome pathway and autophagy. In order to evaluate the cognitive function of male senescence-accelerated mouse prone 8 (SAMP8) mice, behavioral tests, including the Morris water maze and novel object recognition tests, were performed. GB significantly decreased the intracellular pro-inflammatory cytokine levels in lipopolysaccharide-treated BV2 cells and improved cognitive behavior in SAMP8 mice. Moreover, GB deactivated the NLRP3 inflammasome, and this effect was dependent on autophagy. Ubiquitination was associated with GB-induced autophagic NLRP3 degradation. These results were further validated in the hippocampus of SAMP8 mice. Thus, GB exerted a neuroprotective effect on the cognitive function of SAMP8 mice by suppressing the activation of NLRP3 inflammasome via autophagic degradation.

Metal-free three-component assemblies of anilines, α-keto acids and alkyl lactates for quinoline synthesis and their anti-inflammatory activity.

A new and metal-free three-component method for the synthesis of 2,4-disubstituted quinolines via the reactions of anilines, α-keto acids and alkyl lactates is reported. The reactions proceed in the presence of p-toluene sulfonic acid (p-TSA) and tert-butyl peroxybenzoate (TBPB) to provide diverse quinoline products via the construction of new CC double, C-C single and CN double bonds without producing any organic mass-based side product. Notably, the anti-inflammatory activity of the quinolines has been investigated by measuring their ability to inhibit NO release by lipopolysaccharide (LPS) induced RAW264.7 cells, leading to the identification of 4i, 4t and 4x as potent anti-inflammatory compounds in vitro.

In vitro antidiabetic and anti-inflammatory activities of the bark of Ehretia acuminata R.Br.

Ehretia acuminata is native to Southeast Asia, America, and Africa. It is commonly used as fodder and in quite a variety of medicinal applications. E. acuminata is widely used in India, but there are few reports in the literature of studies on its biological properties. In this study, the antidiabetic and anti-inflammatory activities of plant E. acuminata was evaluated. The antidiabetic activity of the different extracts was measured by α-amylase and α-glycosidase inhibition method. The anti-inflammatory activity was evaluated by the egg albumin of hen. Petroleum ether, chloroform, ethyl acetate, ethanol and water extracts of bark of E. acuminata was evaluated for in-vitro anti-inflammatory and antidiabetic activity. Ethyl acetate and ethanol extract showed significant anti-inflammatory effects (IC 50 170 and 172 µg/mL respectively). Chloroform is the only extract that showed significant inhibition against the antidiabetic effect (IC 50 42-45 µg/mL). The findings suggest that the bark of E. acuminata contains potential antidiabetic and anti-inflammatory compounds, which could be tested as drug candidates against diabetic and inflammation-related pathological processes in medicinal chemistry studies.