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Background: With the emergence of many side effects from synthetic drugs, there is an urgent need to find a natural alternative to these products. Therefore, our primary aim was to evaluate the anti-inflammatory activity of Tamarix aphylla (TA) and investigate the potential mechanism underlying this action. Methods: Initially, to ensure the safety of the extract and for dose selection, we performed an acute oral toxicity Assay through the oral administration of graded doses up to 4 g\kg in Wistar rats. then, we used the carrageenan-induced edema model to elucidate the anti-inflammatory activity. Using specific ELISA kits, we measured the levels of TNF-α, IL-1β, COX-2 and NO inside the inflamed paw tissue. Finally, for the in-vitro anti-inflammatory experiment, we used the erythrocyte membrane stability test. Results: Based on the acute oral toxicity assay, T. aphylla was considered generally safe and three different doses of 100, 200, and 400 mg/kg were chosen for further experiments. Additionally, TA expressed a significant (P < 0.05) anti-inflammatory activity, showing the maximum inhibition percentage at the fifth hour of measurement at 53.47% and 70.06%, at doses of 200 and 400 mg/kg respectively, compared to 63.81% for the standard drug. Similarly, we found that TA effectively reduced the levels of TNF-α and IL-1β at all tested doses (100-200-400 mg/kg) to a greater extent than the standard drug. Moreover, at 400 mg/kg, TA was able to significantly lower the levels of COX-2 and NO inside the inflamed tissue to a level comparable (P < 0.05) with that measured inside the paw tissue of normal rats. Finally, Tamarix aphylla at 100, 200 and 400 mg/kg doses significantly (P < 0.05) inhibited the heat-induced hemolysis of RBCs membrane by 67.78, 74.82 and 82.08%, respectively, compared to 83.89% produced by Aspirin. Conclusion: T. aphylla produced a significant (P < 0.05) anti-inflammatory activity compared to the standard drugs either through the reduction of pro-inflammatory mediators or the protection of the lysosomal membrane. [ABSTRACT FROM AUTHOR]

Osteoarthritis (OA) is a severe chronic inflammatory disease. As the main active component of Astragalus mongholicus Bunge, a classic traditional ethnic herb, calycosin exhibits anti-inflammatory action and its mechanism of exact targets for OA have yet to be determined. In this study, we established an anterior cruciate ligament transection (ACLT) mouse model. Mice were randomized to sham, OA, and calycosin groups. Cartilage synthesis markers type II collagen (Col-2) and SRY-Box Transcription Factor 9 (Sox-9) increased significantly after calycosin gavage. While cartilage matrix degradation index cyclooxygenase-2 (COX-2), phosphor-epidermal growth factor receptor (p-EGFR), and matrix metalloproteinase-9 (MMP9) expression were decreased. With the help of network pharmacology and molecular docking, these results were confirmed in chondrocyte ADTC5 cells. Our results indicated that the calycosin treatment significantly improved cartilage damage, this was probably attributed to reversing the imbalance between chondrocyte synthesis and catabolism. [ABSTRACT FROM AUTHOR]

BACKGROUND: Pueraria decoction is a famous prescription of traditional Chinese medicine, which has good anti-inflammatory and analgesic effects. The mechanism of Pueraria decoction in osteoarthritis was analyzed using network pharmacology to obtain the main therapeutic components of Pueraria decoction. OBJECTIVE: To analyze the mechanism of Pueraria decoction in the treatment of osteoarthritis through network pharmacology and animal experiments. METHODS: First, the active ingredients of Pueraria decoction were screened through the Chinese Herbal Medicine Analysis platform (TCMSP) and the genes related to osteoarthritis were collected in the GeneCards database. Second, Cytoscape software was used to construct the “active ingredient-target-disease” network diagram, explore hub genes and analyze gene expression differences. Subsequently, the therapeutic effect of luteolin, one of the main components of Pueraria decoction, was verified in a mouse model of osteoarthritis. Finally, the Kyoto Encyclopedia of Genes and Genomes (KEGG) and the gene ontology (GO) enrichment analyses of the target genes were conducted to further explore the relevant mechanisms. RESULTS AND CONCLUSION: 115 active ingredients and 147 target genes related to osteoarthritis were identified. GO and KEGG analyses found that Pueraria decoction could affect osteoarthritis through a variety of reaction mechanisms and metabolic pathways. Six hub genes and compounds acting on these genes were determined. Luteolin, the main component of Pueraria decoction, could better promote cartilage repair, accelerate the decrease of typy II collagen and inhibit the expression of matrix metalloproteinase 1 and cyclooxygenase 2 in animal experiments. To conclude, Pueraria decoction contains various active ingredients to prevent the progression of osteoarthritis through oxidative stress and metabolic pathways. [ABSTRACT FROM AUTHOR]

Extensive research has been dedicated to develop compounds that can target multiple aspects of Alzheimer's disease (AD) treatment due to a growing understanding of AD's complex multifaceted nature and various interconnected pathological pathways. In the present study, a series of biological assays were performed to evaluate the potential of the tryptamine analogues synthesized earlier in our lab as multi-target-directed ligands (MTDLs) for AD. To assess the inhibitory effects of the compounds, various in vitro assays were employed. Three compounds, SR42, SR25, and SR10, displayed significant AChE inhibitory activity, with IC50 values of 0.70 µM, 0.17 µM, and 1.00 µM, respectively. These values superseded the standard drug donepezil (1.96 µM). In the MAO-B inhibition assay, SR42 (IC50 = 43.21 µM) demonstrated superior inhibitory effects as compared to tryptamine and other derivatives. Moreover, SR22 (84.08%), SR24 (79.30%), and SR42 (75.16%) exhibited notable percent inhibition against the COX-2 enzyme at a tested concentration of 100 µM. To gain insights into their binding mode and to validate the biological results, molecular docking studies were conducted. Overall, the results suggest that SR42, a 4,5 nitro-benzoyl derivative of tryptamine, exhibited significant potential as a MTDL and warrants further investigation for the development of anti-Alzheimer agents. [ABSTRACT FROM AUTHOR]

Traditional Chinese medicine is one of the most commonly used complementary and alternative medicine therapies for depression. Integrated Chinese-western therapies have been extensively applied in numerous diseases due to their superior efficiency in individual treatment. We used the meta-analysis, network pharmacology, and bioinformatics studies to identify the putative role of Longya Lilium combined with Fluoxetine in depression. Depression-like behaviors were mimicked in mice after exposure to the chronic unpredictable mild stress (CUMS). The underlying potential mechanism of this combination therapy was further explored based on in vitro and in vivo experiments to analyze the expression of COX-2, PGE2, and IL-22, activation of microglial cells, and neuron viability and apoptosis in the hippocampus. The antidepressant effect was noted for the combination of Longya Lilium with Fluoxetine in mice compared to a single treatment. COX-2 was mainly expressed in hippocampal CA1 areas. Longya Lilium combined with Fluoxetine reduced the expression of COX-2 and thus alleviated depression-like behavior and neuroinflammation in mice. A decrease of COX-2 curtailed BV-2 microglial cell activation, inflammation, and neuron apoptosis by blunting the PGE2/IL-22 axis. Therefore, a combination of Longya Lilium with Fluoxetine inactivates the COX-2/PGE2/IL-22 axis, consequently relieving the neuroinflammatory response and the resultant depression. [ABSTRACT FROM AUTHOR]

In this study, a series of derivatives of pyrazole hybrid structures containing carbonitrile and substituted thiazole moiety were designed to search for selective COX‐2 inhibition. The designed target structures were synthesized with easy, practical, and efficient procedures. COX‐1/2 inhibition and cytotoxic effects of the synthesized compounds were evaluated in NIH/3T3 and MDA‐MD‐231 cell lines for inhibition concentration and selectivity index. The results showed that the compounds have an inhibitory effect with higher selectivity towards COX‐2 overall in both cell lines and moderate antiproliferative activity by targeting the breast cancer cell line MDA‐MB‐231. Among the 19 compounds synthesized (19 a–t), especially compound 19 m was found to be highly effective with COX‐2 inhibition of 5.63 μM in the NIH/3T3 cell line and 4.12 μM in the MDA‐MB‐231 cell line. Moreover, molecular docking studies showed that the compounds indeed exhibited higher affinity for the COX‐2 active site. The theoretical ADMET properties of the presented compounds were calculated, and the results showed that the compounds may have a more favorable pharmacokinetic effect profile than the selective COX‐2 inhibitor Celecoxib, thus promising COX‐2 inhibitor drug candidates for the future. [ABSTRACT FROM AUTHOR]

For centuries, natural products are regarded as vital medicines for human survival. Clematis terniflora var. mandshurica (Rupr.) Ohwi is an ingredient of the herbal medicine, Wei Ling Xian, which has been used in Chinese medicine to alleviate pain, fever, and inflammation. In particular, C. terniflora leaves have been used to cure various inflammatory diseases, including tonsillitis, cholelithiasis, and conjunctivitis. Based on these properties, this study aimed to scientifically investigate the anti-inflammatory effect of an ethanol extract of leaves of C. terniflora (EELCT) using activated macrophages that play central roles in inflammatory response. In this study, EELCT inhibited the essential inflammatory mediators, such as nitric oxide, cyclooxygenase-2, tumor necrosis factor-α, interleukin- (IL-) 6, IL-1β, and inducible nitric oxide synthase, by suppressing the nuclear factor-κB and mitogen-activated protein kinase activation in macrophages. Acute lung injury (ALI) is a fatal respiratory disease accompanied by serious inflammation. With high mortality rate, the disease has no effective treatments. Therefore, new therapeutic agents must be developed for ALI. We expected that EELCT can be a promising therapeutic agent for ALI by reducing inflammatory responses and evaluated its action in a lipopolysaccharide- (LPS-) induced ALI model. EELCT alleviated histological changes, immune cell infiltration, inflammatory mediator production, and protein-rich pulmonary edema during ALI. Collectively, our results may explain the traditional usage of C. terniflora in inflammatory diseases and suggest the promising potential of EELCT as therapeutic candidate for ALI. [ABSTRACT FROM AUTHOR]

Background: The skin and its appendages are among the main organs susceptible to neoplasms in cats. Squamous cell carcinoma (SCC) is a malignant neoplasm that affects the epidermis, is locally invasive, and presents with low metastases; however, when it occurs, it spreads to the regional lymph nodes, lungs, and bone tissue. It can present in both proliferative and ulcerative forms. Its etiopathogenesis has not been fully established; however, it is associated with chronic sun exposure, papillomavirus infection, immunosuppression, and chronic skin diseases. This tumor mainly affects white-coated cats but also dark cats with hypopigmented areas, which are uncommon in dark animals and in those with good coat coverage. The objective of this study was to report a case of cutaneous SCC in a cat with black fur. Case: A 14-year-old, 4.5-kg, mixed-breed cat with black fur and a history of an ulcerated wound in the periocular region that did not heal even after previous treatment was treated with 30 mg/kg cephalexin twice a day for 15 days, 1 mg/kg prednisolone once a day for 5 days, and daily cleaning of the wound with 1% chlorhexidine twice a day for 15 days. In order to obtain a definitive diagnosis, cytological and histopathological examinations were performed. First, fine needle aspiration, an imprint, and a swab of the periocular lesion were taken. Immature or dysplastic squamous epithelium cells were observed, with keratinized polygonal angular cytoplasm, oval nuclei and coarse chromatin, a high nucleus:cytoplasm ratio, a large amount of red blood cells, and a moderate amount of segmented neutrophils, macrophages, and cocci-shaped bacteria. Fragments of malignant neoplasms invading the muscle tissue were also observed, characterized by "islands" of epithelial cells with large pleomorphic nuclei, multiple nucleoli, numerous mitotic figures, and formation of corneal pearls, leading to a diagnosis of SCC. Importantly, the animal's blood count remained unchanged. Treatment was established with the use of gabapentin [10 mg/kg - twice daily for 10 days], clindamycin [25 mg/kg - twice daily for 14 days], and piroxicam [0.3 mg/kg - every other day for 20 days]. For topical use, a cream was prepared with 5% papain, 4% hydroviton, and sunscreen (SPF 50) for use twice a day, as well as ointment based on gentamicin sulfate, sulfanilamide, sulfadiazine, urea, vitamin A palmitate, 2-3 times a day for 15 days. However, the neoplasm was already invasive, and the animal died before the treatment was completed. Discussion: Although the etiopathogenesis is not well understood, it is known that the occurrence of SCC in animals with dark fur and good coat coverage is slightly associated with chronic exposure to sunlight, which mostly affects cats with light fur or those with hypopigmented areas, as well as hair scarcity. However, in addition to ultraviolet radiation, papillomaviruses and other factors can cause SCC. The best form of diagnosis for this pathology is cytopathological examination, and if this is inconclusive, it is followed by confirmation with histopathological examination. There are several ways to treat this neoplasm, among them are surgical removals, chemotherapies, radiotherapies, photodynamic therapies, cryosurgeries, cyclooxygenase-2 and tyrosine kinase receptor inhibitors, electrochemotherapy and the use of antineoplastic agents therefore, it is important to individualize treatment according to the case and the financial status of the owner. The importance of early diagnosis is emphasized so that the tumor does not become invasive and metastasize over time, thus increasing the chances of a cure. [ABSTRACT FROM AUTHOR]

Copyright of Revista de Ciencias Médicas de Pinar del Río is the property of Editorial Ciencias Medicas and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Capsaicin induces the reversible opening of tight junctions (TJs) and enhances the delivery of hydrophilic macromolecules through a paracellular route. We previously revealed that TRPA1 is involved in the capsaicin-induced Ca2+ influx and TJ permeability increase, although there are no reports that capsaicin directly activates TRPA1. In this study, we investigated the upstream factors of TRPA1 using RNA-seq analysis, and found that the cyclooxygenase 2 (COX2) gene was upregulated by capsaicin. Cyclooxygenase 2 converts arachidonic acid (AA), a metabolite by phospholipase A2 (PLA2), to prostaglandins. Prostaglandin E2 (PGE2) production was stimulated by capsaicin, and capsaicin-induced Ca2+ influx was effectively inhibited by PLA2 and COX2 inhibitors. The AA-induced TJ permeability increase was inhibited by a TRPA1 antagonist, but the capsaicin- and AA-induced TJ permeability increases were hardly inhibited by a COX2 inhibitor. These results suggest that capsaicin-induced PLA2 activation and AA production are the important steps for the TJ permeability increase. [ABSTRACT FROM AUTHOR]

Simple Summary: The use of aspirin has shown a definite role in the prevention of cancer; however, its effect on survival is still debated. The evidence from randomized trials failed to show any benefit, while cohort studies have demonstrated its usefulness. This is attributed to the use of different doses of aspirin in differing studies. This article explores the plausible mechanisms through which aspirin may exert its effect on improving survival. It is possible that the use of aspirin as adjunct to standard care may lead to better survival in cancer, though the actual effect would have to be demonstrated in clinical trials. The benefit of aspirin on cancer survival is debated. Data from randomized clinical trials and cohort studies are discordant, although a meta-analysis shows a clear survival advantage when aspirin is added to the standard of care. However, the mechanism by which aspirin improves cancer survival is not clear. A PubMed search was carried out to identify articles reporting genes and pathways that are associated with aspirin and cancer survival. Gene ontology and pathway enrichment analysis was carried out using web-based tools. Gene–gene and protein–protein interactions were evaluated. Crosstalk between pathways was identified and plotted. Forty-one genes were identified and classified into primary genes (PTGS2 and PTGES2), genes regulating cellular proliferation, interleukin and cytokine genes, and DNA repair genes. The network analysis showed a rich gene–gene and protein–protein interaction between these genes and proteins. Pathway enrichment showed the interleukin and cellular transduction pathways as the main pathways involved in aspirin-related survival, in addition to DNA repair, autophagy, extracellular matrix, and apoptosis pathways. Crosstalk of PTGS2 with EGFR, JAK/AKT, TP53, interleukin/TNFα/NFκB, GSK3B/BRCA/PARP, CXCR/MUC1, and WNT/CTNNB pathways was identified. The results of the present study demonstrate that aspirin improves cancer survival by the interplay of 41 genes through a complex mechanism. PTGS2 is the primary target of aspirin and impacts cancer survival through six primary pathways: the interleukin pathway, extracellular matrix pathway, signal transduction pathway, apoptosis pathway, autophagy pathway, and DNA repair pathway. [ABSTRACT FROM AUTHOR]

In this study, new 1,3-thiazolidin-4-one derivatives containing arylmethylene groups in the 5-position were obtained from 6-(trifluoromethoxy)-1,3-benzothiazol-2-amine (riluzole). Synthesized compounds were characterized by spectral data and elemental analysis. In vitro, cytotoxic activities of the synthesized molecules were evaluated against the human lung cancer (A549) and human prostate cancer (PC-3) cell lines. Compounds were also tested on mouse embryonic fibroblast cells (NIH/3T3) to determine selectivity. Ten target compounds 3-12 were also screened for their COX-1 and COX-2 inhibitory activities. Of these compounds, 4 showed the highest COX-2 inhibition at 10 μM. Molecular docking calculations were performed to understand the binding interactions of compounds with COX-1 and COX-2 proteins. In silico studies of the tested compounds represented important binding modes that may be responsible for their anti-cancer activity via selective inhibition of the COX-2 enzyme. ADMET predictions were conducted to assess the drug-like properties of the novel compounds. [ABSTRACT FROM AUTHOR]

Zirconium, a transition metal with medical importance, is widely used and has a generally safe profile. However, prolonged and continuous exposure can lead to detrimental consequences; this necessitates the development of quick and efficient sensors for the detection of Zr(IV) ion. The current investigation focuses on the synthesis and characterization of 4‐(methylthio)benzaldehyde derived Schiff base functionalized organosilatranes (2a–2b). The probe 2a has been utilized as a UV–visible absorption based, highly selective and sensitive sensor for the detection of Zr(IV) ion with a limit of detection and association constant values of 10.89 × 10−7 M and 3.1 × 104 M−1, respectively. The practical applicability of the synthesized sensor has been determined in water samples, yielding good percentage recovery rates. The cytotoxicity assay has been performed using SAF‐1 cell line, rendering the synthesized compounds non‐toxic. Furthermore, molecular docking has been performed against cyclooxygenase‐2 in order to determine anti‐inflammatory activity of synthesized ligand with a binding energy score of −7.51 kcal mol−1. [ABSTRACT FROM AUTHOR]

Cyclooxygenase (COX)-2 is a crucial mediator contributing to blood–brain barrier damage during cerebral ischemia. The ability of target compounds to inhibit COX-1 and COX-2 enzymes was determined. Compound 4a showed a high COX-2 inhibitory potency and selectivity, which was higher activity than observed for the positive control celecoxib. A docking study was performed for compound 4a to explain its interaction with the COX-2 receptor active site. [ABSTRACT FROM AUTHOR]

Acute Respiratory Distress Syndrome (ARDS) is one of the clinical manifestations in severe COVID-19 patients characterized by acute inflammation resulting in respiratory failure and death. Camellia sinensis L. or green tea extract has many beneficial secondary metabolites including polyphenols which have antiinflammatory and anti-viral roles. This study was aimed to investigate the activity of green tea extract (GTE) as an anti-inflammatory on ARDS model cells. In this study, rat lung alveolar type II epithelial cells line (L2) was induced by lipopolysaccharide (LPS) to mimic the inflammation process in ARDS. These cells were then treated with GTE to determine the GTE effectiveness in reducing the inflammation. The GTE polyphenol constitutions were first confirmed using Liquid Chromatography with Tandem Mass Spectrometry (LC-MS/MS). The cytotoxic assay was conducted using MTS assay kit to determine the safe range of GTE concentrations that used in the next assay. The effectiveness of the GTE was determined by measuring pro-inflammatory cytokines (IL-1ß and IL-6) and inflammation-mediated enzymes (COX-2), both of which were by ELISA method. Furthermore, this study measured the ACE-2 and TMPRSS-2 gene expressions by qRT-PCR method. The results showed that GTE treatment significantly reduced proinflammatory cytokines IL-1ß, IL-6, inflammation-mediated enzyme COX-2, and significantly increased ACE-2 and TMPRSS-2 mRNA expressions. In short, green tea extract possesses the potential to alleviate inflammation. [ABSTRACT FROM AUTHOR]

Objective: To investigate the underlying mechanism of antiinflammatory action of coumarin and eugenol in lipopolysaccharide (LPS)-stimulated RAW 264.7 cells. Methods: RAW 264.7 cells were treated with 2.5 µg/mL of LPS, 50 µM of coumarin, and 50 µM eugenol for 24 h. The viability of the cells was assessed using MTT assay. The production of nitric oxide was determined using Griess reagent and DCFH-DA was used to measure the production of reactive oxygen species. The protein expression of NLRP3, IL-1ß, NF-κB, and cyclooxygenase 2 was assessed using Western blot analysis. Results: Coumarin and eugenol showed anti-inflammatory effects against LPS-induced inflammatory response by ameliorating the expression of NLRP3 inflammasome and NF-κB, which further led to a subsequent reduction in IL-1ß, nitric oxide, and reactive oxygen species. Conclusions: Coumarin and eugenol exert their anti-inflammatory activities by modulating the NLRP3 inflammasome pathway and NF-κB. These compounds may have promising therapeutic applications for the treatment of various inflammatory diseases. [ABSTRACT FROM AUTHOR]

Copyright of Online Turkish Journal of Health Sciences (OTJHS) / Online Türk Sağlık Bilimleri Dergisi is the property of Oguz KARABAY and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

In this study, a zebrafish embryo toxicity model was employed, utilizing 24 h postfertilization (hpf) zebrafish embryos. These embryos were treated with varying concentrations of mercuric chloride for 96 h under static conditions. We assessed multiple parameters that reflected developmental abnormalities, behavioral alterations, morphological anomalies, antioxidant enzyme activities, including those of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPX), and glutathione S‐transferase (GST), immune messenger RNA transcription levels of key factors such as tumor necrosis factor α (TNF‐α), interleukin‐1β (IL‐1β), interleukin‐6 (IL‐6), and cyclooxygenase 2 (COX‐2), as well as protein expression of TNF‐α. The results revealed that embryos exposed to higher concentrations of mercury exhibited reduced hatchability and increased rates of morphological abnormalities and mortality at 48, 72, and 96 hpf. In addition, a concentration‐dependent increase in developmental abnormalities, including cardiac edema, reduced body length, yolk sac edema, scoliosis, and bent tails, was observed. Larval behaviors, such as touch‐induced escape responses, startle reactions, and turning actions, were found to be diminished in a concentration‐dependent manner. Additionally, the activities of various antioxidative enzymes, such as SOD, CAT, and GST, exhibited an increase at higher mercury concentrations, with the exception of GPX activity, which decreased significantly in a dose‐dependent manner (p < 0.05). Pro‐inflammatory cytokine transcription levels, specifically TNF‐α, IL‐1β, IL‐6, and COX‐2, were significantly upregulated in a dose‐dependent manner in the mercuric (II) chloride (HgCl2) treatment group compared with the control group. TNF‐α protein expression was notably elevated in the larvae group treated with 300 and 400 nM HgCl2. [ABSTRACT FROM AUTHOR]

Human 5-lipoxygenase (5-LOX) and cyclooxygenase-2 (COX-2) are potential targets for suppressing pruritic skin inflammation in atopic dermatitis (AD). In addition, Staphylococcus aureus colonization and oxidative stress worsen AD skin conditions. We aimed to investigate anti-inflammatory activity, using 5-LOX and COX-2 inhibitions, and the anti-staphylococcal, and antioxidant potentials of several medicinal plants bio-prospected from traditional medicine related to AD pathogenesis. Essential oils and hexane fractions were prepared and analyzed using gas chromatography–mass spectrometry. Boesenbergia rotunda hexane extract displayed anti-Staphylococcus aureus (MIC = 10 µg/mL) and antioxidant activities (IC50 = 557.97 and 2651.67 µg/mL against DPPH and NO radicals, respectively). A major flavonoid, pinostrobin, was further nonchromatographically isolated. Pinostrobin was shown to be a potent 5-LOX inhibitor (IC50 = 0.499 µM) compared to nordihydroguaiaretic acid (NDGA; IC50 = 5.020 µM) and betamethasone dipropionate (BD; IC50 = 2.077 µM) as the first-line of AD treatment. Additionally, pinostrobin inhibited COX-2 (IC50 = 285.67 µM), which was as effective as diclofenac sodium (IC50 = 290.35 µM) and BD (IC50 = 240.09 µM). This kinetic study and molecular modeling showed the mixed-type inhibition of NDGA and pinostrobin against 5-LOX. This study suggests that B. rotunda and its bioactive pinostrobin have promising properties for AD therapy. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To observe the effect of Gubi Powder, an in-hospital prescription, on inflammatory factors and Notch3/Hes1 and Wnt/β-catenin signaling pathways in rabbits with knee osteoarthritis model, providing new drug ideas for clinical treatment. METHODS: Forty New Zealand rabbits were divided into sham operation group, model group, positive group (diclofenac potassium gel) and Gubi Powder group, with 10 rabbits in each group. The modified Hulth method was used to construct the rabbit knee osteoarthritis model, which lasted for 8 weeks. After modeling, normal saline was applied to the knee joints of the sham operation group and model group, diclofenac potassium gel was applied to the positive group, and Gubi Powder was applied to the Gubi Powder group, 8 hours a day, for 1 week. After administration, animal activity and behaviors were evaluated and scored; serum levels of prostaglandin E2, cyclooxygenase-2, interleukin 1β and tumor necrosis factor α were determined by ELISA; pathological changes of cartilage tissue were observed by hematoxylin-eosin staining and Safranin-O staining; protein levels of matrix metalloproteinases 1, 2, 3, and 13 in cartilage tissue of the knee joint were determined by immunohistochemistry; and protein levels of Notch3, Hes1, Wnt5a, β-catenin, Bcl-2, Bax, and Caspase-3 in cartilage tissue of the knee joint were determined by western blot assay. RESULTS AND CONCLUSION: Compared with the sham operation group, animals in the model group had difficulties in walking, serious cartilage injury in the knee joint, significantly elevated levels of serum prostaglandin E2, cyclooxygenase 2, interleukin 1β and tumor necrosis factor α (P < 0.05), significantly increased protein expression levels of matrix metalloproteinases 1, 2, 3, and 13, Bax, Caspase-3, Wnt5a and β-catenin in cartilage tissue (P < 0.05), and decreased protein expression levels of Notch3, Hes1, and Bcl-2 (P < 0.05). Compared with the model group, the walking condition of animals in the positive group and Gubi Powder group was improved, the serum levels of prostaglandin E2, cyclooxygenase-2, interleukin 1β and tumor necrosis factor α were decreased, cartilage damage of the knee was alleviated, the protein expression levels of matrix metalloproteinases 1, 2, 3, and 13, Bax, Caspase-3, Wnt5a and β-catenin in cartilage tissue were reduced (P < 0.05), and the protein expression levels of Notch3, Hes1, and Bcl-2 were increased (P < 0.05). To conclude, Gubi Powder can alleviate the symptoms of knee osteoarthritis in rabbits, improve the pathological changes of the cartilage, and reduce inflammatory factor levels in serum. The mechanism of action may be related to the inhibition of Notch3/Hes1 and Wnt/β-catenin signaling pathways. [ABSTRACT FROM AUTHOR]

Introduction: Rheumatoid arthritis (RA) is an immune-mediated disease associated with chronic inflammation of numerous joints. Nyctanthes arbortristis (NAT) is a traditional remedy for RA, a chronic inflammatory disorder. Aim: The current project aims to demonstrate the role of the NAT extracts in subacute toxicity, pharmacovigilance, and anti-rheumatic biomarkers. Method: Hydroethanolic extract (1:1) of plant leaves was prepared by using the reflux method. The safety of the dose was evaluated in Sprague–Dawley rats, and the anti-inflammatory effects of NAT on RA symptoms, including paw volumes, body weight, arthritic index, withdrawal latency, hematology and serological test, radiology, and histopathology, were evaluated in Freund’s complete adjuvant (FCA)-induced arthritis Sprague–Dawley rat models. The inflammatory (TNF-α and COX-2) and anti-inflammatory markers (IL-10) were analyzed in control and experimental groups. Result: The study showed that 500 mg/kg BW NAT leaf extract was found to be least toxic without showing any subacute toxicity symptoms. The pharmacovigilance study highlighted the potential side effects of NAT, such as drowsiness, sedation, and lethargy, at high dosages. Treatment with the plant extract mitigated paw edema, restored the immune organ and body weights, and ameliorated the level of blood parameters such as hemoglobin, red blood cells, platelets, white blood cells, aspartate aminotransferase (AST), alanine transaminase (ALT), C-reactive proteins, and rheumatoid factor. Treatment with the plant extracts also reduced the level of cyclooxygenase 2 and TNF-α and increased the level of IL-10 in the serum of arthritic rats dose-dependently. Radiographic analysis of the ankle joint showed an improvement in the hind legs. Histological examination of the ankle joints revealed that the plant extract treatment decreased pannus formation, inflammation, and synovial hyperplasia in arthritic animals. Conclusion: NAT 500 mg/kg could serve as a promising therapeutic option for the treatment of inflammatory arthritis. [ABSTRACT FROM AUTHOR]

Objective: The specific effect of Adipose-Derived Mesenchymal Stem Cells (Ad-MSC) on acute joint inflammation, where the response mostly depends on innate immunity activation, remains elusive. The pathogenesis of gouty arthritis, characterized by the deposition of monosodium urate (MSU) crystals in the joints, associated to acute flares, has been associated to NLRP3 inflammasome activation and subsequent amplification of the inflammatory response. Our aim was to study the effect of human Ad-MSC administration in the clinical inflammatory response of rabbits after MSU injection, and the molecular mechanisms involved. Methods: Ad-MSC were administered by intraarterial route shortly after intraarticular MSU crystal injections. Joint and systemic inflammation was sequentially studied, and the mechanisms involved in NLRP3 inflammasome activation, and the synthesis of inflammatory mediators were assessed in the synovial membranes 72h after insult. Ad-MSC and THP-1-derived macrophages stimulated with MSU were co-cultured in transwell system. Results: A single systemic dose of Ad-MSC accelerated the resolution of local and systemic inflammatory response. In the synovial membrane, Ad-MSC promoted alternatively M2 macrophage presence, inhibiting NLRP3 inflammasome and inducing the production of anti-inflammatory cytokines, such as IL-10 or TGF-β and decreasing nuclear factor-κB activity. Ad-MSC induced a net anti-inflammatory balance in MSU-stimulated THP-1 cells, with a higher increase in IL-10 and IDO expression than that observed for IL-1b and TNF. Conclusion: Our in vivo and in vitro results showed that a single systemic dose of Ad-MSC decrease the intensity and duration of the inflammatory response by an early local COX-2 upregulation and PGE2 release. Ad-MSCs suppressed NF-kB activity, NLRP3 inflammasome, and promoted the presence of M2 alternative macrophages in the synovium. Therefore, this therapeutic approach could be considered as a pharmacological alternative in patients with comorbidities that preclude conventional treatment. [ABSTRACT FROM AUTHOR]

Molecular hybridization has emerged as a promising approach in the treatment of diseases exhibiting multifactorial etiology. With regard to this, dual cyclooxygenase-2/lipoxygenase (COX-2/LOX) inhibitors could be considered a safe alternative to traditional non-steroidal anti-inflammatory drugs (tNSAIDs) and selective COX-2 inhibitors (coxibs) for the treatment of inflammatory conditions. Taking this into account, six novel pyrrole derivatives and pyrrole–cinnamate hybrids were developed as potential COX-2 and soybean LOX (sLOX) inhibitors with antioxidant activity. In silico calculations were performed to predict their ADMET (absorption, distribution, metabolism, excretion, toxicity) properties and drug-likeness, while lipophilicity was experimentally determined as RM values. All synthesized compounds (1–4, 5–8) could be described as drug-like. The results from the docking studies on COX-2 were in accordance with the in vitro studies. According to molecular docking studies on soybean LOX, the compounds displayed allosteric interactions with the enzyme. Pyrrole 2 appeared to be the most potent s-LOX inhibitor (IC50 = 7.5 μM). Hybrids 5 and 6 presented a promising combination of in vitro LOX (IC50 for 5 = 30 μM, IC50 for 6 = 27.5 μM) and COX-2 (IC50 for 5 = 0.55 μM, IC50 for 6 = 7.0 μM) inhibitory activities, and therefore could be used as the lead compounds for the synthesis of more effective multi-target agents. [ABSTRACT FROM AUTHOR]

Inflammation involves the activation of innate immune cells and is believed to play an important role in the development and progression of both infectious and non-infectious diseases such as neurodegeneration, autoimmune diseases, pulmonary and cancer. Inflammation in the brain is marked by the upregulation of translocator protein (TSPO) in microglia. High TSPO levels are also found, for example, in macrophages in cases of rheumatoid arthritis and in malignant tumor cells compared to their relatively low physiological expression. The same applies for cyclooxgenase-2 (COX-2), which is constitutively expressed in the kidney, brain, thymus and gastrointestinal tract, but induced in microglia, macrophages and synoviocytes during inflammation. This puts TSPO and COX-2 in the spotlight as important targets for the diagnosis of inflammation. Imaging modalities, such as positron emission tomography and single-photon emission tomography, can be used to localize inflammatory processes and to track their progression over time. They could also enable the monitoring of the efficacy of therapy and predict its outcome. This review focuses on the current development of PET and SPECT tracers, not only for the detection of neuroinflammation, but also for emerging diagnostic measures in infectious and other non-infectious diseases such as rheumatic arthritis, cancer, cardiac inflammation and in lung diseases. [ABSTRACT FROM AUTHOR]

Chemobrain is a condition that negatively affects cognition in cancer patients undergoing active chemotherapy, as well as following chemotherapy cessation. Chemobrain is also known as chemotherapy-induced cognitive impairment (CICI) and has emerged as a significant medical contingency. There is no therapy to ameliorate this condition, hence identification of novel therapeutic strategies to prevent CICI is of great interest to cancer survivors. Utilizing the platinum-based chemotherapy cisplatin in an investigative approach for CICI, we identified increased expression of cyclooxygenase-2 (COX-2) and prostaglandin E2 (PGE2) in the adult mouse hippocampus, and in human cortical neuron cultures derived from induced pluripotent stem cells (iPSCs). Notably, administration of NS398, a selective COX-2 inhibitor, prevented CICI in vivo without negatively affecting the antitumor efficacy of cisplatin or potentiating tumor growth. Given that dysfunctional mitochondrial bioenergetics plays a prominent role in CICI, we explored the effects of NS398 in cisplatin-induced defects in human cortical mitochondria. We found that cisplatin significantly reduces mitochondrial membrane potential (MMP), increases matrix swelling, causes loss of cristae membrane integrity, impairs ATP production, as well as decreases cell viability and dendrite outgrowth. Pretreatment with NS398 in human cortical neurons attenuated mitochondrial dysfunction caused by cisplatin, while improving cell survival and neurite morphogenesis. These results suggest that aberrant COX-2 inflammatory pathways may contribute in cisplatin-induced mitochondrial damage and cognitive impairments. Therefore, COX-2 signaling may represent a viable therapeutic approach to improve the quality of life for cancer survivors experiencing CICI. [ABSTRACT FROM AUTHOR]

Nine undescribed carotane sesquiterpenes and rare rearranged guaiane sesquiterpenoids (1–9), along with two known analogues (10–11), were obtained from the aerial parts of Daphne penicillata. Their structures and absolute configurations were determined by extensive spectroscopic analyses, NMR/ECD calculations, and single-crystal X-ray diffraction analysis. All the compounds were evaluated for anti-inflammatory and cytotoxic activities. The inhibitory effect of several active sesquiterpenoids against the cyclooxygenase-2 (COX-2) enzyme was also examined by an in vitro enzyme inhibition assay. Furthermore, molecular docking, molecular dynamics (MD) simulation, and binding free energy calculations were applied to further analyze the interactions, stability, and affinity, among which compounds 3 and 4 exhibited high binding affinities and stable binding to the active site of COX-2. [ABSTRACT FROM AUTHOR]

The most prevalent metabolic bone disease, osteoporosis, is characterized by a decrease in bone mineral density and alterations to the bone's microstructure, both of which can result in fragility fractures. It affects a significant section of the population. Acute or chronic pain from these fractures is typical in elderly adults with other coexisting conditions. Since the antiresorptive medication only partially reduces pain, other analgesics are required for effective pain management. NSAIDs or selective COX-2 inhibitors can reduce acute pain, but persistent neuropathic pain is difficult to manage with these drugs. Opioids have their adverse effects and safety concerns, although they can be used to address acute or chronic pain. Hence, a multifaceted approach is to be implemented, including pharmacological and nonpharmacological therapy and surgical treatment in a selected number of cases. This chapter briefly describes the etiology of pain, its mechanism, and pain management in osteoporotic patients. [ABSTRACT FROM AUTHOR]

A new series of bis-triazole 19a-l was synthesised for the purpose of being hybrid molecules with both anti-inflammatory and anti-cancer activities and assessed for cell cycle arrest, NO release. Compounds 19c, 19f, 19h, 19 l exhibited COX-2 selectivity indexes in the range of 18.48 to 49.38 compared to celecoxib S.I. = 21.10), inhibit MCF-7 with IC50 = 9–16 μM compared to tamoxifen (IC50 = 27.9 μM). and showed good inhibitory activity against HEP-3B with IC50 = 4.5–14 μM compared to sorafenib (IC50 = 3.5 μM) (HEP-3B). Moreover, derivatives 19e, 19j, 19k, 19 l inhibit HCT-116 with IC50 = 5.3–13.7 μM compared to 5-FU with IC50 = 4.8 μM (HCT-116). Compounds 19c, 19f, 19h, 19 l showed excellent inhibitory activity against A549 with IC50 = 3–4.5 μM compared to 5-FU with IC50 = 6 μM (A549). Compounds 19c, 19f, 19h, 19 l inhibit aromatase (IC50 of 22.40, 23.20, 22.70, 30.30 μM), EGFR (IC50 of 0.112, 0.205, 0.169 and 0.066 μM) and B-RAFV600E (IC50 of 0.09, 0.06, 0.07 and 0.05 μM). [ABSTRACT FROM AUTHOR]

Two new series of pyrazolyl-thiazolidinone/thiazole derivatives 16a–b and 18a–j were synthesised, merging the scaffolds of celecoxib and dasatinib. Compounds 16a, 16b and 18f inhibit COX-2 with S.I. 134.6, 26.08 and 42.13 respectively (celecoxib S.I. = 24.09). Compounds 16a,16b,18c,18d and 18f inhibit MCF-7 with IC50 = 0.73–6.25 μM (dasatinib IC50 = 7.99 μM) and (doxorubicin IC50 = 3.1 μM) and inhibit A549 with IC50 = 1.64–14.3 μM (dasatinib IC50 = 11.8 μM and doxorubicin IC50 = 2.42 μM) with S.I. (F180/MCF7) of 33.15, 7.13, 18.72, 13.25 and 8.28 respectively higher than dasatinib (4.03) and doxorubicin (3.02) and S.I. (F180/A549) of 14.75, 12.96, 4.16, 7.07 and 18.88 respectively higher than that of dasatinib (S.I. = 2.72) and doxorubicin (S.I = 3.88). Derivatives 16a, 18c, 18d, 18f inhibit EGFR and HER-2 IC50 for EGFR of 0.043, 0.226, 0.388, 0.19 μM respectively and for HER-2 of 0.032, 0.144, 0.195, 0.201 μM respectively. [ABSTRACT FROM AUTHOR]

Multiple inhibitions of CA, COX-2 and 5-LOX enzymes has been recognised as a useful strategy for the development of anti-inflammatory drugs that can avoid the disadvantages of using NSAIDs alone. Here, we report new pyridazine-based sulphonamides (5a-c and 7a-f) as potential multi-target anti-inflammatory candidates. First, the furanone heterocycle in the dual CA/COX-2 inhibitor Polmacoxib was replaced with the pyridazinone one. Then, a hydrophobic tail was appended through benzylation of the 3-hydroxyl group of the pyridazinone scaffold to afford benzyloxy pyridazines 5a-c. Furthermore, the structures were adorned with the polar sulphonate functionality, in pyridazine sulphonates 7a-f, that are expected to be engaged in interactions with the hydrophilic half of the CA binding sites. All of the disclosed pyridazinones were tested for inhibitory activities against 4 hCA isoforms (I, II, IX, and XII), as well as against COX-1/2, and 5-LOX. Furthermore, in vivo anti-inflammatory and analgesic effects of pyridazinones 7a and 7b were examined. [ABSTRACT FROM AUTHOR]

We designed and synthesised novel quinazolinone tethered phenyl urea derivatives (6a–p) that triple target the double mutant EGFRL858R/T790M, COX-2, and 15-LOX. Compounds (6e, 6d, 6j, 6m, and 6n) not only had low micromolar IC50 inhibitory activities against the three targets, but they also showed good selectivity for COX-2 over COX-1 and for EGFRL858R/T790M over wild-type EGFR. Except for 6e and 6n, all of the tested compounds inhibited the NO production significantly more potently than celecoxib, diclofenac, and indomethacin. Compounds 6i and 6k reduced ROS levels more effectively than celecoxib and diclofenac. In terms of inhibiting TNF-α production, 6o-treated cells showed TNF-α level, which is ∼10 times lower than celecoxib. Furthermore, 6e and 6j had the highest anticancer activity against the breast cancer cell line BT-459 with growth inhibition percentages of 67.14 and 70.07%, respectively. Docking studies confirm their favoured binding affinity. The proposed compounds could be promising multi-targeted leads. [ABSTRACT FROM AUTHOR]

New thymol − 1,5-disubstitutedpyrazole hybrids were synthesised as dual COX-2/5-LOX inhibitors. Compounds 8b, 8g, 8c, and 4a displayed in vitro inhibitory activity against COX-2 (IC50 = 0.043, 0.045, 0.063, and 0.068 µM) nearly equal to celecoxib (IC50 = 0.045 µM) with high SI (316, 268, 204, and 151, respectively) comparable to celecoxib (327). All target compounds, 4a–c and 8a–i, showed in vitro 5-LOX inhibitory activity higher than reference quercetin. Besides, they possessed in vivo inhibition of formalin-induced paw oedema higher than celecoxib. In addition, compounds 4a, 4b, 8b, and 8g showed superior gastrointestinal safety profile (no ulceration) as celecoxib and diclofenac sodium in the population of fasted rats. In conclusion, compounds 4a, 8b, and 8g achieved the target goal. They elicited in vitro dual inhibition of COX-2/5-LOX higher than celecoxib and quercetin, in vivo potent anti-inflammatory activity higher than celecoxib and in vivo superior gastrointestinal safety profile (no ulceration) as celecoxib. [ABSTRACT FROM AUTHOR]

Background Cyclooxygenase enzyme is frequently overexpressed in various types of cancer and found to play a crucial role in poor prognosis in cancer patients. In current research, we have reported the new COX-2 inhibitors for cancer treatment using computer-aided drug design and experimental validation. Methods A total of 12,795 compounds from the different databases were used to screen against the COX-2 enzyme. It perceived three new compounds with better binding affinity to the enzyme. Afterwards, physicochemical properties and in silico bioactivity were assessed for efficacy, safety, and structural features required for binding. The molecules were synthesized and confirmed by spectroscopic techniques. Later on, molecules were evaluated for their anti-cancer activity using MCF-7, MDA-MB-231 and SiHa cancer cell lines. Results Compound ZINC5921547 and ZINC48442590 (4a, and 4b) reduced the MCF-7, MDA-MB-231, and SiHa cells proliferation potently than parent compounds. The PG-E2 estimation shown, both compounds act through the COX-2 PGE2 axis. Compound 4a and 4b block the cell cycle at G1-S phase and induce cancer cell death. Conclusions We concluded that compounds 4a and 4b effectively promotes cancer cell death via COX-2 PGE2 axis, and further in vivo studies can be evaluated for development in both compounds as anticancer agents. The compilation of this information will help us to generate better outcome through robust computational methods. The high-quality experimental results may pave the way for identifying effective drug candidates for cancer treatment. [ABSTRACT FROM AUTHOR]

• Mice lacking cyclooxygenase 2 enzyme had abnormal microglia morphology. • Microglia changes were sex-, brain region-, and stage- dependent. • Cyclooxygenase 2 knockin mice had increased microglia density and branch length. • Abnormal percentage of amoeboid and ramified microglia was also observed. • Males show more widespread changes compare to females. Prostaglandin E2 (PGE2) is a signaling molecule produced by cyclooxygenase-2 (COX-2) that is important in healthy brain development. Anomalies in the COX-2/PGE2 pathway due to genetic or environmental factors have been linked to Autism Spectrum Disorders (ASD). Our previous studies showed that COX-2 deficient (COX-2−KI) mice exhibit sex-dependent molecular changes in the brain and associated autism-related behaviors. Here, we aim to determine the effect of COX-2−KI on microglial density and morphology in the developing brain. Microglia normally transition between an amoeboid or ramified morphology depending on their surroundings and are important for the development of the healthy brain, assisting with synaptogenesis, synaptic pruning, and phagocytosis. We use COX-2−KI male and female mice to evaluate microglia density, morphology, and branch length and number in five brain regions (cerebellum, hippocampus, olfactory bulb, prefrontal cortex, and thalamus) at the gestational day 19 (G19) and postnatal day 25 (PN25). We discovered that COX2−KI females were affected at G19 with increased microglial density, altered percentage of amoeboid and ramified microglia, affected branch length, and decreased branching networks in a region-specific manner; these effects persisted to PN25 in select regions. Interestingly, while limited changes were found in G19 COX-2−KI males, at PN25 we found increased microglial density, higher percentages of ramified microglia, and increased branch counts, and length observed in nearly all brain regions tested. Overall, we show for the first time that the COX-2 deficiency in our ASD mouse model influences microglia morphology in a sex- and region- and stage-dependent manner. [ABSTRACT FROM AUTHOR]

Agarwood (Aquilaria crassna) leaves are commonly used as an herbal tea for health supplements. The present study aims to develop the post-harvest process of agarwood leaves using yeast extract (YE) as an elicitor and evaluate its anti-inflammatory and anti-diabetic effects. The results showed that 1% of YE elicitation for 120 min significantly increased genkwanin 5-O-ß-primevoside (1.8-fold), mangiferin (1.3-fold), and total benzophenones (1.2-fold) contents over the control group. The phenylalanine ammonia-lyase (PAL) activity increased in maximal at 30 min after YE treatment. The agarwood leaf elicitation with 1% YE for 120 min showed a higher anti-inflammation effect by downregulation of iNOS, IL-6, and COX-2 in LPS-stimulated RAW264.7 cells and an anti-diabetic effect by enhanced AMPK-a1, AMPK-a2, and GLUT4 in L6 cells over the non-treatment. Our results suggest that YE could be a biotic elicitor to enhance the phytochemical contents and increase the benefit of agarwood leaves as a health supplement. [ABSTRACT FROM AUTHOR]

Malvidin, one of the six most prominent anthocyanins found in various fruits and vegetables, may possess a wide range of health-promoting properties. The biological activity of malvidin and its glycosides is not entirely clear and has been relatively less frequently studied compared to other anthocyanins. Therefore, this study aimed to determine the relationship between the structural derivatives of malvidin and their anti-cholinergic and anti-inflammatory activity. The study selected malvidin (Mv) and its two sugar derivatives: malvidin 3-O-glucoside (Mv 3-glc) and malvidin 3,5-O-diglucoside (Mv 3,5-diglc). The anti-inflammatory activity was assessed by inhibiting the enzymes, specifically COX-1 and COX-2. Additionally, the inhibitory effects on cholinesterase activity, particularly acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), were evaluated. Molecular modeling was also employed to examine and visualize the interactions between enzymes and anthocyanins. The results revealed that the highest inhibitory capacity at concentration 100 µM was demonstrated by Mv 3-glc in relation to AChE (26.3 ± 3.1%) and BChE (22.1 ± 3.0%), highlighting the crucial role of the glycoside substituent at the C3 position of the C ring in determining the inhibitory efficiency of these enzymes. In addition, the glycosylation of malvidin significantly reduced the anti-inflammatory activity of these derivatives compared to the aglycone form. The IC50 parameter demonstrates the following relationship for the COX-1 enzyme: Mv (12.45 ± 0.70 µM) < Mv 3-glc (74.78 ± 0.06 µM) < Mv 3,5-diglc (90.36 ± 1.92 µM). Similarly, for the COX-2 enzyme, we have: Mv (2.76 ± 0.16 µM) < Mv 3-glc (39.92 ± 3.02 µM) < Mv 3.5-diglc (66.45 ± 1.93 µM). All tested forms of malvidin exhibited higher activity towards COX-2 compared to COX-1, indicating their selectivity as inhibitors of COX-2. Theoretical calculations were capable of qualitatively replicating most of the noted patterns in the experimental data, explaining the impact of deprotonation and glycosylation on inhibitory activity. It can be suggested that anthocyanins, such as malvidins, could be valuable in the development of treatments for inflammatory conditions and Alzheimer's disease and deserve further study. [ABSTRACT FROM AUTHOR]

Objectives: This study aimed to determine whether GCSB-5 has anti-inflammatory and antinociceptive effects in mice with collagen-induced arthritis (CIA), an animal model of rheumatoid arthritis (RA), and investigate the influence of GCSB-5 on the mitogen-activated protein kinase (MAPK) pathway. Materials and methods: The experimental animal study was designed to include five groups: CIA mice treated with GCSB-5 (300 mg/kg), GCSB-5 (600 mg/kg), celecoxib (60 mg/kg), or saline for four weeks, and nontreated control mice. The clinical severity of arthritis was scored. Nociceptive thresholds were measured by using a von Frey dynamic plantar analgesimeter. The MAPK pathway was evaluated in mouse synovium. The expression of channels associated with pain signaling was assessed by western blot and immunohistochemical staining. Results: GCSB-5 treatment diminished the severity of clinical arthritis and increased the nociceptive threshold in mice with CIA. Celecoxib, a positive control drug, also showed comparable changes. Clinical arthritis scores were inversely related to mechanical thresholds. GCSB-5 administration decreased the levels of anti-type II collagen antibody and inflammatory cytokines in the sera of mice with CIA. Furthermore, ERK, p38 MAPK, and JNK phosphorylation were downregulated and TRPV1 and ASIC3 expression were decreased in the synovium of GCSB-5-treated mice compared to saline-treated mice. Interleukin-6-induced TRPV1 and ASIC3 upregulation were also inhibited by GCSB-5 in human RA fibroblast-like synoviocytes in vitro. Conclusion: GCSB-5 decreased inflammatory arthritis and pain in a murine model of RA. The results present evidence that GCSB-5 may be beneficial for relieving pain as well as decreasing inflammation in autoimmune arthritis, such as RA. [ABSTRACT FROM AUTHOR]

Three new hetisine type C20-diterpenoid alkaloids, named as trichophorines A–C (1–3), were isolated from Delphinium trichophorum, together with nine known alkaloids (4–12). Their structures were elucidated on the basis of spectroscopic data (1D, 2D NMR, single-crystal X-ray, and HR-ESI-MS). All compounds were evaluated for the inhibitory activities against LPS induced NO production in RAW 264.7 macrophage cells, and none of them showed considerable inhibitory activity. [ABSTRACT FROM AUTHOR]

Herein, we report a facile method for converting carboxylate-containing indomethacin (Idm) into a cyclooxygenase-2 (COX-2) selective inhibitor via the amidation of an unnatural peptide sequence (Nal-Nal-Asp). The resulting indomethacin amides (i.e., Idm-Nal-Nal-Asp) have high selectivity for COX-2, and can self-assemble into a one-component supramolecular hydrogel that acts as a 'self-delivery' system for boosting anti-inflammatory efficacy. Self-assembled Idm-Nal-Nal-Asp hydrogel robustly inhibits COX-2 expression in lipopolysaccharide (LPS)-activated Raw 264.7 macrophages while also exhibits superior anti-inflammatory and antioxidant activities via reactive oxygen species (ROS)-related NF-κB and Nrf2/HO-1 pathways. Moreover, a rabbit model of endotoxin-induced uveitis (EIU) reveals that the Idm-Nal-Nal-Asp hydrogel outperforms clinically used 0.1 wt% diclofenac sodium eye drops in terms of in vivo anti-inflammatory efficacy via topical instillation route. As a rational approach to designing and applying COX-2 selective inhibitors, this work presents a simple method for converting non-selective nonsteriodal anti-inflammatory drugs (NSAIDs) into highly selective COX-2 inhibitors that can self-assemble into supramolecular hydrogel for anti-inflammation applications. [Display omitted] [ABSTRACT FROM AUTHOR]

Background: Breast cancer is one of the most common malignant tumors that endanger women's health internationally, relatively uncommon in men, accounting for only 1% of all cancer cases. Location, way of life, age at marriage, and obesity are a few environmental variables that increase the risk of breast cancer. Aim of study: the study aims to explain how the pro-inflammatory cytokines (IL-6) induce the inflammatory events in patients with breast cancer and to describe whether cyclooxygenase-2 promotes tumor growth in breast cancer or not. Materials and methods: The current case-control cross-sectional study included 45 patients with a history of breast cancer, and it was done in multiple places in Hilla, Babylon Province, between November 2022 and March 2023.Interlukin-6 and Cyclooxygenase-2 by QPCR. Results: The results have shown a significant increase of IL-6 (P < 0.05) in patients compared with control. Also, the results have shown a significant increase (P < 0.05) of COX2 in patients compared with control. Conclusion: There is a significant increase in the means of Interlukin-6 and Cyclooxygenase-2 in the patients with breast cancer. [ABSTRACT FROM AUTHOR]

Inflammation is a natural response of the organism, involving events responsible for releasing chemical mediators and requiring treatments of symptoms such as pain, redness, heat, swelling, and loss of tissue function. Piroxicam (PRX) is a non-steroidal anti-inflammatory drug with the effect of nonselective COX inhibitor activity; however, it shows poor bioavailability caused by the poor and slow water solubility. In this study, we developed PRX nanosuspensions with 200–500 nm in diameter to increase the bioavailability of PRX by improving its solubility. PRX nanosuspensions were fabricated by High pressure homogenization method with PVA, SDS and Tween 80. The nanosuspensions were characterized by XRD, FTIR, DSC, and in vitro release. In vivo pharmacokinetic properties and anti-inflammatory effects were also investigated in rabbits. PRX nanosuspensions significantly increased the solubility (14.89 ± 0.03 mg/L for pure PRX and 16.75 ± 0.05 mg/L for PRX nanosuspensions) and dissolution rate as compared to the pure PRX (p < 0.05). Orally administered PRX nanosuspension (AUC 0-t is 49.26 ± 4.29 μg/mL × h) significantly improved the bioavailability of PRX (AUC 0-t is 28.40 ± 12.11 μg/mL × h). The anti-inflammatory effect of PRX nanosuspension was also investigated in rabbits and it was observed that PRX nanosuspension treatment significantly improved the inhibition of COX-2 and NFκB expression as compared to the PRX treatment (p < 0.05). The results in this study indicate that PRX nanosuspension is a promising nanomedicine for enhancing the anti-inflammatory activity of PRX and has a high potential for the treatment of inflammation. [ABSTRACT FROM AUTHOR]

Background and Objectives: Cyclooxygenase-2 (COX-2) is mostly linked to inflammation and has been validated as a molecular target for treating inflammatory diseases. The present study aimed to identify novel compounds that could inhibit COX-2, which is associated with various diseases including inflammation, and in such a scenario, plant-derived biomolecules have been considered as attractive candidates. Materials and Methods: In the present study, physiochemical properties and toxicity of natural compounds/drugs were determined by SWISSADME and ProTox-II. In the present study, the molecular docking binding features of saffron derivatives (crocetin, picrocrocin, quercetin, safranal, crocin, rutin, and dimethylcrocetin) against human COX-2 protein were assessed. Moreover, protein-protein interactions, topographic properties, gene enrichment analysis and molecular dynamics simulation were also determined. Results: The present study revealed that picrocrocin showed the highest binding affinity of −8.1 kcal/mol when docked against the COX-2 protein. PROCHECK analysis revealed that 90.3% of the protein residues were found in the most favored region. Compartmentalized Protein–Protein Interaction identified 90 interactions with an average interaction score of 0.62, and the highest localization score of 0.99 found in secretory pathways. The Computed Atlas of Surface Topography of Proteins was used to identify binding pockets and important residues that could serve as drug targets. Use of WEBnmα revealed protein dynamics by using normal mode analysis. Ligand and Receptor Dynamics used the Molecular Generalized Born Surface Area approach to determine the binding free energy of the protein. Gene enrichment analysis revealed that ovarian steroidogenesis, was the most significant enrichment pathway. Molecular dynamic simulations were executed for the best docked (COX-2-picrocrocin) complex, and the results displayed conformational alterations with more pronounced surface residue fluctuations in COX-2 with loss of the intra-protein hydrogen bonding network. The direct interaction of picrocrocin with various crucial amino-acid residues like GLN203, TYR385, HIS386 and 388, ASN382, and TRP387 causes modifications in these residues, which ultimately attenuates the activity of COX-2 protein. Conclusions: The present study revealed that picrocrocin was the most effective biomolecule and could be repurposed via computational approaches. However, various in vivo and in vitro observations are still needed. [ABSTRACT FROM AUTHOR]

Carrageenan is a sulfated polysaccharide obtained from red seaweed (Rhodophyceae) and can trigger inflammatory activation in both humans and laboratory animals. This study aimed to investigate the expression of cyclooxygenase-2 (COX-2), cyclooxygenase-1 (COX-1), and interleukin-6 (IL-6) and the number of inflammatory cells (neutrophil) involved in a carrageenan-induced acute inflammatory model in the back skin of mice. Paraffin blocks from the back skin of female Swiss mice aged 8 weeks were used in this study. The back-skins of 4 groups of 5 mice in each group were subcutaneously injected with 1%, 2%, and 4% carrageenan powder in 0.9% buffer saline and 0.9% buffer saline as control. Skin samples on paraffin blocks were taken 6 hours after carrageenan injection. Furthermore, paraffin blocks were stained with hematoxylin-eosin (HE) to count the number of inflammatory cells. Immunohistochemistry staining using anti-COX-2, COX-1, and IL-6 antibodies was performed to determine the role of inflammatory mediators. The results showed that the number of inflammatory cells (neutrophils) increased significantly following an increase in carrageenan concentrations. The COX-2, COX-1, and IL-6 expressed by inflammatory cells increased significantly at carrageenan concentrations of 1% to 4%. Histopathological features supported the results obtained from the calculation of the number of inflammatory cells and the expression of COX-2, COX-1, and IL-6. The inflammatory markers consisting of COX-2, COX-1, and IL-6 were expressed on the back skin of mice at 6 hours post-injection with 1% to 4% carrageenan. It can be concluded that carrageenan can be used for an acute inflammatory model of the back skin of a mouse. This inflammation model is intended to facilitate the evaluation or measurement of therapeutic and inflammatory responses when test substances are administered topically or transdermal. [ABSTRACT FROM AUTHOR]

Our respiratory system is vital to protect us from the surrounding nonsterile environment; therefore, it is critical for a state of homeostasis to be maintained through a balance of inflammatory cues. Recent studies have shown that actively transcribed noncoding regions of the genome are emerging as key regulators of biological processes, including inflammation. lincRNA-Cox2 is one such example of an inflammatory inducible long intergenic noncoding RNA functioning to fine-tune immune gene expression. Using bulk and single-cell RNA sequencing, in addition to FACS, we find that lincRNA-Cox2 is most highly expressed in the lung and is most upregulated after LPS-induced lung injury (acute lung injury [ALI]) within alveolar macrophages, where it functions to regulate inflammation. We previously reported that lincRNA-Cox2 functions to regulate its neighboring protein Ptgs2 in cis, and in this study, we use genetic mouse models to confirm its role in regulating gene expression more broadly in trans during ALI. Il6, Ccl3, and Ccl5 are dysregulated in the lincRNA-Cox2-deficient mice and can be rescued to wild type levels by crossing the deficient mice with our newly generated lincRNA-Cox2 transgenic mice, confirming that this gene functions in trans. Many genes are specifically regulated by lincRNA-Cox2 within alveolar macrophages originating from the bone marrow because the phenotype can be reversed by transplantation of wild type bone marrow into the lincRNA-Cox2-deficient mice. In conclusion, we show that lincRNA-Cox2 is a trans-acting long noncoding RNA that functions to regulate immune responses and maintain homeostasis within the lung at baseline and on LPS-induced ALI.

Fracture healing is highly dependent on an early inflammatory response in which prostaglandin production by cyclo-oxygenases (COX) plays a crucial role. Current patient analgesia regimens favor opioids over Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) since the latter have been implicated in delayed fracture healing. While animal studies broadly support a deleterious role of NSAID treatment to bone-regenerative processes, data for human fracture healing remains contradictory. In this study, we prospectively isolated mouse and human skeletal stem cells (SSCs) from fractures and compared the effect of various NSAIDs on their function. We found that osteochondrogenic differentiation of COX2-expressing mouse SSCs was impaired by NSAID treatment. In contrast, human SSCs (hSSC) downregulated COX2 expression during differentiation and showed impaired osteogenic capacity if COX2 was lentivirally overexpressed. Accordingly, short- and long-term treatment of hSSCs with non-selective and selective COX2 inhibitors did not affect colony forming ability, chondrogenic, and osteogenic differentiation potential in vitro. When hSSCs were transplanted ectopically into NSG mice treated with Indomethacin, graft mineralization was unaltered compared to vehicle injected mice. Thus, our results might contribute to understanding species-specific differences in NSAID sensitivity during fracture healing and support emerging clinical data which conflicts with other earlier observations that NSAID administration for post-operative analgesia for treatment of bone fractures are unsafe for patients.

Background and aimsPhagocytosis (efferocytosis) of apoptotic neutrophils by macrophages anchors the resolution of intestinal inflammation. Efferocytosis prevents secondary necrosis and inhibits further inflammation, and also reprograms macrophages to facilitate tissue repair and promote resolution function. Macrophage efferocytosis and efferocytosis-dependent reprogramming are implicated in the pathogenesis of inflammatory bowel disease. We previously reported that absence of macrophage cyclooxygenase 2 (COX2) exacerbates inflammatory bowel disease-like intestinal inflammation. To elucidate the underlying pathogenic mechanism, we investigated here whether COX2 mediates macrophage efferocytosis and efferocytosis-dependent reprogramming, including intestinal epithelial repair capacity.MethodsUsing apoptotic neutrophils and synthetic apoptotic targets, we determined the effects of macrophage specific Cox2 knockout and pharmacological COX2 inhibition on the efferocytosis capacity of mouse primary macrophages. COX2-mediated efferocytosis-dependent eicosanoid lipidomics was determined by liquid chromatography tandem mass spectrometry. Small intestinal epithelial organoids were employed to assay the effects of COX2 on efferocytosis-dependent intestinal epithelial repair.ResultsLoss of COX2 impaired efferocytosis in mouse primary macrophages, in part, by affecting the binding capacity of macrophages for apoptotic cells. This effect was comparable to that of high-dose lipopolysaccharide and was accompanied by both dysregulation of macrophage polarization and the inhibited expression of genes involved in apoptotic cell binding. COX2 modulated the production of efferocytosis-dependent lipid inflammatory mediators that include the eicosanoids prostaglandin I2, prostaglandin E2, lipoxin A4, and 15d-PGJ2; and further affected secondary efferocytosis. Finally, macrophage efferocytosis induced, in a macrophage COX2-dependent manner, a tissue restitution and repair phenotype in intestinal epithelial organoids.ConclusionsMacrophage COX2 potentiates efferocytosis capacity and efferocytosis-dependent reprogramming, facilitating macrophage intestinal epithelial repair capacity.

The article focuses on the preliminary evaluation of the effectiveness of paracetamol-NSAID (Non-Steroidal Anti-Inflammatory Drug) combinations in managing symptoms of upper and lower respiratory tract infections (URTIs and LRTIs) in primary care settings. It explores the relationship between the use of these combinations and the occurrence of respiratory-related hospitalization or death during a 60-day follow-up period using data from the Italian Health Search Database (HSD).