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Imidazole moieties exhibit a broad range of biological activities, including analgesic, anti-depressant, anticancer, anti-fungal, anti-tubercular, anti-inflammatory, antimicrobial, antiviral, and antifungal properties. In this study, we explored the use of Schiff base for the synthesis of new imidazole derivatives as anti-inflammatory and pain-relieving agents. A series of eight novel imidazole analogues (2a–h) were prepared in three steps with excellent yields. All compounds were characterized using IR, NMR, and mass spectral data. Their analgesic and anti-inflammatory activities were evaluated using hot plate and paw oedema methods. Compound 2 g (1-(2,3-dichlorophenyl)-2-(3-nitrophenyl)-4,5-diphenyl-1H-imidazole) showed significant analgesic activity (89% at 100 mg/kg b.w.), while compounds 2a (2-(2,6-dichlorophenyl)-1-(4-ethoxyphenyl)-4,5-diphenyl-1H-imidazole) and 2b (2-(2,3-dichlorophenyl)-1-(2-chlorophenyl)-4,5-diphenyl-1H-imidazole) exhibited good anti-inflammatory activity (100% at 100 mg/kg b.w.), comparable to diclofenac salt (100% at 50 mg/kg b.w.). Molecular docking studies were conducted using Schrödinger software version 2021-2, employing the OPLS4 force field for both receptor and ligand preparation. The results were visualized using molecular visualization software such as PyMOL. These studies revealed that compound 2g exhibited the highest binding affinity with the COX-2 receptor (−5.516 kcal/mol). Compound 2g formed three conventional hydrogen bonds with residues GLN-242 (bond length: 2.3 Å) and ARG-343 (bond lengths: 2.2 Å & 2.4 Å). This binding affinity was comparable to that of Diclofenac salt, which showed the highest binding affinity of −5.627 kcal/mol with the COX-2 receptor. Diclofenac salt formed two conventional hydrogen bonds with the residues ARG-344 (bond length: 2.0 Å) and TRP-140 (bond length: 1.7 Å). Later, molecular dynamic simulations confirmed the stable binding affinity of compound 2g with the protein. Furthermore, other compounds also demonstrated potential binding to the receptor-binding pocket region. The anti-inflammatory potential of the synthesized compounds was evaluated using the carrageenan-induced rat hind paw oedema model, while the analgesic potential was assessed using the hot plate method. These evaluations were conducted in comparison with Diclofenac sodium, serving as the standard compound. However, compound 2g stood out for its superior analgesic activity, as confirmed by in-vivo examination. These findings suggest that these novel imidazole derivatives have potential as anti-inflammatory and analgesic agents. [ABSTRACT FROM AUTHOR]

Metal-containing compounds are an important class of chemotherapeutics used to treat various manifestations of cancer. Despite the widespread clinical use and success of metallopharmaceuticals, they are ineffective towards a sub-population of tumours called cancer stem cells (CSCs). CSCs evade current chemotherapeutic regimens (including metallopharmaceuticals) and promote cancer relapse and metastasis. Here, we report the synthesis, characterisation and anti-breast CSCs properties of a series of cobalt(III)-polypyridyl complexes with salicylic acid. The lead cobalt(III) complex 6 (containing 3,4,7,8-tetramethyl-1,10-phenanthroline) displayed low micromolar potency towards breast CSCs, significantly lower than the gold-standard anti-breast CSC agent, salinomycin, and the clinically used metallodrug, cisplatin. Mechanistic studies indicate that the cobalt(III) complex 6 induces its anti-breast CSC effect by entering breast CSCs, penetrating the nuclei, damaging nuclear DNA and triggering caspase-dependent apoptosis. The cytotoxic mechanism of action of the cobalt(III) complex 6 is also dependent on the modulation of cyclooxygenase-2 (COX-2) expression. This work highlights the anti-breast CSC properties of cobalt(III) coordination complexes with non-steroidal anti-inflammatory drugs (NSAIDs) and more widely spotlights the importance of metallopharmaceuticals in the development of new anticancer agents that can tackle chemotherapeutic-resistant sub-populations. [ABSTRACT FROM AUTHOR]

Breast cancer remains a formidable public health challenge worldwide, characterized by its initiation within the breast's diverse tissues, particularly the ducts and lobules. This malignancy is predominantly categorized into three subtypes based on receptor status and genetic markers: hormone receptor-positive, HER2-positive, and triple-negative. Each subtype exhibits distinct biological behaviors and responses to treatment, which significantly influence the prognosis and management strategies. The development and metastatic spread of breast cancer are complex processes mediated by interactions between tumor cells and the host microenvironment, involving various cellular and molecular mechanisms. This review highlights the potential therapeutic role of celecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, in addressing the multifaceted aspects of breast cancer progression. Specifically, celecoxib modulates angiogenesis by reducing the levels of vascular endothelial growth factor (VEGF) through decreased PGE2 production, enhances the immune response by alleviating PGE2-mediated immunosuppression, and inhibits metastasis by limiting the activity of matrix metalloproteinases (MMPs). These mechanisms collectively hinder tumor growth, immune evasion, and metastatic spread. By synthesizing recent findings and analyzing the impact of celecoxib on these pathways, this paper seeks to delineate the integrated approaches necessary for managing metastatic breast cancer effectively. [ABSTRACT FROM AUTHOR]

New pyridazine and pyridazinone derivatives 3a–g, 4a–f, 6a, and 6b were designed and synthesized. Cell viability of all compounds was established based on the viability of lipopolysaccharide‐induced RAW264.7 macrophage cells determined via the MTT assay. In vitro inhibition assays on human COX‐1 and COX‐2 enzymes were conducted to probe the newly synthesized compounds' anti‐inflammatory activity. The half maximal inhibitory concentration values for the most active compounds, 3d, 3e, and 4e towards COX‐2 were 0.425, 0.519, and 0.356 µM, respectively, in comparison with celecoxib. The newly synthesized compounds' ability to inhibit the production of certain proinflammatory cytokines, such as inducible nitric oxide synthase, tumor necrosis factor‐α, interleukin‐6, and prostaglandin‐E2, was also estimated in lipopolysaccharide‐induced macrophages (RAW264.7 cells). Compounds 3d and 3e were identified as the most potent cytokine production inhibitors. The results of molecular modeling studies suggested that these compounds were characterized by a reasonable binding affinity toward the active site of COX‐2, when compared to a reference ligand. These results might be taken into consideration in further investigations into new anti‐inflammatory agents. [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]

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]

Most lung cancer instances are non-small cell lung cancers (NSCLC). As stated by recent literature, cycloxygenase-2 (COX-2) is upregulated in lung adenocarcinomas. COX-2 relates to enhanced cell proliferation and reduced apoptosis; both of which are essential for an invasive tumor growth and metastasis. Thus, COX-2 inhibition forms an important checkpoint. Drug repurposing and nano drug delivery systems will enable the faster and more efficacious drug development. This study was designed to prepare, characterize, and establish superior effectiveness of indomethacin (IND), (a nonselective COX-2 inhibitor) as liposomes (IND-Lip). IND-Lip were made using thin film hydration method and physicochemical properties were characterized. Cell viability was performed on NSCLC cell lines (A549, H1299 and H460) Clonogenic, spheroidal, caspase and COX-2 assays were then carried out. IND-Lip were found to have optimum physicochemical properties. Based on IC50 value of 38.4 ± 4.9 µM, A549 cells were used for further assays. From clonogenic assay, % colonies were found to be 25.5 ± 9.5% at 200 µM of IND-Lip. IND-Lip performed significantly better in ex-vivo tumor reduction in 3D spheroid assay at 200 μM concentration, compared to plain IND by Day 15. Finally, a significant inhibition of COX-2 as well as induction of caspase in all IND treated groups was observed. It is of note that liposomes demonstrated a superior efficacy in all studies compared to the plain drug. IND through liposomal delivery system can be a potentially beneficial strategy for lung carcinoma. However, further clinical studies and in-vivo research are essential to comprehend the complete view of this approach. [ABSTRACT FROM AUTHOR]

• Synthesis of novel nitrogen-rich purine-based heterocyclic compound. • Structural analysis through X-ray crystallography. • Multi-approach quantum mechanics (QM) analysis of noncovalent interactions. • Conceptual density functional theory (CDFT) study of chemical reactivity. • ADMET and in silico docking simulations on bioactivity behaviours. We introduce the synthesis and characterization of a novel purine derivative, 2-amino-6‑chloro-N,N-diphenyl-7H-purine-7-carboxamide. X-ray crystallography was utilized to elucidate its molecular and crystal structure. A comprehensive crystal packing analysis uncovered a network of diverse intermolecular interactions, including classical and unconventional hydrogen bonding. Remarkably, a unique halogen···π (C—Cl···π(ring)) interaction was identified and theoretically analyzed within a multi-approach quantum mechanics (QM) framework, revealing its lone-pair⋯π (n→π*) nature. Furthermore, insights into the electronic and chemical reactivity properties are provided by means of Conceptual Density Functional Theory (CDFT) at wB97X-D/aug-cc-pVTZ level. The compound's drug-likeness, pharmacokinetics, and toxicology profiles are assessed using ADMETlab 2.0. Finally, molecular docking simulations were conducted to evaluate its bioactivity as a potential cyclooxygenase-2 (COX-2) inhibitor. This study significantly advances our understanding of purine structure and reactivity, offering valuable insights for the development of targeted purine-based COX-2 inhibitors and anticancer therapeutics. [Display omitted] [ABSTRACT FROM AUTHOR]

Novel quinazolinones conjugated with indole acetamide (4a–c), ibuprofen (7a–e), or thioacetohydrazide (13a,b, and 14a-d) were designed to increase COX-2 selectivity. The three synthesised series exhibited superior COX-2 selectivity compared with the previously reported quinazolinones and their NSAID analogue and had equipotent COX-2 selectivity as celecoxib. Compared with celecoxib, 4 b, 7c, and 13 b showed similar anti-inflammatory activity in vivo, while 13 b and 14a showed superior inhibition of the inflammatory mediator nitric oxide, and 7 showed greater antioxidant potential in macrophages cells. Moreover, all selected compounds showed improved analgesic activity and 13 b completely abolished the pain response. Additionally, compound 4a showed anticancer activity in tested cell lines HCT116, HT29, and HCA7. Docking results were consistent with COX-1/2 enzyme assay results. In silico studies suggest their high oral bioavailability. The overall findings for compounds (4a,b, 7c, 13 b, and 14c) support their potential role as anti-inflammatory agents. [ABSTRACT FROM AUTHOR]

Hydrazone is a bioactive pharmacophore that can be used to design antitumor agents. We synthesised a series of hydrazones (compounds 4–24) incorporating a 4-methylsulfonylbenzene scaffold and analysed their potential antitumor activity. Compounds 6, 9, 16, and 20 had the most antitumor activity with a positive cytotoxic effect (PCE) of 52/59, 27/59, 59/59, and 59/59, respectively, while compounds 5, 10, 14, 15, 18, and 19 had a moderate antitumor activity with a PCE of 11/59–14/59. Compound 20 was the most active and had a mean 50% cell growth inhibition (GI50) of 0.26 µM. Compounds 9 and 20 showed the highest inhibitory activity against COX-2, with a half-maximal inhibitory concentration (IC50) of 2.97 and 6.94 μM, respectively. Compounds 16 and 20 significantly inhibited EGFR (IC50 = 0.2 and 0.19 μM, respectively) and HER2 (IC50 = 0.13 and 0.07 μM, respectively). Molecular docking studies of derivatives 9, 16, and 20 into the binding sites of COX-2, EGFR, and HER2 were carried out to explore the interaction mode and the structural requirements for antitumor activity. Compound 20 (MG_MID = 0.26 µM) is nearly 65-fold more potent than celecoxib (MG_MID = 17.5 µM), 3-fold more potent than 5-Fu (MG_MID = 0.90 µM), 30-fold more potent than erlotinib (MG_MID = 7.68 µM), and 9-fold more potent than gefitinib (MG_MID = 2.1 µM) and sorafenib (MG_MID = 2.33 µM). [ABSTRACT FROM AUTHOR]

We report the anti‐osteosarcoma stem cell (OSC) properties of a series of gallium(III)‐polypyridyl complexes (5‐7) containing diflunisal, a non‐steroidal anti‐inflammatory drug. The most effective complex within the series, 6 (containing 3,4,7,8‐tetramethyl‐1,10‐phenanthroline), displayed similar potency towards bulk osteosarcoma cells and OSCs, in the nanomolar range. Remarkably, 6 exhibited significantly higher monolayer and sarcosphere OSC potency (up to three orders of magnitude) than clinically approved drugs used in frontline (cisplatin and doxorubicin) and secondary (etoposide, ifosfamide, and carboplatin) osteosarcoma treatments. Mechanistic studies show that 6 downregulates cyclooxygenase‐2 (COX‐2) and kills osteosarcoma cells in a COX‐2 dependent manner. Furthermore, 6 induces genomic DNA damage and caspase‐dependent apoptosis. To the best of our knowledge, 6 is the first metal complex to kill osteosarcoma cells by simultaneously inhibiting COX‐2 and damaging nuclear DNA. [ABSTRACT FROM AUTHOR]

Hibiscus sabdariffa and Camellia sinensis are attributed with various properties or health benefits, among which stands out is its anti-inflammatory capacity associated with the presence of bioactive compounds such as flavonoids. The aim of the research was to evaluate the anti-inflammatory effect of the extracts aqueous and methanolic of H. sabdariffa and C. sinensis by inhibition of the enzyme cyclooxygenase-2. Vegetal material corresponding to calyxes of H. sabdariffa and leaves of C. sinensis were used to obtain the extracts. The Folin-Ciocalteu and Marinova method was used for the determination of total phenolic compounds and flavonoids. On the other hand, anti-inflammatory activity was carried out using a commercial kit and a gallic acid standard as a control.The results showed a higher percentage of inhibition in the methanolic extracts of each vegetable material. Statistical difference was observed when buying the aqueous and methanolic of H. sabdariffa (p=0.025), aqueous and methanolic of C. sinensis (p=0.035) extracts. These findings allow us to conclude that the anti-inflammatory activity of the extracts is related to the content of phenolic compounds present in the plant material and to the extraction method. [ABSTRACT FROM AUTHOR]

Objective: Low back pain is frequently treated with nonsteroidal anti-inflammatory drugs (NSAIDs), but little is known about intervertebral disc metabolism of the prostaglandins that are diminished by these drugs. Hence, this study aimed at delineating prostaglandin actions in cytokine activated disc cells by comparing the response of nucleus pulposus (NP) cells to the pro-inflammatory cytokine interleukin (IL)-1β with and without cyclooxygenase 2 (COX-2) inhibition. Methods: NP cells cultured in alginate beads were activated with IL-1β ± the COX-2 inhibitor Sc-58125. Media harvested from cultured cells were analyzed for prostaglandin E2 (PGE2), prostaglandin F2 alpha (PGF2α), IL-6, and matrix metalloproteinase (MMP)-3 by enzymelinked immunosorbent assay and nitric oxide by Griess Reaction. Gene expression along with proteoglycan, collagen, and total protein synthesis were also measured. Results: IL-1β increased culture media PGE2 and PGF2α, but decreased proteoglycan and collagen syntheses as well as mRNA expression of the matrix genes aggrecan, versican, collagen I, and collagen II. COX-2 inhibition partially rescued proteoglycan and collagen syntheses and collagen I mRNA, but decreased collagen II mRNA IL-1β activated NP cells. COX-2 inhibition initially enhanced and subsequently reduced IL-1β induced inducible nitric oxide synthase, without altering medium nitrite. IL-1β induction of MMP-3 mRNA was increased by COX-2 inhibition at 24 and 48 hours. Conclusion: COX-2 inhibition alters the response of NP cells to IL-1β, suggesting IL-1β action on disc cells is mediated at least in part through COX-2 and its prostaglandins. COX-2 inhibition produces minimal effects on several key catabolic mediators, with the exception of MMP-3. Blocking COX-2 might be beneficial for maintaining disc matrix since it provides an overall rescue of IL-1 induced loss of matrix protein synthesis. [ABSTRACT FROM AUTHOR]

A series of d‐glucose derived N‐glycopeptides containing mefenamic acid have been synthesised and in vitro evaluation of all these molecules have been performed as COX‐2 (human) enzyme inhibitor using Enzymes Immuno Assay kit. These studies were further supported by docking experiments on human COX‐2 enzyme (PDB ID: 5IKR). All the compounds exhibited a fair amount of COX‐2 enzyme inhibition during both the modes of study and tryptophan derivative showed the best activity. Acute toxicity (LD50) in rat has also been evaluated using General Unrestricted Structure‐Activity Relationships (GUSAR) software, where acute oral toxicity for most of the molecules was found to be less than the pure mefenamic acid. [ABSTRACT FROM AUTHOR]

Arthrofibrosis is a common complication following total knee arthroplasty caused by pathologic fibroblast activation and excessive collagen deposition around a synovial joint leading to debilitating loss of motion. Treatment options are limited because the pathologic mechanisms remain to be characterized. Dysregulation of the inflammatory cascade may lead to communication between myofibroblasts and immune cells triggering tissue metaplasia, and excessive collagen deposition described clinically as arthrofibrosis. We explored the novel use of celecoxib (selective cyclooxygenase‐2 [COX‐2] inhibitor) to disrupt the downstream effects of the post‐traumatic inflammatory cascade and inhibit scar tissue formation in a validated rabbit model of arthrofibrosis combined with new parameters for quantifying the stiffness of the posterior capsule. Biomechanical and molecular analyses, of contracted rabbit knee posterior capsule tissue after COX‐2 inhibition revealed increased maximal passive extension and down‐regulation of collagen messenger RNA compared with controls. Histopathologic examination suggested a trend of decreased quantities of dense fibrous connective tissue with COX‐2 inhibition. These data may suggest that inhibiting the inflammatory cascade could potentially reduce pathologic myofibroblast activation, thereby reducing scar tissue formation and increasing the range of motion in arthrofibrotic joints. Implementing a multi‐modal pharmacologic approach may simultaneously target numerous cellular components contributing to the complex process of arthrofibrogenesis. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 37:2609–2620, 2019 [ABSTRACT FROM AUTHOR]

Highly divergent complexity molecules, having spirooxindole core structure, possess excellent bioactivities. The 1,3‐dipolar cycloaddition reaction is one of the most efficient approach for the rapid synthesis of spirooxindole analogues. Herein, we report the synthesis of a series of spirooxindolone analogues via multicomponent reaction of chalcone, based on cyclohexanone, substituted isatin (isatin, 5‐Cl‐isatin, and 5‐Br‐isatin), and secondary amine of the amino acids (L‐Proline and Thioproline). The included activities of the resulting spirooxazolines, including anti‐inflammatory, anti‐leishmanial, and cytotoxic activity against 3T3 and HeLa cell lines. Among series of nine diphenyl substituted derivatives of spiro fused benzylidine thioazol indolines (IVa–IVi), compounds IVb (IC50=5.8±0.9 μM), IVc (IC50=2.4±1.3 μM), IVd (IC50=5.0±0.6 μM), and IVg (IC50=10.4±4.6 μM) have shown potent anti‐inflammatory activity, several fold more active than the standard drug, ibuprofen (IC50=11.2±1.9 μM). Whereas, compounds IVa (IC50=18.0±1.1 μM), and IVh (IC50=26.0±3.4 μM) exhibited a significant anti‐inflammatory potential. All other compounds (IVe and IVf) were found to be inactive. Two meta flouro substituted phenyl rings containing compound IVc (IC50=2.4±1.3 μM) was the most potent member of the series. In order to rationalize the observed biological activities of the spirooxindole‐pyrrolothiazole derivatives, in silico studies were also performed. The results of present study identify a new series of potent anti‐inflammatory agents, deserve to be further investigated as leads. [ABSTRACT FROM AUTHOR]

Inflammation is the response of the body to noxious stimuli such as infections, trauma, or injury. Experimental studies have shown that vanillic acid has anti‐inflammatory effects. The objective of this study was to investigate the anti‐inflammatory and antipyretic properties of the derivative of vanillic acid, isopropyl vanillate (ISP‐VT), in mice. The results of this study indicated that ISP‐VT reduced paw edema induced by carrageenan, dextran sulfate (DEX), compound 48/80, serotonin, bradykinin (BK), histamine (HIST), and prostaglandin E2 (PGE2). Furthermore, ISP‐VT reduced recruitment of leukocytes and neutrophils and reduced its adhesion and rolling, and decreased myeloperoxidase enzyme activity (MPO), cytokine levels (tumor necrosis factor‐α and interleukin‐6), and vascular permeability. ISP‐VT also significantly reduced the expression of cyclooxygenase‐2 (COX‐2) in subplantar tissue of mice. ISP‐VT inhibited COX‐2 selectively compared to the standard drug. Our results showed that although ISP‐VT binds to COX‐1, it is less toxic than indomethacin, as evidenced by MPO analysis of gastric tissue. Treatment with the ISP‐VT significantly reduced rectal temperature in yeast‐induced hyperthermia in mice. Our results showed that the main mechanism ISP‐VT‐induced anti‐inflammatory activity is by inhibition of COX‐2. In conclusion, our results indicate that ISP‐VT has potential as an anti‐inflammatory and antipyretic therapeutic compound. [ABSTRACT FROM AUTHOR]

Abstract Background Neo-vascularization, an indispensible phenomenon for tissue regeneration, facilitates repair and remodeling of wound tissues. This process is impaired in chronic wounds due to reduced number and recruitment of endothelial cells (ECs), thereby necessitating development of newer strategies to enhance the EC repertoire as a therapeutic approach. Methods We explored the 'plasticity' of Wharton's jelly derived–mesenchymal stromal cells (WJ-MSCs) using an anti-inflammatory drug-mediated enhanced trans-differentiation into ECs, based on our observation of temporal decrease in COX-2 expression during trans-differentiation of MSCs into ECs at day 7 and 14 along with mature ECs. Results At a physiological level, an increased DiI-labeled acetylated-low density lipoprotein (DiI-Ac-LDL) uptake, proliferation, migration and chick chorio allantoic membrane (CAM)-vasculogenesis occurred while at a molecular level significant up-regulation in messenger RNA (mRNA) and protein expression of endothelial-specific markers, Vegfr2, Pecam, eNOS, VE-Cadh and Tie-2 , along with an activated p-VEGFR2 and its downstream mediators were observed in celecoxib-preconditioned ECs as compared with WJ-MSCs. Green fluorescent protein (GFP)-expressing stable WJ-MSCs and trans-differentiated EC-D14 in the absence/presence of celecoxib were generated using antibiotic selection for intradermal transplantation at the wound site on a murine 'excisional splinting wound' model. Engraftment of transplanted human cells in immunosuppressant-treated mice was confirmed by a significant increase in the expression levels of human gene-specific endothelial markers at the regenerated wound sites. Morphometrically, increased vascularity and percent wound closure were observed in regenerated wounds of mice transplanted with celecoxib-preconditioned-EC-D14. Conclusion Cox-2 inhibition led to an enhanced trans-differentiation of WJ-MSCs into ECs that, when transplanted, accelerated the skin regeneration by engraftment and neo-vascularization at the wound bed, suggesting a plausible new therapeutic role of celecoxib. [ABSTRACT FROM AUTHOR]

Itchy leaves Laportea decumana (Roxb). Wedd is an indigenous plant in Maluku, Indonesia, and is used traditionally to treat complaints such as fatigue and joint and muscle pains. To provide scientific proof of the analgesic effect of L. decumana ethanolic extract tested in in vivo assays while investigating its bioactive phytochemicals using liquid chromatography tandem high-resolution mass spectrometry (LC-HRMS) profiling and Cox-2 inhibition assay. To investigate the analgesic activity of the ethanolic extract, assays were conducted on male mice Balb/c strain by chemical induction using acetic acid (i.p.) and heat induction (hotplate). Mice were divided into six groups consisting of six mice, i.e., the baseline group; positive control group (paracetamol 80 mg/kg BW); groups treated with extracts in dosages of 100, 200, and 400 mg/kg bodyweight (BW); and negative control group (acetic acid 0.6%, i. p.). The crude extract was partitioned with liquid–liquid fractionation to yield hexane, ethyl acetate, and water fractions. The extract and fraction were assayed for Cox-2 enzyme inhibition, and the chemical profiles were analyzed using untargeted LC-HRMS. The analgesic assays revealed the dose-dependent effect of the extracts, of the effect of treatment with 400 mg/kg BW was not significantly different with that of paracetamol (p < 0.05). The ethyl acetate fraction showed IC 50 of 19.25 μg/mL on Cox-2 inhibition (IC 50 celexocib 18.48 μg/mL). LC-HRMS showed a distinctive profile of the ethyl acetate fraction compared with those in the extract and other fractions. This study presents scientific evidence of the analgesic activity of the L. decumana ethanol extract given orally to experimental animals. Inflammatory inhibition plays a role in the overall analgesic mechanism by Cox-2 inhibition of the extract and all fractions. This finding is also supported by the phytochemical profiles of the extract and fractions, showing the presence of compounds reported elsewhere as anti-inflammatory activity. [Display omitted] • Itchy leaves Laportea decumana (Roxb.) Wedd is a indigenous plant that grows in eastern Indonesia, specifically in Maluku. • The local community usually uses its leaves to treat complaints such as pain, fatigue, and muscle pains. • Studies of the analgesic activity and phytochemical profile of this plant's extract may support its development as herbal medicine for analgesia. [ABSTRACT FROM AUTHOR]

Curcumin has shown pharmacological properties against different phenotypes of various disease models. Different synthetic routes have been employed to develop its numerous derivatives for diverse and improved therapeutic roles. In this study, we have synthesized curcumin derivatives containing isoxazole, pyrazoles, and pyrimidines and then the synthesized molecules were evaluated for their anti-inflammatory and antinociceptive activities in experimental animal models. Acute toxicity of synthesized molecules was evaluated in albino mice by oral administration. Any behavioral and neurological changes were observed at dose of 10 mg/kg body weight. Additionally, cyclooxygenase-2 ( COX-2) enzyme inhibition studies were performed through in vitro assays. In vivo anti-inflammatory studies showed that curcumin with pyrimidines was the most potent anti-inflammatory agent which inhibited induced edema from 74.7% to 75.9%. Compounds 7, 9, and 12 exhibited relatively higher prevention of writhing episodes than any other compound with antinociceptive activity of 73.2%, 74.9%, and 71.8%, respectively. This was better than diclofenac sodium (reference drug, 67.1% inhibition). Similarly, COX-2 in vitro inhibition assays results revealed that compound 12 (75.3% inhibition) was the most potent compound. Molecular docking studies of 10, 11, and 12 compounds in human COX-2 binding site revealed the similar binding modes as that of other COX-2-selective inhibitors. [ABSTRACT FROM AUTHOR]

In an aim at developing new antiproliferative agents, new series of benzothiazole/benzoxazole and/or benzimidazole substituted pyrazole derivatives 11a-c , 12a-c and 13a-c were prepared and evaluated for their antiproliferative activity against breast carcinoma (MCF-7) and non-small cell lung cancer (A549) cell lines. The target compound, 2-acetyl-4-[(3-(1H-benzimidazol-2-yl)-phenyl]-hydrazono-5-methyl-2,4-dihydropyrazol-3-one ( 12a ) was the most active compound against both MCF-7 and A549 cell lines with half maximal inhibitory concentrations (IC 50 ) = 6.42 and 8.46 μM, respectively. Furthermore, the inhibitory activity of the all the target compounds against COX enzymes was recorded as a proposed mechanism for their antiproliferative activity. The obtained results revealed that the benzothiazolopyrazolone derivative 13c was the most potent COX-2 inhibitor (IC 50 = 0.10 μM), while the 5-acetylbenzimidazolylpyrazolone derivative 12a was the most COX-2 selective (S.I. = 104.67) in comparison with celecoxib (COX-2 IC 50 = 1.11 μM, S.I. = 13.33). Docking simulation on the most active compounds 12a and 13c had been performed to investigate the binding interaction of these active compounds within the binding site of COX-2 enzyme. Collectively, this work demonstrated the promising activity of the newly designed compounds as leads for further development into antiproliferative agents. [ABSTRACT FROM AUTHOR]

Lignosus rhinocerus (Cooke) Ryvarden (also known as Tiger Milk mushroom, TMM), is a basidiomycete belonging to the Polyporaceae family. It has been documented to be used by traditional Chinese physicians and indigenous people in Southeast Asia to treat a variety of illnesses, such as gastritis, arthritis, and respiratory conditions, as well as to restore patients' physical well-being. TMM has also been used in folk medicine to treat cancer. For example, people from the indigenous Kensiu tribe of northeast Kedah (Malaysia) apply shredded TMM sclerotium mixed with water directly onto breast skin to treat breast cancer, while Chinese practitioners from Hong Kong, China prescribe TMM sclerotium as a treatment for liver cancer. L. rhinocerus has previously been demonstrated to possess selective anti-proliferative properties in vitro , however pre-clinical in vivo research has not yet been conducted. This study aimed to examine the anti-tumor activities of L. rhinocerus TM02®, using two different sample preparations [cold water extract (CWE) and fraction] via various routes of administration (oral and intraperitoneal) on an MCF7-xenograft nude mouse model. This study also investigated the inhibitory effect of TM02® CWE and its fractions against COX-2 in vitro using LPS-induced RAW264.7 macrophages, on the basis of the relationship between COX-2 and metastasis, apoptosis resistance, as well as the proliferation of cancer cells. The first preparation, L. rhinocerus TM02® sclerotium powder (TSP) was dissolved in cold water to obtain the cold water extract (CWE). It was further fractionated based on its molecular weight to obtain the high (HMW), medium (MMW) and low (LMW) molecular weight fractions. The second preparation, known as the TM02® rhinoprolycan fraction (TRF), was obtained by combining the HMW and MMW fractions. TSP was given orally to mimic the daily consumption of a supplement; TRF was administered intraperitoneally to mimic typical tumorous cancer treatment with a rapid and more thorough absorption through the peritoneal cavity. Another experiment was conducted to examine changes in COX-2 activity in LPS-induced RAW264.7 macrophages after a 1-h pre-treatment with CWE, HMW, and MMW. Our results revealed that intraperitoneal TRF-injection (90 μg/g BW) for 20 days reduced initial tumor volume by ∼64.3% (n = 5). The percentage of apoptotic cells was marginally higher in TRF-treated mice vs. control, suggesting that induction of apoptosis as one of the factors that led to tumor shrinkage. TSP (500 μg/g BW) oral treatment (n = 5) for 63 days (inclusive of pre-treatment prior to tumor inoculation) effectively inhibited tumor growth. Four of the five tumors totally regressed, demonstrating the effectiveness of TSP ingestion in suppressing tumor growth. Although no significant changes were found in mouse serum cytokines (TNF-α, IL-5, IL-6 and CCL2), some increasing and decreasing trends were observed. This may suggest the immunomodulatory potential of these treatments that can directly or indirectly affect tumor growth. Pre-treatment with CWE, HMW and MMW significantly reduced COX-2 activity in RAW264.7 macrophages upon 24 h LPS-stimulation, suggesting the potential of L. rhinocerus TM02® extract and fractions in regulating M1/M2 polarization. Based on the findings of our investigation, both the rhinoprolycan fraction and crude sclerotial powder from L. rhinocerus TM02® demonstrated tumor suppressive effects, indicating that they contain substances with strong anticancer potential. The antitumor effects of L. rhinocerus TM02® in our study highlights the potential for further explorations into its mechanism of action and future development as a prophylactic or adjunct therapeutic against tumorous cancer. [Display omitted] • Oral TM02® sclerotia (TSP) treatment suppressed MCF7 tumor growth in nude mice. • Intraperitoneal rhinoprolycan treatment (TRF) suppressed MCF-7 tumor growth in nude mice. • Tumor shrinkage could be led by apoptosis inducing and immunomodulation properties. • TM02® extract and its fractions inhibited COX-2 activities in RAW264.7 macrophages cells. [ABSTRACT FROM AUTHOR]

• New 1,3-diaryl pyrazolyl ester derivatives developed as COX-2 inhibitors with anti-tumor effect. • Top hit Y1–6 exhibiting selective COX-2 inhibitory and anti-proliferation activities. • Inducing both the apoptosis and cell cycle arrest at G2/M phase of MB-MDA-231 cells with Y1–6. • Key residues indicated by docking simulation for improving the binding patterns. Herein, a novel series of 1,3-diaryl pyrazolyl ester derivatives were synthesized and evaluated as potential COX-2 inhibitory candidates with anti-tumor effect. Among the four sub-series, Sub-series 1 with β -naphthalene indicated the highest percentage of generating potential candidates. Preliminary analysis of Structure-Activity Relationship indicated that single electron-withdrawing substitute on the para -position of the aryl introduced by the generation of ester seemed the most effective selection. The top hit, Y1–6 , indicated potent inhibitory activity on COX-2, sound anti-tumor effect, low cyto-toxicity, and high selectivity towards COX-2 from COX-1. In dose-dependent and time-dependent manners, Y1–6 could induce both the apoptosis and cell cycle arrest at G2/M phase of MB-MDA-231 cells. It could induce the generation of ROS and reduce the generation of PGE 2 to realize the inflammation-cancer interaction. Besides, molecular docking simulation suggested the key residues to ensure the firmly binding as ARG106, SER339, HIS75, LEU338 and TRP373. This work was informatic for developing better candidates as well as revealing the mechanism between inflammation and cancer. [Display omitted] A novel series of 1,3-diaryl pyrazolyl ester derivatives were synthesized and evaluated as potential COX-2 inhibitory candidates with anti-tumor effect. The top hit, Y1–6 , indicated potent inhibitory activity on COX-2, sound anti-tumor effect, low cyto-toxicity, and high selectivity towards COX-2 from COX-1. In dose-dependent and time-dependent manners, Y1–6 could induce both the apoptosis and cell cycle arrest at G2/M phase of MB-MDA-231 cells. It could induce the generation of ROS and reduce the generation of PGE 2 to realize the inflammation-cancer interaction. Besides, molecular docking simulation suggested the key residues to ensure the firmly binding. [ABSTRACT FROM AUTHOR]

Interleukin-1β (IL-1β) and prostaglandin (PG) D 2 are endogenous sleep-promoting substances. Since it was reported that a highly selective cyclooxygenase-2 (COX-2) inhibitor, NS398, completely inhibited IL-1β-induced sleep in rats, IL-1β-induced sleep had been believed to be mediated by prostanoids, most probably PGD 2 . However, in the present study, pretreatment of rats with NS398 (3 mg/kg) did not suppress the 64.2% increased non-rapid eye movement (non-REM, NREM) sleep during infusion of IL-1β (10 ng) for 6 h in the nocturnal (active) period between 23:00 and 5:00 into the subarachnoid space of the PGD 2 -sensitive sleep-promoting zone of the basal forebrain. Meanwhile, IL-1β at doses of 1.7 and 5 μg/kg also significantly increased NREM sleep for 6 h after intraperitoneal injection at 20:00 (light-off time) by 76.8% and 121.1%, respectively, in wild-type (WT) mice, by 67.7% and 147.3%, respectively, in WT mice pretreated with NS398 (5 mg/kg) and by 108.9% and 121.6%, respectively, in PGD 2 receptor (DP 1 R) knockout mice. These results indicate that IL-1β-induced NREM sleep is independent of the PGD 2 /DP 1 R system and other COX-2-derived prostaglandins in rats and mice. [ABSTRACT FROM AUTHOR]

Cancer stem cells (CSCs) are thought to be responsible for cancer relapse. CSCs are a subtype of cancer cells with the ability to differentiate, self-renew, and form secondary or tertiary tumors. Current cancer treatments--including chemotherapy, radiation, and surgery--effectively remove bulk cancer cells but are unable to eliminate CSCs. Here, we present the synthesis, characterization, and anti-CSC properties of a cobalt(III)-cyclam complex bearing two tolfenamic acid moieties, 3. Notably, 3 displays sub-micromolar potency towards breast CSCs and bulk breast cancer cells. Detailed mechanistic studies show that 3 is taken up readily by breast CSCs, enters the nucleus, causes DNA damage, and induces caspase-dependent apoptosis. Furthermore, 3 inhibits cyclooxygenase-2 (COX-2) expression in CSCs. The mechanism of action of 3 is similar to that of a naproxen-appended cobalt(III)-cyclam complex, 1 recently reported by our group. The advantage of 3 over 1 is that it has the potential to remove whole tumor populations (bulk cancer cells and CSCs) with a single dose. [ABSTRACT FROM AUTHOR]

Liver metastases are a major cause of colorectal cancer death, and the perioperative period is believed to critically affect the metastatic process. Here we tested whether blocking excess release of catecholamines and prostaglandins during surgical procedures of different extent can reduce experimental liver metastasis of the syngeneic CT26 colon cancer in female and male BALB/c mice. Animals were either treated with the beta-blocker, propranolol, the COX-2 inhibitor, etodolac, both drugs, or vehicle. The role of NK cells in controlling CT26 hepatic metastasis and in mediating the effect of the drugs was assessed by in vivo depletion or stimulation of NK cells, using anti-asialo GM1 or CpG-C, respectively. Surgical extent was manipulated by adding laparotomy to small incision, extending surgical duration, and enabling hypothermia. The results indicated that combined administration of propranolol and etodolac, but neither drug alone, significantly improved host resistance to metastasis. These beneficial effects occurred in both minor and extensive surgeries, in both sexes, and in two tumor inoculation approaches. NK cell-mediated anti-CT26 activity is involved in mediating the beneficial effects of the drugs. Specifically, CpG-C treatment, known to profoundly activate mice marginating-hepatic NK cytotoxicity, reduced CT26 hepatic metastases; and NK-depletion increased metastases and prevented the beneficial effects of the drugs. Overall, given prevalent perioperative psychological and physiological stress responses in patients, and ample prostaglandin release by colorectal tumors and injured tissue, propranolol and etodolac could be tested clinically in laparoscopic and open colorectal surgeries, attempting to reduce patients’ metastatic disease. [ABSTRACT FROM AUTHOR]

Aims Human papillomavirus (HPV) is a known biologic carcinogen which is commonly transmitted through sexual intercourse. CD8 + T cells are known effectors against tumour cells and an important prognostic marker in HPV-induced cancers. COX-2 inhibitors enhance CD8 + T cell activity against some cancers. In this work, we sought to study the presence and activation of CD8 + T lymphocytes in lesions from K14-HPV16 transgenic mice and the immunomodulatory effect of celecoxib (CXB) over these cells. Main methods Skin samples of CXB-treated and untreated HPV16 −/− and HPV16 +/− mice were enzymatically digested and analysed by flow cytometry to assess CD8 + and CD8 + CD107a + T cell infiltrates. Matched skin samples were classified histologically. Key findings HPV16 +/− mice presented higher CD8 + T cell infiltration than HPV16 −/− animals ( P < 0.001). Older HPV16 +/− animals showed epidermal dysplasia and increased percentages of CD8 + CD107a + T cells compared with younger animals with hyperplasia ( P < 0.001), validating this model for testing the effects of celecoxib on CD8 + T cells. CXB-treated HPV16 +/− mice showed higher percentages of CD8 + CD107a + T cells compared with untreated HPV16 +/− animals ( P < 0.01), but no differences were observed concerning the progression of epidermal lesions. Significance These findings indicate that celecoxib enhances the degranulation of CD8 + T cells on HPV16-induced lesions, suggesting the potential clinical use of COX-2 inhibitors. Additionally, this study demonstrates the usefulness of the K14-HPV16 mouse model for testing therapeutic immunomodulatory approaches. [ABSTRACT FROM AUTHOR]

Infections during pregnancy and subsequent maternal immune activation (MIA) increase risk for schizophrenia in offspring. The progeny of rodents injected with the viral infection mimic polyI:C during gestation display brain and behavioural abnormalities but the underlying mechanisms are unknown. Since the blood kynurenine pathway (KP) of tryptophan degradation impacts brain function and is strongly regulated by the immune system, we tested if KP changes occur in polyI:C offspring at preadolescence. We also tested whether MK801-induced hyperlocomotion, a behaviour characteristic of adult polyI:C offspring, is prevented by adolescent treatment with celecoxib, a COX-2 inhibitor that impacts the KP. Pregnant rats were treated with polyI:C (4 mg/kg, i.v.) or vehicle on gestational day 19. Serum levels of KP metabolites were measured in offspring of polyI:C or vehicle treated dams at postnatal day (PND) 31–33 using HPLC/GCMS. Additional polyI:C or vehicle exposed offspring were given celecoxib or vehicle between PND 35 and 46 and tested with MK801 (0.3 mg/kg) in adulthood (PND > 90). Prenatal polyI:C resulted in increases in the serum KP neurotoxic metabolite quinolinic acid at PND 31–33 (105%, p = 0.014). In contrast, the neuroprotective kynurenic acid and its precursor kynurenine were significantly decreased (28% p = 0.027, and 31% p = 0.033, respectively). Picolinic acid, another neuroprotective KP metabolite, was increased (31%, p = 0.014). Adolescent treatment with celecoxib (2.5 and 5 mg/kg/day, i.p.) prevented the development of MK801-induced hyperlocomotion in adult polyI:C offspring. Our study reveals the blood KP as a potential mechanism by which MIA interferes with postnatal brain maturation and associated behavioural disturbances and emphasises the preventative potential of inflammation targeting drugs. [ABSTRACT FROM AUTHOR]

Malignant brain tumors induce pronounced immunosuppression, which diminishes immune responses generated by immunotherapy. Here we report that peripheral immunotherapy, using irradiated unmodified whole tumor cells, and systemic cyclooxygenase-2 inhibition induce cure in glioma-bearing rats (60% cure rate), whereas neither monotherapy was sufficient to cure any animal. Moreover, the combined therapy protected against secondary tumor challenges (89% cure rate) and the secondary immune response was correlated with increased plasma interferon-gamma levels and CD8 + T cells systemically and intratumorally. In conclusion, we demonstrate that cyclooxygenase-2 inhibition is sufficient to render unmodified tumor cells immunogenic in immunotherapy of experimental brain tumors. [ABSTRACT FROM AUTHOR]

A series of fused tricyclic coumarin sulfonate derivatives was synthesized. Their in vitro antiproliferative activities against a panel of 57 human cancer cell lines of nine different cancer types were tested at the NCI. Compounds 1e, 1f, 1h, 1i, and 1o showed the highest mean percentage of inhibition values over the 57 cell line panel at 10 µM, and they were further tested in 5-dose testing mode to determine their IC50 values. Compounds 1e, 1f, and 1o were more selective against leukemia and colon cancer subpanels, while compounds 1h and 1i showed broad-spectrum anticancer activities. Compounds 1e, 1f, 1h, 1i, and 1o demonstrated high selectivity towards cancer cell lines than RAW 264.7 macrophages. Compound 1h exerted lethal effect over NCI-H522 NSCLC, SK-MEL-5 melanoma, and A498 renal cancer cell lines with percentage of inhibition values of 114.10%, 103.23%, and 100.52% at 10 µM concentration, respectively. Moreover, the IC50 value of compound 1o against HT29 colon cancer cell line was 532 nM. Compounds 1e, 1f, 1h, 1i, and 1o were tested for inhibitory effect over cyclooxygenase-2 (COX-2) enzyme as a possible mechanism of action. Furthermore, in silico studies were conducted to check the compliance of those five compounds with Lipinski's rule of five, and hence estimate their oral bioavailability. [ABSTRACT FROM AUTHOR]

Objective: The efficacy of vascular endothelial growth factor (VEGF), COX-2, calcium and aromatase inhibitors in an ovarian hyperstimulation syndrome (OHSS) rat model was tested. Methods: One hundred and eight female Wistar rats were randomly divided in nine groups. The control group received saline, while the OHSS group received rec-FSH for 4 consecutive days. The other seven groups received rec-FSH (4d) and Bevacizumab twice, Parecoxib daily, Verapamil daily, Parecoxib daily and Bevacizumab twice, Verapamil daily and Bevacizumab twice, Parecoxib and Verapamil daily, Letrozole and Meloxicam daily, respectively. All groups received also hCG at the 5th day. Results: All intervention groups were characterized by reduced vascular permeability compared to the OHSS group, which in the groups of Verapamil (Calcium inhibition) and Parecoxib + Verapamil (COX-2 + Calcium inhibition) presented significant statistical difference. The Verapamil group showed the lowest corpus luteum formation, while the Parecoxib (COX-2 inhibition), the Parecoxib + Verapamil (COX-2 + Calcium inhibition), the Bevacizumab + Parecoxib (VEGF + COX-2 inhibition) and the Bevacizumab + Verapamil (VEGF + Calcium inhibition) groups were also characterized by lower corpus luteum numbers compared to the OHSS group. Furthermore, lower graafian follicle formation was observed in the above groups, while the ovarian weight and the hormonal profile were not significantly affected. Conclusions: Studying the different check points of the VEGF pathway, we conclude that targeting calcium pathways could be beneficial for the vascular permeability control in an OHSS animal model. 目的 ：检测血管内皮生长因子（VEGF）、COX-2、钙和芳香化酶抑制剂对卵巢过度刺激综合征（OHSS）大鼠模型的效果。 方法：108只雌性Wistar大鼠随机分成9组。对照组用生理盐水处理、而卵巢过度刺激综合征组用重组-FSH连续用药4天。另外7组分别用4天重组-FSH和两次贝伐单抗；每日帕瑞昔布钠；每日维拉帕米；每日帕瑞昔布钠和两次维拉帕米；每日维拉帕米和两次贝伐单抗；每日帕瑞昔布钠和维拉帕米；每日来曲唑和美洛昔康处理。全部9组在第5天用人绒毛膜促性腺激素处理。 结果：对比卵巢过度刺激综合征组，所有干预组均有血管通透性降低的特征，其中维拉帕米组（钙离子拮抗制）和帕瑞昔布钠+维拉帕米组（COX-2+钙离子拮抗剂）有显著的统计学差异。相比OHSS组，维拉帕米组黄体形成数最少，而帕瑞昔布钠组（COX-2拮抗剂）、帕瑞昔布钠+维拉帕米组（COX-2+钙离子拮抗剂）、帕瑞昔布钠+贝伐单抗组（VEGF+COX-2拮抗剂）和贝伐单抗+维拉帕米（VEGF+钙离子拮抗剂）组也有较少黄体数。此外，以上各组中，形成成熟卵泡的数目也较少，而卵巢重量和激素受到的影响并不明显。 结论：通过研究不同的VEGF通路的检测点，我们得出以下结论：在卵巢过度刺激综合征的动物模型中，钙信号通路可能对控制血管通透性有益。 [ABSTRACT FROM AUTHOR]

Background The epithelial-to-mesenchymal transition (EMT) accompanied by the downregulation of Ecadherin has been thought to promote metastasis. Cyclooxygenase-2 (Cox-2) is presumed to contribute to cancer progression through its multifaceted function, and recently its inverse relationship with E-cadherin was suggested. The aim of the present study was to investigate whether selective Cox-2 inhibitors restore the expression of E-cadherin in head and neck squamous cell carcinoma (HNSCC) cells, and to examine the possible correlations of the expression levels of EMT-related molecules with clinicopathological factors in HNSCC. Methods We used quantitative real-time PCR to examine the effects of three selective Cox-2 inhibitors, i.e., celecoxib, NS-398, and SC-791 on the gene expressions of E-cadherin (CDH-1) and its transcriptional repressors (SIP1, Snail, Twist) in the human HNSCC cell lines HSC-2 and HSC-4. To evaluate the changes in E-cadherin expression on the cell surface, we used a flowcytometer and immunofluorescent staining in addition to Western blotting. We evaluated and statistically analyzed the clinicopathological factors and mRNA expressions of Cox-2, CDH-1 and its repressors in surgical specimens of 40 patients with tongue squamous cell carcinoma (TSCC). Results The selective Cox-2 inhibitors upregulated the E-cadherin expression on the cell surface of the HNSCC cells through the downregulation of its transcriptional repressors. The extent of this effect depended on the baseline expression levels of both E-cadherin and Cox-2 in each cell line. A univariate analysis showed that higher Cox-2 mRNA expression (p = 0.037), lower CDH-1 mRNA expression (p = 0.020), and advanced T-classification (p = 0.036) were significantly correlated with lymph node metastasis in TSCC. A multivariate logistic regression revealed that lower CDH-1 mRNA expression was the independent risk factor affecting lymph node metastasis (p = 0.041). Conclusions These findings suggest that the appropriately selective administration of certain Cox-2 inhibitors may have an anti-metastatic effect through suppression of the EMT by restoring E-cadherin expression. In addition, the downregulation of CDH-1 resulting from the EMT may be closely involved in lymph node metastasis in TSCC. [ABSTRACT FROM AUTHOR]

Abstract: A novel group of 1,4-diaryl-substituted triazoles was designed and synthesized by introducing the cyclooxygenase-2 (COX-2) pharmacophore SO2NH2 attached to one aryl ring and various substituents (H, F, Cl, CH3 or OCH3) attached to the other aryl ring. The effects of size and flexibility of the compounds upon COX-1/COX-2 inhibitory potency and selectivity was studied by increasing the size of an alkyl linker chain [(–CH2) n , where n =0, 1, 2]. In vitro COX-1/COX-2 inhibition studies showed that all compounds (14–18, 21–25 and 28–32) are more potent inhibitors of COX-2 isozyme (IC50 =0.17–28.0μM range) compared to COX-1 isozyme (IC50 =21.0 to >100μM range). Within the group of 1,4 diaryl-substituted triazoles, 4-{2-[4-(4-chloro-phenyl)-[1,2,3]triazol-1-yl]-ethyl}-benzenesulfonamide (compound 30) displayed highest COX-2 inhibitory potency and selectivity (COX-1: IC50 =>100μM, COX-2: IC50 =0.17μM, SI >588). Molecular docking studies using the catalytic site of COX-1 and COX-2, respectively, provided complementary theoretical support for the obtained experimental biological structure–activity relationship data. Results of molecular docking studies revealed that COX-2 pharmacophore SO2NH2 in compound 30 is positioned in the secondary pocket of COX-2 active site; with the nitrogen atom of the SO2NH2 group being hydrogen bonded to Q192 (N⋯O C=2.85Å), and one of the oxygen atoms of SO2NH2 group forming a hydrogen bond to H90 (S O⋯N=2.38Å). [Copyright &y& Elsevier]

Abstract: Antipsychotics, which act predominantly as dopamine D2 receptor antagonists, have several shortcomings. The exact pathophysiological mechanism leading to dopaminergic dysfunction in schizophrenia is still unclear, but inflammation has been postulated to be a key player in the pathophysiology of the disorder. A dysfunction in activation of the type 1 immune response seems to be associated with an imbalance in tryptophan/kynurenine metabolism; the degrading enzymes involved in this metabolism are regulated by cytokines. Kynurenic acid (KYNA), an N-methyl-d-aspartate antagonist, was found to be increased in critical regions of the central nervous system (CNS) in schizophrenia, resulting in reduced glutamatergic neurotransmission. The differential activation of microglial cells and astrocytes as functional carriers of the immune system in the CNS may also contribute to this imbalance. The immunological effects of many existing antipsychotics, however, rebalance in part the immune imbalance and overproduction of KYNA. The immunological imbalance results in an inflammatory state combined with increased prostaglandin E2 production and increased cyclo-oxygenase-2 (COX-2) expression. Growing evidence from clinical studies with COX-2 inhibitors points to favorable effects of anti-inflammatory therapy in schizophrenia, in particular in an early stage of the disorder. Further options for immunomodulating therapies in schizophrenia will be discussed. [Copyright &y& Elsevier]

Abstract: A substantial number of patients with major depressive disorder (MDD) do not respond adequately to current antidepressant pharmacological treatments, which are all more or less based on a gradually increased enhancement of monoaminergic neurotransmission. Although a functional deficiency in monoaminergic neurotransmission may contribute to MDD, the etiology and pathophysiology are far from clarified. Recent studies suggest that inflammatory processes may contribute, since increased levels of pro-inflammatory cytokines and prostaglandin E2 (PGE2) have repeatedly been observed in a subset of patients suffering from MDD. Interestingly, adjunct treatment with the anti-inflammatory drug celecoxib, a cyclo-oxygenase-2 (COX-2) inhibitor which blocks the PGE2-production, has shown to enhance the efficacy of both reboxetine, a selective noradrenaline reuptake inhibitor, as well as fluoxetine, a selective serotonin reuptake inhibitor, in treatment-resistant depression. To examine the neurobiological underpinnings to the clinical observations, we here studied the acute effects of a combined treatment with celecoxib and reboxetine on noradrenaline and dopamine output, as well as celecoxib and fluoxetine on 5-HT output in the medial prefrontal cortex, using in vivo microdialysis in awake freely moving rats. Celecoxib significantly potentiated the effects of reboxetine and fluoxetine on cortical noradrenaline and 5-HT output, respectively, but not the reboxetine-induced dopamine output. Moreover, celecoxib, when given alone, enhanced 5-HT output. These findings provide, in principle, novel experimental support for the clinical utility of combined treatment with antidepressant and anti-inflammatory drugs, such as COX-2 inhibitors, in MDD. [Copyright &y& Elsevier]

Background/Aims: Chronic organ donor shortage has led to the consideration to expand the donor pool with livers from non-heart-beating donors (NHBD), although a higher risk of graft dys- or nonfunction is associated with these livers. We examined the effects of selective cyclooxygenase-2 (COX-2) inhibition on hepatic warm ischemia (WI) reperfusion (I/R) injury of NHBD. Methods: Male Wistar rats were used as donors and meloxicam (5 mg/kg body weight) was administered into the preservation solution. Livers were excised after 60 min of WI in situ, flushed and preserved for 24 h at 4°C. Reperfusion was carried out in vitro at a constant flow for 45 min. During reperfusion (5, 15, 30 and 45 min), enzyme release of alanine aminotransferase and glutamate lactate dehydrogenase were measured as well as portal venous pressure, bile production and oxygen consumption. The production of malondialdehyde was quantified and TUNEL staining was performed. Quantitative PCR analyzed COX-2 mRNA. COX-2 immunohistochemistry and TxB2 detection completed the measurements. Results: Meloxicam treatment led to better functional recovery concerning liver enzyme release, vascular resistance and metabolic activity over time in all animals. Oxidative stress and apoptosis were considerably reduced. Conclusion: Cold storage using meloxicam resulted in significantly better integrity and function of livers retrieved from NHBD. Selective COX-2 inhibition is a new therapeutic approach achieving improved preservation of grafts from NHBD. Copyright © 2011 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

A new group of 5,5-diarylhydantoin derivatives bearing a methylsulfonyl COX-2 pharmacophore at the para position of the C-5 phenyl ring were designed and synthesized as selective COX-2 inhibitors. In vitro COX-1/COX-2 inhibition structure-activity relationships identified 5-[4-(methylsulfonyl)phenyl]-5-phenyl-hydantoin (4) as a highly potent and selective COX-2 inhibitor (COX-2 IC50 = 0.077 μM; selectivity index > 1298). It was more selective than the reference drug celecoxib (COX-2 IC50 = 0.060 μM; selectivity index = 405). A molecular modeling study where 4 was docked in the binding site of COX-2 indicated that the p-MeSO2 COX-2 pharmacophore group on the C-5 phenyl ring is oriented in the vicinity of the COX-2 secondary pocket. The results of this study showed that the type of substituent on the N-3 hydantoin ring substituent is important for COX-2 inhibitory activity. [ABSTRACT FROM AUTHOR]

Abstract: Recent trials support the hypothesis of the role of inflammation in the pathogenesis of schizophrenia. The overall therapeutic benefit of anti-inflammatory medication, in particular cyclo-oxygenase-2 (COX-2) inhibitors in schizophrenia, is still controversial. There are suggestions that therapy with COX-2 inhibitors may influence the early stages of the disease. Taking these findings into account, we conducted a double-blind, placebo-controlled, randomized trial of celecoxib augmentation to amisulpride treatment in patients with a first manifestation of schizophrenia. Forty-nine patients diagnosed with schizophrenia were randomly assigned. They were treated either with amisulpride (200–1000mg) plus celecoxib (400mg) or amisulpride (200–1000mg) plus placebo. Inclusion criterion was the diagnosis of schizophrenia during the past two years according to DSM-IV. The trial lasted six weeks. At weekly intervals an assessment of the psychopathology was performed using the Positive and Negative Symptom Scale (PANSS) and the Global Clinical Impression Scale (CGI). A significantly better outcome was observed in the patient group treated with amisulpride plus celecoxib compared to the group with amisulpride plus placebo (PANSS negative: p =0.03; PANSS global; p =0.05 and PANSS total: p =0.02). In addition, ratings by the CGI scale during therapy with amisulpride and celecoxib showed a significantly better result (p ≤0.001). A significantly superior therapeutic effect could be observed in the celecoxib group compared to placebo in the treatment of early stage schizophrenia. This is the first time an improvement in patients'' negative symptoms has been demonstrated with celecoxib. In future, further trials are needed to investigate the effect of COX-2 inhibitors on prodromal and negative symptoms of schizophrenia. [Copyright &y& Elsevier]

Abstract: Nonsteroidal anti-inflammatory drugs (NSAIDs) such as indomethacin decrease mucosal PGE2 content by inhibiting cyclooxygenase (COX) activity and produce damage in the small intestine. The development of intestinal lesions induced by indomethacin was accompanied by increases in intestinal motility, enterobacterial invasion, and myeloperoxidase (MPO) as well as inducible nitric oxide synthase (iNOS) activity, together with the up-regulation of COX-2 and iNOS mRNA expression. Neither SC-560, a selective COX-1 inhibitor, nor rofecoxib, a selective COX-2 inhibitor, alone caused intestinal damage, but their combined administration provoked lesions in the small intestine. SC-560, but not rofecoxib, caused intestinal hypermotility, bacterial invasion and the expression of COX-2 as well as iNOS mRNA, yet the iNOS and MPO activity was increased only when rofecoxib was administered together with SC-560. Although SC-560 inhibited PG production, the level of PGE2 recovered in a rofecoxib-dependent manner. The intestinal hypermotility in response to indomethacin was prevented by both 16,16-dimethyl PGE2 and atropine but not by ampicillin, yet all these agents inhibited not only the bacterial invasion but also the expression of COX-2 as well as the iNOS activity in the intestinal mucosa following indomethacin treatment, thereby preventing the intestinal damage. These results suggest that inhibition of COX-1, despite causing intestinal hypermotility, bacterial invasion and iNOS expression, up-regulates the expression of COX-2, and the PGE2 derived from COX-2 counteracts the deleterious events caused by COX-1 inhibition and maintains mucosal integrity. These sequences of events explain why intestinal damage occurs when both COX-1 and COX-2 are inhibited. [Copyright &y& Elsevier]

Abstract: Chondrosarcomas are resistant to conventional chemo- and radiotherapy. A subset of chondrosarcomas arises secondarily in the benign tumour syndromes enchondromatosis (EC) and multiple osteochondromas (MO), and prevention of tumour development would greatly improve prognosis. We therefore investigated the effect of selective COX-2 inhibition on chondrosarcoma growth. COX-2 expression was studied in central- and peripheral cartilaginous tumours. The effect of COX-2 inhibition was assessed in four high-grade chondrosarcoma cell lines using celecoxib and NS-398 treatment. COX-2 activity (prostaglandin E2 (PGE2) ELISA) and cell viability were measured. The (prophylactic) effect of celecoxib on chondrosarcoma growth in vivo was studied for 8weeks using a xenograft model of cell line CH2879 in immunoincompetent nude mice. High COX-2 protein expression was mainly found in solitary peripheral chondrosarcoma and in enchondromatosis-related central chondrosarcoma, which was confirmed by qPCR. After 72h of celecoxib treatment, a significant decrease in cell viability was observed in three chondrosarcoma cell lines. In vivo, celecoxib initially slowed tumour growth in chondrosarcoma xenografts; however, after prolonged treatment relapsed tumour growth was observed. Tumour volume was negatively associated with celecoxib serum levels, and seemed smaller in the high-dose prophylactic treatment group. We confirmed the expression of COX-2 in 65% of chondrosarcomas, and COX-2 inhibition by celecoxib diminished cell viability in vitro. The initial response and the decrease in tumour volume with increased celecoxib serum levels in vivo supported a role for celecoxib, although relapsed tumour growth after 6weeks was worrisome. Also the role of high-dose prophylactic celecoxib in preventing the development of benign and malignant cartilage tumours in EC and MO patients deserves further investigation. [Copyright &y& Elsevier]

Abstract: A new group of 1, 3-benthiazinan-4-ones, possessing a methyl sulfonyl pharmacophore, were synthesized and their biological activities were evaluated for cyclooxygenase-2 (COX-2) inhibitory activity. In vitro COX-1/COX-2 inhibition studies identified 3-(p-fluoropheny)-2-(4-methylsulfonylphenyl)-1,3-benzthiazinan-4-one (7b) as a potent (IC50 =0.05μM) and selective (selectivity index=259) COX-2 inhibitor. [Copyright &y& Elsevier]

Abstract: A group of 1,3-diarylurea derivatives, possessing a methylsulfonyl pharmacophore at the para-position of the N-1 phenyl ring, in conjunction with a N-3 substituted-phenyl ring (4-F, 4-Cl, 4-Me, 4-OMe), were designed and synthesized for evaluation as selective cyclooxygenase-2 (COX-2) inhibitors. In vitro COX-1/COX-2 isozyme inhibition structure–activity studies identified 1-(4-methylsulfonylphenyl)-3-(4-methoxyphenyl) urea (4e) as a potent COX-2 inhibitor (IC50 =0.11μM) with a high COX-2 selectivity index (SI=203.6) comparable to the reference drug celecoxib (COX-2 IC50 =0.06μM; COX-2 SI=405). The structure–activity data acquired indicate that the urea moiety constitutes a suitable scaffold to design new acyclic 1,3-diarylurea derivatives with selective COX-2 inhibitory activity. [Copyright &y& Elsevier]

Abstract: Indoles carrying a cyclic ester (γ-butyrolactone) at C-3 position have been synthesized by the allylation of 3-indoleglyoxylate followed by iodocyclisation and the nucleophilic replacement of the iodo-group. Screening of these molecules for COX-2 inhibition and anti-cancer activities has identified compounds 10 and 11 as highly potent and selective for COX-2 as well as showing remarkable anti-cancer activities (better than that of indomethacin). [Copyright &y& Elsevier]

Abstract: A group of 2,3-diaryl-1,3-thiazolidine-4-ones, possessing a methylsulfonyl pharmacophore, were synthesized and their biological activities were evaluated for cyclooxygenase-2 (COX-2) inhibitory activity. [Copyright &y& Elsevier]

Anti-inflammatory efficacy of the fermented wheat germ extract (FWGE, Avemar) in the rat adjuvant arthritis (AA) model was examined. To Wistar rats with AA, different doses of FWGE and anti-inflammatory drugs (indomethacin, dexamethasone) as monotherapies were administered and FWGE and either diclofenac or dexamethasone were also given in combination. Besides plethysmographies of the paws, histological investigations of synovial tissues were also performed along with detection of CD4+ and CD8+ T lymphocytes. Gene expressions of COX-1 and 2 were determined by real-time polymerase chain reaction (PCR). FWGE monotherapy significantly inhibited the development of the secondary (immune-mediated) response in AA, and dexamethasone and indomethacin exerted inhibitory effects in a degree comparable to that of FWGE. Histological analysis of the affected joints confirmed the results. FWGE inhibited COX-1 and -2, while indomethacin enhanced COX-2 gene expressions. FWGE had an additive interaction with diclofenac. It is concluded that FWGE has significant anti-inflammatory efficacy confirmed by plethysmography, histology, and real-time PCR. [ABSTRACT FROM AUTHOR]

Abstract: New insights into the biological properties of cyclooxygenase-2 (COX-2) and its response pathway challenge the hypothesis that COX-2 is simply pro-inflammatory and inhibition of COX-2 solely prevents the development of inflammation and ameliorates inflammatory pain. The present study performed a comprehensive analysis of gene/protein expression induced by a selective inhibitor of COX-2, rofecoxib, compared with a non-selective COX inhibitor, ibuprofen, and placebo in a clinical model of acute inflammatory pain (the surgical extraction of impacted third molars) using microarray analysis followed by quantitative RT-PCR verification and Western blotting. Inhibition of COX-2 modulated gene expression related to inflammation and pain, the arachidonic acid pathway, apoptosis/angiogenesis, cell adhesion and signal transduction. Compared to placebo, rofecoxib treatment increased the gene expression of ANXA3 (annexin 3), SOD2 (superoxide dismutase 2), SOCS3 (suppressor of cytokine signaling 3) and IL1RN (IL1 receptor antagonist) which are associated with inhibition of phospholipase A2 and suppression of cytokine signaling cascades, respectively. Both rofecoxib and ibuprofen treatment increased the gene expression of the pro-inflammatory mediators, IL6 and CCL2 (chemokine C-C motif ligand 2), following tissue injury compared to the placebo treatment. These results indicate a complex role for COX-2 in the inflammatory cascade in addition to the well-characterized COX-dependent pathway, as multiple pathways are also involved in rofecoxib-induced anti-inflammatory and analgesic effects at the gene expression level. These findings may also suggest an alternative hypothesis for the adverse effects attributed to selective inhibition of COX-2. [Copyright &y& Elsevier]

Signs of an inflammatory process, in particular increased pro-inflammatory cytokines and increased levels of prostaglandine E2 (PGE2), have repeatedly been described in major depression (MD). As cyclooxygenase-2 (COX-2) inhibitors inhibit the PGE2 production and the production of pro-inflammatory cytokines, we performed a therapeutic trial with the COX-2 inhibitor celecoxib. In a prospective, double-blind, add-on study, 40 patients suffering from an acute depressive episode were randomly assigned to either reboxetine and celecoxib or to reboxetine plus placebo. After a wash-out period, 20 patients received 4–10 mg reboxetine plus placebo and 20 received reboxetine plus 400 mg celecoxib for 6 weeks. The treatment effect was calculated by analysis of variance. There were no significant differences between groups in age, sex, duration or severity of disease or psychopathology, or reboxetine dose or plasma levels. Over 6 weeks, both groups of patients showed significant improvement in scores of the Hamilton Depression Scale. However, the celecoxib group showed significantly greater improvement compared to the reboxetine-alone group. Additional treatment with celecoxib has significant positive effects on the therapeutic action of reboxetine with regard to depressive symptomatology. Moreover, the fact that treatment with an anti-inflammatory drug showed beneficial effects on MD indicates that inflammation is related to the pathomechanism of the disorder, although the exact mechanisms remain to become elucidated.Molecular Psychiatry (2006) 11, 680–684. doi:10.1038/sj.mp.4001805; published online 21 February 2006 [ABSTRACT FROM AUTHOR]

Abstract: Interleukin-1beta (IL-1β) and amyloid-beta peptide 42 (Aβ42) together induce a robust proinflammatory gene expression program in human neural cells in primary culture. One consistent genetic marker for this triggered inflammatory response is an increase in the expression of cycloooxygenase-2 (COX-2), a prostaglandin synthase also found to be up-regulated in neurological disorders such as Alzheimer''s disease. In this study we provide data illustrating the combined effect of three independent classes of compounds: the glucocorticoid budesonide epimer R, the platelet-activating factor antagonist LAU-8080, and the free radical scavenger phenyl butyl nitrone, upon COX-2 gene activation and prostaglandin E2 (PGE2) levels in [IL-1β+Aβ42]-stressed HN cells. The data indicate that specific combinations of repressors of COX-2 activity are synergistic in modulating the stress-induced up-regulation of COX-2 and PGE2, and this may be of potential therapeutic value in the design of treatment for complex neuroinflammatory disorders. [Copyright &y& Elsevier]

The use of specific COX-2 inhibitors in place of standard nonsteroidals for the treatment of arthritis appears to reduce the risk of serious gastrointestinal toxicity in this group of patients. However, the role played by these inhibitors in the generation or exacerbation of ischaemic cardiovascular disease is less clear. Clinical studies demonstrate that hypertension can be induced or aggravated by COX-2 inhibitors to a degree similar to that which occurs with standard nonsteroidals. Endothelial dysfunction, an indicator of cardiac ischaemia, may also be exacerbated by specific COX-2 inhibition and there is much debate as to whether these changes lead to an absolute increase in ischaemic cardiac events. These effects on cardiovascular risk factors appear all the more important in patients with rheumatoid arthritis where there is an increase in the incidence of ischaemic heart disease. Here we review the available data on COX-2 inhibition and cardiovascular disease and conclude that all patients who started these agents should have a careful assessment and modification of any cardiovascular risk factors.Journal of Human Hypertension (2005) 19, 1-5. doi:10.1038/sj.jhh.1001777 Published online 23 September 2004 [ABSTRACT FROM AUTHOR]

Valdecoxib, a cyclooxygenase (COX)-2 specific inhibitor, is indicated for relief of the signs and symptoms of rheumatoid arthritis, osteoarthritis, and primary dysmenorrhea. Therapeutic doses of COX-2 specific inhibitors are as effective as nonspecific nonsteroidal anti-inflammatory drugs in reducing inflammatory pain while sparing the gastrointestinal and platelet toxicity associated with nonspecific COX-1 inhibition.The aim of this study was to assess the analgesic efficacy and tolerability of valdecoxib 40 mg/d compared with placebo in the treatment of chronic low back pain.This 4-week, prospective, randomized, double-blind placebo-controlled, parallel-group study was conducted at 37 centers across the United States and 5 centers in Canada. Patients aged ≥18 years with chronic low back pain in flare were enrolled. Patients were randomized to receive valdecoxib 40-mg/d or placebo tablets, once daily for 4 weeks. Patients rated low back pain intensity on a visual analog scale and completed the Roland-Morris Disability Questionnaire and the modified Brief Pain Inventory—Short Form (mBPI-SF) at each visit.Two hundred ninety-three patients were enrolled. The valdecoxib group comprised 148 patients (81 women, 67 men; mean [SD] age, 48.6 [13.3] years; mean [SD] body weight, 86.6 [20.9] kg), and the placebo group included 145 patients (85 women, 60 men; mean [SD] age, 48.7 [12.6] years; mean [SD] body weight, 85.6 [19.9] kg). Of the enrolled patients, 249 completed the study: 134 patients (91%) who received valdecoxib and 115 patients (79%) who received placebo. No statistically significant differences in patient baseline characteristics were noted between treatment groups, except in response to 1 mBPI-SF question; patients in the valdecoxib group reported significantly greater interference in relations with other people due to pain than did those in the placebo group (P = 0.048). Changes from baseline in low back pain intensity were significantly greater in valdecoxib-treated patients at each assessment (all, P < 0.001 vs placebo). Pain scores on the mBPI-SF indicated significantly greater pain relief with valdecoxib at each assessment (all, P ≤ 0.014 vs placebo). Improvements in mean Roland-Morris Disability Questionnaire score with valdecoxib were significantly greater than with placebo at each assessment (all, P ≤ 0.003). Although the overall incidence of adverse events (AEs) was significantly higher among patients receiving valdecoxib than those receiving placebo (35.1% vs 24.1%, respectively; P = 0.042), no significant differences were found between groups for the incidence of any individual AE. Most AEs (89% [77/87 total events]) were mild or moderate in severity.In this study of patients with chronic low back pain, valdecoxib 40 mg/d provided rapid relief (within 1 week) and consistent relief (over 4 weeks). In addition, significant improvement in function and decreased disability were found with valdecoxib compared with placebo. [Copyright &y& Elsevier]