Characterization of Phenolic Compounds in Extra Virgin Olive Oil from Granada (Spain) and Evaluation of Its Neuroprotective Action.

The olive oil sector is a fundamental food in the Mediterranean diet. It has been demonstrated that the consumption of extra virgin olive oil (EVOO) with a high content of phenolic compounds is beneficial in the prevention and/or treatment of many diseases. The main objective of this work was to study the relationship between the content of phenolic compounds and the in vitro neuroprotective and anti-inflammatory activity of EVOOs from two PDOs in the province of Granada. To this purpose, the amounts of phenolic compounds were determined by liquid chromatography coupled to mass spectrometry (HPLC-MS) and the inhibitory activity of acetylcholinesterase (AChE) and cyclooxygenase-2 (COX-2) enzymes by spectrophotometric and fluorimetric assays. The main families identified were phenolic alcohols, secoiridoids, lignans, flavonoids, and phenolic acids. The EVOO samples with the highest total concentration of compounds and the highest inhibitory activity belonged to the Picual and Manzanillo varieties. Statistical analysis showed a positive correlation between identified compounds and AChE and COX-2 inhibitory activity, except for lignans. These results confirm EVOO's compounds possess neuroprotective potential.

Repurposed Drugs Celecoxib and Fmoc-L-Leucine Alone and in Combination as Temozolomide-Resistant Antiglioma Agents-Comparative Studies on Normal and Immortalized Cell Lines, and on C. elegans.

Glioblastoma multiforme therapy remains a significant challenge since there is a lack of effective treatment for this cancer. As most of the examined gliomas express or overexpress cyclooxygenase-2 (COX-2) and peroxisome proliferator-activated receptors γ (PPARγ), we decided to use these proteins as therapeutic targets. Toxicity, antiproliferative, proapoptotic, and antimigratory activity of COX-2 inhibitor (celecoxib-CXB) and/or PPARγ agonist (Fmoc-L-Leucine-FL) was examined in vitro on temozolomide resistant U-118 MG glioma cell line and comparatively on BJ normal fibroblasts and immortalized HaCaT keratinocytes. The in vivo activity of both agents was studied on C. elegans nematode. Both drugs effectively destroyed U-118 MG glioma cells via antiproliferative, pro-apoptotic, and anti-migratory effects in a concentration range 50-100 µM. The mechanism of action of CXB and FL against glioma was COX-2 and PPARγ dependent and resulted in up-regulation of these factors. Unlike reports by other authors, we did not observe the expected synergistic or additive effect of both drugs. Comparative studies on normal BJ fibroblast cells and immortalized HaCaT keratinocytes showed that the tested drugs did not have a selective effect on glioma cells and their mechanism of action differs significantly from that observed in the case of glioma. HaCaTs did not react with concomitant changes in the expression of COX-2 and PPARγ and were resistant to FL. Safety tests of repurposing drugs used in cancer therapy tested on C. elegans nematode indicated that CXB, FL, or their mixture at a concentration of up to 100 µM had no significant effect on the entire nematode organism up to 4th day of incubation. After a 7-day treatment, CXB significantly shortened the lifespan of C. elegans at 25-400 µM concentration and body length at 50-400 µM concentration.

New neuroprotective derivatives of cinnamic acid by biotransformation.

Microbial transformation is extensively utilized to generate new metabolites in bulk amounts with more specificity and improved activity. As cinnamic acid was reported to exhibit several important pharmacological properties, microbial transformation was used to obtain its new derivatives with enhanced biological activities. By manipulating the 2-stage fermentation protocol of biotransformation, five metabolites were produced from cinnamic acid. Two of them were new derivatives; N-propyl cinnamamide 2̲ and 2-methyl heptyl benzoate 3̲ produced by Alternaria alternata. The other 3 metabolites, p-hydroxy benzoic acid 4̲, cinnamyl alcohol 5̲ and methyl cinnamate 6̲, were produced by Rhodotorula rubra, Rhizopus species and Penicillium chrysogeneum, respectively. Cinnamic acid and its metabolites were evaluated for their cyclooxygenase (COX) and acetylcholinesterase (AChE) inhibitory activities. Protection against H2O2 and Aß1-42 induced-neurotoxicity in human neuroblastoma (SH-SY5Y) cells was also monitored. Metabolite 4̲ was more potent as a COX-2 inhibitor than the parent compound with an IC50 value of 1.85 ± 0.07 µM. Out of the tested compounds, only metabolite 2̲ showed AChE inhibitory activity with an IC50 value of 8.27 µM. These results were further correlated with an in silico study of the binding interactions of the active metabolites with the active sites of the studied enzymes. Metabolite 3̲ was more potent as a neuroprotective agent against H2O2 and Aß1-42 induced-neurotoxicity than catechin and epigallocatechin-3-gallate as positive controls. This study suggested the two new metabolites 2̲ and 3̲ along with metabolite 4̲ as potential leads for neurodegenerative diseases associated with cholinergic deficiency, neurotoxicity or neuroinflammation.

Comparing anti-tumor and anti-self immunity in a patient with melanoma receiving immune checkpoint blockade.

BACKGROUND: Tumor regression following immune checkpoint blockade (ICB) is often associated with immune-related adverse events (irAEs), marked by inflammation in non-cancerous tissues. This study was undertaken to investigate the functional relationship between anti-tumor and anti-self immunity, to facilitate irAE management while promoting anti-tumor immunity. METHODS: Multiple biopsies from tumor and inflamed tissues were collected from a patient with melanoma experiencing both tumor regression and irAEs on ICB, who underwent rapid autopsy. Immune cells infiltrating melanoma lesions and inflamed normal tissues were subjected to gene expression profiling with multiplex qRT-PCR for 122 candidate genes. Subsequently, immunohistochemistry was conducted to assess the expression of 14 candidate markers of immune cell subsets and checkpoints. TCR-beta sequencing was used to explore T cell clonal repertoires across specimens. RESULTS: While genes involved in MHC I/II antigen presentation, IFN signaling, innate immunity and immunosuppression were abundantly expressed across specimens, irAE tissues over-expressed certain genes associated with immunosuppression (CSF1R, IL10RA, IL27/EBI3, FOXP3, KLRG1, SOCS1, TGFB1), including those in the COX-2/PGE2 pathway (IL1B, PTGER1/EP1 and PTGER4/EP4). Immunohistochemistry revealed similar proportions of immunosuppressive cell subsets and checkpoint molecules across samples. TCRseq did not indicate common TCR repertoires across tumor and inflammation sites, arguing against shared antigen recognition between anti-tumor and anti-self immunity in this patient. CONCLUSIONS: This comprehensive study of a single patient with melanoma experiencing both tumor regression and irAEs on ICB explores the immune landscape across these tissues, revealing similarities between anti-tumor and anti-self immunity. Further, it highlights expression of the COX-2/PGE2 pathway, which is known to be immunosuppressive and potentially mediates ICB resistance. Ongoing clinical trials of COX-2/PGE2 pathway inhibitors targeting the major COX-2 inducer IL-1B, COX-2 itself, or the PGE2 receptors EP2 and EP4 present new opportunities to promote anti-tumor activity, but may also have the potential to enhance the severity of ICB-induced irAEs.

Parecoxib decreases cellular growth and Bcl-2 protein levels in primary cultures of keloid fibroblasts.

Keloids seem to overexpress cyclo-oxygenase-2 (COX-2), suggesting a role in its deregulated pathway in inducing an altered epithelial-mesenchymal interaction, which may be responsible for the overgrowth of dermal components resulting in scars or keloid lesions. This study aimed to evaluate the effect of Parecoxib, a COX-2 inhibitor, on cell growth in fibroblast primary cultures obtained from human keloid tissues. Tissue explants were obtained from patients who underwent intralesional excision of untreated keloids; central fractions were isolated from keloid tissues and used for establishing distinct primary cultures. Appropriate aliquots of Parecoxib, a COX-2 inhibitor were diluted to obtain the concentration used in the experimental protocols in vitro (1, 10 or 100 µM). Treatment with Parecoxib (at all concentrations) caused a significant decrease in cellular growth from 24 hours onwards, and with a maximum at 72 hours (P < .02). Moreover, at 72 hours Parecoxib significantly reduced cellular vitality. Parecoxib treatment also induced an increase in fragmented nuclei with a maximum effect at 100 µM and a significant decrease in Bcl-2 and an increase in activated caspase-3 protein levels at 72 hours compared with control untreated cultures. Our findings suggest a potential use of the COX-2 inhibitor, Parecoxib, as the therapy for keloids.

Combination Nano-Delivery Systems Remodel the Immunosuppressive Tumor Microenvironment for Metastatic Triple-Negative Breast Cancer Therapy.

Triple-negative breast cancer (TNBC) is an aggressive type of breast cancer for which effective therapies are lacking. Targeted remodeling of the immunosuppressive tumor microenvironment (TME) and activation of the body's immune system to fight tumors with well-designed nanoparticles have emerged as pivotal breakthroughs in tumor treatment. To simultaneously remodel the immunosuppressive TME and trigger immune responses, we designed two potential therapeutic nanodelivery systems to inhibit TNBC. First, the bromodomain-containing protein 4 (BRD4) inhibitor JQ1 and the cyclooxygenase-2 (COX-2) inhibitor celecoxib (CXB) were coloaded into chondroitin sulfate (CS) to obtain CS@JQ1/CXB nanoparticles (NPs). Then, the biomimetic nanosystem MM@P3 was prepared by coating branched polymer poly(ß-amino ester) self-assembled NPs with melittin embedded macrophage membranes (MM). Both in vitro and in vivo, the CS@JQ1/CXB and MM@P3 NPs showed excellent immune activation efficiencies. Combination treatment exhibited synergistic cytotoxicity, antimigration ability, and apoptosis-inducing and immune activation effects on TNBC cells and effectively suppressed tumor growth and metastasis in TNBC tumor-bearing mice by activating the tumor immune response and inhibiting angiogenesis. In summary, this study offers a novel combinatorial immunotherapeutic strategy for the clinical TNBC treatment.

Design, synthesis and molecular docking of novel D-ring substituted steroidal 4,5-dihydropyrazole thiazole derivatives that act as iNOS/COX-2 inhibitors with potent anti-inflammatory activity against LPS-induced RAW264.7 macrophage cells.

Inflammation, an important biological protective response to tissue damage or microbial invasion, is considered to be an alarming signal for the progress of varied biological complications. Based on the previous reports in the literature that proved the noticeable efficacy of pyrazole and thiazole scaffold as well as nitrogen heterocyclic based compounds against acute and chronic inflammatory disease, a new set of novel D-ring substituted steroidal 4,5-dihydropyrazole thiazole derivatives were synthesized and evaluated their anti-inflammatory activities in vitro. Preliminary structure-activity relationship (SAR) analysis was conducted by their inhibitory activities against nitric oxide (NO) release in lipopolysaccharide (LPS)-induced RAW 264.7 cells, and the optimal compound 12b [3ß-hydroxy-pregn-5-en-17ß-yl-5'- (o- chlorophenyl)- 1'-(4''- phenyl -[1'', 3'']- thiazol-2''- yl) - 4',5'-dihydro - 1'H-pyrazol - 3'- yl] exhibited more potent anti-inflammatory activity than the positive control treatment methylprednisolone (MPS), with an IC50 value of 2.59 µM on NO production and low cytotoxicity against RAW 264.7 cells. In further mechanism study, our results showed that compound 12b significantly suppressed the production of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and inhibited the expressions of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2) through blocking NF-κB p65 nuclear translocation and phosphorylation of IκBα. Compound 12b also attenuated LPS-induced activation of c-Jun amino-terminal kinase (JNK) and p38 phosphorylation in RAW 264.7 cells. Molecular docking study revealed the strong binding affinity of compound 12b to the active site of the COX-2 proteins, which confirmed that compound 12b acted as an anti-inflammatory mediator. These results indicate that steroidal derivatives bearing 4,5-dihydropyrazole thiazole structure might be considered for further research and scaffold optimization in designing anti-inflammatory drugs and compound 12b might be a promising therapeutic anti-inflammatory drug candidate.

Dual COX-2 and 15-LOX inhibition study of novel 4-arylidine-2-mercapto-1-phenyl-1H-imidazolidin-5(4H)-ones: Design, synthesis, docking, and anti-inflammatory activity.

Novel arylidene-5(4H)-imidazolone derivatives 4a-r were designed and evaluated as multidrug-directed ligands, that is, inflammatory, proinflammatory mediators, and reactive oxygen species (ROS) inhibitors. All of the tested compounds showed cyclooxygenase (COX)-1 inhibitory effect more than celecoxib and less than indomethacin and also demonstrated an improved inhibitory activity against 15-lipoxygenase (15-LOX). Compounds 4f, 4l, and 4p exhibited COX-2 selectivity comparable to that of celecoxib, while 4k was the most selective COX-2 inhibitor. Interestingly, the screened results showed that compound 4k exhibited a superior inhibition effect against 15-LOX and was found to be the most selective COX-2 inhibitor over celecoxib, whereas compound 4f showed promising COX-2 and 15-LOX inhibitory activities besides its inhibitory effect against ROS production and its lowering effect of both tumor necrosis factor-α and interleukin-6 levels by ∼80%. Moreover, compound 4f attenuated the lipopolysaccharide-mediated increase in NF-κB activation in RAW 264.7 macrophages. The preferred binding affinity of these molecules was confirmed by docking studies. We conclude that arylidene-5(4H)-imidazolone scaffolds provide promising hits for developing new synthons with anti-inflammatory and antioxidant activities.

Computational screening of potential anti-inflammatory leads from Jeevaneeya Rasayana plants targeting COX-2 and 5- LOX by molecular docking and dynamic simulation approaches.

Inflammation plays a pivotal role in various pathological processes, ranging from routine injuries and infections to cancer. Cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LOX) are two major enzymes involved in the formation of lipid mediators of inflammation, such as prostaglandins and leukotrienes, through the arachidonic acid pathway. Despite the frequent use of nonsteroidal anti-inflammatory drugs for managing inflammatory disorders by inhibiting these enzymes, there is a wide spectrum of adverse effects linked to their usage. Jeevaneeya Rasayana (JR), a polyherbal formulation traditionally used in India, is renowned for its anti-inflammatory properties. The present study aimed to identify the potential phytocompounds in JR plants against COX-2 and 5-LOX, utilizing molecular docking and dynamic simulations. Among the 429 identified phytocompounds retrieved from publicly available data sources, Terrestribisamide and 1-(9Z-octadecenoyl)-sn-glycero-3-phosphoethanolamine have shown potential binding affinity and favorable interactions with COX-2 and 5-LOX arachidonic acid binding sites. The physicochemical properties and ADMET profiles of these compounds determined their drug-likeness and pharmacokinetics features. Additional validation using molecular dynamics simulations, SASA, Rg, and MM-PBSA binding energy calculations affirmed the stability of the complex formed between those compounds with target proteins. Together, the study identified the effectual binding potential of those bioactive compounds against COX-2 and 5-LOX, providing a viable approach for the development of effective anti-inflammatory medications.

An in situ forming gel co-loaded with pirarubicin and celecoxib inhibits postoperative recurrence and metastasis of breast cancer.

Surgical removal combined with postoperative chemotherapy is still the mainstay of treatment for most solid tumors. Although chemotherapy reduces the risk of recurrence and metastasis after surgery, it may produce serious adverse effects and impair patient compliance. In situ drug delivery systems are promising tools for postoperative cancer treatment, improving drug delivery efficiency and reducing side effects. Herein, an injectable phospholipid-based in situ forming gel (IPG) was prepared for the co-delivery of antitumor agent pirarubicin (THP) and cyclooxygenase-2 (COX-2) inhibitor celecoxib (CXB) in the surgical incision, and the latter are used extensively in adjuvant chemotherapy for cancer. After injection, the IPG co-loaded with THP and CXB (THP-CXB-IPG) underwent spontaneous phase transition and formed a drug reservoir that fitted the irregular surgical incisions perfectly. In vitro drug release studies and in vivo pharmacokinetic analysis had demonstrated the sustained release behaviors of THP-CXB-IPG. The in vivo therapeutic efficacy was evaluated in mice that had undergone surgical resection of breast cancer, and the THP-CXB-IPG showed considerable inhibition of residual tumor growth after surgery and reduced the incidence of pulmonary metastasis. Moreover, it reduced the systemic toxicity of chemotherapeutic agents. Therefore, THP-CXB-IPG can be a promising candidate for preventing postoperative recurrence and metastasis.

Celecoxib: Antiangiogenic and Antitumoral Action / Celecoxib: Acción Antiangiogénica y Antitumoral

SUMMARY: Angiogenesis, a process by which new blood vessels are generated from pre-existing ones, is significantly compromised in tumor development, given that due to the nutritional need of tumor cells, pro-angiogenic signals will be generated to promote this process and thus receive the oxygen and nutrients necessary for its development, in addition to being a key escape route for tumor spread. Although there is currently an increase in the number of studies of various anti-angiogenic therapies that help reduce tumor progression, it is necessary to conduct a review of existing studies of therapeutic alternatives to demonstrate their importance.

La angiogénesis, proceso por el cual se generan nuevos vasos sanguíneos a partir de otros preexistentes, se encuentra comprometida de forma importante en el desarrollo tumoral, dado que por necesidad nutritiva de las células tumorales se generarán señales pro angiogénicas para promover este proceso y así recibir el oxígeno y los nutrientes necesarios para su desarrollo, además de ser una ruta de escape clave para la diseminación tumoral. Si bien, actualmente existe un aumento en la cantidad de estudios de diversas terapias anti angiogénicas que ayudan a reducir el avance tumoral, es necesario realizar una revisión de los estudios existentes de alternativas terapéuticas para demostrar su importancia.

Enhancing therapeutic efficacy in triple-negative breast cancer and melanoma: synergistic effects of modulated electro-hyperthermia (mEHT) with NSAIDs especially COX-2 inhibition in in vivo models.

Triple-negative breast cancer (TNBC) is a leading cause of cancer mortality and lacks modern therapy options. Modulated electro-hyperthermia (mEHT) is an adjuvant therapy with demonstrated clinical efficacy for the treatment of various cancer types. In this study, we report that mEHT monotherapy stimulated interleukin-1 beta (IL-1ß) and interleukin-6 (IL-6) expression, and consequently cyclooxygenase 2 (COX-2), which may favor a cancer-promoting tumor microenvironment. Thus, we combined mEHT with nonsteroid anti-inflammatory drugs (NSAIDs): a nonselective aspirin, or the selective COX-2 inhibitor SC236, in vivo. We demonstrate that NSAIDs synergistically increased the effect of mEHT in the 4T1 TNBC model. Moreover, the strongest tumor destruction ratio was observed in the combination SC236 + mEHT groups. Tumor damage was accompanied by a significant increase in cleaved caspase-3, suggesting that apoptosis played an important role. IL-1ß and COX-2 expression were significantly reduced by the combination therapies. In addition, a custom-made nanostring panel demonstrated significant upregulation of genes participating in the formation of the extracellular matrix. Similarly, in the B16F10 melanoma model, mEHT and aspirin synergistically reduced the number of melanoma nodules in the lungs. In conclusion, mEHT combined with a selective COX-2 inhibitor may offer a new therapeutic option in TNBC.

Harnessing the synergistic potential of NK1R antagonists and selective COX-2 inhibitors for simultaneous targeting of TNBC cells and cancer stem cells.

Triple-negative breast cancer (TNBC) lacks the expression of oestrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2), rendering it unresponsive to endocrine therapy and HER2 targeted treatments. Though certain chemotherapeutics targeting the cell cycle have shown efficacy to a certain extent, the presence of chemotherapy-resistant cancer stem cells (CSCs) presents a significant challenge in tackling TNBC. Multiple lines of evidence suggest the upregulation of neuropeptide Substance P (SP), its NK-1 receptor (NK1R) and the Cyclooxygenase-2 (COX-2) enzyme in TNBC patients. Upregulation of the SP/NK1R system and COX-2 influences major signalling pathways involved in cell proliferation, growth, survival, angiogenesis, inflammation, metastasis and stem cell activity. The simultaneous activation and crosstalk between the pathways activated by SP/NK1R and COX-2 consequently increase the levels of key regulators of self-renewal pathways in CSCs, promoting stemness. The combination therapy with NK1R antagonists and COX-2 inhibitors can simultaneously target TNBC cells and CSCs, thereby enhancing treatment efficacy and reducing the risk of recurrence and relapse. This review discusses the rationale for combining NK1R antagonists and COX-2 inhibitors for the better management of TNBC and a novel strategy to deliver drug cargo precisely to the tumour site to address the challenges associated with off-target binding.

COX 2-inhibitors; a thorough and updated survey into combinational therapies in cancers.

Cyclooxygenase (COX) enzymes are pivotal in inflammation and cancer development. COX-2, in particular, has been implicated in tumor growth, angiogenesis, and immune evasion. Recently, COX-2 inhibitors have arisen as potential therapeutic agents in cancer treatment. In addition, combining COX inhibitors with other treatment modalities has demonstrated the potential to improve therapeutic efficacy. This review aims to investigate the effects of COX inhibition, both alone and in combination with other methods, on signaling pathways and carcinogenesis in various cancers. In this study, a literature search of all major academic databases was conducted (PubMed, Scholar google), including the leading research on the mechanisms of COX-2, COX-2 inhibitors, monotherapy with COX-2 inhibitors, and combining COX-2-inhibitors with chemotherapeutic agents in tumors. The study encompasses preclinical and clinical evidence, highlighting the positive findings and the potential implications for clinical practice. According to preclinical studies, multiple signaling pathways implicated in tumor cell proliferation, survival, invasion, and metastasis can be suppressed by inhibiting COX. In addition, combining COX inhibitors with chemotherapy drugs, targeted therapies, immunotherapies, and miRNA-based approaches has enhanced anti-tumor activity. These results suggest that combination therapy has the potential to overcome resistance mechanisms and improve treatment outcomes. However, caution must be exercised when selecting and administering combination regimens. Not all combinations of COX-2 inhibitors with other drugs result in synergistic effects; some may even have unfavorable interactions. Therefore, personalized approaches that consider the specific characteristics of the cancer and the medications involved are crucial for optimizing therapeutic strategies. In conclusion, as monotherapy or combined with other methods, COX inhibition bears promise in modulating signaling pathways and inhibiting carcinogenesis in various cancers. Additional studies and well-designed clinical trials are required to completely elucidate the efficacy of COX inhibition and combination therapy in enhancing cancer treatment outcomes. This narrative review study provides a detailed summary of COX-2 monotherapy and combination targeted therapy in cancer treatment.

A further pocket or conformational plasticity by mapping COX-1 catalytic site through modified-mofezolac structure-inhibitory activity relationships and their antiplatelet behavior.

Cyclooxygenase enzymes have distinct roles in cardiovascular, neurological, and neurodegenerative disease. They are differently expressed in different type of cancers. Specific and selective COXs inhibitors are needed to be used alone or in combo-therapies. Fully understand the differences at the catalytic site of the two cyclooxygenase (COX) isoforms is still opened to investigation. Thus, two series of novel compounds were designed and synthesized in fair to good yields using the highly selective COX-1 inhibitor mofezolac as the lead compound to explore a COX-1 zone formed by the polar residues Q192, S353, H90 and Y355, as well as hydrophobic amino acids I523, F518 and L352. According to the structure of the COX-1:mofezolac complex, hydrophobic amino acids appear to have free volume eventually accessible to the more sterically hindering groups than the methoxy linked to the phenyl groups of mofezolac, in particular the methoxyphenyl at C4-mofezolac isoxazole. Mofezolac bears two methoxyphenyl groups linked to C3 and C4 of the isoxazole core ring. Thus, in the novel compounds, one or both methoxy groups were replaced by the higher homologous ethoxy, normal and isopropyl, normal and tertiary butyl, and phenyl and benzyl. Furthermore, a major difference between the two sets of compounds is the presence of either a methyl or acetic moiety at the C5 of the isoxazole. Among the C5-methyl series, 12 (direct precursor of mofezolac) (COX-1 IC50 = 0.076 µM and COX-2 IC50 = 0.35 µM) and 15a (ethoxy replacing the two methoxy groups in 12; COX-1 IC50 = 0.23 µM and COX-2 IC50 > 50 µM) were still active and with a Selectivity Index (SI = COX-2 IC50/COX-1 IC50) = 5 and 217, respectively. The other symmetrically substituted alkoxyphenyl moietis were inactive at 50 µM final concentration. Among the asymmetrically substituted, only the 16a (methoxyphenyl on C3-isoxazole and ethoxyphenyl on C4-isoxazole) and 16b (methoxyphenyl on C3-isoxazole and n-propoxyphenyl on C4-isoxazole) were active with SI = 1087 and 38, respectively. Among the set of compounds with the acetic moiety, structurally more similar to mofezolac (SI = 6329), SI ranged between 1.4 and 943. It is noteworthy that 17b (n-propoxyphenyl on both C3- and C4-isoxazole) were found to be a COX-2 slightly selective inhibitor with SI = 0.072 (COX-1 IC50 > 50 µM and COX-2 IC50 = 3.6 µM). Platelet aggregation induced by arachidonic acid (AA) can be in vitro suppressed by the synthesized compounds, without affecting of the secondary hemostasia, confirming the biological effect provided by the selective inhibition of COX-1. A positive profile of hemocompatibility in relation to erythrocyte and platelet toxicity was observed. Additionally, these compounds exhibited a positive profile of hemocompatibility and reduced cytotoxicity. Quantitative structure activity relationship (QSAR) models and molecular modelling (Ligand and Structure based virtual screening procedures) provide key information on the physicochemical and pharmacokinetic properties of the COX-1 inhibitors as well as new insights into the mechanisms of inhibition that will be used to guide the development of more effective and selective compounds. X-ray analysis was used to confirm the chemical structure of 14 (MSA17).

Non-steroidal Anti-inflammatory Drugs and Cyclooxygenase-2 Inhibitors Do Not Affect Healing After Rotator Cuff Repair: A Systematic Review and Meta-analysis.

PURPOSE: To determine whether non-steroidal anti-inflammatory drugs (NSAIDs) and cyclooxygenase-2 (COX-2) inhibitors affect healing rate, functional outcomes, and patient satisfaction after rotator cuff repair. METHODS: Medline, EMBASE, PsychINFO and the Cochrane Library were searched for randomized controlled trials (RCTs) investigating the use of NSAIDs and COX-2 inhibitors after arthroscopic rotator cuff repair. Primary outcomes included healing and retear rate, determined by radiological imaging. Secondary outcomes included shoulder-specific outcome measures and the visual analog scale (VAS). Risk of bias was graded using the Cochrane risk-of-bias v2.0 tool. The GRADE framework was used to assess certainty of findings. RESULTS: Seven RCTs with a total of 507 patients were included (298 randomized to NSAID/COX-2 vs 209 randomized to control). NSAIDs use did not yield a difference in retear rate (P = .77). NSAIDs were shown to significantly reduce pain in the perioperative period (P = .01); however, no significant difference was present at a minimum of 6 months (P = .11). COX-2 inhibitors did not significantly reduce pain (P = .15). Quantitative analysis of ASES and UCLA scores showed NSAIDs significantly improved functional outcomes versus control (P = .004). COX-2 inhibitors did not significantly improve functional outcomes (P = .15). Two trials were deemed "low" risk of bias, four trials were graded to have "some concerns", and one trial was graded to have "high" risk of bias. Retear rate and functional PROMs were deemed to have "low" certainty. VAS pain scale was graded to have "moderate" certainty. CONCLUSIONS: This systematic review and meta-analysis indicates that NSAIDs do not affect healing rate after arthroscopic rotator cuff repair, but they do significantly improve postoperative pain and functional outcomes. No significant difference was seen in pain or functional outcomes with the use of COX-2 inhibitors. LEVEL OF EVIDENCE: Level I, meta-analysis of randomized controlled trials.

Development of novel chromones as antioxidant COX2 inhibitors: in vitro, QSAR, DFT, molecular docking, and molecular dynamics studies.

The chromone derivatives are playing a prominent role in many plant cycles, for instance, the regulation of growth, stimulation of oxygen uptake in plants, and essential food constituents with valuable pro-health properties. Determination of the antioxidant activity of these compounds is an interesting approach to drug design and development. The antioxidant activity of the novel fifteen chromone compounds was estimated by using a spectrophotometric Dichloro-5,6-dicyano 1,4-benzoquinone (DDQ) assay method and the mechanism of antioxidant activity was discussed based on the Density functional theory (DFT) calculations. The compounds showed significant antioxidant activity which was correlated to their molecular structure by considering various molecular descriptors. Further, by using regression analysis QSAR-modeled equation was proposed and it has shown a high correlation coefficient value (0.946. We perform molecular docking and molecular dynamics simulations against the cyclooxygenase (COX2) enzyme to investigate the molecule's anti-inflammatory activity and stability of protein-ligand complexes. Molecular docking and dynamics simulations revealed the compounds B3 and B8 were interacting with essential residues TYR385, HIS386, ASN382, TRP387, and HIS388 in the binding site that were crucial for optimizing heme and the resultant peroxidase and cyclooxygenase activities. The root mean square displacement and root mean square fluctuation plots revealed the stability of the B3-COX2 and B8-COX2 complexes. Based on our results, B3 and B8 compounds are considered as best antioxidants as well as COX2 inhibitors.Communicated by Ramaswamy H. Sarma.

Rosmarinic acid in combination with ginsenoside Rg1 suppresses colon cancer metastasis via co-inhition of COX-2 and PD1/PD-L1 signaling axis.

Metastasis of colorectal cancer (CRC) is a leading cause of mortality among CRC patients. Elevated COX-2 and PD-L1 expression in colon cancer tissue has been linked to distant metastasis of tumor cells. Although COX-2 inhibitors and immune checkpoint inhibitors demonstrate improved anti-tumor efficacy, their toxicity and variable therapeutic effects in individual patients raise concerns. To address this challenge, it is vital to identify traditional Chinese medicine components that modulate COX-2 and PD-1/PD-L1: rosmarinic acid (RA) exerts striking inhibitory effect on COX-2, while ginsenoside Rg1 (GR) possesses the potential to suppress the binding of PD-1/PD-L1. In this study we investigated whether the combination of RA and GR could exert anti-metastatic effects against CRC. MC38 tumor xenograft mouse model with lung metastasis was established. The mice were administered RA (100 mg·kg-1·d-1, i.g.) alone or in combination with GR (100 mg·kg-1·d-1, i.p.). We showed that RA (50, 100, 150 µM) or a COX-2 inhibitor Celecoxib (1, 3, 9 µM) concentration-dependently inhibited the migration and invasion of MC38 cells in vitro. We further demonstrated that RA and Celecoxib inhibited the metastasis of MC38 tumors in vitro and in vivo via interfering with the COX-2-MYO10 signaling axis and inhibiting the generation of filopodia. In the MC38 tumor xenograft mice, RA administration significantly decreased the number of metastatic foci in the lungs detected by Micro CT scanning; RA in combination with GR that had inhibitory effect on the binding of PD-1 and PD-L1 further suppressed the lung metastasis of colon cancer. Compared to COX-2 inhibitors and immune checkpoint inhibitors, RA and GR displayed better safety profiles without disrupting the tissue structures of the liver, stomach and colon, offering insights into the lower toxic effects of clinical traditional Chinese medicine against tumors while retaining its efficacy.

The Cyclooxygenase 2 Inhibitor Etoricoxib as Adjunctive Therapy in Tuberculosis Impairs Macrophage Control of Mycobacterial Growth.

BACKGROUND: Current tuberculosis treatment regimens could be improved by adjunct host-directed therapies (HDT) targeting host responses. We investigated the antimycobacterial capacity of macrophages from patients with tuberculosis in a phase 1/2 randomized clinical trial (TBCOX2) of the cyclooxygenase-2 inhibitor etoricoxib. METHODS: Peripheral blood mononuclear cells from 15 patients with tuberculosis treated with adjunctive COX-2i and 18 controls (standard therapy) were collected on day 56 after treatment initiation. The ex vivo capacity of macrophages to control mycobacterial infection was assessed by challenge with Mycobacterium avium, using an in vitro culture model. Macrophage inflammatory responses were analyzed by gene expression signatures, and concentrations of cytokines were analyzed in supernatants by multiplex. RESULTS: Macrophages from patients receiving adjunctive COX-2i treatment had higher M. avium loads than controls after 6 days, suggesting an impaired capacity to control mycobacterial infection compared to macrophages from the control group. Macrophages from the COX-2i group had lower gene expression of TNF, IL-1B, CCL4, CXCL9, and CXCL10 and lowered production of cytokines IFN-ß and S100A8/A9 than controls. CONCLUSIONS: Our data suggest potential unfavorable effects with impaired macrophage capacity to control mycobacterial growth in patients with tuberculosis receiving COX-2i treatment. Larger clinical trials are required to analyze the safety of COX-2i as HDT in patients with tuberculosis. CLINICAL TRIALS REGISTRATION: NCT02503839.