Inflammation contributes to the rapid progression of high-grade gliomas, indicating that anti-inflammatory strategies targeting NF-κB signaling may offer therapeutic benefit. Cannabidiol (CBD) and celecoxib (CELE) are hydrophobic pharmacological agents whose formulation in lipid carriers may support their combined biological evaluation. In this proof-of-concept study, we investigated liposomal formulations containing CBD, CELE, or both compounds in U-87 MG high-grade glioma cells and in a subcutaneous xenograft model. We assessed cytotoxicity, apoptosis, oxidative stress, Nrf2-dependent responses, NF-κB-centered inflammatory networks, tumor cell invasive properties, and Wnt/β-catenin pathway activity. The nanoformulations induced reactive oxygen species generation by 1.8-fold, which was accompanied by Nrf2 activation. Cationic formulations loaded with the compounds produced more pronounced pro-apoptotic effects (up to 39%) than POPC liposomes, although both types reduced the nuclear translocation of the NF-κB p65 subunit. The CBD + CELE-containing formulation showed a trend toward reduced tumor progression in mice. It is important to note that the in vitro and in vivo nanoformulations were physicochemically related, but not identical, and the in vivo experiment should be interpreted as a preliminary assessment after intratumoral administration. Overall, cationic liposomes co-loaded with CBD + CELE represent a promising platform for further optimization aimed at coordinated modulation of inflammatory, oxidative, and proliferative pathways in glioma. However, additional studies, including tissue distribution, release kinetics, and efficacy in orthotopic glioma models, are needed to fully verify their translational potential.

Inula viscosa is a medicinal plant widely recognized in the Mediterranean area. Endemically, it has been used to manage various inflammatory conditions and alleviate rheumatic discomfort. However, its immunomodulatory mechanisms remain insufficiently characterized. In this study, we investigated the immunosuppressive activity of I. viscosa leaves and flowers methanol extracts, through a combined in vitro, in vivo, phytochemical identification, and in silico approach, using the SRBC-induced humoral immune response model, both extracts at 50 mg/kg significantly (***p < 0.001) reduced hemagglutination titers and (****p < 0.0001) decreased splenic CD138⁺ plasma cell recruitment, restoring white/red pulp architecture, confirming their ability to downregulate antibody-mediated immunity. LC-ESI-MS analysis identified 20 phenolic compounds, including flavonoids and phenolic acids known for antioxidative and immunosuppressive effects. Molecular docking against COX-2 revealed that several phytochemicals, particularly diosmin, silymarin, and quercetin exhibited stronger binding affinities (- 9.7, - 9.1 and - 9.0 kcal/mol, respectively) than diclofenac (- 7.3 kcal/mol), with quercetin showing the most favorable pharmacokinetic profile as ADME evaluations through Lipinski's "rule of five" confirmed that it fulfills the pharmaceutical requirement. These findings align with our previous formaldehyde-induced arthritis study, reinforcing the anti-inflammatory potential of I. viscosa at low doses, through combined antioxidant action, suppression of humoral immune responses, and COX-2 inhibition.

FactsPhotodynamic therapy (PDT) kills cancer cells via the generation of reactive oxygen species but can also trigger harmful protumorigenic effects.Cyclooxygenase-2 (COX-2) overexpression and prostaglandin E2 secretion limit PDT efficacy in many tumors.Combining indomethacin (IMC) COX-2 inhibitor with photosensitizer reduces inflammation and enhances PDT treatment.IMC-conjugated photosensitizers show promising targeted, improved tumor accumulation, and effective cancer phototherapy.Open QuestionsHow can PDT-induced protumorigenic inflammation be effectively minimized?Can IMC conjugation with photosensitizers inhibit inflammation and improve the accumulation of photosensitizers in cancer cells?What design strategies best optimize IMC-conjugated photosensitizers? Photodynamic therapy is a non-invasive treatment that directly kill cancer cells through the generation of reactive oxygen species. However, photodynamic therapy can also paradoxically trigger harmful protumorigenic effects, such as overexpression cyclooxygenase-2 and secretion of prostaglandin E2 in various type of tumors, limiting the overall therapeutic efficacy of photodynamic therapy. The inhibition of prostaglandin E2 secretion using nonselective cyclooxygenase inhibitors such as indomethacin, a widely used anti-inflammatory drug, with photodynamic therapy offers a promising approach for reducing light-induced inflammation and enhancing the effectiveness of photodynamic therapy. In addition, indomethacin and other cyclooxygenase-2 inhibitors have been conjugated with other therapeutic agents to develop tumor-targeted drug delivery systems. Their ability to selectively target and accumulate in cancer cells makes them attractive for delivering a wide range of photosensitizers directly to diseased tissues. Given the considerable progress in this area, this review outlines the photodynamic therapy application of various indomethacin-conjugated photosensitizers for the treatment of cyclooxygenase-2 overexpressed tumor cells, aiming to improve light-mediated effectiveness and reduce off-target effects. Finally, we highlight and discuss future perspectives and challenges in the development of indomethacin-conjugated photodynamic therapy agents.

Activated macrophages are key effector cells in inflammatory diseases, but the therapeutic use of membrane-active agents such as melittin (MEL) is limited by nonspecific cytotoxicity and hemolysis. Here, we developed a hyaluronic acid (HA)-coated MEL-based polymersome (PMHA) for CD44-targeted codelivery of MEL and celecoxib (CXB). MEL was incorporated into the vesicular membrane, whereas CXB was loaded into the hydrophobic domain. PMHA showed a hydrodynamic diameter of 265.5 ± 1.6 nm, a zeta-potential of -21.14 ± 1.1 mV, a CXB encapsulation efficiency of 70.81 ± 4.18%, and a drug loading capacity of 12.87 ± 1.92%. In lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages, anti-CD44 antibody blocking reduced Alexa Fluor 647-labeled PMHA uptake by approximately 37.5%, supporting HA-CD44-mediated internalization. PMHA reduced MEL-associated cytotoxicity and hemolytic activity and enabled pH-responsive CXB release. Codelivery of MEL and CXB suppressed cyclooxygenase-2 (COX-2) and tumor necrosis factor-α (TNF-α) expression, with combination index (CI) values of 0.48 and 0.67, respectively. These findings support further evaluation of PMHA as a macrophage-targeted anti-inflammatory nanoplatform.

Two innovative spectrofluorimetric techniques were developed for the first time to enable simultaneous quantification of ciprofloxacin hydrochloride in binary mixtures with either celecoxib or itopride hydrochloride in biological fluids. The first relied on synchronous spectrofluorimetry at a constant wavelength interval (Δλ = 100 nm), which effectively reduced spectral interference and allowed accurate estimation of celecoxib and ciprofloxacin hydrochloride at their zero-crossing points of 276 and 328 nm, respectively. The second technique leveraged direct spectrofluorimetric measurement of ciprofloxacin hydrochloride and itopride hydrochloride mixture, using excitation at 258 nm that yielded two discrete emission peaks at 351 nm for ITH and 441 nm for CPN. Both methods demonstrated remarkable sensitivity and selectivity, achieving excellent linearity (r = 0.9999) across broad ranges of (0.05-3.0 μg/mL and 0.05-5.0 μg/mL for ciprofloxacin hydrochloride and celecoxib, respectively, and 0.07-4.0 μg/mL for ciprofloxacin hydrochloride and 0.04-9.0 μg/mL for itopride hydrochloride. Comprehensive greenness assessment was performed, which confirmed their low environmental burden. Moreover, whiteness and blueness evaluations highlighted the favorable integration of analytical efficiency with sustainability principles. The proposed strategies combine rapidity, high sensitivity, and environmental safety, providing reliable alternatives for routine quality control of pharmaceutical formulations and accurate determination of CPN mixtures in biological matrices.

Cyclooxygenase-2 (COX-2), an inducible enzyme pivotal to prostaglandin biosynthesis from arachidonic acid, is aberrantly upregulated in inflammatory pathologies, neurodegenerative disorders, and malignancies. Non-invasive real-time quantification of COX-2 expression in vivo via nuclear imaging method (positron emission tomography (PET) and single-photon emission computed tomography (SPECT)) has an important significance. It not only enables disease stratification and prognostic assessment but also clarifies COX-2's pathophysiological roles, thereby guiding therapeutic decision-making. As COX-2 inhibitors are widely used to manage acute/chronic inflammation and pain, their radiolabeling has facilitated the development of targeted molecular probes for COX-2 imaging. This review systematically categorizes radiotracers derived from structurally modified COX-2 inhibitors, with a focus on [11]C-, [18]F-, and [123/124/125]I-labeled compounds, and analyses their synthesis as well as in vitro and in vivo properties in detail. Despite these advances, clinical translation still faces considerable difficulties. Ongoing efforts in structural optimization, combined with the development of advanced COX-2-expressing transgenic models, are expected to address these limitations. Future radiotracers may ultimately enable reliable COX-2 quantification via nuclear imaging, thus bridging a critical gap in precision medicine.

Selective cyclooxygenase-2 (COX-2) inhibitors are often considered when anti-inflammatory analgesia is needed for musculoskeletal pain in patients with inflammatory bowel disease (IBD), but concerns remain about intestinal safety. The clinical evidence on short-term selective COX-2 inhibitor use in IBD, with focus on disease activity outcomes, was reviewed. A prespecified literature search was performed in PubMed and the Cochrane Library supplemented by reference list screening. Clinical trials and clinical studies evaluating celecoxib, etoricoxib or rofecoxib in patients with IBD and musculoskeletal/rheumatological symptoms were considered when gastrointestinal (GI) outcomes were reported. Two placebo-controlled randomised trials did not show higher rates of IBD relapse or symptom aggravation vs placebo during short-term treatment in selected patients, including ulcerative colitis in remission and IBD with rheumatic manifestations. Open-label studies and retrospective series reported variable GI adverse events and occasional symptom worsening, but study populations, baseline disease activity, relapse definitions and follow-up duration differed widely. Overall, the strongest available evidence supports cautious short-term use of selective COX-2 inhibitors in selected patients with IBD in remission when anti-inflammatory analgesia is required. Given the small evidence base and limited follow-up, treatment should be time-limited, use the lowest effective dose and include clinical monitoring.

Aspirin-exacerbated respiratory disease (AERD) presents a challenge in perioperative pain management. Many prescribers are uncertain about COX-2 inhibitor safety, leading to inconsistent prescribing practices and suboptimal analgesia in this group of patients. The aim of this small, single-centre study was to assess healthcare practitioners' confidence in prescribing analgesia for AERD patients and evaluate the impact of a standard operating procedure (SOP) on prescribing practices.

Cyclooxygenase-2 (COX-2), a key enzyme to catalyzes the formation of prostanoids from arachidonic acid, is involved in inflammatory events. Furthermore, the calpain/PARP/NF-κB inflammatory pathway has been implicated in the damage to the neurovascular unit (NVU) following ischemic stroke. This study investigated the effects of parecoxib, a specific COX-2 inhibitor, on calpain, PARP, NF-κB inflammatory signaling, and NVU damage in the rat model of ischemic stroke. Male Sprague-Dawley rats (n = 107) were subjected to 90 min of ischemia, followed by reperfusion. Parecoxib was administered intraperitoneally 5 min post-ischemia, and the activation of calpain, PARP, and NF-κB-inflammatory signaling, and the NVU damage were evaluated 24 h post-ischemia. It was found that parecoxib alleviated neurological deficits, brain swelling and apoptotic cell death, and decreased infarct volumes 24 h post-ischemia. It decreased the levels of calpain 1 and 2, enhanced the levels of calpastatin, and repressed the activities of calpain in penumbra and core. Meanwhile, it reduced the levels of cytosolic PARP and HMGB1, elevated the level of cytosolic IκBα, lowered the levels of nuclear PARP, poly(ADP-ribose) and NF-κB p65, lessened the levels of cytosolic ICAM-1, IL-1β, MMP-2, and MMP-9, and suppressed the MPO activities in penumbra and core. Additionally, it attenuated the NVU and blood-brain barrier damage in penumbra and core. These data demonstrated that parecoxib exerts its protective effects on the NVU by blocking the over-activation of calpain and PARP, as well as by suppressing NF-κB-mediated inflammatory response during ischemic stroke. Moreover, the findings suggest that COX-2 contributes to NVU damage by up-regulating the calpain/PARP/NF-κB inflammatory pathway during brain ischemia.

Chronic inflammation, arising from unregulated inflammatory responses to tissue damage, is linked to 25% of all cancers. Some new benzofuran-thiazole hybrids, H1-H4, were prepared herein and assessed as dual anticancer and anti-inflammatory agents. All hybrids tested displayed good potency against Caco2 cells. Particularly, H4 outperformed doxorubicin in potency, with an IC50 of 0.24 μM. Moreover, H2 and H3 exhibited excellent antiproliferative activity against RAW 264.7 cells, which was found comparable to celecoxib, with IC50 values of 160.75 and 115.76 μM, respectively. The safety of the new hybrids was evaluated against HFB4 cells, as we found that H2 and H3 showed superior selectivity against cancer cells. H2 and H3 were found to significantly increase apoptosis in RAW 264.7 cells, confirming their potential as cytotoxic agents. The anti-inflammatory efficacy of some hybrids was screened. The inhibition of nitric oxide (NO) production in lipopolysaccharide (LPS)-stimulated RAW 264.7 cells was measured to assess the anti-inflammatory effects, where H2 showed significant inhibition at a dose of 100 µM. Also, H3 exhibited comparable cyclooxygenase-2 (COX-2) inhibitory potency to celecoxib with an IC50 of 0.69 μM. At a dose of 1/20 LD50, both H2 and H3 were safe for kidney function in an animal model. However, H2 was safer for gastric tissue, while H3 showed adverse gastric effects at this same concentration. The molecular docking of both hybrids displayed important binding modes with the mouse COX-2 (PDB ID: 7O37).

Fluorescein isothiocyanate (FITC)-labeled cyclooxygenase-2 (COX-2) immobilized chitosan (CS) coated Fe3O4 (FITC-COX-2-CS@Fe3O4, FCICFs) nanocomposites were accurately prepared by solvothermal and crosslinking methods, and employed as drug discovery platforms and fluorescent tracers to specifically screen and evaluate the activity of potential COX-2 inhibitors derived from Yaobitong capsules (YBTC). The FCICFs nanocomposites demonstrated a significant capacity for the selective recognition of positive compounds from artificial mixtures, indicating their substantial utility. Under optimal conditions, the prepared nanocomposites screened fourteen potential COX-2 inhibitors from YBTC, which were identified by UHPLC-MS/MS as tetrahydrocolumbamine, protopine, trahydocoptisine, yuanhunine, rotundine, tetrahydroberberine, thalictrimine, palmatine, dehydrocorydaline, mudanpioside D, astringin, nodakenin, paeoniflorin sulfite and ligustilide. The molecular docking analysis demonstrated a strong binding affinity between 14 small molecule ligands and the COX-2. Furthermore, the screened compounds exhibited significantly enhanced inhibitory activity against COX-2 compared to the YBTC crude extract. Fluorescence cell imaging results indicated that the screened compounds effectively inhibited synovial cell proliferation, suggesting their potential therapeutic efficacy in the treatment of rheumatoid arthritis (RA). The proposed methodology, integrating highly specific screening with in-situ visual imaging, established a robust platform for the efficient and selective screening of plant-derived biologically active molecules.

In this study, new sulfonamide derivatives 5a-g and 10a-e were designed, synthesized, and biologically evaluated for their anti-inflammatory activity. In vitro COX inhibitory assays were performed, and among the synthesized compounds, 5b and 5d emerged as the most promising leads, combining COX-2 inhibition with remarkable selectivity (COX-2 IC50 = 0.13 and 0.05 μM, SI = 9.25 and 12.02, respectively) and hCA II inhibition (Ki = 39.1 nM and 62.6 nM, respectively) with a high selectivity index over hCA I (SI = 933.8 and 704.2, respectively). In vivo evaluations confirmed that compounds 5b and 5d (50 mg/kg) possess promising analgesic and anti-inflammatory effects, with rapid onset, sustained duration of action, and a reduced ulcerogenic liability, indicating an improved gastrointestinal safety profile. Additionally, 5b showed significant and sustained IOP-lowering effects in antiglaucoma animal models. Computational studies and X-ray crystallography were performed as a proof of concept.

Biofilm-associated prosthetic joint infections (PJIs) are becoming an increasing public health concern due to their ability to form biofilm on prosthetic implants and cause significant morbidity owing to antibiotics resistance. Therefore, new drugs and management procedures are required to improve the treatment outcome for PJIs and the drug repurposing is an excellent method to develop new antimicrobials. Thus, the present study evaluated etoricoxib, a selective COX2 inhibitor for its antibacterial and antibiofilm activities against Staphylococcus aureus - one of the major biofilm-forming bacteria causing the PJIs. The anti-S. aureus potential of etoricoxib was analyzed and the minimum inhibitory concentration (MIC) was found to be as low as 25 µg/mL. The killing-kinetics of etoricoxib was observed at 2 h and the drug showed synergistic effect along with ampicillin and tetracycline, reducing the MIC by 4-fold. Further, etoricoxib exhibited antibiofilm activity by inhibiting biofilm formation and displaying mature biofilm eradication by 90% after the treatment. To prevent biofilm formation on implant material, etoricoxib was coated on the implant material and it reduced 80% of bacterial attachment which was further confirmed by FDA/PI staining that revealed 79% of dead cells on the coated material. The docking analysis revealed the strong binding affinity of etoricoxib towards bacterial biofilm adhesion proteins and the drug downregulated the biofilm adhesion protein encoded genes namely icaA, clfA, cna, fnbA, and fib expression levels after the treatment. Moreover, etoricoxib treatment caused S. aureus cell damage resulting in cell death and was noticed through scanning electron microscope (SEM) analysis. Thus, as etoricoxib was effective in eliminating and preventing biofilms and the authors recommend further in vitro and in vivo studies to explore the possibility for new therapeutic option for implant-associated infections.