Search Results (353)

Naturally occurring prostaglandin E₂ (PGE₂) influences cytokine production regulation in bovine neutrophils exposed to Staphylococcus aureus Rosenbach. Here, we employed bovine neutrophils as the primary experimental system, and administered specific inhibitors targeting various receptors, which were subsequently exposed to S. aureus. Cytokine expression levels in dairy cow neutrophils induced by S. aureus via the endogenous PGE₂-EP2/4 receptor pathway were investigated, and its effects on P38, extracellular signal-regulated kinase (ERK), P65 activation, and phagocytic function in Staphylococcus aureus Rosenbach-induced dairy cow neutrophils, were examined. Blocking cyclooxygenase-2 (COX-2) and microsomal prostaglandin E synthase-1 (mPGES-1) enzymes substantially decreased PGE₂ production and release in S. aureus-exposed bovine neutrophils. Cytokine output showed significant reduction compared to that in SA113-infected controls. Phosphorylation of P38, ERK, and P65 signaling molecules was depressed in the infected group. Pharmacological interference with EP2/EP4 receptors similarly diminished cytokine secretion and phosphorylation patterns of P38, ERK, and P65, with preserved cellular phagocytic function. During S. aureus infection of bovine neutrophils, COX-2 and mPGES-1 participated in controlling PGE₂ biosynthesis, and internally produced PGE₂ molecules triggered NF-κB and MAPK inflammatory pathways via EP2/EP4 receptor activation, later adjusting the equilibrium between cytokine types that promote or suppress inflammation. This signaling mechanism coordinated inflammatory phases through receptor-mediated processes. Full article

Diabetic retinopathy (DR), traditionally considered a microvascular complication, is now recognized as a neuroinflammatory disorder involving retinal glial cells. Aldose reductase (AKR1B1), a key enzyme in the polyol pathway, has been implicated in the hyperglycemia-induced inflammatory response in various cell types, although its role in retinal Müller glial cells under acute glucose stress remains unclear. This study investigates AKR1B1 activity and its contribution to inflammatory signaling in MIO-M1 human Müller cells exposed to acute hyperglycemia. AKR1B1 expression and activity, as well as NF-κB activation and COX-2 expression, were evaluated. Sorbinil, a specific AKR1B1 inhibitor, was used to determine the enzyme’s contribution to acute hyperglycemia-induced inflammation. Acute high-glucose treatment significantly increased AKR1B1 activity and sorbitol accumulation without affecting cell viability. In addition, activation of NF-κB and increased expression of cyclooxygenase-2 (COX-2) were observed, both of which were significantly reduced by Sorbinil. Our findings highlight the role of macroglia as active contributors to early inflammatory events in DR and suggest that transient hyperglycemic spikes are sufficient to trigger AKR1B1-dependent glial activation. Full article

Atopic dermatitis (AD) is a chronic, multifactorial inflammatory skin disease characterized by persistent pruritus, immune system dysregulation, and an increased expression of cyclooxygenase-2 (COX-2), an enzyme that plays a central role in the production of prostaglandins and the promotion of inflammatory responses. In this study, we employed a comprehensive computational pipeline to identify phytocompounds capable of inhibiting COX-2 activity, offering an alternative to traditional non-steroidal anti-inflammatory drugs. The African and Traditional Chinese Medicine natural product databases were subjected to molecular screening, which identified six top compounds, namely, Tophit1 (−16.528 kcal/mol), Tophit2 (−10.879 kcal/mol), Tophit3 (−9.760 kcal/mol), Tophit4 (−9.752 kcal/mol), Tophit5 (−8.742 kcal/mol), and Tophit6 (−8.098 kcal/mol), with stronger binding affinities to COX-2 than the control drug rofecoxib (−7.305 kcal/mol). Molecular dynamics simulations over 200 ns, combined with MM/GBSA binding free energy calculations, consistently identified Tophit1 and Tophit2 as the most stable complexes, exhibiting exceptional structural integrity and a strong binding affinity to the target protein. ADMET profiling via SwissADME and pkCSM validated the drug-likeness, oral bioavailability, and safety of the lead compounds, with no Lipinski rule violations and favorable pharmacokinetic and toxicity profiles. These findings underscore the therapeutic potential of the selected phytocompounds as novel COX-2 inhibitors for the management of atopic-prone skin and warrant further experimental validation. Full article

Meloxicam (MLX), a member of the non-steroidal anti-inflammatory drugs (NSAIDs), is a preferential inhibitor of cyclooxygenase-2 (COX-2) responsible for the synthesis of pro-inflammatory prostaglandins. MLX, due to its inhibition of the COX-2 enzyme, which is overexpressed in many cancers, including melanoma, leading to rapid growth, angiogenesis, and metastasis, represents a potentially important compound with anticancer activity. This study aimed to investigate the potential anticancer activity of meloxicam against amelanotic C32 and melanotic COLO 829 melanoma cell lines. The objective was achieved by assessing cell metabolic activity using the WST-1 assay and analyzing mitochondrial potential, levels of reduced thiols, annexin, and caspases 3/7, 8, and 9 by imaging cytometry, as well as assessing reactive oxygen species (ROS) levels using the H₂DCFDA probe. The amelanotic melanoma C32 was more sensitive to MLX exposure, thus exhibiting antiproliferative effects, a disruption of redox homeostasis, a reduction in mitochondrial potential, and an induction of apoptosis. The results provide robust molecular evidence supporting the pharmacological effects of MLX, highlighting its potential as a valuable agent for in vivo melanoma treatment. Full article

Background/Objectives: Fibroproliferative disorders (FPDs), such as Dupuytren’s contracture, scleroderma, capsular contracture, rhinophyma, and keloid scars, are characterised by excessive fibroblast activity and collagen deposition. These conditions are frequently encountered in plastic and reconstructive surgery and remain therapeutically challenging. Cyclooxygenase (COX) inhibitors have emerged as a potential adjunct therapy to modulate fibrotic pathways and improve clinical outcomes. This systematic review aims to evaluate the efficacy and safety profile of COX inhibitors in the management of plastic-surgery-related FPDs. In doing so, it explores how phenotype-guided and route-specific COX-inhibitor use may contribute to precision, patient-centred care. Methods: To identify eligible studies, a comprehensive search was conducted in MEDLINE, Embase, and the Cochrane Library. Data were synthesised using both tabular summaries and narrative analysis. The certainty of evidence was appraised according to the GRADE guidelines. Results: Thirteen studies from 1984 to 2024 met inclusion criteria, addressing FPDs such as hypertrophic scarring, Dupuytren’s contracture, and desmoid tumours, representing 491 patients. Of those, five studies were related to Dupuytren contracture, three studies were related to hypertrophic scar, and one study each was on topics related to scleroderma, keloid scar, osteogenesis imperfecta, actinic keloidalis nuchae/dissecting cellulitis of the scalp, and desmoid tumours. Nine studies reported clinical improvements (four demonstrating statistically significant outcomes), three showed no difference, and one did not assess outcomes. The thirteen studies show minor side effects from oral and topical COX inhibitors. The overall certainty of evidence was graded as “low.” Conclusions: COX inhibitors demonstrate promising efficacy with minimal adverse effects in the management of plastic-surgery-related FPDs. Their accessibility, safety, and potential to reduce fibrosis underscore the need for future high-quality, large-scale studies to establish definitive clinical recommendations. Full article

An experimental model of acute pulmonary damage was developed based on the intravenous injection of the phospholipase A₂ (PLA₂)-rich venom of Pseudechis papuanus (Papuan black snake) in mice. Venom caused pulmonary edema, with the accumulation of a protein-rich exudate, as observed histologically and by analysis of bronchoalveolar lavage fluid (BALF). In parallel, venom induced an increase in all of the pulmonary mechanical parameters evaluated, without causing major effects in terms of tracheal and bronchial reactivity. These effects were abrogated by incubating the venom with the PLA₂ inhibitor varespladib, indicating that this hydrolytic enzyme is responsible for these alterations. The venom was cytotoxic to endothelial cells in culture, hydrolyzed phospholipids of a pulmonary surfactant, and reduced the activity of angiotensin-converting enzyme in the lungs. The pretreatment of mice with the nitric oxide synthase inhibitor L-NAME reduced the protein concentration in the BALF, whereas no effect was observed when mice were pretreated with inhibitors of cyclooxygenase (COX), tumor necrosis factor-α (TNF-α), bradykinin, or neutrophils. Based on these findings, it is proposed that the rapid pathological effect of this venom in the lungs is mediated by (a) the direct cytotoxicity of venom PLA₂ on cells of the capillary–alveolar barrier, (b) the degradation of surfactant factor by PLA₂, (c) the deleterious action of nitric oxide in pulmonary tissue, and (d) the cytotoxic action of free hemoglobin that accumulates in the lungs as a consequence of venom-induced intravascular hemolysis. Our findings offer clues on the mechanisms of pathophysiological alterations induced by PLA₂s in a variety of pulmonary diseases, including acute respiratory distress syndrome (ARDS). Full article

This study investigates the anti-inflammatory effects of the marine diterpene glycosides pseudopterosin A-D (PsA-D) in mitigating nickel sulfate (NiSO₄)-induced skin sensitization. In dermal dendritic cell (DDC) surrogates, PsA-D pre-treatment significantly reduced NiSO₄-induced upregulation of key activation surface markers, cluster of differentiation (CD)54 (~1.2-fold), and CD86 (~1.6-fold). Additionally, PsA-D inhibited the NiSO₄-induced activation of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway by suppressing inhibitor of kappa B alpha (IκBα) degradation. Furthermore, PsA-D suppressed inflammatory responses by inhibiting the NiSO₄-induced secretion of pro-inflammatory cytokines, including interleukin (IL)-8 (~6.8-fold), IL-6 (~2.2-fold), and IL-1β (~5.3-fold). In a full-thickness human skin model incorporating DDC surrogates, topical application of PsA-D effectively attenuated NiSO₄-induced mRNA expression of IL-8 (~2.1-fold), IL-6 (~2.6-fold), and IL-1β (~2.2-fold), along with the key inflammatory mediators cyclooxygenase-2 (COX-2) (~3.5-fold) and NOD-like receptor family pyrin domain-containing 3 (NLRP3) (~2.1-fold). Overall, PsA-D demonstrated comparable efficacy to dexamethasone, a benchmark corticosteroid, providing a promising therapeutic alternative to corticosteroids for the treatment of skin sensitization and allergic contact dermatitis. However, to maximize PsA-D’s therapeutic potential, future studies on optimizing the bioavailability and formulation of PsA-D are required. Full article

This study evaluated the antioxidant capacity of the oxidation products of three flavonols using oxygen radical absorbance capacity—fluorescein assay (ORAC-FL), oxygen radical absorbance capacity—pyrogallol red assay (ORAC-PGR), and the cellular antioxidant activity (CAA) assay in human dermal fibroblast (HFF) cells, with 2,2’-azobis(2-amidinopropane) dihydrochloride (AAPH) as a free radical generator under controlled pH and solvent conditions. At pH 2 in a polar aprotic solvent, BZF-OH (benzofuranone-OH) compounds were formed, while methoxylated analogs were obtained at pH 7 in a polar protic solvent. The products generated at pH 2 exhibited significantly higher antioxidant capacities, demonstrating the influence of the reaction environment on modulating antioxidant properties. The antioxidant activity was observed to reflect the combined action of the flavonol precursor and its oxidation products. This led to the proposal of the Gross Antioxidant Capacity (GAC) concept to integrate the contribution of all generated species. Since chemical assays such as ORAC do not fully capture the complexity of biological systems, they should be complemented with cellular approaches for a more accurate evaluation. Additionally, BZF-OH compounds were analyzed as potential cyclooxygenase-2 (COX-2) inhibitors through docking and molecular dynamics simulations, where BZF-Quer-OH showed binding affinities comparable to celecoxib, a selective COX-2 inhibitor. These findings were complemented by an analysis of COX-2 expression in RAW 264.7 cells treated with lipopolysaccharide (LPS), where treatment with the antioxidants significantly inhibited COX-2 expression. In the case of the oxidation products, only the oxidation product of rhamnetin showed a reduction in COX-2 expression compared to the LPS-treated control. Together, these results highlight that flavonol-derived oxidation products not only retain significant antioxidant capacity but may also possess anti-inflammatory properties, opening new perspectives for the development of innovative therapies targeting oxidative stress and chronic inflammation. Full article

Oxidative stress critically influences the pathophysiology of glioblastoma (GBM), a deadly and aggressive brain tumor. Reactive oxygen species (ROS) regulate cancer cell homeostasis, influencing the treatment response. The transcription factor Nuclear Factor Erythroid 2-Related Factor 2 (Nrf2) activates antioxidant defenses, protecting GBM cells from therapy-induced oxidative stress and contributing to Temozolomide (TMZ) resistance. Cyclooxygenase-2 (COX-2) plays a key role in GBM chemoresistance by modulating the tumor microenvironment and supporting a pro-survival phenotype. The impact of COX-2 inhibition by celecoxib (CXB), a selective COX-2 inhibitor, combined with TMZ on oxidative stress modulation linked to resistance was investigated in GBM primary cultures and cell lines. The drug combination CXB+TMZ was tested on TMZ-sensitive and -resistant cells, and ROS levels and Nrf2 activation were evaluated via a DCFH-DA probe and Western blotting, respectively. The oxidative stress marker malondialdehyde and antioxidant enzymes were assayed using standard methods. COX-2 inhibition combined with TMZ significantly increased ROS, while TMZ alone induced a compensatory antioxidant response, sustaining resistance. Drug combination reduced this response, restoring oxidative stress even in TMZ-resistant cells. Prostaglandin E2 reversed these effects, confirming the role of the COX-2/PGE2 axis in redox balance. Drug combination increased ROS, disrupted redox homeostasis and overcame TMZ resistance, supporting COX-2 inhibition as a promising GBM therapy strategy. Full article

A selective inhibitor of cyclooxygenase-2 (COX-2), Celecoxib (CEB), known for its anti-inflammatory properties, can exhibit polymorphism, with Form III often emerging as an undesired crystalline impurity during the green manufacturing process of the preferred Form I. Controlling the Form III content in the drug product is crucial, as different crystalline forms can impact drug bioavailability and therapeutic efficacy. This study presents a method to quantify the weight percentage of Form III in the bulk of CEB Form I by employing powder X-ray diffraction (PXRD). Initially, pure Form I and III of CEB were characterized using DSC, FTIR, and PXRD, supporting the method’s development. Binary mixtures, with varying ratios of CEB polymorphs Form I and Form III, were prepared and analyzed using continuous scans over an angular (2θ) range of 2–40. The calibration curve was constructed using 2θ unique peaks for Form I and Form III, respectively. Linear regression analysis exhibited a strong linear relationship within the weight ratio range of 1–20%. The developed method was validated to assess recovery, precision, ruggedness, limits of detection, and quantitation. These findings indicate that the method exhibits repeatability, sensitivity, and accuracy. The newly developed and validated PXRD method is applicable for quality control of CEB Form I produced through the green melt crystallization process by detecting low levels of Form III polymorphic impurity. This research significantly contributes to ensuring the clinical efficacy and manufacturing quality of Celecoxib by providing a reliable method for controlling polymorphic impurities. Full article

The inducible enzyme cyclooxygenase-2 (COX-2) and the subsequent synthesis of eicosanoids initiated by this enzyme are important molecular players in bone healing. In this pilot study, the suitability of a novel selective COX-2 inhibitor bearing a nitric oxide (NO)-releasing moiety was investigated as a modulator of healing a critical-size bone defect in rats. A 5 mm femoral defect was randomly filled with no material (negative control, NC), a mixture of collagen and autologous bone fragments (positive control, PC), or polycaprolactone-co-lactide (PCL)-scaffolds coated with two types of artificial extracellular matrix (aECM; collagen/chondroitin sulfate (Col/CS) or collagen/polysulfated hyaluronic acid (Col/sHA3)). Bone healing was monitored by a dual-tracer ([¹⁸F]FDG/[¹⁸F]fluoride) approach using PET/CT imaging in vivo. In addition, ex vivo µCT imaging as well as histological and immunohistochemical studies were performed 16 weeks post-surgery. A significant higher uptake of [¹⁸F]FDG, a surrogate marker for inflammatory infiltrate, but not of [¹⁸F]fluoride, representing bone mineralization, was observed in the implanted PCL-scaffolds coated with either Col/CS or Col/sHA3. Molecular targeting of COX-2 with NO-coxib had no significant effect on tracer uptake in any of the groups. Histological and immunohistochemical staining showed no evidence of a positive or negative influence of NO-coxib treatment on bone healing. Full article

Introduction: Inhibiting cyclooxygenase-2 (COX-2) is a potential strategy in inflammation therapy. Thus, developing COX-2 inhibitors plays a pivotal role in efficient inflammation treatment. This study discloses the synthesis of new heterocyclic compounds incorporating pyridine, pyran, and/or pyrazole moieties as COX-2 inhibitors. Methods: In this study, the Claisen–Schmidt reaction of 1-(5-hydroxy-1,3-diphenyl-1H-pyrazol-4-yl)ethan-1-one 1 and p-methoxybenzaldehyde in ethanol containing aqueous sodium hydroxide (10%) led to the formation of 1-(5-hydroxy-1,3-diphenyl-1H-pyrazol-4-yl)-3-(4-methoxyphenyl)prop-2-en-1-one) 2. The latter compound was allowed to react as a key precursor with various nucleophiles such as ethyl cyanoacetate, malononitrile, cyclohexanone, ethyl acetoacetate, hydrazine, cyano acid hydrazide, hydrazide, and/or thiosemicarbazide to yield new heterocyclic derivatives comprising pyridine, pyran, and/or pyrazole moieties 3–15, according to the Michael addition reaction. The newly synthesized compounds were depicted using spectroscopic techniques such as IR, ¹H-NMR, ¹³C-NMR, and MS. Moreover, their anti-inflammatory efficiency was in vitro evaluated by means of protein denaturation inhibition and cell membrane protection assay. Results: The results of 2^−ΔΔct values of COX-2 expression for compounds 6, 11, 12, and 13 were 6.6, 2.9, 25.8, and 10.1, respectively. Therefore, compound 12, followed by 13, 11, and 6, showed potent anti-inflammatory properties by in vitro evaluation. Further, an in silico molecular docking study was performed on the best-docked compounds and reference drug (Diclofenac) to investigate their binding affinities against the active site of the target enzyme. The obtained results from the in silico study aligned with the biological evaluation. Conclusions: The studies open new doors for designing new heterocycles containing pyridine, pyran, and/or pyrazole moieties as potent anti-inflammatory agents. Full article

Background: Bipolar disorder (BD) is a chronic condition associated with treatment resistance, cognitive decline, structural brain changes, and an approximately 13-year reduction in life expectancy compared to the general population. Depression in BD substantially impairs quality of life, while neuroinflammation and excitotoxicity are thought to contribute to the recurrence of mood episodes and disease progression. Brain-derived neurotrophic factor (BDNF) plays a key role in neuronal growth and function, with its dysregulation being linked to various psychiatric disorders. This study is an extension of a previously published clinical trial and was conducted to assess the effects of three BDNF and BDNF-AS gene polymorphisms (rs1519480, rs6265, and rs10835210) on treatment outcomes and serum BDNF levels in patients with treatment-resistant bipolar disorder depression (TRBDD) over an eight-week period. Methods: This study included 41 participants from a previously conducted randomized clinical trial, all of whom had available BDNF serum samples and genotype data. The participants, aged 21 to 65, were diagnosed with bipolar disorder, and treatment-resistant depression was assessed using the Maudsley Staging Method. Participants were randomly assigned to receive either escitalopram plus a placebo (ESC+PBO) or escitalopram plus celecoxib (ESC+CBX) over an 8-week period. Statistical analyses included a mixed ANOVA and chi-square tests to compare the minor allele carrier status of three SNPs with treatment response and remission rates. Results: Non-carriers of the rs6265 A allele (p = 0.005) and carriers of the rs10835210 A allele (p = 0.007) showed a significantly higher response to treatment with adjunctive celecoxib compared to escitalopram alone. Additionally, remission rates after adjunctive celecoxib were significantly higher in both carriers and non-carriers across all three SNPs compared to escitalopram alone. However, remission rates were notably higher in non-carriers of the rs1519480 G allele and rs10835210 A allele, as well as in carriers of the rs6265 A allele. Conclusions: This study suggests that genetic variations in BDNF and BDNF-AS genes significantly influence treatment response to and remission with escitalopram and celecoxib in bipolar disorder. Full article

Background: The efficacy of cyclooxygenase-2 (COX-2) inhibitors, including celecoxib, in managing knee osteoarthritis (KO) is well-established. Recently, the plant extract cocktail JOINS (SKI306X and its newer formulation, SKCPT) has been shown to be an effective slow-acting drug for KO. Aims: To compare the efficacy and safety of celecoxib and JOINS in patients with KO. Methods: A systematic search of the MEDLINE, Embase, and Cochrane Library databases identified randomized controlled trials (RCTs) assessing the effectiveness and safety of celecoxib and JOINS. The outcomes included pain relief, functional improvement, and safety profiles. Outcome measurements were compared between the celecoxib and JOINS cohorts at the short-term (closest to 3 months) and mid-term (closest to 12 months). Results: Overall, 23 RCTs involving 3367 patients were included in this systematic review. The efficacy of JOINS in reducing pain, as indicated by the visual analog scale (VAS) score, was comparable to that of celecoxib. Regarding functional improvement assessed using the Western Ontario and McMaster University Arthritis Index (WOMAC), JOINS showed improvement comparable to that of celecoxib regardless of follow-up. In addition, no significant difference was observed in the incidence of adverse events between the celecoxib and JOINS cohorts. Conclusions: The results of this study suggest that JOINS could be considered as a pharmacological agent with significant efficacy for pain relief and functional improvement in patients with KO in clinical practice. Full article

Background/Objectives: Interferon gamma (IFN-γ) in the melanoma tumor microenvironment plays opposing roles, orchestrating both pro-tumorigenic activity and anticancer immune responses. Our previous studies demonstrated the role of neuronal nitric oxide synthase (nNOS) in IFN-γ-stimulated melanoma progression. However, the underlying mechanism has not been well defined. This study determined whether the nNOS/NO and COX-2/PGE₂ signaling pathways crosstalk and augment the pro-tumorigenic effects of IFN-γ in melanoma. Methods: Bioinformatic analysis of patient and cellular proteomic data was conducted to identify proteins of interest associated with IFN-γ treatment in melanoma. Changes in protein expression were determined using various analytical techniques including western blot, flow cytometry, and confocal microscopy. The levels of PGE₂ and nitric oxide (NO) were analyzed by HPLC chromatography and flow cytometry. In vivo antitumor efficacy was determined utilizing a human melanoma xenograft mouse model. Results: Our omics analyses revealed that the induction of COX-2 was significantly predictive of IFN-γ treatment in melanoma cells. In the presence of IFN-γ, PGE₂ further enhanced PD-L1 expression and amplified the induction of nNOS, which increased intracellular NO levels. Cotreatment with celecoxib effectively diminished these changes induced by PGE₂. In addition, nNOS blockade using a selective small molecule inhibitor (HH044), efficiently inhibited IFN-γ-induced PGE₂ and COX-2 expression levels in melanoma cells. STAT3 inhibitor napabucasin also inhibited COX-2 expression both in the presence and absence of IFN-γ. Furthermore, celecoxib was shown to enhance HH044 cytotoxicity in vitro and effectively inhibit human melanoma tumor growth in vivo. HH044 treatment also significantly reduced tumor PGE₂ levels in vivo. Conclusions: Our study demonstrates the positive feedback loop linking nNOS-mediated NO signaling to the COX-2/PGE₂ signaling axis in melanoma, which further potentiates the pro-tumorigenic activity of IFN-γ. Full article