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Celecoxib derivatives that contain the pyrazole-linked sulfonamide moiety were synthesized, and the in vitro inhibitory impacts of the aforesaid compounds against the lactoperoxidase (LPO) enzyme were researched. To this end, LPO was purified using the affinity chromatography technique with a yield of 12.63% (319.23-fold). The results showed that the aromatic pyrazole compound (compound 1) containing 2,3-dimethoxyphenyl functional groups was the most effective LPO inhibitor with a K i value of 3.2 ± 0.7 nM and noncompetitive inhibition type. The second section of the study tested the previously synthesized compounds to reveal their antioxidant and antimicrobial properties. The above-mentioned compound also displayed high activity levels compared to standard antibiotics and antifungals, while all other compounds also showed antibacterial activity. In the three antioxidant methods we used, the compound with 2,5-dimethoxy phenyl groups obtained from the reaction of the aromatic pyrazole compound with propionic anhydride in the presence of NEt 3 displayed the highest activity. Furthermore, molecular docking and molecular mechanics studies were conducted to complement and validate the experimental findings. The results obtained from these computational analyses are highly consistent with the experimental data., (© 2024 The Author(s). Journal of Biochemical and Molecular Toxicology published by Wiley Periodicals LLC.)

Purpose: We have previously reported that protracted Cyclooxygenase-2 (COX-2) activity in bone marrow-derived cells (BMDCs) infiltrating into biopsy wounds adjacent to the biopsy cavity of breast tumors in mice promotes M2-shift of macrophages and pro-metastatic changes in cancer cells, effects which were suppressed by oral administration of COX-2 inhibitors. Thus, local control of COX-2 activity in the biopsy wound may mitigate biopsy-induced pro-metastatic changes., Methods: A combinatorial delivery system-thermosensitive biodegradable poly(lactic acid) hydrogel (PLA-gel) incorporating celecoxib-encapsulated poly(lactic-co-glycolic acid) nanoparticles (Cx-NP/PLA-gel)-was injected into the biopsy cavity of Py230 murine breast tumors to achieve local control of COX-2 activity in the wound stroma., Results: A single intra-biopsy cavity injection of PLA-gel loaded with rhodamine-encapsulated nanoparticles (NPs) showed sustained local delivery of rhodamine preferentially to infiltrating BMDCs with minimal to no rhodamine uptake by the reticuloendothelial organs in mice. Moreover, significant reductions in M2-like macrophage density, cancer cell epithelial-to-mesenchymal transition, and blood vessel density were observed in response to a single intra-biopsy cavity injection of Cx-NP/PLA-gel compared to PLA-gel loaded with NPs containing no payload. Accordingly, intra-biopsy cavity injection of Cx-NP/PLA-gel led to significantly fewer metastatic cells in the lungs than control-treated mice., Conclusion: This study provides evidence for the feasibility of sustained, local delivery of payload preferential to BMDCs in the wound stroma adjacent to the biopsy cavity using a combinatorial delivery system to reduce localized inflammation and effectively mitigate breast cancer cell dissemination., (© 2024. The Author(s).)

NLRP1 is predominantly overexpressed in breast cancer tissue, and the evaluated activation of NLRP1 inflammasome is associated with tumor growth, angiogenesis, and metastasis. Therefore, targeting NLRP1 activation could be a crucial strategy in anticancer therapy. In this study, we investigated the hypothesis that NLRP1 pathway may contribute to the cytotoxic effects of celecoxib and nimesulide in MDA-MB-231 cells. First of all, IC 50 values and inhibitory effects on the colony-forming ability of drugs were evaluated in cells. Then, the alterations in the expression levels of NLRP1 inflammasome components induced by drugs were investigated. Subsequently, the release of inflammatory cytokine IL-1β and the activity of caspase-1 in drug-treated cells were measured. According to our results, celecoxib and nimesulide selectively inhibited the viability of MDA-MB-231 cells. These drugs remarkably inhibited the colony-forming ability of cells. The expression levels of NLRP1 inflammasome components decreased in celecoxib-treated cells, accompanied by decreased caspase-1 activity and IL-1β release. In contrast, nimesulide treatment led to the upregulation of the related protein expressions with unchanged caspase-1 activity and increased IL-1β secretion. Our results indicated that the NLRP1 inflammasome pathway might contribute to the antiproliferative effects of celecoxib in MDA-MB-231 cells but is not a crucial mechanism for nimesulide., (© 2024. The Author(s).)

There is growing evidence on the significant role of prolonged inflammation in triggering and progressing of numerous diseases with substantial health and socioeconomic impacts, such as musculoskeletal, cardiovascular and autoimmune disorders, and cancer. Therefore, there is an urgent need to develop therapies that can overcome the main challenges of currently used approaches, such as non-target action, partial modulation of the complex inflammatory pathways, and short-term effects, to effectively manage and resolve chronic inflammatory states. This work investigates the therapeutic synergy of clinically relevant anti-inflammatory agents approaching naïve and classically activated macrophages owing to their central role in inflammation. Aiming at human therapies, a dual-loading nanoplatform reunites molecules with different physico-chemical properties in a single system, seeking to more effectively and comprehensively regulate macrophage functions for precision cell guidance and greater versatility in disease managing. To build this platform, palmitic acid grafted chitosan, superparamagnetic iron oxide nanoparticles, the clinically approved NSAID celecoxib (also known as Celebrex ® ), and RNA technologies were combined into superparamagnetic polymeric micelles (SPMs). Our findings demonstrated that traditional anti-inflammatory drugs such as celecoxib and microRNA molecules were efficiently delivered by the SPMs, altering the inflammatory profile of naïve (M0φ) and M1-primed macrophages (M1φ) assessed by gene and protein expression. The impact of the dual-loaded SPMs in naïve Mφ is an interesting finding towards the modulation of the initial immune response, reducing the potential for chronic inflammation and promoting tissue healing. Collectively, these encouraging results demonstrate the promise of multi-nanomedicine strategies to enhance the efficacy of therapeutic interventions by offering a fresh approach to more precisely and carefully regulated nanotherapeutics delivery.

Objective: To evaluate the potential protective effect of metformin against osteoarthritis development in rats., Methods: The experimental study was conducted at the Iraqi Centre for Cancer Research and Medical Genetics, Mustansiriyah University, Baghdad, Iraq, from December 2021 to February 2022, and comprised male Sprague- Dawley mice who were divided into 5 equal groups: negative control group, osteoarthritis group subjected to monoiodoacetate induction, positive control group treated with celecoxib 30mg/kg, metformin 100mg/kg group, and metformin 200mg/kg group. Body mass index, inflammatory biomarkers, and serum C-terminal cross-linked telopeptide of type II collagen levels were noted for all the animals. Data was analysed using SPSS 24., Results: Of the 35 mice, 7(20%) were in each of the 5 groups. Compared to the osteoarthritis group, metformintreated mice showed significantly reduced body mass index, inflammatory biomarker levels, and blood levels of Cterminal cross-linked telopeptide of type II collagen (p=0.05). Metformin 200mg/kg treatment had more beneficial effects than 100mg/kg dose on inflammatory biomarkers and serum C-terminal cross-linked telopeptide of type II collagen (p=0.05)., Conclusions: A beneficial protective effect against the onset of osteoarthritis was produced by metformin in a dosedependent way. Additionally, metformin could lessen cartilage damage as demonstrated by a decrease in the serum levels of C-terminal cross-linked telopeptide of type II collagen in the osteoarthritis group.

Description of the Work: Leptin is a reliable predictive and surrogate marker of the efficacy of multitargeted treatment of cancer cachexia., Purpose: To the best of our knowledge, no study has assessed the predictive role of biomarkers in establishing the effectiveness of anti-cachectic treatment, which remains a complex issue. Herein, we aimed to find a marker that can detect early response to anti-cachectic treatment., Patients and Methods: From January 2012 to December 2022, all consecutive eligible advanced cancer patients with cachexia were prospectively enrolled in an exploratory and validation cohort according to eligibility criteria. All patients received a combined anti-cachectic treatment consisting of megestrol acetate plus celecoxib plus l-carnitine plus antioxidants that showed efficacy in a previous phase III randomized study. Primary endpoints were an increase in lean body mass (LBM), a decrease in resting energy expenditure (REE), a decrease in fatigue, and improvement in global quality of life., Results: A total of 553 consecutive patients were recruited. Twenty patients dropped out, equally distributed over the exploratory (11 patients) and validation (9 patients) cohorts, for early death due to disease progression. Then, 533 patients were deemed assessable. Leptin level changes inversely correlated with circulating levels of inflammatory mediators and reflected the improvement of body composition, energy metabolism, functional performance, and quality of life. At multivariate regression analysis, at week 8, leptin change was an independent predictor of LBM, skeletal muscle index (SMI), grip strength increase, and REE; at week 16, leptin change was an independent predictor of the same parameters and improvement in Eastern Cooperative Oncology Group performance status. The ability of leptin to predict changes in LBM, SMI, REE, and grip strength was superior to that of other inflammatory markers when comparing the receiver operating curves. Moreover, increasing delta leptin values were associated with significantly better outcomes in LBM, SMI, REE, grip strength, and fatigue., Conclusions: Leptin is a reliable predictive marker for multitargeted anti-cachectic treatment outcomes. Thus, it can be an ideal candidate for monitoring and predicting the effects of anti-cachectic treatment and a surrogate marker of the immune-metabolic actions of the selected drugs., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Benign prostatic hyperplasia (BPH) is a condition generally associated with advanced age in men that can be accompanied by bothersome lower urinary tract symptoms (LUTS) including intermittency, weak stream, straining, urgency, frequency, and incomplete bladder voiding. Pharmacotherapies for LUTS/BPH include alpha-blockers, which relax prostatic and urethral smooth muscle and 5ɑ-reductase inhibitors such as finasteride, which can block conversion of testosterone to dihydrotestosterone thereby reducing prostate volume. Celecoxib is a cyclooxygenase-2 inhibitor that reduces inflammation and has shown some promise in reducing prostatic inflammation and alleviating LUTS for some men with histological BPH. However, finasteride and celecoxib can reduce mitochondrial function in some contexts, potentially impacting their efficacy for alleviating BPH-associated LUTS., Methods: To determine the impact of these pharmacotherapies on mitochondrial function in prostate tissues, we performed immunostaining of mitochondrial Complex I (CI) protein NADH dehydrogenase [ubiquinone] iron-sulfur protein 3 (NDUFS3) and inflammatory cells on BPH specimens from patients naïve to treatment, or who were treated with celecoxib and/or finasteride for 28 days, as well as prostate tissues from male mice treated with celecoxib or vehicle control for 28 days. Quantification and statistical correlation analyses of immunostaining were performed., Results: NDUFS3 immunostaining was decreased in BPH compared to normal adjacent prostate. Patients treated with celecoxib and/or finasteride had significantly decreased NDUFS3 in both BPH and normal tissues, and no change in inflammatory cell infiltration compared to untreated patients. Mice treated with celecoxib also displayed a significant decrease in NDUFS3 immunostaining and no change in inflammatory cell infiltration., Conclusions: These findings suggest that celecoxib and/or finasteride are associated with an overall decrease in NDUFS3 levels in prostate tissues but do not impact the presence of inflammatory cells, suggesting a decline in mitochondrial CI function in the absence of enhanced inflammation. Given that BPH has recently been associated with increased prostatic mitochondrial dysfunction, celecoxib and/or finasteride may exacerbate existing mitochondrial dysfunction in some BPH patients thereby potentially limiting their overall efficacy in providing metabolic stability and symptom relief., (© 2024 The Author(s). The Prostate published by Wiley Periodicals LLC.)

Objective: The synergistic inhibitory effect of celecoxib (CXB) and dimethyl-celecoxib (DMC) plus paclitaxel (PA) or cisplatin (CP) on human cervix HeLa and SiHa cells was assessed at multiple cellular levels in order to elucidate the biochemical mechanisms triggered by the synergistic drug combinations., Methods: The effect of CXB (5 μM)/CP (2 μM) or CXB (5 μM)/PA (15 μM) and DMC (15 μM)/CP (5 μM) or DMC (15 μM)/PA (20 μM) for 24 h was assayed on cancer cell proliferation, energy metabolism, mitophagy, ROS production, glycoprotein-P activity, DNA stability and apoptosis/necrosis., Results: Drug combinations synergistically decreased HeLa and SiHa cell proliferation (>75%) and arrested cellular cycle by decreasing S and G2/M phases as well as the Ki67 content (HeLa) by 7.5-30 times. Cell viability was preserved (>90%) and no apparent effects on non-cancer cell growth were observed. Mitochondrial and glycolytic protein contents (44-95%) and ΔΨm (45-50%) in HeLa cells and oxidative phosphorylation and glycolysis fluxes (70-90%) in HeLa and SiHa cells were severely decreased, which in turn promoted a drastic fall in the ATP supply (85-88%). High levels of mitophagy proteins in HeLa cells and active mitochondrial digestion in HeLa and SiHa cells was observed. Mitochondrial fission and microtubule proteins were also affected. Intracellular ROS content (2-2.3-fold) and ROS production was stimulated (2.3-4 times), whereas content and activity of glycoprotein-P (45-85%) were diminished. DNA fragmentation was not observed and apoptosis/necrosis was not detected suggesting that cell death could be mainly associated to mitophagy induction., Conclusions: CXB or DMC combination with canonical chemotherapy may be a promising chemotherapy strategy against cervical cancer growth, because it can selectively block multiple cell processes including inhibition of energy pathways and in consequence ATP-dependent processes such as cell proliferation, glycoprotein-P activity, ROS production and mitophagy, with no apparent effects on non-cancer cells., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Robledo-Cadena et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Celecoxib, an anti-inflammatory drug, combined therapies using antimicrobials and immune modulator drugs are being studied., Objective: To assess whether Celecoxib has direct in vitro antifungal effect against the Paracoccidioides brasiliensis, the causative agent of Paracoccidioidomycosis-(PCM) and also if it improves the in vivo activity of neutrophils-(PMN) in an experimental murine subcutaneous-(air pouch) model of the disease., Methods: The antifungal activity of Celecoxib(6 mg/mL) on P. brasiliensis-(Pb18) was evaluated using the microdilution technique. Splenocytes co-cultured with Pb18 and treated with Celecoxib(6 mg/mL) were co-cultured for 24, 48 and 72-hours. Swiss mice were inoculated with Pb18 and treated with Celecoxib(6 mg/kg) in the subcutaneous air pouch. Neutrophils were collected from the air pouch. Mitochondrial activity, reactive oxygen production, catalase, peroxidase, cytokines and chemokines, nitrogen species, total protein, microbicidal activity of PMNs and viable Pb18 cells numbers were analyzed., Results: Celecoxib had no cytotoxic effect on splenocytes co-cultured with Pb18, but had a marked direct antifungal effect, inhibiting fungal growth both in vitro and in vivo. Celecoxib interaction with immune system cells in the air pouch, it leads to activation of PMNs, as confirmed by several parameters (mitochondrial activity, reactive oxygen species, peroxidase, KC and IL-6 increase, killing constant and phagocytosis). Celecoxib was able to reduce IL-4, IL-10 and IL-12 cytokine production. The number of recovered viable Pb18 decreased dramatically., Conclusions: This is the first report of the direct antifungal activity of Celecoxib against P. brasiliensis. The use of Celecoxib opens a new possibility for future treatment of PCM., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier B.V.)

Preeclampsia (PE) is often associated with multiple organ damage that remains noticeable postnatally. Here, we tested the hypotheses that antenatal therapy with nonsteroidal antiinflammatory drugs (NSAIDs) refashions liver damage induced by PE in weaning rats and that the high mobility group box 1 (HMGB1) signaling modulates this interaction. PE was induced by pharmacologic nitric oxide deprivation during the last week of gestation (N ω -nitro-L-arginine methyl ester, L-NAME, 50 mg/kg/day, oral gavage). Compared with control rats, weaning PE rats revealed substantial rises in serum transaminases together with histopathological signs of hepatic cytoplasmic changes, portal inflammation, and central vein dilation. While gestational NSAIDs reversed the elevated transaminases, they had no effects (celecoxib, naproxen) or even worsened (diclofenac) the structural damage. Molecularly, celecoxib was the most effective NSAID in (i) reversing PE-evoked upregulation of hepatic HMGB1 gene expression and concomitant increments and decrements in mitogen-activated protein kinases MAPK ERK and MAPK p38 expression, respectively, and (ii) elevating and suppressing serum interleukin-10 and tumor necrosis factor-α, respectively. Alternatively, rises in serum interleukin-1β and shifts in macrophage polarization towards an inflammatory phenotype caused by PE were comparably diminished by all NSAIDs. The data disclose an advantageous therapeutic potential for gestational celecoxib over diclofenac or naproxen in controlling hepatic dysfunction and HMGB1-interrelated inflammatory and oxidative sequels of PE., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Immunotherapy has captured attention for its high clinical efficacy. However, its efficacy is limited by inadequate immune activation. Therefore, a platform to activate the immune system and amplify the host's immune response against tumors is urgently needed. Herein, a self-delivery photodynamic nanodrug (VAC@HSA) is reported as inducing immunogenic cell death (ICD), promoting the recruitment of dendritic cells (DCs), and normalizing tumor blood vessels. Firstly, verteporfin with laser assistance releases tumor-associated antigen to induce ICD, while celecoxib downregulates prostaglandin E2 and releases CCL5 to activate DC recruitment. Moreover, vasculature is normalized through axitinib, which contributes to reducing tumor hypoxia and reversing the immunosuppressive effects of vascular endothelial growth factor. This joint action promotes the infiltration of immune effector cells into the tumor. Therefore, the amplified photodynamic nanodrug with excellent biocompatibility effectively inhibits tumor growth and lung metastasis and produces a cascade of immune responses. Our study demonstrates a practically innovative strategy for activating cancer immunotherapy, which can alter the "cold" properties of tumors., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Background: Diclofenac sodium (DS) and celecoxib (CEL) are primary anti-inflammatory agents used in the treatment of osteoarthritis (OA). Formulating these drugs into extended-release versions can effectively address the issue of multiple daily doses. In this study, we designed and synthesized a novel poly(lactic-co-glycolic acid) (PLGA) nanoliposome as a dual-drug delivery sustained-release formulation (PPLs-DS-CEL) to achieve long-lasting synergistic treatment of OA with both DS and CEL., Methods: PPLs-DS-CEL was synthesized by the reverse evaporation method and evaluated for its physicochemical properties, encapsulation efficiency, drug release kinetics and biological properties. A rat OA model was established to assess the therapeutic efficacy and biosafety of PPLs-DS-CEL., Results: The particle size of PPLs-DS-CEL was 218.36 ± 6.27 nm, with a potential of 32.56 ± 3.28 mv, indicating a homogeneous vesicle size. The encapsulation of DS and CEL by PPLs-DS-CEL was 95.18 ± 4.43% and 93.63 ± 5.11%, with drug loading of 9.56 ± 0.32% and 9.68 ± 0.34%, respectively. PPLs-DS-CEL exhibited low cytotoxicity and hemolysis, and was able to achieve long-lasting synergistic analgesic and anti-inflammatory therapeutic effects in OA through slow release of DS and CEL, demonstrating good biosafety properties., Conclusion: This study developed a novel sustained-release nanoliposomes formulation capable of co-loading two drugs for the long-acting synergistic treatment of OA. It offers a new and effective therapeutic strategy for OA treatment in the clinic settings and presents a promising approach for drug delivery systems., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

The present work is designed to explore the anti-inflammatory properties of AA and its modulatory effects on celecoxib (CEL) and ketoprofen (KET) through in vitro, ex vivo, in vivo, and in silico approaches. Different concentrations of AA were utilized to evaluate the membrane-stabilizing potential via egg albumin and the Human Red Blood Cell (HRBC) denaturation model. In the animal model, formalin (50 μL) was injected into the right hind paw of young chicks to induce inflammation. AA was administered at 20 and 40 mg/kg (p.o.) to the experimental animals. We used CEL and KET as positive controls. The vehicle was provided as a control group. Two combinations of AA with CEL and KET were also investigated in all tests to assess the modulatory activity of AA. In addition, in silico investigation was used for predictions about drug-likeness, pharmacokinetics, and toxicity of the selected chemical compounds, and the study also evaluated the binding affinity, visualization, and stability of ligand-receptor interactions through molecular dynamic (MD) simulation. Results manifested that AA concentration-dependently significantly inhibited the egg albumin denaturation (IC 50 : 27.53 ± 0.88 μg/ml) and breakdown of HRBC (IC 50 : 15.69 ± 0.75 μg/ml), indicating the membrane stabilizing potential compared to the control group. AA also significantly (p < 0.05) lessened the frequency of licking and alleviated the paw edema in a dose-dependent manner in an in vivo test. However, AA reduced the activity of CEL and KET in combination treatment. AA showed good pharmacokinetic characteristics to be considered as a therapeutic candidate. Additionally, the in silico study displayed that AA demonstrated a relatively higher docking score of -9.1 kcal/mol with the cyclooxygenase-2 (COX-2) enzyme and stable binding in MD simulation. Whereas the standard ligand (CEL) expressed the highest binding value of -9.2 kcal/mol to the COX-2., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financialinterestsor personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: The clinical presentations of Parkinson's disease (PD), a chronic neurodegenerative condition, include bradykinesia, hypokinesia, stiffness, resting tremor, and postural instability. Recently, neuroinflammation is involved in pathogenesis of PD. Application of nonsteroidal anti-inflammatory drugs captured attention to treat these neuroinflammation., Aim: To investigate the possible effectiveness of celecoxib in patients with PD treated with conventional treatment., Methods: Sixty outpatients who fulfilled the inclusion requirements for PD were enrolled in this randomized, prospective, and controlled study. The patients were allocated into two groups at random (n = 30); the control group received standard PD treatment, consisting of levodopa/carbidopa, and the celecoxib group received standard PD treatment plus celecoxib. A neurologist evaluated each patient at the beginning of the treatment and after 6 months. Assessment of Unified Parkinson's disease rating scale (UPDRS) for each patient. Before and after treatment, α -synuclein (α-Syn), tumor necrosis factor alpha (TNF-α), Toll like receptors-4 (TLR-4), nuclear factor erythroid 2-related factor 2 (Nrf-2) and brain-derived neurotropic factor (BDNF) were assessed. Paired and unpaired t tests were used to assess statistical significance within and between groups respectively., Results: The celecoxib group exhibited a significant and statistical reduction in the level of measured parameters by unpaired t test as followed: TLR-4 (p = 0.004), TNF-α (p = 0.042), and α-Syn (p = 0.004) apart from a significant increase in BDNF (p = 0.0005) and Nrf-2 (p = 0.004), in comparison with the control group. Also, UPDRS was significantly decreased in celecoxib group (p < 0.05)., Conclusion: Celecoxib could be a promising adjuvant therapy in managing patients with PD., Trial Registration Number: NCT05962957., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background: Non-steroidal anti-inflammatory drugs (NSAIDs) possess analgesic and anti-inflammatory properties by inhibiting cyclooxygenase (COX) enzymes. Conflicting evidence exists on whether NSAIDs influence signaling related to muscle adaptations and exercise with some research finding a reduction in muscle protein synthesis signaling via the AKT-mTOR pathway, changes in satellite cell signaling, reductions in muscle protein degradation, and reductions in cell proliferation. In this study, we determined if a single maximal dose of flurbiprofen (FLU), celecoxib (CEL), ibuprofen (IBU), or a placebo (PLA) affects the short-term muscle signaling responses to plyometric exercise., Methods: This was a block randomized, double-masked, crossover design, where 12 participants performed four plyometric exercise bouts consisting of 10 sets of 10 plyometric jumps at 40% 1RM. Two hours before exercise, participants consumed a single dose of celecoxib (CEL 200 mg), IBU (800 mg), FLU (100 mg) or PLA with food. Muscle biopsy samples were collected before and 3-h after exercise from the vastus lateralis. Data were analyzed using a repeated measures (RM) ANOVA, ANOVA, or a Friedman test. Significance was considered at p < 0.05., Results: We found no treatment effects on the mRNA expression of PTSG1, PTSG2, MYC, TBP, RPLOP, MYOD1, Pax7, MYOG, Atrogin-1, or MURF1 (all, p > 0.05). We also found no treatment effects on AKT-mTOR signaling or MAPK signaling measured through the phosphorylation status of mTORS2441, mTORS2448, RPS6 235/236, RPS 240/244, 4EBP1, ERK1/2, p38 T180/182 normalized to their respective total abundance (all, p > 0.05). However, we did find a significant difference between MNK1 T197/202 in PLA compared to FLU (p < .05)., Conclusion: A single, maximal dose of IBU, CEL, or FLU taken prior to exercise did not affect the signaling of muscle protein synthesis, protein degradation, or ribosome biogenesis three hours after a plyometric training bout., Competing Interests: Declarations Conflict of interest The authors declare they have nothing to disclose and no conflicts of interest. The views expressed in this manuscript are those of the authors and do not reflect the official policy of the Department of Army, Department of Defense, or the U.S. Government. The results of the present study do not constitute endorsement by ACSM. The results of the study are presented clearly, honestly, and without fabrication, falsification, or inappropriate data manipulation., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

The aim of this study was to develop and evaluate bilosomes loaded with Celecoxib (CXB) for the efficient treatment of Alzheimer. The thin-film hydration approach was utilized in the formulation of CXB bilosomes (CXB-BLs). The study used a 2 3 -factorial design to investigate the impact of several formulation variables. Three separate parameters were investigated: bile salt type (X 1 ), medication amount (X 2 ), and lipid-bile salt ratio (X 3 ). The dependent responses included entrapment efficiency (Y 1 : EE %), particle size (Y 2 : PS), and zeta potential ( Y3 : ZP). The formulation factors were statistically optimized using the Design-Expert ® program. The vesicles demonstrated remarkable CXB encapsulation efficiency, ranging from 94.16 ± 1.91 to 98.38 ± 0.85%. The vesicle sizes ranged from 241.8 ± 6.74 to 352 ± 2.34 nm. The produced formulations have high negative zeta potential values, indicating strong stability. Transmission electron microscopy (TEM) revealed that the optimized vesicles had a spherical form. CXB release from BLs was biphasic, with the release pattern following Higuchi's model. In vivo studies confirmed the efficiency of CXB-BLs in management of lipopolysaccharide-induced Alzheimer as CXB-BLs ameliorated cognitive dysfunction, decreased acetylcholinesterase (AChE), and inhibited neuro-inflammation and neuro-degeneration through reducing Toll-like receptor (TLR4), and Interleukin-1β (IL-1β) levels. The findings suggested that the created CXB-BLs could be a potential drug delivery strategy for Alzheimer's treatment., (© 2024. The Author(s).)

Objective: To investigate the role of an inflammatory microenvironment induced by Porphyromonasgingivalis ( P. gingivalis ) in the occurrence of esophageal squamous cell carcinoma (ESCC) in mice. Methods: A total of 180 C57BL/6 mice were randomly divided into 6 groups, i.e. control group, P. gingivalis group, 4NQO group, 4NQO + P. gingivalis group, 4NQO + P. gingivalis + celecoxib group, and 4NQO + P. gingivalis + antibiotic cocktail (ABC, including metronidazole, neomycin, ampicillin, and vancomycin) group, with 30 mice in each group, using the random number table. All mice were normalized by treatment with ABC in drinking water for 2 weeks. In the following 2 weeks, the mice in the control group and the P. gingivalis group were given drinking water, while the other 4 groups were treated with 30 μg/ml 4NQO in the drinking water. In weeks 11-12, the mice in the P. gingivalis group, the 4NQO + P. gingivalis group, the 4NQO + P. gingivalis + celecoxib group, and the 4NQO + P. gingivalis + ABC group were subjected to ligation of the second molar in oral cavity followed by oral P. gingivalis infection thrice weekly for 24 weeks in weeks 11-34. In weeks 13-34, the mice in 4NQO + P. gingivalis +celecoxib group and 4NQO + P. gingivalis + ABC group were administered with celecoxib and ABC for 22 weeks, respectively. At the end of 34 weeks, gross and microscopic alterations were examined followed by RT-qPCR and immunohistochemistry to examine the expression profiles of inflammatory- and tumor-molecules in esophagi of mice. Results: At 34 weeks, 4NQO treatment alone did not affect the foci of papillary hyperproliferation, diseased area, and the thickness of the esophageal wall, but significantly enhanced the foci of hyperproliferation (median 1.00, P ＜0.05) and mild/moderate dysplasia (median 2.00, P ＜0.01). In addition, the expression levels of IL-6 [8.35(3.45,8.99)], IL-1β [6.90(2.01,9.72)], TNF-α [12.04(3.31,14.08)], c-myc [2.21(1.80,3.04)], pSTAT3, Ki-67, and pH2AX were higher than those in the control group. The pathological changes of the esophageal mucosa were significantly more overt in the 4NQO + P. gingivalis group in terms of the foci of papillary hyperproliferation (median 2.00), diseased area (median 2.51 mm 2 ), the thickness of the esophageal wall (median 172.52 μm), the foci of hyperproliferation (median 1.00, P ＜0.05), and mild/moderate dysplasia (median 1.00, P ＜0.01). In mice of the 4NQO + P. gingivalis group, the expression levels of IL-6 [12.27(5.35,22.08)], IL-1β [13.89(10.04,15.96)], TNF-α [19.56(6.07,20.36)], IFN-γ [11.37(8.23,20.07)], c-myc [2.62(1.51,4.25)], cyclin D1 [4.52(2.68,7.83)], nuclear pSTAT3, COX-2, Ki-67, and pH2AX were significantly increased compared with the mice in the control group. In mice of the 4NQO + P. gingivalis group, the diseased area, invasive malignant foci as well as pSTAT3 and pH2AX expression were significantly blunted by celecoxib. Treatment with ABC markedly reduced the papillary hyperproliferative foci, invasive malignant foci, and pSTAT3 expression but not pH2AX. Conclusions: P. gingivalis promotes the occurrence of esophageal squamous cell carcinoma in mice by inducing an inflammatory microenvironment primed with 4NQO induced DNA damage. Clearance of P. gingivalis with ABC or anti-inflammatory intervention holds promise for prevention of esophageal squamous cell malignant pathogenesis via blockage of IL-6/STAT3 signaling and amelioration of inflammation.

Musculoskeletal infections (MIs) are among the most difficult-to-treat staphylococcal diseases due to antibiotic resistance. This has encouraged the development of innovative strategies, such as combination therapy, to combat MI. The aim of this study was to investigate the in vitro antistaphylococcal activity of anti-inflammatory drugs and the combined antimicrobial effect of celecoxib and oxacillin. The minimum inhibitory concentrations (MICs) of 17 anti-inflammatory drugs against standard strains and clinical isolates of S. aureus , including methicillin-resistant strains (MRSAs), were determined using the broth microdilution method. The fractional inhibitory concentration indices (FICIs) were evaluated using checkerboard assays. Celecoxib produced the most potent antistaphylococcal effect against all tested strains (MICs ranging from 32 to 64 mg/L), followed by that of diacerein against MRSA3 and MRSA ATCC 33592 (MIC 64 mg/L). Several synergistic effects were observed against the tested S. aureus strains, including MRSA (FICI ranging from 0.087 to 0.471). The strongest synergistic interaction (FICI 0.087) was against MRSA ATCC 33592 at a celecoxib concentration of 2 mg/L, with a 19-fold oxacillin MIC reduction (from 512 to 26.888 mg/L). This is the first report on the combined antistaphylococcal effect of celecoxib and oxacillin. These findings suggest celecoxib and its combination with oxacillin as perspective agents for research focused on the development of novel therapies for MI caused by S. aureus. This study further indicates that celecoxib could resensitize certain MRSA strains, in some cases, to be susceptible to β-lactams (e.g., oxacillin) that were not previously tested. It is essential to mention that the in vitro concentrations of anti-inflammatory drugs are higher than those typically obtained in patients. Therefore, an alternative option for its administration could be the use of a drug delivery system for the controlled slow release from an implant at the infection site.

Recent evidence suggests the mechanistic role of mitochondria and oxidative stress in the development of celecoxib-induced cardiotoxicity. On the other, it has reported the positive effects of vitamin D on oxidative stress and the maintenance of mitochondrial functions. This current study examined the cardiac effects of celecoxib, doxorubicin, vitamin D, and a combination of them in rats. The effect of 10 days of celecoxib (100 mg/kg/day), doxorubicin (2.5 mg/kg), vitamin D (60,000 U/kg), and their combination was studied on cardiac function according to serum lactate dehydrogenase (LDH), creatine kinase (CK), glutathione (GSH), and malondialdehyde (MDA) levels as well as mitochondrial succinate dehydrogenases (SDH) activity, reactive oxygen species (ROS) production, mitochondrial swelling, and mitochondrial membrane potential (MMP). Results showed that celecoxib and its combination with doxorubicin led to abnormality in paws and limbs, increased pressure in the eyes, blindness and animal death (in about 75% of the animals under study). Moreover, celecoxib and its combination with doxorubicin significantly increased cardiotoxicity biomarkers, oxidative stress markers (GSH and MDA), and mitochondrial toxicity parameters (SDH, ROS formation, MMP collapse, mitochondrial swelling). However, the combination of vitamin D with celecoxib and celecoxib + doxorubicin caused a significant reversal of deformity in paws and limbs, increased pressure in the eye, blindness, and animal death, as well as cardiotoxicity, oxidative stress, and mitochondrial parameters. This study proved for the first time the beneficial effect of vitamin D on celecoxib-induced cardiotoxicity, which is aggravated in the presence of doxorubicin through the maintenance of mitochondrial functions and its antioxidant potential., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Aims: This study aimed at investigating the efficacy of metformin as adjuvant therapy for obese knee osteoarthritis (OA) patients, considering its anti-inflammatory and cartilage-protective effects., Patients and Methods: In this randomized, double-blind, placebo-controlled study, 50 obese knee OA patients were assigned randomly to two groups, the metformin group (n = 25) which was treated with metformin 500 mg orally BID plus celecoxib 200 mg orally once daily, and the placebo group (n = 25) which was treated with placebo tablets BID plus celecoxib 200 mg orally once daily for 12 weeks. Cartilage Oligomeric Matrix Protein (COMP), C-terminal cross-linked telopeptide of type I collagen (CTX-1), and Interleukin 1-beta (IL-1β) serum levels were measured, while Western Ontario and McMaster Universities Arthritis Index (WOMAC) score assessed knee pain, stiffness, and physical function at baseline and after 12 weeks., Results: Following a 12-week treatment, the metformin group exhibited significantly reduced levels of COMP, CTX-1, and IL-1β in the serum compared to the placebo group (p = 0.0081, p = 0.0106, and p = 0.0223, respectively). Furthermore, metformin group produced significant improvements in WOMAC total scale (p < 0.0001), specifically in knee pain, stiffness, and physical function compared to placebo group (p < 0.0001, p < 0.0001, and p < 0.0001, respectively)., Conclusion: Metformin as an adjuvant therapy in obese knee OA patients may have beneficial effects on cartilage degradation and inflammation, as evidenced by the significant decreases in serum COMP, CTX-1, and IL-1β levels. Additionally, metformin may improve clinical outcomes, as shown by the significant improvements in WOMAC scores., Gov Id: NCT05638893/Registered December 6, 2022 - Retrospectively., (© 2024. The Author(s).)

The development of targeted drug delivery systems has been a pivotal area in nanomedicine, addressing challenges like low drug loading capacity, uncontrolled release, and systemic toxicity. This study aims to develop and evaluate dual-functionalized mesoporous silica nanoparticles (MSN) for targeted delivery of celecoxib, enhancing drug loading, achieving controlled release, and reducing systemic toxicity through amine grafting and imidazolyl polyethyleneimine (PEI) gatekeepers. MSN were synthesized using the sol-gel method and functionalized with (3-aminopropyl) triethoxysilane (APTES) to create amine-grafted MSN (MSN-NH 2 ). Celecoxib was loaded into MSN-NH 2 , followed by conjugation of imidazole-functionalized PEI (IP) gatekeepers synthesized via carbodiimide coupling. Characterization was conducted using Fourier-transform infrared spectroscopy (FTIR) and proton nuclear magnetic resonance ( 1 H-NMR). Drug loading capacity, entrapment efficiency, and in vitro drug release at pH 5.5 and 7.4 were evaluated. Cytotoxicity was assessed using the MTT assay on RAW 264.7 macrophages. The synthesized IP was confirmed by FTIR and 1 H-NMR. Amine-grafted MSN demonstrated a celecoxib loading capacity of 12.91 ± 2.02%, 2.1 times higher than non-functionalized MSN. In vitro release studies showed pH-responsive behavior with significantly higher celecoxib release from MSN-NH 2 -celecoxib-IP at pH 5.5 compared to pH 7.4, achieving a 33% increase in release rate within 2 h. Cytotoxicity tests indicated significantly higher cell viability for IP-treated cells compared to PEI-treated cells, confirming reduced toxicity. The dual-functionalization of MSN with amine grafting and imidazolyl PEI gatekeepers enhances celecoxib loading and provides controlled pH-responsive drug release while reducing systemic toxicity. These findings highlight the potential of this advanced drug delivery system for targeted anti-inflammatory and anticancer therapies., Competing Interests: The authors declare no conflicts of interest.

Soft tissue injuries often involve muscle and peripheral nerves and are qualitatively distinct from single-tissue injuries. Prior research suggests that damaged innervation compromises wound healing. To test this in a traumatic injury context, we developed a novel mouse model of nerve and lower limb polytrauma, which features greater pain hypersensitivity and more sustained macrophage infiltration than either injury in isolation. We also show that macrophages are crucial mediators of pain hypersensitivity in this model by delivering macrophage-targeted nanoemulsions laden with the cyclooxygenase-2 (COX-2) inhibitor celecoxib. This treatment was more effective in males than females, and more effective when delivered 3 days post-injury than 7 days post-injury. The COX-2 inhibiting nanoemulsion drove widespread anti-inflammatory changes in cytokine expression in polytrauma-affected peripheral nerves. Our data shed new light on the modulation of inflammation by injured nerve input and demonstrate macrophage-targeted nanoimmunomodulation can produce rapid and sustained pain relief following complex injuries., Competing Interests: The authors report no conflicts of interest in this work., (© 2024 Cortez et al.)

Immuno-photodynamic therapy (IPDT) has emerged as a new modality for cancer treatment. Novel photosensitizers can help achieve the promise inherent in IPDT, namely, the complete eradication of a tumor without recurrence. We report here a small molecule photosensitizer conjugate, LuCXB. This IPDT agent integrates a celecoxib (cyclooxygenase-2 inhibitor) moiety with a near-infrared absorbing lutetium texaphyrin photocatalytic core. In aqueous environments, the two components of LuCXB are self-associated through inferred donor-acceptor interactions. A consequence of this intramolecular association is that upon photoirradiation with 730 nm light, LuCXB produces superoxide radicals (O 2 -• ) via a type I photodynamic pathway; this provides a first line of defense against the tumor while promoting IPDT. For in vivo therapeutic applications, we prepared a CD133-targeting, aptamer-functionalized exosome-based nanophotosensitizer (Ex-apt@LuCXB) designed to target cancer stem cells. Ex-apt@LuCXB was found to display good photosensitivity, acceptable biocompatibility, and robust tumor targetability. Under conditions of photoirradiation, Ex-apt@LuCXB acts to amplify IPDT while exerting a significant antitumor effect in both liver and breast cancer mouse models. The observed therapeutic effects are attributed to a synergistic mechanism that combines antiangiogenesis and photoinduced cancer immunotherapy.

Background: Epilepsy poses a significant global health challenge, particularly in regions with limited financial resources hindering access to treatment. Recent research highlights neuroinflammation, particularly involving cyclooxygenase-2 (COX-2) pathways, as a promising avenue for epilepsy management., Methods: This study aimed to develop a Cyclooxygenase-2 inhibitor with potential anticonvulsant properties. A promising drug candidate was identified and chemically linked with phospholipids through docking analyses. The activation of this prodrug was assessed using phospholipase A2 (PLA2)-mediated hydrolysis studies. The conjugate's confirmation and cytotoxicity were evaluated using Fourier Transform Infrared Spectroscopy (FT-IR), Differential Scanning Calorimetry (DSC), and Sulphoramide B (SRB) assays., Results: Docking studies revealed that the Celecoxib-Phospholipid conjugate exhibited a superior affinity for PLA2 compared to other drug-phospholipid conjugates. FT-IR spectroscopy confirmed the successful synthesis of the conjugate, while DSC analysis confirmed its purity and formation. PLA2-mediated hydrolysis experiments demonstrated selective activation of the prodrug depending on PLA2 concentration. SRB experiments indicated dose-dependent cytotoxic effects of Celecoxib, phospholipid non-toxicity, and efficient celecoxib-phospholipid conjugation., Conclusion: This study successfully developed a Celecoxib-phospholipid conjugate with potential anticonvulsant properties. The prodrug's specific activation and cytotoxicity profile makes it a promising therapeutic candidate. Further investigation into underlying mechanisms and in vivo studies is necessary to assess its translational potential fully., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

This study explored the antimicrobial effects of ketoprofen, piroxicam, and celecoxib alone or combined with calcium hydroxide (CH) against two strains of Enterococcus faecalis (E. faecalis) and assessed the influence of such combinations on the pH of CH. Minimum inhibitory concentrations (MICs) of the three tested NSAIDs were determined. Tested pastes were placed into wells punched in seeded agar plates and the bacterial inhibition zones were measured. Antibiofilm activity was assessed against 3 weeks of biofilm induced in bovine dentine blocks. The pH of the pastes was measured at four-time intervals. MIC values were 3.12, 25, and 25 mg/ml for ketoprofen, piroxicam, and celecoxib, respectively, and were similar for both bacterial strains except for celecoxib, which showed 8% growth at the highest tested concentration against vancomycin-resistant E. faecalis. Ketoprofen had the largest mean inhibition zone that was comparable to CH. None of the six tested pastes exhibited antibiofilm activity of a significant level in comparison to CH. A noticeable increase in the antibiofilm activity was found when 20% NSAIDs were added to CH while maintaining an alkaline pH. Ketoprofen was found to be the most effective among the tested NSAIDs. Although its effect was comparable to CH, adding ketoprofen at a ratio of 20% resulted in 50% higher antimicrobial action than CH alone. Accordingly, incorporating NSAIDs in inter-appointment dressing has the potential to utilize their anti-inflammatory, local analgesic, and antibacterial actions, which overcome the limitations of CH and improve the outcome of root canal treatment., (© 2024. The Author(s), under exclusive licence to The Society of The Nippon Dental University.)

Depression and anxiety disorders have their pathophysiologies linked to inflammation and oxidative stress. In this context, celecoxib (CLX) and etoricoxib (ETR) inhibit cyclooxygenase 2 (COX-2), an enzyme expressed by cells involved in the inflammatory process and found in the brain. Studies have been using CLX as a possible drug in the treatment of depression, although its mechanisms at the central nervous system level are not fully elucidated. In this study, the effects of CLX and ETR on behavioral, oxidative, and inflammatory changes induced by systemic exposure to Escherichia coli lipopolysaccharide (LPS) were evaluated in adult male swiss mice. For ten days, the animals received intraperitoneal injections of LPS at 0.5 mg/kg. From the sixth to the tenth day, one hour after LPS exposure, they were treated orally with CLX (15 mg/kg), ETR (10 mg/kg), or fluoxetine (FLU) (20 mg/kg). Twenty-four hours after the last oral administration, the animals underwent evaluation of locomotor activity (open field test), predictive tests for depressive-like behavior (forced swim and tail suspension tests), and anxiolytic-like effect (elevated plus maze and hole board tests). Subsequently, the hippocampus, prefrontal cortex and striatum were dissected for the measurement of oxidative and nitrosative parameters (malondialdehyde, nitrite, and glutathione) and quantification of pro-inflammatory cytokines (IL-1β and IL-6). LPS induced depressive and anxious-like behavior, and treatment with CLX or ETR was able to reverse most of the behavioral changes. It was evidenced that nitrosative stress and the degree of lipid peroxidation induced by LPS were reduced in different brain areas after treatment with the drugs, as well as the endogenous defense system against free radicals was strengthened. CLX and ETR also significantly reduced LPS-induced cytokine levels. These data are expected to expand information on the role of inflammation in depression and anxiety and provide insights into possible mechanisms of COX-2 inhibitors in psychiatric disorders with a neurobiological basis in inflammation and oxidative stress., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Triple-negative breast cancer (TNBC) is a highly aggressive malignancy that lacks effective targeted therapies. Inducing immunogenic cell death (ICD) in tumor cells represents a promising strategy to enhance therapeutic efficacy by promoting antitumor immunity. Paclitaxel (PTX), a commonly used chemotherapy drug for TNBC, can induce ICD; however, the resulting immunogenicity is limited. Thus, there is an urgent need to explore strategies that improve the effectiveness of ICD in TNBC by incorporating immunoregulatory agents. This study investigated the potential of celecoxib (CXB) to enhance PTX-induced ICD by blocking the biosynthesis of PGE 2 in the tumor cells. We observed that the combination of CXB and PTX promoted the maturation of dendritic cells and primed a T cell-dependent immune response, leading to enhanced tumor rejection in a vaccination assay. To further optimize drug delivery in vivo , we developed cRGD-modified liposomes for the targeted codelivery of CXB and PTX. This delivery system significantly improved drug accumulation and triggered robust antitumor immunity in an orthotopic mouse model of TNBC. Moreover, it served as an in situ vaccine to inhibit tumor recurrence and lung metastasis. Overall, our findings provide in-depth insights into the therapeutic mechanism underlying the combination of CXB and PTX, highlighting their potential as effective immune-based therapies for TNBC.

Gain-of-function mutation in the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) catalytic subunit alpha gene (PIK3CA) is a significant factor in head and neck cancer (HNC). Patients with HNC harboring PIK3CA mutations receive therapeutic benefits from the use of non-steroidal anti-inflammatory drugs (NSAIDs). However, the molecular mechanisms underlying these effects remain unknown. Here, we examined the Detroit562 and FaDu cell lines as HNC models with and without a hyperactive PIK3CA mutation (H1047R), respectively, regarding their possible distinct responses to the NSAIDs celecoxib and sulindac sulfide (SUS). Detroit562 cells exhibited relatively high PI3K/Akt pathway-dependent cyclooxygenase-2 (COX-2) expression, associated with cell proliferation. Celecoxib treatment restricted cell proliferation and upregulated endoplasmic reticulum (ER) stress-related markers, including GRP78, C/EBP-homologous protein, activating transcription factor 4, death receptor 5, and reactive oxygen species (ROS). These effects were much stronger in Detroit562 cells than in FaDu cells and were largely COX-2-independent. SUS treatment yielded similar results. Salubrinal (an ER stress inhibitor) and N-acetyl-L-cysteine (a ROS scavenger) prevented NSAID-induced ROS generation and ER stress, respectively, indicating crosstalk between ER and oxidative stress. In addition, celecoxib and/or SUS elevated cleaved caspase-3 levels, Bcl-2-associated X protein/Bcl-2-interacting mediator of cell death expression, and mitochondrial damage, which was more pronounced in Detroit562 than in FaDu cells. Salubrinal and N-acetyl-L-cysteine attenuated celecoxib-induced mitochondrial dysfunction. Collectively, our results suggest that celecoxib and SUS efficiently suppress activating PIK3CA mutation-harboring HNC progression by inducing ER and oxidative stress and mitochondrial dysfunction, leading to apoptotic cell death, further supporting NSAID treatment as a useful strategy for oncogenic PIK3CA-mutated HNC therapy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Cluster-like collective cell migration of fibroblasts is one of the main factors of adhesion in injured tissues. In this research, a microdot biomaterial system is constructed using α-helical polypeptide nanoparticles and anti-inflammatory micelles, which are prepared by ring-opening polymerization of α-amino acids-N-carboxylic anhydrides (NCAs) and lactide, respectively. The microdot biomaterial system slowly releases functionalized polypeptides targeting mitochondria and promoting the influx of extracellular calcium ions under the inflammatory environment, thus inhibiting the expression of N-cadherin mediating cell-cell interaction, and promoting apoptosis of cluster fibroblasts, synergistically inhibiting the migration of fibroblast clusters at the site of tendon injury. Meanwhile, the anti-inflammatory micelles are celecoxib (Cex) solubilized by PEG/polyester, which can improve the inflammatory microenvironment at the injury site for a long time. In vitro, the microdot biomaterial system can effectively inhibit the migration of the cluster fibroblasts by inhibiting the expression of N-cadherin between cell-cell and promoting apoptosis. In vivo, the microdot biomaterial system can promote apoptosis while achieving long-acting anti-inflammation effects, and reduce the expression of vimentin and α-smooth muscle actin (α-SMA) in fibroblasts. Thus, this microdot biomaterial system provides new ideas for the prevention and treatment of tendon adhesion by inhibiting the cluster migration of fibroblasts., (© 2024 Wiley‐VCH GmbH.)

Background/aim: Synovial sarcoma (SS) is a rare malignant tumor with a poor survival rate. We previously reported that a combination of auranofin (AUR), a thioredoxin reductase inhibitor, and celecoxib (CE), an anti-inflammatory drug, significantly impedes the local progression of osteosarcoma (OS). However, the role of redox regulation in SS remains to be elucidated. This study aimed to investigate the efficacy of combined treatment of AUR and CE on the local progression of SS in vivo., Materials and Methods: Nu/nu mice were implanted with the human SS cell line, Aska-SS, and treated with vehicle control, AUR, or a combination of AUR and CE (AUR-CE). Primary tumor size and weight were evaluated for the study duration and upon resection, respectively. Hematoxylin and eosin (H&E) and Ki-67 staining were performed to assess the local progression of SS., Results: A statistically significant reduction in tumor size and weight was observed in the AUR- and AUR-CE-treated groups upon excision compared to that in the vehicle-treated group. The AUR-CE-treated group showed synergistic inhibition of local tumor growth. H&E staining of local SS tumors revealed decreased cell density and nuclear deformation in the AUR- and AUR-CE-treated groups compared to those in the vehicle-treated group. Immunohistochemical staining revealed a statistically significant decrease in Ki-67-positive cells in the AUR-CE-treated group compared to the vehicle-treated group., Conclusion: The combination of AUR and CE showed significant potential for delaying the local progression of SS. These findings support the repurposing of AUR and CE as early treatment options for SS., (Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Acetaminophen and ibuprofen are widely administered to babies due to their presumed safety as over-the-counter drugs. However, no reports exist on the effects of cyclooxygenase inhibitors on undifferentiated spermatogonia and spermatogonial stem cells. Infancy represents a critical period for spermatogonial stem cell formation and disrupting spermatogonial stem cells or their precursors may be associated with infertility and testicular cancer formation., Objectives: The goal of this study was to examine the molecular and functional impact of cyclooxygenase inhibition and silencing on early steps of undifferentiated spermatogonia (u spg) and spermatogonial stem cell development, to assess the potential reproductive risk of pharmaceutical cyclooxygenase inhibitors., Methods: The effects of cyclooxygenase inhibition were assessed using the mouse C18-4 undifferentiated juvenile spermatogonial cell line model, previously shown to include cells with spermatogonial stem cell features, by measuring prostaglandins, cell proliferation, and differentiation, using cyclooxygenase 1- and cyclooxygenase 2-selective inhibitors NS398, celecoxib, and FR122047, acetaminophen, and ibuprofen. Cyclooxygenase 1 gene silencing was achieved using a stable short-hairpin RNA approach and clone selection, then assessing gene and protein expression in RNA sequencing, quantitative real-time polymerase chain reaction, and immunofluorescence studies., Results: Cyclooxygenase 2 inhibitors NS398 and celecoxib, as well as acetaminophen, but not ibuprofen, dose-dependently decreased retinoic acid-induced expression of the spg differentiation gene Stra8, while NS398 decreased the spg differentiation marker Kit, suggesting that cyclooxygenase 2 is positively associated with spg differentiation. In contrast, short-hairpin RNA-based cyclooxygenase 1 silencing in C18-4 cells altered cellular morphology and upregulated Stra8 and Kit, implying that cyclooxygenase 1 prevented spg differentiation. Furthermore, RNA sequencing analysis of cyclooxygenase 1 knockdown cells indicated the activation of several signaling pathways including the TGFb, Wnt, and Notch pathways, compared to control C18-4 cells. Notch pathway genes were upregulated by selective cyclooxygenase inhibitors, acetaminophen and ibuprofen., Conclusion: We report that cyclooxygenase 1 and 2 differentially regulate undifferentiated spermatogonia/spermatogonial stem cell differentiation. Cyclooxygenases regulate Notch3 expression, with the Notch pathway targeted by PGD2. These data suggest an interaction between the eicosanoid and Notch signaling pathways that may be critical for the development of spermatogonial stem cells and subsequent spermatogenesis, cautioning about using cyclooxygenase inhibitors in infants., (© 2023 The Authors. Andrology published by Wiley Periodicals LLC on behalf of American Society of Andrology and European Academy of Andrology.)

Utilization of injectable hydrogels stands as a paradigm of minimally invasive intervention in the context of intervertebral disc degeneration treatment. Restoration of nucleus pulposus (NP) function exerts a profound influence in alleviating back pain. This study introduces an innovative class of injectable shear-thinning hydrogels, founded on quaternized chitosan (QCS), gelatin (GEL), and laponite (LAP) with the capacity for sustained release of the anti-inflammatory drug, celecoxib (CLX). First, synthesis of Magnesium-Aluminum-Layered double hydroxide (LDH) was achieved through a co-precipitation methodology, as a carrier for celecoxib and a source of Mg ions. Intercalation of celecoxib within LDH layers (LDH-CLX) was verified through a battery of analytical techniques, including FTIR, XRD, SEM, EDAX, TGA and UV-visible spectroscopy confirmed a drug loading efficiency of 39.22 ± 0.09 % within LDH. Then, LDH-CLX was loaded in the optimal GEL-QCS-LAP hydrogel under physiological conditions. Release behavior (15 days profile), mechanical properties, swelling ratio, and degradation rate of the resulting composite were evaluated. A G* of 15-47 kPa was recorded for the hydrogel at 22-40 °C, indicating gel stability in this temperature range. Self-healing properties and injectability of the composite were proved by rheological measurements. Also, ex vivo injection into intervertebral disc of sheep, evidenced in situ forming and NP cavity filling behavior of the hydrogel. Support of GEL-QCS-LAP/LDH-CLX (containing mg 2+ ions) for viability and proliferation (from ~94 % on day 1 to ~134 % on day 7) of NP cells proved using MTT assay, DAPI and Live/Dead assays. The hydrogel could significantly upregulate secretion of glycosaminoglycan (GAG, from 4.68 ± 0.1 to 27.54 ± 1.0 μg/ml), when LHD-CLX3% was loaded. We conclude that presence of mg 2+ ion and celecoxib in the hydrogel can lead to creation of a suitable environment that encourages GAG secretion. In conclusion, the formulated hydrogel holds promise as a minimally invasive candidate for degenerative disc repair., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: The exact mechanisms linking the gut microbiota and social behavior are still under investigation. We aimed to explore the role of the gut microbiota in shaping social behavior deficits using selectively bred mice possessing dominant (Dom) or submissive (Sub) behavior features. Sub mice exhibit asocial, depressive- and anxiety-like behaviors, as well as systemic inflammation, all of which are shaped by their impaired gut microbiota composition., Methods: An age-dependent comparative analysis of the gut microbiota composition of Dom and Sub mice was performed using 16S rRNA sequencing, from early infancy to adulthood. Dom and Sub gastrointestinal (GI) tract anatomy, function, and immune profiling analyses were performed using histology, RT-PCR, flow cytometry, cytokine array, and dextran-FITC permeability assays. Short chain fatty acids (SCFA) levels in the colons of Dom and Sub mice were quantified using targeted metabolomics. To support our findings, adult Sub mice were orally treated with hyaluronic acid (HA) (30 mg/kg) or with the non-steroidal anti-inflammatory agent celecoxib (16 mg/kg)., Results: We demonstrate that from early infancy the Sub mouse gut microbiota lacks essential bacteria for immune maturation, including Lactobacillus and Bifidobacterium genera. Furthermore, from birth, Sub mice possess a thicker colon mucin layer, and from early adulthood, they exhibit shorter colonic length, altered colon integrity with increased gut permeability, reduced SCFA levels and decreased regulatory T-cells, compared to Dom mice. Therapeutic intervention in adult Sub mice treated with HA, celecoxib, or both agents, rescued Sub mice phenotypes. HA treatment reduced Sub mouse gut permeability, increased colon length, and improved mouse social behavior deficits. Treatment with celecoxib increased sociability, reduced depressive- and anxiety-like behaviors, and increased colon length, and a combined treatment resulted in similar effects as celecoxib administered as a single agent., Conclusions: Overall, our data suggest that treating colon inflammation and decreasing gut permeability can restore gut physiology and prevent social deficits later in life. These findings provide critical insights into the importance of early life gut microbiota in shaping gut immunity, functionality, and social behavior, and may be beneficial for the development of future therapeutic strategies., (© 2024. The Author(s).)

Breast cancer is a major global health issue, causing high incidence and mortality rates as well as psychological stress for patients. Chemotherapy resistance is a common challenge, and the Aldo-keto reductase family one-member C3 enzyme is associated with resistance to anthracyclines like doxorubicin. Recent studies have identified celecoxib as a potential treatment for breast cancer. Virtual screening was conducted using a quantitative structure-activity relationship model to develop similar drugs; this involved backpropagation of artificial neural networks and structure-based virtual screening. The screening revealed that the C-6 molecule had a higher affinity for the enzyme (-11.4 kcal/mol), a lower half-maximal inhibitory concentration value (1.7 µM), and a safer toxicological profile than celecoxib. The compound C-6 was synthesized with an 82% yield, and its biological activity was evaluated. The results showed that C-6 had a more substantial cytotoxic effect on MCF-7 cells (62%) compared to DOX (63%) and celecoxib (79.5%). Additionally, C-6 had a less harmful impact on healthy L929 cells than DOX and celecoxib. These findings suggest that C-6 has promising potential as a breast cancer treatment.

Improving inflammation may serve as useful therapeutic interventions for the hindlimb unloading-induced disuse muscle atrophy. Celecoxib is a selective non-steroidal anti-inflammatory drug. We aimed to determine the role and mechanism of celecoxib in hindlimb unloading-induced disuse muscle atrophy. Celecoxib significantly attenuated the decrease in soleus muscle mass, hindlimb muscle function and the shift from slow- to fast-twitch muscle fibers caused by hindlimb unloading in rats. Importantly, celecoxib inhibited the increased expression of inflammatory factors, macrophage infiltration in damaged soleus muscle. Mechanistically, Celecoxib could significantly reduce oxidative stress and endoplasmic reticulum stress in soleus muscle of unloaded rats. Furthermore, celecoxib inhibited muscle proteolysis by reducing the levels of MAFbx, MuRF1, and autophagy related proteins maybe by inhibiting the activation of pro-inflammatory STAT3 pathway in vivo and in vitro. This study is the first to demonstrate that celecoxib can attenuate disuse muscle atrophy caused by hindlimb unloading via suppressing inflammation, oxidative stress and endoplasmic reticulum stress probably, improving target muscle function and reversing the shift of muscle fiber types by inhibiting STAT3 pathways-mediated inflammatory cascade. This study not only enriches the potential molecular regulatory mechanisms, but also provides new potential therapeutic targets for disuse muscle atrophy., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background: Ample research shows that anti-inflammatory drugs, particularly celecoxib, exert antidepressant effects, especially in patients with microglia activation. However, substantial cardiovascular adverse effects limit celecoxib's usefulness. Given that cannabidiol (CBD) exerts anti-inflammatory, microglia-suppressive, and antidepressant effects, we hypothesized that it may potentiate the therapeutic effects of celecoxib. Methods: The effects of celecoxib, CBD, and their combination were examined in murine models of antidepressant- and anxiolytic-like behavioral responsiveness, including the forced swim test (FST), elevated plus maze (EPM), lipopolysaccharide (LPS)-induced neuroinflammation, and chronic social defeat stress (CSDS), as well as in microglia cell cultures. Results: Acute administration of a combination of celecoxib plus CBD, at doses that had no effects by themselves (10 and 5 mg/kg, respectively), produced significant antidepressant- and anxiolytic-like effects in the FST and EPM, in male and female mice. In the LPS model, combinations of celecoxib (10 or 20 mg/kg) plus CBD (30 mg/kg) reversed the anxiety-like behavior in the open-field test (OFT) and anhedonia in the sucrose preference test (SPT), with minimal effects of celecoxib or CBD by themselves. In the CSDS paradigm, a combination of celecoxib plus CBD (each at 30 mg/kg) reversed the deficits in the OFT, EPM, social exploration, and SPT, whereas celecoxib or CBD by themselves had partial effects. In BV2 microglia cultures stimulated with LPS or α-synuclein, CBD markedly potentiated the suppressive effects of celecoxib over TNFα (tumor necrosis factor-α) and IL (interleukin)-1β secretion. Conclusions: Combinations of celecoxib plus CBD produce efficacious antidepressant- and anxiolytic-like effects, which may depend on their synergistic microglia-suppressive effects.

Introduction: Ulcerative colitis (UC) is an inflammatory intestine disease characterized by dysfunction of the intestinal mucosal barrier, ferroptosis, and apoptosis. Previous researches suggest that celecoxib, a nonsteroidal anti-inflammatory drug, holds promise in alleviating inflammation in UC. Therefore, this study aims to investigate the effects and mechanisms of celecoxib in UC., Methods: To identify ferroptosis-related drugs and genes associated with UC, we utilized the Gene Expression Omnibus (GEO), FerrDb databases, and DGIdb database. Subsequently, we established a 2.5% DSS (Dextran sulfate sodium)-induced colitis model in mice and treated them with 10 mg/kg of celecoxib to validate the bioinformatics results. We evaluated histological pathologies, inflammatory response, intestinal barrier function, ferroptosis markers, and apoptosis regulators., Results: Celecoxib treatment significantly ameliorated DSS-induced UC in mice, as evidenced by the body weight change curve, colon length change curve, disease activity index (DAI) score, and histological index score. Celecoxib treatment reduced the level of pro-inflammatory factors and promoted the expressions of intestinal tight junction proteins such as Claudin-1 and Occludin, thereby restoring the integrity of the intestinal mucosal barrier. Furthermore, celecoxib treatment reversed the ferroptosis characteristics in DSS-induced mice by increasing glutathione (GSH), decreasing malondialdehyde (MDA), and increasing the expression of GPX-4 and xCT. Additionally, apoptosis was induced in mice with UC, as evidenced by increased Caspase3, BAD, P53, BAX, Caspase9 and Aifm1 production, and decreased expression of BCL-XL and BCL2. Celecoxib treatment significantly reversed the apoptotic changes in DSS-induced mice., Conclusion: Our findings suggest that celecoxib effectively treats DSS-induced UC in mice by inhibiting ferroptosis and apoptosis.

Osteoarthritis (OA) is the most common form of arthritis, with intra-articular (IA) delivery of therapeutics being the current best option to treat pain and inflammation. However, IA delivery is challenging due to the rapid clearance of therapeutics from the joint and the need for repeated injections. Thus, there is a need for long-acting delivery systems that increase the drug retention time in joints with the capacity to penetrate OA cartilage. As pharmaceutical utility also demands that this is achieved using biocompatible materials that provide colloidal stability, our aim was to develop a nanoparticle (NP) delivery system loaded with the COX-2 inhibitor celecoxib that can meet these criteria. We devised a reproducible and economical method to synthesize the colloidally stable albumin NPs loaded with celecoxib without the use of any of the following conditions: high temperatures at which albumin denaturation occurs, polymer coatings, oils, Class 1/2 solvents, and chemical protein cross-linkers. The spherical NP suspensions were biocompatible, monodisperse with average diameters of 72 nm (ideal for OA cartilage penetration), and they were stable over 6 months at 4 °C. Moreover, the NPs loaded celecoxib at higher levels than those required for the therapeutic response in arthritic joints. For these reasons, they are the first of their kind. Labeled NPs were internalized by primary human articular chondrocytes cultured from the knee joints of OA patients. The NPs reduced the concentration of inflammatory mediator prostaglandin E 2 released by the primaries, an indication of retained bioactivity following NP synthesis. Similar results were observed in lipopolysaccharide-stimulated human THP-1 monocytes. The IA administration of these NPs is expected to avoid side-effects associated with oral administration of celecoxib and to maintain a high local concentration in the knee joint over a sustained period. They are now ready for evaluation by IA administration in animal models of OA.

Background: Celecoxib, a cyclooxygenase-2 selective inhibitor non-steroidal anti-inflammatory drugs, is used for the management of short- and long-term pain as well as in other inflammatory conditions. Unfortunately, its chronic use is highly associated with serious abnormal cardiovascular events. The current study was designed to explore the effect of long-term administration of celecoxib on the cardiac tissues of male albino rats. The study also examined the alleged cardioprotective effect of royal jelly., Methods: Thirty, male albino rats were randomly divided into 3 equal groups; 10 each: (1) rats served as the control group and received no drug; (2) rats received celecoxib (50 mg/kg/day, orally), for 30 consecutive days; (3) rats received celecoxib (50 mg/kg/day, orally) plus royal jelly (300 mg/kg/day, orally) for 30 consecutive days. Sera were collected to assay cardiac enzymes and oxidant/antioxidant status. Rats were euthanatized and cardiac tissues were dissected for quantitative estimation of apoptotic genes (Bax) and anti-apoptotic gene (Bcl-2)., Results: Long-term celecoxib administration caused cardiotoxicity in male albino rats as manifested by significant elevation of serum levels of creatine phosphokinase (CPK), creatine kinase-MB (CK-MB), and lactate dehydrogenase (LDH), with ameliorative effects of royal jelly against celecoxib-induced cardiotoxicity as manifested by significantly decrease in serum CPK, CK-MB, and LDH levels. It also showed a significant decrease in the oxidative stress indicator malondialdehyde (MDA) levels and the bax gene. Additionally, it demonstrated significant increases in the bcl-2 gene and superoxide dismutase (SOD) levels, which contribute to its therapeutic effects against celecoxib-induced cardiotoxicity., Conclusion: Long-term celecoxib administration caused cardiotoxicity in male albino rats with protective effect of royal jelly being given together. It could be concluded that royal jelly may prove a useful adjunct in patients being prescribed celecoxib., Trial Registration: Not applicable., (© 2024. The Author(s).)

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.

Background/aim: Osteosarcoma (OS) is a rare malignant tumor with a poor survival rate. Our previous study reported that auranofin (AUR), a thioredoxin reductase inhibitor, suppresses OS pulmonary metastases; however, the local progression of OS is not affected, in vivo. Nonetheless, the development of augmentation therapy with AUR to inhibit OS local progression remains challenging. Celecoxib (CE), an anti-inflammatory drug, potently enhances the therapeutic activity of AUR against colon cancer. Consequently, this study investigated the combined effects of AUR and CE on OS local progression and pulmonary metastases, in vivo., Materials and Methods: C3H/HeSlc mice were implanted with the murine OS cell line, LM8. The mice were treated either with a vehicle control, AUR, or combination of AUR and CE (AUR-CE). The primary tumor size and weight were evaluated for the study duration and at resection, respectively. Hematoxylin and eosin and Ki-67 staining were performed to evaluate OS local progression and pulmonary metastases., Results: Mice in the AUR-CE group showed statistically significantly suppressed tumor sizes and weights at the time of excision compared with those in the vehicle. The mice in the AUR group did not show a statistically significant effect. Histopathological analysis of the primary tumor revealed a statistically significant decrease of the Ki-67-positive cells in the AUR-CE group compared with the vehicle group. Histopathological and quantitative analyses demonstrated that the AUR and AUR-CE groups had statistically significant reductions in the development of OS pulmonary metastases compared with the vehicle group., Conclusion: The combination of AUR and CE significantly inhibited OS local progression and pulmonary metastases., (Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Objective: Endometriosis is an estrogen-dependent chronic inflammatory disease in women of reproductive age. A review of the literature revealed that cytokines and inflammatory factors are associated with endometriosis-associated infertility. Interleukin 33 (IL-33) is a strong inducer of other pro-inflammatory cytokines. Vascular cell adhesion molecule-1 (VCAM-1) plays a central role in recruiting inflammatory cells, whose expression facilitates leukocyte adhesion and is rapidly induced by pro-inflammatory cytokines. Many studies have indicated that VCAM-1 expression is high in endometriosis; however, whether the expression of VCAM-1 is related to IL-33 is unclear., Materials and Methods: Human ovarian endometriotic stromal cells (hOVEN-SCs) were treated with IL-33 to enable investigation of cell characterization, gene and protein expression, and signal pathways. Proliferation potential was measured using an MTT assay. Gene expression was analyzed using reverse transcription-polymerase chain reaction. Protein expression assay was performed using western blot analysis., Results: This study investigated the effects of IL-33 on VCAM-1 and COX-2 expression in hOVEN-SCs. First, the results revealed that the IL-33/ST2/mitogen-activated protein kinase (MAPK) signaling pathway could increase the expression of VCAM-1 and COX-2 in hOVEN-SCs. Second, we discovered that COX-2 expression was essential for IL-33-induced VCAM-1 expression because the effects could be negated through NS398, a selective COX-2 inhibitor. Finally, treatment of IL-33-treated hOVEN-SCs with celecoxib significantly and dose-responsively decreased VCAM-1 expression., Conclusion: Taken together, these results indicate that IL-33 can upregulate VCAM-1 expression in hOVEN-SCs through the IL-33/ST2/MAPK/COX-2 signaling pathway and thereby contribute to endometriosis., Competing Interests: Conflict of interest The authors have no conflicts of interest relevant to this article., (Copyright © 2024. Published by Elsevier B.V.)

Matrix metalloproteinases (MMPs) are proteolytic enzymes that play a role in healing, including reducing inflammation, promoting fibroblast and keratinocyte migration, and modifying scar tissue. Due to their pleiotropic functions in the wound-healing process in diabetic wounds, MMPs constitute a significant cause of delayed wound closure. COX-2 inhibitors are proven to inhibit inflammation. The present study aims to repurpose celecoxib against MMP-2, MMP-8 and MMP-9 through in silico approaches, such as molecular docking, molecular dynamics, and MMPB/SA analysis. We considered five selective COX-2 inhibitors (celecoxib, etoricoxib, lumiracoxib, rofecoxib and valdecoxib) for our study against MMPs. Based on molecular docking study and hydrogen bonding pattern, celecoxib in complex with three MMPs was further analyzed using 1 µs (1000 ns) molecular dynamics simulation and MMPB/SA techniques. These studies identified that celecoxib exhibited significant binding affinity -8.8, -7.9 and -8.3 kcal/mol, respectively, against MMP-2, MMP-8 and MMP-9. Celecoxib formed hydrogen bonding and hydrophobic (π-π) interactions with crucial substrate pocket amino acids, which may be accountable for their inhibitory nature. The MMPB/SA studies showed that electrostatic and van der Waal energy terms favoured the total free binding energy component, while polar solvation terms were highly disfavored. The in silico analysis of the secondary structures showed that the celecoxib binding conformation maintains relatively stable along the simulation trajectories. These findings provide some key clues regarding the accommodation of celecoxib in the substrate binding S1' pocket and also provide structural insights and challenges in repurposing drugs as new MMP inhibitors with anti-inflammatory and anti-inflammatory wound-healing properties.Communicated by Ramaswamy H. Sarma.

Background: Many urothelial bladder carcinoma (UBC) patients don't respond to immune checkpoint blockade (ICB) therapy, possibly due to tumor-associated neutrophils (TANs) suppressing lymphocyte immune response., Methods: We conducted a meta-analysis on the predictive value of neutrophil-lymphocyte ratio (NLR) in ICB response and investigated TANs' role in UBC. We used RNA-sequencing, HALO spatial analysis, single-cell RNA-sequencing, and flow cytometry to study the impacts of TANs and prostaglandin E2 (PGE2) on IDO1 expression. Animal experiments evaluated celecoxib's efficacy in targeting PGE2 synthesis., Results: Our analysis showed that higher TAN infiltration predicted worse outcomes in UBC patients receiving ICB therapy. Our research revealed that TANs promote IDO1 expression in cancer cells, resulting in immunosuppression. We also found that PGE2 synthesized by COX-2 in neutrophils played a key role in upregulating IDO1 in cancer cells. Animal experiments showed that targeting PGE2 synthesis in neutrophils with celecoxib enhanced the efficacy of ICB treatment., Conclusions: TAN-secreted PGE2 upregulates IDO1, dampening T cell function in UBC. Celecoxib targeting of PGE2 synthesis represents a promising approach to enhance ICB efficacy in UBC., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

In this study, a series of rhodanine derivatives containing 5-aryloxypyrazole moiety were identified as potential agents with anti-inflammatory and anticancer properties. Most of the synthesized compounds demonstrated anti-inflammatory and anticancer activity. Notably, compound 7 g (94.1 %) exhibited significant anti-inflammatory activity compared with the reference drugs celecoxib (52.5 %) and hydrocortisone (79.4 %). Compound 7 g, at various concentrations, effectively inhibited nitric oxide (NO) production in a dose-dependent manner. Western blot results showed that compound 7 g could prevents LPS-induced expression of inflammatory mediators in macrophages. Enzyme-linked immunosorbent assay (ELISA) assay suggested that 7 g is a promising compound capable of blocking the downstream signaling of COX-2. In summary, these findings indicate that compound 7 g could be a promising candidate for further investigation., (© 2024 Wiley-VHCA AG, Zurich, Switzerland.)

Rheumatoid arthritis (RA) is a chronic disease characterized by joint inflammation and severe disability. However, there is a lack of safe and effective drugs for treating RA. In our previous study, we discovered that myricetin (MC) and celecoxib have a synergistic effect in the treatment of RA. We conducted in vitro and in vivo experiments to further investigate the effects and mechanisms of action of MC. Our findings demonstrated that MC treatment effectively reduced the release of neutrophil extracellular traps (NETs) and alleviated the inflammatory response in RA. Mechanistic studies showed that MC prevents the entry of PADI4 and MPO into the cell nucleus, thereby protecting DNA from decondensation. In a rat arthritis model, MC improved histological changes in ankle joints and suppressed NET-related signaling factors. In conclusion, MC protects the ankle joints against arthritis by inhibiting MPO and PADI4, thereby reducing NET release. The pharmacological mechanism of MC in RA involves the inhibition of NET release., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Context: Celecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, has been shown to exhibit anti-depressive effects in clinical trials. However, the direct mechanism underlying its effect on neuroinflammation remains unclear. Neuroinflammatory reaction from astrocytes leads to depression, and our previous study found that gap junction disorder between astrocytes aggravated neuroinflammatory reaction in depressed mice., Objective: To investigate the potential mechanism of celecoxib's effects on astrocytic gap junctions during the central nervous inflammation-induced depression., Materials & Methods: Stereotaxic injection of lipopolysaccharide (LPS) into the prefrontal cortex (PFC) to establish a model of major depressive disorder (MDD). Celecoxib was administrated into PFC 15 min after LPS injection. The depressive performance was tested by tail suspension test and forced swimming test, and the levels of proinflammation cytokines were determined at mRNA and protein levels. Resting-state functional connection (rsFC) was employed to assess changes in the default mode network (DMN). Additionally, astrocytic gap junctions were also determined by lucifer yellow (LY) diffusion and transmission electron microscope (TEM), and the expression of connexin 43 (Cx43) was measured by western blotting, quantitative polymerase chain reaction, and immunofluorescence., Results: LPS injection induced significant depressive performance, which was ameliorated by celecoxib treatment. Celecoxib also improved rsFC in the DMN. Furthermore, celecoxib improved astrocytic gap junctions as evidenced by increased LY diffusion, shortened gap junction width, and normalized levels of phosphorylated Cx43. Celecoxib also blocked the phosphorylation of p65, and inhibition of p65 abolished the improvement of Cx43., Discussion & Conclusion: Anti-depressive effects of celecoxib are mediated, at least in part, by the inhibition of nuclear factor- kappa B (NF-κB) and the subsequent improvement of astrocytic gap junction function., Competing Interests: Declaration of Competing Interest The authors declare that there are no competing interests to declare., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

In our previous study, we reported that 2, 5-dimethyl-celecoxib (DM-C), a derivative of celecoxib, prevents cardiac remodeling in different mouse models of heart failure, including myocardial infarction (MI). The inflammatory response after MI affects the progression of cardiac remodeling, wherein the immune cells, mainly macrophages, play crucial roles. Therefore, we evaluated the effect of DM-C on macrophages in a cryoinjury-induced myocardial infarction (CMI) mouse model. We observed that DM-C attenuated the deterioration of left ventricular ejection fraction and cardiac fibrosis 14 d after CMI. Gene expression of pro-inflammatory cytokines at the infarct site was reduced by DM-C treatment. Analysis of macrophage surface antigens revealed that DM-C induced transient accumulation of macrophages at the infarct site without affecting their polarization. In vitro experiments using peritoneal monocytes/macrophages revealed that DM-C did not directly increase the phagocytic ability of the macrophages but increased their number, thereby upregulating the clearance capacity. Moreover, DM-C rapidly excluded the cells expressing necrotic cell marker from the infarct site. These results suggested that DM-C enhanced the clearance capacity of macrophages by transiently increasing their number at the infarct site, and terminated the escape from the inflammatory phase earlier, thereby suppressing excessive cardiac remodeling and ameliorating cardiac dysfunction., Competing Interests: Declaration of competing interest The authors declare that they have no competing financial interests or personal relationships that may have influenced the work reported in this study., (Copyright © 2024 The Authors. Production and hosting by Elsevier B.V. All rights reserved.)

Background: Splenomegaly can exacerbate liver cirrhosis and portal hypertension. We have previously demonstrated that cyclooxygenase-2 (COX-2) inhibitor can attenuate cirrhotic splenomegaly. However, the mechanism of cirrhotic splenomegaly remains unclear, thus becoming the focus of the present study., Materials and Methods: Thioacetamide (TAA) intraperitoneal injection was used to induce cirrhotic splenomegaly. Rats were randomized into the control, TAA and TAA + celecoxib groups. Histological analysis and high-throughput RNA sequencing of the spleen were conducted. Splenic collagen III, α-SMA, Ki-67, and VEGF were quantified., Results: A total of 1461 differentially expressed genes (DEGs) were identified in the spleens of the TAA group compared to the control group. The immune response and immune cell activation might be the major signaling pathways involved in the pathogenesis of cirrhotic splenomegaly. With its immunoregulatory effect, celecoxib presents to ameliorate cirrhotic splenomegaly and liver cirrhosis. Furthermore, 304 coexisting DEGs were obtained between TAA vs. control and TAA + celecoxib vs. TAA. Gene ontology (GO) and KEGG analyses collectively indicated that celecoxib may attenuate cirrhotic splenomegaly through the suppression of splenic immune cell proliferation, inflammation, immune regulation, and fibrogenesis. The impacts on these factors were subsequently validated by the decreased splenic Ki-67-positive cells, macrophages, fibrotic areas, and mRNA levels of collagen III and α-SMA., Conclusions: Celecoxib attenuates cirrhotic splenomegaly by inhibiting splenic immune cell proliferation, inflammation, and fibrogenesis. The current study sheds light on the therapeutic strategy of liver cirrhosis by targeting splenic abnormalities and provides COX-2 inhibitors as a novel medical treatment for cirrhotic splenomegaly.

Objectives: NSAIDs, like celecoxib, are widely used to treat pain, fever, and inflammation, with celecoxib being particularly effective in managing arthritis symptoms and acute or chronic pain especially with its favorable gastrointestinal tolerability. The study aimed at exploring the effect of chronic administration of celecoxib on hepatic tissues in male albino rats. It also examined the royal jelly celecoxib interplay., Methods: 50 male albino rats in 5 equal groups; Group 1: received no drug. Group 2: received celecoxib (50 mg/kg/day, orally), for 30 successive days. Group 3: received celecoxib plus royal jelly (300 mg/kg/day, orally) for 30 successive days. Group 4: received celecoxib, for 30 days, then were left untreated for another 30 days. Group 5: received celecoxib plus royal jelly for 30 days, then were left untreated for another 30 days., Results: Chronic celecoxib administration caused hepatotoxicity in male albino rats, with ameliorative effect of royal jelly. Celecoxib discontinuation significantly diminished the celecoxib-induced toxicity, and normal liver enzymes and serum protein levels were regained in the case of dual medications (celecoxib+RJ) discontinuation., Conclusions: Long-term celecoxib administration caused hepatotoxicity, with ameliorative effects of royal jelly against celecoxib-induced oxidative and apoptotic stress. In addition, it could be concluded that royal jelly may prove a useful adjunct in patients being prescribed celecoxib., (© 2024 Walter de Gruyter GmbH, Berlin/Boston.)