Cyclooxygenase Inhibitor Research Articles

Acetaminophen as a possible treatment option for pachydermoperiostosis carrying mutated SLCO2A1: Case series.

Pachydermoperiostosis (PDP) is a genetic disease characterized by digital clubbing, periostosis, and pachydermia. PDP with these three features, along with cutis verticis gyrata (CVG), is categorized as the "complete form," whereas cases without CVG are categorized as the "incomplete form." The condition is linked to elevated levels of systemic prostaglandin E2 (PGE2). About half of PDP patients experience arthralgia. The standard treatment for PDP is selective cyclooxygenase (COX)-2 inhibitors, but long-term usage can cause gastrointestinal side effects. Additionally, mutations in the SLCO2A1 can lead to chronic enteropathy associated with the SLCO2A1 gene (CEAS), making the use of selective COX-2 inhibitors particularly risky for PDP patients with CEAS. This has prompted the search for alternative treatments. In this study, five PDP patients-three with the complete form and two with the incomplete form-were treated with acetaminophen. The PGE-major urinary metabolite (PGE-MUM) was monitored as a biomarker of disease activity, reflecting systemic PGE2 levels. Before treatment, PGE-MUM levels were significantly elevated in patients with complete form and mildly elevated in those with incomplete form. Following acetaminophen, PGE-MUM levels decreased in patients with complete form, and all patients reported improvement in arthralgia without developing gastrointestinal symptoms. In conclusion, acetaminophen shows promise as an alternative treatment for PDP, effectively reducing PGE-MUM levels in certain patients and alleviating arthralgia while avoiding the gastrointestinal side effects associated with long-term COX-2 inhibitor usage.

Therapeutic potential of traditional herbal plants and their polyphenols in alleviation of mercury toxicity.

Mercury (Hg) is a major environmental contaminant significantly impacting human health. As a naturally occurring element, mercury has been extensively mobilized into aquatic and terrestrial ecosystems over thousands of years, largely due to anthropogenic activities such as mining and metal extraction. Acute mercury toxicity causes extensive physiological damage, affecting vital organs including the kidneys, heart, liver, brain, and skin. Phytochemicals, known for their diverse pharmacological properties, have shown promise in mitigating metal-induced toxicities, including mercury. These compounds exhibit protective effects against mercury-induced multi-organ damage through mechanisms such as reactive oxygen species (ROS) scavenging, cyclooxygenase (COX) inhibition, and anti-inflammatory activity. This review explores the therapeutic potential of traditional herbal plants and their phytoconstituents in alleviating mercury-induced toxicity. Key findings highlight several plants with hepatoprotective effects, mitigating necrosis and anatomical distortion in liver cells. Phytochemicals such as quercetin, rutin, salicylic acid, ferulic acid, 6-gingerol, and 6-shogaol play pivotal roles in downregulating molecular pathways activated by mercury exposure. Other bioactive compounds, including acetogenin and gallic acid, exhibit potent antioxidant properties, with mechanisms such as ROS scavenging and inhibition of lipid peroxidation. This review also highlights certain compounds, such as aloe-emodin and gentisic acid, which exhibit potential for mitigating mercury toxicity through mechanisms like inhibiting oxidative stress and enhancing cellular defense pathways. However, these compounds remain underexplored, with no significant studies conducted to evaluate their efficacy against mercury-induced toxicity, presenting a critical area for future research. These findings underscore the potential of phytochemicals as effective agents in combating mercury toxicity through antioxidant mechanisms, cellular signalling regulation, and heavy metal chelation.

Intravenously Administered Nonsteroidal Anti-Inflammatory Drugs in Clinical Practice: A Narrative Review

Intravenously administered nonsteroidal anti-inflammatory drugs (NSAIDs) constitute a crucial component of multimodal analgesia strategies in surgical settings. This narrative review aims to provide an up-to-date evaluation of the efficacy, safety, and clinical use of intravenous (IV) NSAIDs for perioperative pain management in adults and children. The NSAIDs and selective COX-2 inhibitors (coxibs) approved in Europe for the short-term symptomatic treatment of acute, moderate perioperative pain via IV infusion in adults and/or children have been influenced by US and global guidelines and practice: the drugs primarily reviewed here are ibuprofen, ketorolac, ketoprofen, naproxen, paracetamol, and acetylsalicylic acid. Furthermore, intravenous ibuprofen is authorized for the short-term symptomatic treatment of fever. In contrast to intravenous ketoprofen, intravenous ibuprofen is authorized for administration to children over 6 years of age or weighing more than 20 kg. Overall, IV ibuprofen had a more favorable profile with regard to peri- and postoperative opioid sparing and pain relief. Oral ibuprofen and IV ibuprofen have similar levels of efficacy, although IV ibuprofen has a shorter onset of action and is required in patients who are unable to take oral medications. The frequency of significant adverse events appears to be similar for ibuprofen and paracetamol. Systematic reviews and meta-analyses report that intravenous NSAIDs reduce postoperative opioid consumption by approximately 20–60%, improving pain management with fewer opioid-related side effects. In indications in infants, the choice of medication is limited, and the oral route is not always feasible; IV formulations of ibuprofen are preferred in this setting. Topics for further research should include head-to-head trials of IV NSAIDs.

Combined Endocannabinoid and Cyclooxygenase Inhibition Additively Attenuates Post-Surgical Pain.

Introduction: Post-surgical pain arises following a clinical operation, often persisting throughout recovery. While current treatments reduce pain, repeated use increases the probability of adverse events. monoacylglycerol lipase (MAGL) inhibition has previously been shown to produce analgesia, either through CB1 or CB2 mechanisms, dependent on the underlying pain phenotype. Thus, this study investigated the analgesic potential of inhibiting MAGL, alone and in combination with the analgesic non-steroidal anti-inflammatory drug (NSAID) diclofenac sodium in a model of post-surgical pain. Methods: Male and female C57BL/6J mice were subjected to hindpaw incision (HPI) surgery. Mechanical allodynia, climbing, grip strength, and thermal preference were measured 24 h following HPI. The dose-dependent anti-allodynic effects of the MAGL inhibitors (irreversible MAGL inhibitor [JZL184] and selective MAGL inhibitor [MJN110]) and the NSAID diclofenac, as well as the additive potential of combined MAGL and cyclooxygenase (COX) inhibition, were assessed. Selective antagonists of CB1 and CB2 receptors were used to challenge the cannabinoid-receptor mechanism of JZL184. Similarly, the anti-allodynic effects of the CB2-selective agonist (LY2828360) were tested. JZL184 was administered repeatedly to determine tolerance. Finally, hindpaw cytokines were quantified via multiplex ELISA 24 h after HPI surgery. Results: Approximately 24 h post-surgery, the MAGL inhibitors JZL184 (≥4 mg/kg) or MJN110 (≥5 mg/kg), as well as the NSAID diclofenac sodium (≥16.67 mg/kg), attenuated HPI-induced mechanical allodynia, as assessed with von Frey filaments. The anti-allodynic effects of JZL184 (40 mg/kg) were blocked by pre-treatment of the CB2 antagonist SR144528 (3 mg/kg) but not the CB1-selective antagonist rimonabant (SR141716A; 3 mg/kg), suggesting a CB2-mediated mechanism of anti-allodynia via MAGL inhibition. Similarly, LY2828360 (3 mg/kg) reduced HPI-induced allodynia. Moreover, when administered repeatedly, the anti-allodynic effects of JZL184 (8 mg/kg) persisted and did not undergo tolerance. A separate cohort was administered a sub-analgesic dose of JZL184 (1 mg/kg), diclofenac sodium (1.85 mg/kg), or both compounds concurrently. This subthreshold JZL184 and diclofenac sodium combination attenuated HPI-induced allodynia, suggesting an additive drug interaction. Finally, HPI per se increased pro-inflammatory cytokine levels, which were unaltered by MAGL inhibition despite the anti-allodynia assessed behaviorally. Conclusion: These data support simultaneously targeting endocannabinoids and COX enzymes as a potential post-operative pain management approach.

How can you manage an indomethacin-responsive headache in someone who cannot take indomethacin?

Paroxysmal hemicrania and hemicrania continua are rare primary headache disorders which are distinguished by an absolute response to indomethacin. As a matter of importance, no guidelines have been proposed for alternative therapeutic options in case of indomethacin intolerance. The purpose of this review is to provide an update on the current findings, especially focusing on the past 18 months, in the treatment of both paroxysmal hemicrania and hemicrania continua and to provide proposed management recommendations based on summarized evidence. Apart from well recognized gastrolesive effects of indomethacin, a substantial number of patients may suffer from neuropsychiatric adverse reactions. Recent studies demonstrated that melatonin, which has been known for its effectiveness for hemicrania continua, is also useful for paroxysmal hemicrania. Promising nonpharmacological treatment option, which is noninvasive vagus nerve stimulation, has been shown to be beneficial for both indomethacin-responsive headache disorders allowing the reduction of indomethacin dosage. Although the data on substitutive medication choice for indomethacin are currently scarce, the most consistent results have been repeatedly achieved with acemethacin, selective COX-2 inhibitors, and anticonvulsants. However, considering the crucial role of pathophysiology, research investigating the efficacy of drugs targeting the trigemino-vascular system activation, as well as controlled trials assessing the efficacy involving the aforementioned therapeutic options are still vague. In spite of numerous reports suggesting reliable alternatives to indomethacin, the consensus on pharmacological therapy guidelines for indomethacin-responsive headache disorders has not yet been reached. Further research and agreement from the experts' standpoint are needed for an establishment of reliable treatment recommendations.

Potential COX-2 inhibitors modulating NF-κB/MAPK signaling pathways: Design, synthesis and evaluation of anti-inflammatory activity of Pterostilbene-carboxylic acid derivatives with an oxime ether moiety

In this work, a series of novel Pterostilbene–oxime ether–carboxylic acid (POC) derivatives (d1–d10, e1–e10 and 1–13) were designed, synthesized, and characterized by spectroscopic techniques. In order to further determine the absolute configuration of these compounds, one of them, compound d3, was investigated by X-ray single crystal diffraction method. d3 had a triclinic crystal with P-1 space group, and its CHCH and CHN was confirmed as E configuration. A strong hydrogen bond was formed between the hydrogen atom in CHCH moiety and the nitrogen atom in CHN moiety, which was a vital factor in the formation and stability of E configuration in the CHCH and CHN. The safety and anti-inflammatory activities of compounds (d1–d10, e1–e10 and 1–13) in vitro were evaluated. At 20 μM, compounds (d1–d10, e1–e10 and 1–13 were non-toxic and exhibited weak to strong inhibitory effects on the LPS-induced NO release. Among them, five compounds (1, 2, 7, 8 and 9) showed excellent anti-inflammatory effects with IC50 (NO) values ranging from 9.87 to 19.78 μM, as well as strong COX-2 inhibitory abilities with IC50 (COX-2) values ranging from 85.44 to 140.88 nM. Moreover, there was a rough positive correlation between their anti-inflammatory properties and the COX-2 inhibitory abilities. Compounds (1, 2, 7, 8 and 9) smoothly docked with COX-2 protein (PDB ID: 5KIR) to form stable complexes with strong hydrogen bonds, with an affinity range of −8.3 to −9.9 kcal/mol. SAR indicated that the amidation of POC at R2 position was more favorable for enhancing the compound’s biological actives than esterification. In addition, the 4-fluobenzyl substitution at R2 position of the oxime ether moiety can obviously enhance the activity of above amide derivates. Introducing acyl groups (CO(CH2)nCH3, n = 2, 4 and 6) into NH(CH2)3OH group to form ester chain is disadvantageous for activity enhancing, moreover, the longer the carbon chain, the poorer the activity. The strongest COX-2 inhibitor (IC50 (COX-2) = 85.44 ± 3.88 nM), compound 7, exerted as anti-inflammatory activities (IC50 (NO) = 9.87 ± 1.38 μM) by down-regulating the expression of COX-2 and iNOS, and modulating NF-κB/MAPK signaling pathways.

Synthesis, anticancer and anti-inflammatory evaluation of novel quinoxaline-1,3,4-oxadiazole derivatives as EGFR and COX-2 inhibitors

Synthesis, anticancer and anti-inflammatory evaluation of novel quinoxaline-1,3,4-oxadiazole derivatives as EGFR and COX-2 inhibitors

The changing landscape of emergency contraception.

NPs play a pivotal role in preventing unintended pregnancies in the US. This article provides a comprehensive update on emergency contraception (EC) trends, emphasizing the persistent challenge of reducing unintended pregnancies-a key health priority in the Healthy People 2030 initiative. Despite a declining trend in unintended pregnancy rates from 2010 to 2019, national goals have not been met, and healthcare disparities persist. NPs should be aware of EC methods and prescribing implications. In addition, NPs should be aware of ongoing research focusing on EC options such as levonorgestrel intrauterine devices and the promising addition of cyclooxygenase-2 inhibitors to oral EC options.

Pomegranate as a natural remedy for gastric ulcers prevention: a review of its gastroprotective mechanisms and pharmacological benefits.

Gastric ulcers (GUs) represent a common gastrointestinal disorder characterized by mucosal damage and inflammation, often precipitated by factors such as Helicobacter pylori infection and the consumption of COX inhibitors. This comprehensive review investigates the role of oxidative stress and inflammation in the pathogenesis of GUs and assesses the potential therapeutic effects of Punica granatum (pomegranate, Pg) supplementation. Utilizing a series of experimental models, including indomethacin, aspirin, and alcohol-induced ulcers, we demonstrate that Pg extracts possess significant gastroprotective properties. The antioxidant activity of Pg is ascribed to its capacity to neutralize reactive oxygen species (ROS), enhance the activity of endogenous antioxidants such as superoxide dismutase (SOD) and catalase (CAT), and diminish lipid peroxidation. Furthermore, the anti-inflammatory effects of Pg are mediated through the suppression of pro-inflammatory cytokines such as TNF-α and IL-1β, in conjunction with the promotion of gastric mucosal protective agents. Histological analyses indicate that Pg extract preserves the architecture of gastric tissue and alleviates ulcer severity. These findings highlight the potential of Pg as a natural remedy for GUs, thereby necessitating further investigation into its mechanisms of action and optimal therapeutic formulations.

Exploration of novel isoniazid embedded 1,3,4-oxadiazole hybrids as anti-TB, antioxidant, and COX inhibitors: synthesis, spectral analysis, and molecular modeling studies

Exploration of novel isoniazid embedded 1,3,4-oxadiazole hybrids as anti-TB, antioxidant, and COX inhibitors: synthesis, spectral analysis, and molecular modeling studies

Chemoprevention Strategies for Precancerous Gastric Lesions Beyond Helicobacter pylori Eradication.

Gastric cancer (GC) is a significant global health challenge, particularly in high-incidence regions like East Asia. Despite improvements in screening and treatment, the progressive nature of precancerous lesions-such as atrophic gastritis, intestinal metaplasia, and dysplasia-necessitates effective prevention strategies. This review evaluates the role of chemoprevention in GC, focusing on agents designed to target these precancerous lesions. The interventions examined include nonsteroidal anti-inflammatory drugs (NSAIDs), COX-2 inhibitors, antioxidants, vitamins, folic acid, bioactive compounds, traditional herbal medicines, and emerging agents like metformin. Additionally, the potential of oxygen radical scavengers, anti-inflammatory agents, and pathway-specific inhibitors is explored. While promising, the clinical effectiveness of these agents varies, and significant challenges remain in translating preclinical successes into clinical practice. Large-scale clinical trials are essential to validate these strategies and determine their role in GC prevention, particularly for high-risk populations. Integrating chemoprevention with existing GC management protocols may offer a more comprehensive approach to reducing GC incidence and improving outcomes.

Environmentally Friendly Green O-Alkylation Reaction for Ethenzamide Synthesis

Ethenzamide (2-ethoxybenzamide), besides acetylsalicylic acid, is one of the mostly used salicylic acid derivatives in pharmaceuticals. It has analgesic and anti-inflammatory effects that originate from the inhibition of cyclooxygenase (COX-1) activity, thus blocking prostaglandin synthesis. In this work, efficient and eco-friendly methods were developed for the synthesis of ethenzamide via the O-alkylation reaction of salicylamide. The reactions were carried out under conventional conditions in a solvent-free system using variant solvents and different phase transfer catalysts (PTC) in the presence of microwave radiation or ultrasonic conditions. It was shown that in solvent-free conditions using TBAB as a catalyst, ethenzamide can be obtained within 15 min at 80 °C with 79% yield. Meanwhile, using microwave radiation under the same conditions, the reaction time can be shortened to 90 s with 92% yield. Notably, high yields can be achieved under PTC in water (or organic solvent-free) conditions using microwave radiation (2 min, 94%) or ultrasound (10 min, 95% efficiency). The studies prove that the PTC synthesis process of ethenzamide can be conducted under mild conditions, with a shorter reaction time and remarkably lower energy consumption in comparison to conventional processes, thus actualizing “green chemistry” for practical ethenzamide preparation.

Navigating the Double- Edged Sword of Diclofenac: Pain Relief and Associated Cardiovascular Safety

Diclofenac sodium (DFS) is a widely prescribed nonsteroidal anti-inflammatory drug (NSAID) effective in managing pain and inflammation in patients with arthritis and musculoskeletal conditions. While DFS is known for its rapid analgesic effects and broad therapeutic indications, it also poses significant cardiovascular (CV) safety concerns. Research highlights that prolonged or high-dose use of diclofenac increases the risk of myocardial infarction, stroke, and thrombotic events. Despite clinical guidelines discouraging its use in patients with heart conditions, a large percentage of individuals continue its use after hospital discharge. This review explores the dual nature of diclofenac’s benefits for pain relief and its associated cardiovascular risks, discussing pharmacokinetics, therapeutic indications, adverse effects, and regulatory recommendations. Key words: Diclofenac, Nonsteroidal Anti-inflammatory Drugs (NSAIDs), Cardiovascular Risk, Pain Relief, COX-1 and COX-2 Inhibition, Myocardial Infarction, Prostaglandins, Thrombosis, Atherosclerosis

The role of cyclooxygenase-2 (COX-2) and inflammatory markers in the progress of Alport syndrome in Egyptian children

BackgroundChronic inflammation and its control are crucial to the responses of glomerular and renal tubular cells. This contributes to the pathogenic mechanisms and advancement of the disease in Alport syndrome. The study aimed to elucidate the role of cyclooxygenase-2, Interleukin 4, Plasminogen activating inhibitor 1, and Prostaglandin E2 in the development and course of Alport syndrome.MethodsIn our study inflammatory markers were evaluated in 26 Alport syndrome patients, 15 males and 11 females and 24 controls.ResultsTheir age ranged from 4 to 16 years (mean ± SD was 8.50 ± 2.877) and 24 were normal controls matching age and sex. The serum levels of cyclooxygenase-2, Prostaglandin E2, Interleukin 4, and Plasminogen activating inhibitor 1 were evaluated in all patients. The serum level of cyclooxygenase-2, Prostaglandin E2, Interleukin 4, and Plasminogen activating inhibitor 1 were all increased significantly in the Alport syndrome patients compared to control (588.68 ± 73.08, 42.57 ± 4.18, 42.32 ± 3.49, and 846.47 ± 45.433, respectively versus controls (369.12 ± 50.28, 25.52 ± 4.98, 28.89 ± 3.19, and 312.79 ± 40.53 respectively).ConclusionThe role of inflammatory markers cyclooxygenase-2, Prostaglandin E2, Interleukin 4, and Plasminogen activating inhibitor 1 in Alport syndrome that are causally connected and have a role in the development and course of Alport disease was delineated. This may highlight and speculate an innovative strategy for targeting the creation of safe and efficient anti-inflammatory treatments to inhibit disease progression in Alport syndrome.

Effects of Salmonella Typhimurium infection on intestinal flora and intestinal tissue arachidonic acid metabolism in Wenchang chickens

Salmonella infections can lead to intestinal inflammation and metabolic disorders in birds. However, whether arachidonic acid (ARA) metabolism is involved in Salmonella-induced intestinal inflammation remains unclear. This experiment investigated the changes in cecal flora and ARA metabolism in Hainan Wenchang chickens infected with S. Typhimurium using 16s rDNA sequencing and targeted metabolomics. The results showed that the levels of ARA metabolites were increased in the cecum tissue of Wenchang chickens after infection with S. Typhimurium, including prostaglandin E2 (PGE2), prostaglandin F2α (PGF2α), lipoxin A4 (LXA4), ± 8(9)-EET, ± 11(12)-EET, and ± 8,9-DiHETrE. The content of key enzymes for ARA production and metabolism (Phospholipase A2 PLA2 and Cyclooxygenase-2 COX-2) in chicken cecum tissues was increased after S. Typhimurium infection. The relative mRNA levels of inflammatory factors were also increased after infection, including Interferon-γ (IFN-γ), Transforming growth factor-β1 (TGF-β1), Interleukin-4 (IL-4), and Interleukin-6 (IL-6). In HD11 cells, the use of a cyclooxygenase (COX) inhibitor reduced the increased levels of COX-2 and PGF2α induced by S. Typhimurium infection and effectively reduced the inflammatory response. In addition, the number of beneficial genera (e.g., Bifidobacterium, Lactobacillus, and Odorobacterium) in the cecum of Wenchang chickens was significantly reduced after infection with S. Typhimurium. The present study revealed the structure of cecal flora in S. Typhimurium-infected Wenchang chickens. In addition, this study demonstrated that S. Typhimurium activates the ARA cyclooxygenase metabolic pathway, which in turn mediates the development of intestinal inflammation in Wenchang chickens. The results can provide data support and theoretical support for the prevention and control of avian salmonellosis.

Indobufen versus aspirin in patients with indication for antiplatelet therapy: A systematic review and meta-analysis.

Aspirin is commonly recommended for individuals who have experienced stroke or myocardial infarction (MI). Indobufen, a cyclooxygenase-1 inhibitor, has been studied as a potential alternative. We conducted a meta-analysis and trial sequential analysis (TSA) to compare indobufen with aspirin in patients requiring antiplatelet therapy. We searched PubMed, Scopus, and Cochrane Central for studies that compared indobufen and aspirin antiplatelet therapies. We focused on efficacy outcomes, such as composite vascular events, MI, and ischemic stroke, and safety outcomes, such as major bleeding and any bleeding. Heterogeneity was assessed using I2 statistics, and our analysis followed the PRISMA guidelines. The review included 5 studies with 11,943 patients (indobufen n = 5952 49.84 %), three involving post-MI and two involving post-stroke patients. No significant differences were found between the groups in composite vascular events at 90 days (RR 0.84; 95 % CI 0.46-1.53; p = 0.560; I2 = 53 %) and 1-year (RR 1.13; 95 % CI 0.99-1.29; p = 0.08; I2 = 0 %). MI (RR 0.73; 95 % CI 0.43-1.22; p = 0.22; I2 = 0 %), ischemic stroke (RR 1.16; 95 % CI 0.99-1.37; p = 0.06; I2 = 0 %), and cardiovascular death (RR 1.35; 95 % CI 0.80-2.26; p = 0.257; I2 = 0 %) at 1-year also showed no significant differences. Major bleeding at 1 year (RR 0.73; 95 % CI 0.41-1.31; p = 0.297; I2 = 64 %) was comparable, but any bleeding at 1 year showed a significant difference (RR 0.65; 95 % CI 0.43-0.98; p = 0.03; I2 = 87 %) favoring indobufen. Subgroup analysis of RCTs showed marginally significant increased risk regarding ischemic stroke with indobufen (RR 1.18; 95 % CI 1.00-1.39; p = 0.05). The efficacy and safety of antiplatelet therapy with indobufen were comparable to those of aspirin alone. Therefore, indobufen can be considered as a suitable alternative for patients who are intolerant or hypersensitive to aspirin. Nevertheless, additional trials involving larger populations are required to establish their clinical applicability.

PET Quantification in Healthy Humans of Cyclooxygenase-2, a Potential Biomarker of Neuroinflammation.

Cyclooxygenase-2 (COX-2) is present in a healthy brain at low densities but can be markedly upregulated by excitatory input and by inflammogens. This study evaluated the sensitivity of the PET radioligand [11C]-6-methoxy-2-(4-(methylsulfonyl)phenyl)-N-(thiophen-2-ylmethyl)pyrimidin-4-amine ([11C]MC1) to detect COX-2 density in a healthy human brain. Methods: The specificity of [11C]MC1 was confirmed using lipopolysaccharide-injected rats and transgenic mice expressing the human COX-2 gene, with 120-min baseline and blocked scans using COX-1 and COX-2 selective agents. Twenty-seven healthy participants were injected with [11C]MC1. Ten of these participants received 2 PET scans: a baseline study followed by blockade with celecoxib (600 mg orally), a preferential COX-2 inhibitor. Seventeen participants underwent test-retest imaging. All scans included concurrent arterial sampling. The tissue-to-plasma ratio at equilibrium (i.e., total distribution volume) was determined using a 2-tissue compartment model (2TCM). Results: In humanized transgenic COX-2 mice, 70%-90% of [11C]MC1 brain uptake was blocked by nonradioactive MC1 and celecoxib (a COX-2 selective inhibitor) but not by PS13 (a COX-1 selective inhibitor), thereby confirming specific binding to human COX-2. Radioactivity in the human brain peaked at a concentration of about 4.0 SUV, indicating good passage through the blood-brain barrier. Values for the total distribution volume achieved stability after 80 min, indicating no radiometabolite contamination. Celecoxib reduced radioligand binding in neocortical areas by 25% but had little or no effect in subcortical regions and the cerebellum, which correlated with COX-2 messenger RNA expression levels. Binding site occupancy by celecoxib was virtually complete, as determined by the Lassen plots. Test-retest reliability was moderate (intraclass correlation coefficient, 0.65) but had relatively large variability (absolute retest variability, 20%). Reference tissue methods yielded results comparable to those of 2TCM but reduced retest variability by up to 75% and reduced intersubject variability (coefficient of variation) by about half. Thus, compared with 2TCM, which requires arterial blood, the reference tissue method is expected to significantly reduce the sample sizes required to detect statistically significant differences between groups. Conclusion: [11C]MC1 has adequate sensitivity to measure the low density of COX-2 in a healthy human brain, suggesting it can also quantify the COX-2 elevations expected in human disorders associated with neuroinflammation.

Effect of perioperative analgesia on immunity in lung cancer.

COX inhibitors are frequently used for pain management during the perioperative period and may influence tumor progression and the tumor microenvironment by modulating inflammation and immune responses. This study investigates the effects of COX inhibitors on tumor growth and the immune microenvironment. In vivo experiments demonstrate that COX inhibitors can reduce tumor cell growth, elevate PD-L1 expression on tumor cells, and enhance the proportion of myeloid cells within the tumor immune microenvironment. Furthermore, COX inhibitors are found to improve the efficacy of the immune checkpoint inhibitor anti-PD-L1. These results underscore the influence of perioperative COX inhibitors on tumor immunity and suggest potential new strategies for optimizing tumor immunotherapy.

Inhibition of PDT-induced PGE2 surge for enhanced photo-immunotherapy.

Nowadays, photodynamic therapy (PDT) offers a non-invasive tumor treatment with high safety profiles and minimal side effects, implying a promising clinical application for patients with malignant tumors. However, the lack of efficacy in metastasis and recurrence still notably limits its application. To solve this problem, one promising strategy is to improve the immune response activated by PDT. Unfortunately, tumor cells derived PGE2 could create immunosuppressive microenvironments and impair the function of multiple immune cells, leading to a failure of immune system activation. Moreover, our research revealed the up-regulation of Ptgs2 in tumor cells after the PDT process, which is associated with a series of pro-tumor effects, including proliferation, invasion, metastasis, apoptotic resistance, and immune evasion. Consequently, controlling the PGE2 surge induced by PDT is crucial for optimizing the efficacy of photo-immunotherapy. Therefore, we combined the regulation of the COX2-PGE2 axis with PDT. The addition of COX inhibitors (COX-Is) could improve the efficiency of PDT, reduce the immunosuppressive effect of PGE2, and help dying tumor cells activate the immune system. Herein, a tumor-targeted nano-delivery platform (FI@T-Lipo) was developed using advanced microfluidic technology. FI@T-Lipo based PDT showed a systemic therapeutic effect in triple negative breast cancer through reclaiming the anti-tumor effect of the immune system under COX2-PGE2 blockage. In a word, we developed an in-situ tumor vaccination strategy based on COX-Is enhanced PDT, which could alleviate intra-tumoral immune suppression and boost immune system activation. Our study offers a promising modality for advancing clinical treatment strategies for metastatic malignant tumors.

Vasoactive properties of hydro-methanol pod powder extract of Acacia nilotica in porcine coronary artery: Role of Nitric Oxide (NO)

Background: Acacia nilotica is a plant used in traditional medicine in Senegal for treatment of high blood pressure. The aim of this study was to determine whether a hydro-methanolic pod powder extract of Acacia nilotica (MSAN01) can induce a relaxant effect in porcine coronary arteries and to elucidate the underlying mechanism. Methods: Porcine coronary artery rings were suspended in organ chambers to record changes in isometric forces. Rings with intact endothelium were incubated with or without L-Nitro Arginine (L-NA, 300 µM) to block NO synthase; 1,12 bis[(2-methylquinolin-4-yl)amino]dodecane (UCL, 100 nM), an inhibitor of small-conductance calcium-activated potassium channels (SKCa); and Tram-34 (1 µM), an inhibitor of intermediate-conductance calcium-activated potassium channels (IKCa); or indomethacin (INDO, 10 µM), a cyclooxygenase inhibitor, before contraction with U46619 (1-60 nM), a thromboxane A2 analogue, and subsequent generation of a concentration-relaxation curve to hydro-methanolic pod powder extract of Acacia nilotica (MSAN01). In some experiments, the endothelium was removed before contraction with U46619 (1-60 nM) and concentration-relaxation with MSAN01. Bradykinin was used to verify the presence of functional endothelium. Results: Exposure The hydro-ethanolic pod powder extract of Acacia nilotica induces a vasodilatory effect in porcine coronary arteries pre-contracted with U46619. This effect is endothelium-dependent and mediated by nitric oxide (NO). Conclusion: It Acacia nilotica induces vascular relaxation, which may explain the beneficial effects of this plant in the treatment of high blood pressure in Africa.