Cyclooxygenase Inhibitor Research Articles

Pyrimidine Derivatives as Selective COX-2 Inhibitors with Anti-Inflammatory and Antioxidant Properties.

Pyrimidine derivatives exhibit a wide range of biological activities, including anti-inflammatory properties. The aim of this study was to investigate the effects of tested pyrimidine derivatives on the activity of cyclooxygenase isoenzymes (COX-1 and COX-2), antioxidant properties, and their ability to inhibit the growth of inflammatory cells. In vitro tests were conducted to assess the ability of pyrimidine derivatives L1-L4 to inhibit COX-1 and COX-2 activity using the TMPD oxidation assay (N,N,N',N'-tetramethyl-p-phenylenediamine). The compounds' ability to inhibit the growth of lipopolysaccharide (LPS)-stimulated THP-1 (human leukemia monocytic) monocyte cells and their impact on reactive oxygen species (ROS) levels in an inflammatory model were also evaluated. The binding properties of human serum albumin (HSA) were assessed using UV-Vis spectroscopy, circular dichroism (CD), and isothermal titration calorimetry (ITC). Among the tested pyrimidine derivatives, L1 and L2 showed high selectivity towards COX-2, outperforming piroxicam and achieving results comparable to meloxicam. In the sulforhodamine B (SRB) assay, L1 and L2 demonstrated dose-dependent inhibition of LPS-stimulated THP-1 cell growth. Additionally, ROS assays indicated that these compounds reduced free radical levels, confirming their antioxidant properties. Binding studies with albumin revealed that L1 and L2 formed stable complexes with HSA. These results suggest that these compounds could serve as a basis for further research into anti-inflammatory and anticancer drugs with reduced toxicity.

Computational exploration of novel ketoprofen derivatives: Molecular dynamics simulations and MM-PBSA calculations for COX-2 inhibition as promising anti-inflammatory drugs

Computer-aided drug design is widely employed to identify novel compounds for therapeutic applications. Ketoprofen (KTP), a commonly used and marketed nonsteroidal anti-inflammatory drug (NSAID), is effective in treating pain, fever, inflammation, and some cancers. In this research, we explored the behavior of six analogues designed by structurally modifying the KTP molecule. Specifically, KTP-A and KTP-B contain a –CN group at the ortho position, KTP-C and KTP-D have a –CN group at the meta position, and KTP-E and KTP-F feature a –CF3 group at the meta position. To assess these analogues, we conducted molecular dynamics simulations (MD) to study their inhibitory effects on human cyclooxygenase 2 (COX-2), providing detailed insights into the structure and dynamics of the protein both with and without ligands. MD simulation, enhanced by technological advances, has proven to be a powerful tool for new drug discovery. We further quantified the binding affinity of these drug molecules toward COX-2 using molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) binding free energy calculations. The dynamic properties were evaluated through analyses of root mean square deviations (RMSD), root mean square fluctuations (RMSF), radius of gyration (Rg), solvent-accessible surface area (SASA), covariance matrix, principal component analysis (PCA), and Gibbs free energy landscapes (FEL). Ultimately, this study confirms that the six KTP derivatives are promising candidates for the treatment of inflammation, with KTP-B standing out as particularly effective.

Anti-oxidant, anti-apoptotic and anti-inflammatory effects of geraniin in spinal cord injury in rat: role of COX-2.

Spinal cord injury (SCI) is devastating diseases affecting the degeneration of the spinal column, and vascular problems. However, the currently available therapeutic interventions are insufficient to address the effect of SCI which leads to significant impact on the morbidity and mortality of patients. In the present manuscript, we intend to investigate the pharmacological effect of geraniin on the SCI in Sprague-Dawley (SD) rats. The SCI in rats were induced by the conventional weight-drop method and treated with GER (2.5, 5, and 10 mg/kg). Subsequently, the locomotor activity of rats with SCI was assessed using Basso, Beattie, and Bresnahan (BBB) scores, while oxidative stress indicators and inflammatory variables were analyzed using commercially available kits. Additionally, neuronal death was quantified using TUNEL labeling. The enzymatic activity of caspase 3, 8, and 9 was also assessed. Furthermore, the expression levels of Bcl2, Bax, and COX-2 in rat spinal cords after SCI were analyzed by RT-PCR analysis. Our research indicated that therapy with GER in a manner that depends on the dosage could enhance the functional recovery, as well as reduce the occurrence of apoptosis, mitigate the inflammatory and oxidative response in rats with SCI. Furthermore, it was observed that GER increased the expression of Bcl2 and decreased the expression of Bax and COX-2. The concentration of caspase-3, -8, and -9 was observed to be decreased in SCI rats treated with GER. GER might protect the spinal cord from SCI by reducing apoptosis, oxidative stress, and inflammatory response through the inhibition of COX-2.

Protective effects of licofelone on scopolamine-induced spatial learning and memory impairment by enhancing parkin-dependent mitophagy and promotion of neural regeneration and in adult mice

Inhibition of COX and LOX could contribute to memory formation and prevention of neurodegeneration, by alleviation of neuroinflammation and improvement of mitochondrial homeostasis. We aimed to assess the effect of licofelone, a dual COX and 5-LOX inhibitor on memory formation, neural apoptosis, neural regeneration, and mitophagy in acute and chronic dosages, given that licofelone could regulate nitric oxide levels. Y-maze and Passive Avoidance tests were used to evaluate memory function in NMRI mice using the EthoVision setting, following scopolamine administration (1 mg/kg, i.p.) as an acute amnestic drug. Hippocampi were used to evaluate the levels of apoptosis via TUNEL assay, neural regeneration via immunohistochemistry method detecting doublecortin and nestin, and mitophagy via Western blot of mitophagy proteins Parkin and ATG5. While acute high-dose licofelone (20 mg/kg) could reverse amnestic effects of scopolamine in passive avoidance test (p = 0.0001), Chronic licofelone (10 mg/kg for 10 consecutive days) could improve performance in Y-maze (p = 0.0007). Molecular analysis revealed that the chronic form of the drug could enhance neural regeneration in CA1 and SGZ regions, reset mitophagy levels as much as the healthy state, and reduce apoptosis rate. Licofelone appears to show a desirable anti-amnestic profile in a low dose chronically; it is hence recommended for future clinical studies on the prevention of neuroinflammation and memory deficit.

Hemin-induced platelet activation is regulated by the ACKR3 chemokine surface receptor and has implications for passivation of vulnerable atherosclerotic plaques.

In vulnerable atherosclerotic plaques, intraplaque hemorrhages (IPH) result in hemolysis of red blood cells and release of hemoglobin and free hemin. Hemin activates platelets and leads to thrombosis. Agonism of the inhibitory platelet receptor ACKR3 inhibits hemin-dependent platelet activation and thrombus formation. To characterize the effect of hemin and ACKR3 agonism on isolated human platelets, multi-color flow cytometry and classical experimental setup such as light transmission aggregometry and a flow chamber assay were used. Hemin induces platelet aggregation and ex vivo platelet-dependent thrombus formation on immobilized collagen under a low shear rate of 500 s-1, indicating that free hemin is a strong activator of platelet-dependent thrombosis. Recently, we described that ACKR3 is a prominent inhibitory receptor of platelet activation. Specific ACKR3 agonists but not conventional antiplatelet compounds such as COX-1 inhibitor (indometacin), ADP-receptor blocker (cangrelor), or PAR1 inhibitor (ML161) inhibit both hemin-dependent aggregation and thrombus formation. To further characterize the effect of hemin on platelet subpopulations, we established a multi-color flow cytometry assay. We found that hemin induces procoagulant (CD42bpos/PAC-1neg/AnnexinVpos), aggregatory (CD42bpos/PAC-1pos/AnnexinVneg), and inflammatory (CD42bpos/CXCR4pos/ACKR3pos/AnnexinVpos) platelet subpopulations. Treatment with ACKR3 agonists significantly decreased the formation of procoagulant and ACKR3pos platelets in response to hemin. We conclude that hemin is a strong activator for the formation of procoagulant platelets and thrombus formation which is dependent on the function of ACKR3. Activation of ACKR3 using specific agonists may offer a therapeutic strategy to regulate the vulnerability of atherosclerotic plaques in areas of IPH.

Pharmacological management of osteoarthritis: judicious use of nonsteroidal anti-inflammatory drugs

Background: Osteoarthritis (OA) is a chronic disease characterized by persistent pain and joint deformation. Effective pain management in patients with OA necessitates accurate diagnosis and appropriate treatment planning, considering the prolonged therapy required for OA. Although non-steroidal anti-inflammatory drugs (NSAIDs) are widely used for pain management in patients with OA, their long-term use can lead to various adverse effects that warrant careful consideration.Current Concepts: NSAIDs inhibit cyclo-oxygenase (COX) enzymes and produce an anti-inflammatory and analgesic effect. However, this mechanism of action can produce adverse gastrointestinal, cardiovascular, and renal effects. The relative risk of gastrointestinal and cardiovascular adverse events depends on the COX selectivity of NSAIDs. Consequently, selective COX-2 inhibitor or concomitant proton pump inhibitor administration is recommended in patients at a high risk of gastrointestinal complications. Minimizing NSAID use is advised in patients at a high risk of cardiovascular adverse events; however, if this is unavoidable, short-term administration of naproxen or low-dose celecoxib should be considered. COX selectivity is not associated with adverse renal events. Therefore, acetaminophen is preferred in patients with impaired renal function, and short-term use of NSAID patches or topical formulations may be useful.Discussion and Conclusion: The choice of NSAIDs for OA should be tailored to patients’ needs, considering their risk factors, potential drug interactions, and other relevant factors. Additionally, incorporation of nonpharmacological interventions can minimize the NSAID dosage and reduce the risk of adverse effects, and regular monitoring is essential to identify adverse effects.

In Vitro Evaluation of Pharmacokinetic Properties of Selected Dual COX-2 and 5-LOX Inhibitors.

Evaluation of pharmacokinetic properties is a significant step at the early stages of drug development. In this study, an in vitro evaluation of the pharmacokinetic properties of five newly synthesized compounds was performed. These compounds belong to N-hydroxyurea and hydroxamic acid derivatives and analogs of NSAIDs indomethacin, flurbiprofen, diclofenac, ibuprofen, and naproxen (compounds 1, 2, 3, 11, and 12, respectively) with dual COX-2 and 5-LOX inhibitory activity. Two in vitro methods (biopartitioning micellar chromatography (BMC) and PAMPA) were used to evaluate passive gastrointestinal absorption, while high-performance affinity chromatography (HPAC) and differential pulse voltammetry (DPV) were used to evaluate binding to human serum albumin (HSA). The introduction of N-hydroxyurea and hydroxamic acid groups into the structure of NSAIDs decreases both expected passive gastrointestinal absorption (BMC k values were from 3.02 to 9.50, while for NSAIDs were from 5.29 to 13.36; PAMPA -logPe values were between 3.81 and 4.76, while for NSAIDs were ≤3.46) and HSA binding (HPAC logk values were from 2.03 to 9.54, while for NSAIDs were ≥11.03; DPV peak potential shifts were between 7 and 34, while for NSAIDs were ≥54). Structural modifications of all tested compounds that increase lipophilicity could be considered to enhance their passive gastrointestinal absorption. Considering lower expected HSA binding and higher lipophilicity of tested compounds compared to corresponding NSAIDs, it can be expected that the volume of distribution of compounds 1, 2, 3, 11, and 12 will be higher. Reduced HSA binding may also decrease interactions with other drugs in comparison to corresponding NSAIDs. All tested compounds showed significant microsomal instability (25.07-58.44% decrease in concentration) in comparison to indomethacin (14.47%) and diclofenac (20.99%).

Cost-utility analysis of duloxetine in osteoarthritis: from Chinese healthcare perspective

ABSTRACT Objectives To estimate the cost-utility of duloxetine compared with that of a placebo, common traditional nonsteroidal anti-inflammatory drugs (NSAIDs) and cyclooxygenase-2 (COX-2) inhibitors for the treatment of osteoarthritis (OA) from a Chinese healthcare perspective. Methods A Markov model was constructed. The costs and utility inputs were obtained from the database and published literature. Incremental cost-effectiveness ratio (ICER) was the main model outputs. Subgroup analyses were also conducted for patients at high risk of gastrointestinal (GI) or cardiovascular (CV) AEs. Deterministic and probabilistic sensitivity analyses were performed. Results The model estimated an ICER of $3409.21/QALY for duloxetine compared with etoricoxib, with duloxetine dominating other active treatment strategies in patients at a low risk of GI and CV AEs. The ICER for duloxetine over etoricoxib was $322.21/QALY in patients at high risk of GI and CV AEs. These results were consistent with the sensitivity analyses; 53.64% and 53.93% of the patients were willing to use duloxetine comparing with etoricoxib, for which the thresholds were 1.0 and 3.0 per capita gross domestic product (GDP), respectively. Conclusions Duloxetine is a valuable option for patients with OA; however, uncertainties exist in the model, and these suggestions can be adopted with caution.

Piperine exerts anti-inflammatory effects and antagonises the properties of celecoxib and ketoprofen: in vivo and molecular docking studies

This study evaluates the anti-inflammatory effects of a natural product, piperine (PPN), using in vivo and in silico methodologies. In the in vivo segment, inflammation was induced in the right hind paw of young chicks via a formalin (50 μL) injection. PPN was orally administered at doses of 25 and 50 mg/kg with or without celecoxib (CXB) and/or ketoprofen (KPN) (42 mg/kg). The vehicle acted as the negative control group (NC). The in silico analysis predicted the drug-likeness, pharmacokinetics, and toxicity profile of PPN, along with evaluating its binding affinity and ligand-receptor interactions. Results indicate that PPN significantly (p < 0.05) reduced licking frequency and paw edoema in a dose-dependent manner. However, in combination therapy, PPN diminished the effects of both CXB and KPN. PPN showed high affinity (–8.6 kcal/mol) towards the COX-2 enzyme. Therefore, PPN exerts anti-inflammatory effects in chicks through COX-2 inhibition pathways and antagonises CXB and KPN activities.

In-vitro anti-acne activity of Teucrium oliverianum methanolic extract against Cutibacterium acnes.

Acne vulgaris is a skin infection widely seen in adolescents between 10-19years with males affected more than females. It mainly affects the face but may also affect the back and chest. The symptoms vary with mild acne manifesting as comedones and moderate acne as inflammatory lesions (papulopustular), nodules, and mild scarring while severe acne has the same symptoms that have not subsided within 6months of treatment. Various treatments including topical medications containing different antibiotics are used to treat acne. Recently, herbal treatments have been shown as better alternatives to conventional treatment. Teucrium oliverianum Ging. ex Benth (Lamiaceae) is traditionally used for skin infections such as wound healing and biofilm formation. Methanolic extract of T. oliverianum was subjected to liquid chromatography-mass spectrometry (LC-MS) analysis, and its antibacterial effect against Cutibacterium acnes. The anti-acne, anti-inflammatory, and antioxidant effects were also assessed using HaCaT cells infected with C. acnes. The cytotoxicity of the extract was evaluated using a neutral red uptake assay, and anti-inflammatory effects were determined by measuring TNF-α, IL-1β, INF-γ, and COX2 inhibition. The antioxidant action was assessed by ROS generation in HaCaT cells infected with C. acnes. LC-MS analysis of the extract showed the presence of 16 different metabolites with L-carnitine, esculin sesquihydrate, and gamma-linoleic acid as major metabolites. The methanolic extract of T. oliverianum showed an antibacterial effect against C. acnes with an IC50 value of 263.2μg/mL. The extract attenuated the cytotoxicity of C. acnes on the HaCaT cell and the IC50 was found to be 676.2μg/mL. It also decreased dose-dependently the expression of TNF-α, IL-1β, INF-γ, and inhibited COX2 in the HaCaT cells infected with C. acnes. It also decreased the generation of reactive oxygen species. The results support the use of T. oliverianum as an anti-acne agent but it possesses mild antibacterial action. It showed anti-inflammatory effects in HaCaT cells infected with C. acnes. It is also an effective antioxidant and decreased the generation of reactive oxygen species. Comparison of the anti-acne effects and adverse reactions of extract with other treatments will provide more insight into its clinical efficacy and toxicity.

Personalized management of aspirin-exacerbated respiratory disease: From clinical presentation to therapeutic strategies

Aspirin-exacerbated respiratory disease (AERD), defined as the triad of asthma, chronic rhinosinusitis with nasal polyps (CRSwNP), and development of upper- and/or lower-respiratory symptoms after exposure to aspirin or other cyclooxygenase-1 inhibitors, has a prevalence of up to 30% for adults with asthma and with CRSwNP. The pathogenesis is likely due to a combination of abnormal genetic variants and environmental exposures, which results in types 1, 2, and/or 3 inflammation and dysregulation of arachidonic acid metabolism. Patients with AERD often fail to respond to conservative medical treatment, including all topical corticosteroids, antileukotrienes, and saline solution irrigation; furthermore, short courses of SCS generally provide only temporary improvement. Advanced therapeutic options include endoscopic sinus surgery; aspirin treatment after aspirin desensitization; and biologics, e.g., dupilumab, omalizumab, and mepolizumab. A successful and long-lasting clinical response often requires combination or sequential treatments with more than one of these therapeutic approaches. After a review of the efficacy, safety, and logistical considerations of each of these therapeutic options, an algorithmic approach for patient management is presented.

Aspirin's Antiplatelet Effects Promote Arteriovenous Fistula Maturation in Hemodialysis Patients: A Systematic Review

Background: Arteriovenous fistula (AVF) is the preferred vascular access for hemodialysis, offering superior long-term patency and lower infection rates compared to other options. However, AVF maturation remains a significant challenge. This systematic review aims to evaluate the efficacy of aspirin in promoting AVF maturation and preventing failure in hemodialysis patients. Methods: A comprehensive search of electronic databases, including ScienceDirect, SpringerLink, PubMed, Cochrane, and ProQuest, was conducted from 2014 to 2024. Studies investigating the impact of aspirin on AVF maturation and failure were included. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed. Results: Five studies met the inclusion criteria, encompassing a total of 982 participants. Four studies indicated that aspirin significantly enhanced AVF maturation by increasing flow volume and promoting the development of a robust fistula. However, one study found that aspirin did not significantly reduce the risk of thrombosis or AVF failure. Conclusion: Aspirin appears to be a promising adjunct therapy for promoting AVF maturation in hemodialysis patients. Its antiplatelet effects, primarily through cyclooxygenase inhibition and reduced platelet activation, contribute to improved flow volume and fistula maturation. While the evidence for aspirin's role in preventing AVF failure is mixed, its potential benefits in enhancing maturation warrant further investigation.

Balancing Relief and Pain: Effects of COX-2 Inhibitor Valdecoxib

Valdecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, was initially acclaimed for its gastrointestinal safety and effectiveness in managing chronic inflammatory conditions and pain. It reduced gastrointestinal complications compared to other anti-inflammatory drugs, benefiting patients with complex medication regimens. The injectable form, parecoxib, was seen as promising for acute post-surgery pain management. However, clinical trials in high-risk cardiovascular patients, particularly those undergoing coronary artery bypass grafting, revealed increased risks when using higher doses of parecoxib. These findings led to the re-evaluation of valdecoxib’s safety profile and its subsequent market withdrawal due to cardiovascular concerns and reports of serious skin reactions. Despite its withdrawal, valdecoxib has garnered interest for repurposing in other conditions. Its pharmacodynamic and pharmacokinetic properties suggest potential in qualifying palmitate-induced insulin resistance in type 2 diabetes and inhibiting matrix metalloproteinases for wound healing. Its efficacy against SARS-CoV-2 highlights drug repurposing strategies for health crises like COVID-19. Valdecoxib's established success in arthritis, dysmenorrhea, and postoperative pain, along with its potential in treating glaucoma, underscores the value of repurposing existing drugs for new therapeutic purposes. In conclusion, valdecoxib exemplifies the balance between drug safety, clinical utility, and innovative repurposing. The aim of this study is to fully harness drug potential in medical science through a concerted effort made by the scientific community, regulatory bodies, and industry stakeholders to navigate the technological and regulatory hurdles.

Efficacy, Safety, and Economic Feasibility of Dokhwalgisaeng-Tang for Degenerative Knee Osteoarthritis: Protocol for a Multicenter, Randomized, Assessor Blinded, Controlled Trial.

Knee osteoarthritis (KOA) is one of the most prevalent degenerative joint diseases worldwide. The herbal decoction, Dokhwalgisaeng-tang (DHGST), has been commonly used in East Asia to treat osteoarthritis. However, there is insufficient evidence to draw clear conclusions concerning its effectiveness and safety for patients with KOA. We aim to determine the efficacy, safety, and economic feasibility of DHGST compared with Celecoxib, an oral COX-2 inhibitor, for patients with degenerative KOA. This multicenter, randomized, noninferiority trial, involving 160 participants who will be randomized using block randomization with 1:1 allocation, will compare DHGST and Celecoxib. The total trial period is 24weeks after random allocation, comprising 12weeks of treatment and 12weeks of follow-up. Participants with KOA will be administered 200 mg of DHGST (treatment group) or Celecoxib capsules (control group) for 12weeks. Efficacy and safety evaluations will be conducted at weeks 0, 4, 8, and 12, and 24. The primary outcome measurement is the Korean Western Ontario McMaster score at week 12. Changes in pain intensity using a 100 mm visual analog scale, changes in quality of life using a EuroQol 5-dimension 5-level self-report survey, and patient satisfaction will also be measured to evaluate effectiveness between the two groups. A trial-based economic feasibility evaluation will be conducted to analyze treatment cost-effectiveness from societal and healthcare system perspectives. Drug safety will be assessed through adverse reactions and laboratory test findings. This trial protocol has the following limitations. Applying a double-dummy design is not possible, as the tablet and granule forms can easily be distinguished visually, and achieving participant blinding is challenging. The trial findings are intended to inform participants, physicians, and other stakeholders in determining whether DHGST could be used as an alternative therapeutic option for KOA. KCT0008424 (Clinical Research Information Service of the Republic of Korea), registered on 12 May 2023.

A novel cocrystal approach celecoxib with piperine: Simultaneously enhance dissolution rate and compressibility

Celecoxib, a selective COX-2 inhibitor non-steroidal anti-inflammatory drug (NSAID), exhibits analgesic and anti-inflammatory properties similar to piperine, the secondary metabolite of Piper nigrum L. Unfortunately, celecoxib has a low compressibility and low dissolution rate in aqueous medium. This study aimed to prepare a cocrystal of celecoxib and piperine to enhance the dissolution rate and compressibility properties of celecoxib. The cocrystal was synthesized using the seeding method and thoroughly characterized using Powder X-ray diffraction (XRD), differential scanning calorimetry (DSC), infrared spectrophotometry, and single-crystal X-ray diffraction techniques. The complete change in PXRD, decrease in melting point in DSC measurements, and shift in the NH stretching band in the FT-IR spectrum suggested the formation of cocrystals phase. Single-crystal XRD confirmed the formation of an equimolar ratio of cocrystals of celecoxib and piperine. The intrinsic dissolution test was conducted to confirm the impact on the cocrystal to dissolution, and it showed a slight increase compared to intact celecoxib. To assess the physico-mechanical properties, the cocrystal powders were compressed into tablets with varying forces. The results demonstrated a significant improvement in compressibility compared with intact celecoxib owing to the slip plane in the crystal lattice of the cocrystal. In conclusion, our novel celecoxib-piperine cocrystal exhibited distinct physicochemical characteristics compared to intact celecoxib, showing enhanced dissolution rate and compressibility.

Aspirin reduces Ponatinib-induced cardiovascular toxic phenotypes and death in zebrafish

BackgroundPonatinib (Iclusig) is an oral tyrosine kinase BCR-ABL inhibitor for treating patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) and chronic myeloid leukemia (CML) who are resistant to the therapies with other tyrosine kinase inhibitors. However, adverse cardiovascular events caused by Ponatinib are a serious issue that affects patients' survival rates. Thus, it is necessary to search for candidate drugs to reduce the cardiovascular toxicity of Ponatinib. PurposeTo investigate the effects of Aspirin on Ponatinib-induced cardiovascular toxicity in zebrafish. MethodsAB strain of wild type zebrafish (Danio rerio), Tg (cmlc2: GFP) transgenic zebrafish, and Tg (gata1: dsRed) transgenic zebrafish were used as in vivo models to assess survival, blood flow, cardiac morphology, and function. Thrombus formation was detected using O-dianisidine staining. The transcriptome of zebrafish larvae treated with Ponatinib was assessed using RNA sequencing. ResultsPonatinib not only reduced survival rate but also caused cardiovascular toxic events such as pericardial edema, abnormal heart structure, low heart rate, and thrombosis. In addition, whole-body transcriptome analysis showed that Ponatinib up-regulated the expression of cyclooxygenase-1 (COX-1). Compared with other antithrombotic drugs, a COX-1 inhibitor Aspirin more effectively reduced ponatinib-induced cardiovascular toxicity events and improved the survival rate of zebrafish larvae. ConclusionOur findings suggest that Aspirin exhibits the potential to reduce Ponatinib-induced cardiovascular toxicity.

Long-term intermittent oral administration of selective COX-2 inhibitor improved the clinical outcomes of COVID-19 in patients with cirrhosis.

Patients with cirrhosis are more susceptible to coronavirus disease 2019 (COVID-19) due to immune dysfunction. In this retrospective study we aimed to investigate whether suppression of mild systemic inflammation with selective cyclooxygenase-2 inhibitor (COX-2-I) during chronic care of cirrhotic patients would reduce the occurrence of acute decompensated events and improve patient prognosis of COVID-19. Medical records of cirrhotic patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection were sequentially reviewed. The patients were divided into the COX-2-I and control groups depending on whether they took oral selective COX-2-I for over 3 months or not. The primary outcomes included the occurrence of severe/critical COVID-19, acute decompensated events, and acute-on-chronic liver failure (ACLF). After propensity score matching analysis, there were 314 cases in the control group and 118 cases in the COX-2-I group. Compared with the control group, the risk of severe/critical COVID-19 in the COX-2-I group was significantly decreased by 83.1% (p = 0.004). Acute decompensated events and ACLF occurred in 23 (7.32%) and nine (2.87%) cases in the control group, but none in the COX-2-I group (p = 0.003 and 0.122). The rate of hospitalization in the COX-2-I group was significantly lower than that of the control group (3.39% vs 13.06%, p = 0.003). No patient in the COX-2-I group required intensive care unit admission. Long-term intermittent oral administration of selective COX-2-I in cirrhotic patients significantly reduces the occurrence of severe/critical COVID-19, acute decompensated events, and ACLF. It may also be used for systemic inflammation caused by other pathogens.

In-silico Investigation and Development of Cyclooxygenase-2 (1CX2) Selective Inhibition as a Possible Anti-Inflammatory Activity

Nonsteroidal anti-inflammatory drugs (NSAIDs) that specifically target the enzyme cyclooxygenase-2, or COX-2, which causes inflammation and discomfort, are known as COX-2 inhibitors. The objective of this work is to perform the anti-inflammatory activity, and molecular docking studies of compounds. We aim to develop new drug phytochemicals as anti-inflammatory agents targeting COX-2(PDB ID: 1CX2) for treatment. To find potential molecules, the PyRx 0.8 tool has been used to dock 37 potent molecules against COX-2 (PDB ID: 1CX2). The top scorer molecules (phytochemicals) (Dihydromyricetin, Catechin, Chlorogenic acid, Chrysin, and Emodin) were selected. Prior to further analysis, the compounds underwent thorough in vivo evaluation to assess their toxicity and anti-inflammatory properties. The results indicated that dihydromyricetin, catechin, and chlorogenic acid were the sole substances that exhibited both negligible acute toxicity and superior anti-inflammatory properties, surpassing the efficacy of diclofenac sodium, the established medicine. Among the compounds that were evaluated, Dihydromyricetin was shown to possess the most powerful anti-inflammatory properties due to its trihydroxy phenyl chroman-4-one substitution. Correlated to diclofenac (-8.5 Kcal/mol), dihydromyricetin and catechin showed significant bounden affinity, with the lowest binding free energies (-9.9 and -9.2 Kcal/mol) according to the computational study. This correlation between in silico and in vivo studies validated these compound’s powerful anti-inflammatory properties.

Signaling Pathways in Clear Cell Renal Cell Carcinoma and Candidate Drugs Unveiled through Transcriptomic Network Analysis of Hub Genes

Clear cell renal cell carcinoma (ccRCC) is a type of kidney cancer. It advances quickly and often metastasizes, making the prognosis for patients challenging. This study used weighted gene co-expression network analysis (WGCNA) to study gene expression data of different stages of ccRCC obtained in the GEO database. The analysis identified three significant highly preserved gene modules across the datasets: GSE53757, GSE22541, GSE66272, and GSE73731. Functional annotation and pathway enrichment analysis using DAVID revealed inflammatory pathways (e.g., NF-kB, Hippo, and HIF-1 pathways) that may drive ccRCC development and progression. The study also introduced the involvement of viral infections associated with the disease in the metabolic reprogramming of ccRCC. A drug repurposing analysis was also conducted to identify potential drug candidates for ccRCC using the upregulated and downregulated hub genes. The top candidates are ziprasidone (dopamine and serotonin receptor antagonist) and fentiazac (cyclooxygenase inhibitor). Other drug candidates were also obtained, such as phosphodiesterase/DNA methyltransferase/ATM kinase inhibitors, acetylcholine antagonists, and NAD precursors. Overall, the study’s findings suggest that identifying several genes and signaling pathways related to ccRCC may uncover new targets, biomarkers, and even drugs that can be repurposed, which can help develop new and effective treatments for the disease.

Zirconium/niacin metal-organic framework preparation, characterization and assessment as a catalyst in one-pot synthesis of xanthene-1,8-dione derivatives with docking validation as anti-inflammatory

The zirconium/niacin metal-organic framework (MOF) was prepared by an efficient solvothermal method and the nanostructure of MOF was identified by IR, SEM, EDX, XRD, BET and TEM. The prepared Zr-MOF was evaluated as a catalyst in organic synthesis. Tetrahydro xanthene-1,8‑dione derivatives were synthesized by a one-pot reaction between 2 mol of dimedone and 1 mole of aromatic aldehyde in the presence of the catalytic amount of Zr-MOF under solvent-free conditions. The prepared ligands were evaluated as COX-1 and COX-2 inhibitors and the data obtained explained that the ligands 4-(3,3,6,6-tetramethyl-1,8-dioxo-2,3,4,5,6,7,8,9-octahydro-1H-xanthen-9-yl)phenyl benzoate (3 g), 3,3,6,6-tetramethyl-9-(5-methylfuran-2-yl)-3,4,5,6,7,9-hexahydro-1H-xanthene-1,8(2H)‑dione (3i) and 9-(3-(4-chlorophenyl)-1-phenyl-1H-pyrazol-4-yl)-3,3,6,6-tetramethyl-3,4,5,6,7,9-hexahydro-1H-xanthene-1,8(2H)‑dione (3j) gave the promised data.