Flufenamic Acid Research Articles (Page 1)

Pharmacological inhibition of Trypanosoma cruzi aldo-keto reductase (TcAKR) and its effect on benznidazole resistance.

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by persistent joint inflammation and progressive structural damage, with early diagnosis remaining a significant clinical challenge. Circulating microRNAs (miRNAs) have emerged as promising biomarkers for disease diagnosis, prognosis, and therapeutic response due to their critical roles in gene regulation. However, the specific miRNAs causally involved in RA pathogenesis remain largely unidentified. We conducted a 2-sample Mendelian randomization (MR) analysis using summary-level data from the largest available genome-wide association study of circulating cis-miRNA expression quantitative trait loci (cis-miR-eQTLs) and RA genome-wide association study summary statistics. The inverse variance weighted method served as the primary analytical approach, supplemented by comprehensive sensitivity analyses including Cochran Q test, MR-Egger intercept test, MR-PRESSO, and leave-one-out analysis to ensure result robustness. Additionally, we performed target gene prediction, gene ontology and kyoto encyclopedia of genes and genomes enrichment analyses, and druggable analysis to explore the underlying biological mechanisms and therapeutic potential of the causal miRNAs. Our MR analysis identified 8 circulating miRNAs with significant causal associations with RA risk. Notably, hsa-miR-130a-3p (P = 6.5332 × 10−5, OR = 1.0720, 95% CI = 1.0360–1.1092) emerged as a key risk factor, while hsa-miR-204-5p (P = 6.2123 × 10−4, OR = 0.9707, 95% CI = 0.9543–0.9874) demonstrated a protective effect. Bioinformatics analyses revealed that hsa-miR-130a-3p may modulate the TGF-β, Hippo, and mTOR signaling pathways by interacting with competing endogenous RNAs (ceRNAs) such as H19 and regulating hub proteins including TNF, UBB, PPARG, and TGFBR1. Resveratrol and flufenamic acid were identified as candidate therapeutic agents targeting its downstream pathways. Conversely, hsa-miR-204-5p was predicted to influence the AMPK, cGMP-PKG, and cAMP signaling pathways via ceRNAs like NEAT1 and NORAD, affecting key proteins such as BCL2, SIRT1, and HMGA2, with cilostazol, melatonin, and curcumin identified as potential modulators. This study provides novel causal evidence implicating hsa-miR-130a-3p and hsa-miR-204-5p in RA pathogenesis. These findings highlight their potential as circulating biomarkers for early diagnosis and risk assessment, as well as therapeutic targets for miRNA-based intervention strategies, thereby offering valuable insights for advancing precision medicine in RA management.

Mechanism of the reaction between flufenamic acid and CO2 in its saturated solution in supercritical CO2

The search for drugs that extend lifespan in human-like biological models is a frontier area in biomedical research. In this study, we report a novel electrochemical approach using flufenamic acid (FFA), a widely known nonsteroidal anti-inflammatory drug (NSAID), to generate and detect its pharmacologically active metabolites. Electrochemical oxidation of FFA on multi-walled carbon nanotubes(MWCNT)-modified electrode yielded hydroxylated derivatives, primarily 4-hydroxy FFA (m/z 297.05g/mol) and a polyhydroxylated product termed FFA-Redox (m/z 243.05g/mol), as surface-confined species (MWCNT@FFA-Redox). To establish biological relevance, Caenorhabditis elegans (C. elegans) were exposed to FFA, resulting in in vivo formation of metabolites identical to those generated electrochemically. This confirmed the physiological significance of the electrosynthesized compounds. Lifespan assays demonstrated that FFA-Redox prolonged the survival of C. elegans by up to 40% under Klebsiella pneumoniae infection and by up to 80% under Staphylococcus aureus infection. This protective effect was attributed to reduced levels of intracellular reactive oxygen species (ROS). Mechanistic insights suggest that FFA-Redox induces a "de-aging" response by enhancing the expression of superoxide dismutase (SOD), a key antioxidant enzyme activated during oxidative stress.

This study explores how intermolecular interactions govern the composition of saturated solutions of influence flufenamic acid (FlA) in deep eutectic solvents (DESs). Using choline chloride (ChCl) or menthol (Men) as the HBAs and various polyols as the HBDs, FlA solubility was measured in different DES systems. The experimental values along with intermolecular interactions quantified via COSMOtherm-derived Gibbs free energies were used in the determination of component distributions for varying DES formulations. It was inferred that DES systems primarily consist of molecular complexes (dimers and hetero-pairs) rather than monomers due to their high association propensity. In the case of ChCl-based DESs, the HBA-HBD hetero-pairs are favored and strongly dominate. In contrast, Men-based DESs exhibited a strong attraction to HBDs; however, their self-association led to the predominance of HBD dimers. Solubility of FlA correlated with solute-containing hetero-pairs, peaking at optimal HBA-HBD ratios. These insights support in developing a rationale for DES design for pharmaceutical applications. The conclusions of this study were inferred from a novel crafted physically constrained iterative algorithm that reliably determines molecular composition from the equilibrium constants, overcoming the limitations of conventional numerical solvers in highly associated systems.

This study presents an electrochemical platform for thedetectionof flufenamic acid using a bamboo biochar-modified screen-printedelectrode (denoted as SPE/BCB). The proposed sensor exhibited highanalytical performance, with a sensitivity of 2.30 μA/μmolL–1 and an ultralow detection limit of 1.3 nmolL–1, across a broad linear range (0.05–13.32μmol L–1). Compared with conventional electrodessuch as glassy carbon, carbon paste, and modified pyrolytic graphiteelectrodes, the SPE/BCB sensor offers advantages in terms of cost-effectiveness,ease of fabrication, and disposability. The incorporation of bamboobiochar enhances the electrochemical performance while providing anenvironmentally friendly approach. Furthermore, the sensor demonstratesexcellent selectivity, remaining unaffected by common organic interferents,making it suitable for environmental applications. Its ability toaccurately quantify FFA in complex aqueous matrices, including riverand tap water, highlights its potential as an effective tool for environmentalmonitoring.

BackgroundIschemic heart disease (IHD) remains a leading cause of global morbidity and mortality, necessitating the search for novel therapeutic approaches. Recent studies have identified bitter taste receptors (TAS2Rs) in vascular smooth muscle cells as potential therapeutic targets because of their vasorelaxant properties. This study investigated the vasorelaxant effects of TAS2R agonists on porcine coronary arteries ex vivo and explored their potential as novel therapeutic targets for IHD.MethodsIsolated porcine coronary artery rings were precontracted using U46619 and treated with TAS2R agonists, including flufenamic acid, dapsone, phenanthroline, chloroquine, and quinine. Vasorelaxation induced by TAS2R agonists was quantitatively assessed, and pharmacological inhibitors were used to elucidate the underlying mechanisms of vasorelaxation. Real-time PCR analysis was conducted to confirm the expression of specific TAS2R subtypes in porcine coronary arterial tissue.ResultsTAS2R agonists induced concentration-dependent vasorelaxation, with flufenamic acid showing potent effects, exhibiting an EC50 of 30.4 μM, whereas phenanthroline and chloroquine exhibited moderate responses. In contrast, quinine and dapsone showed mild relaxation. The flufenamic acid-induced effect was attenuated by NG-nitro-L-arginine (47.4% ± 3.04%), apamin (49.2% ± 3.7%), and glibenclamide (49.6% ± 1.5%), indicating the involvement of nitric oxide signaling and potassium channels. PCR analysis revealed the differential expression of TAS2R subtypes, with TAS2R42 showing the highest expression, followed by subtypes 40, 10, and 38.ConclusionThis study showed that TAS2R agonists, especially flufenamic acid, phenanthroline, and chloroquine, induced vasorelaxation in isolated porcine coronary arteries. The vasorelaxation mechanism of flufenamic acid may involve nitric oxide signaling and potassium channels. The expression of specific TAS2R subtypes, together with functional observations, suggest that bitter taste receptors play a role in coronary vascular regulation, warranting further investigation into their therapeutic potential.

Herein, we report a Cu catalyst system for umpolung Chan-Lam amination, enabling the efficient synthesis of unsymmetrical diarylamines from arylboronic esters and aryl azides. This sustainable approach facilitates C-N bond formation even at 35 °C without any additional ligands using an easily accessible catalyst and substrates. Mechanistic and computational studies revealed the intermediacy of the Cu(II) species. This method provides a cost-effective route to diarylamines, and it was successfully applied to the gram-scale synthesis of a flufenamic acid derivative.

ImportanceTransient receptor potential canonical 6 (TRPC6) and TRPC3 are involved in bone remodeling and other biological processes.ObjectiveTo investigate the effects of TRPC6 activator, flufenamic acid (FFA), and TRPC3 inhibitor, pyrazole 3 (PYR), in human periodontal ligament (hPDL) cells and periodontitis mice.MethodsThe effects of FFA and PYR on osteoblastogenesis were evaluated in hPDL cells. To investigate periodontitis induction, mice were randomized to control (C), periodontitis (P), and FFA-treated periodontitis (P+FFA) groups. To investigate periodontitis recovery, mice were randomized to day 0 C (D0C), D0P, D3P, D3P+PYR, D7P, and D7P+PYR groups. Alveolar bone (AB) area, osteoclast formation, osteoid area, and Runt-related transcription factor 2 (RUNX2) and receptor activator of nuclear factor-κB ligand (RANKL) expression were evaluated.ResultsAB area was greater in the P+FFA group than in the P group, whereas the number of osteoclasts and RANKL expression were lower. AB and osteoid areas were larger in the D7P+PYR group than in the D7P group. RUNX2-positive osteoblasts were elevated in the D3P+PYR group compared to the D0C and D0P groups. Osteocalcin expression was significantly greater on D28 of osteoblast differentiation in hPDL cells in the PYR group compared to the differentiation group.Conclusions and RelevanceThese results suggest that FFA attenuates AB loss by inhibiting RANKL expression and osteoclast formation and that PYR contributes to AB recovery by enhancing new bone formation.

An effective approach for water pollution remediation and structural-optical analysis of gamma-irradiated flufenamic acid

Synergistic integration of CaMoO4 decorated functionalized carbon nanofibers for enhanced electrochemical detection of flufenamic acid: Experimental and DFT approach

Our research, which employs a comprehensive approach combining high-pressure and magic angle spinning (MAS) NMR spectroscopy methods, investigates the structural and sorption characteristics of composite materials based on cellulose aerogels. The 13C NMR studies, conducted in supercritical CO2, revealed kinetic parameters for the sorption processes that significantly differ from those of silica-based analogs. The analysis of chemical shifts from 19F MAS NMR spectra led to the first identification of two stable phase states of flufenamic acid within the cellulose aerogel: an amorphous phase within the pore volume (-62.15 ppm) and a liquid-like phase on the surface of the pores (-65.09 ppm), with a ratio of 2:1. These findings, which contrast starkly with previous data for silica systems, where only a liquid-like state was observed, underscore the unique three-dimensional architecture and highly developed porous structure of cellulose aerogels. These features appear to stabilize metastable amorphous phases of active pharmaceutical ingredients (APIs), opening up new perspectives for the use of cellulose aerogels in the controlled stabilization of metastable phases of APIs in composite materials.

Insight on a novel drug-drug salt levofloxacin-flufenamate crystal structures, physicochemical properties, potency, and anti-inflammation improvement.

Intracellular calcium (Ca2+) release via phospholipase C (PLC) following G-protein-coupled receptor (GPCR) activation is typically linked to membrane depolarization and airway smooth muscle (ASM) contraction. However, recent findings show that bitter taste receptor agonists, such as chloroquine (CQ), induce a paradoxical and potent relaxation response despite activating the Ca2+ signaling pathway. This relaxation has been hypothesized to be driven by a distinct compartmentalization of calcium ions toward the cellular periphery, subsequently leading to membrane hyperpolarization, in contrast to the contractile effects of histamine. In this study, we further investigate the spatiotemporal dynamics of Ca2+ signaling in ASM cells using single-cell microscopy and deep learning-based segmentation, integrating the results into a comprehensive model of ASM ion channel dynamics to compare the effects of histamine, CQ, and flufenamic acid (FFA). Our results show that histamine induces a strong, synchronized calcium release, nearly twice as high as that of CQ, which produces a sustained but lower-magnitude response. Per-cell analysis reveals more variable and asynchronous Ca2+ signaling for CQ and FFA, with higher entropy compared with histamine. Integrating these findings into an ASM ion channel model, we observed that histamine-mediated Ca2+ release activates voltage-gated Ca2+ and Na+ channels (leading to depolarization). In contrast, CQ preferentially engages BKCa, SKCa, and chloride channels (promoting hyperpolarization). These findings provide insights into the unique mechanisms by which bitter taste receptor agonists can modulate ASM tone, offering potential therapeutic strategies for relaxing ASM and alleviating airway hyperresponsiveness in conditions such as asthma.NEW & NOTEWORTHY Using machine-learning methods, these studies identify spatiotemporal differences in calcium responses between agonists of Gq-coupled receptors and bitter taste receptors in airway smooth muscle cells. The findings provide deeper insights into the mechanism of action of bitter tastant-induced airway smooth muscle relaxation.

Nanostructured drug-delivery systems with enhanced therapeutic potential have gained attention in biomedical applications. Here, flufenamic acid (FFA)-loaded chitosan/poly(vinyl alcohol) (CHS/PVA; CSPA)-based electrospun nanofibers were fabricated and characterized for antibacterial, anticancer, and antioxidant activities. The FFA-loaded CSPA (FCSPA) nanofibers were characterized by scanning electron microscopy, Fourier-transform infrared spectroscopy, X-ray diffraction (XRD), and differential scanning calorimetry to evaluate their formation process, functional group interactions, and crystallinity. Notably, the average diameter of FCSPA nanofibers decreased with increasing CSPA contents (CSPA-1 to CSPA-3), indicating that FFA addition to CSPA-3 significantly decreased its diameter. Additionally, XRD confirmed the dispersion of FFA within the CSPA amorphous matrix, enhancing drug stability. FCSPA nanofibers exhibited a high swelling ratio (significantly higher than that of the CSPA samples). Biodegradation studies revealed that FCSPA exhibited accelerated weight loss after 72 h, indicating its improved degradation compared with those of other formulations. Furthermore, it exhibited a significantly high drug-encapsulation efficiency, ensuring sustained release. FCSPA nanofibers exhibited excellent antibacterial activity, inhibiting Staphylococcus aureus and Escherichia coli. Regarding anticancer activity, FCSPA decreased HCT-116 cell viability, highlighting its controlled drug-delivery potential. Moreover, FCSPA demonstrated superior antioxidation, scavenging DPPH free radicals. These findings highlight FCSPA nanofibers as multifunctional platforms with wound-healing, drug-delivery, and tissue-engineering potential.

Coamorphous mixtures (CAMs) prepared with two drugs have the potential to enhance the oral absorption of poorly soluble drugs and achieve combination therapy. From a practical standpoint, improving the glass transition temperature (Tg) of CAMs is desirable as it enhances stability and extends shelf life during storage. Toward the eventual goal of developing highly stable CAMs, this study establishes a generalized framework that systematically relates elevated Tg values of CAMs to intermolecular interactions based on specific functional groups. CAMs were prepared via quench-cooling using various combinations of indomethacin, ketoprofen, flurbiprofen, flufenamic acid, aripiprazole, bifonazole, and clotrimazole. CAMs prepared with drugs containing the COOH group exhibited significant positive deviations from the Tg values predicted by the Gordon-Taylor equation (i.e., ideal mixing behavior). COOH-associated hydrogen bonding was determined to be a key factor for Tg elevation, with synergistic contributions from π-π interactions and halogen bonding. In CAMs exhibiting the largest Tg deviations, contributions from ionic bonding were crucial, and were likely favored by differences in the pKa values of the constituent drugs. Continuity in Tg as a function of varying molar ratios indicated that stoichiometric pairing had a relatively minor contribution, while a decrease in the width of the glass transition suggested enhancement of molecular cooperativity as a possible mechanism for CAM stabilization. In contrast, non-COOH hydrogen bonding, π-π interactions, and halogen bonding on their own did not result in any meaningful Tg deviations from theoretical predictions. Systematic correlations between Tg deviations and molecular interactions reported in this study can lead to generalized design rules for the development of stable CAMs.

The influence of solute concentration and filtration on mesoscale clusters of flufenamic acid, a typical pharmaceutical compound, in ethanol.

Downregulation and inhibition of TRPM2 calcium channel prevent oxidative stress-induced endothelial dysfunction in the EA.hy926 endothelial cells model - Preliminary studies.

This study investigated the role of various polymers as precipitation inhibitors in solutions of flufenamic acid (FFA) and its cocrystals with theophylline (FFA-TP) and nicotinamide (FFA-NIC). Through a combination of NMR spectroscopy, molecular dynamics simulations, and nucleation studies using Crystal16, we evaluated the effects of polyethylene glycol (PEG), polyvinylpyrrolidone-vinyl acetate (PVP-VA), and soluplus (SOL), both individually and in combinations, on the nucleation, diffusion, and self-association of FFA molecules in solution. 1H NMR and DOSY measurements revealed that while PEG was highly effective in reducing molecular mobility, thus significantly delaying nucleation, PVP-VA facilitated nucleation by enhancing FFA diffusion and aggregation. SOL provided a balance, enhancing molecular mobility but maintaining a delayed nucleation effect, likely due to micellar encapsulation, as evidenced by line broadening in 1H NMR. Combination systems such as PVP-VA-PEG and PVP-VA-SOL showed synergistic effects, with PVP-VA-SOL proving particularly effective in inhibiting FFA nucleation across all systems. Molecular dynamics simulations supported these findings by highlighting changes in intermolecular interactions and aggregation tendencies in the presence of each polymer. This comprehensive analysis suggested that selecting appropriate polymeric excipients, or combinations thereof, can finely tune the nucleation behaviors of drug solutions, offering a strategic approach to optimizing the stability of supersaturated drug solutions.

Transient receptor potential melastatin type 2 (TRPM2) is a nonselective cation channel involved in synaptic plasticity. We investigated its role in contextual fear conditioning and extinction of conditioned fear using Trpm2-deficient (Trpm2−/−) mice. Trpm2−/− mice exhibited reduced acquisition of contextual fear memory during conditioning but had an intact freezing response to conditioning context 24 h after conditioning. They also showed a reduced freezing response to extinction training, indicating facilitated extinction. Consistent with this, infusion of flufenamic acid (FFA), a TRPM2 antagonist, into the dentate gyrus (DG) of the hippocampus in fear-conditioned mice facilitated extinction of contextual fear. The enhanced extinction in Trpm2−/− and FFA-treated mice was associated with down-regulation of immediate-early genes (IEGs) including Npas4, c-Fos, Arc and Egr1 in the hippocampus after extinction training. Our results indicate that TRPM2 plays a positive role in retention of contextual fear memory by modulating neuronal activity in the hippocampus, and suggest that TRPM2 activity could potentially be targeted to strengthen extinction-based exposure therapies for post-traumatic stress disorder (PTSD).