Search Results (1,538)

Background/Objective: Pharmacological interventions often exert systemic effects beyond their primary targets, underscoring the need for a comprehensive evaluation of their metabolic impact. Etodolac is a nonsteroidal anti-inflammatory drug (NSAID) that alleviates pain, fever, and inflammation by inhibiting cyclooxygenase-2 (COX-2), thereby reducing prostaglandin synthesis. While its pharmacological effects are well known, the broader metabolic impact and potential mechanisms underlying improved clinical outcomes remain underexplored. Untargeted metabolomics, which profiles the metabolome without prior selection, is an emerging tool in clinical pharmacology for elucidating drug-induced metabolic changes. In this study, untargeted metabolomics was applied to investigate metabolic changes following a single oral dose of etodolac in healthy male volunteers. By analyzing serial blood samples over time, we identified endogenous metabolites whose concentrations were positively or inversely associated with the drug’s plasma levels. This approach provides a window into both therapeutic pathways and potential off-target effects, offering a promising strategy for early-stage drug evaluation and multi-target discovery using minimal human exposure. Methods: Thirty healthy participants received a 400 mg dose of Etodolac. Plasma samples were collected at five time points: pre-dose, before Cmax, at Cmax, after Cmax, and 36 h post-dose (n = 150). Samples underwent LC/MS-based untargeted metabolomics profiling and pharmacokinetic analysis. A total of 997 metabolites were significantly dysregulated between the pre-dose and Cmax time points, with 875 upregulated and 122 downregulated. Among these, 80 human endogenous metabolites were identified as being influenced by Etodolac. Results: A total of 17 metabolites exhibited time-dependent changes closely aligned with Etodolac’s pharmacokinetic profile, while 27 displayed inverse trends. Conclusions: Etodolac influences various metabolic pathways, including arachidonic acid metabolism, sphingolipid metabolism, and the biosynthesis of unsaturated fatty acids. These selective metabolic alterations complement its COX-2 inhibition and may contribute to its anti-inflammatory effects. This study provides new insights into Etodolac’s metabolic impact under healthy conditions and may inform future therapeutic strategies targeting inflammation. Full article

Background: Pain is a complex phenomenon characterized by unpleasant experiences with profound heterogeneity influenced by biological, psychological, and social factors. According to the National Health Interview Survey, 50.2 million U.S. adults (20.5%) experience pain on most days, with the annual cost of prescription medication for pain reaching approximately USD 17.8 billion. Theranostic pain nanomedicine therefore emerges as an attractive analgesic strategy with the potential for increased efficacy, reduced side-effects, and treatment personalization. Theranostic nanomedicine combines drug delivery and diagnostic features, allowing for real-time monitoring of analgesic efficacy in vivo using molecular imaging. However, clinical translation of these nanomedicines are challenging due to complex manufacturing methodologies, lack of standardized quality control, and potentially high costs. Quality by Design (QbD) can navigate these challenges and lead to the development of an optimal pain nanomedicine. Our lab previously reported a macrophage-targeted perfluorocarbon nanoemulsion (PFC NE) that demonstrated analgesic efficacy across multiple rodent pain models in both sexes. Here, we report PFC-free, biphasic nanoemulsions formulated with a biocompatible and non-immunogenic plant-based coconut oil loaded with a COX-2 inhibitor and a clinical-grade, indocyanine green (ICG) near-infrared fluorescent (NIRF) dye for parenteral theranostic analgesic nanomedicine. Methods: Critical process parameters and material attributes were identified through the FMECA (Failure, Modes, Effects, and Criticality Analysis) method and optimized using a 3 × 2 full-factorial design of experiments. We investigated the impact of the oil-to-surfactant ratio (w/w) with three different surfactant systems on the colloidal properties of NE. Small-scale (100 mL) batches were manufactured using sonication and microfluidization, and the final formulation was scaled up to 500 mL with microfluidization. The colloidal stability of NE was assessed using dynamic light scattering (DLS) and drug quantification was conducted through reverse-phase HPLC. An in vitro drug release study was conducted using the dialysis bag method, accompanied by HPLC quantification. The formulation was further evaluated for cell viability, cellular uptake, and COX-2 inhibition in the RAW 264.7 macrophage cell line. Results: Nanoemulsion droplet size increased with a higher oil-to-surfactant ratio (w/w) but was no significant impact by the type of surfactant system used. Thermal cycling and serum stability studies confirmed NE colloidal stability upon exposure to high and low temperatures and biological fluids. We also demonstrated the necessity of a solubilizer for long-term fluorescence stability of ICG. The nanoemulsion showed no cellular toxicity and effectively inhibited PGE2 in activated macrophages. Conclusions: To our knowledge, this is the first instance of a celecoxib-loaded theranostic platform developed using a plant-derived hydrocarbon oil, applying the QbD approach that demonstrated COX-2 inhibition. Full article

Background: Probiotics are live microorganisms known for their health-promoting effects, particularly in modulating immune responses and reducing inflammation within the gastrointestinal tract. Emerging evidence suggests probiotics may also influence respiratory health, prompting investigation into their potential therapeutic application in lung inflammation. Methods: This study examined the anti-inflammatory effects of Ligilactobacillus salivarius (LS01 DSM 22775) and Bifidobacterium breve (B632 DSM 24706) on inflamed pulmonary epithelial cells. Lung carcinoma epithelial cells (A549) and normal bronchial epithelial cells (16HBE) were stimulated with IL-1β and treated with viable and heat-treated probiotics. Results: CCL-2 levels were significantly reduced by up to 40%, in A549 by viable form (10⁵–10⁷ AFU/g), instead of in 16HBE by heat-treated form (10⁷–10⁹ TFU/g). In A549 cells, TNF-α decreased by 20–80% with all formulations; instead, in 16HBE cells, IL-8 was reduced by viable strains (10⁷ AFU/g) by approximately 50%, while heat-treated strains (10⁹ TFU/g) decreased both IL-6 and IL-8 by 50%. All effective treatments completely inhibited IL-4 and eotaxin and suppressed NF-κB activation in both cell lines, with up to 80% reduction in phospho-p65 levels. In A549 cells, heat-treated strains fully blocked PGE2 production; instead, all four probiotics significantly inhibited COX-2 expression by approximately 50%. Conclusions: These findings demonstrate that both viable and heat-treated probiotics can modulate inflammatory responses in pulmonary epithelial cells, suggesting their potential application in inflammatory respiratory diseases. Heat-treated formulations may be particularly suited for local administration via inhalation, offering a promising strategy for targeting airway inflammation directly. Full article

Chamaecyparis obtusa (Siebold & Zucc.) Endl. (C. obtusa) is an evergreen conifer native to temperate regions such as South Korea and Japan, traditionally used for its anti-inflammatory properties. However, the molecular mechanisms underlying the anti-inflammatory effects of C. obtusa bark extracts remain poorly understood. In this study, I compared the biological activities of C. obtusa bark extracts prepared using boiling water (COWB) and 70% ethanol (COEB), and investigated their anti-inflammatory mechanisms in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. COEB significantly suppressed both mRNA and protein expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), along with decreased production of their respective inflammatory mediators, nitric oxide (NO) and prostaglandin E₂ (PGE₂). Additionally, COEB selectively downregulated interleukin (IL)-1β expression, without affecting tumor necrosis factor-α (TNF-α), and unexpectedly upregulated IL-6. Notably, COEB did not inhibit the LPS-induced activation of major inflammatory signaling pathways, including mitogen-activated protein kinase (MAPK), nuclear factor-kappa B (NF-κB), and Janus kinase/signal transducer and activator of transcription (JAK/STAT). These findings suggest that COEB exerts anti-inflammatory effects by modulating key inflammatory mediators independently of canonical signaling pathways and may offer a novel therapeutic strategy for controlling inflammation. Full article

Rosemary (Salvia rosmarinus) is renowned for its antioxidant, anti-inflammatory, and antihyperglycemic properties, largely attributed to its rich phytochemical profile. This study evaluates the potential of metabolites from Pseudomonas shirazensis NFV3, formulated in silver nanoparticles (AgNPs), to enhance the bioactivity of rosemary extracts in postharvest applications. Rosemary stems were treated with AgNPs coated with bacterial metabolites (NP), bacterial cells, or metabolites (LM), and the extracts’ phytochemical composition and bioactivities were assessed. HPLC and HPLC–MS analyses revealed that the NP treatment induced significant metabolic remodeling, particularly upregulating rosmarinic acid and selected triterpenes (ursolic and betulinic acids), while reducing carnosic acid levels. NP-treated extracts exhibited significantly enhanced inhibition of cyclooxygenase (COX-1 and COX-2), indicating improved anti-inflammatory potential. The α-glucosidase inhibition and antioxidant activity (DPPH assay) of the extracts were not substantially altered, suggesting the selective enhancement of pharmacological functions. These findings demonstrate that nanoparticle-based elicitation selectively remodels secondary metabolism in rosemary, improving extract quality and bioactivity. This strategy offers a novel, sustainable tool for optimizing plant-based therapeutics in the phytopharmaceutical industry. Full article

Gaultherin [methyl salicylate 2-O-β-D-xylopyranosyl-(1→6)-β-D-glucopyranoside] is a natural salicylate found in some plant species belonging primarily to the Ericaceae and Rosaceae families. Biological studies conducted since the beginning of the 21st century have suggested the potential use of gaultherin in treating various diseases related to inflammation and oxidative stress, including rheumatoid arthritis, sciatica, neuralgia, and muscular pain. The accumulated results indicated a targeted range of biological effects, particularly anti-inflammatory, antipyretic, and anti-rheumatic properties associated with reduced adverse outcomes. The molecular mechanisms involve the influence on several signalling pathways, including NF-κB, MAPK, and potentially AMPK, as well as the inhibition of critical pro-inflammatory enzymes, such as COX-2. This inhibition is achieved without affecting the COX-1 isoform, thereby preventing side effects such as bleeding ulcers or intracranial haemorrhage. This overview summarises the current knowledge about pharmacokinetics, molecular mechanisms, pharmacology, and biocompatibility of gaultherin. Additionally, four methods for isolating gaultherin from plant material and its distribution within the plant kingdom were the focal points of review and discussion. The paper also describes significant differences between synthetic aspirin and natural gaultherin in their biological potential and side effects, resulting from their different mechanisms of action. As a prodrug of salicylic acid, gaultherin releases salicylic acid gradually through enzymatic hydrolysis in the gastrointestinal tract. This controlled release minimises direct gastric irritation and accounts for its superior gastrointestinal safety profile compared to aspirin. Unlike aspirin, which irreversibly inhibits COX-1 and can lead to serious side effects with chronic use, gaultherin selectively inhibits COX-2 while sparing COX-1. These properties position gaultherin as a compelling natural alternative for patients requiring long-term anti-inflammatory therapy with reduced risk of gastrointestinal or bleeding complications. Full article

Background: Programmed cell death-related genes (PCDRGs) have been reported to play an important role in diagnosis, treatment and immunity regarding cancer, but their prognostic value and therapeutic potential in acute myeloid leukemia (AML) patients still need to be fully explored. Methods: Cox regression analysis and Least Absolute Shrinkage and Selection Operator (LASSO) analysis were used to identify PCDRGs significantly associated with the prognosis of AML patients. Furthermore, a prognostic risk model for AML patients was constructed based on the selected PCDRGs, and their immune microenvironment and biological pathways were analyzed. Cell experiments ultimately confirmed the potential role of PCDRGs in AML. Results: The results yielded four PCDRGs that were used to develop a prognostic risk model, and the prognostic significance of this model was confirmed using an independent external AML patient cohort. This prognostic risk model provides an independent prognostic risk factor for AML patients. This prognostic feature is related to immune cell infiltration in AML patients. The inhibition of solute carrier family 39 member 14 (SLC39A14) expression enhanced apoptosis and inhibited cell cycle progression in AML cells. Conclusions: This study integrates bioinformatics analysis and cellular experiments to reveal potential gene therapy targets and prognostic gene markers in AML. Full article

Cannabis sativa L. is a phytochemically rich plant with therapeutic potential across various clinical domains, including pain, inflammation, and neurological disorders. Among its constituents, terpenes are gaining recognition for their capacity to modulate the pathophysiological processes underlying chronic pain syndromes. Traditionally valued for their aromatic qualities, terpenes such as myrcene, β-caryophyllene (BCP), limonene, pinene, linalool, and humulene have demonstrated a broad spectrum of biological activities. Beyond their observable analgesic, anti-inflammatory, and anxiolytic outcomes, these compounds exert their actions through distinct molecular mechanisms. These include the activation of cannabinoid receptor type 2 (CB₂), the modulation of transient receptor potential (TRP) and adenosine receptors, and the inhibition of pro-inflammatory signalling pathways such as Nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-κB) and Cyclooxygenase-2 (COX-2). This narrative review synthesizes the current preclinical and emerging clinical data on terpene-mediated analgesia, highlighting both monoterpenes and sesquiterpenes, and discusses their potential for synergistic interaction with cannabinoids, the so-called entourage effect. Although preclinical findings are promising, clinical translation is limited by methodological variability, the lack of standardized formulations, and insufficient pharmacokinetic characterization. Further human studies are essential to clarify their therapeutic potential. Full article

Tea is one of the most consumed beverages in the world, belonging to the category of compounds known as tannins and flavonoids. One of the polyphenols found in large amounts in green tea leaves (Camellia sinensis) is epigallocatechin-3-O-gallate (EGCG). Though EGCG has shown some pharmacological effects, to date, it has not been utilised as a therapeutic agent. This is attributed to the fact that EGCG lacks adequate stability, and it is known to degrade through epimerization or auto-oxidation processes, especially when it is exposed to light, temperature fluctuations, some pH values, or the presence of oxygen. Consuming green tea with EGCG can alleviate the effects of bone diseases, such as osteoporosis, and support faster bone regeneration in the case of fractures. Therefore, this review focuses on the current state of research, highlighting the effects of EGCG on bone biology, such as enhancing osteoblast differentiation, promoting bone mineralisation, improving bone microarchitecture, and inhibiting osteoclastogenesis through the modulation of the RANK/RANKL/OPG pathway. Additionally, EGCG exerts antioxidant, anti-inflammatory, and dose-dependent effects on bone cells. It also downregulates inflammatory markers (TNF-α, IL-1β, and COX-2) and reduces oxidative stress via the inhibition of reactive oxygen species generation and the activation of protective signalling pathways (e.g., MAPK and NF-κB). Studies in animal models confirm that EGCG supplementation leads to increased bone mass and strength. These findings collectively support the further exploration of EGCG as an adjunct in the treatment and prevention of metabolic bone diseases. The authors aim to present the relationship between EGCG and bone health, highlighting issues for future research and clinical applications. Full article

Background: Natural products are key sources of anti-inflammatory agents, yet the potential of fish visceral extracts remains largely unexplored. This study evaluated the anti-inflammatory activity of a spleen extract from rainbow trout (Oncorhynchus mykiss). Methods: A crude spleen extract and its four solvent fractions were tested in LPS-stimulated RAW264.7 macrophages. Nitric oxide production and expression of iNOS, COX-2, and cytokines were assessed by qRT-PCR and Western blotting. The most active fraction, OSB (n-butanol layer), was further analyzed for its effects on NF-κB signaling, macrophage polarization, and ROS generation. Results: The crude spleen extract significantly reduced NO production and downregulated iNOS and COX-2 expression at both the transcriptional and translational levels. Among the four fractions, the OSB fraction exhibited the most potent and consistent anti-inflammatory effects. OSB markedly suppressed LPS-induced expression of iNOS, COX-2, and pro-inflammatory cytokines, while enhancing anti-inflammatory cytokines. Mechanistic analyses demonstrated that OSB inhibited NF-κB activation by preventing the nuclear translocation of the p65 subunit. Additionally, OSB attenuated LPS-induced ROS production and reduced the expression of M1 macrophage markers, indicating inhibition of M1 polarization. Conclusions: The OSB fraction from rainbow trout spleen exhibits potent anti-inflammatory activity by modulating the NF-κB pathway and suppressing M1 macrophage polarization, suggesting its potential as a natural therapeutic agent. Full article

Background: Ibuprofen is one of the most accessible non-steroidal anti-inflammatory drugs (NSADs), exhibiting non-selective reversible inhibition on COX-1 and COX-2. A series of common adverse reactions have been mentioned through the years: gastrointestinal (gastritis, ulceration, hemorrhage, or perforation), renal, hematologic, and cardiovascular. Objective: The aim of this study was to assess the real-world impact of ibuprofen regarding cardiovascular safety, utilizing an established pharmacovigilance database. Methods: Descriptive and disproportionality-based methods were used. Forty specific descriptors of cardiovascular effects were selected. Eight other NSADs and the combination of ibuprofen and pseudoephedrine were used as comparators. Results: A total of 58,760 cases were identified as being associated with ibuprofen in EudraVigilance. Stroke was reported for ibuprofen with a lower probability compared with etoricoxib (ROR: 0.34; 95% CI: 0.21–0.55), celecoxib (ROR: 0.07; 95% CI: 0.06–0.10), meloxicam (ROR: 0.25; 95% CI: 0.14–0.43), acetylsalicylic acid (ROR: 0.07; 95% CI: 0.05–0.09), and ibuprofen/pseudoephedrine (ROR: 0.11; 95% CI: 0.05–0.25). Thrombosis was reported for ibuprofen with a higher probability only relative to ketoprofen (ROR: 2.95; 95% CI: 1.71–5.09). Hypertension was reported for ibuprofen as being more probable than for acetylsalicylic acid (ROR: 1.58; 95% CI: 1.43–1.76). Myocardial infarction was reported as being more probable for ibuprofen than ketoprofen (ROR: 2.31; 95% CI: 1.57–3.40) or nimesulide (ROR: 2.43; 95% CI: 1.25–4.73). Conclusions: Overall, according to our study, the probability of reported cardiovascular adverse reactions is lower than those determined for the rest of the NSAIDs; however, taking into consideration the inherent limitations of the study, further clinical investigations would contribute to a better understanding of the cardiovascular safety of ibuprofen. Full article

Background/Objectives: Inflammation is a crucial and complex mechanism that protects the body against infections. In our study, we propose to provide scientific evidence for the anti-inflammatory properties of 1,3,5-triazine derivatives. Methods: Initially, we ensured the safety of the three synthesized derivatives by administering graded doses of up to 2000 mg/kg intraperitoneally in Wistar rats. Thus, the three derivatives were considered generally safe. We also evaluated their ability to reduce carrageenan-induced rat paw edema. Results: Compounds 1, 2, and 3 demonstrated stronger anti-inflammatory activity than indomethacin (10 mg/kg), achieving maximum inhibition at the fourth hour with percentages of 96.31%, 72.08%, and 99.69%, respectively, at a dose of 200 mg/kg, compared to 57.66% for the standard drug. To explore the mechanism, levels of pro-inflammatory cytokines (TNF-α, IL-1α, IL-1β, IL-6, CRP) and oxidative stress markers were measured in paw tissue. All three compounds significantly reduced these markers more effectively than indomethacin and enhanced antioxidant levels (SOD and GSH) beyond those achieved by the standard treatment. Additionally, the compounds reduced COX-1 and COX-2 levels to values comparable to those in the normal (non-inflamed) control group. Conclusions: Compounds 1, 2, and 3 at doses of 200 mg/kg significantly (p  < 0.05) inhibited the heat-induced hemolysis of red blood cell (RBC) membranes by 94.6%, 93.9%, and 95.2%, respectively, compared to 94.5% produced by indomethacin. Consequently, we concluded that 1,3,5-triazine derivatives are a safe antioxidant agent with significant anti-inflammatory activity. Full article

Young leaves of reed (Phragmites communis) have been reported to exhibit antioxidant effects; however, their anti-inflammatory properties have not yet been investigated. In this study, we evaluated the effects of young reed leaf extract (PCE) on LPS-induced inflammation in RAW 264.7 cells and elucidated the underlying molecular mechanisms. Our results demonstrate that PCE significantly inhibited the production of nitric oxide (NO) by approximately 45% at 100 μg/mL (p < 0.01) and pro-inflammatory cytokines such as IL-6, TNF-α, and GM-CSF by 40–60% (p < 0.01) in LPS-stimulated RAW 264.7 macrophages, without cytotoxicity up to 100 μg/mL. PCE also downregulated the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) and upregulated heme oxygenase-1 (HO-1) expression by approximately 2-fold at 100 μg/mL (p < 0.05). Mechanistically, these effects were associated with the inhibition of IκBα phosphorylation/degradation, IKKα/β phosphorylation, and AP-1 activation via the suppression of JNK and ERK signaling pathways, as well as the inhibition of STAT1/3 phosphorylation. Collectively, our findings suggest that PCE exerts anti-inflammatory effects by modulating the IκB, AP-1, and STAT1/3 signaling pathways, thereby suppressing inflammatory mediator production and enhancing antioxidant defense mechanisms in LPS-treated macrophages. Full article

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

Background/Objectives: The influence of single-nucleotide polymorphisms (SNPs) on hepatocellular carcinoma (HCC) in terms of etiological factors remains to be explored. This study evaluated the distribution of PNPLA3 rs738409, TM6SF2 rs58542926, and HSD17B13 rs6834314 and overall survival of HCC patients with metabolic dysfunction-associated steatotic liver disease (MASLD-HCC) and viral-related HCC (VIRAL-HCC). Methods: This study included 564 patients with HCC: 254 with MASLD-HCC and 310 with VIRAL-HCC. The SNPs were determined by real-time PCR using TaqMan assays. Results: The mean ages of patients with MASLD-HCC and VIRAL-HCC were 68.4 vs. 60.9 years (p < 0.001), with a significant difference between groups. The prevalence of PNPLA3 GG genotype in MASLD-HCC was significantly higher in MASLD-HCC than in VIRAL-HCC (24.0% vs. 15.5%, OR = 1.86, 95% CI = 1.14–3.05, p = 0.009). Similarly, the prevalence of TM6SF2 TT genotype in MASLD-HCC and VIRAL-HCC was 7.1% vs. 2.6% (OR = 3.39, 95% CI = 1.36–9.21, p = 0.003), while HSD17B13 GG genotype in the corresponding groups was 7.1% vs. 12.6% (OR = 0.53, 95% CI = 0.27–1.01, p = 0.039). The overall median survival of MASLD-HCC was significantly shorter than that of the VIRAL-HCC group (42 vs. 66 months, p = 0.035). In Cox regression hazard analysis, HSD17B13 GG genotype was significantly associated with a lower mortality rate in MASLD-HCC (HR = 0.38, 95% CI = 0.18–0.81, p = 0.011). In contrast, PNPLA3 and TM6SF2 were not associated with overall survival in patients with MASLD-HCC or VIRAL-HCC. Conclusions: Our data demonstrated that the prevalence of the SNPs significantly differed between MASLD-HCC and VIRAL-HCC. The HSD176B13 GG genotype was also associated with a survival benefit in Thai patients with MASLD-HCC. Thus, assessing the HSD176B13 genotype might be beneficial in risk stratification and potential therapeutic inhibition of HSD17B13 among patients with MASLD-HCC. Full article