Search Results (1,956)

Background: Acetaminophen (APAP) is a popular and safe pain reliever. Due to its widespread availability, it is commonly implicated in intentional or unintentional overdoses, which result in severe liver impairment. Pristimerin (Prist) is a natural triterpenoid that has potent antioxidant and anti-inflammatory properties. Our goal was to explore the protective effects of Prist against APAP-induced acute liver damage. Method: Mice were divided into six groups: control, Prist control, N-acetylcysteine (NAC) + APAP, APAP, and two Prist + APAP groups. Prist (0.4 and 0.8 mg/kg) was given for five days and APAP on day 5. Liver and blood samples were taken 24 h after APAP administration and submitted for different biochemical and molecular assessments. Results: Prist counteracted APAP-induced acute liver damage, as it decreased general liver dysfunction biomarkers, and attenuated APAP-induced histopathological lesions. Prist decreased oxidative stress and enforced hepatic antioxidants. Notably, Prist significantly reduced the genetic and protein expressions of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-II), p-phosphatidylinositol-3-kinase (p-PI3K), p-protein kinase B (p-AKT), and the inflammatory cytokines: nuclear factor kappa B (NF-κB), tumor necrosis factor-α (TNF-α), and interleukins-(IL-6 and IL-1β) in hepatic tissues. Additionally, the m-RNA and protein levels of the apoptotic Bcl2-associated X protein (BAX) and caspase-3 were lowered and the anti-apoptotic B-cell leukemia/lymphoma 2 (BCL-2) was increased upon Prist administration. Conclusion: Prist ameliorated APAP-induced liver injury in mice via its potent anti-inflammatory/antioxidative and anti-apoptotic activities. These effects were mediated through modulation of NF-κB/iNOS/COX-II/cytokines, PI3K/AKT, and BAX/BCL-2/caspase-3 signaling pathways. 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

Black Chiloe’s giant garlic is a functional food produced by a mild Maillard reaction that contains relevant bioactive molecules like organosulfur compounds (OSCs) and (poly)phenols (PPs). Compared with raw garlic, black garlic has a higher content of PPs and S-allyl cysteine (SAC), a key OSC due to its bioactivities. The objective of the present work was to optimize by chemometric tools a green microwave-assisted extraction (MAE) of SAC and PPs present in black Chiloe’s giant garlic to detect and identify novel bioactive molecules with antioxidant and/or inhibitory activities over cyclooxygenase, α-glucosidase, and acetylcholinesterase enzymes. The MAE factors were optimized using a central composite design, establishing optimal PP and SAC yields at 67 °C, 0% ethanol, 12 min and 30 °C, 40% ethanol, 3 min, respectively. PP and SAC values were 9.19 ± 0.18 mg GAE/g DW and 2.55 ± 0.10 mg SAC/g DW. Applying effect-directed analysis using high-performance thin layer chromatography-bioassay and mass spectrometry, the bioactive molecules present in the MAE extract with antioxidant and inhibitory activities over cyclooxygenase, α-glucosidase, and acetylcholinesterase enzymes were identified as N-fructosyl-glutamyl-S-(1-propenyl)cysteine, N-fructosyl-glutamylphenylalanine, and Harmane. 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

Background: Pharmaceutical compounds frequently co-occur in environmental waters, but studies on their combined effects on animals and humans remain limited. The present study investigated the individual and combined short-term effects of ketoprofen (Kp, a nonsteroidal anti-inflammatory drug inhibiting cyclooxygenase-2), valproic acid (VPA, an anticonvulsant acting as a voltage-gated sodium channel modulator), and meropenem (Mp, a β-lactam antibiotic) at environmentally relevant concentrations on zebrafish behavior, acetylcholinesterase (AChE) activity, and oxidative status. Methods: Adult zebrafish were exposed for 4 days to Kp, VPA, Mp, and their binary and ternary mixtures. Behavioral effects were assessed using 3D novel tank and social behavior tests, while the oxidative stress response was assessed through malondialdehyde (MDA) content, superoxide dismutase (SOD), and glutathione peroxidase (GPx) activities. Results: Zebrafish exposed to Mp showed a notable increase in immobility, whereas those exposed to VPA and Mp + Kp exhibited a significant augmentation of average velocity and counter-clockwise rotations. All treated groups exhibited a notable increase in the time spent near the walls (thigmotaxis), and except for the control and Mp-exposed zebrafish, the other groups mostly stayed in the bottom tank zone (geotaxis). Kp, VPA + Kp, and VPA + Mp + Kp treatments impaired social behavior, with zebrafish displaying less interest in conspecifics. Biochemical analysis demonstrated that both the individual drugs and their combination caused oxidative stress, characterized by decreased GPx activity and increased SOD activity and MDA levels. Moreover, AChE activity was more strongly inhibited in zebrafish exposed to the binary and ternary mixtures than to individual drugs. Conclusions: The results indicate that acute exposure to individual and/or combined pharmaceuticals induces behavioral changes, oxidative damage, and AChE inhibition in zebrafish, highlighting the need to assess the effects of pharmaceutical mixtures for comprehensive ecosystem risks evaluation. Full article

Naturally occurring prostaglandin E₂ (PGE₂) influences cytokine production regulation in bovine neutrophils exposed to Staphylococcus aureus Rosenbach. Here, we employed bovine neutrophils as the primary experimental system, and administered specific inhibitors targeting various receptors, which were subsequently exposed to S. aureus. Cytokine expression levels in dairy cow neutrophils induced by S. aureus via the endogenous PGE₂-EP2/4 receptor pathway were investigated, and its effects on P38, extracellular signal-regulated kinase (ERK), P65 activation, and phagocytic function in Staphylococcus aureus Rosenbach-induced dairy cow neutrophils, were examined. Blocking cyclooxygenase-2 (COX-2) and microsomal prostaglandin E synthase-1 (mPGES-1) enzymes substantially decreased PGE₂ production and release in S. aureus-exposed bovine neutrophils. Cytokine output showed significant reduction compared to that in SA113-infected controls. Phosphorylation of P38, ERK, and P65 signaling molecules was depressed in the infected group. Pharmacological interference with EP2/EP4 receptors similarly diminished cytokine secretion and phosphorylation patterns of P38, ERK, and P65, with preserved cellular phagocytic function. During S. aureus infection of bovine neutrophils, COX-2 and mPGES-1 participated in controlling PGE₂ biosynthesis, and internally produced PGE₂ molecules triggered NF-κB and MAPK inflammatory pathways via EP2/EP4 receptor activation, later adjusting the equilibrium between cytokine types that promote or suppress inflammation. This signaling mechanism coordinated inflammatory phases through receptor-mediated processes. Full article

Although it is more than a century since it was first marketed, acetaminophen remains one of the most popular analgesic agents. In addition, acetaminophen has recently been applied to multimodal analgesia in combination with non-steroidal anti-inflammatory drugs, and its consumption significantly increased during the pandemic of coronavirus disease 2019 as well as diclofenac and ibuprofen. However, the detailed mode of analgesic action of acetaminophen is still unclear. In the present study, we comprehensively discuss conventional, recognized, and postulated mechanisms of analgesic acetaminophen and highlight the current mechanistic concepts while comparing with diclofenac and ibuprofen. Acetaminophen inhibits cyclooxygenase with selectivity for cyclooxygenase-2, which is higher than that of ibuprofen but lower than that of diclofenac. In contrast to diclofenac and ibuprofen, however, anti-inflammatory effects of acetaminophen depend on the extracellular conditions of inflamed tissues. Since the discovery of cyclooxygenase-3 in the canine brain, acetaminophen had been hypothesized to inhibit such a cyclooxygenase-1 variant selectively. However, this hypothesis was abandoned because cyclooxygenase-3 was revealed not to be physiologically and clinically relevant to humans. Recent studies suggest that acetaminophen is deacetylated to 4-aminophenol in the liver and after crossing the blood–brain barrier, it is metabolically converted into N-(4-hydroxyphenyl)arachidonoylamide. This metabolite exhibits bioactivities by targeting transient receptor potential vanilloid 1 channel, cannabinoid receptor 1, Cav3.2 calcium channel, anandamide, and cyclooxygenase, mediating acetaminophen analgesia. These targets may be partly associated with diclofenac and ibuprofen. The perspective of acetaminophen as a prodrug will be crucial for a future strategy to develop analgesics with higher tolerability and activity. Full article

Background: Peritoneal stretching from CO₂ insufflation is a primary mechanism of pain associated with laparoscopy. Cyclooxygenase-2 inhibitors are promising anti-inflammatory and analgesic agents. This study aimed to evaluate the effect of celecoxib on postoperative pain reduction and associated changes in peritoneal gene expression after laparoendoscopic single-site (LESS) surgery for benign gynecologic disease. Methods: In this randomized, double-blind, placebo-controlled pilot study, 70 patients were randomly assigned to receive either celecoxib or placebo (400 mg) 40 min before surgery. Peritoneal tissues were collected before and after CO₂ insufflation. We analyzed changes in expressions of prostaglandin I₂ synthase, prostaglandin E synthase (PTGES), PTGES3, aldo-keto reductase family 1 member C1, and 15-hydroxyprostaglandin dehydrogenase (HPGD). Numeric Rating Scale (NRS) pain scores were also compared between groups. Results: A total of 62 patients completed the study: 30 in the celecoxib group and 32 in the placebo group. The mean CO₂ exposure time was 60.4 min. In a quantitative real-time polymerase chain reaction analysis, HPGD mRNA expression significantly increased after surgery in patients exposed to CO₂ for more than 60 min. Patients treated with celecoxib showed a significantly higher rate of grade 3 expression (83.3% vs. 37.5%; p = 0.01) and a level 2 increase in HPGD expression on in situ hybridization (58.3% vs. 12.5%; p = 0.01), despite no significant difference on immunohistochemistry. Moreover, celecoxib effectively reduced NRS pain scores compared to placebo. Conclusions: In this pilot study, celecoxib appeared to reduce postoperative pain and was associated with increased HPGD mRNA expression in the peritoneal tissue of patients with prolonged CO₂ exposure during LESS surgery. These exploratory findings warrant confirmation in larger trials with functional validation of HPGD expression (ClinicalTrials.gov, NCT03391570). Full article

Neurotrophins and inflammatory mediators are known to influence endometrial function, but their interplay in luminal epithelial cells remains poorly characterized. In this study, sheep endometrial luminal epithelial cells (SELECs) were treated with nerve growth factor (NGF), lipopolysaccharide (LPS), or both, and the effects on gene expression and prostaglandin secretion were evaluated. NGF stimulation alone induced a clear transcriptional activation of NGF, neurotrophic receptor tyrosine kinase 1 (NTRK1), p75 neurotrophin receptor (p75NTR), cyclooxygenase 2 (COX2), and steroidogenic acute regulatory protein (STAR). LPS treatment selectively increased Toll-like receptor 4 (TLR4), COX2, and insulin-like growth factor binding protein 6 (IGFBP6). Combined NGF and LPS treatment did not enhance the transcriptional response beyond that induced by NGF alone, except for STAR. However, co-treatment resulted in a modest increase in prostaglandin production, particularly prostaglandin F2α (PGF2α), but not prostaglandin E2 (PGE2), compared to single treatments, suggesting a possible post-transcriptional modulation rather than a transcriptional synergy. These findings indicate that NGF acts as the primary transcriptional driver in SELECs, while LPS contributes selectively and may enhance prostaglandin output. The observed increase in prostaglandin production may involve post-transcriptional mechanisms, although this remains to be confirmed. Full article

This study systematically reviews the non-traditional pharmacological effects of diclofenac, a well-known nonsteroidal anti-inflammatory drug, to explore its potential for drug repositioning beyond its established analgesic and anti-inflammatory applications. A comprehensive literature search was conducted using the PubMed, Scopus and Web of Science databases, covering studies from 1981 to 2025. It was revealed that over 94% of records in Scopus and Web of Science are duplicated in PubMed, so the latter was used for the search in our study. After duplicate removal and independent screening, 89 from 1123 retrieved studies were selected for the search. The analysis revealed a broad spectrum of diclofenac’s non-traditional pharmacological activities, including neuroprotective, antiamyloid, anticancer, antiviral, immunomodulatory, antibacterial, antifungal, anticonvulsant, radioprotective, and antioxidant properties, primarily identified through preclinical In vitro and In vivo studies. These effects are mediated through diverse molecular pathways beyond cyclooxygenase inhibition, such as modulation of neurotransmitter release, apoptosis, and cellular proliferation. Diclofenac showed potential for repositioning in oncology, neurodegenerative disorders, infectious diseases, and immune-mediated conditions. Its hepatotoxicity and cardiovascular risks necessitate strategies like advanced drug formulations, dose optimization, and personalized medicine to enhance safety. Large-scale randomized clinical trials are essential to validate these findings and ensure safe therapeutic expansion. 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

Diabetic retinopathy (DR), traditionally considered a microvascular complication, is now recognized as a neuroinflammatory disorder involving retinal glial cells. Aldose reductase (AKR1B1), a key enzyme in the polyol pathway, has been implicated in the hyperglycemia-induced inflammatory response in various cell types, although its role in retinal Müller glial cells under acute glucose stress remains unclear. This study investigates AKR1B1 activity and its contribution to inflammatory signaling in MIO-M1 human Müller cells exposed to acute hyperglycemia. AKR1B1 expression and activity, as well as NF-κB activation and COX-2 expression, were evaluated. Sorbinil, a specific AKR1B1 inhibitor, was used to determine the enzyme’s contribution to acute hyperglycemia-induced inflammation. Acute high-glucose treatment significantly increased AKR1B1 activity and sorbitol accumulation without affecting cell viability. In addition, activation of NF-κB and increased expression of cyclooxygenase-2 (COX-2) were observed, both of which were significantly reduced by Sorbinil. Our findings highlight the role of macroglia as active contributors to early inflammatory events in DR and suggest that transient hyperglycemic spikes are sufficient to trigger AKR1B1-dependent glial activation. 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

The incidence of Hashimoto’s disease (HD) increases with age and in people who have other autoimmune diseases. It is characterized by lymphocytic infiltration, fibrosis, and atrophy of the thyroid parenchyma with the simultaneous presence of thyroid peroxidase antibodies (ATPO) and/or thyroglobulin antibodies (ATG). Eicosanoids are formed via the cyclooxygenase (COX), lipoxygenase (LOX), and monooxygenase (CYP450) pathways with arachidonic acid (ARA), resulting in the production of epoxyeicosatrienoic acids (EETs) or hydroxyeicosatetraenoic acids (HETEs). These eicosanoids can act in an autocrine or paracrine manner on target cells. This study aimed to examine whether a gluten-free diet (GFD) can modulate the enzymatic pathways of the pro-inflammatory ARA cascade. The study material consisted of serum samples from Caucasian female patients with HD aged 18–55 years. Participants were enrolled in the study based on the presence of an ultrasound characteristic of HD, and elevated serum levels of anti-thyroid peroxidase antibodies and anti-thyroglobulin antibodies. Patients with confirmed celiac disease did not participate in the study. A total of 78 samples were analyzed, with 39 collected after 3 months of following a GFD. Eicosanoids (thromboxane B2, prostaglandin E2, leukotriene B4, and 16R-hydroxy-5Z,8Z,11Z,14Z-eicosatetraenoic acid (16-RS HETE)) were extracted using high-performance liquid chromatography. The contribution of leukotriene (LTB) was analyzed in the LOX pathway, prostaglandins (PGE2) and thromboxane (TXB2) were selected for the involvement of the COX pathway, and 16RS HETE was used for the CYP450 pathway. All parameters were analyzed before and after a 3-month dietary intervention that included a gluten-free diet. In the obtained results, only one mediator, leukotriene B4, was significant (p < 0.05). The mean level on the initial visit was 0.202 ± 0.11 (SD), while it was 0.421 ± 0.27 (SD) on the subsequent visit, indicating a significant increase in its level after implementing a GFD. Although there was a trend in the CYP 450 pathway of decreased 16-RS HETE, the presented correlations show that thromboxane B4 and 16RS-HETE were positively correlated with the body mass and body fat mass of the examined patients. There was a trend in the CYP 450 pathway of decreased 16-RS HETE after GFD. Thromboxane B4 and 16RS-HETE levels before GFD were positively correlated with the body mass and body fat mass of the examined patients. A gluten-free diet in HD does not suppress the synthetic pathways of LOX, COX, or cytochrome P450 (CYP450). The level of adipose tissue has a greater impact on the inflammatory processes in HD than a gluten-free diet. This study does not confirm the suppressive effect of a gluten-free diet on the pro-inflammatory arachidonic acid cascade in any of the three analyzed mediator synthesis LOX, COX, CYP450 pathways. Full article