Search Results (2,142)

Combination analgesic therapy is commonly used to improve pain control, yet conventional molecular docking approaches typically evaluate individual ligands and provide limited insight into potential intermolecular associations between co-administered drugs. In this study, paracetamol, codeine, and their proposed 1:1 and 2:1 non-covalent assemblies were investigated using lipophilicity analysis, molecular docking, short molecular dynamics relaxation, electrostatic potential surface mapping, and HOMO–LUMO analysis. Docking simulations were performed against cyclooxygenase-1 (COX-1), cyclooxygenase-2 (COX-2), and the μ-opioid receptor (MOR). The proposed assemblies produced docking scores that differed from those of the individual compounds, with the most pronounced differences observed for the cyclooxygenase targets. The 2:1 assemblies generally exhibited the most favorable docking scores, whereas the predicted interaction profiles at MOR appeared to be more dependent on molecular orientation. Molecular dynamics relaxation and electronic structure analyses further revealed differences in the energetic and electronic characteristics of the investigated configurations. These findings support the theoretical feasibility of distinct interaction patterns among the proposed paracetamol–codeine assemblies within the applied computational framework. However, the reported docking scores represent relative computational values rather than experimentally validated binding affinities, and the short-timescale molecular dynamics simulations provide only preliminary information regarding conformational stability. Furthermore, the existence and biological relevance of the proposed assemblies under physiological conditions remain to be established. This study provides a computational basis for future investigations of intermolecular associations in multicomponent drug systems. Full article

Oxidative stress and inflammation are central environmental contributors to skin aging, accelerating extracellular matrix (ECM) breakdown and loss of dermal structure. Although Nypa fruticans is recognized for its antioxidant properties, the constituents responsible for these effects remain undefined. To address this, we screened five major polyphenols—protocatechuic acid (PA), hydroxybenzoic acid (HA), procyanidin B1 (PB), catechin (CA), and epicatechin (EC)—for protective activity in two inflammatory skin cell models: human dermal fibroblasts (HDFs) stimulated with tumor necrosis factor-α (TNF-α), and human epidermal keratinocytes (HEKs) co-stimulated with TNF-α and interferon-γ (IFN-γ). PB emerged as the most consistently active compound. In fibroblasts, it suppressed intracellular reactive oxygen species, limited matrix metalloproteinase-1 (MMP-1) release, and restored pro-collagen I α1 output. In keratinocytes, it reduced both pro-inflammatory cytokines—interleukin (IL)-6, IL-8, and IL-1β and inflammatory mediators, including prostaglandin E₂ (PGE₂), cyclooxygenase-2 (COX-2), and nitric oxide (NO). At the transcriptional level, PB shifted the ECM balance by lowering MMP expression while elevating collagen- and hyaluronan-associated genes. Collectively, these results position PB as a principal driver of the protective activity of Nypa fruticans (N. fruticans) leaves under inflammatory conditions. Mechanistically, PB suppressed nuclear factor kappa B (NF-κB) activation and promoted nuclear factor erythroid 2-related factor 2 (Nrf2) nuclear translocation in keratinocytes, supporting its dual anti-inflammatory and antioxidant activities. Full article

Although oxidative stress plays a critical role in age-related macular degeneration (AMD) progression, natural product–derived single compounds against AMD remain largely unexplored. We investigated the protective effects and underlying mechanism of α-iso-cubebene against AMD-like retinal injury. Alterations in key phenotypes for AMD were analyzed in AMD-mimicking models using ARPE-19 cells co-treated with blue light (BL) and N-retinylidene-N-retinylethanolamine (A2E), as well as BL-exposed BALB/c mice. In BL+A2E-treated ARPE-19 cells, α-iso-cubebene reduced intracellular reactive oxygen species (ROS) and nitric oxide (NO) production and restored superoxide dismutase (SOD) activity and nuclear factor erythroid 2–related factor 2 (Nrf2), suggesting enhancement of the antioxidant defense system. Furthermore, α-iso-cubebene improved cell viability, reduced apoptotic cell populations, and regulated apoptosis-related signaling pathways under oxidative stress conditions. It also attenuated cyclooxygenase-2 (COX-2)-mediated inducible nitric oxide synthase (iNOS) signaling and was associated with reduced inflammasome-related signaling. Importantly, these protective effects were consistently observed regarding the protection of histopathological structure and normalization of inflammatory cytokines in the retina of BL-exposed BALB/c mice. Collectively, our results demonstrate that α-iso-cubebene, as a potential therapeutic candidate, alleviates AMD-like retinal injury and was associated with enhanced antioxidant responses and reduced inflammatory and apoptotic signaling markers. Full article

Polyelectrolyte complex (PEC)-based carriers offer a promising strategy to improve the oral delivery of anti-inflammatory agents with limited bioavailability or variable pharmacodynamic profiles. This study evaluated the anti-inflammatory and antinociceptive effects of previously optimized formulations of chitosan/xanthan gum PEC microparticles loaded with either ibuprofen or escin, using the carrageenan-induced paw edema model, histopathological and cyclooxygenase-2 (COX-2) immunohistochemical analyses, and the hot plate test. Ibuprofen-loaded microparticles significantly reduced paw swelling during the peak inflammatory phase (5–6 h after treatment administration), although no significant differences in overall edema response or antinociceptive activity were observed compared with free ibuprofen. In contrast, escin-loaded microparticles at 10 mg/kg produced the most pronounced anti-inflammatory effect, significantly reducing paw swelling, edema area under the curve (AUC), histopathological lesion scores, and COX-2 expression compared with both the negative control and the corresponding free escin formulation. Escin-loaded microparticles also showed stronger and more sustained antinociceptive activity than free escin. However, the 20 mg/kg formulation did not provide additional anti-inflammatory or antinociceptive benefits. These findings demonstrate that chitosan/xanthan gum PEC microparticles can enhance the pharmacodynamic performance of orally administered anti-inflammatory agents. The magnitude of this effect depended on the incorporated drug and was particularly notable for escin, for which microencapsulation improved both anti-inflammatory and antinociceptive efficacy. Full article

Atopic dermatitis (AD) is a chronic inflammatory dermatosis driven by skin barrier impairment and immune dysregulation. This study aimed to investigate the anti-inflammatory and barrier-related effects of the ethanol extract of Bidens bipinnata L. fruits (EEBB) in a calcipotriol (MC903)-induced AD-like dermatitis mouse model and lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages. In vivo, repeated topical application of EEBB (60, 180, and 600 μg/day) significantly attenuated MC903-induced AD-like clinical symptoms, skin weight, and erythema index. Notably, EEBB significantly improved skin hydration-related parameters, including relative skin hydration readings and the post-application moisture retention profile, and partially restored filaggrin and loricrin expression in lesional skin, whereas dexamethasone showed limited effects on these hydration-related parameters under the present conditions. Histopathologically, EEBB ameliorated epidermal lesions and reduced inflammatory cell infiltration. Mechanistically, EEBB suppressed the levels of pro-inflammatory (TNF-α, IFN-γ) and Th2 (IL-4, IL-5) cytokines in lesional skin. In vitro, EEBB significantly inhibited the production of nitric oxide (NO) and prostaglandin E₂ (PGE₂), and downregulated inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) protein expression in RAW 264.7 cells. These effects were associated with inhibited phosphorylation of JNK and p38 MAPK, with no marked effect on ERK phosphorylation under the present conditions. In conclusion, EEBB effectively alleviated AD-like dermatitis, accompanied by improved skin hydration and restoration of barrier-related protein expression, attenuation of local inflammatory responses, and targeted inhibition of the MAPK signaling pathway. Full article

Background: Eggshell membrane peptides (ESMPs) are natural bioactive compounds with reported chondroprotective properties. However, their regulatory effects on canine chondrocytes remain unclear. This study investigated ESMP in an interleukin-1β (IL-1β)-induced inflammatory model of canine chondrocytes. Methods: Chondrocytes were assigned to control (Cont), IL-1β, and ESMP + IL-1β groups. Cell viability was assessed using the Cell Counting Kit-8 (CCK-8) assay. NF-κB p65 nuclear translocation was evaluated by immunofluorescence staining. Real-time quantitative PCR (RT-qPCR) and Western blotting (WB) were used to measure mRNA and protein expression levels, respectively. Results: ESMP inhibited IL-1β-induced NF-κB p65 nuclear translocation and reduced the IL-1β-induced increases in interleukin-6 (IL-6), cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), and matrix metalloproteinase-13 (MMP-13) at both mRNA and protein levels. ESMP also decreased IL-6, nitric oxide (NO), and prostaglandin E₂ (PGE₂) levels in culture supernatants. ESMP reversed the IL-1β-induced reduction in type II collagen α1 chain (COL2A1) and aggrecan (ACAN) expression at both transcriptional and protein levels. Conclusions: ESMP attenuates IL-1β-induced inflammatory responses and extracellular matrix degradation in canine chondrocytes, potentially associated with suppression of NF-κB p65 nuclear translocation. This supports its potential application in promoting joint health in dogs. Full article

Background: Gentamicin-induced nephrotoxicity limits clinical pharmacotherapy and involves multiple converging stress-response pathways. Ellagic acid (EA) has renoprotective potential, yet its role in coordinating endoplasmic reticulum (ER) stress-mediated apoptosis, autophagy, and inflammation remains unclear. We hypothesized that EA co-treatment would protect the kidney by modulating ER stress-dependent pathways and associated inflammatory and adaptive signaling. Methods: For an integrated mechanistic analysis in a rat model of gentamicin nephrotoxicity, 40 male Sprague-Dawley rats were assigned to control, gentamicin (100 mg/kg), EA (100 mg/kg), and gentamicin + EA groups for 14 days. Renal function, oxidative stress, inflammatory mediators, ER stress markers, apoptosis, autophagy, tubular injury markers, and histopathological changes were assessed. Results: Gentamicin induced renal dysfunction, tubular injury, and ER stress across all unfolded protein response (UPR) branches (IRE1α, PERK, ATF6), C/EBP homologous protein (CHOP)-associated apoptosis, dysregulated autophagy, and upregulated kidney injury molecule-1 (KIM-1). A selective inflammatory signature was observed, with increased cyclooxygenase-2 (COX-2) and interleukin-6 (IL-6), whereas tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1β) remained unchanged. Co-administration of ellagic acid with gentamicin significantly improved renal function markers compared to the gentamicin group. In contrast, ellagic acid alone did not show significant differences compared to the control group. Notably, gentamicin induced compensatory upregulation of nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) expression, while ellagic acid co-treatment attenuated this compensatory upregulation, likely secondary to reduced oxidative stress burden. Conclusions: This study provides integrated evidence that ER stress is closely associated with gentamicin nephrotoxicity. The key novel findings include selective suppression of IL-6, modulation of the apoptosis-autophagy balance, and attenuation of Nrf2/HO-1 signaling without direct reactive oxygen species (ROS) scavenging, demonstrating a multi-target framework for EA’s renoprotective effects. These findings suggest that ellagic acid mitigates renal injury in a context-dependent manner rather than confirming a direct causal mechanism. Full article

Carbon monoxide (CO) is a gasotransmitter generated by heme oxygenase (HO) isoforms during heme catabolism. The inducible HO-1 produces CO under conditions of redox imbalance, such as oxidative stress and inflammation. On the other hand, HO-2 constitutively generates CO, primarily during the physiological turnover of heme. Extensive evidence indicates that CO exerts autocrine effects by targeting hemoproteins, including soluble guanylyl cyclase, cyclooxygenase, and cytochromes. Furthermore, CO regulates many biological processes within the brain, including mitochondrial biogenesis, potassium channel activity, mitogen-activated protein kinase and phosphatidylinositol-3-kinase/Akt signaling. It also controls the activity of transcription factors, such as hypoxia-inducible factor-1 and peroxisome proliferator-activated receptor-γ. Through these mechanisms, CO modulates inflammatory gene expression, promotes anti-apoptotic signaling, and contributes to local stress responses. Conversely, CO produced in the hypothalamus inhibits the stress-induced release of corticotropin-releasing hormone and arginine vasopressin under pro-inflammatory conditions, resulting in reduced adrenocorticotropin hormone release and cortisol secretion from the anterior pituitary and adrenal cortex, respectively. Moreover, hypothalamic CO acts in a paracrine manner to modulate glucocorticoid release during psychological stress, including restraint or water deprivation. Together, these findings support the view that endogenous CO is a key modulator of the stress axis, exerting pleiotropic effects that integrate neuroendocrine, immune, and metabolic responses. Full article

Compounds from olive (Olea europaea L.) and pomegranate (Punica granatum L.) have many beneficial effects on human health. This review paper considers the inhibitory potential, under in vitro conditions, of bioactive components of olive and pomegranate on different enzyme systems. Research shows that olive polyphenols (oleuropein, hydroxytyrosol, luteolin, and oleocanthal), as well as pomegranate polyphenols (punicalagin, urolithin A, ellagic acid), inhibit cyclooxygenase and lipoxygenase enzymes, which are associated with inflammatory processes. They also show an inhibitory effect on acetylcholinesterase, butyrylcholinesterase, and β-secretase, which opens up the possibility of a strong neuroprotective effect. Olive and pomegranate polyphenols also have an inhibitory effect on enzymes involved in carbohydrate metabolism, such as amylase and glucosidase, and can help fight diabetes and regulate human metabolism. In addition, polyphenols and extracts of both plants showed an inhibitory effect on cytochrome P450 enzymes, which metabolize most drugs. These data open up the possibility of interactions with certain groups of drugs. The current evidence supports the view that olive and pomegranate polyphenols act as biologically versatile compounds with considerable pharmaceutical and nutraceutical potential. Future investigations integrating enzymology, metabolomics, molecular docking, and clinical validation will be essential for translating these promising in vitro findings into evidence-based therapeutic applications. Full article

Vitex madiensis Oliv. (Lamiaceae) is a species growing in tropical and subtropical regions throughout the world. In several African countries, the different organs of this plant, leaves, fruits, stem bark and roots are used in folk medicine for the treatment of headaches, toothaches, aches and pains. In this study, we investigated the phytochemical profile of Vitex madiensis leaf extracts using LC-MS. The antioxidant and anti-inflammatory potential of crude extracts, fractions, and pure molecules was evaluated using reactive oxygen species (ROSs) production assays and cyclooxygenase-2 inhibition assays. A bio-guided fractionation was carried out to identify the most active fractions and resulted in the isolation of four phytoecdysteroids from the n-butanol fraction: 20-hydroxyecdysone, ajugasterone C, vitexirone, and pterosterone. 20-hydroxyecdysone showed very good anti-inflammatory properties with a significant reduction of more than 70% of COX-2 expression in induced LPS-stimulated human blood leukocytes compared to the control. This study confirmed the therapeutic potential of phytoecdysteroids. Full article

Background: Actinic keratoses are common keratinocytic precursor lesions arising within chronically ultraviolet-damaged skin and are associated with an increased risk of progression to cutaneous squamous cell carcinoma. The concept of field cancerization has shifted therapeutic strategies from the treatment of isolated visible lesions toward broader field-directed approaches targeting both clinical and subclinical disease. Methods: This narrative review summarizes the rationale, mechanisms of action, efficacy profile, tolerability, and practical limitations of currently available field-directed therapies for actinic keratosis, including 5-fluorouracil, imiquimod, diclofenac, photodynamic therapy, and tirbanibulin. Based on their distinct biological targets, we propose a mechanism-based framework for sequential treatment strategies. Results: Available therapies act through partially non-overlapping mechanisms, including cytotoxic activity, immune activation, cyclooxygenase-2 inhibition, photodynamic oxidative damage, and tubulin/Src pathway inhibition. These complementary effects provide a biological rationale for sequential regimens aimed at addressing the heterogeneity of field cancerization. However, direct clinical evidence supporting specific treatment sequences remains limited, and proposed regimens should be interpreted as hypothesis-generating rather than as validated therapeutic protocols. Conclusions: Mechanism-based sequential field therapy may represent a rational strategy to optimize long-term control of actinic keratosis and field cancerization. Prospective comparative studies are needed to define optimal sequences, treatment intervals, patient selection criteria, and clinically meaningful endpoints, including sustained field clearance, recurrence reduction, tolerability, adherence, and prevention of progression to invasive cutaneous squamous cell carcinoma. Full article

Objective: Nutritional modulation of the immune function provides a promising strategy to mitigate systemic inflammation associated with viral and bacterial infections. This study evaluated the immunomodulatory and anti-inflammatory effects of a novel phycocyanin oligopeptide (PC-O) supplement, alone or in combination with selenium (Se) and zinc (Zn), in a lipopolysaccharide (LPS)-induced murine model of inflammation. Methods: Forty-two male BALB/c mice were pretreated with Se, Zn, PC-O or a combination of these for 14 days, followed by LPS administration to induce systemic inflammation. Serum biochemical markers, tissue oxidative stress parameters, pro-inflammatory cytokines, antioxidant enzyme activities, histopathological alterations, Zn transporter expression, and inflammatory signaling proteins were evaluated. Results: LPS administration induced pronounced hepatic and pulmonary inflammation, characterized by elevated IL-1β, IL-6, and TNF-α levels, increased oxidative stress, and disrupted expression of Zn transporters. While PC-O, Se, or Zn alone partially attenuated these effects, combined supplementation produced the most substantial protective response. Notably, the combination group demonstrated significant reductions in rectal temperature, hepatic enzymes (ALT and AST), lipid peroxidation, and cytokine expression, alongside restored antioxidant enzyme activities and normalized Zn transporter levels. Protein expression analyses revealed marked suppression of NF-κB, cyclooxygenase-2 (COX-2), and inducible nitric oxide synthase (iNOS) in liver and lung tissues. Conclusions: Combined supplementation with PC-O, Se, and Zn provides enhanced protection against LPS-induced inflammation, likely through coordinated antioxidant and anti-inflammatory mechanisms. This nutritional strategy may help strengthen host defense and limit inflammation-driven tissue injury. Full article

Background: Sambucus ebulus L. berries contain numerous bioactive compounds, but their volatile molecular composition has not yet been fully characterized. In this study, we analyzed the volatile components of the essential oil and aqueous infusion prepared from dried S. ebulus fruits, followed by multitarget in silico analysis of the major compounds against the following enzymes implicated in neuroinflammation and oxidative stress, namely cyclooxygenase-2 (COX2), monoamine oxidases (MAO-A and MAO-B), acetylcholinesterase (AChE), and butyrylcholinesterase (BChE), for which inhibitory activity of plant-derived compounds has previously been reported. Methods: Steam distillation, gas chromatography-mass spectrometry (GC-MS), and gas chromatography-flame ionization detection (GC-FID) were employed for compound isolation and analysis. Molecular docking studies were performed using Schrödinger software (version 2025-1). Results: Fatty acid esters and hexahydrofarnesyl acetone predominated in the essential oil, whereas linalool was identified as the major constituent of the infusion. MAO-A was predicted to be the most favorable interaction target for hexahydrofarnesyl acetone and other major constituents. Conclusions: Our findings expand the currently limited available data on the volatile composition of S. ebulus fruits and characterize the volatile profile of its fruit infusion for the first time. The in silico analyses suggest that S. ebulus volatile constituents may interact with several target enzymes implicated in neurodegeneration and inflammation. Full article

The Senegal tree (Sengalia senegal) is the primary plant source of Gum Arabic (GA), a natural secretion rich in soluble fiber and bioactive polysaccharides. It has longstanding uses in traditional medicine, nutrition, and pharmaceuticals. The present study aimed to evaluate the phytochemical profile, antimicrobial, anti-inflammatory, and anticancer activities of GA methanolic extract (GAME), supported by molecular docking analysis of its key compounds. The gas chromatography–mass spectrometry (GCMS) analysis of the GAME identified many compounds, such as 9-octadecenoic acid (38.29%), methyl ester (15.52), 1,2-benzenedicarboxylic acid, 3-nitro (9.8%), hexadecadienoic acid, methyl ester (8.5), and á-d-mannofuranoside, methyl (7.38). The molecular docking analysis showed that 9-octadecenoic acid had strong binding affinity with target proteins, which included xanthine oxidase (XO), lipoxygenase (LOX), and cyclooxygenase-2 (COX-2), with the highest affinity to XO (−137.03 kcal/mol) and lipoxygenase (−135.09 kcal/mol). GAME possessed broad-spectrum antibacterial activity against Salmonella typhimurium (S. typhimurium), Escherichia coli (E. coli), Pseudomonas aeruginosa (P. aeruginosa), and Staphylococcus aureus (S. aureus), with a zone of inhibition from 16.28 to 16.93 mm. B. subtilis was resistant to the tested extract. The extract also showed good membrane stability and potent inhibition of albumin, XO, LOX, and COX-2, with IC₅₀ values of 31.62, 13.02, 27.6, and 28.99 μg/mL, respectively. The cytotoxic assessment demonstrated moderate, dose-dependent effects on the Caco-2 (colorectal adenocarcinoma) and HeLa (cervical carcinoma) cell lines. These findings highlight the therapeutic potential of GA as a natural plant source of antibacterial, anti-inflammatory and anticancer agents. The combination of molecular docking with in vitro assays provides strong evidence supporting its application in the development of plant-based pharmaceuticals. This research suggests that GA could be a useful ingredient in the creation of anti-inflammatory and antibacterial drugs derived from plants. Full article

Dicarbadodecaboranes (12) (carboranes) are versatile molecular building blocks with unique properties, which allow the expansion of classical medicinal-chemical space. To enable single-photon emission computed tomography (SPECT) imaging of cyclooxygenase-2 (COX-2), we investigated the feasibility of introducing iodine-123 into nido-indoborin 1, a nido-carborane analog of indomethacin with potent and selective cyclooxygenase-2 inhibitory activity. An electrophilic iodination strategy afforded two regioisomers, 2a and 2b, bearing the iodine at the carborane cluster. Compared to nido-indoborin, a reduced COX-2 inhibition potency and selectivity were observed, with 2b exhibiting the more favorable inhibition profile. Radiosynthesis of [¹²³I]2b was achieved by N-chlorosuccinimide–mediated electrophilic substitution of 1, and conditions were optimized, leading to an isolated radiochemical yield of 4%. While the radiotracer displayed high stability in phosphate buffer, ester hydrolysis was observed in human plasma and murine liver microsomes with no significant deiodination in vitro. Cell uptake studies indicated partial COX-2–dependent accumulation but also revealed substantial non-specific uptake and unexpected enhancement of radiotracer uptake in the presence of carborane-based blocking agents. In vivo pilot imaging studies in mice bearing U87 xenografts showed renal and hepatobiliary clearance without measurable tumor accumulation but evidence of deiodination over time. Overall, iodination was feasible, but the resulting compounds lacked the required COX-2-selective tumor accumulation for further radiotracer development. Full article