Search Results (1,857)

Compounds containing the 1,2,4-triazole moiety in their structure exhibit broad biological activities. Many of these compounds demonstrate anti-inflammatory activity in vitro through various mechanisms, such as inhibiting COX-1/COX-2 and LOX, modulating pro-inflammatory cytokine levels, or having effects on other specific enzymes. Some also display activities in vivo. In many publications, the activities of new 1,2,4-triazole-based compounds exceed those of the reference drugs, suggesting their promising potential as new therapeutic agents. This review of active 1,2,4-triazole derivatives with anti-inflammatory activity is based on literature published from 2015–2024. Full article

Inflammation and oxidative stress are crucial for osteoarthritis (OA) pathogenesis. Despite the potential of pharmacological pretreatment of chondrocytes in preventing OA, its efficacy in preventing the progression of cartilage damage and promoting its recovery has not been examined. In this study, an H₂O₂-induced human OA-like chondrocyte cell model was created using H1467 primary human chondrocytes to evaluate the efficacy of interleukin (IL)-6 and cyclooxygenase (COX)-2 inhibitors (tocilizumab and celecoxib, respectively) in the prevention and treatment of cartilage damage. H₂O₂ significantly elevated the IL-6, COX-2, and matrix metalloproteinase (MMP)-13 levels. Although monotherapy decreased the levels, nuclear shrinkage and altered cell morphology, similar to those in the H₂O₂ group, were observed. The expression of these factors was significantly lower in the combination therapy group, and the cell morphology was maintained. Moreover, the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway was activated, and levels of the antioxidant protein heme oxygenase-1 (HO-1) were increased, especially in the combination group, indicating an anti-inflammatory effect. The treatment groups, particularly the combination group, demonstrated increased cell viability. Overall, the drug combination exhibited superior efficacy in preventing the progression of cartilage damage and promoted its recovery compared with the monotherapy. Given that the drugs herein are already in clinical use, they are suitable candidates for OA treatment. Full article

The design of novel anti-inflammatory drugs remains a critical area of research in the development of effective treatments for inflammatory diseases. In this study, a series of 1,2-benzothiazine was evaluated through a multifaceted approach. In particular, we investigated the potential interactions of the potential drugs with lipid bilayers, an important consideration for membrane permeability and overall pharmacokinetics. In addition, we evaluated their ability to inhibit cyclooxygenase 1 and cyclooxygenase 2 activity and selectivity using both a cyclooxygenase inhibition assay and molecular docking simulations. To evaluate their therapeutic potential, we performed in vitro assays to measure cytokine mRNA expression in inflamed cells. The antioxidant activity was evaluated using both in vitro assays, such as 2,2-diphenyl-1-picrylhydrazyl and 2,2-azino-bis-3-ethylbenzothiazoline-6-sulphonic acid scavenging, to determine the compounds’ capacity to neutralize free radicals and reduce oxidative stress. Theoretical calculations, including density functional theory, were used to predict the reactivity profiles of the compounds. Full article

Campylaephora hypnaeoides (C. hypnaeoides) was extracted using fermented ethanol. The effect of fermented ethanol extract of C. hypnaeoides (FeCH) on chondrocyte viability was analyzed by 3-(4,5-dimethylthiazol-2-yl)-2,5-iphenyltetrazolium bromide assay, which showed no cytotoxicity at 2 mg/mL. FeCH pretreatment in IL-1β-stimulated chondrocytes significantly inhibited the accumulation of nitric oxide and prostaglandin E₂, which was analyzed using the ELISA assay. In addition, protein expression levels of inflammatory-related factors, such as inducible nitric oxide synthase, cyclooxygenase-2, interleukin-6, tumor necrosis factor-alpha, and cartilage-degrading-related enzymes, such as matrix metalloproteinases-1, -3, and -13, and a disintegrin and metalloproteinase with thrombospondin motifs-4 and -5 were significantly decreased in IL-1β-stimulated chondrocytes pretreated with FeCH, which were analyzed using western blot analysis. In addition, as a result of analyzing the content of collagen type II (Col II) and proteoglycan through western blot analysis and alcian blue staining, FeCH pretreatment prevented the degradation of Col II and proteoglycan. It was analyzed through western blot analysis that the chondroprotective effect of FeCH may be mediated through MAPKs and NF-κB-signaling mechanisms. In an in vivo study, an osteoarthritis experimental animal model with damaged medial meniscus (DMM) was utilized and orally administered daily for 8 weeks after surgery. At the study end point, knee joints were harvested and subjected to histological analysis with safranin O staining. As a result, articular cartilage was significantly protected in the FeCH group compared to the DMM group. These results suggest FeCH as a candidate material for the development of pharmaceutical materials for the treatment or prevention of degenerative arthritis. Full article

A possible involvement of immune- and vasoregulatory PACAP signaling at the PAC1 receptor in atherogenesis and plaque-associated vascular inflammation has been suggested. Therefore, we tested the PAC1 receptor agonist Maxadilan and the PAC1 selective antagonist M65 on plaque development and lumen stenosis in the ApoE^−/− atherosclerosis model for possible effects on atherogenesis. Adult male ApoE^−/− mice were fed a cholesterol-enriched diet (CED) or standard chow (SC) treated with Maxadilan, M65 or Sham. Effects of treatment on atherosclerotic plaques, lumen stenosis, apoptosis and pro-inflammatory signatures were analyzed in the brachiocephalic trunk (BT). The percentage of Maxadilan treated mice exhibiting plaques under SC and CED was lower than that of Sham or M65 treatment indicating opposite effects of Maxadilan and M65. Maxadilan application inhibited lumen stenosis in SC and CED mice compared to the Sham mice. In spite of increased cholesterol levels, lumen stenosis of Maxadilan-treated mice was similar under CED and SC. In contrast, M65 under SC or CED did not reveal a significant influence on lumen stenosis. Maxadilan significantly reduced the TNF-α-immunoreactive (TNF-α⁺) area in the plaques under CED, but not under SC. In contrast, the IL-1β⁺ area was reduced after Maxadilan treatment in SC mice but remained unchanged in CED mice compared to Sham mice. Maxadilan reduced caspase-3 immunoreactive (caspase-3⁺) in the tunica media under both, SC and CED without affecting lipid content in plaques. Despite persistent hypercholesterolemia, Maxadilan reduces lumen stenosis, apoptosis and TNF-α driven inflammation. Our data suggest that Maxadilan provides atheroprotection by acting downstream of hypercholesterolemia-induced vascular inflammation. This implicates the potential of PAC1-specific agonist drugs against atherosclerosis even beyond statins and PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitors. Full article

A novel screening platform based on an Fe₃O₄@C@PDA-Ni²⁺@COX-2 ligand fishing combination with high-performance liquid chromatography–mass spectrometry was first designed, synthesized, and employed to screen and identify COX-2 inhibitors from Panax notoginseng leaves. The obtained magnetic nanoparticles exhibit outstanding preconcentration ability that allows for controlling the enzyme orientation to avoid enzyme active site blocking, conformational changes, or denaturing during immobilization. The as-prepared Fe₃O₄@C@PDA-Ni²⁺@COX-2 composite was carefully characterized by scanning electron microscopy (SEM), transmission electron microscopy (TEM), Fourier-transform infrared spectrometry (FT-IR), Xray powder diffraction (XRD), thermal gravimetric analyzer (TGA), vibrating sample magnetometer (VSM), and Zeta potential analysis. The analytical parameters influencing the magnetic solid-phase fishing efficiency were optimized by univariate and multivariate methods (Box–Behnken design) by testing a positive control and celecoxib with active and inactive COX-2. Under the optimized ligand fishing conditions, twelve potential COX-2 inhibitors were screened and characterized in Panax notoginseng leaves. The results indicate that the proposed method provides a simple, feasible, selective, and effective platform for the efficient screening and identification of active compounds from Chinese herbal medicine. It has guiding significance for the synthesis and development of novel anti-inflammatory drugs, and provides a reference for the efficient discovery of anti-inflammatory drugs or lead compounds from the complex system of Chinese herbal medicine. Full article

In patients with aspirin-exacerbated respiratory disease (AERD), there is disparate regulation of prostaglandin E2 (PGE₂) and prostaglandin D₂ (PGD₂). Both prostanoids are synthesised by cyclooxygenase 1 (COX-1) and cyclooxygenase 2 (COX-2). However, while the basal synthesis of PGE₂ tends to decrease, that of PGD₂ increases in patients with AERD. Furthermore, both behave differently in response to the inhibitory action of NSAIDs on COX-1: PGE₂ levels decrease while PGD₂ increases. Increased PGD₂ release correlates with nasal, bronchial, and extra-pulmonary symptoms caused by aspirin in AERD. The proposed hypothesis establishes that the answer to this paradoxical dissociation can be found in the airway epithelium. This is based on the observation that reduced COX-2 mRNA and/or protein expression is associated with reduced PGE₂ synthesis in cultured fibroblast and epithelial cells from AERD compared to patients with asthma who are aspirin-tolerant and healthy subjects. The low production of PGE₂ by the airway epithelium in AERD results in an excessive release of alarmins (TSLP, IL-33), which in turn contributes to activating group 2 innate lymphoid cells (ILC2s) and PGD₂ synthesis by mast cells and eosinophils. Aspirin, by further increasing the diminished PGE₂ regulation capacity in AERD, leads to respiratory reactions associated with the surge in PGD₂ from mast cells and eosinophils. In summary, the downregulation of COX-2 and the subsequent low production of PGE₂ by airway cells account for the apparently paradoxical increased production of PGD₂ by mast cells and eosinophils at the baseline and after aspirin provocation in patients with AERD. A better understanding of the role of the airway epithelium would contribute to elucidating the mechanism of AERD. Full article

Background/Objectives: Particulate matter (PM) is an environmental pollutant that negatively affects human health, particularly skin health. In this study, we investigated the inhibitory effects of broccoli sprout extract (BSE) on PM-induced skin aging and inflammation in human keratinocytes. Methods: HaCaT keratinocytes were pretreated with BSE before exposure to PM. Cell viability was assessed using the MTT assay. The expression of skin aging and inflammation markers (MMP-1, COX-2, IL-6) was measured using Western blot, ELISA, and qRT-PCR. Reactive oxygen species levels were determined using the DCF-DA assay. Kinase assays and pull-down assays were conducted to investigate the interaction between BSE and p38α MAPK. Results: Our findings demonstrate that BSE effectively suppressed the expression of MMP-1, COX-2, and IL-6—critical skin aging and inflammation markers—by inhibiting p38 MAPK activity. BSE binds directly to p38α without competing with ATP, thereby selectively inhibiting its activity and downstream signaling pathways, including MSK1/2, AP-1, and NF-κB. Conclusions: These results suggest that BSE is a potential functional ingredient in skincare products to mitigate PM-induced skin damage. Full article

Klebsiella pneumoniae (K. pneumoniae) is a significant pathogen associated with clinical mastitis in cattle. Anti-inflammatory drugs are necessary to alleviate pain and inflammation during clinical mastitis. Among many drugs, meloxicam (MEL) has been widely used in clinical mastitis because of its excellent inhibitory effect on the cyclooxygenase-2 (COX-2) enzyme. However, the effectiveness of MEL on the inflammatory response and oxidative stress induced by K. pneumoniae are unclear. In the present study, primary BMECs were infected with K. pneumoniae in the presence or absence of plasma maintenance concentration of MEL (0.5 and 5 μM). Following 1 or 3 h of combined treatment with K. pneumoniae and MEL, BMECs were gathered to assess the related indicators. The results showed that MEL at plasma maintenance concentrations exerted no influence on the viability of uninfected BMECs and also had no impact on bacterial load in BMECs. At these concentrations, MEL was able to inhibit the mRNA expression of COX-2, Interleukin (IL)-1β, Tumor necrosis factor α (TNF-α), and IL-6 while simultaneously elevating the mRNA levels of IL-8 in K. pneumoniae-infected BMECs. MEL had clear effects on relieving oxidative stress by increasing the activity of superoxide dismutase (SOD) and catalase (CAT) and the level of total antioxidant capacity (T-AOC). The mechanisms by which MEL mitigated the inflammatory response and oxidative stress were partially attributed to inhibition of the nuclear transcription factor-kappa B (NF-κB) signaling pathway and improvement of the activation of the nuclear factor erythroid 2-related factors (Nrf2) signaling pathway. To conclude, the results manifested that MEL at plasma maintenance concentrations protected BMECs from inflammatory and oxidative damage induced by K. pneumoniae. Full article

Premature skin aging, also known as photoaging, refers to the changes in the structure and function of the skin caused by chronic sun exposure. The ultraviolet radiation in sunlight is one of the key factors that cause photoaging. Thus, matrix metalloproteinases (MMPs), transforming growth factor beta-1 (TGFB1), and nuclear factor kappa B (NF-κB) signaling can be an effective therapeutic strategy for ultraviolet B (UVB) exposure. In this study, we used human dermal fibroblast and mouse macrophage cells to identify the mediators of skin photoaging. Quercitrin isolated from ‘Green Ball’ apple peel was treated to UVB-irradiated fibroblast cells and lipopolysaccharide (LPS)-induced macrophages to identify the photoaging prevention effect of quercitrin. Genes that are associated with photoaging were determined by using enzyme-linked immunosorbent assay (ELISA), Western blot, and quantitative polymerase chain reaction (qPCR). Quercitrin increased the collagen biosynthesis in UVB-irradiated fibroblast cells via regulating MMPs, TIMP metallopeptidase inhibitor 1 (TIMP-1), TGFB1, hyaluronan synthase 2 (HAS2), and collagen type I alpha 1 chain (COL1A2). In addition, quercitrin regulated p-65, inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2), and its mediators (prostaglandin E2 and nitric oxide), in the NF-κB signaling process, and it inhibited the production of cytokines in LPS-induced macrophages. These results indicate that quercitrin can improve photoaging damaged skin by regulating MMPs, TGFB1, and NF-κB signaling pathway modulators. Full article

Background: Psoriatic arthritis (PsA), a chronic inflammatory disease, mainly affects the joints, with approximately 30% of psoriasis patients eventually developing PsA. Characterized by both innate and adaptive immune responses, PsA poses significant challenges for effective treatment. Recent advances in drug delivery systems have sparked interest in developing novel formulations to improve therapeutic outcomes. The current research focuses on the development and evaluation of a nanosponge-loaded, cyclo-oxygenase-2 (COX-2) inhibitor-based topical gel for the treatment of PsA. Methods: Nanosponges (NSs) were prepared by using beta-cyclodextrin as a polymer and dimethyl carbonate (DMC) as a crosslinker by melting, and gels were prepared by employing carbopol and badam gum as polymers. Results: Solubility studies confirmed that the prepared nanosponges were highly soluble. FT-IR studies confirmed the formation of hydrogen bonds between lumiracoxib and beta-cyclodextrin. SEM confirmed that the prepared formulations were roughly spherical and porous in nature. The average particle size was 190.5 ± 0.02 nm, with a zeta potential of −18.9 mv. XRD studies showed that the crystallinity of lumiracoxib decreased after encapsulation, which helped to increase its solubility. The optimized nanosponges (NS2) were incorporated in an optimized gel (FG10) to formulate a nanosponge-loaded topical gel. The optimized gel formulation exhibited a homogeneous consistency, with a pH of 6.8 and a viscosity of 1.15 PaS, indicating its suitability for topical application and stability. The in vitro diffusion studies for the topical gel showed drug release of 82.32% in 24 h. The optimized formulation demonstrated significant antipsoriatic activity, as confirmed through cytotoxicity studies conducted on HaCaT cells. Conclusions: On the basis of the findings, it can be concluded that the prepared nanosponge-loaded topical gel formulation presents a promising solution for the effective management of PsA, offering enhanced drug solubility, sustained release, and improved therapeutic potential. Full article

Background/Objectives: Diabetes mellitus (DM), a widespread endocrine disorder characterized by chronic hyperglycemia, can cause nerve damage and increase the risk of neurodegenerative diseases such as Alzheimer’s disease (AD). Effective blood glucose management is essential, and sitagliptin (SITG), a dipeptidyl peptidase-4 (DPP-4) inhibitor, may offer neuroprotective benefits in type 2 diabetes mellitus (T2DM). Methods: T2DM was induced in rats using nicotinamide (NICO) and streptozotocin (STZ), and biomarkers of AD and DM-linked enzymes, inflammation, oxidative stress, and apoptosis were evaluated in the brain. Computational studies supported the in vivo findings. Results: SITG significantly reduced the brain enzyme levels of acetylcholinesterase (AChE), beta-secretase-1 (BACE-1), DPP-4, and glycogen synthase kinase-3β (GSK-3β) in T2DM-induced rats. It also reduced inflammation by lowering cyclooxygenase-2 (COX-2), prostaglandin E2 (PGE2), tumor necrosis factor-α (TNF-α), and nuclear factor-κB (NF-κB). Additionally, SITG improved oxidative stress markers by reducing malondialdehyde (MDA) and enhancing glutathione (GSH). It increased anti-apoptotic B-cell lymphoma protein-2 (Bcl-2) while reducing pro-apoptotic markers such as Bcl-2-associated X (BAX) and Caspace-3. SITG also lowered blood glucose levels and improved plasma insulin levels. To explore potential molecular level mechanisms, docking was performed on AChE, COX-2, GSK-3β, BACE-1, and Caspace-3. The potential binding affinity of SITG for the above-mentioned target enzymes were 10.8, 8.0, 9.7, 7.7, and 7.9 kcal/mol, respectively, comparable to co-crystallized ligands. Further binding mode analysis of the lowest energy conformation revealed interactions with the critical residues. Conclusions: These findings highlight SITG’s neuroprotective molecular targets in T2DM-associated neurodegeneration and its potential as a therapeutic approach for AD, warranting further clinical investigations. Full article

Sorbus commixta Hedl. is a traditional medicinal plant in Korea, China, and Japan with known antioxidative, anti-inflammatory, anti-atherogenic, and anti-melanin activities. However, its anti-neuroinflammatory effects remain largely unknown. In this study, we investigated the inhibitory effects of S. commixta fruit extracts on lipopolysaccharide-stimulated pro-inflammatory factors in BV-2 microglia. We compared the anti-neuroinflammatory activity of S. commixta fruit water extract (SFW) and 70% ethanol extract using a nitric oxide assay. Our data indicated that the SFW (25–100 μg/mL) treatment significantly inhibited excessive nitric oxide production in lipopolysaccharide-stimulated BV-2 microglia compared to the 70% ethanol extract. It also attenuated the expression of inducible nitric oxide synthase, cyclooxygenase-2, and pro-inflammatory cytokines such as interleukin-6 and tumor necrosis factor α. Moreover, SFW exhibited its anti-inflammatory properties by downregulating the expression of factors involved in the extracellular signal-regulated kinase, c-Jun N-terminal kinase, and p38 mitogen-activated protein kinase pathways and by suppressing nuclear factor kappa B. Caffeic acid was identified as a primary component of SFW showing anti-neuroinflammatory activity. These findings suggest that SFW may offer substantial therapeutic potential for the treatment of neurodegenerative diseases involving microglia activation. Full article

Polygonum aviculare L. (PAL), commonly known as knotgrass, has been utilized as a traditional folk medicine across Asian, African, Latin American and Middle Eastern countries to treat various inflammatory diseases, including arthritis and airway inflammation. Numerous medicinal herbs exert anti-inflammatory and antioxidative effects that are mediated through the activation of nuclear factor-erythroid 2-related factor 2 (Nrf2) and the inhibition of nuclear factor kappa B (NF-κB). However, the underlying molecular mechanisms linking the antioxidative and anti-inflammatory effects remain poorly understood. Heme oxygenase-1 (HO-1) is an antioxidant enzyme that catalyzes heme degradation, ultimately leading to the production of carbon monoxide (CO). Elevated levels of CO have been correlated with the decreased level of inducible nitric oxide synthase (iNOS). In this study, we examined whether HO-1 plays a key role in the relationship between the antioxidative and anti-inflammatory properties of PAL. The anti-inflammatory and antioxidative activities of PAL in an in vitro system were evaluated by determining NF-κB activity, antioxidant response element (ARE) activity, pro-inflammatory cytokine and protein levels, as well as antioxidant protein levels. To examine whether HO-1 inhibition interfered with the anti-inflammatory effect of PAL, we measured nitrite, reactive oxygen species, iNOS, and HO-1 levels in RAW 264.7 murine macrophages pre-treated with Tin protoporphyrin (SnPP, an HO-1 inhibitor). Our results demonstrated that PAL increased ARE activity and the Nrf2-regulated HO-1 level, exerting antioxidative activities in RAW 264.7 macrophages. Additionally, PAL reduced cyclooxygenase-2 (COX-2) and iNOS protein levels by inactivating NF-κB in lipopolysaccharide (LPS)-activated RAW 264.7 macrophages. Further investigation using the HO-1 inhibitor revealed that HO-1 inhibition promoted iNOS expression, subsequently elevating nitric oxide (NO) generation in LPS-activated RAW 264.7 macrophages treated with PAL compared to those in the macrophages without the HO-1 inhibitor. Overall, our findings suggest that HO-1 induction by PAL may exert anti-inflammatory effects through the reduction of the iNOS protein level. Hence, this study paves the way for further investigation to understand molecular mechanisms underlying the antioxidative and anti-inflammatory activities of medicinal herbs. Full article

Background: Bondarzewia dickinsii (BD) is a newly discovered edible mushroom with rich nutritional components. This study presents a thorough analysis of the components of BD, examining its inhibitory effects and the underlying mechanisms by which BD influences colitis-associated cancer (CAC). Methods: AOM/DSS-induced CAC mice (male C57BL/6) were used, and a histopathological analysis, intestinal microbiota assessment, and metabolomics profiling were carried out, as well as an evaluation of relevant proteins and factors, to investigate the CAC-inhibitory effects of BD. Results: BD is rich in nutritional components, including a total sugar content of 37.29% and total protein content of 24.9%. BD significantly diminished colon inflammation, as well as the size and quantity of tumors. In addition, BD modified the diversity of intestinal microbiota and changed the levels of 19 serum metabolites, including arachidonic acid. BD significantly reduced prostaglandin E2 (PGE2) and cyclooxygenase-2 (COX-2) in colon tissue. Furthermore, it was found to inhibit the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/COX-2 signaling pathway. Conclusions: In general, BD inhibited the onset and progression of CAC by modulating the composition of intestinal microbiota and metabolite levels, suppressing the PI3K/AKT/COX-2 pathway, and decreasing PGE2 expression. This study provides a significant reference for the development of BD as a dietary supplement and pharmaceutical agent in the treatment of CAC. Full article