Cyclooxygenase Research Articles

Exploring Xiaojianzhong decoction's potential in gastric cancer treatment: Integrative insights and experimental validation

Gastric cancer (GC) remains a formidable global health concern with significant morbidity and mortality rates, despite the fact that numerous advances have been made to improve conventional therapies. Xiaojianzhong decoction (XJZ), a traditional Chinese medicine, has garnered academic attention as a multicomponent, multitarget approach to managing GC. The present editorial explores the potential of XJZ in the treatment of GC through a comprehensive analysis of network pharmacology and experimental validation. Network pharmacology was used to identify key molecular targets of XJZ, including interleukin 6, prostaglandin-endoperoxide synthase 2, and matrix metalloproteinase 9, and in vitro experiments were used to confirm the efficacy of XJZ in inhibiting cell proliferation, inducing apoptosis, and modulating gene expression associated with GC progression. This editorial highlights XJZ as a promising therapeutic strategy for GC and indicates a need for further clinical exploration and validation of its efficacy.

Esomeprazole inhibits liver inflammation and carcinogenesis by suppressing farnesoid X receptors and NF-κB signaling.

The activity of proton pump inhibitors (PPIs) hinders the function of proton pumps that generate stomach acid. Nuclear factor kappa B (NF-κB) is a transcriptional factor engaged in inflammation, immunity and the formation of cancer. The farnesoid X receptor (FXR) is a nuclear receptor that governs the metabolism of bile acids and the metabolic functioning of the liver. The impact of PPIs on the signaling of FXRs and NF-κB is not well understood. We aimed to study the effects of esomeprazole on FXRs and NF-κB signaling in liver cells. For the liver cell model, we used the human liver cell line HepaG2. Cells were treated with lipopolysaccharides (LPS) and esomeprazole, and then we assessed the effects of esomeprazole on inflammatory and carcinogenic markers, NF-κB and FXR. We applied the techniques of western blotting, reverse-transcription polymerase chain reaction (RT-PCR), confocal microscopic imaging, and electrophoretic mobility shift assay (EMSA). Lipopolysaccharides-induced FXRs and NF-κB signaling upregulated the NF-κB-associated cytokines interleukin 6 (IL-6), cyclooxygenase-2 (COX-2) and tumor necrosis factor alpha (TNF-α). Esomeprazole inhibited the upregulation of all these cytokines. Additionally, esomeprazole inhibited LPS-induced FXR expression and NF-κB signaling in HepaG2 cells. The net effect on FXRs and NF-κB signaling was the lower levels of the associated inflammatory and carcinogenic cytokines. Our study provides insight into the potential therapeutic effects of esomeprazole on hepatic inflammation and carcinogenesis by inhibiting LPS-induced NF-κB and FXR expression in HepG2 cells.

Acid-sensing ion channel-1 contributes to the failure of myelin sheath regeneration following spinal cord injury by transcellular delivery of PGE2

BackgroundTraumatic injuries to spinal cord lead to severe motor, sensory, and autonomic dysfunction. The accumulation of inhibitory compounds plays a pivotal role in the secondary damage to sparing neural tissue and the failure of axonal regeneration and remyelination. Acid-sensing ion channel-1(ASIC1A) is widely activated following neurotrauma, including spinal cord injury (SCI). However, its role in SCI remains elusive.MethodsThe effects of acidic environment on the differentiation and genes changes of neural stem cells (NSCs) were assessed by immunofluorescence staining and RNA-sequencing analysis, respectively. The expression of ASIC1A and prostaglandin endoperoxide synthase 2 (PTGS2) were detected by western blot and immunofluorescence staining. The concentration of prostaglandin E2 (PGE2) within NSC-derived extracellular vesicles were evaluated by ELISA. Small-interfering RNAs (siRNAs) were used to knock down Asic1a and Ptgs2 expression in NSCs. The myelin sheath regeneration and axonal remyelination in rats and Asic1a-KO mice were assessed by immunofluorescence staining.ResultsFollowing injury to the spinal cord, ASIC1A was found to be colocalized and upregulated in NSCs. ASIC1A activation prevents the differentiation of NSCs into oligodendrocytes by upregulating PTGS2, which leads to increased production and release of PGE2 within extracellular vesicles (EVs). ASIC1A or PTGS2 deficiency in NSCs counters the ASIC1A-related effects on mediating NSC differentiation by reducing PGE2 expression within NSC-derived EVs. Furthermore, intervention in ASIC1A signaling by administration of ASIC1A inhibitors or genetic deletion of ASIC1A demonstrated a pronounced advantage in enhancing myelin sheath regeneration and axonal remyelination.ConclusionsThe activation of ASIC1A prevents NSC differentiation into oligodendrocytes via the transcellular NSC-to-NSC delivery of PGE2, resulting in the failure of myelin sheath regeneration and axonal remyelination following SCI. The inhibition of ASIC1A presents a promising therapeutic strategy for the treatment of SCI.Graphical

Investigation of the association between COX-2 polymorphisms and external apical root resorption in orthodontically treated patients.

To evaluate the association between single nucleotide polymorphisms (SNPs) in cyclooxygenase-2 (COX-2) and external apical root resorption (EARR) after orthodontic treatment. This study analyzed the orthodontic records of patients from Regensburg University Hospital and two collaborating private practices. EARR was analyzed in the maxillary central incisors and first mandibular molars using pre- and post-treatment cephalometric and panoramic radiographs, respectively. Genomic DNA was obtained from salivary oral cells. Two SNPs in COX-2, rs5275 (3 prime untranslated region variant) and rs689466 (upstream transcript variant, downstream transcript variant), were genotyped using real-time Polymerase chain reaction (PCR). The linear regression models were fitted to assess the effects of the evaluated SNPs at a significance level of 5%. A total of 143 biologically unrelated patients (mean age: 13.5 ± 4.5 years) were included in the study. The F-test showed that only the regression for EARR in the mandibular molars in the dominant model for rs5275 G allele had a good fit (F = 3.50, P = 0.034). The model showed that individuals carrying at least one G allele for rs5275 had a 17% increase in EARR in the molars compared to common AA homozygotes (exp(B) = 1.17; 95% CI: 1.04, 1.32; P = 0.010). Although an effect of the G allele (rs5275) was detected, this effect did not explain much of the variability in EARR (adjusted R2 = 0.04). The results suggested that patients carrying the polymorphic form of the rs5275 were more likely to have EARR in the mandibular molars; therefore, COX-2 could have an effect on EARR. The knowledge of the genetic background concerning EARR after orthodontic treatment would aid in clinical practice to screen for associated genetic factors and potentially aid its prevention and management, considering that patients' genetic profiles would soon be available.

Novel Benzimidazole Derivatives as Potent Inhibitors of Microsomal Prostaglandin E2 Synthase 1 for the Potential Treatment of Inflammation, Pain, and Fever.

Microsomal prostaglandin E2 synthase 1 (mPGES-1) is a promising target for treating inflammatory diseases and pain. This study introduces a novel series of benzimidazoles, with the most potent analogs exhibiting IC50 values of 0.27-7.0 nM in a cell-free assay for prostaglandin (PG)E2 production. Compound 44 (AGU654) demonstrated remarkable selectivity for mPGES-1 (IC50 = 2.9 nM) over COX-1, COX-2, 5-LOX, and FLAP, along with excellent bioavailability. Metabololipidomics analysis with activated human monocyte-derived macrophages and human whole blood revealed that AGU654 selectively suppresses PGE2 production triggered by bacterial exotoxins while sparing other prostaglandins. Furthermore, in vivo studies showed that AGU654 significantly alleviated fever, inflammation, and inflammatory pain in preclinical guinea pig models, suggesting that it could be an effective strategy for managing inflammatory diseases. In conclusion, these benzimidazole derivatives warrant further exploration into new and alternative analogs, potentially uncovering novel compounds with a favorable pharmacological profile possessing significant anti-inflammatory and analgesic properties.

Evaluation of the anti-arthritic properties of Litsea glutinosa (L.) C.B. Rob Bark: An integrated analysis utilizing in-silico, in-vitro, and in-vivo approaches, along with identification of major compounds

The current study explored the anti-arthritic properties of Litsea glutinosa bark extracts. The dried bark of L. glutinosa was defatted with n-hexane and extracted by methanol using a soxhlet apparatus. The bioactive compounds present in the extract were analysed by GC-MS and LC-MS. The methanol extract of L. glutinosa (MELG) was evaluated at different concentrations (25–400 mg/ml) for its in-vitro anti-arthritic efficacy using membrane stabilization and protein denaturation techniques. In in-vivo evaluation paw diameter, arthritic score, arthritic index, body weight, organ weight, and haematological and biochemical parameters were measured to assess anti-arthritic potential. Subsequently, pro-inflammatory and inflammatory cytokines such as tumour necrosis factor-alpha (TNF-α), interleukin 6 (IL-6), IL-1β, cyclooxygenase-2 (COX-2), IL-13, and IL-10 were determined. The Compounds identified by GC–MS and LC-MS were subjected to an in-silico molecular docking analysis utilizing AutoDock 4.2 and BIOVIA-Discovery Studio Visualizer against COX-2, IL-1β, IL-6, and TNF-α. The in vitro anti-arthritic effect of MELG exhibited a dose-dependent reduction in membrane stabilization (67.9 % at 400 µg/ml) and protein denaturation assay (66.6 % at 400 µg/ml). MELG treated rats improved all arthritic parameters. Significant restoration of pro-inflammatory cytokines was observed in rats administered with MELG (200 & 400 mg/kg). In the MELG (400 mg/kg) treated group, there was a significant reduction in IL-10 (P˂0.001) and IL-13 (P˂0.05) levels and a substantial rise in IL-6 (P˂0.01), TNF-α (P̂˂0.001), and IL-1β (P˂0.01) levels. The presence of phytoconstituents was analyzed by GC–MS (Fourteen compounds) and LC-MS (Ten compounds). Boldine identified by LC-MS analysis, exhibited good docking scores against COX-2 (-8.7), IL-1β (-6.3 kcal/mol), IL-6 (-6.2 kcal/mol), and TNF-α (-6.7 kcal/mol).The presence of bioactive compound, boldine in MELG might be responsible for its anti-arthritic activity.

Correlation between serum levels of cyclooxygenase-2, aquaporin-1, pepsinogen I, gastrin-17 and pathological features of Laryngeal Cancer.

To explore the association between the levels of cyclooxygenase-2 (COX-2), aquaporin-1 (AQP1), pepsinogen I (PGI), and gastrin-17 (G17) and pathological features of laryngeal cancer (LC). Clinical data of 120 patients with LC, treated in Shanghai Jiao Tong University School of Medicine from May 2022 to May 2023, as well as 120 healthy individuals who underwent physical examinations during the same period, were retrospectively analyzed. Serum levels of COX-2, AQP1, PGI, and G17 of LC patients and the healthy cohort were compared, and their association with pathological features of LC was investigated. LC was associated with significantly higher serum levels of COX-2, AQP1, and G17 and lower of PGI compared to the control group (P<0.05). Levels of COX-2, AQP1, and G17 positively correlated with the tumor, node and metastasis (TNM) staging, infiltration depth, and the lymph node metastases, and negatively correlated with the degree of differentiation (P<0.05). There was a significant negative correlation between the level of PGI and TNM staging, infiltration depth, and lymph node metastases. PG1 also positively correlated with the degree of differentiation (P<0.05). Area under curve (AUC) of combined COX-2, AQP1, PG-I, and G17 was significantly higher than that of each index alone (P<0.05). Levels of COX-2, AQP1, PGI, and G17 showed significant association with specific pathological features of LC. Serum levels of COX-2, AQP1, PGI, and G17 have certain predictive value for LC, and the combined predictive value of these four indicators is higher than that of a single indicator.

Exploring the Promising Role of Guggulipid in Rheumatoid Arthritis Management: An In-depth Analysis.

Guggulipid, an oleo-gum resin extracted from the bark of Commiphora wightii of the Burseraceae family, holds a significant place in Ayurvedic medicine due to its historical use in treating various disorders, including inflammation, gout, rheumatism, obesity, and lipid metabolism imbalances. This comprehensive review aims to elucidate the molecular targets of guggulipids and explore their cellular responses. Furthermore, it summarizes the findings from in-vitro, in-vivo, and clinical investigations related to arthritis and various inflammatory conditions. A comprehensive survey encompassing in-vitro, in-vivo, and clinical studies has been conducted to explore the therapeutic capacity of guggulipid in the management of rheumatoid arthritis. Various molecular pathways, such as cyclooxygenase-2 (COX-2), vascular endothelial growth factor (VEGF), PI3-kinase/AKT, JAK/STAT, nitric oxide synthase (iNOS), and NFκB signaling pathways, have been targeted to assess the antiarthritic and anti-inflammatory effects of this compound. The research findings reveal that guggulipid demonstrates notable antiarthritic and anti-inflammatory effects by targeting key molecular pathways involved in inflammatory responses. These pathways include COX-2, VEGF, PI3-kinase/AKT, JAK/STAT, iNOS, and NFκB signaling pathways. in-vitro, in-vivo, and clinical studies collectively support the therapeutic potential of guggulipid in managing rheumatoid arthritis and related inflammatory conditions. This review provides a deeper understanding of the therapeutic mechanisms and potential of guggulipid in the management of rheumatoid arthritis. The collective evidence strongly supports the promising role of guggulipid as a therapeutic agent, encouraging further research and development in guggulipid-based treatments for these conditions.

Simulated microgravity environment inhibits matrix mineralization during the osteoblast to osteocyte differentiation

This study investigates the effects of microgravity on the differentiation and mineralization of IDG-SW3 osteocyte-like cells to understand the response of bone cells to microgravity and develop strategies to mitigate bone loss in astronauts. IDG-SW3 cells were cultured in collagen-coated dishes and subjected to a 3D clinostat to simulate microgravity 14 days after initiating differentiation. The static group remained under normal gravity. Cells were analyzed on days 14, 18, 22, and 26. Alizarin red staining demonstrated a substantial and time-dependent increase in mineralization in the static group, whereas the microgravity group exhibited little detectable mineralization throughout the experimental period. Quantitative RT-PCR revealed significant upregulation of Rankl, Alpl, Dmp1, and Fgf23 and downregulation of Sost and Phex in the microgravity group. RNA sequencing on day 26 showed distinct gene expression profiles between conditions. Heatmaps highlighted upregulated genes (Ptgs2, Alpl, Comp, Atf4, Lox) and downregulated genes (Rspo2, Ank, Ptn, Mmp13, Aspn, Spp1) under microgravity. Gene ontology (GO) enrichment analysis indicated that upregulated genes were associated with cytoskeletal organization and receptor activities, while downregulated genes were linked to extracellular matrix components and immune response. These findings provide insights into the molecular mechanisms of bone loss in space and emphasize the importance of gravity in bone remodeling. Future studies should validate these genes' functions in osteocyte biology under microgravity.

Broccoli Sprout Extract Suppresses Particulate-Matter-Induced Matrix-Metalloproteinase (MMP)-1 and Cyclooxygenase (COX)-2 Expression in Human Keratinocytes by Direct Targeting of p38 MAP Kinase

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.

Evaluation of safety and efficacy of Brazilian brown propolis from Araucaria sp. in preventing colon cancer

ABSTRACT Brazilian propolis produced by honeybees have been widely studied, but few data exist regarding the safety and pharmacological potential of this natural product. The aim of the present study was to examine the toxicity, genotoxicity, and chemoprevention effects attributed to exposure to the brown propolis hydroalcoholic extract (BPHE) of Araucaria sp. Acute oral toxicity test was conducted using Wistar Hannover rats, demonstrating that the highest dose tested (2,000 mg/kg b.w.) produced no apparent adverse effects or lethality. The micronucleus (MN) genotoxicity test was conducted using peripheral blood from Swiss mice, which also noted that BPHE did not induce significant chromosomal damage. It is of interest that BPHE at a dose of 12 mg/kg b.w. exhibited antigenotoxic effects against the doxorubicin (DXR)-induced damage. However, BPHE did not influence the depletion of reduced glutathione induced by DXR in mice. It is noteworthy that BPHE exerted chemopreventive effects at doses 6, 12, and 24 mg/kg b.w. The determination of this effect of BPHE on colon carcinogenesis was examined using aberrant crypt foci (ACF) as evidenced by histological analysis. The colons of animals treated with BPHE (12 mg/kg b.w.) exhibited a significant reduction in staining for proliferating cell nuclear antigen (PCNA) and cyclooxygenase-2 (COX-2) protein following 1,2-dimethylhydrazine (DMH)-and BPHE combined treatments. Hence, it is conceivable that the anti-inflammatory activity of the chemical constituents of BPHE are involved in its chemopreventive action against colon carcinogenesis as evidenced from ACF assay. Therefore, BHPE was found to be a safe product, without any apparent significant acute adverse risk. Further, the extract exhibited antigenotoxic and anticarcinogenic activities which may be considered for beneficial uses in colon carcinogenesis.

Correlation analysis of LXR and its target genes COX2 and CETP with the severity of OSAHS in obese young rats.

To analyse the relationships between the expression levels of liver X receptor (LXR), cyclooxygenase-2(COX2) and cholesterol ester transfer protein (CETP) and the severity of obstructive sleep apnoea hypopnoea syndrome (OSAHS) in obese young rats, to obtain information for basic research on OSAHS in obese children. Twenty-four 3-4-week-old young rats were randomly assigned to the normal control group, obesity group, OSAHS group, obesity and OSAHS group. We used polysomnography to measure the obstructive apnoea hypopnoea index (OAHI) to assess the severity of OSAHS and western blotting to test the expression levels of LXRα, COX2, and CETP in the liver, heart, kidney, and brain tissues. LXR, COX2, and CETP expression levels in the remaining groups were considerably higher than those in the control group (P < 0.05). Compared with those in the obesity group, LXRα, COX2, and CETP expression levels in the obesity and OSAHS group were considerably greater in the liver, kidney, and heart tissues (P < 0.05); the brain tissues of the obesity and OSAHS group showed considerably higher expression levels of COX2 and CETP (P < 0.05). Compared with those in the OSAHS group, LXRα, COX2, and CETP expression levels in the obesity and OSAHS group were significantly greater in all tissues (P < 0.05). The expression levels of LXRα, COX2, and CETP and obesity increased with increasing OSAHS severity (r = 0.777, P < 0.01; r = 0.728, P < 0.01; r = 0.793, P < 0.01; r = 0.786, P < 0.01; and r = 0.698, P < 0.01), and the oxygen concentration increased with decreasing OSAHS severity(r=-0.576, P < 0.01). LXR, COX2, and CETP expression levels were significantly increased in the liver, kidney, heart, and brain tissues of young rats with obesity and OSAHS, and were positively correlated with the severity of OSAHS.

Unveiling the anxiolytic and analgesic effects of citronellal in Swiss mice: in vivo and in silico insights into COX and GABAA receptor pathways.

This study aims to evaluate the analgesic and anxiolytic effects of citronellal (CTL) in Swiss mice using two new sensitive and economic mouse models along with possible molecular mechanisms through in silico studies. For this, we employed marble displacement and spiked-field apparatus to check the anxiolytic and analgesic effects, respectively. In silico studies were done against cyclooxygenase (COX) enzymes and GABAA receptor subunits. Findings suggest that the test sample CTL significantly reduced the number of marbles displaces (NMD), square crosses (NSC), paw massages (NPM), and escaping attempts (NEA) in animals than the control group. CTL exhibited better effects in the perforated-field study compared to the reference drug diclofenac sodium. In both cases, CTL (200mg/kg) significantly reduced the test parameters when combined with the standard drugs (diazepam or diclofenac sodium). In in silico studies, CTL showed binding affinities of - 5.5, - 5.2, - 4.8, and - 4.8kcal/mol with the COX1, COX2, and GABAA receptors (α2 and α3 subunits), respectively. Taken together, CTL may exert anxiolytic- analgesic-like effects on mice, possibly through the GABAA receptor and COXs interaction pathways. These new tools might be used to check the anxiolytic and analgesic properties of a wide variety of test substances.

GPX4 Promoter Hypermethylation Induced by Ischemia/Reperfusion Injury Regulates Hepatocytic Ferroptosis.

Glutathione peroxidase 4 (GPX4) is a key factor in ferroptosis, which is involved in ischemia-reperfusion injury. However, little is known about its role in hepatic ischemia-reperfusion injury (HIRI). This study aimed to investigate the role of GPX4 methylation in ferroptosis during HIRI. For the in vitro experiments, an oxygen and glucose deprivation cell model was established. For the in vivo experiments, an ischemia-reperfusion model was created by subjecting mice to simulated HIRI. Ferroptosis occurrence, GPX4 promoter methylation, and global methylation levels were then assessed. Ferroptosis was observed in oxygen and glucose deprivation, characterized by a significant decrease in cellular viability (P < 0.05), an increase in lipid peroxidation (P < 0.01), iron overload (P < 0.05), and down-regulation of GPX4 (P < 0.05). This ferroptosis was exacerbated by GPX4 knockdown (P < 0.01) and mitigated by exogenous glutathione (P < 0.01). Similarly, ferroptosis was evident in mice subjected to HIRI, with a down-regulation of GPX4 mRNA and protein expression (all P < 0.01), and an upregulation of acyl-CoA synthetase long-chain family member 4 mRNA and protein (all P < 0.01), as well as prostaglandin-endoperoxide synthase 2 mRNA and protein expression (all P < 0.05). Methylation levels increased, evidenced by upregulation of DNA methylation transferase expression (P < 0.05) and down-regulation of Ten-eleven translocation family demethylases (P < 0.01), along with an upregulation of GPX4 promoter methylation. Ferroptosis may be the primary mode of cell death in hepatocytes following ischemia-reperfusion injury. The methylation of the GPX4 promoter and elevated levels of global hepatic methylation are involved in the regulation of ferroptosis.

Interaction of meloxicam derivatives with phosphatidylcholine bilayers: A calorimetric study.

The drug interactions with the lipid membranes are crucial in many biochemical processes. Phospholipid model membranes are often used to assess such interactions. Our team has been researching new compounds with anti-inflammatory and analgesic effects for many years. Such compounds are derivatives of the well-known non-steroidal anti-inflammatory drug (NSAID) - meloxicam (MLX). Their biological target is cyclooxygenase (COX) - a membrane protein. The NSAIDs are mainly taken orally; therefore, drug-membrane interaction is a preliminary stage in the body. The purpose of the present work was to investigate the ability of 2 new MLX derivatives (compound PR51 and PR52) to interact with model membranes, in comparison to known NSAIDs medicine - MLX. The differential scanning calorimetry (DSC) method was used to study those interactions. As a model membrane, bilayers obtained from a phospholipid (1,2-dipalmitoyl-sn-glycero-3-phosphatidylcholine (DPPC)) were used. Calorimetric measurements were performed using a differential scanning calorimeter DSC 214 Polyma equipped with an intracooler IC70. All examined compounds decreased the main transition temperature of DPPC in a concentration-dependent manner. The addition of studied compounds to DPPC also resulted in broadening of the transition peaks. Moreover, all examined compounds decreased the enthalpy of the DPPC main phase transition. For all DPPC gel-liquid crystalline phase transition parameters, the most pronounced effects were found for PR51 compound. We have shown that the above interactions depend on the chemical structure of individual compound. All studied compounds alter biophysical properties of phospholipid bilayer.

Photoaging Protective Effects of Quercitrin Isolated from ‘Green Ball’ Apple Peel

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.

Cyclodextrin-Nanosponge-Loaded Cyclo-Oxygenase-2 Inhibitor-Based Topical Gel for Treatment of Psoriatic Arthritis: Formulation Design, Development, and In vitro Evaluations

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.

Assessment of clot-lysing and membrane-stabilizing capacity of ascorbic acid: In vitro approach with molecular docking

This study aimed to evaluate the clot-lysing and membrane stabilizing capacities of ascorbic acid (AA) using in vitro and in silico methods. For this, we used in vitro clot lysis and hemolyzing tests to check the anti-atherothrombosis and membrane-stabilizing properties of AA, respectively. Additionally, molecular docking studies were performed to investigate AA’s interactions with cyclooxygenase-1 (COX-1) and plasminogen enzymes. Findings suggest that AA exhibited a concentration-dependent effect, with 43.95 ± 1.27 % clot lysis and 64.46 ± 0.01 % membrane stabilization at 100 µg/mL. The IC50 values for clot lysis and membrane stabilization were 215.19 ± 1.09 and 57.21 ± 2.11 µg/mL, respectively. In silico analysis showed strong binding affinities of AA with COX-1 (−6.2 kcal/mol) and plasminogen (−5.8 kcal/mol), supporting its observed clot lysis and membrane protection activities. Taken together, AA showed moderate clot-lysing and robust membrane-stabilizing effects, which may be due to its strong antioxidant and anti-inflammatory properties. AA might be a good therapeutic agent for atherothrombosis and membrane damage, highlighting the need for further investigation into its underlying molecular mechanisms and potential clinical applications. AA shows promising clot-lysing and membrane-stabilizing effects, highlighting its therapeutic potential for atherothrombosis and membrane damage.

Hydroethanolic Extract of Polygonum aviculare L. Mediates the Anti-Inflammatory Activity in RAW 264.7 Murine Macrophages Through Induction of Heme Oxygenase-1 and Inhibition of Inducible Nitric Oxide Synthase

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.

A sulfonimide derivative of bezafibrate as a dual inhibitor of cyclooxygenase-2 and PPARα

BackgroundPPARα and cyclooxygenase (COX)-2 are overexpressed in certain types of cancer. Thus, developing a dual inhibitor that targets both could be more effective as an anticancer agent than single inhibitors. We have previously shown that an analog of the bezafibrate named AA520 is a PPARα antagonist. Herein, we report the identification of AA520 as a potent COX-2 inhibitor using in silico approaches. In addition, we performed a thorough pharmacological characterization of AA520 towards COX-1 and COX-2 in different in vitro models.MethodsAA520 was characterized for inhibiting platelet COX-1 and monocyte COX-2 activity in human whole blood (HWB) and for effects on lipidomics of eicosanoids using LC-MS/MS. The kinetics of the interaction of AA520 with COX-2 was assessed in the human colon cancer cell line, HCA-7, expressing only COX-2, by testing the COX-2 activity after extensive washing of the cells. The impact of AA520 on cancer cell viability, metabolic activity, and cytotoxicity was tested using the MTT reagent.ResultsIn HWB, AA520 inhibited in a concentration-dependent fashion LPS-stimulated leukocyte prostaglandin (PG) E2 generation with an IC50 of 0.10 (95% CI: 0.05–0.263) μM while platelet COX-1 was not affected up to 300 μM. AA520 did not affect LPS-induced monocyte COX-2 expression, and other eicosanoids generated by enzymatic and nonenzymatic pathways. AA520 inhibited COX-2-dependent PGE2 generation in the colon cancer cell line HCA7. Comparison of the inhibition of COX-2 and its reversibility by AA520, indomethacin (a time-dependent inhibitor), acetylsalicylic acid (ASA) (an irreversible inhibitor), and ibuprofen (a reversible inhibitor) showed that the compound is acting by forming a tightly bound COX-2 interaction. This was confirmed by docking and molecular dynamics studies. Moreover, AA520 (1 μM) significantly reduced MTT in HCA7 cells.ConclusionWe have identified a highly selective COX-2 inhibitor with a unique scaffold. This inhibitor retains PPARα antagonism at the same concentration range. It has the potential to be effective in treating certain types of cancer, such as hepatocellular carcinoma (HCC) and renal cell carcinoma (RCC), where COX-2 and PPARα are overexpressed.