Design, synthesis, and biological evaluation of novel imidazole derivatives as analgesic and anti-inflammatory agents: experimental and molecular docking insights.

Imidazole moieties exhibit a broad range of biological activities, including analgesic, anti-depressant, anticancer, anti-fungal, anti-tubercular, anti-inflammatory, antimicrobial, antiviral, and antifungal properties. In this study, we explored the use of Schiff base for the synthesis of new imidazole derivatives as anti-inflammatory and pain-relieving agents. A series of eight novel imidazole analogues (2a-h) were prepared in three steps with excellent yields. All compounds were characterized using IR, NMR, and mass spectral data. Their analgesic and anti-inflammatory activities were evaluated using hot plate and paw oedema methods. Compound 2 g (1-(2,3-dichlorophenyl)-2-(3-nitrophenyl)-4,5-diphenyl-1H-imidazole) showed significant analgesic activity (89% at 100 mg/kg b.w.), while compounds 2a (2-(2,6-dichlorophenyl)-1-(4-ethoxyphenyl)-4,5-diphenyl-1H-imidazole) and 2b (2-(2,3-dichlorophenyl)-1-(2-chlorophenyl)-4,5-diphenyl-1H-imidazole) exhibited good anti-inflammatory activity (100% at 100 mg/kg b.w.), comparable to diclofenac salt (100% at 50 mg/kg b.w.). Molecular docking studies were conducted using Schrödinger software version 2021-2, employing the OPLS4 force field for both receptor and ligand preparation. The results were visualized using molecular visualization software such as PyMOL. These studies revealed that compound 2g exhibited the highest binding affinity with the COX-2 receptor (-5.516 kcal/mol). Compound 2g formed three conventional hydrogen bonds with residues GLN-242 (bond length: 2.3 Å) and ARG-343 (bond lengths: 2.2 Å & 2.4 Å). This binding affinity was comparable to that of Diclofenac salt, which showed the highest binding affinity of -5.627 kcal/mol with the COX-2 receptor. Diclofenac salt formed two conventional hydrogen bonds with the residues ARG-344 (bond length: 2.0 Å) and TRP-140 (bond length: 1.7 Å). Later, molecular dynamic simulations confirmed the stable binding affinity of compound 2g with the protein. Furthermore, other compounds also demonstrated potential binding to the receptor-binding pocket region. The anti-inflammatory potential of the synthesized compounds was evaluated using the carrageenan-induced rat hind paw oedema model, while the analgesic potential was assessed using the hot plate method. These evaluations were conducted in comparison with Diclofenac sodium, serving as the standard compound. However, compound 2g stood out for its superior analgesic activity, as confirmed by in-vivo examination. These findings suggest that these novel imidazole derivatives have potential as anti-inflammatory and analgesic agents.

Design, Synthesis and Biological ActivitiesEvaluation of Novel Pterostilbene-urea DerivativesasPotential Anti-inflammatory Agents.

To remove the toxicity of 10-Pterostilbene methylamine hydrochloride derivatives (PMDS ． HCl) and develop novel anti-inflammatory agents, twenty-five Pterostilbene-urea derivatives (PUDs, Q1-Q25) derived from PMDs were designed, synthesized, characterized by spectroscopic techniques and their anti-inflammatory activity in vitro were evaluated. Results exhibited that compounds (Q1-Q25) were low toxic or non-toxic toward RAW264.7 and L02 cell lines at 20 µM/L. Eight bioactive agents (Q4-Q10, Q20) displayed obvious inhibition ability against LPS-induced NO release, with IC50(NO) values ranged from 9.96 to 33.89 µM/L. Meanwhile, they were potential COX-2 inhibitors with IC50(COX-2) values ranging from 39.42 to 179.84 nM/L. A roughly positive correlation were observed between the inhibitory abilities on LPS-induced NO release and those on COX-2. Q7 , Q10and Q20 manifested stronger COX-2 inhibitory abilities than Celecoxib . The strongest anti-inflammatory agent, Q20 (IC50 (NO) = 9.96 µM/L, IC50(COX-2) = 39.42 nM/L) effectively inhibited the secretion of pro-inflammatory factors such as IL-1ß (IC50 = 12.30 µM/L) and TNF-α (IC50 = 9.07 µM/L) in a dose-dependent manner. Western Blot analysis indicated that at low micromolar concentrations, Q20 obviously down-regulated the expression of COX-2, iNOS as well as TLR4 protein, and suppressed the activation of NLRP3 inflammasome and NF-κB signal pathway.

Myricetin-loaded SBA-15 silica nanoparticles for enhanced management of pyrexia, pain, and inflammation through modulation of MAPK/NF-κB and COX-2/PGE-2 pathways: Evidence from the biochemical, histological, and metabolomic analysis.

Myricetin (MYR) is a natural flavonoid that has several biological functions. However, some of its beneficial effects are diminished due to low water solubility, stability, and bioavailability. Herein, several kinds of silica nanoparticles (MCM-41 and SBA-15) were loaded with MYR to improve its biological activity as an analgesic, antipyretic, and anti-inflammatory component, thereby overcoming its drawbacks. The nanoparticles (MYR@SBA-15) were formulated optimally, transforming MYR into an amorphous state. This transformation was confirmed via several strategies, including differential scanning calorimetry, Fourier transform infrared spectroscopy, and powder x-ray diffraction. As a result, there was a significant enhancement in the solubility and rate of dissolution in water. The anti-inflammatory benefits as an innovative strategy and the underlying mechanism of action of MYR and its SBA-15 silica nanoparticles (MYR@SBA-15) were investigated based on the biochemical, histological, immunohistochemical, and metabolomic assays alongside their antipyretic and analgesic characteristics. Compared to the usage of raw MYR, the administration of MYR@SBA-15 at doses of 25, 50, and 100 mg/kg significantly decreases pain perception by inhibiting the body's writhing motions induced by acetic acid. Furthermore, it helps regulate increased body temperature caused by baking yeast and effectively stabilizes it. It reduces the release of NO and PGE-2 in a concentration-dependent manner by down-regulating iNOS and COX-2 expression in the inflammatory model. MYR and MYR@SBA-15 also inhibit the nuclear translocation of NF-κB, downregulate the expression of mitogen-activated protein kinases (MAPKs), such as p38, ERK1/2, and JNK protein, and reduce the generation of proinflammatory cytokines, such as TNF-α. In addition, inflammatory cardinal signs like paw edema caused by carrageenan in rats are greatly suppressed by MYR and MYR@SBA-15 treatment when compared to the untreated group. More noteworthy outcomes are shown in the MYR@SBA-15, particularly at a dose of 100 mg/kg. These results of biochemical and immuno-histochemistry suggest that MYR@SBA-15 may be a useful analgesic antipyretic and may also help reduce inflammation by altering MAPKs/NF-κB and COX-2/PGE-2 signaling cascades. Serum metabolomics study demonstrated modifications in various low molecular weight metabolites with arthritis development. These metabolite levels were restored to normal when MYR@SBA-15 was administered via modulating several metabolic pathways, i.e., pyrimidine, energy metabolism, and proteins. Overall, MYR-loaded SBA-15 silica nanoparticles have demonstrated significant promise in enhancing the disturbed metaboloic pathways and providing a substantial capacity to regulate several oxidative stress and inflammatory mediators.

Northward migration past the Nearctic biogeographical divide; neotropical Gyrodactylus spp. infecting Astyanax have crossed the Trans-Mexican Volcanic Belt.

The neotropical fish genus Astyanax (Characidae) and its associated helminths migrated northward from South America following the Great American Biotic Interchange (GABI): ca. 150 Astyanax spp. are found throughout South and Central America, up to the Mexico-USA border. Most characids are distributed south of the Trans-Mexican Volcanic Belt (TMVB), which bisects the country and represents a major transition zone between the neotropical and nearctic realms. Here, we characterize parasites of the monogenean genus Gyrodactylus infecting Astyanax spp. in Mexico: Astyanax aeneus south of the TMBV, Astyanax mexicanus north of it. Based on morphological, phylogenetic (internal transcribed spacer (ITS) and cytochrome oxidase subunit II (cox 2)) and statistical analyses of morphometric data, we confirmed the validity of Gyrodactylus pakan and Gyrodactylus teken, and erected two new species, Gyrodactylus aphaa n. sp. and Gyrodactylus ricardoi n. sp. These four gyrodactylids are part of a complex of morphologically cryptic species, which are phylogenetically closely related to each other, and sister species to Gyrodactylus carolinae and Gyrodactylus heteracanthus, parasites of characins in Brazil. Four gyrodactylid lineages (G. pakan, G. ricardoi n. sp., G. teken, Gyrodactylus sp. A) are distributed north of the TMVB; G. pakan is also widely distributed south of the TMVB, together with G. aphaa n. sp. Based on the ITS phylogeny, Brazilian parasites form a sister clade to all Mexican gyrodactylids, whose derived clades are distributed in progressively more northerly latitudes in Mexico - the three most-derived species north of the TMVB. This would suggest that gyrodactylid species diverged gradually, presumably as their characid fish hosts colonized and adapted to new environments north of the TMVB.

Computational exploration of novel ketoprofen derivatives: Molecular dynamics simulations and MM-PBSA calculations for COX-2 inhibition as promising anti-inflammatory drugs.

Computer-aided drug design is widely employed to identify novel compounds for therapeutic applications. Ketoprofen (KTP), a commonly used and marketed nonsteroidal anti-inflammatory drug (NSAID), is effective in treating pain, fever, inflammation, and some cancers. In this research, we explored the behavior of six analogues designed by structurally modifying the KTP molecule. Specifically, KTP-A and KTP-B contain a -CN group at the ortho position, KTP-C and KTP-D have a -CN group at the meta position, and KTP-E and KTP-F feature a -CF3 group at the meta position. To assess these analogues, we conducted molecular dynamics simulations (MD) to study their inhibitory effects on human cyclooxygenase 2 (COX-2), providing detailed insights into the structure and dynamics of the protein both with and without ligands. MD simulation, enhanced by technological advances, has proven to be a powerful tool for new drug discovery. We further quantified the binding affinity of these drug molecules toward COX-2 using molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) binding free energy calculations. The dynamic properties were evaluated through analyses of root mean square deviations (RMSD), root mean square fluctuations (RMSF), radius of gyration (Rg), solvent-accessible surface area (SASA), covariance matrix, principal component analysis (PCA), and Gibbs free energy landscapes (FEL). Ultimately, this study confirms that the six KTP derivatives are promising candidates for the treatment of inflammation, with KTP-B standing out as particularly effective.

Screening bioactive compounds from Fangji Huangqi decoction for treating rheumatoid arthritis via COX-2 magnetic ligand fishing combined with in vivo validation.

ETHNOPHARMACOLOGICAL RELEVANCE: Fangji Huangqi Decoction (FHD) is a classical Chinese compound formula for treating rheumatoid arthritis (RA) with satisfactory effects. FHD is reputed for its ability to tonify qi with strengthening exterior, and dispel wind while removing dampness, but its mechanisms and bioactive compounds for treating RA remain unclear. AIM OF THE STUDY: The aim of this study was to explore the key target and bioactive compounds that were responsible for FHD-mediated improvements in RA. MATERIALS AND METHODS: Using network pharmacology, we discovered that cyclooxygenase-2 (COX-2) was the key target of FHD against RA. We utilized a ligand fishing technique with COX-2 immobilized magnetic beads to recognize the bioactive components that act on COX-2. Then we carried out an in vitro assay of COX-2 enzyme inhibition and in vivo assay of carrageenan-induced inflammation and collagen-induced arthritis (CIA) to validate the bioactive effects of these captured ingredients. In the CIA assay, micro-CT, hematoxylin‒eosin staining and safranin-O/fast green staining were employed to assess the influence of the captured ligand on bone damage, pathological injury and cartilage destruction, respectively. Immunohistochemistry (IHC) and enzyme-linked immunosorbent assays (ELISAs) were used to detect the expression of COX-2 target in the ankle joint. interleukin-6 (IL-6) levels in the serum were also detected by ELISA. Molecular docking was used to reveal the binding mechanism of the COX-2 protein and the captured ligand. RESULTS: Eleven ligands, including tetrandrine, fangchinoline, cyclanoline, licochalcone B, ononin, calycosin and liquiritin, were specifically bound to the COX-2 protein, as determined by ultrahigh-performance liquid chromatography-mass spectrometry (UPLC-MS), seven of which were present at high levels. One ligand, tetrandrine, not only had a great inhibitory effect on COX-2 enzyme activity but also significantly reduced carrageenan-induced inflammation. In the CIA assay, middle- and high-dose tetrandrine (25 and 50 mg/kg) had effects comparable to those of FHD and celecoxib on ameliorating RA symptoms in CIA mice via the COX-2 target. Furthermore, compared with the low-dose tetrandrine group (12.5 mg/kg), the FHD group exhibited significantly lower arthritis index scores and serum IL-6 expression, although the content of tetrandrine in FHD extract solution was approximately 0.1% of that in the low-dose tetrandrine group. CONCLUSIONS: Hence, we inferred that tetrandrine was the main bioactive component responsible for the effects of FHD against RA by suppressing the expression of the COX-2 protein and inhibiting the enzyme catalytic activity of COX-2. The reason for these effects may be that tetrandrine can interact with the residue Tyr385 of COX-2, the enzymatic catalytic site of COX-2 to transform arachidonic acid (AA) to prostaglandin E2 (PGE2), and thereby reduce the production of prostaglandins and inflammatory metabolites. Moreover, in addition to tetrandrine, FHD contains other compounds that could supplement the activity of tetrandrine when FHD was used to treat RA, which is manifested the "multi-component" characteristic of how Traditional Chinese Medicine formulas treat diseases.

Advances, limitations and perspectives in the use of celecoxib-loaded nanocarriers in therapeutics of cancer.

Cancer is highlighted as a major global health challenge in the XXI century. The cyclooxygenase-2 (COX-2) enzyme rises as a widespread tumor progression marker. Celecoxib (CXB) is a selective COX-2 inhibitor used in adjuvant cancer therapy, but high concentrations are required in humans. In this sense, the development of nanocarriers has been proposed once they can improve the biopharmaceutical, pharmacokinetic and pharmacological properties of drugs. In this context, this article reviews the progress in the development of CXB-loaded nanocarriers over the past decade and their prospects. Recent advances in the field of CXB-loaded nanocarriers demonstrate the use of complex formulations and the increasing importance of in vivo studies. The types of CXB-loaded nanocarriers that have been developed are heterogeneous and based on polymers and lipids together or separately. It was found that the work on CXB-loaded nanocarriers is carried out using established techniques and raw materials, such as poly (lactic-co-glicolic acid), cholesterol, phospholipids and poly(ethyleneglycol). The main improvements that have been achieved are the use of cell surface ligands, the simultaneous delivery of different synergistic agents, and the presence of materials that can provide imaging properties and other advanced features. The combination of CXB with other anti-inflammatory drugs and/or apoptosis inducers appears to hold effective pharmacological promise. The greatest advance to date from a clinical perspective is the ability of CXB to enhance the cytotoxic effects of established chemotherapeutic agents.

Kaempferia galanga L. alleviates the expression of COX-2 and NF-kappaB-p65 in the oral mucosa ulcer of Wistar rats and exhibits no irritation toward the vascular membrane of chicken eggs and the skin of albino rabbits.

The global incidence of recurrent aphthous stomatitis in 2018 reached 5-66 % of the population, while in Indonesia 8 %. Moreover, the prevalence of oral mucosal fibrosis and recurrent aphthous stomatitis among male doctors and nurses in China was 21.24 % and 24.27 %, respectively. Our previous study has shown that the ethanol extract of Kaempferia galanga L. rhizome (EKGR) revealed an accelerated wound-healing effect in the oral mucosa ulcer of Wistar rats. This study aims to explore the effects of EKGR on the expression of NF-kappaB-p65 and COX-2 in the tongue tissue of male Wistar rats by Western blot analysis and immunohistochemistry technique, its safety towards the vascular membrane of the egg chorioallantoic membrane, and its single-dose application on the skin of male rabbits. The rats were randomly assigned into 7 groups: the normal control; the negative control; the positive control (treated with triamcinolone acetonide); and 4 treatment groups of EKGR (0.5 %; 1 %; 2 %; 4 %). Western blot and immunohistochemistry methods were used to measure the expression of NF-kappaB-p65 and COX-2. The hen's egg test-chorioallantoic membrane assay was employed to predict the safety of EKGR towards the vascular membrane. Moreover, the effect of 200 mg/kg BW EKGR application on the dorsal skin of male albino rabbits was also evaluated. EKGR inhibits the expression of NF-kappaB-p65 and COX-2 as proven by WB and IHC results. In the HET-CAM assay, all concentrations of EKGR do not induce irritation responses, which elicits the safety of EKGR. The administration of EKGR causes mild irritation to the dorsal skin of male rabbits but does not induce erythema and edema, no significant changes in BW, no toxic effects on organ macroscopic examination or histopathology, and does not induce abnormalities in the hematological profile of male albino rabbits. EKGR has confirmed its anti-inflammatory activity by suppressing the expression of COX-2 and NF-kappaB-p65 in the oral mucosa ulcer of Wistar rats. EKGR is safe as it does not exhibit irritating potential and harmful effects.

The Expression of Cyclooxygenase-2 in Cervical Intraepithelial Neoplasia and Cervical Cancer.

Aim To examine the relationship between tumor differentiation, parametrial, and lymphovascular invasion, as well as the differential expression pattern of cyclooxygenase-2 (COX-2) in cervical intraepithelial neoplasia and various forms of cervical cancer. Methods Histologically diagnosed cases of in-situ and malignant lesions of the cervix were included in the study. Two sections were cut from paraffin blocks. One section was stained with Haematoxylin and Eosin (H&E) for morphologic diagnosis, and the other sections were subjected to COX-2 immunohistochemical staining. Cases of colon carcinoma were taken as positive controls. Cytoplasmic and membrane staining of tumor cells were considered as positive staining, and grading was done. Results Out of the 62 patients, 40 cases (64.5%) showed positive expression of COX-2 in squamous cell carcinoma when compared to in-situ cervical intraepithelial neoplasia and adenocarcinoma. The results were statistically significant, with a p-value of 0.003. Conclusion COX-2 expression is directly proportional to the level of grading of the tumor. The higher the grading, the higher the expression of COX-2. Selective COX-2 inhibitors increase the efficacy of chemotherapy or radiotherapy.

Do NSAIDs affect bone healing rate, delay union, or cause non-union: an updated systematic review and meta-analysis.

Introduction: Nonsteroidal anti-inflammatory drugs (NSAIDs) may potentially delay or cause non-union of fractures by inhibiting prostaglandin synthesis. However, studies have shown conflicting results. This systematic review and meta-analysis aim to synthesize current evidence on the potential influence of NSAIDs on bone healing. Methods: We conducted a comprehensive search of PubMed, Embase, and Cochrane CENTRAL databases for studies published up to 25 July 2023. Specific keywords included "NSAID," "nonsteroidal anti-inflammatory drug," "cyclooxygenase-2 inhibitor," "bone healing," "non-union," "pseudoarthrosis," "delayed union," and "atrophic bone." Eligible studies included prospective, retrospective, and case-controlled studies assessing the correlation between NSAID use and bone healing outcomes. The leave-one-out approach was used to test the robustness of the meta-analysis results. Results: A total of 20 studies with 523,240 patients were included in the analysis. The mean patient age ranged from 6.7 to 77.0 years, with follow-up durations from 3 to 67 months. The meta-analysis revealed no significant difference in non-union or delayed union between NSAID users and non-users [pooled adjusted odds ratio (OR) = 1.11; 95% confidence interval (CI): 0.99-1.23]. Initial analysis identified a significant association between NSAID usage and an increased risk of reoperation, but this association became insignificant upon sensitivity analysis (crude OR = 1.42; 95% CI: 0.88-2.28). Discussion: NSAIDs may have a minimal impact on non-union or delayed union risks. However, caution is advised due to the limited number of studies and the absence of a specific focus on NSAID types and dosages. Further research is necessary to better understand the implications of NSAID use on bone healing.

Indoxyl sulfate induces retinal microvascular injury via COX-2/PGE2 activation in diabetic retinopathy.

BACKGROUND: Diabetic retinopathy (DR), the principal cause of acquired blindness among the working-age population, is the most frequent microvascular complication of diabetes. Although metabolic disorders are hypothesized to play a role in its pathogenesis, the underlying mechanism remains largely elusive. METHODS: To elucidate the mechanism, we initially compared metabolite profiles of vitreous fluid between 23 patients with DR and 12 non-diabetic controls using liquid chromatography/tandem mass spectrometry, identifying the distinct metabolite indoxyl sulfate (IS). Subsequently, streptozotocin (STZ)-induced diabetic and IS-injected rat models were established to examine the effects of IS on retinal microvasculature. RNA sequencing was conducted to identify potential regulatory mechanisms in IS-treated human retinal endothelial cells (HREC). Finally, target gene knockdown in HREC and treatment of IS-injected rats with inhibitors (targeting IS production or downstream regulators) were employed to elucidate the detailed mechanisms and identify therapeutic targets for DR. RESULTS: Metabolomics identified 172 significantly altered metabolites in the vitreous humor of diabetics, including the dysregulated tryptophan metabolite indoxyl sulfate (IS). IS was observed to breach the blood-retinal barrier and accumulate in the intraocular fluid of diabetic rats. Both in vivo and in vitro experiments indicated that elevated levels of IS induced endothelial apoptosis and disrupted cell junctions. RNA sequencing pinpointed prostaglandin E2 (PGE2) synthetase-cyclooxygenase 2 (COX-2) as a potential target of IS. Validation experiments demonstrated that IS enhanced COX-2 expression, which subsequently increased PGE2 secretion by promoting transcription factor EGR1 binding to COX-2 DNA following entry into cells via organic anion transporting polypeptides (OATP2B1). Furthermore, inhibition of COX-2 in vivo or silencing EGR1/OATP2B1 in HREC mitigated IS-induced microcapillary damage and the activation of COX-2/PGE2. CONCLUSION: Our study demonstrated that indoxyl sulfate (IS), a uremic toxin originating from the gut microbiota product indole, increased significantly and contributed to retinal microvascular damage in diabetic retinopathy (DR). Mechanistically, IS impaired retinal microvascular integrity by inducing the expression of COX-2 and the production of PGE2. Consequently, targeting the gut microbiota or the PGE2 pathway may offer effective therapeutic strategies for the treatment of DR.

The ABA/LANCL1-2 Hormone/Receptors System Controls ROS Production in Cardiomyocytes through ERRα.

Rat H9c2 cardiomyocytes overexpressing the abscisic acid (ABA) hormone receptors LANCL1 and LANCL2 have an increased mitochondrial proton gradient, respiration, and vitality after hypoxia/reoxygenation. Our aim was to investigate the role of the ABA/LANCL1-2 system in ROS turnover in H9c2 cells. H9c2 cells were retrovirally infected to induce the overexpression or silencing of LANCL1 and LANCL2, without or with the concomitant silencing of the transcription factor ERRα. Enzymes involved in radical production or scavenging were studied by qRT-PCR and Western blot. The mitochondrial proton gradient and ROS were measured with specific fluorescent probes. ROS-generating enzymes decreased, ROS-scavenging enzymes increased, and mitochondrial ROS were reduced in LANCL1/2-overexpressing vs. control cells infected with the empty vector, while the opposite occurred in LANCL1/2-silenced cells. The knockdown of ERRα abrogated all beneficial effects on ROS turnover in LANCL1/2 overexpressing cells. Taken together, these results indicate that the ABA/LANCL1-2 system controls ROS turnover in H9c2 via ERRα. The ABA/LANCL system emerges as a promising target to improve cardiomyocyte mitochondrial function and resilience to oxidative stress.

Mechanism Actions of Coniferyl Alcohol in Improving Cardiac Dysfunction in Renovascular Hypertension Studied by Experimental Verification and Network Pharmacology.

Renovascular hypertension (RH), a secondary hypertension, can significantly impact heart health, resulting in heart damage and dysfunction, thereby elevating the risk of cardiovascular diseases. Coniferol (CA), which has vascular relaxation properties, is expected to be able to treat hypertension-related diseases. However, its potential effects on cardiac function after RH remain unclear. In this study, in combination with network pharmacology, the antihypertensive and cardioprotective effects of CA in a two-kidney, one-clip (2K1C) mice model and its ability to mitigate angiotensin II (Ang II)-induced hypertrophy in H9C2 cells were investigated. The findings revealed that CA effectively reduced blood pressure, myocardial tissue damage, and inflammation after RH. The possible targets of CA for RH treatment were screened by network pharmacology. The interleukin-17 (IL-17) and tumor necrosis factor (TNF) signaling pathways were identified using a Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. The inflammatory response was identified using a Gene Ontology (GO) enrichment analysis. Western blot analysis confirmed that CA reduced the expression of IL-17, matrix metallopeptidase 9 (MMP9), cyclooxygenase 2 (COX2), and TNF α in heart tissues and the H9C2 cells. In summary, CA inhibited cardiac inflammation and fibrohypertrophy following RH. This effect was closely linked to the expression of MMP9/COX2/TNF α/IL-17. This study sheds light on the therapeutic potential of CA for treating RH-induced myocardial hypertrophy and provides insights into its underlying mechanisms, positioning CA as a promising candidate for future drug development.

Impact of Toceranib Phosphate and Carprofen on Survival and Quality of Life in Dogs with Inflammatory Mammary Carcinomas.

Canine inflammatory mammary carcinoma (IMC) is an aggressive and rare type of mammary gland cancer in dogs where vascular endothelial growth factor and cyclooxigenase-2 overexpression usually occur, which contribute to its invasive and angiogenic nature. This study aimed to evaluate the efficacy and safety of a combined treatment regimen of toceranib phosphate and carprofen in dogs with measurable IMC. Fifteen female dogs with histopathologically confirmed IMC were included, undergoing a regimen of toceranib (2.4-2.75 mg/kg PO, three times weekly) and carprofen (4.4 mg/kg/24 h PO). Initial evaluations included physical exams, tumor measurements, complete blood count, biochemistry, urinalysis, three view thoracic radiographs, and abdominal ultrasound. Follow-up assessments of physical condition and quality of life (QOL) were conducted bi-weekly, with tumor response evaluations monthly, using RECIST v1.0 criteria. While no complete or partial responses were observed, 60% of the dogs maintained stable disease, with a median progression-free survival of 76 days and an overall survival of 90 days. Notably, 60% of the dogs showed clinical benefit through improved QOL and disease stabilization. The treatment was well-tolerated, with only grade I/II toxicities reported. Despite limited biological activity against the cancer, this protocol may enhance QOL in dogs with IMC, offering a valuable palliative option.

Discovery of metabolite from the insect-derived endophytic Penicillium chrysogenum and their COX-2 inhibitory activity.

Three new N-alkylated amino acid derivatives, penichrysoamides A-C (1-3), along with a new citric acid derivative, penichrysoacid A (4), a new chromanone lactone penichrysoacid B (5), and a new amide derivative, penichrysoamide D (6), as well as seven known benzamide derivatives (7-13), were isolated from the endophytic fungus Penicillium chrysogenum derived from the insect Periplaneta americana. The structures of these compounds, including their absolute configurations, were elucidated using spectroscopic and computational techniques. Biological evaluation revealed that compounds 8-13 exhibited significant COX-2 inhibitory activity, with IC50 values ranging from 275 nM to 1350 nM.

Shedding Light on the COVID-19 Pandemic: Placental Expression of Cell Biomarkers in Negative, Vaccinated, and Positive Pregnant Women.

Background: We investigated the expression of inflammation, placental development, and function markers, including cluster of differentiation 44 (CD44), osteopontin (OPN), and cyclooxygenase-2 (COX-2), to shed light on the controversy regarding the impact of the COVID-19 epidemic on fetal development and pregnancy outcomes. Methods: We immunohistochemically analyzed placental tissue from 170 patients (65 COVID-positive and unvaccinated women; 35 Pfeizer-vaccinated and COVID-negative women; and 70 COVID-negative and unvaccinated women, without any other associated pathology) for particularities in the expression of these three molecules. Results: CD44 expression was highest in COVID-negative and unvaccinated women, moderate in COVID-positive cases, and lowest in vaccinated and COVID-negative women. OPN expression was highest in COVID-negative and Pfeizer-vaccinated cases, moderate in COVID-negative and unvaccinated cases, and lowest in COVID-positive cases. COX-2 expression was increased in COVID-negative and unvaccinated women, modestly elevated in COVID-positive and unvaccinated cases, and lowest in vaccinated cases. Conclusions: These findings reflected an alteration in the placental structure and consequent function due to altered expression of the three studied molecules.

Treatment of metastatic apocrine sweat gland adenocarcinoma in a cat with association of surgical resection and angular oris reconstruction, extensive lymphadenectomy, electrochemotherapy and systemic chemotherapy.

Apocrine sweat gland adenocarcinoma (ASGAC) is a rare skin carcinoma in cats. In some cases, this tumor occurs in anatomical sites of challenging wide surgical resection, which increases the need for adjuvant therapies for residual disease. These include radiotherapy or electrochemotherapy (ECT), local treatments for invasive tumors in companion animals often associated with surgery. However, the current literature for ASGAC treatment is limited and there are no reports of ECT as an adjuvant therapy. In this case report, we account for the case of an 11-year-old cat with a history of a non-ulcerated recurrent ASGAC, measuring 1.3 × 1.0 cm, located by the rostral mandibular region. Surgical resection included the angularis oris axial flap for facial reconstruction associated with electroporation of the surgical bed and, post-operatively, in the surgical scar. Histopathological results confirmed the presence of a recurrent ASGAC. Immunostaining revealed cyclooxygenase 2 (COX-2) expression with a score of 6, 50 % positivity in Ki-67, and positive for pan-cytokeratin (PCK AE-1/ AE-3). A selective COX-2 inhibitor was initiated along with systemic chemotherapy with chlorambucil. The local approach including surgery and ECT was chosen due to the unfavorable anatomical site for extensive resection and the unavailability of radiotherapy. Subsequently, carboplatin chemotherapy was required due to metastasis in the mandibular lymph node. This case report supports the effectiveness of a multimodal treatment including surgery, ECT, and chemotherapy in a cat with recurrent ASGAC.

Dimethyl phthalate exposure induces cognitive impairment via COX2-mediated neuroinflammation.

AIM: The present work explored the mechanism of dimethyl phthalate (DMP, the environmental contaminant) exposure in inducing cognitive impairment. METHODS: Targets and regulatory networks related to DMP-brain injury-cognitive impairment were analyzed through network pharmacology. DMP exposure was carried out to simulate DMP environmental uptake, whereas Morris water maze was performed for examining cognitive impairment. Additionally, inflammatory cytokine levels within tissues were measured. hematoxylin-eosin staining(H&E) and Nissl staining was conducted to examine brain tissue injury, while Western blot was carried out for identifying protein levels. After applying.Small interfering RNA(siRNA-COX2) and celecoxib-COX2 inhibitors separately, we analyzed impacts of DMP. Besides, in vitro experiments were performed to analyze impacts of DMP on microglial activation. RESULTS: As suggested by network pharmacology,Cyclooxygenase-2-PTGS2 (COX2) showed significant relation to DMP, and it exerted its effect via COX2. Following DMP exposure, mice experienced obvious cognitive impairment and brain damage, besides, microglial cells were activated, and inflammatory cytokines were up-regulated. Applying siRNA-COX2 and celecoxib-COX2 suppressed DMP's impact and mitigated mouse cognitive impairment. Based on in vitro analysis, DMP led to microglial activation and neuroinflammation. CONCLUSION: DMP exposure causes neuroinflammation via the COX2-regulated microglial activation, thus leading to cognitive impairment. COX2 may serve as the key action target of DMP.

Novel efficacy of pregnane and flavonoid glycosides from Desmidorchis flava in in vivo nociceptive and inflammatory paradigms and their target prediction by cheminformatics approach.

Inflammation is associated with multiple life-threatening conditions. Desmidorchis flava is an edible plant and traditionally used for managing various diseases. Three novel molecules, namely desmiflavaside-C (1), nizwaside (2), and desmiflanoside (3) were isolated from Desmidorchis flava, and their structures were confirmed by mass spectrometry and through reported literature. These compounds were in vivo examined for antinociceptive (tonic visceral nociception) and anti-inflammatory (carrageenan induced paw edema) activities. Significant antinociceptive potential was demonstrated by compound 1 at 0.5 and 1 mg/kg doses followed by compounds 2 and 3. At similar doses, significant anti-inflammatory activity was noted for all the tested compounds. Their antinociceptive and anti-inflammatory activities were comparable to the reference standards. In silico predicted binding modes suggests that these compounds may target allosteric sites of COX-1 and COX-2 enzymes to elicit their anti-inflammatory activities. These isolated natural products may have therapeutic potential in conditions afflicted with pain and inflammation.

Explore on screening COX-2 inhibitors from the essential oil of Solanum lyratum Thunb. By molecular docking and molecular dynamics simulation.

This study aimed to investigate Solanum lyratum Thunb. with respect to the potential ingredients with anti-inflammatory activity from its essential oil by silico study. To this regard, the essential oil of Solanum lyratum Thunb. was extracted by hydrodistillation. 25 compounds were identified by GC-MS. Using virtual screening, molecular docking and molecular dynamics simulation of the 25 identified compounds, the ones showing anti-inflammatory activity on COX-2 were identified. According to the drug-like principle and the prediction of ADEMT properties, the six compounds of Spathulenol, Cedrol, Juniper camphor, Santalol, Nootkatone and 7,9-Di-tert-butyl-1-oxaspiro[4.5]deca-6,9-diene-2,8-dione were identified and then studied for molecular docking, and based on which the top two compounds of binding free energy were studied by the molecular dynamics simulation. The molecular docking data indicated that the binding free energies of Spathulenol, Cedrol, Juniper camphor, Santalol, Nootkatone and 7,9-Di-tert-butyl-1-oxaspiro[4.5]deca-6,9-diene-2,8-dione to COX-2 protein were -5.65, -7.19, -6.35, -4.94, -5.82 and -5.14 kcal/mol, respectively. The findings showed the steady interactions of hydrogen bonds and hydrophobic bonds between both the top two compounds of binding free energy and the active site residues of COX-2 (4M11) throughout the simulation via hydrogen bonds and hydrophobic bonds. The very study shall be supportive for in vitro and in vivo studies in developing drug products using the lead bioactive ingredients for anti-inflammatory in the future.