The reorientation of Callisia fragrans (Lindl.) Woodson, from therapeutic to ornamental use, exemplifies a broader domestication trend, favoring aesthetics over medicinal properties. Renewed phytomedicinal interest and the rise of plant extract markets drive demand for organic, sustainable consumer products, heightening the competition for superior cultivars. Synthetic polyploidization using oryzalin was conducted to obtain high-quality cultivars of C. fragrans, facilitating enhanced phenotypic and biological traits without genetic modification. This study aimed to explore the metabolic spectrum and biological activities of oryzalin-induced polyploid C. fragrans for its advanced medicinal application. Flow cytometric analysis confirmed the ploidy level of the plants. Consequently, GC-FID and 1H NMR analyses revealed distinct metabolite profiles, with increased ethyl stearate, malic acid, gallic acid, fumaric acid, and unique compounds like (Z)-11-eicosenoic acid and dodecan-1-ol in polyploids. Polyploid extracts demonstrated exceptional antioxidant capacity, with DPPH, ORAC, and ABTS assays showing higher radical scavenging and oxygen absorbance abilities than diploid extracts. The polyploid extract showed enhanced antimicrobial activity against skin pathogens, including Methicillin-resistant Staphylococcus aureus (MRSA). Callisia extracts, meticulously at a low concentration of 25 µg/mL, showed cytoprotective effects on HT-29 cells, mitigating H₂O₂-induced oxidative stress. Furthermore, treatment with polyploid extract was associated with the downregulation of the expression of pro-inflammatory enzymes COX-1 and COX-2, suggesting a potentially greater anti-inflammatory effect compared to the diploid extract. These findings depict enhanced metabolite accumulation and biological activities in polyploid compared than diploid progenitor, highlighting the potential of the novel polyploid C. fragrans variety for future therapeutic applications, particularly in pharmaceutical and cosmetic industries.
- Keywords
- Anti-inflammatory activity, Antioxidant activity, GC-FID, NMR, Polyploidization, Skin infection,
- MeSH
- Antioxidants pharmacology metabolism MeSH
- Cyclooxygenase 1 metabolism MeSH
- Cyclooxygenase 2 metabolism genetics MeSH
- Genotype MeSH
- Humans MeSH
- Polyploidy * MeSH
- Plant Extracts * pharmacology chemistry MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Names of Substances
- Antioxidants MeSH
- Cyclooxygenase 1 MeSH
- Cyclooxygenase 2 MeSH
- Plant Extracts * MeSH
The mechanism of rotator cuff injury remains to be elucidated. And COX-2 plays a dual role in skeletal muscle injury and regeneration, would be associated with the development of rotator cuff injury. Therefore, we chose human skeletal muscle cells (HSKMC) as an in vitro muscle tissue model and transfected lentivirus with overexpressed COX-2 to simulate the in vitro environment of rotator cuff injury. To investigate the specific molecular biological mechanism of COX-2, transcriptome sequencing (RNA-Seq) was used to analyze the differentially expressed mRNAs in HSKMC overexpressing COX-2. Enrichment analysis was performed to analyze these differentially expressed genes and real-time quantitative PCR (RT-qPCR) was used to examine the mRNA levels of genes induced by overexpression. Subsequently, the role of COX-2 in cell proliferation was confirmed by cell counting kit-8 (CCK-8), and focal adhesion kinase (FAK) and signal transducer and activator of transcription 3 (STAT3) phosphorylation induced by COX-2 was utilized by western blotting (WB). The results showed that total of 30,759 differentially expressed genes were obtained, and the expression of CYP4F3 and GPR87 was significantly increased. COX-2 could bind CYP4F3 and GPR87 and co-localize with them in the cytoplasm. Finally, COX-2 promoted the proliferation of human skeletal muscle cells by activating the FAK and STAT3 pathways.
- MeSH
- Cyclooxygenase 2 * metabolism genetics MeSH
- Muscle Fibers, Skeletal metabolism enzymology pathology MeSH
- Muscle, Skeletal metabolism pathology MeSH
- Cells, Cultured MeSH
- Humans MeSH
- Rotator Cuff Injuries * metabolism pathology enzymology genetics MeSH
- Cell Proliferation MeSH
- STAT3 Transcription Factor metabolism MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Names of Substances
- Cyclooxygenase 2 * MeSH
- PTGS2 protein, human MeSH Browser
- STAT3 protein, human MeSH Browser
- STAT3 Transcription Factor MeSH
The objective of this study was to evaluate whether RSV inhibits neutrophil extracellular traps (NETs) that induce joint hyperalgesia in C57BL/6 mice after adjuvant-induced arthritis. A subplantar injection of Freund's complete adjuvant was administered to C57BL/6 mice on day 0 for immunization in the AIA model. Resveratrol (RSV, 25 mg/kg) was administered intraperitoneally once daily starting on day 22 and continuing for two weeks. The effects of mechanical hyperalgesia and edema formation have been assessed in addition to histopathological scoring. Mice were sacrificed on day 35 to determine cytokine levels and PADI4 and COX-2 expression levels. ELISA was used to quantify neutrophil extracellular traps (NETs) along with neutrophil elastase-DNA and myeloperoxidase-DNA complexes in neutrophils. An immunohistochemical stain was performed on knee joints to determine the presence of nuclear factor kappa B p65 (NF-kappaB p65). AIA mice were found to have higher levels of NET in joints and their joint cells demonstrated an increased expression of the PADI4 gene. Treatment with RSV in AIA mice (25 mg/kg, i.p.) significantly (P<0.05) inhibited joint hyperalgesia, resulting in a significant increase in mechanical threshold, a decrease in articular edema, a decrease in the production of inflammatory cytokines, increased COX-2 expression, and a decrease in the immunostaining of NF-kappaB. Furthermore, treatment with RSV significantly reduced the amount of neutrophil elastase (NE)-DNA and MPO-DNA complexes, which were used as indicators of NET formation (P<0.05). This study indicates that RSV reduces NET production and hyperalgesia by reducing inflammation mediated by PADI4 and COX-2. According to these data, NETs contribute to joint pain and resveratrol can be used to treat pain in RA through this pathway.
- MeSH
- Cyclooxygenase 2 MeSH
- Cytokines metabolism MeSH
- DNA metabolism MeSH
- Edema metabolism MeSH
- Extracellular Traps * metabolism MeSH
- Hyperalgesia drug therapy metabolism MeSH
- Leukocyte Elastase metabolism pharmacology MeSH
- Mice, Inbred C57BL MeSH
- Mice MeSH
- Neutrophils metabolism MeSH
- NF-kappa B metabolism MeSH
- Resveratrol pharmacology therapeutic use metabolism MeSH
- Arthritis, Rheumatoid * metabolism MeSH
- Toll-Like Receptor 4 metabolism MeSH
- Inflammation metabolism MeSH
- Animals MeSH
- Check Tag
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Names of Substances
- Cyclooxygenase 2 MeSH
- Cytokines MeSH
- DNA MeSH
- Leukocyte Elastase MeSH
- NF-kappa B MeSH
- Resveratrol MeSH
- Toll-Like Receptor 4 MeSH
The main goal of this article is to present the results of the synthesis of new alkyl derivatives of 5-(2-bromo4-fluorophenyl)-4-ethyl-4H-1,2,4-triazole-3-thiol and molecular docking studies against COX-1 and COX-2. Previous studies have established a wide range of biological activity of 1,2,4-triazole derivatives. Therefore, it was essential to determine how a new series of 1,2,4-triazole derivatives would provide potential anti-inflammatory activity. To reach the goal, raw alkyl derivatives of 5-(2-bromo-4-fluorophenyl)-4-ethyl-4H-1,2,4-triazole-3-thiols (2a-2i) from 5-(2-bromo-4-fluorophenyl)-4-ethyl-4H-1,2,4-triazole3-thiol (1e) were obtained. The structure of the synthesized compounds was confirmed by 1H-NMR elemental analyses. The individuality and purity of compounds were confirmed by the method of liquid chromatography-mass spectrometry. These compounds have a relatively simple synthesis scheme, which gives them an advantage in creating a potential drug, and the appearance of alkyl radicals in the molecule should positively affect pharmacokinetic indicators, stability, selectivity, and bioavailability. An in silico study was conducted for the synthesized compounds, namely molecular docking, in relation to the interaction with COX-1 and COX-2. Based on the selectivity indexes of binding modes observed for the selected compounds (2e, 2g) with active COX-1 centers, it was found that compounds can reliably exhibit their anti-inflammatory effect through the prostaglandin biosynthesis pathway, inhibiting COX-1 instead of COX-2. The effect of hydrophobic interactions of alkyl groups of 1,2,4-triazole derivatives on changes in affinity and selectivity to COX-1 or COX-2 has also been proven. Therefore, derivatives of 1,2,4 are promising candidates for improvement, further study, and future development of new, more powerful antiinflammatory drugs for therapeutic use.
- Keywords
- 1,2,4-triazole, anti-inflammatory activity, in silico, molecular docking, synthesis,
- MeSH
- Anti-Inflammatory Agents * pharmacology MeSH
- Cyclooxygenase 2 metabolism MeSH
- Molecular Docking Simulation MeSH
- Sulfhydryl Compounds * chemistry MeSH
- Publication type
- Journal Article MeSH
- Names of Substances
- 1,2,4-triazole MeSH Browser
- Anti-Inflammatory Agents * MeSH
- Cyclooxygenase 2 MeSH
- Sulfhydryl Compounds * MeSH
AIMS: The effect of polyphenolic fraction of Lonicera caerulea (PFLC) and alkaloid fraction of Macleaya cordata (AFMC) mix on the production of inflammatory mediators in human gingival fibroblasts pretreated with lipopolysaccharide (LPS) was investigated. In addition, protective effects of mucoadhesive paste containing combination of PFLC and AFMC (0.05% and 0.01%, respectively; n=15, Group A) and placebo (n=15, Group B) were evaluated in patients after surgical extraction of lower third molars. METHODS: Gingival fibroblasts were pre-treated with LPS (10 µg/mL; 24 h) and PFLC/AFMC (25/0.25; 50/0.25; 100/0.25; 25/0.5; 50/0.5; 100/0.5 µg/mL) in serum-free medium was applied for 4 h. Then the interleukin-6 (IL-6), reactive oxygen species (ROS) generation, level of intracellular glutathione (GSH) and expression of cyclooxygenase-2 (COX-2) were evaluated. The study was a 6-day, single-center, randomized, double-blind and placebo-controlled trial consisting of two parallel treatment arms. A modified Oral health impact profile questionnaire including both general oral condition and extraction related questions, was used to evaluate the oral condition and other changes before (day 0) and on the days 1, 3 and 6 after surgical extraction. RESULTS AND CONCLUSION: The combination of PFLC with AFMC caused a reduction of ROS generation, reduced IL-6 production and suppressed the expression of COX-2. In group A the paste treatment contributed to improvement of oral health-related quality of life. Topical application of PFLC and AFMC into the extraction wound improved post-extraction site wound healing probably by antioxidant and anti-inflammatory mechanisms.
- Keywords
- Lonicera caerulea, Macleaya cordata, anthocyanins, gingival fibroblast, isoquinolinium alkaloids, third molar surgery,
- MeSH
- Alkaloids * pharmacology MeSH
- Cyclooxygenase 2 pharmacology MeSH
- Phenols pharmacology MeSH
- Fibroblasts metabolism MeSH
- Wound Healing MeSH
- Interleukin-6 MeSH
- Quality of Life MeSH
- Humans MeSH
- Lipopolysaccharides pharmacology MeSH
- Molar, Third * surgery metabolism MeSH
- Reactive Oxygen Species metabolism pharmacology MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Randomized Controlled Trial MeSH
- Names of Substances
- Alkaloids * MeSH
- Cyclooxygenase 2 MeSH
- Phenols MeSH
- Interleukin-6 MeSH
- Lipopolysaccharides MeSH
- Reactive Oxygen Species MeSH
Pain is a serious subjective experience, which, although it has a protective nature, it physically and mentally exhausts the patient. The pharmacological field of development and research in the treatment and relief of pain has been dynamic and interesting ever since the isolation of salicylic acid. After discovering the molecular nature of cyclooxygenase and its inhibition, research focused on selective COX-2 inhibitors, but they were a big disappointment. Today, the possibility of contributing to safe and effective analgesic-antiphlogistic treatment for the patient with a combination of drugs is emerging again.
- Keywords
- coxibs, cyclooxygenase inhibition, non-steroidal anti-inflammatory drugs,
- MeSH
- Anti-Inflammatory Agents, Non-Steroidal * pharmacology therapeutic use MeSH
- Pain drug therapy MeSH
- Cyclooxygenase 2 MeSH
- Cyclooxygenase 2 Inhibitors * therapeutic use pharmacology MeSH
- Humans MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Names of Substances
- Anti-Inflammatory Agents, Non-Steroidal * MeSH
- Cyclooxygenase 2 MeSH
- Cyclooxygenase 2 Inhibitors * MeSH
Selective cyclooxygenase (COX)-1 inhibitors can be employed as potential cardioprotective drugs. Moreover, COX-1 plays a key role in inflammatory processes and its activity is associated with some types of cancer. In this work, we designed and synthesized a set of compounds that structurally mimic the selective COX-1 inhibitors, SC-560 and mofezolac, the central cores of which were replaced either with triazole or benzene rings. The advantage of this approach is a relatively simple synthesis in comparison with the syntheses of parent compounds. The newly synthesized compounds exhibited remarkable activity and selectivity toward COX-1 in the enzymatic in vitro assay. The most potent compound, 10a (IC50 = 3 nM for COX-1 and 850 nM for COX-2), was as active as SC-560 (IC50 = 2.4 nM for COX-1 and 470 nM for COX-2) toward COX-1 and it was even more selective. The in vitro COX-1 enzymatic activity was further confirmed in the cell-based whole-blood antiplatelet assay, where three out of four selected compounds (10a,c,d, and 3b) exerted outstanding IC50 values in the nanomolar range (9-252 nM). Moreover, docking simulations were performed to reveal key interactions within the COX-1 binding pocket. Furthermore, the toxicity of the selected compounds was tested using the normal human kidney HK-2 cell line.
- Keywords
- cyclooxygenase, cytotoxicity, docking, platelets, selectivity,
- MeSH
- Anti-Inflammatory Agents, Non-Steroidal * pharmacology MeSH
- Cyclooxygenase 2 metabolism MeSH
- Cyclooxygenase 2 Inhibitors * pharmacology chemistry MeSH
- Humans MeSH
- Molecular Structure MeSH
- Molecular Docking Simulation MeSH
- Structure-Activity Relationship MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Names of Substances
- Anti-Inflammatory Agents, Non-Steroidal * MeSH
- Cyclooxygenase 2 MeSH
- Cyclooxygenase 2 Inhibitors * MeSH
- mofezolac MeSH Browser
- SC 560 MeSH Browser
NSAIDs are promising agents for preventing cold injury (frigoprotectors). The influence of prophylactic administration of the non-selective COX inhibitor diclofenac sodium (7 mg/kg) and the highly selective COX-2 inhibitor etoricoxib (5 mg/kg) on cyclooxygenase pathway biomarkers was studied on the model of acute general cooling (air hypothermia at -18 °С for 2 hours). Diclofenac completely prevented a decrease in body temperature, surpassing etoricoxib. In the liver of the rats immediately after cold exposure, the content of COX-1 was increased moderately and the content of COX-2 highly significantly. Very significantly, the level of PGE2 decreased, and the levels of PGF2α, especially PGI2 and TXB2, were elevated. In the blood serum, the level of COX-1 was decreased, and the changes in COX-2 and prostaglandins levels were similar to those in the liver. Diclofenac exerted a moderate effect towards the normalization of both COX isoforms in the liver, moderately increased the content of PGE2, and decreased - PGF2α and TXB2 without changing the level of PGI2. In serum, diclofenac reduced COX-1 level to subnormal values, and its effect on other biomarkers was similar to that in the liver, except for a moderate decrease in PGI2. Thus, diclofenac was inferior to etoricoxib, which normalized COX-1, COX-2, PGE2, and PGI2 in the liver and reduced the content of PGF2α and TXB2 in the liver to subnormal values. At the same time, in the blood serum, it decreased COX-1, COX-2, and PGE2 to subnormal values, normalized PGF2α, and PGI2, and significantly reduced TXB2. The opposite degree of intensity of the influence of diclofenac and etoricoxib on the cyclooxygenase pathway and body temperature indicates a dissociation of anti-inflammatory and frigoprotective activity. Inhibition of oxidative stress is not determinative for the frigoprotective activity of NSAIDs since diclofenac, despite the weaker influence on the content of 8-isoprostane in the liver, still exerts the maximum frigoprotective activity.
- Keywords
- Body temperature, body temperature, cold injury prevention, cyclooxygenase, diclofenac sodium, etoricoxib, frigoprotective activity, prostaglandins,
- MeSH
- Anti-Inflammatory Agents, Non-Steroidal pharmacology MeSH
- Cyclooxygenase 2 MeSH
- Diclofenac pharmacology MeSH
- Dinoprost MeSH
- Dinoprostone MeSH
- Etoricoxib MeSH
- Hypothermia * MeSH
- Rats MeSH
- Arachidonic Acid MeSH
- Body Temperature MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Names of Substances
- Anti-Inflammatory Agents, Non-Steroidal MeSH
- Cyclooxygenase 2 MeSH
- Diclofenac MeSH
- Dinoprost MeSH
- Dinoprostone MeSH
- Etoricoxib MeSH
- Arachidonic Acid MeSH
The TGF-β signaling pathway is involved in numerous cellular processes, and its deregulation may result in cancer development. One of the key processes in tumor progression and metastasis is epithelial to mesenchymal transition (EMT), in which TGF-β signaling plays important roles. Recently, AGR2 was identified as a crucial component of the cellular machinery responsible for maintaining the epithelial phenotype, thereby interfering with the induction of mesenchymal phenotype cells by TGF-β effects in cancer. Here, we performed transcriptomic profiling of A549 lung cancer cells with CRISPR-Cas9 mediated AGR2 knockout with and without TGF-β treatment. We identified significant changes in transcripts associated with focal adhesion and eicosanoid production, in particular arachidonic acid metabolism. Changes in transcripts associated with the focal adhesion pathway were validated by RT-qPCR of COL4A1, COL4A2, FLNA, VAV3, VEGFA, and VINC mRNAs. In addition, immunofluorescence showed the formation of stress fibers and vinculin foci in cells without AGR2 and in response to TGF-β treatment, with synergistic effects observed. These findings imply that both AGR2 downregulation and TGF-β have a role in focal adhesion formation and cancer cell migration and invasion. Transcripts associated with arachidonic acid metabolism were downregulated after both AGR2 knockout and TGF-β treatment and were validated by RT-qPCR of GPX2, PTGS2, and PLA2G4A. Since PGE2 is a product of arachidonic acid metabolism, its lowered concentration in media from AGR2-knockout cells was confirmed by ELISA. Together, our results demonstrate that AGR2 downregulation and TGF-β have an essential role in focal adhesion formation; moreover, we have identified AGR2 as an important component of the arachidonic acid metabolic pathway.
- Keywords
- AGR2, EMT, RNAseq, TGF-β, arachidonic acid, focal adhesion,
- MeSH
- Cyclooxygenase 2 genetics MeSH
- Epithelial-Mesenchymal Transition * genetics MeSH
- Arachidonic Acid MeSH
- Cell Line, Tumor MeSH
- Cell Movement genetics MeSH
- Prostaglandins E MeSH
- Gene Expression Regulation, Neoplastic * MeSH
- Transforming Growth Factor beta genetics MeSH
- Vinculin genetics MeSH
- Publication type
- Journal Article MeSH
- Names of Substances
- Cyclooxygenase 2 MeSH
- Arachidonic Acid MeSH
- Prostaglandins E MeSH
- Transforming Growth Factor beta MeSH
- Vinculin MeSH
Mesenchymal stem cells (MSCs) represent a population of adult stem cells that have potent immunoregulatory, anti-inflammatory, and antiapoptotic properties. In addition, they have ability to migrate to the site of inflammation or injury, where they contribute to the regeneration and healing process. For these properties, MSCs have been used as therapeutic cells in several models, including treatment of damages or disorders of the ocular surface. If the damage of the ocular surface is extensive and involves a limbal region where limbal stem cell reside, MSC therapy has been proved as the effective treatment approach. Although the anti-inflammatory properties of MSCs have been well characterized, mechanisms of antiapoptotic action of MSCs are not well recognized. Using a chemically damaged cornea in a mouse model, we showed that the injury decreases expression of the gene for antiapoptotic molecule Bcl-2 and increases the expression of proapoptotic genes Bax and p53. These changes were attenuated by local transplantation of MSCs after corneal damage. The antiapoptotic effect of MSCs was tested in an in vitro model of co-cultivation of corneal explants with MSCs. The apoptosis of corneal cells in the explants was induced by proinflammatory cytokines and was significantly inhibited in the presence of MSCs. The antiapoptotic effect of MSCs was mediated by paracrine action, as confirmed by separation of the explants in inserts or by supernatants from MSCs. In addition, MSCs decreased the expression of genes for the molecules associated with endoplasmic reticulum stress Atf4, Bip, and p21, which are associated with apoptosis. The results show that MSCs inhibit the expression of proapoptotic genes and decrease the number of apoptotic cells in the damaged corneas, and this action might be one of the mechanisms of the therapeutic action of MSCs.
- Keywords
- Bax, Bcl-2, antiapoptotic properties, cornea, mesenchymal stem cells, mouse model,
- MeSH
- Apoptosis genetics MeSH
- Cyclooxygenase 2 genetics metabolism MeSH
- Cytokines genetics metabolism MeSH
- Hepatocyte Growth Factor genetics metabolism MeSH
- Keratitis genetics metabolism pathology MeSH
- Cells, Cultured MeSH
- Humans MeSH
- Mesenchymal Stem Cells cytology metabolism MeSH
- Disease Models, Animal * MeSH
- Mice, Inbred BALB C MeSH
- Mice MeSH
- Reverse Transcriptase Polymerase Chain Reaction MeSH
- Corneal Injuries genetics metabolism therapy MeSH
- Gene Expression Regulation * MeSH
- Cornea metabolism MeSH
- Mesenchymal Stem Cell Transplantation methods MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Mice MeSH
- Female MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- Cyclooxygenase 2 MeSH
- Cytokines MeSH
- Hepatocyte Growth Factor MeSH
