The effective treatment of inflammatory diseases, particularly their chronic forms, is a key task of modern medicine. Herein, we report the synthesis and evaluation of biocompatible polymer conjugates based on N-2-(hydroxypropyl)methacrylamide copolymers enabling the controlled release of acetylsalicylic acid (ASA)-based anti-inflammatory drugs under specific stimuli. All polymer nanotherapeutics were proposed as water-soluble drug delivery systems with a hydrodynamic size below 10 nm ensuring suitability for the parenteral application and preventing opsonization by the reticuloendothelial system. The nanotherapeutics bearing an ester-bound ASA exhibited long-term release of the ASA/salicylic acid mixture, while the nanotherapeutics carrying salicylic acid hydrazide (SAH) ensured the selective release of SAH in the acidic inflammatory environment thanks to the pH-sensitive hydrazone bond between the polymer carrier and SAH. The ASA- and SAH-containing nanotherapeutics inhibited both cyclooxygenase isoforms and/or the production of pro-inflammatory mediators. Thanks to their favorable design, they can preferentially accumulate in the inflamed tissue, resulting in reduced side effects and lower dosage, and thus more effective and safer treatment.
- MeSH
- akrylamidy chemie farmakologie aplikace a dávkování MeSH
- antiflogistika farmakologie aplikace a dávkování chemie MeSH
- Aspirin * aplikace a dávkování farmakologie chemie MeSH
- cyklooxygenasy metabolismus MeSH
- inhibitory cyklooxygenasy farmakologie aplikace a dávkování chemie MeSH
- léky s prodlouženým účinkem * MeSH
- mediátory zánětu metabolismus MeSH
- myši MeSH
- nanočástice * chemie MeSH
- nosiče léků chemie MeSH
- polymery * chemie aplikace a dávkování MeSH
- uvolňování léčiv MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- MeSH
- akutní bolest * farmakoterapie MeSH
- antirevmatika * farmakologie škodlivé účinky terapeutické užití MeSH
- inhibitory cyklooxygenasy 2 farmakologie terapeutické užití MeSH
- inhibitory cyklooxygenasy farmakologie terapeutické užití MeSH
- lidé MeSH
- neopioidní analgetika terapeutické užití MeSH
- Check Tag
- lidé MeSH
The aim of the study was to broadly determine the biological activities of purple potato ethanolic extract of the Blue Congo variety (BCE). The antioxidant activity of BCE was determined in relation to liposome membranes, and peroxidation was induced by UVB and AAPH. To clarify the antioxidant activity of BCE, we investigated its interactions with hydrophilic and hydrophobic regions of a membrane using fluorimetric and FTIR methods. Next, we investigated the cytotoxicity and pro-apoptotic activities of BCE in two human colon cancer cell lines (HT-29 and Caco-2) and in normal cells (IPEC-J2). In addition, the ability to inhibit enzymes that are involved in pro-inflammatory reactions was examined. Furthermore, BCE interactions with serum albumin and plasmid DNA were investigated using steady state fluorescence spectroscopy and a single molecule fluorescence technique (TCSPC-FCS). We proved that BCE effectively protects lipid membranes against the process of peroxidation and successfully inhibits the cyclooxygenase and lipoxygenase enzymes. Furthermore, it interacts with the hydrophilic and hydrophobic parts of lipid membranes as well as with albumin and plasmid DNA. It was observed that BCE is more cytotoxic against colon cancer cell lines than normal IPEC-J2 cells; it also induces apoptosis in cancer cell lines, but does not induce cell death in normal cells.
- MeSH
- albuminy MeSH
- antioxidancia chemie farmakologie MeSH
- fytogenní protinádorové látky chemie farmakologie MeSH
- inhibitory cyklooxygenasy chemie farmakologie MeSH
- inhibitory lipoxygenas chemie farmakologie MeSH
- lidé MeSH
- lipidy chemie MeSH
- liposomy MeSH
- nádorové buněčné linie MeSH
- plazmidy MeSH
- reaktivní formy kyslíku MeSH
- rostlinné extrakty chemie farmakologie MeSH
- sérový albumin chemie metabolismus MeSH
- Solanum tuberosum chemie MeSH
- vazba proteinů MeSH
- viabilita buněk účinky léků MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Based on the significant anti-inflammatory activity of natural quinone primin (5a), series of 1,4-benzoquinones, hydroquinones, and related resorcinols were designed, synthesized, characterized and tested for their ability to inhibit the activity of cyclooxygenase (COX-1 and COX-2) and 5-lipoxygenase (5-LOX) enzymes. Structural modifications resulted in the identification of two compounds 5b (2-methoxy-6-undecyl-1,4-benzoquinone) and 6b (2-methoxy-6-undecyl-1,4-hydroquinone) as potent dual COX/5-LOX inhibitors. The IC50 values evaluated in vitro using enzymatic assay were for compound 5b IC50 = 1.07, 0.57, and 0.34 μM and for compound 6b IC50 = 1.07, 0.55, and 0.28 μM for COX-1, COX-2, and 5-LOX enzyme, respectively. In addition, compound 6d was identified as the most potent 5-LOX inhibitor (IC50 = 0.14 μM; reference inhibitor zileuton IC50 = 0.66 μM) from the tested compounds while its inhibitory potential against COX enzymes (IC50 = 2.65 and 2.71 μM for COX-1 and COX-2, respectively) was comparable with the reference inhibitor ibuprofen (IC50 = 4.50 and 2.46 μM, respectively). The most important structural modification leading to increased inhibitory activity towards both COXs and 5-LOX was the elongation of alkyl chain in position 6 from 5 to 11 carbons. Moreover, the monoacetylation in ortho position of bromo-hydroquinone 13 led to the discovery of potent (IC50 = 0.17 μM) 5-LOX inhibitor 17 (2-bromo-6-methoxy-1,4-benzoquinone) while bromination stabilized the hydroquinone form. Docking analysis revealed the interaction of compounds with Tyr355 and Arg120 in the catalytic site of COX enzymes, while the hydrophobic parts of the molecules filled the hydrophobic substrate channel leading up to Tyr385. In the allosteric catalytic site of 5-LOX, compounds bound to Tyr142 and formed aromatic interactions with Arg138. Taken together, we identified optimal alkyl chain length for dual COX/5-LOX inhibition and investigated other structural modifications influencing COX and 5-LOX inhibitory activity.
- MeSH
- benzochinony chemie MeSH
- inhibitory cyklooxygenasy chemická syntéza chemie farmakologie MeSH
- inhibitory lipoxygenas chemická syntéza chemie farmakologie MeSH
- katalytická doména MeSH
- oxidace-redukce MeSH
- počítačová simulace MeSH
- resorcinoly chemie MeSH
- simulace molekulového dockingu MeSH
- spektrální analýza metody MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Publikační typ
- časopisecké články MeSH
SCOPE: Intake of flavonoids from the diet can be substantial, and epidemiological studies suggest that these compounds can decrease the incidence of cardiovascular diseases by involvement with increased platelet aggregation. Although parent flavonoids possess antiplatelet effects, the clinical importance is disputable due to their very low bioavailability. Most of them are metabolized by human colon bacteria to smaller phenolic compounds, which reach higher plasma concentrations than the parent flavonoids. In this study, a series of 29 known flavonoid metabolites is tested for antiplatelet potential. METHODS AND RESULTS: Four compounds appear to have a biologically relevant antiplatelet effect using whole human blood. 4-Methylcatechol (4-MC) is clearly the most efficient being about 10× times more active than clinically used acetylsalicylic acid. This ex vivo effect is also confirmed using a potentially novel in-vivo-like ex ovo hen's egg model of thrombosis, where 4-MC significantly increases the survival of the eggs. The mechanism of action is studied and it seems that it is mainly based on the influence on intracellular calcium signaling. CONCLUSION: This study shows that some flavonoid metabolites formed by human microflora have a strong antiplatelet effect. This information can help to explain the antiplatelet potential of orally given flavonoids.
- MeSH
- agregace trombocytů účinky léků MeSH
- inhibitory agregace trombocytů farmakologie MeSH
- inhibitory cyklooxygenasy farmakologie MeSH
- inhibitory enzymů farmakologie MeSH
- katecholy farmakologie MeSH
- kuřecí embryo MeSH
- kyselina arachidonová farmakologie MeSH
- lidé MeSH
- preklinické hodnocení léčiv metody MeSH
- pyrogalol farmakologie MeSH
- serotonin metabolismus MeSH
- thromboxan-A-synthasa antagonisté a inhibitory MeSH
- trombóza farmakoterapie MeSH
- zvířata MeSH
- Check Tag
- kuřecí embryo MeSH
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Non-steroidal anti-inflammatory drugs (NSAIDs) play an effective chemopreventive action against a variety of cancers. The present study aimed at targeting pro-inflammatory cyclooxygenase (COX) and NF-kB mediated inflammatory pathways in 9,10-dimethylbenzanthracene (DMBA) induced lung cancer in BALB/C mice and chemoprotective action of NSAIDs. Animals were divided into five groups and treated with NSAIDs, intratracheally, daily for a period of 18 weeks. Group 1 as control, received vehicle treatment; Group 2 received single dose of DMBA (10 mg/kg bw); Group 3, 4 and 5 besides DMBA treatment, also received Aspirin (60 mg/kg bw), Celecoxib (6.0 mg/kg bw) and Etoricoxib (0.6 mg/kg bw), respectively. DMBA induce DNA damage, apoptosis and expression of COX-1, COX-2 and NF-κB using immunofluorescence and blot analysis were done. The present study demonstrated the formation of micronuclei, over-expression of COX-2 and NF-κB in DMBA induced lung tumorigenesis and thereby suggesting a marked role of inflammation in the tumour progression. Results indicate the formation of micronuclei in DMBA group, which were significantly reduced in aspirin treated group, and totally absent in the celecoxib and etoricoxib groups. In conclusion, co-administration of etoricoxib and celecoxib has significantly reduced the inflammatory potential of the growing neoplasm in DMBA induced lung cancer in male BALB/C mice.
- MeSH
- anthraceny aplikace a dávkování farmakologie MeSH
- antiflogistika nesteroidní * aplikace a dávkování farmakologie MeSH
- chemoprofylaxe MeSH
- DNA účinky léků MeSH
- inhibitory cyklooxygenasy aplikace a dávkování farmakologie MeSH
- modely nemocí na zvířatech MeSH
- myši inbrední BALB C MeSH
- nádory plic genetika imunologie prevence a kontrola MeSH
- zánět farmakoterapie imunologie patofyziologie MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- práce podpořená grantem MeSH
- MeSH
- analgetika * klasifikace terapeutické užití MeSH
- antiflogistika nesteroidní aplikace a dávkování klasifikace škodlivé účinky terapeutické užití MeSH
- bolest * diagnóza farmakoterapie klasifikace MeSH
- chronická nemoc MeSH
- inhibitory cyklooxygenasy farmakologie klasifikace MeSH
- klinické rozhodování MeSH
- kombinovaná farmakoterapie MeSH
- lidé MeSH
- neopioidní analgetika farmakologie klasifikace terapeutické užití MeSH
- opioidní analgetika aplikace a dávkování klasifikace škodlivé účinky terapeutické užití MeSH
- paracetamol aplikace a dávkování škodlivé účinky terapeutické užití MeSH
- poruchy spojené s užíváním opiátů klasifikace MeSH
- srdeční selhání komplikace MeSH
- Check Tag
- lidé MeSH
- MeSH
- antirevmatika farmakologie terapeutické užití MeSH
- bisfosfonáty farmakologie terapeutické užití MeSH
- diklofenak farmakologie terapeutické užití MeSH
- hormony kůry nadledvin farmakologie terapeutické užití MeSH
- ibuprofen farmakologie terapeutické užití MeSH
- inhibitory cyklooxygenasy farmakologie terapeutické užití MeSH
- kmenové buňky MeSH
- kyselina hyaluronová farmakologie terapeutické užití MeSH
- lidé MeSH
- management bolesti metody MeSH
- management nemoci MeSH
- opioidní analgetika farmakologie terapeutické užití MeSH
- osteoartróza * farmakoterapie terapie MeSH
- plazma bohatá na destičky MeSH
- směrnice pro lékařskou praxi jako téma MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
