Ibuprofen (IBU) is a non-steroidal anti-inflammatory drug (NSAID) commonly used in the treatment of pain, fever and inflammation. However, the administration of IBU in its free carboxylic acid form is strongly dependent on its limited solubility in aqueous solution. This mandates for an increased drug concentration to reach the therapeutic window, and promotes the alternative use of IBU sodium salt, even if this latter form poses significant constraints in terms of tunable release due to its uncontrolled and rapid diffusion. A potential solution is represented by oral administration through physical encapsulation of ibuprofen in designed carriers, despite this route limits the application of this therapeutic agent. In this work, we propose the covalent tethering of ibuprofen to a hydrogel matrix via esterification reaction. Exploiting the cleavability of the ester bond under physiological conditions, we propose a controlled drug delivery system where the whole drug payload can be released, thus overcoming the questioned aspects of over-dosage and solubility-dependent administration. In particular, we tested the biological activity of cleaved ibuprofen in terms of cyclooxygenase inhibition, reporting that chemical tethering did not alter the efficiency of the NSAID. Moreover, due to the sol-gel transition of the hydrogel matrix, these ibuprofen-functionalized hydrogels could be used as injectable tools in several clinical scenarios, performing a localized drug release and opening advanced avenues for in situ treatments.

• MeSH
• akrylové pryskyřice chemie   MeSH
• aplikace orální MeSH
• cyklooxygenasy metabolismus   MeSH
• enzymatické testy MeSH
• hydrogely chemie   MeSH
• ibuprofen aplikace a dávkování   farmakokinetika   MeSH
• inhibitory cyklooxygenasy aplikace a dávkování   farmakokinetika   MeSH
• léky s prodlouženým účinkem aplikace a dávkování   farmakokinetika   MeSH
• lidé MeSH
• nádorové buněčné linie MeSH
• nosiče léků chemie   MeSH
• propylenglykoly chemie   MeSH
• rozpustnost MeSH
• sefarosa chemie   MeSH
• uvolňování léčiv MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Stilbenoids are important components of foods (e.g., peanuts, grapes, various edible berries), beverages (wine, white tea), and medicinal plants. Many publications have described the anti-inflammatory potential of stilbenoids, including the widely known trans-resveratrol and its analogues. However, comparatively little information is available regarding the activity of their prenylated derivatives. One new prenylated stilbenoid (2) was isolated from Artocarpus altilis and characterized structurally based on 1D and 2D NMR analysis and HRMS. Three other prenylated stilbenoids were prepared synthetically (9-11). Their antiphlogistic potential was determined by testing them together with known natural prenylated stilbenoids from Macaranga siamensis and Artocarpus heterophyllus in both cell-free and cell assays. The inhibition of 5-lipoxygenase (5-LOX) was also shown by simulated molecular docking for the most active stilbenoids in order to elucidate the mode of interaction between these compounds and the enzyme. Their effects on the pro-inflammatory nuclear factor-κB (NF-κB) and the activator protein 1 (AP-1) signaling pathway were also analyzed. The THP1-XBlue-MD2-CD14 cell line was used as a model for determining their anti-inflammatory potential, and lipopolysaccharide (LPS) stimulation of Toll-like receptor 4 induced a signaling cascade leading to the activation of NF-κB/AP-1. The ability of prenylated stilbenoids to attenuate the production of pro-inflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) was further evaluated using LPS-stimulated THP-1 macrophages.

• MeSH
• buněčné linie MeSH
• cyklooxygenasy metabolismus   MeSH
• inhibitory enzymů farmakologie   MeSH
• lidé MeSH
• lipoxygenasy metabolismus   MeSH
• NF-kappa B antagonisté a inhibitory   MeSH
• prenylace * MeSH
• signální transdukce účinky léků   MeSH
• stilbeny farmakologie   MeSH
• transkripční faktor AP-1 antagonisté a inhibitory   MeSH
• zánět prevence a kontrola   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Mitochondrial protein homeostasis is crucial for cellular function and integrity and is therefore maintained by several classes of proteins possessing chaperone and/or proteolytic activities. In the present study, we focused on characterization of LACE1 (lactation elevated 1) function in mitochondrial protein homeostasis. LACE1 is the human homologue of yeast mitochondrial Afg1 (ATPase family gene 1) ATPase, a member of the SEC18-NSF, PAS1, CDC48-VCP, TBP family. Yeast Afg1 was shown to mediate degradation of mitochondrially encoded complex IV subunits, and, on the basis of its similarity to CDC48 (p97/VCP), it was suggested to facilitate extraction of polytopic membrane proteins. We show that LACE1, which is a mitochondrial integral membrane protein, exists as part of three complexes of approximately 140, 400 and 500 kDa and is essential for maintenance of fused mitochondrial reticulum and lamellar cristae morphology. We demonstrate that LACE1 mediates degradation of nuclear-encoded complex IV subunits COX4 (cytochrome c oxidase 4), COX5A and COX6A, and is required for normal activity of complexes III and IV of the respiratory chain. Using affinity purification of LACE1-FLAG expressed in a LACE1-knockdown background, we show that the protein interacts physically with COX4 and COX5A subunits of complex IV and with mitochondrial inner-membrane protease YME1L. Finally, we demonstrate by ectopic expression of both K142A Walker A and E214Q Walker B mutants, that an intact ATPase domain is essential for LACE1-mediated degradation of nuclear-encoded complex IV subunits. Thus the present study establishes LACE1 as a novel factor with a crucial role in mitochondrial protein homeostasis.

• MeSH
• adenosintrifosfatasy genetika   metabolismus   MeSH
• cyklooxygenasy genetika   metabolismus   MeSH
• GTP-fosfohydrolasy genetika   metabolismus   MeSH
• HEK293 buňky MeSH
• konformace proteinů MeSH
• lidé MeSH
• messenger RNA genetika   metabolismus   MeSH
• mitochondriální proteiny genetika   metabolismus   MeSH
• mitochondrie ultrastruktura   MeSH
• mutace MeSH
• podjednotky proteinů MeSH
• regulace genové exprese enzymů fyziologie   MeSH
• RNA interference MeSH
• spotřeba kyslíku MeSH
• transport elektronů fyziologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

BACKGROUND: Long-chain n-3 polyunsaturated fatty acids (LC n-3 PUFA) of marine origin exert multiple beneficial effects on health. Our previous study in mice showed that reduction of adiposity by LC n-3 PUFA was associated with both, a shift in adipose tissue metabolism and a decrease in tissue cellularity. The aim of this study was to further characterize the effects of LC n-3 PUFA on fat cell proliferation and differentiation in obese mice. METHODS: A model of inducible and reversible lipoatrophy (aP2-Cre-ERT2 PPARγL2/L2 mice) was used, in which the death of mature adipocytes could be achieved by a selective ablation of peroxisome proliferator-activated receptor γ in response to i.p. injection of tamoxifen. Before the injection, obesity was induced in male mice by 8-week-feeding a corn oil-based high-fat diet (cHF) and, subsequently, mice were randomly assigned (day 0) to one of the following groups: (i) mice injected by corn-oil-vehicle only, i.e."control" mice, and fed cHF; (ii) mice injected by tamoxifen in corn oil, i.e. "mutant" mice, fed cHF; (iii) control mice fed cHF diet with15% of dietary lipids replaced by LC n-3 PUFA concentrate (cHF+F); and (iv) mutant mice fed cHF+F. Blood and tissue samples were collected at days 14 and 42. RESULTS: Mutant mice achieved a maximum weight loss within 10 days post-injection, followed by a compensatory body weight gain, which was significantly faster in the cHF as compared with the cHF+F mutant mice. Also in control mice, body weight gain was depressed in response to dietary LC n-3 PUFA. At day 42, body weights in all groups stabilized, with no significant differences in adipocyte size between the groups, although body weight and adiposity was lower in the cHF+F as compared with the cHF mice, with a stronger effect in the mutant than in control mice. Gene expression analysis documented depression of adipocyte maturation during the reconstitution of adipose tissue in the cHF+F mutant mice. CONCLUSION: Dietary LC n-3 PUFA could reduce both hypertrophy and hyperplasia of fat cells in vivo. Results are in agreement with the involvement of fat cell turnover in control of adiposity.

• MeSH
• cyklooxygenasy genetika   metabolismus   MeSH
• epididymis metabolismus   patologie   MeSH
• exprese genu MeSH
• genový knockout MeSH
• kukuřičný olej škodlivé účinky   MeSH
• kyseliny mastné omega-3 farmakologie   MeSH
• myši transgenní MeSH
• myši MeSH
• obezita chemicky indukované   prevence a kontrola   MeSH
• PPAR alfa genetika   metabolismus   MeSH
• PPAR gama genetika   MeSH
• preklinické hodnocení léčiv MeSH
• proliferace buněk účinky léků   MeSH
• proteiny genetika   metabolismus   MeSH
• stearyl-CoA-desaturasa genetika   metabolismus   MeSH
• trans-aktivátory genetika   metabolismus   MeSH
• tukové buňky účinky léků   patologie   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Endothelium-dependent contraction elicited by high concentrations of acetylcholine was described in hypertensive as well as in aged normotensive rats. The contribution of endothelium-derived constricting factor (EDCF) to norepinephrine-induced contraction is still unknown. We aimed to compare EDCF participation to norepinephrine-induced arterial contraction in spontaneously hypertensive rats (SHR) and aged normotensive Wistar-Kyoto (WKY) rats. Femoral arteries from either adult (7-months-old) or aged (14-months-old) animals were placed in myograph and norepinephrine-induced concentration-response curves were recorded under control conditions and in the presence of indomethacin (cyclooxygenase inhibitor, 10(-5) mol/l) or L-NNA (NO synthase inhibitor, 10(-4) mol/l) or both. Norepinephrine-induced concentration-response curve was enhanced in SHR compared to WKY rats, but concentration-response curve of aged WKY rats was similar to those of adult SHR. Cyclooxygenase inhibition largely attenuated concentration-response curves in all groups. However, this effect was greater in aged WKY rats and adult SHR compared to adult WKY rats. NO synthase inhibition augmented norepinephrine-induced contraction in arteries of adult WKY rats, but not in arteries from aged WKY rats or adult SHR. The combined administration of L-NNA and indomethacin had no additive effects on concentration-response curves. EDCF contribution to norepinephrine-induced contractions of arteries was considerably greater in adult SHR (80±3%) and aged WKY rats (86±2%) compared to adult WKY rats (35±10%). The inhibition of NO synthase augmented EDCF contribution to norepinephrine-induced contraction only in arteries from adult WKY rats (76±9%). We conclude that EDCF contribution to norepinephrine-induced contraction of conduit arteries is similarly enhanced in adult hypertensive and aged normotensive rats.

• MeSH
• acetylcholin farmakologie   MeSH
• arteria femoralis účinky léků   metabolismus   fyziologie   MeSH
• cyklooxygenasy metabolismus   MeSH
• endoteliny metabolismus   MeSH
• hypertenze metabolismus   patofyziologie   MeSH
• indomethacin farmakologie   MeSH
• inhibitory cyklooxygenasy farmakologie   MeSH
• krysa rodu rattus MeSH
• noradrenalin farmakologie   MeSH
• stárnutí metabolismus   fyziologie   MeSH
• synthasa oxidu dusnatého antagonisté a inhibitory   MeSH
• vazokonstrikce účinky léků   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• techniky in vitro MeSH

Because insulin resistance is inevitably associated with cardiovascular complications, there is a need to further investigate the potential involvement of oxidative stress and the cyclo-oxygenase (COX) pathway in the vascular modifications associated to this pathological context. Endothelial function was evaluated in control and fructose-fed rats (FFR) by i) in vitro study of endothelium-dependent and -independent relaxations of aortic rings, and ii) in vivo telemetric evaluation of pressor response to norepinephrine. After 9 weeks of diet, FFR displayed hypertriglyceridemia, hyperinsulinemia and exaggerated response to glucose overload. Aortic rings from control rats and FFR exhibited comparable endothelium-dependent relaxations to Ach. In the presence of indomethacin, relaxations were significantly reduced. FFR showed exaggerated pressor responses to norepinephrine that were abolished with indomethacin. Urinary nitrites/nitrates, 8-isoprostanes and thromboxane B2 excretion levels were markedly enhanced in FFR, whereas the plasma levels of 6-keto prostaglandin F1? were unchanged. In conclusion, fructose overload in rats induced hypertriglyceridemia and insulin resistance associated with an enhanced oxidative stress. This was associated with COX pathway dysregulation which could be one of the contributors to subsequent vascular dysfunction. Consequently, reduction of oxidative stress and regulation of the COX pathway could represent new potential therapeutic strategies to limit vascular dysfunction and subsequent cardiovascular complications associated with insulin resistance.

• MeSH
• cévní endotel fyziologie   MeSH
• cyklooxygenasy metabolismus   MeSH
• inzulin metabolismus   MeSH
• inzulinová rezistence fyziologie   MeSH
• krysa rodu rattus MeSH
• noradrenalin farmakologie   MeSH
• oxidační stres fyziologie   MeSH
• potkani Wistar MeSH
• signální transdukce MeSH
• vazokonstriktory farmakologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH

Effects of ETB receptor stimulation and its subcellular pathways were evaluated in carbachol pre-contracted rabbit iris sphincter muscles (n=51). ETB stimulation with sarafotoxin (SRTX-c; 10-10-10-6 M) was tested in the absence (n=7) or presence of 10-5 M of: BQ-788 (ETB2 receptor antagonist; n=6), L-NA (NOS inhibitor; n=7) or indomethacin (cyclooxygenase inhibitor; n=10). Effects of ETB stimulation by endothelin-1 (ET-1; 10-10– 10-7 M) in the presence of an ETA receptor antagonist (BQ-123; 10-5 M; n=7) and of ETB1 stimulation by IRL-1620 (10-10–10-7 M; n=7) were also tested. Finally, the effects of SRTX-c (10-9–10-7 M) in electric field stimulation (EFS) contraction were evaluated (n=7). ETB receptor stimulation by SRTX-c or ET-1 in presence of BQ-123 promoted a concentration-dependent relaxation of the rabbit iris sphincter muscle by 10.8±2.0 % and 9.4±1.8 %, respectively. This effect was blocked by BQ-788 (-2.3±2.0 %), L-NA (4.5±2.3 %) or indomethacin (2.3±2.9 %). Selective ETB1 stimulation by IRL-1620 did not relax the iris sphincter muscle (0.9±5.4 %). EFS elicited contraction was not altered by SRTX-c. In conclusion, ETB receptor stimulation relaxes the carbachol precontracted iris sphincter muscle, an effect that is mediated by the ETB2 receptor subtype, through NO and the release of prostaglandins.

• MeSH
• cyklooxygenasy metabolismus   MeSH
• elektrická stimulace MeSH
• endotelin-1 metabolismus   MeSH
• endoteliny farmakologie   MeSH
• financování organizované MeSH
• hladké svalstvo metabolismus   účinky léků   MeSH
• indomethacin farmakologie   MeSH
• inhibitory enzymů MeSH
• iris metabolismus   účinky léků   MeSH
• karbachol farmakologie   MeSH
• králíci MeSH
• nitroarginin farmakologie   MeSH
• oligopeptidy farmakologie   MeSH
• oxid dusnatý metabolismus   MeSH
• peptidové fragmenty farmakologie   MeSH
• peptidy farmakologie   MeSH
• piperidiny farmakologie   MeSH
• prostaglandiny metabolismus   MeSH
• receptor endotelinu A metabolismus   MeSH
• receptor endotelinu B agonisté   metabolismus   MeSH
• relaxace svalu účinky léků   MeSH
• synthasa oxidu dusnatého antagonisté a inhibitory   metabolismus   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• zvířata MeSH
• Check Tag
• králíci MeSH
• mužské pohlaví MeSH
• zvířata MeSH

• MeSH
• chinony aplikace a dávkování   farmakologie   terapeutické užití   MeSH
• cyklooxygenasy metabolismus   MeSH
• dinoproston biosyntéza   MeSH
• finanční podpora výzkumu jako téma MeSH
• fytoterapie MeSH
• inhibiční koncentrace 50 MeSH
• inhibitory cyklooxygenasy aplikace a dávkování   farmakologie   terapeutické užití   MeSH
• lidé MeSH
• membránové proteiny MeSH
• Nigella sativa MeSH
• rostlinné extrakty aplikace a dávkování   farmakologie   terapeutické užití   MeSH
• thymol aplikace a dávkování   farmakologie   terapeutické užití   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• Check Tag
• lidé MeSH

• MeSH
• cyklooxygenasy genetika   metabolismus   MeSH
• dermatomyozitida enzymologie   etiologie   patologie   MeSH
• dospělí MeSH
• finanční podpora výzkumu jako téma MeSH
• izoenzymy genetika   metabolismus   MeSH
• kosterní svaly enzymologie   patologie   MeSH
• lidé MeSH
• messenger RNA metabolismus   MeSH
• regulace genové exprese enzymů MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH

• MeSH
• bolest metabolismus   MeSH
• centrální nervový systém metabolismus   MeSH
• cyklooxygenasy fyziologie   metabolismus   MeSH
• finanční podpora výzkumu jako téma MeSH
• fosfolipasy metabolismus   MeSH
• inhibitory cyklooxygenasy farmakologie   terapeutické užití   MeSH
• lidé MeSH
• mícha metabolismus   MeSH
• prostaglandiny metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• přehledy MeSH