Helicobacter pylori colonizes the human gastric mucosa of more than half of the human population and has a unique lipopolysaccharide (LPS) structure. LPS is the most dominant and suitable pathogen-associated molecular pattern that is detected via pattern recognition receptors. Although the priming effect of H. pylori LPS on reactive oxygen species (ROS) production of PMNs is lower than that of Escherichia coli O111:B4 LPS, LPS released from H. pylori associated with antibiotics eradication therapy may activate PMNs and increase ROS production. In addition, we describe the effects of H. pylori and E. coli O111:B4 LPSs on gene expression and the anti-inflammatory effect of lansoprazole (LPZ) in human polymorphonuclear leukocytes. LPS isolated from H. pylori and E. coli O111:B4 alters toll-like receptor 2 (TLR) and TLR4 expressions similarly. However, LPS from E. coli O111:B4 and H. pylori caused a 1.8-fold and 1.5-fold increase, respectively, in CD14 expression. All LPS subtypes upregulated TNFα and IL6 expression in a concentration-dependent manner. Although E. coli O111:B4 LPS upregulated IL8R mRNA levels, H. pylori LPS did not (≦ 100 ng/mL). Gene expression levels of ITGAM demonstrated no significant change on using both LPSs. These different effects on the gene expression in PMNs may depend on variations in LPS structural modifications related to the acquired immunomodulatory properties of H. pylori LPS. Proton pump inhibitors, i.e., LPZ, are used in combination with antibiotics for the eradication therapy of H. pylori. LPZ and its acid-activated sulphenamide form AG-2000 suppress ROS production of PMNs in a dose-dependent manner. These results suggest that LPZ combination with antibiotics for H. pylori eradication reduces gastric inflammation by suppressing ROS release from PMNs.

• MeSH
• cytokiny metabolismus   genetika   MeSH
• Escherichia coli účinky léků   genetika   MeSH
• Helicobacter pylori * účinky léků   genetika   MeSH
• inhibitory protonové pumpy * farmakologie   chemie   MeSH
• lanzoprazol * farmakologie   chemie   MeSH
• lidé MeSH
• lipopolysacharidy * metabolismus   farmakologie   MeSH
• neutrofily * účinky léků   imunologie   MeSH
• reaktivní formy kyslíku metabolismus   MeSH
• toll-like receptor 4 metabolismus   genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

To improve the treatment of psoriasiform inflammation, we developed actively targeted nanocarriers loaded with the phosphodiesterase 4 inhibitor AN2728. Methods: Phospholipid-poly(lactic-co-glycolic acid) nanohybrids were prepared and conjugated with monovalent anti-desmoglein 3 antibody to bind keratinocytes. Results: The actively targeted nanohybrids were 229 nm in mean size with a nearly neutral surface charge. Flow cytometry and confocal microscopy showed a 9-fold increase in keratinocyte uptake of targeted nanohybrids relative to non-targeted nanoparticles. The nanoparticles localized mainly in lysosomes after internalization. AN2728-loaded antibody-conjugated nanocarriers inhibited cytokine/chemokine overexpression in activated keratinocytes without affecting cell viability. The targeted nanohybrids also suppressed neutrophil migration by reducing CXCL1 and CXCL2 release from keratinocytes. Following subcutaneous administration in mice, the nanohybrids distributed to the epidermis and hair follicles. In a psoriasis-like skin mouse model, the actively targeted nanoparticles were superior to free drug and non-targeted nanoparticles in mitigating skin inflammation. Intervention with the targeted nanosystem reduced the epidermal thickness of the psoriasiform lesion from 191 to 42 µm, decreased the Psoriasis Area Severity Index by 74%, restored barrier function, and returned chemokine levels to baseline. Conclusions: Our developed nanosystem was safe and demonstrated efficient targeting properties for the treatment of cutaneous inflammation.

• MeSH
• bicyklické sloučeniny heterocyklické aplikace a dávkování   farmakologie   MeSH
• buněčné linie keratinocytů HaCaT MeSH
• chemokin CXCL1 účinky léků   imunologie   MeSH
• chemokin CXCL2 účinky léků   imunologie   MeSH
• chemotaxe účinky léků   MeSH
• desmoglein 3 imunologie   MeSH
• epidermis MeSH
• fosfolipidy * MeSH
• imunokonjugáty farmakologie   MeSH
• inhibitory fosfodiesterasy 4 aplikace a dávkování   farmakologie   MeSH
• keratinocyty účinky léků   imunologie   MeSH
• kopolymer kyseliny glykolové a mléčné * MeSH
• lidé MeSH
• lyzozomy metabolismus   ultrastruktura   MeSH
• modely nemocí na zvířatech MeSH
• myši MeSH
• nanočástice * MeSH
• neutrofily účinky léků   MeSH
• nosiče léků MeSH
• protilátky imunologie   MeSH
• psoriáza imunologie   patologie   MeSH
• sloučeniny boru aplikace a dávkování   farmakologie   MeSH
• systémy cílené aplikace léků MeSH
• vlasový folikul MeSH
• zánět MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

• Klíčová slova
• pegfilgrastim,
• MeSH
• febrilní neutropenie vyvolaná chemoterapií * farmakoterapie   prevence a kontrola   MeSH
• filgrastim aplikace a dávkování   škodlivé účinky   MeSH
• lidé MeSH
• nádory komplikace   MeSH
• neutrofily účinky léků   MeSH
• nežádoucí účinky léčiv MeSH
• riziko MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• práce podpořená grantem MeSH

Natural compounds offer a wide spectrum of potential active substances, but often they have a poor bioavailability. To increase the bioavailability and bioactivity of the natural anti-inflammatory molecules curcumin and diplacone, we used glucan particles (GPs), hollow shells from Saccharomyces cerevisiae composed mainly of β-1,3-d-glucan. Their indigestibility and relative stability in the gut combined with their immunomodulatory effects makes them promising carriers for such compounds. This study aimed to determine how curcumin and diplacone, either alone or incorporated in GPs, affect the immunomodulatory activity of the latter by assessing the respiratory burst response and the secretion of pro-inflammatory cytokines by primary porcine innate immune cells. Incorporating curcumin and diplacone into GPs by controlled evaporation of the organic solvent substantially reduced the respiratory burst response mediated by GPs. Incorporated curcumin in GPs also reduced GPs mediated secretion of IL-1β and TNF-α by innate immune cells. The obtained results indicate a potentially beneficial effect of the incorporation of curcumin or diplacone into GPs against inflammation.

• MeSH
• antiflogistika chemie   farmakologie   MeSH
• beta-glukany chemie   izolace a purifikace   farmakologie   MeSH
• flavanony chemie   farmakologie   MeSH
• imunologické faktory chemie   izolace a purifikace   farmakologie   MeSH
• interleukin-1beta metabolismus   MeSH
• kultivované buňky MeSH
• kurkumin chemie   farmakologie   MeSH
• leukocyty mononukleární účinky léků   imunologie   metabolismus   MeSH
• neutrofily účinky léků   imunologie   metabolismus   MeSH
• nosiče léků * MeSH
• příprava léků MeSH
• respirační vzplanutí účinky léků   MeSH
• rozpouštědla chemie   MeSH
• Saccharomyces cerevisiae chemie   MeSH
• Sus scrofa MeSH
• TNF-alfa metabolismus   MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Aim: We aimed to develop nanoemulsions containing phosphodiesterase 4 inhibitor rolipram with different droplet sizes, to evaluate the anti-inflammatory effect against activated neutrophils and a related lung injury. Materials & methods: We prepared nanoemulsions of three different sizes, 68, 133 and 188 nm. Results: The nanoemulsion inhibited the superoxide anion but not elastase release in primary human neutrophils. The large-sized nanoemulsions were mostly internalized by neutrophils, resulting in the reduction of intracellular Ca2+ half-life. The peripheral organ distribution of near-infrared dye-tagged nanoemulsions increased, following the decrease in droplet diameter. Rolipram entrapment into intravenous nanoemulsions ameliorated pulmonary inflammation. The smallest droplet size showed improvement, compared with the largest size. Conclusion: We established a foundation for the development of nanoemulsions against inflamed lung disease.

• MeSH
• antiflogistika * farmakologie   MeSH
• emulze MeSH
• lidé MeSH
• nanomedicína MeSH
• neutrofily účinky léků   MeSH
• zánět * farmakoterapie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

OBJECTIVES: To obtain routine clinical practice data on cabazitaxel usage patterns for patients with metastatic castration-resistant prostate cancer (mCRPC) and to describe physician-assessed cabazitaxel effectiveness, health-related quality of life (HRQoL) and safety. PATIENTS AND METHODS: CAPRISTANA was an international, observational cohort study examining cabazitaxel use for the treatment of patients with mCRPC. Effectiveness was assessed by overall survival (OS), progression-free survival (PFS), time to treatment failure (TTF) and disease control rate. HRQoL was assessed using the Functional Assessment of Cancer Therapy-Prostate questionnaire (FACT-P) and the three-level European Quality of Life questionnaire (EQ-5D-3L). Safety was assessed by adverse event (AE) reporting. RESULTS: A total of 189 patients were treated across 54 centres between April 2012 and June 2016. At baseline, 58.7% had ≥1 comorbidity, 93.7% had an Eastern Cooperative Oncology Group performance status ≤1, and 60.1% had a Gleason score at diagnosis of ≥8. Patients received a median of 6 cabazitaxel cycles; 84.7% received cabazitaxel as second-line therapy. The median OS, PFS and TTF were 13.2, 5.6 and 4.4 months, respectively. Cabazitaxel led to disease control in 52.9% of patients. HRQoL was maintained (40.3%) or improved (32.2%) in 72.5% of patients based on total FACT-P scores. Interestingly, 53.6% of patients reported pain improvement and a further 21.2% maintained pain control based on FACT-P prostate cancer-specific pain scores. The most common treatment-related grade ≥3 AEs were neutropenia (7.9%) and anaemia (2.1%). CONCLUSION: Patients in CAPRISTANA treated with cabazitaxel had similar disease outcomes and safety profiles compared with large phase III clinical trials. Most patients had maintained or improved HRQoL scores; >70% of patients had maintained or improved pain control.

• MeSH
• doba přežití bez progrese choroby MeSH
• docetaxel škodlivé účinky   terapeutické užití   MeSH
• dospělí MeSH
• kvalita života MeSH
• lidé středního věku MeSH
• lidé MeSH
• míra přežití MeSH
• nádory prostaty rezistentní na kastraci farmakoterapie   mortalita   patologie   MeSH
• následné studie MeSH
• neutrofily účinky léků   MeSH
• protokoly antitumorózní kombinované chemoterapie * MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• taxoidy terapeutické užití   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• pozorovací studie MeSH
• práce podpořená grantem MeSH

Papillon-Lefèvre syndrome (PLS) is characterized by nonfunctional neutrophil serine proteases (NSPs) and fulminant periodontal inflammation of unknown cause. Here we investigated neutrophil extracellular trap (NET)-associated aggregation and cytokine/chemokine-release/degradation by normal and NSP-deficient human and mouse granulocytes. Stimulated with solid or soluble NET inducers, normal neutrophils formed aggregates and both released and degraded cytokines/chemokines. With increasing cell density, proteolytic degradation outweighed release. Maximum output of cytokines/chemokines occurred mostly at densities between 2 × 107 and 4 × 107 neutrophils/cm3. Assessment of neutrophil density in vivo showed that these concentrations are surpassed during inflammation. Association with aggregated NETs conferred protection of neutrophil elastase against α1-antitrypsin. In contrast, eosinophils did not influence cytokine/chemokine concentrations. The proteolytic degradation of inflammatory mediators seen in NETs was abrogated in Papillon-Lefèvre syndrome (PLS) neutrophils. In summary, neutrophil-driven proteolysis of inflammatory mediators works as a built-in safeguard for inflammation. The absence of this negative feedback mechanism might be responsible for the nonresolving periodontitis seen in PLS.-Hahn, J., Schauer, C., Czegley, C., Kling, L., Petru, L., Schmid, B., Weidner, D., Reinwald, C., Biermann, M. H. C., Blunder, S., Ernst, J., Lesner, A., Bäuerle, T., Palmisano, R., Christiansen, S., Herrmann, M., Bozec, A., Gruber, R., Schett, G., Hoffmann, M. H. Aggregated neutrophil extracellular traps resolve inflammation by proteolysis of cytokines and chemokines and protection from antiproteases.

• MeSH
• chemokiny metabolismus   MeSH
• cytokiny metabolismus   MeSH
• dospělí MeSH
• extracelulární pasti metabolismus   MeSH
• inhibitory proteas metabolismus   MeSH
• ionomycin farmakologie   MeSH
• kyselina močová farmakologie   MeSH
• lidé MeSH
• mediátory zánětu metabolismus   MeSH
• mladiství MeSH
• myši inbrední BALB C MeSH
• myši MeSH
• NADPH-oxidasy genetika   MeSH
• neutrofily účinky léků   metabolismus   MeSH
• parodontitida metabolismus   MeSH
• proteolýza MeSH
• tetradekanoylforbolacetát farmakologie   MeSH
• zánět prevence a kontrola   MeSH
• zvířata MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

The synthesis of inhibitors of SphK2 with novel structural scaffolds is reported. These compounds were designed from a molecular modeling study, in which the molecular interactions stabilizing the different complexes were taken into account. Particularly interesting is that 7-bromo-2-(2-phenylethyl)-2,3,4,5-tetrahydro-1,4-epoxynaphtho[1,2-b]azepine, which is a selective inhibitor of SphK2, does not exert any cytotoxic effects and has a potent anti-inflammatory effect. It was found to inhibit mononuclear cell adhesion to the dysfunctional endothelium with minimal impact on neutrophil-endothelial cell interactions. The information obtained from our theoretical and experimental study can be useful in the search for inhibitors of SphK2 that play a prominent role in different diseases, especially in inflammatory and cardiovascular disorders.

• MeSH
• antiflogistika chemická syntéza   chemie   farmakologie   toxicita   MeSH
• azepiny chemická syntéza   chemie   farmakologie   MeSH
• buněčná adheze účinky léků   MeSH
• cévní endotel účinky léků   imunologie   MeSH
• endoteliální buňky pupečníkové žíly (lidské) MeSH
• epoxidové sloučeniny chemická syntéza   chemie   farmakologie   MeSH
• fosfotransferasy s alkoholovou skupinou jako akceptorem antagonisté a inhibitory   MeSH
• inhibitory enzymů chemická syntéza   chemie   farmakologie   toxicita   MeSH
• lidé MeSH
• neutrofily účinky léků   imunologie   MeSH
• racionální návrh léčiv MeSH
• simulace molekulového dockingu MeSH
• vazba proteinů MeSH
• viabilita buněk účinky léků   MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

The fused quinazolinone derivative, RX-207, is chemically and functionally related to small molecule inhibitors of protein binding to glycosaminoglycans (SMIGs). Composed of a planar aromatic amine scaffold, it inhibits protein binding to glycosaminoglycans (GAGs). RX-207 reduced neutrophil migration in thioglycollate-induced peritonitis (37%), inhibited carrageenan-induced paw edema (32%) and cerulein-induced pancreatitis (28%), and increased animal survival in the mouse model of cecal ligation and puncture (CLP)-induced sepsis (60%). The mechanism of RX-207 action, analyzed by UV spectroscopy, confirmed that which was elucidated for chemically related anti-inflammatory SMIGs. RX-207 binding to cell surface GAGs can account for the inhibition of neutrophil recruitment via the micro-vasculature and as a consequence, the reduction of neutrophil mediated tissue damage in the animal models of inflammation and improved survival of mice in CLP-induced sepsis.

• MeSH
• antiflogistika farmakologie   MeSH
• buněčná adheze účinky léků   MeSH
• cékum mikrobiologie   chirurgie   MeSH
• chinazolinony farmakologie   MeSH
• edém chemicky indukované   metabolismus   patologie   prevence a kontrola   MeSH
• glykosaminoglykany metabolismus   MeSH
• infiltrace neutrofily účinky léků   MeSH
• ligace MeSH
• modely nemocí na zvířatech MeSH
• myši inbrední BALB C MeSH
• neutrofily účinky léků   metabolismus   mikrobiologie   MeSH
• pankreatitida chemicky indukované   metabolismus   patologie   prevence a kontrola   MeSH
• peritonitida chemicky indukované   metabolismus   patologie   prevence a kontrola   MeSH
• punkce MeSH
• sepse metabolismus   mikrobiologie   patologie   prevence a kontrola   MeSH
• vazba proteinů MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Objective- The leukocyte heme-enzyme MPO (myeloperoxidase) exerts proinflammatory effects on the vascular system primarily linked to its catalytic properties. Recent studies have shown that MPO, depending on its cationic charge, mediates neutrophil recruitment and activation. Here, we further investigated MPO's extracatalytic properties and its effect on endothelial glycocalyx (EG) integrity. Approach and Results- In vivo staining of murine cremaster muscle vessels with Alcian Blue 8GX provided evidence of an MPO-dependent decrease in anionic charge of the EG. MPO binding to the glycocalyx was further characterized using Chinese hamster ovary cells and its glycosaminoglycan mutants-pgsA-745 (mutant Chinese hamster ovary cells lacking heparan sulfate and chondroitin sulfate glycosaminoglycan) and pgsD-677 (mutant Chinese hamster ovary cells lacking heparan sulfate glycosaminoglycan), which revealed heparan sulfate as the main mediator of MPO binding. Further, EG integrity was assessed in terms of thickness using intravital microscopy of murine cremaster muscle. A significant reduction in EG thickness was observed on infusion of catalytically active MPO, as well as mutant inactive MPO and cationic polymer polylysine. Similar effects were also observed in wild-type mice after a local inflammatory stimulus but not in MPO-knockout mice. The reduction in EG thickness was reversed after removal of vessel-bound MPO, suggesting a possible physical collapse of the EG. Last, experiments with in vivo neutrophil depletion revealed that MPO also induced neutrophil-mediated shedding of the EG core protein, Sdc1 (syndecan-1). Conclusions- These findings provide evidence that MPO, via ionic interaction with heparan sulfate side chains, can cause neutrophil-dependent Sdc1 shedding and collapse of the EG structure.

• MeSH
• aktivace neutrofilů MeSH
• břišní svaly krevní zásobení   MeSH
• CHO buňky MeSH
• Cricetulus MeSH
• endoteliální buňky pupečníkové žíly (lidské) účinky léků   metabolismus   patologie   MeSH
• endoteliální buňky účinky léků   metabolismus   patologie   MeSH
• glykokalyx účinky léků   metabolismus   patologie   MeSH
• heparansulfát proteoglykany metabolismus   MeSH
• kationty MeSH
• lidé MeSH
• myši inbrední C57BL MeSH
• myši knockoutované MeSH
• neutrofily účinky léků   metabolismus   MeSH
• peroxidasa nedostatek   genetika   metabolismus   farmakologie   MeSH
• syndekan-1 metabolismus   MeSH
• vazba proteinů MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH