Anti-inflammatory and antioxidant activity of 8-methoxy-1,3-dimethyl-2,6-dioxo-purin-7-yl derivatives with terminal carboxylic, ester or amide moieties in animal models

The previous studies in a series of 8-methoxy-1,3-dimethyl-2,6-dioxo-purin-7-yl derivatives revealed their analgesic properties. We extended the study with these compounds in aim to assess their impact on inflammatory process. For this purpose we used: the zymosan-induced peritonitis and the carrageenan induced edema model. Furthermore, the antioxidant activity of the investigated compounds by the FRAP assay was determined. For the most active derivatives from evaluated series their influence on plasma TNF-α level was also tested in vivo. All investigated purine-2,6-dione derivatives 1-11 decreased neutrophils count and inhibited intensity of early vascular permeability. Furthermore, all evaluated compounds reduced the volume of edema caused by subcutaneous injection of carrageenan. Derivatives 1 (with ester moiety), 3 and 4 (with carboxylic group) showed the highest activity in the zymosan-induced peritonitis. In addition, a significant inhibition of plasma TNF-α level in rats with endotoxemia was observed following intraperitoneal administration of these compounds. In turn, compounds 6 and 8-11 containing amide moiety showed the greatest anti-inflammatory (antiedematous) effect in the carrageenan-induced paw edema model. All compounds did not show significant antioxidant properties. The present studies revealed that the presented purine-2,6-dione derivatives exhibit a significant anti-inflammatory activity and this effect may result from their ability to lower TNF-α level

Differences in the prognosis of HPV16-positive patients with squamous cell carcinoma of head and neck according to viral load and expression of P16

Purpose To evaluate the impact of HPV16 load (VL-the number of virus genome copies per cell) and P16 expression on prognosis of patients with squamous cell carcinomas (SCCs) of head and neck (HN). Materials and methods HPV16 presence was assessed in the group of 109 patients with HNSCCs by quantitative polymerase chain reaction (qPCR). VL (assessed by qPCR) and P16 expression (evaluated by immunohistochemistry) were analysed only in the subgroup of HPV16-positive tumours. These features were correlated with 5-year overall survival (OS) and disease-free survival (DFS). Results HPV16 infection was found in 36 tumours (33.0%). Virus-positive patients had better OS and DFS than those without infection (P = 0.041 and 0.005). Among HPV16-positive HNSCCs, 18 (50.0%) had higher VL (median value > 6764.3 copies/cell) and 25 (73.5%) P16 over expression. The significant differences in OS and DFS (P = 0.008 and 0.004) were noticed according to VL, wherein 100% DFS was found for patients with higher VL. According to P16 expression, significant difference was found only for OS (P = 0.020). In multivariate analysis, VL (P = 0.045; HR = 2.795; CI 0.121-1.060) and the level of smoking (P = 0.023, HR = 2.253; CI 1.124-4.514) were independent factors affecting DFS of HPV16-positive patients. Conclusion On the basis of viral load, it is possible to differentiate prognosis of patients with HPV16-positive HNSCCs. In this subgroup, viral load has stronger prognostic potential than P16 expression

Pan-Phosphodiesterase Inhibitors Attenuate TGF-β-Induced Pro-Fibrotic Phenotype in Alveolar Epithelial Type II Cells by Downregulating Smad-2 Phosphorylation

Airway remodeling is a pathological process that accompanies many chronic lung diseases. One of the important players in this process are epithelial cells, which under the influence of pro-inflammatory and pro-fibrotic factors present in the airway niche, actively participate in the remodeling process by increasing extracellular matrix secretion, acquiring migration properties, and overproducing pro-fibrotic transducers. Here, we investigated the effect of three new 8-arylalkylamino- and 8-alkoxy-1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-yl-N-(5-(tert-butyl)-2-hydroxyphenyl)butanamides (1, 2, and 3), representing prominent pan-phosphodiesterase (pan-PDE) inhibitors on transforming growth factor type β (TGF-β)-induced alveolar epithelial type II cells (A549 cell line) of a pro-fibrotic phenotype. Our results demonstrate for the first time the strong activity of pan-PDE inhibitors in the prevention of TGF-β-induced mesenchymal markers’ expression and A549 cells’ migration. We also showed an increased p-CREB and decreased p-Smad-2 phosphorylation in TGF-β-induced A549 cells treated with 1, 2, and 3 derivatives, thereby confirming a pan-PDE inhibitor mesenchymal phenotype reducing effect in alveolar epithelial type II cells via suppression of the canonical Smad signaling pathway. Our observations confirmed that PDE inhibitors, and especially those active against various isoforms involved in the airway remodeling, constitute an interesting group of compounds modulating the pro-fibrotic response of epithelial cells

Epigenetic silicification of the Upper Oxfordian limestones in the Sokole Hills (Kraków-Częstochowa Upland) : relationship to facies development and tectonics

A spectacular epigenetic silicification was encountered in the Oxfordian bedded limestones exposed in the Sokole Hills situated in the Kraków-Częstochowa Upland. The main epigenetic mineral is microcrystalline quartz ac- companied by minor goethite, hematite, barite, galena and sphalerite. Locally, the mineralized limestones reveal Pb and Cu contents exceeding over 150 times the background values of these metals in unmineralized limestones. The epigenetic mineralization of the bedded limestones was probably a two-stage process. During the first, Early Cretaceous stage, silicified limestones formed at the erosional surface of a denuded carbonate complex. Such sili- cification greatly limited the progress of the first karstification phase of the Upper Jurassic carbonates initiated in the Hauterivian. The sources of silica accumulated in the limestones were descending solutions enriched in silica derived from the weathering zone. This silicification affected the topmost part of the Upper Jurassic massive lime- stones and the deeper portions of the bedded limestones along the fracture systems and stylolites. Early Cretaceous tectonic activity generated new dislocations and re-opened the existing faults, which were sub- sequently filled with permeable Albian quartz sands. These openings became the migration pathways for ascend- ing, warm, relict, sulphide-carrying hydrothermal solutions at the second formation stage of the epigenetic miner- alization. The newly supplied silica from the Albian sands precipitated on the silicified limestones and, as concentric rims, on brecciated, early diagenetic cherts. The second-stage mineralization proceeded under phreatic conditions, presumably close to a fluctuating mixing zone of ascending, warm hydrothermal solutions and descending cold groundwaters. The brecciated cherts acting as silica crystallization nuclei indicate that the last mineralization stage probably followed the final phase of Cenozoic faulting

A novel, pan-PDE inhibitor exerts anti-fibrotic effects in human lung fibroblasts via inhibition of TGF-β\beta signaling and activation of cAMP/PKA signaling

Phosphodiesterase (PDE) inhibitors are currently a widespread and extensively studied group of anti-inflammatory and anti-fibrotic compounds which may find use in the treatment of numerous lung diseases, including asthma and chronic obstructive pulmonary disease. Several PDE inhibitors are currently in clinical development, and some of them, e.g., roflumilast, are already recommended for clinical use. Due to numerous reports indicating that elevated intracellular cAMP levels may contribute to the alleviation of inflammation and airway fibrosis, new and effective PDE inhibitors are constantly being sought. Recently, a group of 7,8-disubstituted purine-2,6-dione derivatives, representing a novel and prominent pan-PDE inhibitors has been synthesized. Some of them were reported to modulate transient receptor potential ankyrin 1 (TRPA1) ion channels as well. In this study, we investigated the effect of selected derivatives (832-a pan-PDE inhibitor, 869-a TRPA1 modulator, and 145-a pan-PDE inhibitor and a weak TRPA1 modulator) on cellular responses related to airway remodeling using MRC-5 human lung fibroblasts. Compound 145 exerted the most considerable effect in limiting fibroblast to myofibroblasts transition (FMT) as well as proliferation, migration, and contraction. The effect of this compound appeared to depend mainly on its strong PDE inhibitory properties, and not on its effects on TRPA1 modulation. The strong anti-remodeling effects of 145 required activation of the cAMP/protein kinase A (PKA)/cAMP response element-binding protein (CREB) pathway leading to inhibition of transforming growth factor type β1 (TGF-β1) and Smad-dependent signaling in MRC-5 cells. These data suggest that the TGF-β pathway is a major target for PDE inhibitors leading to inhibitory effects on cell responses involved in airway remodeling. These potent, pan-PDE inhibitors from the group of 7,8-disubstituted purine-2,6-dione derivatives, thus represent promising anti-remodeling drug candidates for further research

Synthesis and in vitro evaluation of anti-inflammatory, antioxidant, and anti-fibrotic effects of new 8-aminopurine-2,6-dione-based phosphodiesterase inhibitors as promising anti-asthmatic agents

Phosphodiesterase (PDE) inhibitors are currently an extensively studied group of compounds that can bring many benefits in the treatment of various inflammatory and fibrotic diseases, including asthma. Herein, we describe a series of novel N’-phenyl- or N’-benzylbutanamide and N’-arylidenebutanehydrazide derivatives of 8-aminopurine-2,6-dione (27–43) and characterized them as prominent pan-PDE inhibitors. Most of the compounds exhibited antioxidant and anti-inflammatory activity in lipopolysaccharide (LPS)-induced murine macrophages RAW264.7. The most active compounds (32–35 and 38) were evaluated in human bronchial epithelial cells (HBECs) derived from asthmatics. To better map the bronchial microenvironment in asthma, HBECs after exposure to selected 8-aminopurine-2,6-dione derivatives were incubated in the presence of two proinflammatory and/or profibrotic factors: transforming growth factor type β (TGF-β) and interleukin 13 (IL-13). Compounds 32–35 and 38 significantly reduced both IL-13- and TGF-β-induced expression of proinflammatory and profibrotic mediators, respectively. Detailed analysis of their inhibition preferences for selected PDEs showed high affinity for isoenzymes important in the pathogenesis of asthma, including PDE1, PDE3, PDE4, PDE7, and PDE8. The presented data confirm that structural modifications within the 7 and 8 positions of the purine-2,6-dione core result in obtaining preferable pan-PDE inhibitors which in turn exert an excellent anti-inflammatory and anti-fibrotic effect in the bronchial epithelial cells derived from asthmatic patients. This dual-acting pan-PDE inhibitors constitute interesting and promising lead structures for further anti-asthmatic agent discovery

Les Lituaniens de Prusse dans la Grande Guerre

Presque Lituaniens, presque Allemands Parmi les nombreuses minorités nationales de la Prusse, les Lituaniens formaient l’un des groupes les moins importants. Ils compensaient leur faiblesse numérique par la densité de leur peuplement, concentré dans quelques districts ruraux (Landkreise) de Prusse-Orientale, notamment celui de Heydekrug (Szyłokarczma en polonais, Šilutė en lituanien) où ils formaient 57,8 % de la population, et celui de Memel (Klaipeda) dont ils représentaient 50,5 % des habi..

Dendrogeomorfological verification of landslide activity recognized in the project „System Osłony Przeciwosuwiskowej” – example from Sułków (Wielickie Foothils)

Osuwiska są jednym z głównych form występujących w Karpatach fliszowych. Aż 95% osuwisk w Polsce zlokalizowanych jest w Karpatach. Wykształcanie przez drzewa dekoncentrycznych przyrostów rocznych w wyniku naprężeń działających na drzewo umożliwia wykonanie badań aktywności osuwiska metodą dendrogeomorfologiczną. Celem pracy było określenie stopnia aktywności osuwiska oraz porównanie wyników z klasyfikacją projektu „System Osłony Przeciwosuwiskowej” (SOPO). Okazało się, że wyniki badań dendrogeomorfologicznych odbiegają od klasyfikacji SOPO. Aktywna część osuwiska jest wewnętrznie zróżnicowana. Obszar, który w wyniku badań dendrogeomorfologicznych został uznany jako bardzo aktywny, według SOPO jest nieaktywny albo nie został uznany jako część osuwiska.Landslides are one of main forms which appear in Flysh Carpathians. Even 95% landslides in Poland are localized in Carpathians. Trees creates eccentric tree-rings as a result of mechanical stress caused by the landslide activity. Therefore, landslide activity could be measured using dendrogeomorphological methods. The purpose of the work was to determine the degree of activity of the landslide and to compare results with classification of the project „System Osłony Przeciwosuwiskowej” (SOPO). It was concluded that the results of dendrogeomorphological analysis deviate from SOPO classification. Active part of landslide is internally more differentiated than it was assumed in SOPO project. The area, which as a result of dendrogeomorphological research was admitted as very active, according to SOPO is inactive or isn’t recognized as a part of landslide

Morphological features and the strength-speed fitness of female volleyballers at a high sports level

Introduction: Modern volleyball requires players to present a high level of strength and speed fitness. Efficiency in this discipline is also significantly determined by the level of development of the somatic features, including especially body height and shoulder range. The main aim of the study was to assess the level of development of the most important morpho-functional features characterizing female volleyball players at high sports level against the background of non-training women. Material and methods: 13 female players representing the 1st league volleyball club took part in the research. The control group consisted of 11 women not exercising any form of competitive sport. Measurements of basic somatic features were carried out: body height, body weight and its tissue components. In addition, explosive strength of the lower limbs tests (CMJ) and the Wingate test was performed. On the basis of statistical analysis, the most important somatic features and motor fitness indicators characterizing I-league volleyballers were selected. Results: The greatest differences between volleyball players and non-training women in terms of morphological features was recorded for lean body mass (LBM [kg], Z = 6.63, p <0.01). However, in terms of motor fitness indicators, the largest differences were found in terms of peak power, average power and CMJ [cm] and CMJ power [W/kg]. Calculated, respectively: Z = 2.59, p <0.001; Z = 3.22, p <0.001; Z = 2.75, p <0.001, Z = 2.54, p <0.001). Conclusions: Our research confirmed importance of selected morpho-functional features conducive to high efficiency of Female’s volleyball. Jumping tests (e.g. CMJ) assessing the motor potential of lower limbs of volleyball players have practical value in the context of recruitment, selection and control of female's volleyball training. The Wingate test, as a diagnostic tool, can be used as an adjunct to retinal specific tests.Wstęp: Współczesna siatkówka wymaga od zawodników prezentowania wysokiego poziomu rozwoju możliwości siłowo-szybkościowych. Efektywność w tej dyscyplinie jest także istotnie determinowana poziomem rozwoju podstawowych cechy budowy somatycznej, w tym przede wszystkim wysokością ciała oraz zasięgiem ramion. Głównym celem badań była ocena poziomu rozwoju najistotniejszych cech morfo-funkcjonalnych charakteryzujących siatkarki występujące na drugim poziomie krajowych rozgrywek ligowych na tle kobiet nietrenujących. Materiał i metody: W badaniach wzięło udział 13 zawodniczek reprezentujących I-ligowy klub siatkarski. Grupę kontrolną stanowiło 11 kobiet nietrenujących żadnej formy sportu. Przeprowadzono pomiary podstawowych cech budowy somatycznej: wysokość ciała, masę ciała i jej komponenty tkankowe. Ponadto zmierzono siłę eksplozywną kończyn dolnych (CMJ) oraz przeprowadzono test Wingate. Na podstawie analizy statystycznej wyselekcjonowano najistotniejsze cechy budowy somatycznej i wskaźniki sprawności motorycznej charakteryzujące I-ligowe siatkarki. Wyniki: Największe zróżnicowanie pomiędzy siatkarkami a nietrenującymi w zakresie cech morfologicznych odnotowano dla masy ciała szczupłego (LBM [kg], Z=6,63, p<0,01). Natomiast w zakresie wskaźników wysiłkowych największe różnice stwierdzono w zakresie piku mocy, mocy średniej oraz wyskoku CMJ i mocy względnej wyskoku CMJ. Obliczono odpowiednio: Z=2,59, p<0,001; Z=3,22, p<0,001; Z=2,75, p<0,001, Z=2,54, p<0,001). Wnioski: Badania własne wykazały i potwierdziły wysokie znaczenie wybranych cech morfo-funkcjonalnych sprzyjających wysokiej efektywności gry w siatkówce kobiet. Testy bazujące na skokach (np. CMJ) oceniające potencjał motoryczny kończyn dolnych siatkarek, mają wartość praktyczną w kontekście naboru, selekcji oraz kontroli treningu w siatkówce kobiet. Test Wingate, jako narzędzie diagnostyczne, może być stosowany jako uzupełnienie do prób o charakterze specyficznym w siatkówce