Increased cell volume, accumulation of lipid droplets in the cytoplasm, and nuclear degeneration are phenomena indicating terminal differentiation of human sebocytes followed by holocrine secretion and cell death. The molecular pathways of natural and induced sebocyte elimination are still unknown, however. In this study, SZ95 sebocytes were found to exhibit DNA fragmentation after a 6 h culture followed by increased lactate dehydrogenase release after 24 h, indicating cell damage. With the help of morphologic studies and using Oil Red detection of cellular lipids, cell enlargement, accumulation of lipid droplets in the cytoplasm, and nuclear fragmentation could be observed under treatment with arachidonic acid. Staurosporine, a potent inhibitor of phospholipid Ca2+-dependent protein kinase, increased externalized phosphatidylserine levels on SZ95 sebocytes, detected by annexin V/propidium iodide flow cytometry, as early as after 1 h, whereas dose-dependent reduction of bcl-2 mRNA and protein expression, enhanced DNA fragmentation, and increased caspase 3 levels, detected by caspase 3 inhibitor/propidium iodide flow cytometry, were found after 6 h of treatment. SZ95 sebocyte death was detected as early as after 6 h of SZ95 sebocyte treatment with high staurosporine concentrations (10(-6)-10(-5) M). 5Alpha-dihydrotestosterone (10(-8)-10(-5) M) did not affect externalized phosphatidylserine levels and DNA fragmentation in SZ95 sebocytes but slightly decreased lactate dehydrogenase cell release. Neither acitretin nor 13-cis retinoic acid (10(-8)-10(-5) M) affected externalized phosphatidylserine levels, DNA fragmentation, and lactate dehydrogenase cell release, despite the increased caspase 3 levels under treatment with 13-cis retinoic acid. The combined staurosporine and 13-cis retinoic acid treatment enhanced DNA fragmentation in SZ95 sebocytes to the same magnitude as in cells only treated with staurosporine. In conclusion, SZ95 sebocytes in vitro undergo apoptosis, which can be enhanced by the terminal differentiation inductor arachidonic acid or by staurosporine and leads to cell death. 5Alpha-dihydrotestosterone inhibits SZ95 sebocyte death without involving apoptotic pathways, and retinoids did not affect the programmed death of human sebocytes. The latter result fits well with the currently reported inability of normal skin cells to undergo apoptosis after treatment with retinoids, in contrast to their malignant counterparts.

Inhibition of oncogenic transcriptional programs is a promising therapeutic strategy. A substituted tricyclic benzimidazole, SEL120-34A, is a novel inhibitor of Cyclin-dependent kinase 8 (CDK8), which regulates transcription by associating with the Mediator complex. X-ray crystallography has shown SEL120-34A to be a type I inhibitor forming halogen bonds with the protein's hinge region and hydrophobic complementarities within its front pocket. SEL120-34A inhibits phosphorylation of STAT1 S727 and STAT5 S726 in cancer cells in vitro. Consistently, regulation of STATs- and NUP98-HOXA9- dependent transcription has been observed as a dominant mechanism of action in vivo. Treatment with the compound resulted in a differential efficacy on AML cells with elevated STAT5 S726 levels and stem cell characteristics. In contrast, resistant cells were negative for activated STAT5 and revealed lineage commitment. In vivo efficacy in xenotransplanted AML models correlated with significant repression of STAT5 S726. Favorable pharmacokinetics, confirmed safety and in vivo efficacy provide a rationale for the further clinical development of SEL120-34A as a personalized therapeutic approach in AML.

No abstract

Central Pamir-Alai, which is located almost entirely within the area of Tajikistan, is one of the world hotspots of biodiversity, harbouring ca. 4,300 species and 1,400 endemic plants. The first application of the IUCN Red List criteria reveals that among all native species occurring in Tajikistan 1,627 taxa (38.11%) are threatened, including 23 extinct (0.54%), 271 (6.34%) critically endangered (CR), 717 (16.79%) endangered (EN) and 639 (14.96%) vulnerable (VU). Globally, 20 taxa are extinct, 711 (16.65%) threatened, including 144 (3.37%) critically endangered, 322 (7.54%) endangered and 245 (5.73%) vulnerable. As we found positive correlation between human density and the number of threatened species, we suspect this indirect factor responsible for the species diversity decline. Extinct or threatened taxa have short blooming periods in spring or early summer, have limited geographical range and inhabit mainly valley bottoms at lower altitudes. Threatened taxa occupy extremely dry or wet habitats, such as deserts, semi-deserts, water reservoirs and fens. The group of threatened plants consists mostly of Central Asian, Indo-Indochinese and Arctic species. Ornamental plants have a higher extinction risk than other plants, but species collected for medicinal reasons and used for forage or food reveal lower retreatment rate. Our assessment fills a gap for important plant area and provides the data for raising the effectiveness of plant diversity conservation. Species diversity loss still remains one of the main imperatives of our time and therefore one of the main topics of scientific studies. Currently, hundreds of plant species and many habitat types are globally threatened 1,2. A range of factors are responsible for these declines, with human population growth, habitat fragmentation and climate change regarded as the most crucial 3. The continuing decline of plant diversity demands continuous research on evaluation of the conservation status of flora with the use of comprehensive International Union for Conservation of Nature (IUCN) criteria (www.iucnredlist.org). These criteria are widely recognised as the most comprehensive tool for assessing the global conservation status of species and categorising plants according to their estimated risk of extinction (e.g. Orsenigo et al. 4 , Maes et al. 5). As the most effective conservation actions, policies and law implementation take place at the national scale, numerous countries have established national lists of threatened species with the use of IUCN criteria and guidelines at regional levels (Rossi et al. 6). Despite some biases and shortcomings of scientific foundations 7 , red lists are widely accepted as an appropriate measure for setting conservation priorities. In some countries, including Tajikistan, they also have a legal status and directly influence the state governance of the plant diversity 8. However, based on the information available in the National Red List Database 9 , almost 20% of Eurasian countries still have no available red lists for vascular p...

In summary, present study indicates a different mechanism of proliferative action of parabens in investigated cell lines. In MCF-7 breast cancer cell line it is probably due to stimulatory action on estradiol secretion and aromatase activity. In MCF-10A by an unknown mechanism, independent on stimulatory action on estradiol section, which requires further investigation.

No abstract

Aims Understanding fine‐grain diversity patterns across large spatial extents is fundamental for macroecological research and biodiversity conservation. Using the GrassPlot database, we provide benchmarks of fine‐grain richness values of Palaearctic open habitats for vascular plants, bryophytes, lichens and complete vegetation (i.e., the sum of the former three groups). Location Palaearctic biogeographic realm. Methods We used 126,524 plots of eight standard grain sizes from the GrassPlot database: 0.0001, 0.001, 0.01, 0.1, 1, 10, 100 and 1,000 m2 and calculated the mean richness and standard deviations, as well as maximum, minimum, median, and first and third quartiles for each combination of grain size, taxonomic group, biome, region, vegetation type and phytosociological class. Results Patterns of plant diversity in vegetation types and biomes differ across grain sizes and taxonomic groups. Overall, secondary (mostly semi‐natural) grasslands and natural grasslands are the richest vegetation type. The open‐access file ”GrassPlot Diversity Benchmarks” and the web tool “GrassPlot Diversity Explorer” are now available online (https://edgg.org/databases/GrasslandDiversityExplorer) and provide more insights into species richness patterns in the Palaearctic open habitats. Conclusions The GrassPlot Diversity Benchmarks provide high‐quality data on species richness in open habitat types across the Palaearctic. These benchmark data can be used in vegetation ecology, macroecology, biodiversity conservation and data quality checking. While the amount of data in the underlying GrassPlot database and their spatial coverage are smaller than in other extensive vegetation‐plot databases, species recordings in GrassPlot are on average more complete, making it a valuable complementary data source in macroecology.

The potency of flavonoids (isoflavones, flavones, and flavanones) to inhibit efflux of 2',7'-bis-(carboxypropyl)-5(6)-carboxyfluorescein (BCPCF) from human erythrocytes was investigated. Structure-activity relationship analysis showed that the strongest inhibitors were found among flavanones bearing a hydrophobic prenyl, geranyl, or lavandulyl group at position 8 (and hydroxyl groups at 5 and 7) in ring A. A prenyl group at position 5' or stilbene at positions 4'-5' in ring B further seemed to increase inhibitor potency. The most efficient flavanones, euchrestaflavanone A and sophoraflavanone H, were approximately 20 times more efficient than genistein, and induced 50% inhibition of BCPCF efflux (IC50) at 3 microM (60 min, 37 degrees C). This is comparable to IC50 of benzbromarone (4 microM) and lower than IC50 of indomethacin (10 microM), both known MRP1 (ABCC1) inhibitors. It is suggested that BCPCF efflux is mainly due to MRP1 activity. Our results indicate that flavonoid molecular structure provides a promising base for development of potent MRP1 inhibitors.