Archangelolide: A sesquiterpene lactone with immunobiological potential from Laserpitium archangelica.

Sesquiterpene lactones are secondary plant metabolites with sundry biological effects. In plants, they are synthesized, among others, for pesticidal and antimicrobial effects. Two such compounds, archangelolide and trilobolide of the guaianolide type, are structurally similar to the well-known and clinically tested lactone thapsigargin. While trilobolide has already been studied by us and others, there are only scarce reports on the biological activity of archangelolide. Here we present the preparation of its fluorescent derivative based on a dansyl moiety using azide-alkyne Huisgen cycloaddition having obtained the two sesquiterpene lactones from the seeds of Laserpitium archangelica Wulfen using supercritical CO2 extraction. We show that dansyl-archangelolide localizes in the endoplasmic reticulum of living cells similarly to trilobolide; localization in mitochondria was also detected. This led us to a more detailed study of the anticancer potential of archangelolide. Interestingly, we found that neither archangelolide nor its dansyl conjugate did exhibit cytotoxic effects in contrast to the structurally closely related counterparts trilobolide and thapsigargin. We explain this observation by a molecular dynamics simulation, in which, in contrast to trilobolide, archangelolide did not bind into the sarco/endoplasmic reticular calcium ATPase cavity utilized by thapsigargin. Last, but not least, archangelolide exhibited anti-inflammatory activity, which makes it promising compound for medicinal purposes.

Constitutively active Lyn kinase causes a cutaneous small vessel vasculitis and liver fibrosis syndrome.

Neutrophilic inflammation is a hallmark of many monogenic autoinflammatory diseases; pathomechanisms that regulate extravasation of damaging immune cells into surrounding tissues are poorly understood. Here we identified three unrelated boys with perinatal-onset of neutrophilic cutaneous small vessel vasculitis and systemic inflammation. Two patients developed liver fibrosis in their first year of life. Next-generation sequencing identified two de novo truncating variants in the Src-family tyrosine kinase, LYN, p.Y508*, p.Q507* and a de novo missense variant, p.Y508F, that result in constitutive activation of Lyn kinase. Functional studies revealed increased expression of ICAM-1 on induced patient-derived endothelial cells (iECs) and of ß2-integrins on patient neutrophils that increase neutrophil adhesion and vascular transendothelial migration (TEM). Treatment with TNF inhibition improved systemic inflammation; and liver fibrosis resolved on treatment with the Src kinase inhibitor dasatinib. Our findings reveal a critical role for Lyn kinase in modulating inflammatory signals, regulating microvascular permeability and neutrophil recruitment, and in promoting hepatic fibrosis.

A critical review of field techniques employed in the survey of large woody debris in river corridors: a central European perspective.

In forested watersheds, large woody debris (LWD) is an integral component of river channels and floodplains. Fallen trees have a significant impact on physical and ecological processes in fluvial ecosystems. An enormous body of literature concerning LWD in river corridors is currently available. However, synthesis and statistical treatment of the published data are hampered by the heterogeneity of methodological approaches. Likewise, the precision and accuracy of data arising out of published surveys have yet to be assessed. For this review, a literature scrutiny of 100 randomly selected research papers was made to examine the most frequently surveyed LWD variables and field procedures. Some 29 variables arose for individual LWD pieces, and 15 variables for wood accumulations. The literature survey revealed a large variability in field procedures for LWD surveys. In many studies (32), description of field procedure proved less than adequate, rendering the results impossible to reproduce in comparable fashion by other researchers. This contribution identifies the main methodological problems and sources of error associated with the mapping and measurement of the most frequently surveyed variables of LWD, both as individual pieces and in accumulations. The discussion stems from our own field experience with LWD survey in river systems of various geomorphic styles and types of riparian vegetation in the Czech Republic in the 2004-10 period. We modelled variability in terms of LWD number, volume, and biomass for three geomorphologically contrasting river systems. The results appeared to be sensitive, in the main, to sampling strategy and prevailing field conditions; less variability was produced by errors of measurement. Finally, we propose a comprehensive standard field procedure for LWD surveyors, including a total of 20 variables describing spatial position, structural characteristics and the functions and dynamics of LWD. However, resources are only rarely available for highly time-demanding surveys. We therefore include a set of core LWD metrics for routine baseline surveys of individual LWD pieces (diameter, length, rootwad size, preservation of branches and rootwad, geomorphological/ecological function, stability/mobility) and wood accumulations (number of LWD pieces, geometrical dimensions, channel blockage, wood/air ratio), which may provide useful background information for river management, hydromorphological assessment, habitat evaluation, and inter-regional comparisons.

Sarco/Endoplasmic Reticulum Calcium ATPase Inhibitors: Beyond Anticancer Perspective.

The sarco/endoplasmic reticulum calcium ATPase (SERCA), which plays a key role in the maintenance of Ca2+ ion homeostasis, is an extensively studied enzyme, the inhibition of which has a considerable impact on cell life and death decision. To date, several SERCA inhibitors have been thoroughly studied and the most notable one, a derivative of the sesquiterpene lactone thapsigargin, is gradually approaching a clinical application. Meanwhile, new compounds with SERCA-inhibiting properties of natural, synthetic, or semisynthetic origin are being discovered and/or developed; some of these might also be suitable for the development of new drugs with improved performance. This review brings an up-to-date comprehensive overview of recently discovered compounds with the potential of SERCA inhibition, discusses their mechanism of action, and highlights their potential clinical applications, such as cancer treatment.

Argon plasma-treated fluorinated ethylene propylene: Growth of primary dermal fibroblasts and mesenchymal stem cells.

Surface modification is an important step in making a synthetic polymer cytocompatible. We have previously reported improved cytocompatibility of immortalized human keratinocytes (HaCaT) with the otherwise bioinert fluorinated ethylene propylene (FEP) upon treatment with argon plasma discharge. In this article, we show that FEP modified with Ar plasma with the power of 3 and 8 W for 40 and 240 s served as a suitable material for cultivation of primary human dermal fibroblasts (HDF), which showed significantly improved proliferation and spreading comparable to standard tissue culture polystyrene. We also evaluated focal adhesions formed by HDF cells on modified FEP, which were far more numerous compared to pristine FEP. Moreover, we attempted spontaneous osteogenic differentiation of adipose-derived mesenchymal stem cells modified with human telomerase reverse transcriptase on Ar plasma-modified FEP. While the spontaneous osteogenic differentiation was unsuccessful, the cells were able to adhere and differentiated on tested matrices upon the administration of osteodifferentiation medium. These combined findings suggest that the treatment of FEP with Ar plasma comprises and efficient method to enable the adhesion and proliferation of various cell types on an otherwise largely bioinert material.