Diarylheptanoids from Green Alder Bark and Their Potential for DNA Protection

Nine diarylheptanoids, 1 – 9 , catechin ( 11 ), and a phenolic glucoside, 10 , were isolated from the bark of green alder (Alnus viridis). Four of the isolated compounds, i.e., 2, 5, 8, 10 , are new. The structures of 1 – 11 were determined on the basis of spectroscopic data. All isolated compounds were evaluated for their in vitro protective effects on chromosome aberrations in peripheral human lymphocytes using cytokinesis‐block micronucleus (CBMN) assay. Almost all of them exerted a pronounced effect of decreasing DNA damage of human lymphocytes, acting stronger than the known synthetic protector amifostine.     

Genetic variation and relationship of alfalfa populations and their progenies based on RAPD markers

The aim of investigation was to evaluate genetic variation and relationship among alfalfa populations and their offspring, with minimal cost, by using DNA marker analysis. RAPD analysis was performed on bulked DNA samples of five alfalfa parental populations and their progenies: 20 F1 populations from reciprocal diallel crosses and five S1 populations from self-pollination. Twenty primers generated 217 bands, ranging in size from 300 to 6000 bp, with the average number of bands per primer of 10.85 and polymorphism information content of 0.246. Percentage of polymorphic loci, effective number of alleles, expected heterozygosity and Shannon’s information index were used to estimate genetic variation. Higher diversity was observed in F1 progeny populations, while genetic variation in parental populations and S1 progenies remained similar. The genetic relatedness of alfalfa populations was analysed by UPGMA and Bayesian model-based clustering approach. In both types of analysis selfpollinated progenies were grouped. Furthermore, the hybrid offspring where Zuzana, and RSI 20 were maternal parents were placed in separate groups. The results indicate that use of RAPD markers on bulked DNA samples can be fast and cost-effective way for differentiation of alfalfa parental populations and their offspring, as well as for evaluation of their genetic relationships.     

Discovery of Triterpenoids as Reversible Inhibitors of α/β-hydrolase Domain Containing 12 (ABHD12)

Background

α/β-hydrolase domain containing (ABHD)12 is a recently discovered serine hydrolase that acts in vivo as a lysophospholipase for lysophosphatidylserine. Dysfunctional ABHD12 has been linked to the rare neurodegenerative disorder called PHARC (polyneuropathy, hearing loss, ataxia, retinosis pigmentosa, cataract). In vitro, ABHD12 has been implicated in the metabolism of the endocannabinoid 2-arachidonoylglycerol (2-AG). Further studies on ABHD12 function are hampered as no selective inhibitor have been identified to date. In contrast to the situation with the other endocannabinoid hydrolases, ABHD12 has remained a challenging target for inhibitor development as no crystal structures are available to facilitate drug design.

Methodology/Principal Findings

Here we report the unexpected discovery that certain triterpene-based structures inhibit human ABHD12 hydrolase activity in a reversible manner, the best compounds showing submicromolar potency. Based on structure activity relationship (SAR) data collected for 68 natural and synthetic triterpenoid structures, a pharmacophore model has been constructed. A pentacyclic triterpene backbone with carboxyl group at position 17, small hydrophobic substituent at the position 4, hydrogen bond donor or acceptor at position 3 accompanied with four axial methyl substituents was found crucial for ABHD12 inhibitor activity. Although the triterpenoids typically may have multiple protein targets, we witnessed unprecedented selectivity for ABHD12 among the metabolic serine hydrolases, as activity-based protein profiling of mouse brain membrane proteome indicated that the representative ABHD12 inhibitors did not inhibit other serine hydrolases, nor did they target cannabinoid receptors.

Conclusions/Significance

We have identified reversibly-acting triterpene-based inhibitors that show remarkable selectivity for ABHD12 over other metabolic serine hydrolases. Based on SAR data, we have constructed the first pharmacophore model of ABHD12 inhibitors. This model should pave the way for further discovery of novel lead structures for ABHD12 selective inhibitors.     

The Effect of Personality on Daily Life Emotional Processes

Personality features are associated with individual differences in daily emotional life, such as negative and positive affectivity, affect variability and affect reactivity. The existing literature is somewhat mixed and inconclusive about the nature of these associations. The aim of this study was to shed light on what personality features represent in daily life by investigating the effect of the Five Factor traits on different daily emotional processes using an ecologically valid method. The Experience Sampling Method was used to collect repeated reports of daily affect and experiences from 104 healthy university students during one week of their normal lives. Personality traits of the Five Factor model were assessed using NEO Five Factor Inventory. Hierarchical linear modeling was used to analyze the effect of the personality traits on daily emotional processes. Neuroticism predicted higher negative and lower positive affect, higher affect variability, more negative subjective evaluations of daily incidents, and higher reactivity to stressors. Conscientiousness, by contrast, predicted lower average level, variability, and reactivity of negative affect. Agreeableness was associated with higher positive and lower negative affect, lower variability of sadness, and more positive subjective evaluations of daily incidents. Extraversion predicted higher positive affect and more positive subjective evaluations of daily activities. Openness had no effect on average level of affect, but predicted higher reactivity to daily stressors. The results show that the personality features independently predict different aspects of daily emotional processes. Neuroticism was associated with all of the processes. Identifying these processes can help us to better understand individual differences in daily emotional life.     

The search for common anthropogenic impacts on biodiversity: a global network

We introduce an initiative to assess and compare landscape changes related to human activities on a global scale, using a single group of invertebrates. The GLOBENET programme uses common field methodology (pitfall trapping), to appraise assemblages of ground beetles (Coleoptera, Carabidae) in visually-similar land-mosaics (urban-rural gradients). Carabids were selected as the focal taxon as they are sufficiently varied (both taxonomically and ecologically), abundant and sensitive to the environment. However, work on other taxa is comparable with the GLOBENET framework. The continuum of decreasing human pressure from city centres into the surrounding countryside was selected to represent human-caused disturbance for this initial stage of GLOBENET because these gradients can be found virtually all over the world. Through the broad-scale assessment envisioned in the GLOBENET programme, we seek to separate general, repeated effects on biodiversity from those that depend on local environments or particular biotic assemblages. Based on this understanding we aim to develop simple tools and protocols for assessing ecological effects of human-caused landscape changes, which could help to sustainably manage landscapes for biodiversity and for human requirements. For instance, the response of different functional groups of carabids to these landscape changes may help guide management practices. Further GLOBENET developments and information are available at our website: http://www.helsinki.fi/science/globenet/     

Redox Mechanism of S-Nitrosothiol Modulation of Neuronal CaV3.2 T-Type Calcium Channels

T-type calcium channels in the dorsal root ganglia (DRG) have a central function in tuning neuronal excitability and are implicated in sensory processing including pain. Previous studies have implicated redox agents in control of T-channel activity; however, the mechanisms involved are not completely understood. Here, we recorded T-type calcium currents from acutely dissociated DRG neurons from young rats and investigated the mechanisms of Ca_V3.2 T-type channel modulation by S-nitrosothiols (SNOs). We found that extracellular application of S-nitrosoglutathione (GSNO) and S-nitroso-N-acetyl-penicillamine rapidly reduced T-type current amplitudes. GSNO did not affect voltage dependence of steady-state inactivation and macroscopic current kinetics of T-type channels. The effects of GSNO were abolished by pretreatment of the cells with N-ethylmaleimide, an irreversible alkylating agent, but not by pretreatment with 1H-(1,2,4) oxadiazolo (4,3-a) quinoxalin-1-one, a specific soluble guanylyl cyclase inhibitor, suggesting a potential effect of GSNO on putative extracellular thiol residues on T-type channels. Expression of wild-type Ca_V3.2 channels or a quadruple Cys-Ala mutant in human embryonic kidney cells revealed that Cys residues in repeats I and II on the extracellular face of the channel were required for channel inhibition by GSNO. We propose that SNO-related molecules in vivo may lead to alterations of T-type channel-dependent neuronal excitability in sensory neurons and in the central nervous system in both physiological and pathological conditions such as neuronal ischemia/hypoxia.