New inhibitors of fungal 17β-hydroxysteroid dehydrogenase based on the [1,5]-benzodiazepine scaffold

The synthesis and activity of a new series of non-steroidal inhibitors of 17β-hydroxysteroid dehydrogenase that are based on a 1,5-benzodiazepine scaffold are presented. Their inhibitory potential was screened against 17β-hydroxysteroid dehydrogenase from the fungus Cochliobolus lunatus (17β-HSDcl), a model enzyme of the short-chain dehydrogenase/reductase superfamily. Some of these compounds are potent inhibitors of 17β-HSDcl activity, with IC₅₀ values in the low micromolar range and represent promising lead compounds that should be further developed and investigated as inhibitors of human 17β-HSD isoforms, which are the enzymes associated with the development of many hormone-dependent and neuronal diseases.     

Aryl derivatives of 3H-1,2-benzoxathiepine 2,2-dioxide as carbonic anhydrase inhibitors

Abstract

A new series of homosulfocoumarins (3H-1,2-benzoxathiepine 2,2-dioxides) possessing various substitution patterns and moieties in the 7, 8 or 9 position of the heterocylic ring were prepared by original procedures and investigated for the inhibition of four physiologically relevant carbonic anhydrase (CA, EC 4.2.1.1) isoforms, the human (h) hCA I, II, IX and XII. The 8-substituted homosulfocoumarins were the most effective hCA IX/XII inhibitors followed by the 7-substituted derivatives, whereas the substitution pattern in position 9 led to less effective binders for the transmembrane, tumour-associated isoforms IX/XII. The cytosolic isoforms hCA I and II were not inhibited by these compounds, similar to the sulfocoumarins/coumarins investigated earlier. As hCA IX and XII are validated anti-tumour targets, with one sulphonamide (SLC-0111) in Phase Ib/II clinical trials, finding derivatives with better selectivity for inhibiting the tumour-associated isoforms over the cytosolic ones, as the homosulfocoumarins reported here, is of crucial importance.     

Sulfocoumarins as dual inhibitors of human carbonic anhydrase isoforms IX/XII and of human thioredoxin reductase

Abstract

The hypothesis that sulfocoumarin acting as inhibitors of human carbonic anhydrase (CA, EC 4.2.1.1) cancer-associated isoforms hCA IX and – hCA XII is being able to also inhibit thioredoxin reductase was verified and confirmed. The dual targeting of two cancer cell defence mechanisms, i.e. hypoxia and oxidative stress, may both contribute to the observed antiproliferative profile of these compounds against many cancer cell lines. This unprecedented dual anticancer mechanism may lead to a new approach for designing innovative therapeutic agents.     

Continuous production of selenomethionine-enriched Chlorella sorokiniana biomass in a photobioreactor

This article describes the enrichment of the fresh-water green microalga Chlorella sorokiniana in selenomethionine (SeMet). The microalga was cultivated in a 2.2 L glass-vessel photobioreactor, in a culture medium supplemented with selenate (SeO₄^2?) concentrations ranging from 5 to 50 mg L^?1. Although selenate exposure lowered culture viability, C. sorokiniana grew well at all tested selenate concentrations, however cultures supplemented with 50 mg L^?1 selenate did not remain stable at steady state. A suitable selenate concentration in fresh culture medium for continuous operation was determined, which allowed stable long-term cultivation at steady state and maximal SeMet productivity. In order to do that, the effect of dilution rate on biomass productivity, viability and SeMet content of C. sorokiniana at several selenate concentrations were determined in the photobioreactor. A maximal SeMet productivity of 21 μg L^?1 day^?1 was obtained with 40 mg L^?1 selenate in the culture medium. Then a continuous cultivation process at several dilution rates was performed at 40 mg L^?1 selenate obtaining a maximum of 246 μg L^?1 day^?1 SeMet at a low dilution rate of 0.49 day^?1, calculated on total daily effluent volume. This paper describes for the first time an efficient long-term continuous cultivation of C. sorokiniana for the production of biomass enriched in the high value amino acid SeMet, at laboratory scale.     

Interrelationships between distinct circadian manifestations of possible bruxism,perceived stress,chronotype and social jetlag in a population of undergraduate students

ABSTRACT

This study investigates the recently hypothesized association between distinct circadian manifestations of possible bruxism in subjects with different chronotype profiles, social jetlag and levels of perceived stress. A cross-sectional study was performed by surveying dental students’ of Lithuanian University of Health Sciences. A survey instrument was designed and pilot tested for reliability and validity prior to full-scale administration. The instrument consisted of four sections: socio-demographic questions, bruxism-related items, the Perceived Stress Scale and the Munich ChronoType Questionnaire. The study included 228 students (82.5% females; mean age 22.67 ± 2.27). Awake grinding was significantly associated with later chronotype values (p = 0,039). Despite the lack of significance, binary regression models demonstrated that students with later chronotypes report higher rates of possible bruxism, especially as far as awake grinding (p = .170; OR = 1.89) and sleep grinding (p = .140; OR = 1.60) are concerned. There were no significant associations between perceived stress, social jetlag and bruxism. The scores of perceived stress did not correlate with chronotype values, although a high positive correlation was found between chronotype and social jetlag (r = 0.516, p = .000). It can be concluded that later chronotypes increase the odds for self-reported bruxism, and are significantly associated with higher rates of awake grinding and social jetlag. No interrelationships were found between perceived stress, possible bruxism and social jetlag.     

A review of the West Palaearctic aphidiines (Hymenoptera: Braconidae: Aphidiinae) parasitic on Uroleucon spp., with the description of a new species

A review of aphidiine wasps (Hymenoptera: Braconidae) parasitizing the Uroleucon species in the West Palaearctic is presented. Eleven species are keyed and illustrated. In addition, a new hymenopteran parasitoid species: Praon nonveilleri n. sp. from Uroleucon inulicola (Hille Ris Lambers) infesting Inula ensifolia L., is described. The new species is diagnosed and illustrated. It belongs to the “dorsale-yomenaé” species group and was collected from the Djetinja canyon in Serbia and Montenegro. The aphidiines presented in this work were identified from 97 aphid taxons occurring on 236 plant taxons. Furthermore, 361 original parasitoid – host aphid – host plant associations of the species mentioned in the key are presented. Finally, phylogenetic relationships inside the “dorsale-yomenae” species group and related species were reconstructed using cladistic distance methods.     

The impact of vegetation characteristics and prey availability on breeding habitat use and diet of Little Owls Athene noctua in Central European farmland

Capsule Foraging habitats are determined by vegetation characteristics rather than the availability of insect prey.

Aims To determine the diet composition of Little Owls in relation to the availability of insects at foraging sites, and to elucidate the main factors determining the owls’ habitat choice.

Methods The feeding ecology of Little Owls was studied during the 2002 breeding season in the agricultural landscape of western Bohemia (Czech Republic), where its population is in decline. Diet composition was determined by pellet analysis. Insect availability was studied using pitfall traps in the two most important Little Owl foraging habitats. For both habitats, we assessed the main vegetative characteristics (average and maximum vegetation height, vegetation density).

Results Based on number, insects were the most dominant prey, followed by small mammals; based on weight, insects comprised only a minor part of the diet. Among insect prey, Carabidae beetles were the most abundant. The proportion of insect numbers was strongly positively correlated with advancing day of the season and negatively correlated with the proportion of vertebrates. Although the highest densities of Carabidae were found in cornfields Little Owls significantly preferred grassland habitats, probably because of the lower vegetation cover.

Conclusions The availability of short sward vegetation in grassland habitats during the breeding season may play a key role in the conservation of Little Owls in central European farmland.     

HLA-C, DRB1 and DQB1 alleles involved in genetic predisposition to psoriasis vulgaris in the Slovak population

Psoriasis vulgaris is a complex chronic skin disease with immunological and genetic background. The most important predisposing genetic factors in psoriasis are genes of the human leukocyte antigen (HLA) region. Accumulative evidence has shown that several HLA alleles are closely associated with psoriasis; however, they tend to vary in different racial and ethnic backgrounds. One hundred forty-seven unrelated Slovak patients with psoriasis vulgaris (average age at onset 28?±?14 years) were genotyped for the HLA-C, DQB1 and DRB1 alleles by the polymerase chain reaction using sequence-specific primers. Allele frequencies observed in the group of psoriatic patients were compared to those obtained in the ethnically matched control group comprising 194 subjects with no history of psoriasis. Susceptibility to psoriasis vulgaris in our study group is significantly associated with HLA-C*06 (odds ratio (OR)?=?3.85), DRB1*07 (OR?=?2.56) and DQB1*02 (OR?=?1.09), respectively, whereas DRB*01 (OR?=?0.05) is associated negatively. Hereby, we provide the first report on the association of HLA-C, DRB1 and DQB1 alleles with psoriasis in the Slovak population. Our findings confirm HLA-C*06 and DRB1*07 as the most important genetic risk factors for psoriasis. However, the role of HLA genes as causative in the pathogenesis of the disease remains unclear. Identification of genetic factors that increase the risk of psoriasis is a precondition that helps to elucidate the pathogenesis of this troubling disease and identify targets for a more specific and effective therapy.