Optimization and preclinical evaluation of novel histamine H3 receptor ligands: Acetyl and propionyl phenoxyalkyl piperazine derivatives

As a continuation of our search for novel histamine H₃ receptor ligands, a series of new acetyl and propionyl phenoxyalkylamine derivatives (2–25) was synthesized. Compounds with three to four carbon atoms alkyl chain spacer, composed of six various 4N-substituted piperazine moieties were evaluated for their binding properties at human histamine H₃ receptors (hH₃R). In vitro test results proved the 4-pyridylpiperazine moiety as crucial element for high hH₃R affinity (hH₃R K_i?=?5.2–115?nM). Moreover introduction of carbonyl group containing residues in the lipophilic part of molecules instead of branched alkyl substituents resulted in increased affinity in correlation to previously described series, whereas propionyl derivatives showed slightly higher affinities than those of acetyl (16 and 22vs.4 and 10; hH₃R K_i?=?5.2 and 15.4?nM vs. 10.2 and 115?nM, respectively). These findings were confirmed by molecular modelling studies, demonstrating multiple ligand-receptor interactions. Furthermore, pharmacological in vivo test results of compound 4 clearly indicate that it may affect the amount of calories consumed, thus act as an anorectic compound. Likewise, its protective action against hyperglycemia and the development of overweight has been shown. In order to estimate drug-likeness of compound 4, in silico and experimental evaluation of metabolic stability in human liver microsomes was performed.     

Citrate usage in the leading causes of blindness: new possibilities for the old metabolite

Introduction

Citrate is an old metabolite which is best known for the role in the Krebs cycle. Citrate is widely used in many branches of medicine. In ophthalmology citrate is considered as a therapeutic agent and an useful diagnostic tool—biomarker.

Objectives

To summarize the published literature on citrate usage in the leading causes of blindness and highlight the new possibilities for this old metabolite.

Methods

We conducted a systematic search of the scientific literature about citrate usage in ophthalmology up to January 2018. The reference lists of identified articles were searched for providing in-depth information.

Results

This systematic review included 30 articles. The role of citrate in the leading causes of blindness is presented.

Conclusions

Citrate might help inhibit cataract progression, in case of questions confirm glaucoma diagnosis or improve cornea repair treatment as adjuvant agent (therapy of ulcerating cornea after alkali injury, crosslinking procedure). However, the knowledge about possible citrate usage in ophthalmology is not widely known. Promoting recent scientific knowledge about citrate usage in ophthalmology may not only benefit of medical improvement but may also limit economic costs caused by leading causes of blindness. Further studies on citrate usage in ophthalmology should continuously be the field of scientific interest.

     

Blood parasites shape extreme major histocompatibility complex diversity in a migratory passerine

Pathogens are one of the main forces driving the evolution and maintenance of the highly polymorphic genes of the vertebrate major histocompatibility complex (MHC). Although MHC proteins are crucial in pathogen recognition, it is still poorly understood how pathogen‐mediated selection promotes and maintains MHC diversity, and especially so in host species with highly duplicated MHC genes. Sedge warblers (Acrocephalus schoenobaenus) have highly duplicated MHC genes, and using data from high‐throughput MHC genotyping, we were able to investigate to what extent avian malaria parasites explain temporal MHC class I supertype fluctuations in a long‐term study population. We investigated infection status and infection intensities of two different strains of Haemoproteus, that is avian malaria parasites that are known to have significant fitness consequences in sedge warblers. We found that prevalence of avian malaria in carriers of specific MHC class I supertypes was a significant predictor of their frequency changes between years. This finding suggests that avian malaria infections partly drive the temporal fluctuations of the MHC class I supertypes. Furthermore, we found that individuals with a large number of different supertypes had higher resistance to avian malaria, but there was no evidence for an optimal MHC class I diversity. Thus, the two studied malaria parasite strains appear to select for a high MHC class I supertype diversity. Such selection may explain the maintenance of the extremely high number of MHC class I gene copies in sedge warblers and possibly also in other passerines where avian malaria is a common disease.     

The in vitro effect of progesterone on the orexin system in porcine uterine tissues during early pregnancy

Background

Orexin A (OXA) and orexin B (OXB) are hypothalamic-derived peptides that participate in the regulation of energy metabolism, food intake and reproductive function by influencing the hypothalamic-pituitary-ovarian axis. Orexins are also produced in the endometrium, myometrium and placenta, which suggests that they could act as a link between energy metabolism and the reproductive system. Changes in the expression of orexin and the orexin receptor genes and proteins during the oestrous cycle and early gestation in pigs imply that orexin activity may be regulated by local factors within the uterus. The aim of this study was to investigate the influence of progesterone (P₄) on the expression of orexin system genes, and proteins in the porcine uterus during early gestation. Gene expression was analyzed by real-time PCR. Adiponectin secretion was determined by ELISA, and the receptors proteins content was defined using western blot analysis.

Results

In the endometrium, P₄ enhanced OXA secretion on days 10 to 11 of gestation and OXB secretion on days 12 to 13. In the myometrium, P₄ inhibited the secretion of both orexins on days 15 to 16 and OXB secretion also on days 12 to 13. In the endometrium, P₄ inhibited the expression of orexin receptor 1 (OX1R) protein at nearly all times analyzed, whereas the expression of orexin receptor 2 (OX2R) protein was inhibited only on days 15 to 16 of gestation. In the myometrium, P₄ stimulated OX1R protein expression on days 12 to 13 and 15 to 16 of gestation and inhibited OX1R protein expression on days 27 to 28. The expression of OX2R protein in the myometrium increased on days 12 to 13 and decreased on days 10 to 11 and 15 to 16.

Conclusions

The results indicate that P₄ could regulate the expression of the orexin system in the porcine uterus during early pregnancy, which suggests the presence of a local feedback loop that could play an important role in the regulation of maternal metabolism during pregnancy. The findings may contribute to the existing knowledge of the mechanisms linking maternal energy metabolism with the regulation of the reproductive system during pregnancy.

     

The role of Ca2+ ions in modulating changes induced in bean plants by an excess of Cu2+ ions. Chlorophyll fluorescence measurements

Ca²⁺-dependent influence of excess Cu²⁺ on the photosynthetic akpparatus monitored through chlorophyll fluorescence measurements was investigated in runner bean plants (Phaseolus coccineus L. cv. Pie kny Ja?) at three different growth stages. It was observed that the toxic effect of excess Cu²⁺ on plants depends both on their growth stages and the Ca²⁺ content in the medium. Increased Ca²⁺ content limits Cu²⁺ action on plants at their initial growth stage (I) through: stabilization of the PSII complex (increase of the ratio of variable to minimal fluorescence [F_v/F₀]), improved electron flow and reoxidative processes of the quinone primary electron acceptor of PSII (Q_A) (increase of quantum yield of PSII electron transport [φ_e] and photochemical quenching of fluorescence [q_P] values) and elimination of nonphotochemical energy dissipation (decrease of nonphotochemical fluorescence quenching from the Stern-Volmer equation [NPQ] and fraction of the absorbed light energy not used for photochemistry [LNU] values). At this growth stage excess Cu²⁺ decreases the rates of Q_A reduction as a result of decreased PSII activity at its donor side only at lower Ca²⁺ level. At the intermediate growth stage (II) the plants were less sensitive to Cu²⁺ treatment and also to changed Ca²⁺ content. A weakening of some photochemical processes by excess Cu²⁺ could be observed only at a higher Ca²⁺ dose. At the final growth stage of plants (III) Ca²⁺ ions exerted a decisively different effect on the mechanism of excess Cu²⁺ action on bean plants, visualized by decreased PSII stabilization and utilization of absorbed light energy at increased Ca²⁺ content in the medium.     

Role of sensory input from the lungs in control of muscle sympathetic nerve activity during and after apnea in humans.

We reasoned that, if the lung inflation reflex contributes importantly to apnea-induced sympathetic activation, such activation would be attenuated in bilateral lung transplant recipients (LTX). We measured muscle sympathetic nerve activity (MSNA; intraneural electrodes), heart rate, mean arterial pressure, tidal volume, end-tidal Pco(2), and arterial oxygen saturation in seven LTX and seven healthy control subjects (Con) before, during, and after 20-s end-expiratory breath holds. Our evidence for denervation in LTX was 1) greatly attenuated respiratory sinus arrhythmia and 2) absence of cough reflex below the level of the carina. During apnea, the temporal pattern and the peak increase in MSNA were virtually identical in LTX and Con (347 +/- 99 and 359 +/- 46% of baseline, respectively; P > 0.05). In contrast, the amount of MSNA present in the first 5 s after resumption of breathing was greater in LTX vs. Con (101 +/- 4 vs. 38 +/- 7% of baseline, respectively; P < 0.05). There were no between-group differences in apnea-induced hypoxemia or hypercapnia, hemodynamic, or ventilatory responses. Thus cessation of the rhythmic sympathoinhibitory feedback that normally accompanies eupneic breathing does not contribute importantly to sympathetic excitation during apnea. In contrast, vagal afferent input elicited by hyperventilation-induced lung stretch plays an important role in the profound, rapid sympathetic inhibition that occurs after resumption of breathing after apnea.     

Heritability of some characters of rye under open pollination

Summary Present investigations cover the correlation between four characters of maternal plants of rye and the corresponding characters in their offspring. Tabulated results pertain to four two-year periods for the Exp. Sta. Chory and two such periods for the Exp. Sta. Laski, involving several plant material groups derived from various crosses with Dakowskie Selekcyjne rye.The effects of average grain weight per ear of the maternal plant on the corresponding yields in the offspring have proved rather small, but sporadically approaching or attaining the limits of significance. The influence of resistance to lodging of the maternal plant on that same character in the offspring has proved no greater, but, in spite of the considerable multidirectional differentiation of the coefficients of correlation and regression, in 4 groups out of a total of 27 they surpassed the limits of significance, sometimes attaining high values.In contrast to these two characters, but in agreement with expectations, there was a fairly pronounced effect of 1000 grain weight and of the maternal plant height on the same characters in the offspring. Significant coefficients of regression for the former characters ranged from 0.11 to 0.22 g, and for the latter from 0.03 to 0.37 cm.The present paper also includes less numerous results of analogous investigations on the relation of characters determined in the microtrials with those examined in the next generation. These results indicate good transmission of earliness, measured by the date of earing, and of the weight of 1000 grains, but a much weaker transmission of resistance to lodging and of grain yields.The conclusions drawn on breeding strategy suggest opportunities for efficient selection under the method of recombination towards short straw and a high 1000 grain weight within maternal plants, and also the advisability of shifting the main impact of selection for yield and resistance to lodging onto the following generations.     

The search for polyprenols in dendroflora of Vietnam

The occurrence of polyprenols in leaves of over 340 species of dendroflora in natural habitats in the regions of Hanoi and Hue in Vietnam was studied. Plant material was collected in the late autumn (October/November) during the end of a vegetation season. Leaves of about 200 plant species did not contain detectable amounts of polyprenols in contrast to few systematic families, e.g. Moraceae, Euphorbiaceae, where polyprenols were highly abundant and their pattern could be used as a chemotaxonomic criterion. Most often dominating polyprenols were prenol-11 and prenol-12. In several angiosperm species prenol-13 and detectable amounts of prenol-14 were also found. The incidence of prenol-13 and -14 was not restricted to a specific taxonomic group since species exhibiting domination of such longer chain polyprenols belonged to various systematic families. In some plants (e.g. Ceiba pentandra) alpha-cis polyprenols were accompanied by alpha-trans counterparts. This report describes several new plant species that may serve as natural sources of long chain polyprenols.