Synthesis and biological activity of new series of N-modified analogues of the N/OFQ(1–13)NH2 with aminophosphonate moiety

New series of N-modified analogues of the N/OFQ(1-13)NH(2) with aminophosphonate moiety have been synthesized and investigated for biological activity. These peptides were prepared by solid-phase peptide synthesis-Fmoc-strategy. The N/OFQ(1-13)NH(2) analogues were tested for agonistic activity in vitro on electrically stimulated rat vas deferens smooth-muscle preparations isolated from Wistar albino rats. Our study has shown that the selectivity of the peptides containing 1-[(methoxyphosphono)methylamino]cycloalkanecarboxylic acids to the N-side of Phe is not changed-they remain selective agonists of NOP receptors. The derivative with the largest ring (NOC-6) demonstrated efficacy similar to that of N/OFQ(1-13)NH(2), but in a 10-fold higher concentration. The agonistic activity of newly synthesized N-modified analogues of N/OFQ(1-13)NH(2) with aminophosphonate moiety was investigated for the first time.     

Activation of the TLR4 signaling pathway and abnormal cholesterol efflux lead to emphysema in ApoE-deficient mice

Smokers with airflow obstruction have an increased risk of atherosclerosis, but the relationship between the pathogenesis of these diseases is not well understood. To determine whether hypercholesterolemia alters lung inflammation and emphysema formation, we examined the lung phenotype of two hypercholesterolemic murine models of atherosclerosis at baseline and on a high-fat diet. Airspace enlargement developed in the lungs of apolipoprotein E-deficient (Apoe(-/-)) mice exposed to a Western-type diet for 10 wk. An elevated number of macrophages and lymphocytes accompanied by an increase in matrix metalloproteinase-9 (MMP-9) activity and MMP-12 expression was observed in the lungs of Apoe(-/-) mice on a Western-type diet. In contrast, low-density lipoprotein receptor-deficient (Ldlr(-/-)) mice did not exhibit lung destruction or inflammatory changes. Most importantly, we revealed augmented expression of the downstream targets of the Toll-like receptor (TLR) pathway, interleukin-1 receptor-associated kinase 1, and granulocyte colony-stimulating factor, in the lungs of Apoe(-/-) mice fed with a Western-type diet. In addition, we demonstrated overexpression of MMP-9 in Apoe(-/-) macrophages treated with TLR4 ligand, augmented with the addition of oxidized LDL, suggesting that emphysema in these mice results from the activation of the TLR pathway secondary to known abnormal cholesterol efflux. Our findings indicate that, in Apoe(-/-) mice fed with an atherogenic diet, abnormal cholesterol efflux leads to increased systemic inflammation with subsequent lung damage and emphysema formation.     

The possibility of increasing the precision of biochemical diagnostics of Gaucher disease

Estimation of chitotriosidase activity is proposed for final diagnostics of Gaucher disease. Using this method the diagnosis has not been confirmed in one patient of 25 ones with this preliminary diagnosis. The problems of complex diagnostics of Gaucher disease are discussed.     

Osteoclasts degrade endosteal components and promote mobilization of hematopoietic progenitor cells

Here we investigated the potential role of bone-resorbing osteoclasts in homeostasis and stress-induced mobilization of hematopoietic progenitors. Different stress situations induced activity of osteoclasts (OCLs) along the stem cell-rich endosteum region of bone, secretion of proteolytic enzymes and mobilization of progenitors. Specific stimulation of OCLs with RANKL recruited mainly immature progenitors to the circulation in a CXCR4- and MMP-9-dependent manner; however, RANKL did not induce mobilization in young female PTPepsilon-knockout mice with defective OCL bone adhesion and resorption. Inhibition of OCLs with calcitonin reduced progenitor egress in homeostasis, G-CSF mobilization and stress situations. RANKL-stimulated bone-resorbing OCLs also reduced the stem cell niche components SDF-1, stem cell factor (SCF) and osteopontin along the endosteum, which was associated with progenitor mobilization. Finally, the major bone-resorbing proteinase, cathepsin K, also cleaved SDF-1 and SCF. Our findings indicate involvement of OCLs in selective progenitor recruitment as part of homeostasis and host defense, linking bone remodeling with regulation of hematopoiesis.     

Comparison of the somatic TADs and lampbrush chromomere-loop complexes in transcriptionally active prophase I oocytes

Chromosoma - In diplotene oocyte nuclei of all vertebrate species, except mammals, chromosomes lack interchromosomal contacts and chromatin is linearly compartmentalized into distinct...     

Overexpression of CUG triplet repeat-binding protein, CUGBP1, in mice inhibits myogenesis

Accumulation of RNA CUG repeats in myotonic dystrophy type 1 (DM1) patients leads to the induction of a CUG-binding protein, CUGBP1, which increases translation of several proteins that are required for myogenesis. In this paper, we examine the role of overexpression of CUGBP1 in DM1 muscle pathology using transgenic mice that overexpress CUGBP1 in skeletal muscle. Our data demonstrate that the elevation of CUGBP1 in skeletal muscle causes overexpression of MEF2A and p21 to levels that are significantly higher than those in skeletal muscle of wild type animals. A similar induction of these proteins is observed in skeletal muscle of DM1 patients with increased levels of CUGBP1. Immunohistological analysis showed that the skeletal muscle from mice overexpressing CUGBP1 is characterized by a developmental delay, muscular dystrophy, and myofiber-type switch: increase of slow/oxidative fibers and the reduction of fast fibers. Examination of molecular mechanisms by which CUGBP1 up-regulates MEF2A shows that CUGBP1 increases translation of MEF2A via direct interaction with GCN repeats located within MEF2A mRNA. Our data suggest that CUGBP1-mediated overexpression of MEF2A and p21 inhibits myogenesis and contributes to the development of muscle deficiency in DM1 patients.     

Regulation of posttetanic increase in choline sensitivity in Helix neurons by Na,K-pump: the role of Na/Ca-exchange and of mobilized calcium

We studied the role of Na/Ca-exchange and intracellular mobilized calcium in ouabain-mediated suppression of potentiation of cholinosensitivity of somatic membrane in Helix LPa3 and RPa3 command neurons of defensive behaviour after electrical orthodromic tetanisation of n. intestinalis. Cholinosensitivity of neurons was assessed by the amplitude of the inward current evoked by acetylcholine. Inhibitor of a Na/Ca-exchange benzamil and specific inhibitor of Ca-ATPase in endoplasmic reticulum thapsigargin prevented the development of the posttetanic potentiation (PTP). PTP did not arise and at joint action of ouabain with benzamil or thapsigargin. It was concluded that Na/Ca-exchange and mobilized calcium are involved in development of PTP of cholinosensitivity in somatic neuronal membrane and its regulation by Na,K-pump.     

Blue, red and blue plus red light control of chlorophyll content and CO2 gas exchange in barley leaves: Quantitative description of the effects of light quality and fluence rate

The dependence of the Chl content and the rate of CO₂ gas exchange (RGE) on both blue and red quanta fluence rates have been studied in primary leaves of barley ( Hordeum vulgare L. cv. Viner). Empirical equations connecting the two photosynthetic indices with fluence rates of blue or red light were developed. These equations consist of 3 (Chl content) or 2 (RGE) terms, each reflecting the involvement of a specific reaction in the long-term light control of the development of the photosynthetic apparatus. On the basis of the equations the effects of mixed blue plus red light on both the Chl content and RGE were calculated. An additive mode of the co-action of blue and red light in the range of high PFDs (10–170 μmol m⁻² s⁻¹) becomes evident from the comparison of the experimental results and calculated data. The results indicate the involvement of phytochrome, cryptochrome and chlorophyll in the long-term regulation of the Chl content and RGE.