Nuclear factor kappa B as a potential target for pharmacological correction endothelium-associated pathology

The nuclear factor kappa B (NF-κB) is one of transcription factors. A high interest in studying the biological role of the signal system and its contribution to the development of cardiovascular, oncological and autoimmune diseases is obvious. A number of stimuli (proinflammatory cytokines: tumor necrosis factor α, interleukin 1β, ligand CD40 and others) trigger the canonical and non-canonical pathways of NF-κB signaling, which increase the expression of genes regulating synthesis of cytokines and chemokines, cell proliferation and differentiation, angiogenesis, immune reactions and apoptosis. However, pathological activation of NF-κB violates the balance of substances participating in the normal activity of the cardiovascular system. This leads to the development and progression of endothelium-associated pathology and comorbidit

The influence of the concentration of montmorillonite containing sorbent and pH of the culture medium on the antibiotic sensitivity of Escherichia coli, as well as the effect of ground on growth of Escherichia

The aim of this work was the comparative sensitivity test of E. coli to enrofloxacin and doxycycline and bactericidal action of montmorillonite containing sorbent and its combination with enrofloxacin, as well as the influence of the concentration of the enriched montmorillonite containing sorbent and pH of the culture medium on the antibiotic sensitivity of Escherichia coli. The sensitivity test of Escherichia coli to enrofloxacin, and the combination of enrofloxacin with sorbent was performd by the method of double serial dilutions of drugs in a liquid culture mediu

Particle Motion in Rapidly Oscillating Potentials: The Role of the Potential's Initial Phase

Rapidly oscillating potentials with a vanishing time average have been used for a long time to trap charged particles in source-free regions. It has been argued that the motion of a particle in such a potential can be approximately described by a time independent effective potential, which does not depend upon the initial phase of the oscillating potential. However, here we show that the motion of a particle and its trapping condition significantly depend upon this initial phase for arbitrarily high frequencies of the potential's oscillation. We explain this novel phenomenon by showing that the motion of a particle is determined by the effective potential stated in the literature only if its initial conditions are transformed according to a transformation which we show to significantly depend on the potential's initial phase for arbitrarily high frequencies. We confirm our theoretical findings by numerical simulations. Further, we demonstrate that the found phenomenon offers new ways to manipulate the dynamics of particles which are trapped by rapidly oscillating potentials. Finally, we propose a simple experiment to verify the theoretical findings of this work.Comment: 9 pages, 8 figures, published in PR

Structural Basis of p75 Transmembrane Domain Dimerization

Dimerization of single span transmembrane receptors underlies their mechanism of activation. p75 neurotrophin receptor plays an important role in the nervous system, but the understanding of p75 activation mechanism is still incomplete. The transmembrane (TM) domain of p75 stabilizes the receptor dimers through a disulfide bond, essential for the NGF signaling. Here we solved by NMR the three-dimensional structure of the p75-TM-WT and the functionally inactive p75-TM-C257A dimers. Upon reconstitution in lipid micelles, p75-TM-WT forms the disulfide-linked dimers spontaneously. Under reducing conditions, p75-TM-WT is in a monomer-dimer equilibrium with the Cys(257) residue located on the dimer interface. In contrast, p75-TM-C257A forms dimers through the AXXXG motif on the opposite face of the α-helix. Biochemical and cross-linking experiments indicate that AXXXG motif is not on the dimer interface of p75-TM-WT, suggesting that the conformation of p75-TM-C257A may be not functionally relevant. However, rather than mediating p75 homodimerization, mutagenesis of the AXXXG motif reveals its functional role in the regulated intramembrane proteolysis of p75 catalyzed by the γ-secretase complex. Our structural data provide an insight into the key role of the Cys(257) in stabilization of the weak transmembrane dimer in a conformation required for the NGF signaling.This work was supported in part by Russian Science Foundation Project 14-50-00131 (to A. S. A.) (NMR structural studies) and Spanish Ministry of Economy and Competitiveness (MINECO) Project BFU2013-42746-P (to M. V.). The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.S

H2S in geothermal power plants: from waste to additional resource for energy and environment

Geothermal energy is a sustainable and clean energy source. Unfortunately, utilization of high-enthalpy geothermal systems is generally associated with emissions of gases like carbon dioxide (CO2), hydrogen sulfide (H2S), hydrogen (H2), nitrogen (N2), methane (CH4), and argon (Ar). The emission of some of these gases, particularly CO2, H2S and H2, is one of the main environmental concerns associated with the use of geothermal energy. The sequestration of these gases and their geological storage is the most diffuse viable option for reducing emissions. However, there is interesting technology, called AG2STM, that allows to convert H2S and CO2 into syngas. In this work, the match of this technology with geothermal power plant is analyzed as a new potential industrial route. The study is based on two different geothermal power plants located in Hellisheiði and Nesjavellirn (Iceland) that globally emit 61,800 t of CO2 and 28,200 t/y of H2S. The simulations provide some interesting results: (I) the total conversion of H2S that avoids its underground re-injection with the related environmental problem, (II) the reduction of CO2 emissions (about 8 %) and (III) the increasing of the global thermal energy produced with the same amount initial geothermal energy. The latter is due to the possibility to burn extra hydrogen coming from the AG2STM process. Finally, other advantages of this match are the production of an extra medium pressure steam and the possible reuse of the amount of H2 related to the geothermal plants emissions. Copyright © 2018, AIDIC Servizi S.r.l

The role of ascorbate in antioxidant protection of biomembranes: Interaction with vitamin E and coenzyme Q

One of the vital roles of ascorbic acid (vitamin C) is to act as an antioxidant to protect cellular components from free radical damage. Ascorbic acid has been shown to scavenge free radicals directly in the aqueous phases of cells and the circulatory system. Ascorbic acid has also been proven to protect membrane and other hydrophobic compartments from such damage by regenerating the antioxidant form of vitamin E. In addition, reduced coenzyme Q, also a resident of hydrophobic compartments, interacts with vitamin E to regenerate its antioxidant form. The mechanism of vitamin C antioxidant function, the myriad of pathologies resulting from its clinical deficiency, and the many health benefits it provides, are reviewed.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/44796/1/10863_2004_Article_BF00762775.pd

Nuclear factor kappa B as a potential target for pharmacological correction endothelium-associated pathology

The nuclear factor kappa B (NF-κB) is one of transcription factors. A high interest in studying the biological role of the signal system and its contribution to the development of cardiovascular, oncological and autoimmune diseases is obvious. A number of stimuli (proinflammatory cytokines: tumor necrosis factor α, interleukin 1β, ligand CD40 and others) trigger the canonical and non-canonical pathways of NF-κB signaling, which increase the expression of genes regulating synthesis of cytokines and chemokines, cell proliferation and differentiation, angiogenesis, immune reactions and apoptosis. However, pathological activation of NF-κB violates the balance of substances participating in the normal activity of the cardiovascular system. This leads to the development and progression of endothelium-associated pathology and comorbidit

Revising the mechanism of p75NTR activation: intrinsically monomeric state of death domains invokes the "helper" hypothesis

Abstract The neurotrophin receptor p75NTR plays crucial roles in neuron development and regulates important neuronal processes like degeneration, apoptosis and cell survival. At the same time the detailed mechanism of signal transduction is unclear. One of the main hypotheses known as the snail-tong mechanism assumes that in the inactive state, the death domains interact with each other and in response to ligand binding there is a conformational change leading to their exposure. Here, we show that neither rat nor human p75NTR death domains homodimerize in solution. Moreover, there is no interaction between the death domains in a more native context: the dimerization of transmembrane domains in liposomes and the presence of activating mutation in extracellular juxtamembrane region do not lead to intracellular domain interaction. These findings suggest that the activation mechanism of p75NTR should be revised. Thus, we propose a novel model of p75NTR functioning based on interaction with “helper” protein

The influence of the concentration of montmorillonite containing sorbent and pH of the culture medium on the antibiotic sensitivity of Escherichia coli, as well as the effect of ground on growth of Escherichia

The aim of this work was the comparative sensitivity test of E. coli to enrofloxacin and doxycycline and bactericidal action of montmorillonite containing sorbent and its combination with enrofloxacin, as well as the influence of the concentration of the enriched montmorillonite containing sorbent and pH of the culture medium on the antibiotic sensitivity of Escherichia coli. The sensitivity test of Escherichia coli to enrofloxacin, and the combination of enrofloxacin with sorbent was performd by the method of double serial dilutions of drugs in a liquid culture mediu

Structure of human TRPV4 in complex with GTPase RhoA

Abstract Transient receptor potential (TRP) channel TRPV4 is a polymodal cellular sensor that responds to moderate heat, cell swelling, shear stress, and small-molecule ligands. It is involved in thermogenesis, regulation of vascular tone, bone homeostasis, renal and pulmonary functions. TRPV4 is implicated in neuromuscular and skeletal disorders, pulmonary edema, and cancers, and represents an important drug target. The cytoskeletal remodeling GTPase RhoA has been shown to suppress TRPV4 activity. Here, we present a structure of the human TRPV4-RhoA complex that shows RhoA interaction with the membrane-facing surface of the TRPV4 ankyrin repeat domains. The contact interface reveals residues that are mutated in neuropathies, providing an insight into the disease pathogenesis. We also identify the binding sites of the TRPV4 agonist 4α-PDD and the inhibitor HC-067047 at the base of the S1-S4 bundle, and show that agonist binding leads to pore opening, while channel inhibition involves a π-to-α transition in the pore-forming helix S6. Our structures elucidate the interaction interface between hTRPV4 and RhoA, as well as residues at this interface that are involved in TRPV4 disease-causing mutations. They shed light on TRPV4 activation and inhibition and provide a template for the design of future therapeutics for treatment of TRPV4-related diseases