Endothelial S1pr1 regulates pressure overload‐induced cardiac remodelling through AKT‐eNOS pathway

Cardiac vascular microenvironment is crucial for cardiac remodelling during the process of heart failure. Sphingosine 1‐phosphate (S1P) tightly regulates vascular homeostasis via its receptor, S1pr1. We therefore hypothesize that endothelial S1pr1 might be involved in pathological cardiac remodelling. In this study, heart failure was induced by transverse aortic constriction (TAC) operation. S1pr1 expression is significantly increased in microvascular endothelial cells (ECs) of post‐TAC hearts. Endothelial‐specific deletion of S1pr1 significantly aggravated cardiac dysfunction and deteriorated cardiac hypertrophy and fibrosis in myocardium. In vitro experiments demonstrated that S1P/S1pr1 praxis activated AKT/eNOS signalling pathway, leading to more production of nitric oxide (NO), which is an essential cardiac protective factor. Inhibition of AKT/eNOS pathway reversed the inhibitory effect of EC‐S1pr1‐overexpression on angiotensin II (AngII)‐induced cardiomyocyte (CM) hypertrophy, as well as on TGF‐β‐mediated cardiac fibroblast proliferation and transformation towards myofibroblasts. Finally, pharmacological activation of S1pr1 ameliorated TAC‐induced cardiac hypertrophy and fibrosis, leading to an improvement in cardiac function. Together, our results suggest that EC‐S1pr1 might prevent the development of pressure overload‐induced heart failure via AKT/eNOS pathway, and thus pharmacological activation of S1pr1 or EC‐targeting S1pr1‐AKT‐eNOS pathway could provide a future novel therapy to improve cardiac function during heart failure development.     

First results obtained with a sweeping pulsed radar reflectometer in the Globus-M tokamak

A weeping pulsed radar reflectometer designed for measuring the spatial electron density distribution in the Globus-M spherical tokamak with a minor plasma radius of a=24 cm, a major radius of R=36 cm, a toroidal field of B _T=0.5 T, a plasma current of I _p=200 kA, and an average density of n=(3–10)×10¹³ cm^?3 is described. The reflectometer operation is based on the reflection of microwaves with a carrier frequency f from a plasma layer with the critical density n=(0.0111f)², where n is the electron density in units of 10¹⁴ cm^?3 and f is the microwave frequency in GHz. By simultaneously probing the plasma at different frequencies, it is possible to recover the electron density profile. Microwave pulses with different frequencies are obtained by frequency sweeping. To increase the range of measured densities, channels with fixed frequencies are also used; as a result, the instrument has eleven frequency channels: a 19.5-GHz channel, eight channels in the 26-to 40-GHz frequency range, a 51.5-GHz channel, and a 60-GHz channel, which corresponds to eleven points in the density profile: 0.47×10¹³ cm^?3, eight points in the (0.8–1.95)×10¹³-cm^?3 range, 3.27×10¹³ cm^?3, and 4.5×10¹³ cm^?3. The reflectometer allows detailed measurements of the density profile with a time resolution of several tens of microseconds, which can be useful, in particular, in studying the processes related to the formation of an internal transport barrier in plasma. The first results obtained using this reflectometer in the Globus-M tokamak under various operating conditions are discussed.     

Structure-activity relationships and docking studies of synthetic 2-arylindole derivatives determined with aromatase and quinone reductase 1

In our ongoing effort of discovering anticancer and chemopreventive agents, a series of 2-arylindole derivatives were synthesized and evaluated toward aromatase and quinone reductase 1 (QR1). Biological evaluation revealed that several compounds (e.g., 2d, IC₅₀?=?1.61?μM; 21, IC₅₀?=?3.05?μM; and 27, IC₅₀?=?3.34?μM) showed aromatase inhibitory activity with half maximal inhibitory concentration (IC₅₀) values in the low micromolar concentrations. With regard to the QR1 induction activity, 11 exhibited the highest QR1 induction ratio (IR) with a low concentration to double activity (CD) value (IR?=?8.34, CD?=?2.75?μM), while 7 showed the most potent CD value of 1.12?μM. A dual acting compound 24 showed aromatase inhibition (IC₅₀?=?9.00?μM) as well as QR1 induction (CD?=?5.76?μM) activities. Computational docking studies using CDOCKER (Discovery Studio 3.5) provided insight in regard to the potential binding modes of 2-arylindoles within the aromatase active site. Predominantly, the 2-arylindoles preferred binding with the 2-aryl group toward a small hydrophobic pocket within the active site. The C-5 electron withdrawing group on indole was predicted to have an important role and formed a hydrogen bond with Ser478 (OH). Alternatively, meta-pyridyl analogs may orient with the pyridyl 3′-nitrogen coordinating with the heme group.     

Synthetic transformations of higher terpenoids. XXVI. 16-acetylaminomethyllabdanoids and their cytotoxicity

Coupling of methyl 16-aminomethyllambertianate with N-Boc-protected ω-amino acids resulted in 16-(N-Boc-aminononan)- and 16-(N-Boc-aminoundecan)amidomethyllabdanoids. Interaction of methyl aminomethyllambertianate with bicyclo[2.2.1]hept-5-en-2,3-dicarboxylic acid anhydride led to the amide of bicyclo[2.2.1]heptan-1,2-dicarboxylic acid with a labdanoid substituent. Reaction of methyl 16-aminomethyllambertianate with chloroacetyl chloride resulted in methyl 16-(chloroacetylaminomethyl)lambertianate; coupling of the latter with methyl esters of amino acids gave the corresponding amides of methyl lambertianate. The compounds obtained were more cytotoxic toward CEM-13, MT-4, and U-937 tumor cell lines as compared with lambertianic acid; the dose inhibiting tumor cell viability by 50% (CCID₅₀) of the more active compounds was 3.9–9.9 μM.     

Experimental and theoretical studies of the spatial distribution of the ionization rate in a non-self-sustained discharge controlled by a fast electron beam

The spatial distribution of the current density of fast electrons and the ionization rate in a gap filled with atmospheric-pressure air under the conditions of a non-self-sustained discharge controlled by a fast electron beam were investigated. The experiments were carried out in a gas-discharge chamber with a grid electrode arranged in parallel to the exit window of the ionization source. Spatial variations in the current density of fast electrons resulting from the grid were measured. The propagation of the electron beam through the discharge system was simulated numerically by the Monte Carlo method in the so-called “effective collision” approximation. The calculated results agree well with the experimental data.     

Experimental verification of the method for detection of water microleakages in plasma vacuum chambers by using the hydroxyl spectrum

Experimental determination of the sensitivity of the method for detection of water microleakages in the cooling systems of the plasma vacuum chambers of complex electrophysical devices (such as tokamaks, fuel elements of nuclear reactors, and plasmachemical reactors) is considered. It was shown that the spectroscopic method for detection of water microleakages by using the hydroxyl radiation spectrum makes it possible to detect leakages at a level of 10⁻⁵ Pa m³ s⁻¹. The spatial resolution of the method allows one to localize defects with an accuracy of several centimeters.     

Comparative study of powdered and microcrystalline cellulose samples of a various natural origins: Physical and chemical characteristics

This project studies the dependence of the physical and chemical properties of powdered cellulose on their natural origin and conditions of preparation. We studied the effect of chemical composition and properties of the original native cellulose on the general characteristics of the powdered and microcrystalline cellulose obtained from arboreal and herbaceous cellulose, which were prepared under identical conditions of hydrolysis.     

Dynamics of body mass and oxygen consumption in the ontogeny of the Spanish ribbed newt (<Emphasis Type=Italic>Pleurodeles waltl</Emphasis>): 2. Larval stage

The correlation between characteristics of growth and energy metabolism during the larval stage of development of the Spanish ribbed newt (Pleurodeles waltl) has been studied. During this period, its body mass is found to increase 140 times and the oxygen consumption rate, 77 times. The highest rate of specific body mass increase and oxygen consumption rate are noted in the early larval stage. Later, these characteristics decrease except for a brief period before completion of metamorphosis when the rate specific body mass increase rises. Comparison of the studied characteristics allows us to note a similar pattern in changes of the specific growth rate and the oxygen consumption rate during the premetamorphic development of the Spanish ribbed newt.