Intracellular Cholesterol Lowering as Novel Target for Anti‐Atherosclerotic Therapy

Atherosclerosis and disorders associated with cardiovascular system remain the major problem of modern medicine and the leading cause of mortality in developed countries. According to the current knowledge, atherosclerosis development can begin early in life. Clinically silent early‐stage lesions can be detected in a large population of young adults. Despite substantial progress in the recent years, therapy of atherosclerosis mostly remains limited to plasma lipid profile correction. Moreover, no therapy is currently available for the treatment of asymptomatic early stages of the disease. The existing synthetic drugs could not be used for this purpose, because of the unfavourable risk/benefit ratio and high cost of treatment, which has to be long‐lasting. In this regard, medications based on natural agents with anti‐atherosclerotic activity may offer interesting possibilities. Current research should focus on detection and evaluation of such agents. One of the important tools for anti‐atherosclerotic drug evaluation is a cell‐based model, which allows measurement of intracellular lipid accumulation. Anti‐atherosclerotic activity of various substances can therefore be evaluated by the decrease of intracellular lipid storage. In this chapter, we will discuss the development and application of cellular models based on primary culture of human arterial wall cells that are suitable for detection and measurement of anti‐atherosclerotic activity of various substances. Using these models, several natural agents have been successfully evaluated, which led to the development of pharmaceutical products with anti‐atherosclerotic activity based on botanicals

Lithium Experiment on Solar Neutrinos to Weight the CNO Cycle

The measurement of the flux of beryllium neutrinos with the accuracy of about 10% and CNO neutrinos with the accuracy 30% will enable to find the flux of pp-neutrinos in the source with the accuracy better than 1% using the luminosity constraint. The future experiments on \nu e- scattering will enable to measure with very good accuracy the flux of beryllium and pp-neutrinos on the Earth. The ratio of the flux of pp-neutrinos on the Earth and in the source will enable to find with very good accuracy a mixing angle theta solar. Lithium detector has high sensitivity to CNO neutrinos and can find the contribution of CNO cycle to the energy generated in the Sun. This will be a stringent test of the theory of stellar evolution and combined with other experiments will provide a precise determination of the flux of pp-neutrinos in the source and a mixing angle theta solar. The work on the development of the technology of lithium experiment is now in progress.Comment: Minor corrections, one reference added, 11 pages, 2 figures, talk given at NANP 2003, Dubna, Russia, June 200

Enhancement of keV X-rays from low-density cellulose triacetate (TAC) foam targets

The interaction of a high-power laser with a low-density foam target can in some instances result in a significant enhancement in x-ray generation relative to that when the same laser is incident upon a homogenous solid. In this paper, we present x-ray emission studies from foam targets where the density is varied from under-dense to over-dense. The targets are irradiated with the first harmonic of Nd:Glass laser. The laser intensity on the target was approximately 2 × 1014 W/cm2 with the pulse duration of 500 ps. Mass-matched cellulose triacetate foam targets with densities of 2 mg/cc, 4 mg/cc, 7 mg/cc, and 20 mg/cc were used. The areal density presented by the targets on the laser beam axis was held constant at 0.2 mg/cm2 by varying the target thickness in inverse proportion to the density. The x-ray yield in the spectral range (5-8 keV) and (4.5-16 keV) was found to be enhanced by approximately 2.3 times in foam targets with the density of 2 mg/cc (under-dense) compared with foam targets with the density of 20 mg/cc (over-dense)

X-ray tomography characterization of density gradient aerogel in laser targets

The low-density solid laser target characterization studies begun with the SkyScan 1074 computer microtomograph (CMT) [1, 2] are now continued with higher resolution of SkyScan 1174. The research is particularly focused on the possibility to obtain, control and measure precisely the gradient density polymers for laser target production. Repeatability of the samples and possibility to obtain stable gradients are analysed. The measurements were performed on the mm-scale divinyl benzene (DVB) rods.Publisher PDFPeer reviewe

Antimicrobial Resistance: A Risk Factor for the Biosafety System

Scientific relevance. In recent years, antimicrobial resistance in pathogenic microorganisms has become a global problem that threatens the health of humans and animals and poses a risk to the biosafety of Russia.Aim. The study aimed to analyse the prevalence of antimicrobial resistance, consider the risks and medical consequences of this biological phenomenon, and suggest ways to optimise the use of existing antimicrobial agents and search for new ones.Discussion. The emergence of antibiotic resistance in bacteria is a natural biological process; the selection of resistant microorganisms occurs constantly with the use of the entire spectrum of antimicrobial agents in healthcare, agriculture, and other fields. The World Health Organisation (WHO) monitors these processes using the Global Antimicrobial Resistance Surveillance System (GLASS). Russia has adopted the Strategy to prevent the spread of antimicrobial resistance in the Russian Federation to 2030. The country has established a regulatory framework that supports the operation of the national antimicrobial resistance prevention system. The strategy to prevent the spread of antimicrobial resistance is being implemented through making organisational arrangements and developing novel medicines with mechanisms of action based on an understanding of the molecular mechanisms of infection and resistance. This review considers the main approaches to designing exploratory studies and evaluating the antimicrobial activity of the innovative molecules obtained. The rapid development of synthetic biology increases the likelihood of creating synthetic biological pathogens with high virulence and resistance to antimicrobial agents, which might pose risks of artificial epidemics.Conclusions. The antimicrobial resistance prevention system in Russia should be considered a strategically essential medical technology ensuring the biosafety of the country and the people

Circulating Atherogenic Multiple-Modified Low-Density Lipoprotein: Pathophysiology and Clinical Applications

Low-density lipoprotein (LDL) circulating in human bloodstream is the source of lipids that accumulate in arterial intimal cells in atherosclerosis. In-vitro–modified LDL (acetylated, exposed to malondialdehyde, oxidized with transition metal ions, etc.) is atherogenic, that is, it causes accumulation of lipids in cultured cells. We have found that LDL circulating in the atherosclerosis patients’ blood is atherogenic, while LDL from healthy donors is not. Atherogenic LDL was found to be desialylated. Moreover, only the desialylated subfraction of human LDL was atherogenic. Desialylated LDL is generally denser, smaller, and more electronegative than native LDL. Consequently, these LDL types are multiply modified, and according to our observations, desialylation is probably the principal and foremost cause of lipoprotein atherogenicity. It was found that desialylated LDL of coronary atherosclerosis patients was also oxidized. Complex formation further increases LDL atherogenicity, with LDL associates, immune complexes with antibodies recognizing modified LDL and complexes with extracellular matrix components being most atherogenic. We hypothesized that a nonlipid factor might be extracted from the blood serum using a column with immobilized LDL. This treatment not only allowed revealing the nonlipid factor of blood atherogenicity but also opened the prospect for reducing atherogenicity in patients

A Lithium Experiment in the Program of Solar Neutrino Research

The experiments sensitive to pp-neutrinos from the Sun are very perspective for the precise measurement of a mixing angle $\theta_{12}$. A $\nu$e$^{-}$ scattering experiment (Xmass) and/or a charged-current experiment (the indium detector) can measure the flux of electron pp-neutrinos. One can find the total flux of pp-neutrinos from a luminosity constraint after the contribution of $^7$Be and CNO neutrinos to the total luminosity of the Sun are measured. The radiochemical experiment utilizing a lithium target has the high sensitivity to the CNO neutrinos, thus, it has a good promise for the precise measurement of a mixing angle and for the test of a current theory of the evolution of the stars.Comment: 6 pages, 2 figures, 1 table, A report made by A.Kopylov at International Conference NANP-2005, June 2005, Dubna, Russi

Use of Natural Products for Direct Anti-Atherosclerotic Therapy

Atherosclerosis and vascular disorders, which result from atherosclerosis, represent one of the major problems in the modern medicine and public health. Atherosclerosis is characterized by structural and functional changes of large arteries. The approaches for the treatment of atherosclerosis require at least the prevention of growth of atherosclerotic lesions and reduction in the lipid core mass, which would followed by plaque stabilization. Taken together, these approaches could theoretically result in the regression of arterial lesions. Atherosclerosis develops in the arterial wall and remains asymptomatic until ischemia of distal organs is evident. Therapy of clinical manifestations of atherosclerosis is largely aimed at reducing symptoms or affecting hemodynamic response and often does not affect the cause or course of disease, namely the atherosclerotic lesion itself. Of course, anti-atherosclerotic effects of statins revealed in many prospective clinical trials may be considered; however, statins have never been recognized as the drugs indicated just for direct treatment or prevention of atherosclerosis. They are used predominately in the course of hypolipidemic therapy, and the effects of treatment are estimated by success in reaching the target level of low density lipoprotein (LDL) cholesterol, but not the regression of atherosclerotic lesion or intimamedia thickness. The last should be considered as beneficial effect, which is mainly due to pleiotropic mechanisms of action. Atherosclerosis develops over many years, so anti-atherosclerotic therapy should be a long-term or even lifelong therapy. Tachyphylaxis, long-term toxicity and cost amongst other issues may present problems for the use of conventional medications in a long-term. Drugs based on natural products can be a good alternative

Small Dense Low-Density Lipoprotein as Biomarker for Atherosclerotic Diseases

Low-density lipoprotein (LDL) plays a key role in the development and progression of atherosclerosis and cardiovascular disease. LDL consists of several subclasses of particles with different sizes and densities, including large buoyant (lb) and intermediate and small dense (sd) LDLs. It has been well documented that sdLDL has a greater atherogenic potential than that of other LDL subfractions and that sdLDL cholesterol (sdLDL-C) proportion is a better marker for prediction of cardiovascular disease than that of total LDL-C. Circulating sdLDL readily undergoes multiple atherogenic modifications in blood plasma, such as desialylation, glycation, and oxidation, that further increase its atherogenicity. Modified sdLDL is a potent inductor of inflammatory processes associated with cardiovascular disease. Several laboratory methods have been developed for separation of LDL subclasses, and the results obtained by different methods can not be directly compared in most cases. Recently, the development of homogeneous assays facilitated the LDL subfraction analysis making possible large clinical studies evaluating the significance of sdLDL in the development of cardiovascular disease. Further studies are needed to establish guidelines for sdLDL evaluation and correction in clinical practice

The Interaction of Plasma Sialylated and Desialylated Lipoproteins with Collagen from the Intima and Media of Uninvolved and Atherosclerotic Human Aorta

We have evaluated the binding of sialylated and desialylated lipoproteins to collagen isolated from the proteoglycan and musculoelastic layers of intima and media of uninvolved human aorta and atherosclerotic lesions. Comparing various collagen preparations from the uninvolved intima-media, the binding of sialylated apoB-containing lipoproteins was best to collagen from the intimal PG-rich layer. Binding of sialylated apoB-containing lipoproteins to collagen from this layer of fatty streak and fibroatheroma was 1.4- and 3.1-fold lower, respectively, in comparison with normal intima. Desialylated VLDL versus sialylated one exhibited a greater binding (1.4- to 3.0-fold) to all the collagen preparations examined. Desialylated IDL and LDL showed a higher binding than sialylated ones when collagen from the intimal layers of fibroatheroma was used. Binding of desialylated HDL to collagen from the intimal PG-rich layer of normal tissue, initial lesion, and fatty streak was 1.2- to 2.0-fold higher compared with sialylated HDL