The Role of Natural Low Molecular Weight Dicarbonyls in Atherogenesis and Diabetogenesis.

This review summarises the data from long-term experimental studies and literature data on the role of oxidatively modified low-density lipoproteins (LDL) in atherogenesis and diabetogenesis. It was shown that not "oxidized" (lipoperoxide-containing) LDL, but dicarbonyl-modified LDL are atherogenic (actively captured by cultured macrophages with the help of scavenger receptors), and also cause expression of lectin like oxidized low density lipoprotein receptor 1 () and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 1 () genes in endotheliocytes, which stimulate apoptosis and endothelial dysfunction. The obtained data allowed us to justify new approaches to pharmacotherapy of atherosclerosis and diabetes mellitus.

Dicarbonyl-Modified Low-Density Lipoproteins Are Key Inducers of LOX-1 and NOX1 Gene Expression in the Cultured Human Umbilical Vein Endotheliocytes.

Expression of LOX-1 and NOX1 genes in the human umbilical vein endotheliocytes (HUVECs) cultured in the presence of low-density lipoproteins (LDL) modified with various natural dicarbonyls was investigated for the first time. It was found that among the investigated dicarbonyl-modified LDLs (malondialdehyde (MDA)-modified LDLs, glyoxal-modified LDLs, and methylglyoxal-modified LDLs), the MDA-modified LDLs caused the greatest induction of the LOX-1 and NOX1 genes, as well as of the genes of antioxidant enzymes and genes of proapoptotic factors in HUVECs. Key role of the dicarbonyl-modified LDLs in the molecular mechanisms of vascular wall damage and endothelial dysfunction is discussed.

Differences in Structural Changes and Pathophysiological Effects of Low-Density Lipoprotein Particles upon Accumulation of Acylhydroperoxy Derivatives in Their Outer Phospholipid Monolayer or upon Modification of Apoprotein B-100 by Natural Dicarbonyls.

Nanoparticles of the lipid-transporting system of the organism, low-density lipoproteins (LDL) of blood plasma, are prone to free radical peroxidation with formation of their main modified forms - oxidized LDL itself (containing hydroperoxy-acyls in phospholipids of the outer layer of particles) and dicarbonyl-modified LDL (apoprotein B-100 in which chemically modified via the Maillard reaction). Based on the study of free radical oxidation kinetics of LDLs, it was found that the existing in the literature designation of "oxidized lipoproteins" is incorrect because it does not reveal the nature of oxidative modification of LDLs. It was shown in this study that the "atherogenic" LDLs (particles of which are actively captured by the cultured macrophages) are not the oxidized LDL (in which LOOH-derivatives of phospholipids are formed by enzymatic oxidation by C-15 lipoxygenase of rabbit reticulocytes), but dicarbonyl-modified LDLs.

Clearance and Utilization of Dicarbonyl-Modified LDL in Monkeys and Humans.

The kinetics of elimination of various dicarbonyl-modified low-density lipoproteins from the bloodstream of monkeys were investigated. The low-density lipoproteins (LDL) in the monkey blood plasma were isolated by density gradient ultracentrifugation and labeled in vitro with the fluorescent dye FITC; thereupon, they were modified with different natural low molecular-weight dicarbonyls: malondialdehyde (MDA), glyoxal, or methylglyoxal. The control native FITC-labeled LDL and dicarbonyl-modified FITC-labeled LDL were injected into the monkey's ulnar vein; thereafter, blood samples were taken at fixed time intervals during 24 h.

Adsorption of Acylhydroperoxy-Derivatives of Phospholipids from Biomembranes by Blood Plasma Lipoproteins.

It has been established that acylhydroperoxy derivatives of phospholipids from oxidized rat liver mitochondria are captured predominantly by LDL particles but not by HDL during co-incubation with blood plasma lipoproteins, which refutes the previously suggested hypothesis about the involvement of HDL in the reverse transport of oxidized phospholipids and confirms the possibility of different mechanisms of lipohydroperoxide accumulation in LDL during oxidative stress.

[The anti-ischemic and antioxidant activity of the pharmacological agonist of galanin receptor GalR2 and carnosine in in vitro and in vivo model systems].

Antioxidant and anti-ischemic properties of the pharmacological agonist of galanin receptor GalR2 WTLNSAGYLLGPβAH (Gal) and its C-terminal fragment, dipeptide carnosine (βAH), were studied in the model of regional ischemia and reperfusion of the rat heart in vivo in the dose range of 0.5-5.0 mg/kg and Cu²⁺-induced free radical oxidation of low density lipoproteins (LDL) of human plasma in vitro for peptide concentrations of 0.

Antioxidant Properties of Galanin and Its N-Terminal Fragments in in vitro and in vivo Oxidative Stress Modeling.

Antioxidant properties of rat galanin GWTLNSAGYLLGPHAIDNHRSFSDKHGLT-NH2 (Gal), N-terminal fragment of galanin (2-15 aa) WTLNSAGYLLGPHA (G1), and its modified analogue WTLNSAGYLLGPβAH (G2) were studied in vivo in the rat model of regional myocardial ischemia and reperfusion and in vitro in the process of Cu2+-induced free radical oxidation of human blood plasma low-density lipoproteins. Intravenous administration of G1, G2, and Gal to rats after ischemia induction reduced the infarction size and activities of the necrosis markers, creatine kinase-MB and lactate dehydrogenase, in blood plasma at the end of reperfusion. G1, G2, and Gal reduced formation of the spin adducts of hydroxyl radicals in the interstitium of the area at risk during reperfusion, moreover, G2 and Gal also reduced formation of the secondary products of lipid peroxidation in the reperfused myocardium.

[Impact of summer heat waves on key parameters of oxidative stress in patients with coronary artery disease].

Aim: To assess the impact of summer heat waves on key parameters of oxidative stress in patients with coronary heart disease.

Materials And Methods: We included 30 male patients aged 5213 years with stable angina pectoris of IIIII functional class with at least one coronary artery stenosis proved by angiography (ischemic group) in comparison with 10 male patients aged 487 years with no angiographic sings of significant coronary stenosis and without angina manifestation (non-ischemic group). The following parameters were studied: activity of superoxide dismutase (Cu,Zn-SOD), catalase (CAT), glutathione peroxidase (GSH-Px), the level of malondialdehyde (MDA) and MDA-modified low-density lipoproteins (MDA-LDL).

The Mechanisms of Cardiac Protection Using a Synthetic Agonist of Galanin Receptors during Chronic Administration of Doxorubicin.

The use of the anticancer drug doxorubicin (Dox) is limited by its cardiotoxic effect. The aim of this work was to study the effect of a new synthetic agonist of the galanin receptor GalR1-3 [βAla14, His15]-galanine (2-15) (G) on the metabolism, antioxidant enzyme activity, and cardiac function in rats with cardiomyopathy (CM) caused by chronic administration of Dox. Coadministration of peptide G and Dox significantly increased the fractional shortening (FS) and ejection fraction (EF) by an average of 30 ± 4% compared with the indices in the Dox group.

Galanin receptors activation modulates myocardial metabolic and antioxidant responses to ischaemia/reperfusion stress.

The mechanisms of protective action of the neuropeptide galanin and its N-terminal fragments against myocardial ischaemia/reperfusion (I/R) injury remain obscure. The aim of this work was to study effects of a novel peptide agonist of galanin receptors [βAla14, His15]-galanin (2-15) (G1) and the full-length galanin (G2) on energy and antioxidant status of the heart with acute infarction. The peptides were synthesized by the automatic solid phase method using Fmoc technology.

Oxidative and carbonyl stress as a factors of the modification of proteins and DNA destruction in diabetes.

Aim: To study the oxidative damage of biopolymers (proteins and nucleic acids) in blood of patients with type 2 diabetes mellitus (DM).

Materials And Methods: In the blood of 50 patients with DM and 25 patients without disorders of carbohydrate metabolism were estimated: the level of oxidized low-density lipoprotein (oxLDL) by immunochemical method, the content of SH-groups in plasma proteins, the activity of Cu, Zn-superoxide dismutase (SOD) in erythrocytes, the length of telomere in leukocyte DNA, the level of 8-hydroxy-2'-deoxygunosine (8-oxo-dG) in plasma and urine.

Results: It is shown that in DM patients the level of oxLDL increases and the content of SH-groups in proteins and peptides of the blood plasma decreases, which indicates the development of oxidative stress.

Methylglyoxal as a scavenger for superoxide anion-radical.

Methylglyoxal at a concentration of 5 mM caused a significant inhibition of superoxide anion radical (O2 (·-)) comparable to the effect of Tirone. In the process of O2 (·-) generation in the system of egg phosphatidylcholine liposome peroxidation induced by the azo-initiator AIBN, a marked inhibition of chemiluminescence in the presence of 100 mM methylglyoxal was found. At the same time, methylglyoxal did not inhibit free radical peroxidation of low-density lipoprotein particles, which indicates the absence of interaction with methylglyoxal alkoxyl and peroxyl polyenoic lipid radicals.

Fructose as an inducer of free radical peroxidation of natural lipid-protein supramolecular complexes.

D-fructose strongly stimulates peroxidation of natural lipid-protein supramolecular complexes in vitro regardless of the oxidation initiation method. Fructose (ketose) intensifies free radical peroxidation to a much greater extent than glucose (aldose), which is important for the etiology and pathogenesis of diabetes mellitus.

[Registration of the protein in the serum with a field-effect nanotransistor biosensor].

A method for detection of cancer-associated protein D-NFATc1 in serum using nanowire (NW) biosensor based on field-effect nanotransistor is developed. Field-effect nanotransistor was fabricated on the basis of «silicon-on-insulator» structures. For the biospecific detection of target protein, the NW surface was modified with aptamers against the target protein.

[Impact of a cold wave on disease course, hemodynamics, carbohydrate metabolism, and blood rheological properties in cardiac patents].

Aim: To study the impact of cold waves on disease course, hemodynamics, lipid and carbohydrate metabolisms, oxidative stress, and blood rheological properties in patients with cardiovascular diseases (CVD).

Subjects And Methods: 24 men and 36 women (their mean age was 62.9±9.

Antioxidant Action of Apelin-12 Peptide and Its Structural Analog In Vitro.

The effects of C-terminal fragment of natural peptide apelin-12 H-Arg-Pro-Arg-Leu-Ser-His-Lys-Gly-Pro-Met-Pro-Phe-OH (A12) and its structural analog H-(N(α)Me)Arg-Pro-Arg-Leu-Ser-His-Lys-Gly-Pro-Nle-Pro-Phe-OH (AI) on Cu(2+)-induced free radical oxidation of low-density lipoprotein in human blood plasma and activity of commercially available enzymes superoxide dismutase and catalase in a concentration range of 0.01-1 mM were examined. A12 and AI had no effect on superoxide dismutase and catalase activities during 24-h co-incubation with these enzymes at 4°C.

Aldehyde inhibition of antioxidant enzymes in the blood of diabetic patients.

Background: The aim of the present study was to examine the effect of aldehyde modification on antioxidant enzyme activity in diabetic patients.

Methods: The activity of commercially available antioxidant enzymes (catalase, glutathione peroxidase [GPx], and Cu,Zn-superoxide dismutase [SOD]) was determined in vitro prior to and after aldehyde modification. The activity of erythrocyte Cu,Zn-SOD was assayed in blood drawn from healthy donors, diabetic patients with decompensated carbohydrate metabolism, and diabetic patients after glucose-lowering therapy.

[Using meldonium to improve the adaptation of patients with cardiovascular disease to the effects of heat and correction of associated oxidative stress].

Given that prolonged exposure to extreme climatic situations may play a role independent of stress factors, influencing the course of the underlying disease, the authors considered appropriate assessment of the effectiveness of additional prophylactic administration of drugs that increase the body's resistance to stress (adaptogens). The purpose of the study - to evaluate the effect of oxidative stress on meldonium, hemodynamics and quality of life of patients with cardiovascular disease (CVD) in extreme climatic conditions (summer heat). The study included 56 patients with CVD aged 38-75 years.

The initiation of free radical peroxidation of low-density lipoproteins by glucose and its metabolite methylglyoxal: a common molecular mechanism of vascular wall injure in atherosclerosis and diabetes.

It was found that glucose in the range of concentrations 12.5-100 mM stimulated Cu(2+)-mediated free radical peroxidation of low-density lipoproteins (LDL) from human blood plasma. Considering the kinetic parameters of LDL peroxidation we proposed that intensification of this process may be caused by formation of free radical intermediates of glucose auto-oxidation.

Apelin-12 and its structural analog enhance antioxidant defense in experimental myocardial ischemia and reperfusion.

This study investigated the effects of peptide apelin-12 (H-Arg-Pro-Arg-Leu-Ser-His-Lys-Gly-Pro-Met-Pro-Phe-OH, A12) and its novel structural analog (H-(N(α)Me)Arg-Pro-Arg-Leu-Ser-His-Lys-Gly-Pro-Nle-Pro-Phe-OH, AI) on myocardial antioxidant enzyme activities, lipid peroxidation, and reactive oxygen species formation in ex vivo and in vivo models of myocardial ischemia/reperfusion (I/R) injury. Isolated working rat hearts were subjected to global ischemia and reperfusion. Infusion of 140 μM A12 or AI before global ischemia improved cardiac function recovery; increased the activity of Cu,Zn superoxide dismutase (Cu,Zn SOD), catalase (CAT), and glutathione peroxidase (GSH-Px); decreased malondialdehyde (MDA) content in reperfused heart; and reduced the formation of hydroxyl radical adduct of the spin trap 5,5-dimethyl-1-pyrroline-N-oxide in the myocardial effluent during early reperfusion compared with these indices in control.

[Antioxidant properties of apelin-12 and its structural analogue in experimental ischemia and reperfusion].

Effects of apelin-12 H-Arg-Pro-Arg-Leu-Ser-His-Lys-Gly-Pro-Met-Pro-Phe-OH (A12) and its modified analogue H-(NMe)Arg-Pro-Arg-Leu-Ser-His-Lys-Gly-Pro-Nle-Pro-Phe-OH (I) on activity of antioxidant enzymes, formation of malonic dialdehyde (MDA) and generation of reactive oxygen species (ROS) were studied in ex vivo and in vivo models of myocardial ischemia and reperfusion (I/R) injury in Wistar rats. Preischemic infusion of peptide A12 or AI enhanced cardiac function recovery of isolated perfused heart and was accompanied by a marked attenuation of ROS generation detected by electron paramagnetic resonance (EPR) technique in myocardial effluent at early reperfusion compared with control. Intravenous administration (i.

[The influence of natural dicarbonils on the antioxidant enzymes activity in vitro and in vivo].

Natural dicarbonyls, which may be accumulated during oxidative stress in atherosclerosis (e.g. malondialdehyde) or carbonyl stress in diabetes mellitus (glyoxal and methylglyoxal) effectively inhibited the activities of commercial preparations of antioxidant enzymes: catalase, Cu, Zn-superoxide dismutase (Cu, Zn-SOD) and Se-contained glutathione peroxidase from human and bovine erythrocytes and also rat liver glutathione-S-transferase.

[Suppression of viability of staphylococci cells by 1270 nm laser beam].

Aim: Study the effect of 1270 nm wavelength laser exposure on the viability of Staphylococcus aureus and S. epidermidis cells in vitro.

Materials And Methods: Reference strain S.

[The influence of glucose on the free radical peroxidation of low density lipoproteins in vitro and in vivo].

It was shown that glucose in concentration 12.5-100 mM stimulated of Cu(2+)-mediated free radical peroxidation of low density lipoproteins (LDL) from human blood plasma. On the base investigation of kinetic parameters of LDL peroxidation it was stated that intensification of this process in the conditions of our experiments is caused by formation of free radical intermediates of glucose autoxidation during active oxygen species generation in the presence of metal ions with variable valence.

[The role of oxidative processes in augmentation of atherogenity of low density lipoprotein particles].

We investigated action of natural dicarbonyl compounds which are formed in atherosclerosis and diabetes on properties of low density lipoproteins (LDL) such as surface charge, conformational changes of apoB100, susceptibility to oxidation. and aggregation rate. It was found that malonic dialdehyde (MDA) compared with glyoxal and methylglyoxal is more effective modificating agent of protein part of LDL particle.