WO2012026850A1 - Procédé de test rapide d'athérogénicité du sang - Google Patents

Procédé de test rapide d'athérogénicité du sang Download PDF

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WO2012026850A1
WO2012026850A1 PCT/RU2011/000620 RU2011000620W WO2012026850A1 WO 2012026850 A1 WO2012026850 A1 WO 2012026850A1 RU 2011000620 W RU2011000620 W RU 2011000620W WO 2012026850 A1 WO2012026850 A1 WO 2012026850A1
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mmlp
pvp
serum
blood
buffer
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PCT/RU2011/000620
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Russian (ru)
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Батожаб Батожаргалович ШОЙБОНОВ
Валерия Юрьевна БАРОНЕЦ
Леонид Федорович ПАНЧЕНКО
Аслан Амирханович КУБАТИЕВ
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Учреждение Российской Академии Медицинских Наук Нии Общей Патологии И Патофизиологии Рамн
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Priority to EA201200991A priority Critical patent/EA201200991A1/ru
Publication of WO2012026850A1 publication Critical patent/WO2012026850A1/fr

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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/92—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving lipids, e.g. cholesterol, lipoproteins, or their receptors
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/32—Cardiovascular disorders
    • G01N2800/323—Arteriosclerosis, Stenosis
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/52—Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis

Definitions

  • the invention relates to clinical biochemistry, and can be used for rapid diagnosis of atherosclerosis at the preclinical stage.
  • Atherosclerosis is a chronic autoimmune disease of the arteries that occurs as a result of lipid metabolism disturbance and is accompanied by the deposition of lipids and macrophages in the intimal-medial layer of blood vessels. Deposits form in the form of atheromatous plaques. Subsequent growth of connective tissue in them (sclerosis), and calcium deposition lead to deformation and narrowing of the lumen of the arteries up to clogging. Every year, statistics inexorably notes an increase in indicators of morbidity and mortality from cardiovascular diseases, and in the first place, such as stroke and myocardial infarction. According to the forecast of the World Health Organization, mortality in the world from cardiovascular diseases by 2020 may reach 25 million people per year. Currently, against the backdrop of rapid progress in the development of new drugs for the treatment of atherosclerosis, there is an urgent need for new markers of atherogenesis, which could become a kind of measure of the effectiveness of the tested drugs and significantly reduce the test time.
  • Atherosclerotic plaques The formation of atherosclerotic plaques, platelet adhesion, the threat of thrombosis - a “pre-thrombotic” condition in atherosclerosis.
  • Violation of the blood supply to organs and tissues coronary heart disease, brain, acute myocardial infarction, strokes, etc.).
  • Atherosclerosis is made at stage 5, when a relatively healthy person aged 40 - 50 years develops complications of undiagnosed atherosclerosis in the form of acute stroke or myocardial infarction.
  • Modified (oxidized) lipoproteins are one of the key factors in atherosclerosis leading to cardiovascular disease (CVD), the leading cause of death in developed countries. Most CVDs are due to coronary arteriosclerosis.
  • CVDs cardiovascular disease
  • One of the key points in the pathogenesis of atherosclerosis is the intracellular accumulation of lipids in the proteoglycan layer of the intima of the arteries.
  • Low density lipoproteins isolated from the blood of patiens with coronary heart disease induce the accumulation of lipids in human aortic cells // Exp. Mol. Pathol.-1989.-V.50.-P.337-347).
  • mmLP multi-modified low-density lipoproteins
  • mmLP have a low content of sialic acids, mannose and other monosaccharides. It was shown that mmLP selectively bind and activate the C1 component of the complement system (Biro A., Thielens NM, Cervenak L., et al. Modified low density lipoproteins differentially bind and activate the CI complex of complement // Mol. Immunol.-2007.- V. 44, N ° 6 - P. l 169-1177). Oxidation-Modified Low Density Lipoproteins (OHLPs) are immunogenic and induce autoimmune response in humans.
  • OHLPs Oxidation-Modified Low Density Lipoproteins
  • Autoantibodies to oXLP are predominantly pro-inflammatory IgGl and IgG3 isotypes and, when the immune complex is formed, activate the classical complement system pathway and trigger phagocytosis by cells expressing Fey receptors (Saad AF, Virella G., Chassereau C, et al. OxLDL immune regulate complement and induce cytokine production by MonoMac 6 cells and human macrophages // J. Lipid Res - 2006.-V.47.-P.1875- 1983).
  • modified oxidized lipoproteins are enzyme-linked immunosorbent assays using monoclonal antibodies to oxLP, MDA-modified drugs, excessively glycosylated drugs ([Virella G., Derrick M.V., Pate V., et al. Development of capture assay for different modification of human low-density lipoprotein // Clinical and Diagnostic Lab. Immunol. 2005. -V. 12, jVe 1.- P.68-75).
  • reagent which is a mixture of 6 components: 0.2 M potassium phosphate, 0.12 M potassium iodide, 0.1 mM sodium azide, 2 g / l polyethylene glycol, 0.1 g / l alkylbenzyldimethylammonium chloride, HMM ammonium molybdate), 24 ⁇ M ethylenediaminetetraacetic acid, 20 ⁇ M butylated hydroxytoluene).
  • reagent which is a mixture of 6 components: 0.2 M potassium phosphate, 0.12 M potassium iodide, 0.1 mM sodium azide, 2 g / l polyethylene glycol, 0.1 g / l alkylbenzyldimethylammonium chloride, HMM ammonium molybdate
  • 24 ⁇ M ethylenediaminetetraacetic acid 20 ⁇ M butylated hydroxytoluene
  • LDL must be isolated from serum by ultracentrifugation. This operation takes a total of about 2 days;
  • Isolated LDL must be dialyzed from excess NaBr added during the isolation period for at least 8 hours;
  • the commercial preparation proposed in the prototype is a mixture of 6 reagents and is manufactured by Merk (Germany), Katal. No 14106.
  • the disadvantage of this method is the complexity, high cost, complexity, duration of the study (more than 2 days).
  • the objective of the invention is to develop a method that eliminates the above disadvantages, expanding the arsenal of methods for the early diagnosis of atherosclerosis for clinical diagnostic laboratories due to the simplification of technology, reducing the time of the procedure (up to 10 min), as well as its multiple cost reduction.
  • the problem is solved by adding a solution of polyvinylpyrrolidone (PVP) to human blood serum, determining the degree of turbidity of the serum solution by the turbidimetric method and calculating the content [mmLP] using the formula below.
  • PVP polyvinylpyrrolidone
  • the technical result obtained by the implementation of the invention is to expand the arsenal of reagents for the specific aggregation of mmLP, obtain a test system to determine the level of [mmLP], simplify, reduce the duration of the research procedure, as well as reduce its cost.
  • Buffer-1 for aggregation of mmLP is prepared by dissolving 10 g of PVP (relative molecular weight of 12600 ⁇ 2700) in 100 ml of 0.01 M Tris-HCl buffer, pH 7.4, containing 0.1 M NaCl. Buffer-2 differs from Buffer-1 in the absence of PVP. Buffer-1 is added to blood serum, mixed thoroughly, incubated, the degree of turbidity is measured spectrophotometrically and the level of [mmLP] is calculated by the formula: [mmLP], ED - [ ⁇ réelle - ⁇ ⁇ ] ⁇ 100, where:
  • [mmLP] the level of mmLP content in the experimental sample in arbitrary units (UNITS);
  • E is the optical density of the control sample, serum with the appropriate amount of buffer-2 without PVP (control buffer), units opt. pl .;
  • Example 1 Determination of the optimal concentration of PVP for the precipitation of mmLP in the blood serum of patients with cardiovascular diseases. 100-500 ⁇ l of a 10% solution of PVP in 0.01 M Tris-HC1 buffer, pH 7.4, containing 0.15 M NaCl, is added to 50 ⁇ l of the pulled blood serum from 10 patients with cardiovascular diseases (CVD). mix thoroughly and incubate at room temperature for 10 min in 9 well flat-bottomed cuvettes of the FP-901 biochemistry analyzer (Labsystem, Finland). The degree of turbidity is determined turbidimetrically at a wavelength of 450 nm. Serum samples with an appropriate amount of 0.01 M Tris-HC1 buffer, pH 7.4, containing 0, 15 M NaCl are used as the blank.
  • Example 2 Determination of cholesterol, triacylglyceride (TAG) and total proteins in PVP precipitates.
  • TAG triacylglyceride
  • the following experiments were performed to confirm the presence of mmLP in PVP precipitates. From 0.5 ml of the pulled serum of patients with coronary heart disease and control healthy donors, PVP precipitates were prepared under conditions of 8.9% PVP. The precipitate was precipitated by centrifugation at 6000 rpm for 20 min at 23 ° C. The supernatant was carefully decanted, the PVP precipitate was washed 2 times with 8.9%) PVP solution and resuspended in 0.5 ml of 0.01 M Tris-HC1 buffer, pH 7.4, containing 0.15 M NaCl. In the obtained PVP precipitates, the content of cholesterol, TAG, and total proteins was determined using reagents of the company Deacon-DS, Russia. The results are presented in table 3.
  • the cholesterol content in the PVP-precipitate of the pulsed serum of patients with coronary heart disease is 12 times higher, and the TAG is 16 times higher than in the PVP-precipitate from healthy donor serum.
  • the total protein content is 1, 3 times higher in PVP-precipitate patients.
  • Example 3 The selection of the optimal incubation time of a mixture of serum with PVP for the aggregation of mmLP. 400 ⁇ l of a 10% solution of PVP in 0.01 M Tris-HC1 buffer, pH 7.4 containing 0.15 M NaCl is added to 50 ⁇ l of the pulled serum of patients with coronary artery disease and healthy donors, and they are thoroughly mixed and incubated at room temperature for 10, 20 , 30 and 60 min in 9 well flat-bottomed cuvettes of biochemical analysis of the torus FP-901 ("Labsystem", Finland). The degree of turbidity is determined turbidimetrically at a wavelength of 450 nm.
  • Serum samples with an appropriate amount of 0.01 M Tris-HC1 buffer, pH 7.4, containing 0.1 M NaCl are used as the blank.
  • the results are shown in table 4.
  • the aggregation of mmLP proceeds for a maximum of 10 minutes. With further incubation, there is a slight aggregation of the residual amount of mmLP (approximately 8%).
  • the level of mmLP in the pulsed serum of healthy donors during an incubation of 60 min remains unchanged at the level of 8.3 PIECES.
  • Example 4 Determination of complement binding of guinea pig with mmLP precipitates as a function of concentration.
  • a solution of PVP-precipitate (4.3 mg / ml protein) prepared from the pulled serum of patients with coronary artery disease and diluted 1: 99 with VBS buffer.
  • 20 ⁇ l of a solution diluted 1: 19 of guinea pig complement are added.
  • the total volume was adjusted to 0.3 ml with VBS 2+ buffer and incubated for 20 min at 37 ° C.
  • 200 ⁇ l of sheep erythrocytes sensitized with rabbit antibodies (EA) were added and incubated for 30 min at 37 ° C.
  • mmLP precipitated in a solution of 8.9% PVP have complement-binding ability, and the effect is dose-dependent.
  • concentration of PVP 8.9%>
  • a decrease in the amount of precipitated cholesterol, TAG, proteins, as well as a complement of the binding activity of PVP precipitates is observed in the system (data not shown).
  • the determination of the complement-binding ability of the PVP precipitate indicates the presence of mmLP and the specific interaction of mmLP with the complement of guinea pig.
  • the determination of cholesterol, TAG and total proteins in the PVP precipitate at a concentration of 8.9%), as well as the maximum complement-binding ability confirms the optimal concentration of 8.9% PVP in the system for the specific aggregation of mmLP from the serum of patients with atherosclerotic disease.
  • Example 5 The effect of mmLP on platelet aggregation.
  • mmLPs were prepared under 8.9% PVP conditions as described in Example 2.
  • blood was obtained from the marginal vein of the rabbit ear in a 3.8% sodium citrate solution (9: 1 by volume). Centrifuged blood at 150 g for 10 min. The supernatant, which is a platelet-rich plasma (BTP) of blood, was used to analyze platelet aggregation.
  • BTP platelet-rich plasma
  • Platelet aggregation studies were carried out according to the Born method (Born GV Aggregation of blood platelets by ADP and its reversal // Nature. - 1962. - V. 194. - P.
  • O'Brien JR Platelet aggregation Part I
  • O'Brien JR Platelet aggregation Part II
  • Some resalts from a new method of study // J. Clin. Path. - 1962. - V.15, J4S 5 - P. 452-455 Some resalts from a new method of study // J. Clin. Path. - 1962. - V.15, J4S 5 - P. 452-455
  • the principle of the method is based on a change in the optical density of BTP upon the addition of aggregation inductors. During aggregation, the platelet suspension becomes more transparent and, due to a decrease in optical density, the light transmission increases. This is graphically displayed by the deviation of the curve from the zero line (0% aggregation) to 100% aggregation.
  • the degree of platelet aggregation under the action of mmLP was characterized by the value of V op / V k , where V op and B k are the change in light transmission of platelet-rich plasma containing mmLP and the control sample, respectively.
  • V op and B k are the change in light transmission of platelet-rich plasma containing mmLP and the control sample, respectively.
  • the PVP precipitate prepared from the serum of patients with coronary artery disease causes platelet hyperreactivity.
  • Example 6 The effect of concentration and incubation time mmLP on platelet aggregation. Definition: 0.25 ml of TBP was placed in an aggregometer cuvette, heated to 37 ° C for 1 min with constant stirring, and 0% aggregation was set. Increasing concentrations of mmLP preparation prepared from the serum of patients with coronary artery disease were added to the experimental sample, they were additionally incubated for 4 min and platelet aggregation was performed by the introduction of an ADP inducer (final concentration of 1.25 ⁇ M). Aggregation for 5 minutes was recorded. The results are presented in table 7.
  • the effect of enhancing platelet aggregation under the influence of mmLP 1) depends on the concentration, and the effect of saturation is observed; 2) preliminary incubation is practically not required for the binding of mmLP to platelets, which indicates a very high affinity and is most likely associated with the interaction of mmLP with scavenger receptors on the platelet membrane.
  • Example 7 The effect of serum storage on the level of mmLP.
  • the level of mmLP was determined by the proposed method on the day of blood sampling and after 7 days of storage at 4 ° C in the serum of patients with coronary artery disease and healthy donors. The results are presented in table 8.
  • the degree of turbidity was determined turbidimetrically at a wavelength of 450 nm. Serum samples with an appropriate amount of buffer-2 (0.01 M Tris-HCl buffer, pH 7.4, containing 0.15 M NaCl) were used as a blank. The levels of [mmLP] were calculated using the formula above. The results are shown in table 9.
  • the level of [mmLP] ranged from 1.1 to 9.9 units. and the average value was 4.59 ⁇ 2.58.
  • the content [mmLP] ranged from 9.9 to 37.1 units. and the average value was 21, 26 ⁇ 10.64 UE, which is 4.6 times more than the normal indicator. It should be noted that when using other biochemical analyzers in each laboratory, the range of normal values [mmLP] for the examined population should be specified.
  • mmLP have a pro-inflammatory effect due to the binding and activation of the complement system; b) mmLPs have a thrombogenic effect due to platelet hyperaggregation.
  • Example 9 Determination by rapid method of the optimal concentration of PVP to detect atherogenic plasma of patients with cardiovascular diseases.
  • citrated blood plasma of a person For the development of rapid determination used citrated blood plasma of a person. To 50 ⁇ l of the pulsed blood plasma from 10 patients with coronary heart disease (CHD), 100-800 ⁇ l of a 10% solution of PVP in 0.01 M Tris-HC1 buffer, pH 7.4, containing 0.15 M NaCl are added. mix thoroughly and incubate at room temperature for 10 minutes. The degree of turbidity of the solution is determined visually in comparison with the control sample and is estimated as weak turbidity - (+) and strong - (++++). As a control, use blood plasma samples with the appropriate amount buffer not containing PVP, and evaluated as - (-). The results are shown in table 10.
  • Example 10 Rapid determination of blood atherogenicity in patients with coronary heart disease and healthy donors.
  • Studies of the atherogenicity of blood plasma by the proposed express method were performed in 64 patients with coronary heart disease with instrumentally confirmed coronary artery atherosclerosis and 60 healthy donors (control group).
  • 400 ⁇ l of buffer-1 (10% PVP in 0.01 M Tris-HCl buffer, pH 7.4 containing 0, 15 M NaCl) was added to 50 ⁇ l of the studied blood plasma, thoroughly mixed and incubated at room temperature for 10 min in transparent test tubes. The degree of turbidity (atherogenicity) was determined visually in comparison with the control sample.
  • As a control used plasma samples with the appropriate amount buffer-2 (0.01 M Tris-HC1 buffer, pH 7.4, containing 0.1 M NaCl). The results are shown in table 12.
  • Example 11 The study of blood atherogenicity in 750 employees of the company "MOSENERGO" undergoing a routine medical examination. During the medical examination, blood was examined for glucose and lipid profile. Additionally, all employees were examined for blood atherogenicity by the developed method. Blood atherogenicity was detected in 288 (38.4%) relatively healthy employees. From the group with atherogenic blood (elevated mmLP), 21 people under the age of 40 years with normal lipid profiles were selected for further instrumental examination for changes in the intimal-medial layer of the carotid arteries. To assess the condition of the wall of the carotid arteries, high-resolution ultrafonography was used in the B mode using a linear vascular sensor with a frequency of 7.5 MHz.
  • the examination protocol included scanning the left and right carotid arteries and the area of the carotid sinus with focusing on the posterior wall of the arteries in three fixed projections - anterolateral, lateral and posterolateral. The examination was carried out in a prone position after a 15-minute rest. All measurements were performed sequentially for one session. The scanning procedure was recorded on a super-VHS PAL high-definition video recorder. Records were analyzed by a certified operator. The thickness of the intimal-medial layer of the carotid arteries was measured using the Prosound computer program (R. Seltzer, USA). The measurement was carried out on a section of the common carotid artery 10 mm long, opposite the beginning of the carotid sinus.
  • the thickness of the intimal-medial layer of the posterior wall of the common carotid artery was determined as the distance from the leading edge of the first echogenic zone to the leading edge of the second echogenic zone.
  • the average value of three measurements was considered as an integral indicator of the intimal-medial layer thickness.
  • the developed express method for determining blood atherogenicity allows one to detect earlier pre-atherosclerotic conditions at the stage of morphological changes in the intimal-medial layer of the carotid arteries. Subsequently, persons with instrumentally confirmed carotid atherosclerosis arteries were instrumentally examined for coronary arteriosclerosis and coronary arteriosclerosis was not detected.
  • the proposed method is simple, includes only 2 operations: mixing serum with a solution of PVP and registration of turbidity. To prepare the buffer, widespread reagents are needed: PVP, NaCl, and Tris-HCl.
  • PVP polyvinyl
  • NaCl aqueous cellulose
  • Tris-HCl aqueous cellulose
  • the method allows to detect the presence of mmLP directly in serum without prior fractionation. The method is fast (10 min for 1 analysis).
  • the use of a simple and quick method for determining blood atherosclerosis makes it possible to identify preclinical conditions of atherosclerosis, can serve as a specific biochemical marker for the treatment of atherosclerotic diseases, allows for an in-depth study of the pathogenesis of atherosclerosis, enables their early prevention and allows monitoring the effectiveness of the therapy.
  • the content of cholesterol, TAG and proteins in PVP-precipitates prepared from the pulled blood serum of patients with coronary artery disease and healthy donors
  • mmLP Atherogenicity

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Abstract

L'invention concerne la biochimie clinique et peut s'utiliser pour le test rapide d'athérogénicité du sang par l'agrégation de lipoprotéines du sang à modifications multiples. Ces lipoprotéines à modifications multiples sont agrégées dans un tampon comprenant 10% PVP 12600, avec un rapport plasma : tampon de 1 : 8. Le procédé permet de détecter les stades précliniques d'athérosclérose avant toute modifications morphologique du complexe intima-médian des artères brachio-céphaliques. Le système de test de l'invention peut s'utiliser également pour le contrôle de l'efficacité d'une thérapie de maladies artérioscléreuses.
PCT/RU2011/000620 2010-08-24 2011-08-16 Procédé de test rapide d'athérogénicité du sang WO2012026850A1 (fr)

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RU2501013C1 (ru) * 2012-07-26 2013-12-10 Батожаб Батожаргалович Шойбонов Способ определения минимально модифицированных липопротеинов низкой плотности в сыворотке или плазме крови человека
RU2497116C1 (ru) * 2012-08-10 2013-10-27 Батожаб Батожаргалович Шойбонов Способ определения атерогенности крови человека
RU2549467C1 (ru) * 2013-12-19 2015-04-27 Федеральное государственное бюджетное учреждение "Научно-исследовательский институт нормальной физиологии им. П.К. Анохина" Российской академии медицинских наук (ФГБУ "НИИНФ им. П.К. Анохина" РАМН) Способ определения атерогенности иммунных комплексов
RU2549466C1 (ru) * 2013-12-19 2015-04-27 Федеральное Государственное Бюджетное Учреждение "Нии Общей Патологии И Патофизиологии" Рамн Экспресс-способ определения атерогенности иммунных комплексов сыворотки крови человека
RU2696569C1 (ru) * 2018-11-15 2019-08-05 Федеральное государственное бюджетное образовательное учреждение высшего образования "Российский экономический университет им. Г.В. Плеханова" Способ определения атерогенной активности пищевых продуктов

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SU1467516A1 (ru) * 1986-07-14 1989-03-23 Белорусский Научно-Исследовательский Институт Туберкулеза Способ определени атерогенного нарушени липопротеинового спектра плазмы крови
RU94010187A (ru) * 1994-03-22 1996-09-27 Институт хирургии Восточно-сибирского научного центра СО РАМН Способ определения агрегационной способности атерогенных липопротеинов
MXPA06012139A (es) * 2004-04-20 2007-01-17 Kimberly Clark Co Sistema y metodo optico para determinar la distribucion de particulas de lipido en una muestra.

Patent Citations (3)

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SU1467516A1 (ru) * 1986-07-14 1989-03-23 Белорусский Научно-Исследовательский Институт Туберкулеза Способ определени атерогенного нарушени липопротеинового спектра плазмы крови
RU94010187A (ru) * 1994-03-22 1996-09-27 Институт хирургии Восточно-сибирского научного центра СО РАМН Способ определения агрегационной способности атерогенных липопротеинов
MXPA06012139A (es) * 2004-04-20 2007-01-17 Kimberly Clark Co Sistema y metodo optico para determinar la distribucion de particulas de lipido en una muestra.

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
M. EL-SAADANI ET AL.: "A spectrophotometric assay for lipid peroxides in serum lipoproteins using a commercially available reagent.", JOURNAL OF LIPID RESEARCH, vol. 30, 1989, pages 627 - 630 *

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