Changes induced in mouse lipid metabolism by simultaneous impact of antisense oligonucleotide derivatives to <i>apoB</i>, <i>PCSK9</i>, and <i>apoCIII</i> mRNAs

Development of new drugs able to decrease the level of “bad” cholesterol, in particular, based on antisense oligonucleotide derivatives (ASOs), remains relevant for the patients with familial hypercholesterolemia and/or intolerant to statins. The goal of the work was to assess the changes in the lipid metabolism caused by variants of joint impact of the ASOs targeted to the mRNAs of its key genes: apoB, PCSK9, and apoCIII. Female C57BL/6J mice; nuclease-protected 13- and 20-nucleotide ASOs, and standard protocols for quantification of lipoproteins (HDL CHL, non-HDL CHL, and total CHL) and ALT in the blood serum were used in the work. The following combinations of ASOs were four times injected to the mouse caudal vein: 1) ASO to apoB, 2) ASO to apoCIII, 3) ASO to apoB and ASO to PCSK9, 4) ASO to apoB, ASO to PCSK9, and ASO to apoCIII, 5) ASO to apoB (three doses), ASO to PCSK9, and ASO to apoCIII (two doses), 6) ASO to PCSK9 and (ASO to apoCIII – only in the fourth administration). Triple weekly administration of these ASO combinations resulted in a decrease in non-HDL CHL by 25, 16, 35, 47, 60, and 7 %, respectively, as compared with the control and 1.8-, 1.5-, 1.9-, 2.4-, 3.1, and 1.24-fold higher HDL CHL/ non-HDL CHL ratio. The subsequent ASO injection with concurrent switching to a high-fat diet after 1 week resulted in a decrease in the non-HDL CHL by 28, 2, 28, 70, 33, and 49 % for ASOs (1–6), respectively, as compared with the control; the HDL CHL/non-HDL CHL ratio was 1.5-, 1.1-, 2-, 3.7-, 1.9-, and 2-fold better. The ALT concentration for all ASO combinations remained within the norm for the control animals, demonstrating the absence of any hepatotoxic effect. The best efficiency of ASOs requires selection of concentrations for single ASOs and their combinations as well as of the order and timing of administration. Thus, a new antisense approach is proposed

Половозрастные особенности распространенности метаболически здорового фенотипа ожирения

Aim. The study objective was to assess the age and gender characteristics of the metabolically healthy obesity phenotype (MHO) prevalence, taking into account various classifications.Materials and methods. The materials used are the cross-sectional studies of the population cohort (Health, Alcohol and Psychosocial factors in Eastern Europe (HAPIEE) project, Novosibirsk), with the total of 3,197 people, among them 857 men (26.8%) and 2,340 women (73.2%), with BMI ≥30 kg/m². The MHO is defined according to different classifications: 1. IDF (International Diabetes Federation, 2005) – Waist circumference (WC) ≥ 94 cm in men and ≥80 cm in women and one or none of the components of metabolic syndrome (MS); 2. NCEP ATP III (the National Cholesterol Education Program Adult Treatment Panel III, 2001) in the presence of 2 and / or less components of the metabolic syndrome and 3. RSC (The Royal Society of Chemistry) – the index of waist circumference / hip circumference (WC / HC) ≤0.9 in men and ≤0.85 in women.Results. According to IDF the frequency of MHO in the group was 23.2%; NCEP ATP III – 41.8; RSC criteria – 27.1%. The frequency of MHO was higher in women than in men, and it significantly decreased with the age in women population. In all classifications, increased average blood pressure (BP) level, with normal average values of the level of triglycerides (TG) and high-density lipoprotein (HDL) is typical for persons with MHO. The surveyed according to the RSC criteria people with MHO demonstrate higher frequency levels of all cardio metabolic risk factors than those surveyed with the use of other criteria of MHO.Conclusion. The frequency of MHO varies depending on the used classification. In women, the frequency of MHO is reliably higher than in men. With the age, a significant reduction of the frequency of MHO in women is manifested. The frequency of arterial hypertension and abdominal obesity, the level of fasting blood glucose and LDL (low density lipoprotein), hypertriglyceridemia is higher in persons with MHO according to the criteria RSC.Цель. Изучить половозрастные особенности метаболически здорового фенотипа ожирения (МЗФО).Материалы и методы. Использованы материалы кросс-секционного исследования популяционной когорты (проект HAPIEE, г. Новосибирск) (n = 3 197 человек, среди них 857 (26,8%) мужчин и 2 340 (73,2%) женщин, с индексом массы тела (ИМТ) ≥30 кг/м²). МЗФО определен в соответствии с различными классификациями: 1) IDF (2005) – окружность талии (ОТ) ≥94 см у мужчин и ≥80 см у женщин и любой компонент метаболического синдрома (МС) по IDF или без него; 2) NCEP ATP III (2001) при наличии 2 и (или) менее компонентов МС; 3) критерии РКО (2017) – индекс окружность талии / окружность бедер (ОТ / ОБ) ≤0,9 у мужчин и ОТ / ОБ ≤ 0,85 у женщин.Результаты. Среди лиц с ожирением частота МЗФО по критериям IDF – 23,2%; NCEP ATP III – 41,8%; РКО – 27,1%. Частота МЗФО выше у женщин, чем у мужчин, и она значимо снижается с возрастом в женской популяции. Для лиц с МЗФО по всем классификациям характерно повышенное среднее значение артериального давления при нормальных средних значениях уровня триглицеридов и холестерина липопротеидов высокой плотности. Обследованные с МЗФО по критериям РКО демонстрируют более высокие показатели частоты всех изучаемых кардиометаболических факторов риска, чем при использовании других критериев МЗФО.Выводы. Частота МЗФО варьирует в зависимости от используемой классификации. У женщин частота МЗФО достоверно выше, чем у мужчин. С возрастом отмечается значимое снижение частоты МЗФО у женщин. Частота артериальной гипертонии, абдоминального ожирения, уровень глюкозы крови натощак, холестерина липопротеидов низкой плотности и гипертриглицеридемия выше у лиц с наличием МЗФО по критериям РКО

INCREASED LDLP SENSITIVITY TO OXIDATION AS A RISK FACTOR FOR ATHEROSCLEROSIS

Increased LDLP sensitivity to oxidation as a risk factor for atherosclerosis

Association of SP-A and SP-D Surfactant Proteins with the Severity of CommunityAcquired Pneumonia

Relevance. In current clinical practice, there is a need for research to find new diagnostic tests for the purpose of determining the patients with the highest risk of death from pneumonia. Surfactant proteins SP-A and SP-D play a key role in the pathogenesis of the response to microbial invasion of lung tissue, which participate in a cascade of reactions of both innate and adaptive immunity, and therefore proteins SP-A and SP-D may be considered as markers of the severity of community-acquired pneumonia (CAP).Aim of study. To evaluate the associations of surfactant proteins SP-A and SP-D in blood plasma with the severity of CAP.Material and methods. The study included 247 patients admitted to the therapeutic department. The group of patients with CAP (n=188) was divided into groups of severe (n=103) and non-severe (n=85) pneumonia. The comparison group (n=59) consisted of patients without acute and chronic diseases of the bronchi and lungs. The mean age (years, Me, 25th; 75th percentile) of patients was 55 (47; 68), 55 (47; 70), and 61 (37; 63) years, respectively. All patients underwent clinical, functional, diagnostic and laboratory studies (including determination of the content of SP-A and SP-D proteins by enzyme immunoassay).Results. In the group of patients with severe pneumonia unlike mild pneumonia, and group of comparison higher levels of proteins SP-A and SP-D were observed. Correlation analysis described below revealed statistically significant connection: protein SP-D — direct relation with leukocyte levels (r=0.320, p&lt;0.0001), erythrocyte sedimentation rate (r=0.331, p&lt;0.0001), inverse relation with blood oxygen saturation (r=-0.407, p&lt;0.0001), for SP-A protein — direct relation with body temperature (r=0.355, p&lt;0.0001), erythrocyte sedimentation rate (r=0.369, p&lt;0.0001) in the blood C-reactive protein (r=0.446, p&lt;0.0001), SP-D (r=0.357, p&lt;0.0001), and also relation with the duration of clinical symptoms (r=0.528, p&lt;0.0001) and blood oxygen saturation (r=-0.401, p&lt;0.0001). When conducting ROCanalysis for the surfactant protein SP-A, the area under the ROC- curve was 0.70, the optimal sensitivity for severe pneumonia was 68%, the specificity was 69% at the SP-A level in blood plasma equal to 42.9 ng/ml. When performing ROC analysis for the surfactant protein SP-D, the area under the ROC curve was 0.64 for severe pneumonia, the optimal sensitivity was 62%, and the specificity was 62% at the SP-D content in blood plasma equal to 319.2 ng/ml.Conclusion. According to the results of this study, the SP-A and SP-D proteins are associated with clinical and laboratory signs that reflect the severity of CAP. Thus, SP-A and SP-D are new laboratory markers of CAP severity

P83

To evaluate the clinical symptoms in pancreatic cancer patients (PCa) and compare some biochemical blood serum parameters in patients with different pathology of the pancreas (PCa, acute (OP) and chronic pancreatitis (CP)). Materials and methods: During a one-time clinical research on the type of “series of cases” 130 patients were examined (42 patients with OP, 81 – CP and 7 patients with PCa). The diagnosis of PCa, OP, CP was verified by clinical and instrumental methods. Glucose, cholesterol, triglyceride and bilirubin serum levels were determined by ELISA. Results: The mean age of patients with PCa was 63.6 ± 4.9 years, morbidity duration of PCa – 3.5 ± 1.1 months. Among patients with PCa, 83.3% of people – smoked, 16.7% – smoked every day. Half of the respondents PCa patients noted that over the last year they did not drink alcohol; 16.7% of people – drank alcohol several times a year, and 33.3% of patients consumed alcohol 1–2 times a month. BMI of PCa patients was equal to 26.3 ± 3.5 kg/m2, in OP patients – 23.8 ± 1.0 kg/m2, in CP patients – 26.3 ± 0.6 kg/m2, p > 0.05. In this case, 85.7% of PCa patients noted a significant decrease in body weight (11.7 ± 6.0 kg) for 3–4 months after the onset of symptoms. There was no pain in 42.8% of PCa patients, and frequent pain noted only in 28.6% of persons. Among CP patients, frequent and persistent pain noted in 65.5% of patients and among OP patients in 48.6% of cases. All PCa patients experienced pain in the right upper quadrant. Pain was of low intensity in 75% of cases and moderate in 25% of cases. Elimination of pain was observed in half of the PCa patients, and 1/4 of patients continued to experience pain. Episodes of nausea and vomiting noted in 25% of PCa patients. Bloated feeling in the stomach and overflow were noted in 42.8% of the all surveyed PCa persons. The level of glucose in PCa patients exceeded the normal limits and was significantly higher compared to that in OP and CP patients (8.5 ± 1.4 mmol/L, 5.4 ± 0.3 and 5.1 ± 0.1 mmol/L, respectively, p  0.05). However, the total cholesterol in CP patients was significantly higher than that in PCa and OP patients (5.8 ± 0.1, 5.0 ± 0.6 and 4.1 ± 0.2 mmol/L, p < 0.05). In PCa patients, the elevated levels of some markers of cholestasis and hepatocyte injury were also found: ALP – 185.0 ± 12.7 IU/L, ALT – 108.4 ± 33.5 IU/L, AST – 85.3 ± 31.5 IU/L, amylase – 44.9 ± 14.9 IU/L, fibrinogen – 2696.6 ± 398.6 g/L. Conclusion: The combination of nonspecific clinical signs (pain, dyspepsia) with biochemical markers of biliary pathology and endocrine pancreatic insufficiency – of PCa patients demonstrates the obligatoriness of differential diagnostic pancreatic and biliary pathology in their earlier stages

Assessment of calcification of the coronary arteries and long-term prognosis of cardiovascular disease

Vascular calcification is a distinctive feature of cardiovascular diseases of atherosclerotic origin. Visualization of calcifications is carried out by invasive and non-invasive methods. Knowledge of the presence and degree of calcification can predict clinical outcomes in patients at high risk of coronary events, help in the prevention and treatment of coronary heart disease.The article presents a brief description of the methods of visualization of vascular calcium and a review of studies on the relationship of calcification with the risk of long-term adverse cardiovascular events

Associations of polyphenolic compounds consumption and the risk of dyslipidemia in the Siberian population

Aim. To identify associations of polyphenols consumption in general, as well as their classes with the risk of dyslipidemia in the population of Novosibirsk aged 45-69.Material and methods. In 2003-2005, in the frames of the HAPIEE international project “Determinants of cardiovascular diseases in Eastern Europe: a multicenter cohort study” the population sample aged 45-69 (9360 people, 4266 men and 5094 women, average age - 57.6 years) was examined in Novosibirsk. For the analysis of nutrition, a Food Frequency Questionnaire (FFQ) was used (141 product names). The content of polyphenolic compounds and their classes was evaluated using the European database Phenol-Explorer 3.6. The eating habits of the population and typically consumed foods were taken into account. The determination of total cholesterol and HDL cholesterol levels were carried out by enzymatic method. Hypercholesterolemia was diagnosed with cholesterol level greater than 5.0 mmol/l (190 mg/dL). Levels of HDL cholesterol &lt;1.0 mmol/l in men and &lt;1.2 mmol/l in women were considered as high-density lipoprotein hypocholesterolemia (hypoHDL-C). The concentration of low-density lipoprotein cholesterol was calculated with the Friedewald formula (1972). HyperLDL-C was diagnosed if level of LDL cholesterol was &lt;3.0 mmol / l.Results. The chance of developing of hypercholesterolemia in the quartile with the highest consumption of “other polyphenols” was 20% less (OR 1.2 confidence interval (CI 1.01-0.14), p = 0.033), phenolic acids by 20% (OR 1.2 (CI 1.01-1.42), p = 0.04) and stilbenes by 37% (OR 1.37 (CI 1.15-1.64), p = 0.001) less than in the quartile of low consumption. The risk of developing hypoHDL-C was lower in the quartile of high polyphenols consumption in general by 18% (OR 1.18 (CI 1.002-1.4), p = 0.051), phenolic acids by 32% (OR 1.32 (CI 1.11-1.57), p = 0.001) and the groups of “other polyphenols” by 20% (OR 1.2 (CI 1.01-1.41), p = 0.04). The chance of hyperLDL-C in the high quartile of consumption of “other polyphenols” decreased by 16% (OR 1.16 (CI 1.002-1.355), p = 0.049) and lignans - by 33% (OR 1.33 (CI 1.14-1, 56), p &lt;0.001) compared with low consumption.Conclusion. Thus, the consumption of polyphenols in general and in classes (phenolic acids, stilbenes, and “other polyphenols”) decreased the risk of dyslipidemia in Siberian population