Alzheimer’s disease (AD) affects not only the central nervous system, but also peripheral blood cells including neutrophils and platelets, which actively participate in pathogenesis of AD through a vicious cycle between platelets aggregation and production of excessive amyloid beta (Aβ). Platelets adhesion on amyloid plaques also increases the risk of cerebral microcirculation disorders. Moreover, activated platelets release soluble adhesion molecules that cause migration, adhesion/activation of neutrophils and formation of neutrophil extracellular traps (NETs), which may damage blood brain barrier and destroy brain parenchyma. The present study examined the effects of intermittent hypoxic-hyperoxic training (IHHT) on elderly patients with mild cognitive impairment (MCI), a precursor of AD. Twenty-one participants (age 51–74 years) were divided into three groups: Healthy Control (n = 7), MCI+Sham (n = 6), and MCI+IHHT (n = 8). IHHT was carried out five times per week for three weeks (total 15 sessions). Each IHHT session consisted of four cycles of 5-min hypoxia (12% FIO2) and 3-min hyperoxia (33% FIO2). Cognitive parameters, Aβ and amyloid precursor protein (APP) expression, microRNA 29, and long non-coding RNA in isolated platelets as well as NETs in peripheral blood were investigated. We found an initial decline in cognitive function indices in both MCI+Sham and MCI+IHHT groups and significant correlations between cognitive test scores and the levels of circulating biomarkers of AD. Whereas sham training led to no change in these parameters, IHHT resulted in the improvement in cognitive test scores, along with significant increase in APP ratio and decrease in Aβ expression and NETs formation one day after the end of three-week IHHT. Such effects on Aβ expression and NETs formation remained more pronounced one month after IHHT. In conclusion, our results from this pilot study suggested a potential utility of IHHT as a new non-pharmacological therapy to improve cognitive function in pre-AD patients and slow down the development of AD.
Different allelic variants of genes that encode ATP-sensitive potassium (K ) channels' subunits may contribute to the development of heart failure. The purpose of the work to investigate SNPs in genes that encode K channels in relation to echocardiographic parameters in chronic heart failure (CHF) patients. Ninety-nine people with CHF of ischemic origin with left ventricular systolic dysfunction were examined. The control group is represented by 108 clinically healthy subjects. KCNJ11 polymorphisms Ile337Val and Glu23Lys, and ABCC8 polymorphism Ser1369Ala were genotyped using polymerase chain reaction. In CHF patients, the frequency of the Ile337Val genotype was: Ile/Ile, 40.4%; Ile/Val, 45.5%; and Val/Val, 14.1%. The patients with the Val/Val genotype had left ventricular (LV) mass that was 334.15 g, which was 27.3% (P < 0.05) lower versus Ile/Val patients (425.48 g). The index of this parameter was also significantly lower (28.4%, P < 0.05). In CHF patients, the frequency of Glu23Lys and Ser1369Ala was: Glu/Glu and Ser/Ser, 43.4%; heterozygote, 44.4%; Lys/Lys and Ala/Ala, 12.2%. The patients with the Lys/Lys and Ala/Ala genotypes had a significantly lower LV mass index and LV end-diastolic volume (22.9% and 26.8%, P < 0.05) versus heterozygotes. Thus, the greatest LV mass and LV end-diastolic volume values are associated with heterozygotes, while the smallest are associated with minor homozygotes.
Наведено результати визначення 10 поліморфізмів генів системи матриксного Gla-протеїну (ген MGP-T-138 →С (rs1800802), G-7 →A (rs1800801), Thr 83 →Ala (rs4236); ген VDR-FokI (rs2228570), BsmI (rs1544410), ApaI (rs7975232), TaqI (rs731236), ген GGCX-Arg 325 →Gln (rs699664), ген VKORС1-T 2255 →C (rs2359612), ген BMP-2-Ser 37 →Ala (rs2273073)) у 170 хворих з ішемічним атеротромботичним інсультом (ІАТІ) і 124 здорових індивідуумів (контрольна група). Встановлено, що існує зв'язок між ІАТІ і поліморфними варіантами генів MGP (G-7 →A) та VKORC1 (Т 2255 →С). Ризик розвитку ІАТІ у носіїв мінорного алеля A/A (G-7 →A-поліморфізм) у 2,6 вищий, ніж у носіїв основного алеля (G/A+G/G), а у осіб з генотипом С/С (Т 2255 →С-поліморфізм) у 2,2 раза більший, ніж у гомозигот за основним алелем. Збіг у пацієнтів генотипів T/C і G/G, C/C і G/A, а також генотипу A/A (G-7 →Aполіморфізм) із будь-яким з генотипів за Т 2255 →С-поліморфізмом збільшує ризик розвитку ІАТІ.
An increase in CYP2E1 expression is a key factor in the development of diabetic oxidative liver damage. Long-term treatment with omega-3 PUFAs, which are CYP2E1 substrates, may affect CYP2E1 expression in the liver. In this work, we performed Western blot analysis, biochemical methods, and microscopic ultrastructural studies of the liver in a streptozotocin-induced rat model of type 1 diabetes to investigate whether long-term treatment with omega-3 PUFAs could induce CYP2E1-dependent oxidative stress and diabetic liver pathology. Significant hyperglycemia and lack of natural weight gain were observed in the diabetic rats compared to non-diabetic controls. A 2.5-fold increase in CYP2E1 expression (protein content and activity) was also observed in the diabetic rats. In addition, signs of oxidative stress were found in the liver of the diabetic rats. A significant increase in transaminases and GGT level in blood serum was also observed, which could indicate marked destruction of liver tissue. Diabetic dyslipidemia (increased triacylglycerol levels and decreased HDL-C levels) was found. Treatment of the diabetic animals with an omega-3-enriched pharmaceutical composition of PUFAs had no effect on CYP2E1 levels but contributed to a two-fold decrease in enzyme activity. The intensity of lipid peroxidation also remained close to the diabetic group. However, at the same time, antioxidant protection was provided by induction of antioxidant enzyme activity. Examination of the liver ultrastructure revealed no characteristic signs of diabetic pathology. However, omega-3 PUFAs did not normalize blood glucose levels and serum lipid profile. Thus, long-term treatment of diabetic rats with omega-3 PUFAs does not increase the risk of CYP2E1-dependent oxidative stress and development of liver pathology but prevents some diabetic ultrastructural damage to hepatocytes.
MicroRNAs (miRNAs) are important regulators of heart function and then an intriguing therapeutic target for plenty of diseases. The problem raised is that many data in this area are contradictory, thus limiting the use of miRNA-based therapy. The goal of this review is to describe the hub-mechanisms regulating the biogenesis and function of miRNAs, which could help in clarifying some contradictions in the miRNA world. With this scope, we analyse an array of factors, including several known agents of stress response, mediators of epigenetic changes, regulators of alternative splicing, RNA editing, protein synthesis and folding and proteolytic systems. All these factors are important in cardiovascular function and most of them regulate miRNA biogenesis, but their influence on miRNAs was shown for non-cardiac cells or some specific cardiac pathologies. Finally, we consider that studying the stress response factors, which are upstream regulators of miRNA biogenesis, in the diseased heart could help in (1) explaining some contradictions concerning miRNAs in heart pathology, (2) making the role of miRNAs in pathogenesis of cardiovascular disease more clear, and therefore, (3) getting powerful targets for its molecular therapy.
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