RETRACTED: Serebrovska et al. Intermittent Hypoxia-Hyperoxia Training Improves Cognitive Function and Decreases Circulating Biomarkers of Alzheimer's Disease in Patients with Mild Cognitive Impairment: A Pilot Study. Int. J. Mol. Sci. 2019, 20, 5405.

The journal Int [...].

Downregulation of lncRNAs Gomafu, NONMMUT033604.2, and NONMMUT064397.2 in the hippocampus of mice with model of post-traumatic stress disorder.

OBJECTIVES: Molecular mechanisms of post-traumatic stress disorder (PTSD) development have been analysed by evaluati-ng changes in the expression level of long non-coding RNA (lncRNA) as a potential biomarker of the disease and as one of the molecular aspects associated with the disease development. METHODS: In our study, we used quantitative polymerase chain reaction (qPCR) to evaluate changes in the expression level of long non-coding RNA - Gomafu, NONMMUT033604.2, and NONMMUT064397.2 - in the hippocampus of mice that were subjected to an artificially induced middle single prolonged stress (mSPS) model of post-traumatic stress disorder. RESULTS: We found a significant reduction in the expression levels of each of the three lncRNAs tested: Gomafu in 45.4 times, NONMMUT033604.2 in 53.4 times, and NONMMUT064397.2 in 5.2 times. The results of the present study provide evidence that the mSPS model effectively induces PTSD-like behaviour in mice leading to a significant decrease in the expression level of Gomafu, NONMMUT033604.2 and NONMMUT064397.2 lncRNA in mice hippocampus. CONCLUSIONS: This data provides evidence that the three studied lncRNAs could be potential biomarkers of PTSD development.

Hyperhomocysteinemia in men and women of married couples with reproductive disorders. What is the difference?

Hyperhomocysteinemia (HHcy) is an autosomal recessive inherited metabolic disease caused by variations in folate metabolism genes, characterized by impaired methionine metabolism and accumulation of homocysteine (Hcy) in the blood serum. It was shown that men usually have higher plasma Hcy levels than women, but have not yet assessed the leading factors of these differences, which is important for the development of personalized protocols for the prevention of folate metabolism disorders in couples with reproductive disorders. This study aimed to analyze the effect of intergenic and gene-factor interactions on the risk of developing HHcy in men and women of married couples with reproductive disorders. In our study were involved 206 married Caucasian couples (206 males and 206 females) from central regions of Ukraine with early pregnancy losses in the anamnesis. We found that the incidence of HHcy in men was significantly higher than in women. Gender differences in folic acid and vitamin B12 levels were identified. The best predictors of HHcy in men (MTRR (A66G), MTHFR (C677T), MTR (A2756G), vitamin B12 level) and in women (MTHFR (C677T), MTR (A2756G), vitamin B12 level) were selected by binary logistic regression. There was no significant difference in the distribution of genotypes by the studied gene variants when comparing men and women with HHcy. Our findings demonstrate that there is a gender difference in the development of HHcy. This difference is caused by intergenic interaction and by environmental factors, in particular, nutrition and vitamins consumption.

Treatment with omega-3 PUFAs does not increase the risk of CYP2E1-dependent oxidative stress and diabetic liver pathology.

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.

Intermittent Hypoxia-Hyperoxia Training Improves Cognitive Function and Decreases Circulating Biomarkers of Alzheimer's Disease in Patients with Mild Cognitive Impairment: A Pilot Study.

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 (Aß). 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, Aß 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 Aß expression and NETs formation one day after the end of three-week IHHT. Such effects on Aß 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.

MicroRNA-15a tissue expression is a prognostic marker for survival in patients with clear cell renal cell carcinoma.

None of the currently investigated molecular markers demonstrated sufficient accuracy in prognostication of the renal cell carcinoma (RCC) oncologic outcomes; thus, none of them has been recommended for the application in the routine clinical practice. The role of miR-15a as a potential prognostic marker for RCC is still not unveiled. The aim of our study was to assess the expression of miR-15a in tumor tissues of the patients with RCC and to evaluate the possibility of its usage as a prognostic molecular biomarker of this disease. The retrospective included 64 adult patients with clear cell RCC (ccRCC) in whom radical or partial nephrectomy was conducted. After deparaffinization of formalin-fixed paraffin-embedded (FFPE) ccRCC specimens, the tissue expression of miR-15a was measured using the reverse transcription and quantitative polymerase chain reaction in the real time. For the reference, the expression of miR-15a was estimated in 15 FFPE tissue specimens of the normal renal parenchyma. Survival analysis involved all cases of non-metastatic RCCs (n = 57). Five-year cancer-specific survival (CSS) was estimated by means of the Kaplan-Meier method and was calculated from the date of surgery to the date of death. Patients with the RCC were characterized by significantly upregulated tumor tissue mean levels of miR-15a compared to the healthy controls: 0.10 ± 2.62 relative units (RU) versus 4.84E - 03 ± 3.11E - 03 RU (p < 0.001). Overexpression of miR-15a was strongly associated with poor histologic prognostic features of ccRCC. Poorly differentiated tumors tend to have more pronounced upregulation of miR-15a compared to highly differentiated lesions: Mean expression values were 4.57 ± 3.19 RU for Fuhrman grade 4 versus 0.02 ± 0.01 RU for Fuhrman grade 1 (p < 0.001). The metastatic involvement of the regional lymphatic nodules (N +) was associated with significantly upregulated miRNA-15a in comparison with N - cases: Mean expression values were 4.92 ± 2.80 RU versus 1.10 ± 2.29 RU, respectively (p < 0.001). In patients with miR-15a expression in RCC tissues ≤ 0.10 RU, mean 5-year CSS was significantly longer compared to patients with expression levels above this threshold: 92.31% (mean duration of survival-59.88 ± 0.12 months) versus 54.8% (mean duration of survival-49.74 ± 2.16 months), respectively (p < 0.001). The tissue expression of miR-15a could be used as a potential prognostic molecular biomarker for conventional RCC.

Stress response factors as hub-regulators of microRNA biogenesis: implication to the diseased heart.

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.

Does proteasome regulate the level of microRNA-1 in cardiomyocytes? Application to anoxia-reoxygenation.

Proteasome and microRNAs play a critical role in almost all processes in a living organism, including pathology of the heart; however, their interaction is still in question. In the present study, we have found that proteasome inhibitor provoked increase of mature but not immature microRNA-1 in cultured cardiomyocytes, and tested the hypothesis that mature microRNA-1 can be a substrate for endonuclease activity of proteasome. In our in vitro experiments, we have found that proteasome fraction II is able to degrade both mature and primary but not precursor microRNA-1. However, this in vitro effect was not abolished by chemical inhibitor of proteolytic activities of proteasome. These data let us summarize that proteasome has the complex effect on the level of microRNA-1.