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.

Investigation of the mechanisms of phenotypic realization of allelic polymorphism of the eNOS gene has shown that the level of eNOS mRNA and activity of this enzyme in platelets depends from genotype. We identified a T(-786)-->C polymorphism in the promoter region, a variable number of tandem repeats (4a/4b) in intron 4 and the G(894)-->T polymorphism in exon 7 of the eNOS gene in isolated human platelets. We measured eNOS mRNA in isolated platelets by reverse transcription-PCR and eNOS enzyme activity by fluorimetric detection system FCANOS-1 using diaminofluorescein diacetate (DAF-2A). It was shown that the level of eNOS mRNA is the lowest for the -786C/C promoter genotype. In exon 7 homozygotes (894T/T) the level of RNA is lower than in normal homozygotes (894G/G), but higher than in heterozygotes (894G/T). The eNOS activity in platelets is lower in carriers of the 786C/C promoter genotype than in normal homozygotes (2.1 times; P=0.03), and lower comparing to heterozygotes (2.9 times; P>0.05). The eNOS activity accompanying the 894T/T variant of exon 7 is also lower than in normal homozygotes (P>0.05). Regarding the polymorphism in intron 4 - the enzyme's activity is lower in carriers of the 4a/4a genotype comparing to normal homozygotes (1.7 times; P>0.05) and lower than in heterozygotes (1.9 times; P>0.05). These results allow one to conclude that the T(-786)-->C polymorphism of the eNOS gene promoter most significantly affects the gene expression and eNOS activity.

Asthma and hypertension are complex diseases coinciding more frequently than expected by chance. Unraveling the mechanisms of comorbidity of asthma and hypertension is necessary for choosing the most appropriate treatment plan for patients with this comorbidity. Since both diseases have a strong genetic component in this article we aimed to find and study genes simultaneously associated with asthma and hypertension. We identified 330 shared genes and found that they form six modules on the interaction network. A strong overlap between genes associated with asthma and hypertension was found on the level of eQTL regulated genes and between targets of drugs relevant for asthma and hypertension. This suggests that the phenomenon of comorbidity of asthma and hypertension may be explained by altered genetic regulation or result from drug side effects. In this work we also demonstrate that not only drug indications but also contraindications provide an important source of molecular evidence helpful to uncover disease mechanisms. These findings give a clue to the possible mechanisms of comorbidity and highlight the direction for future research.

Upregulation of Ca2+-permeable AMPA receptors (CP-AMPARs) in dorsal horn (DH) neurons has been causally linked to persistent inflammatory pain. This upregulation, demonstrated for both synaptic and extrasynaptic AMPARs, depends on the protein kinase C alpha (PKCα) activation; hence, spinal PKC inhibition has alleviated peripheral nociceptive hypersensitivity. However, whether targeting the spinal PKCα would alleviate both pain development and maintenance has not been explored yet (essential to pharmacological translation). Similarly, if it could balance the upregulated postsynaptic CP-AMPARs also remains unknown. Here, we utilized pharmacological and genetic inhibition of spinal PKCα in various schemes of pain treatment in an animal model of long-lasting peripheral inflammation. Pharmacological inhibition (pre- or post-treatment) reduced the peripheral nociceptive hypersensitivity and accompanying locomotive deficit and anxiety in rats with induced inflammation. These effects were dose-dependent and observed for both pain development and maintenance. Gene-therapy (knockdown of PKCα) was also found to relieve inflammatory pain when applied as pre- or post-treatment. Moreover, the revealed therapeutic effects were accompanied with the declined upregulation of CP-AMPARs at the DH synapses between primary afferents and sensory interneurons. Our results provide a new focus on the mechanism-based pain treatment through interference with molecular mechanisms of AMPAR trafficking in central pain pathways.

BACKGROUNDːObesity is a widespread problem within modern society, serving to increase the risk of cardiovascular, metabolic, and neurodegenerative disorders. Peroxisome proliferator-activated receptor gamma (PPARγ) and PPARγ coactivator 1 α (PGC1α) play a key role in the regulation of cellular energy metabolism and is implicated in the pathology of these diseases. This study examined the association between polymorphisms of the PPARG and PPARGC1A genes and individual variability in weight loss in response to physical activity intervention. METHODS AND RESULTSːThirty-nine obese Ukrainian women (44.4 ± 7.5 years, BMI > 30.0 kg/m 2 ) undertook a 3-month fitness program whilst following a hypocaloric diet (~1500 calories). Anthropometric and biochemical measurements took place before and after the program. Single nucleotide polymorphisms within or near PPARG (n=94) and PPARGC1A (n=138) were identified and expression of PPARG mRNA was measured via reverse transcription and amplification. The association between DNA polymorphisms and exercise-induced weight loss, initial body mass, biochemistry and PPARG expression was determined using one-way analysis of variance (ANOVA).The present intervention induced significant fat loss in all participants (total fat: 40.3±5.3 vs 36.4±5.7%; P<0.00001). Only one polymorphism (rs17650401 C/T) within the PPARGC1A gene was found to be associated with fat loss efficiency after correction for multiple testing, with T allele carriers showing the greatest reduction in body fat percentage (2.5-fold; P=0.00013) compared to non-carriers. CONCLUSIONSː PPARGC1A (rs17650401) is associated with fat loss efficiency of the fitness program in obese women. Further studies are warranted to test whether this variation is associated with fat oxidation.