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 [...].

Upregulation of ATP-Sensitive Potassium Channels as the Potential Mechanism of Cardioprotection and Vasorelaxation Under the Action of Pyridoxal-5-Phosphate in Old Rats.

Background: The aging process is accompanied by the weakening of the protective systems of the organism, in particular by the decrease in the expression of ATP-sensitive potassium (KATP) channels and in the synthesis of H2S. The aim of our work was to investigate the role of KATP channels in the cardioprotection induced by pyridoxal-5-phosphate (PLP) in aging. Methods: Experiments were performed on adult and old (aged 24 months) male Wistar rats, which were divided into 3 groups: adults, old, and old PLP-treated rats. PLP was administered orally once a day for 14 days at a dose of 0.7 mg/kg. The levels of mRNA expression of subunits KATP channels were determined by reverse transcription and real-time polymerase chain reaction analysis. Protein expression levels were determined by the Western blot. Cardiac tissue morphology was determined using transverse 6 µm deparaffinized sections stained with picrosirius red staining. Vasorelaxation responses of isolated aortic rings and the function of Langendorff-perfused isolated hearts during ischemia-reperfusion, H2S levels, and markers of oxidative stress were also studied. Results: Administration of PLP to old rats reduces cardiac fibrosis and improves cardiac function during ischemia-reperfusion and vasorelaxation responses to KATP channels opening. At the same time, there was a significant increase in mRNA and protein expression of SUR2 and Kir6.1 subunits of KATP channels, H2S production, and reduced markers of oxidative stress. The specific KATP channel inhibitor-glibenclamide prevented the enhancement of vasodilator responses and anti-ischemic protection in PLP-treated animals. Conclusions: We suggest that this potential therapeutic effect of PLP in old animals may be a result of increased expression of KATP channels and H2S production.

Pharmacophore modeling, docking and molecular dynamics simulation for identification of novel human protein kinase C beta (PKCß) inhibitors.

Protein kinase Cß (PKCß) is considered as an attractive molecular target for the treatment of COVID-19-related acute respiratory distress syndrome (ARDS). Several classes of inhibitors have been already identified. In this article, we developed and validated ligand-based PKCß pharmacophore models based on the chemical structures of the known inhibitors. The most accurate pharmacophore model, which correctly predicted more than 70% active compounds of test set, included three aromatic pharmacophore features without vectors, one hydrogen bond acceptor pharmacophore feature, one hydrophobic pharmacophore feature and 158 excluded volumes. This pharmacophore model was used for virtual screening of compound collection in order to identify novel potent PKCß inhibitors. Also, molecular docking of compound collection was performed and 28 compounds which were selected simultaneously by two approaches as top-scored were proposed for further biological research. Supplementary Information: The online version contains supplementary material available at 10.1007/s11224-022-02075-y.

SINGLE NUCLEOTIDE POLYMORPHISM RS4696480 OF TLR2 GENE ASSOCIATES WITH SEVERITY OF ATOPIC DERMATITIS IN CHILDREN, BUT NOT WITH IGE SENSITIZATION TO MALASSEZIA.

OBJECTIVE: The aim: Malassezia has been linked to atopic dermatitis, and TLRs are suggested to mediate influence of Malassezia spp on human cells. The aim of the study was to examine if TLR2 rs4696480 polymorphism predisposes to atopic dermatitis, IgE sensitization to Malassezia or to severe phenotype of atopic dermatitis. PATIENTS AND METHODS: Materials and methods: The study included 103 patients with eczema and 84 healthy children. Specific IgE against Malassezia mix (m227) was analyzed in 47 patients using immunochemiluminescent method on the ImmunoCAP 100 (Thermo Fisher Scientific Inc., Phadia, Sweden). Genotyping for TLR2 rs4696480 was performed by using Real-time PCR. RESULTS: Results: Increased IgE to Malassezia spp. was observed in 34,3 % of children with eczema. Higher Malassezia spp.-specific IgE titre positively correlated with duration of atopic dermatitis and a higher total IgE. There were no difference in allele distribution among patients and control group (OR=1.096 (0.549- 2.191) for AT, OR=0.946 (0.430- 2.078) for TT, р > 0,05). TLR2 polymorphism rs4696480 was not associated with Malassezia spp.-sIgE. AA-genotype was significantly more frequent among patients with severe and moderate-to-severe AD (OR=6.395 (1.240-32.991). CONCLUSION: Conclusions: AA variant of TLR2 rs4696480 polymorphism predisposes to severe phenotype of AD.

Response of Circulating Inflammatory Markers to Intermittent Hypoxia-Hyperoxia Training in Healthy Elderly People and Patients with Mild Cognitive Impairment.

Intermittent hypoxia-hyperoxia training (IHHT) is a non-pharmacological therapeutic modality for management of some chronic- and age-related pathologies, such as Alzheimer's disease (AD). Our previous studies demonstrated significant improvement of cognitive function after IHHT in the patients with mild cognitive impairment (MCI). The present study further investigated the effects of IHHT on pro-inflammatory factors in healthy elderly individuals and patients with early signs of AD. Twenty-nine subjects (13 healthy subjects without signs of cognitive impairment syndrome and 16 patients diagnosed with MCI; age 52 to 76 years) were divided into four groups: Healthy+Sham (n = 7), Healthy+IHHT (n = 6), MCI+Sham (n = 6), and MCI+IHHT (n = 10). IHHT was carried out 5 days per week for 3 weeks (total 15 sessions), and each daily session included 4 cycles of 5-min hypoxia (12% FIO2) and 3-min hyperoxia (33% FIO2). Decline in cognitive function indices was observed initially in both MCI+Sham and MCI+IHHT groups. The sham training did not alter any of the parameters, whereas IHHT resulted in improvement in latency of cognitive evoked potentials, along with elevation in APP110, GDF15 expression, and MMP9 activity in both healthy subjects and those with MCI. Increased MMP2 activity, HMGB1, and P-selectin expression and decreased NETs formation and Aß expression were also observed in the MCI+IHHT group. There was a negative correlation between MoCA score and the plasma GDF15 expression (R = −0.5799, p < 0.05) before the initiation of IHHT. The enhanced expression of GDF15 was also associated with longer latency of the event-related potentials P330 and N200 (R = 0.6263, p < 0.05 and R = 0.5715, p < 0.05, respectively). In conclusion, IHHT upregulated circulating levels of some inflammatory markers, which may represent potential triggers for cellular adaptive reprogramming, leading to therapeutic effects against cognitive dysfunction and neuropathological changes during progression of AD. Further investigation is needed to clarify if there is a causative relationship between the improved cognitive function and the elevated inflammatory markers following IHHT.

Cardiac dysfunction in spontaneously hypertensive old rats is associated with a significant decrease of SUR2 expression.

ATP-sensitive potassium (KATP) channels are participants of mechanisms of pathological myocardial remodeling containment. The aim of our work was to find the association of changes in the expression of Kir6.1, Kir6.2, SUR1, and SUR2 subunits of KATP channels with changes in heart function and structure during aging under conditions of the constant increase of vascular pressure. The experiments were carried out on young and old spontaneously hypertensive rats (SHR) and Wistar rats. The expression levels of KATP channels subunits were determined using reverse transcription and quantitative PCR. It is shown that the mRNA expression level of Kir6.1 in young SHR rats is significantly lower (6.3-fold, p = 0.035) than that of young Wistar rats that may be one of the causes of arterial hypertension in SHR. At the same time, mRNA expression of both Kir6.1 and Kir6.2 in old SHR rats was significantly higher (6.8-fold, p = 0.003, and 5.9-fold, p = 0.006, respectively) than in young hypertensive animals. In both groups of old animals, SUR2 expression was significantly reduced compared to young animals, in Wistar rats at 3.87-fold (p = 0.028) and in SHR rats at 48.2-fold (p = 0.033). Changes in SUR1 expression were not significant. Thus, significant changes in the cardiovascular system, including impaired function and structure of the heart in old SHR rats, were associated with a significant decrease in SUR2 expression that may be one of the mechanisms of heart failure decompensation. Therefore, it can be assumed that increased expression of SUR2 may be one of the protective mechanisms against pathological myocardial remodeling.

THE EFFECT OF DIET ENRICHED WITH PYROPHOSPHATE (E450) ON EXPRESSION OF GENES ENCODING BONE MORPHOGENETIC PROTEIN AND OSTEOCALCIN IN MOUSE EMBRYONIC MANDIBLE TISSUES.

OBJECTIVE: The aim: Of our study was to measure the mRNA expression of the investigated odontogenesis factors in mandible tissue of mouse embryos (17th day of pregnancy) gestated by females, kept on a E450 rich diet since 30 days before fertilization to gestation. PATIENTS AND METHODS: Materials and methods: The effect of food supplements was studied in «Overload phosphates model¼. Experiments were carried out on white nonlinear outbred mice with mass 25-28g (n=40). The females from the control group were fed with standard rodent food, whereas the experimental females were fed with pyrophosphate-enriched food. The materials, used for the molecular genetic study, were the lower jaws of 17-days old mouse embryos (E-17). RESULTS: Results: The investigated BMP2 and osteocalcin genes are expressed at approximately the same level. Pyrophosphate-rich diet does not alter BMP2 gene expression, but it significantly increases the expression of osteocalcin. CONCLUSION: Conclusions: The present study is the first one to describe the impact of the pyrophosphate-rich diet on mRNA expression of key osteogenesis regulators - osteocalcin and BMP2.

Regulation of microrna expression level by choleretic therapy in functional disorders of the gallbladder and оddi's sphincter in children.

OBJECTIVE: The alm: To study the effect of choleretic therapy on the level of microRNA expression in functional disorders of the gallbladder and Oddi's sphincter in children. PATIENTS AND METHODS: Materials and methods: Fifty patients with functional disorders of the gallbladder and Oddi's sphincter who received standard therapy in combination with ursodeoxycholic acid, 20 patients - standard therapy without ursodeoxycholic acid, and 20 healthy children were examined. The level of expression of microRNA-378f, microRNA-4311, microRNA-4714- 3p in the blood serum by the method of real-time polymerase chain reaction with reverse transcription according to the protocol TaqMan Gene Expression Assays was performed. RESULTS: Results: It was demonstrated that the activity profile of microRNA-4714-3p was significantly lower in those examined with functional disorders of the gallbladder and Oddi's sphincter than in practically healthy children (p<0.05). After standard therapy combined with ursodeoxycholic acid in children with functional disorders of the gallbladder and Oddi's sphincter, the level of expression of microRNA-378f is significantly higher than before therapy (5.23±0.70 SU and 2.02±0.57 SU respectively) (p<0.05). Against the background of standard therapy with the addition of ursodeoxycholic acid or without it, the expression profile of microRNA-4714-3p in the blood serum in children with functional disorders of the gallbladder and Oddi's sphincter significantly decreased (1.93±0.58 SU and 1,14±0,53 SU respectively) (p<0.05). CONCLUSION: Conclusions: Ursodeoxycholic acid in children with functional disorders of the gallbladder and Oddi's sphincter affects the activity of generation of gene regulators of the cellular mechanisms of microRNA-378f and microRNA-4714-3p.

Bioethical problems arising in the study of single-nucleotide gene polymorphisms of occupational diseases.

In Ukraine, about 3 million people work in hazardous and dangerous conditions. The study of hereditary specificity in development of occupational diseases is being actively conducted through molecular genetic analysis of single-nucleotide gene polymorphisms. While studying single-nucleotide gene polymorphisms of occupational diseases, many complicated bioethical questions arise regarding the confidentiality of personal data, the choice between the profession chosen and the risk to one's own health. Complicated bioethical issues that arise when studying single-nucleotide gene polymorphisms of occupational diseases need to be actively discussed, not only by physicians, occupational pathologists, employers, scientists, but also by politicians and lawyers, taking into account ethical and social norms and implications.

Expressions of microRNA-29a and microRNA-34a in pleomorphic adenomas of salivary glands.

BACKGROUND: The most common type of salivary gland tumor is pleomorphic adenoma. The genetic area of focus in the diagnosis of salivary gland tumors is a study of the role of miRNA. METHODS: Twenty-two patients with pleomorphic adenomas of the salivary glands were used for the examinations. The histological typing of the salivary gland tumors was performed when using routine staining with hematoxylin and eosin, as well as with immunohistochemistry. The expressions of miR-34a and miR-29a were evaluated by using reverse transcription and the quantitative polymerase chain reaction in a real-time setting. In addition, the study also calculated the levels of expression of miR-29a and miR-34a in the venous blood. RESULTS: The majority of patients-15 (68.18%) and 22 (100.00%) had a positive response to human papillomavirus (HPV) and pleomorphic adenoma gene 1 (PLAG1), respectively. The conducted analyses of the expressions of miR-34a and miR-29a showed that the highest expression was observed in the salivary gland tissue adjacent to the tumor (1,052.02±367.20 and 111.93±56.97, versus 47.72±28.93 and 8.12±4.40 in the intact salivary gland tissue, respectively). CONCLUSIONS: There was a sufficiently high level of miR-34a and miR-29a expressions in the tissues of the tumor of pleomorphic adenomas of the salivary glands when compared with the intact salivary gland tissue.

Comorbidity of asthma and hypertension may be mediated by shared genetic dysregulation and drug side effects.

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.

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.

Cholesterol enriched diet suppresses ATF6 and PERK and upregulates the IRE1 pathways of the unfolded protein response in spontaneously hypertensive rats: Relevance to pathophysiology of atherosclerosis in the setting of hypertension.

Many studies have been dedicated to hypertension and hypercholesterolemia, as they are the primary conditions that influence the unfolded protein response (UPR). However, the concurrent effects of these two factors are unknown. Our research used spontaneously hypertensive rats (SHR) fed a cholesterol enriched diet (CED) as model of atherosclerosis formation to discover what effect the simultaneous actions of hypertension and hypercholesterolemia have on the UPR. The combination of hypertension and consumption of a CED (not the CED alone) caused the formation of early atherosclerotic features. Both increased expression of the CCAAT-enhancer-binding protein (CHOP) and the insulin induced gene 1 (INSIG1), which is the target gene of the sterol regulatory element-binding protein 1-c (SREBP1-c), and decreased expression of the spliced x-box binding protein1 (sXBP1) mRNA were observed in the SHR fed a CED. Cholesterol overload strongly suppressed glucose regulated protein 78 (GRP78), glucose regulated protein 94 (GRP 94), and the expression of CHOP and INSIG1 mRNA in both normotensive and hypertensive rats. Unlike other UPR factors, the sXBP1 mRNA expression was strongly downregulated in SHR fed a normal diet but upregulated in those fed a CED. The changes to UPR in the SHR fed a CED were associated with improvement of the initially impaired heart function of the rats.

Allelic polymorphisms of dna repair genes and their influence on the formation of resistance to the development of bronchopulmonary pathology under the action of industrial aerosols.

OBJECTIVE: Introduction: The frequency of alleles and genotypes of DNA repair genes in people working due to the influence of industrial aerosols (miners and workers of asbestos-cement plants (n = 215)) was studied. The aim of the work was to identify allelic polymorphisms affecting the formation of resistance or leading to an increased risk of developing bronchopulmonary pathology. PATIENTS AND METHODS: Materials and methods: In 90 patients with bronchopulmonary pathology and 125 persons working under the same conditions but without respiratory system diseases, the polymerase chain reaction in real time was determined by the polymorphisms of DNA repair genes: XPD (rs13181, rs799793), ERCC1 (rs11615), XRCC1 ( rs25487) and XRCC3 (rs861539), ATM (rs664677), XRCC7 (rs7003908) and MLH1 (rs1799977). RESULTS: Results: In the course of this study the alleles and genotypes contributing to resistance to the development of respiratory system pathologies were determined: XRCC1•G/A (rs25487) (OR=0.57; 95% CI: 0.32-1.02; P≤0.040; Χ²=4.14); MLH1•A (rs1799977) (OR=0.62; 95% CI: 0.40-0.96; P≤0.020; Χ²=5.06); MLH1•A/A (rs1799977) (OR=0.43; 95% CI: 0.24-0.79; P≤0.003; Χ²=8.73). Also, we established the alleles and genotypes associated with the risk of developing bronchopulmonary pathology: XPD•C/C (rs13181) (OR=2.20, 95% CI: 1.02-4.77; P≤0.020; Χ²=4.85); XRCC1•A/A (rs25487) (OR=3.37; 95 % CI: 1.22-9.63; P≤0.008; Χ²=6.94); ATM•T/T (rs664677) (OR=2.48; 95% CI: 1.16-5.31; Р≤0.010; Χ²=6.61); MLH1•G (rs1799977) (OR=1.61; 95% CI: 1.04-2.49; P≤0.020; Χ²=5.06); MLH1•A/G (rs1799977) (OR=2.32; 95% CI: 1.29-4.21; P≤0.002; Χ²=9.01). CONCLUSION: Conclusions: The results indicate the influence of allelic polymorphisms of DNA repair genes on the formation of resistance to the development of bronchopulmonary pathology under the action of industrial aerosols and open up prospects for the development of modern preventive measures.

Molecular Relationships between Bronchial Asthma and Hypertension as Comorbid Diseases.

Comorbidity, a co-incidence of several disorders in an individual, is a common phenomenon. Their development is governed by multiple factors, including genetic variation. The current study was set up to look at associations between isolated and comorbid diseases of bronchial asthma and hypertension, on one hand, and single nucleotide polymorphisms associated with regulation of gene expression (eQTL), on the other hand. A total of 96 eQTL SNPs were genotyped in 587 Russian individuals. Bronchial asthma alone was found to be associated with rs1927914 (TLR4), rs1928298 (intergenic variant), and rs1980616 (SERPINA1); hypertension alone was found to be associated with rs11065987 (intergenic variant); rs2284033 (IL2RB), rs11191582 (NT5C2), and rs11669386 (CARD8); comorbidity between asthma and hypertension was found to be associated with rs1010461 (ANG/RNASE4), rs7038716, rs7026297 (LOC105376244), rs7025144 (intergenic variant), and rs2022318 (intergenic variant). The results suggest that genetic background of comorbidity of asthma and hypertension is different from genetic backgrounds of both diseases manifesting isolated.

Correction to: Cardiospecific deletion of αE-catenin leads to heart failure and lethality in mice.

The original version of this article unfortunately contained a mistake. The published paper presented an incorrect version of Table 1. The corrected Table is given here.

Cardiospecific deletion of αE-catenin leads to heart failure and lethality in mice.

αE-catenin is a component of adherens junctions that link the cadherin-catenin complex to the actin cytoskeleton. The signaling function of this protein was recently revealed. In the present study, we investigated the role of αE-catenin in the pathogenesis of heart failure. We mated αE-catenin conditional knockout mice with αMHC-Cre mice and evaluated their mutant offspring. We found that αE-catenin knockout caused enlargement of the heart and atria, fibrosis, the upregulation of hypertrophic genes, and the dysregulation of fatty acid metabolism via the transcriptional activity of Yap and ß-catenin. The activation of canonical Wnt and Yap decreased the activity of main regulators of energy metabolism (i.e., adenosine monophosphate-activated protein kinase and peroxisome proliferator-activated receptor α) and dysregulated hypertrophic pathway activity (i.e., phosphatidylinositide 3-kinase/Akt, cyclic adenosine monophosphate/protein kinase A, and MEK1/extracellular signal regulated kinase 1/2). The loss of αE-catenin also negatively affected cardio-hemodynamic function via the protein kinase A pathway. Overall, we found that the embryonic heart-specific ablation of αE-catenin leads to the development of heart failure with age and premature death in mice. Thus, αE-catenin appears to have a crucial signaling function in the postnatal heart, and the dysfunction of this gene causes heart failure through canonical Wnt and Yap activation.

Novel candidate genes important for asthma and hypertension comorbidity revealed from associative gene networks.

BACKGROUND: Hypertension and bronchial asthma are a major issue for people's health. As of 2014, approximately one billion adults, or ~ 22% of the world population, have had hypertension. As of 2011, 235-330 million people globally have been affected by asthma and approximately 250,000-345,000 people have died each year from the disease. The development of the effective treatment therapies against these diseases is complicated by their comorbidity features. This is often a major problem in diagnosis and their treatment. Hence, in this study the bioinformatical methodology for the analysis of the comorbidity of these two diseases have been developed. As such, the search for candidate genes related to the comorbid conditions of asthma and hypertension can help in elucidating the molecular mechanisms underlying the comorbid condition of these two diseases, and can also be useful for genotyping and identifying new drug targets. RESULTS: Using ANDSystem, the reconstruction and analysis of gene networks associated with asthma and hypertension was carried out. The gene network of asthma included 755 genes/proteins and 62,603 interactions, while the gene network of hypertension - 713 genes/proteins and 45,479 interactions. Two hundred and five genes/proteins and 9638 interactions were shared between asthma and hypertension. An approach for ranking genes implicated in the comorbid condition of two diseases was proposed. The approach is based on nine criteria for ranking genes by their importance, including standard methods of gene prioritization (Endeavor, ToppGene) as well as original criteria that take into account the characteristics of an associative gene network and the presence of known polymorphisms in the analysed genes. According to the proposed approach, the genes IL10, TLR4, and CAT had the highest priority in the development of comorbidity of these two diseases. Additionally, it was revealed that the list of top genes is enriched with apoptotic genes and genes involved in biological processes related to the functioning of central nervous system. CONCLUSIONS: The application of methods of reconstruction and analysis of gene networks is a productive tool for studying the molecular mechanisms of comorbid conditions. The method put forth to rank genes by their importance to the comorbid condition of asthma and hypertension was employed that resulted in prediction of 10 genes, playing the key role in the development of the comorbid condition. The results can be utilised to plan experiments for identification of novel candidate genes along with searching for novel pharmacological targets.

Search for New Candidate Genes Involved in the Comorbidity of Asthma and Hypertension Based on Automatic Analysis of Scientific Literature.

Comorbid states of diseases significantly complicate diagnosis and treatment. Molecular mechanisms of comorbid states of asthma and hypertension are still poorly understood. Prioritization is a way for identifying genes involved in complex phenotypic traits. Existing methods of prioritization consider genetic, expression and evolutionary data, molecular-genetic networks and other. In the case of molecular-genetic networks, as a rule, protein-protein interactions and KEGG networks are used. ANDSystem allows reconstructing associative gene networks, which include more than 20 types of interactions, including protein-protein interactions, expression regulation, transport, catalysis, etc. In this work, a set of genes has been prioritized to find genes potentially involved in asthma and hypertension comorbidity. The prioritization was carried out using well-known methods (ToppGene and Endeavor) and a cross-talk centrality criterion, calculated by analysis of associative gene networks from ANDSystem. The identified genes, including IL1A, CD40LG, STAT3, IL15, FAS, APP, TLR2, C3, IL13 and CXCL10, may be involved in the molecular mechanisms of comorbid asthma/hypertension. An analysis of the dynamics of the frequency of mentioning the most priority genes in scientific publications revealed that the top 100 priority genes are significantly enriched with genes with increased positive dynamics, which may be a positive sign for further studies of these genes.

GenCoNet - A Graph Database for the Analysis of Comorbidities by Gene Networks.

The prevalence of comorbid diseases poses a major health issue for millions of people worldwide and an enormous socio-economic burden for society. The molecular mechanisms for the development of comorbidities need to be investigated. For this purpose, a workflow system was developed to aggregate data on biomedical entities from heterogeneous data sources. The process of integrating and merging all data sources of the workflow system was implemented as a semi-automatic pipeline that provides the import, fusion, and analysis of the highly connected biomedical data in a Neo4j database GenCoNet. As a starting point, data on the common comorbid diseases essential hypertension and bronchial asthma was integrated. GenCoNet (https://genconet.kalis-amts.de) is a curated database that provides a better understanding of hereditary bases of comorbidities.