A growing body of evidence points to the role of glucose variability (GV) in the development of the microvascular and macrovascular complications of diabetes. In this review, we summarize data on GV-induced biochemical, cellular and molecular events involved in the pathogenesis of diabetic complications. Current data indicate that the deteriorating effect of GV on target organs can be realized through oxidative stress, glycation, chronic low-grade inflammation, endothelial dysfunction, platelet activation, impaired angiogenesis and renal fibrosis. The effects of GV on oxidative stress, inflammation, endothelial dysfunction and hypercoagulability could be aggravated by hypoglycemia, associated with high GV. Oscillating hyperglycemia contributes to beta cell dysfunction, which leads to a further increase in GV and completes the vicious circle. In cells, the GV-induced cytotoxic effect includes mitochondrial dysfunction, endoplasmic reticulum stress and disturbances in autophagic flux, which are accompanied by reduced viability, activation of apoptosis and abnormalities in cell proliferation. These effects are realized through the up- and down-regulation of a large number of genes and the activity of signaling pathways such as PI3K/Akt, NF-κB, MAPK (ERK), JNK and TGF-β/Smad. Epigenetic modifications mediate the postponed effects of glucose fluctuations. The multiple deteriorative effects of GV provide further support for considering it as a therapeutic target in diabetes.

Sufficient knowledge of molecular and genetic interactions, which comprise the entire basis of the functioning of living systems, is one of the necessary requirements for successfully answering almost any research question in the field of biology and medicine. To date, more than 24 million scientific papers can be found in PubMed, with many of them containing descriptions of a wide range of biological processes. The analysis of such tremendous amounts of data requires the use of automated text-mining approaches. Although a handful of tools have recently been developed to meet this need, none of them provide error-free extraction of highly detailed information. The ANDSystem package was developed for the reconstruction and analysis of molecular genetic networks based on an automated text-mining technique. It provides a detailed description of the various types of interactions between genes, proteins, microRNA's, metabolites, cellular components, pathways and diseases, taking into account the specificity of cell lines and organisms. Although the accuracy of ANDSystem is comparable to other well known text-mining tools, such as Pathway Studio and STRING, it outperforms them in having the ability to identify an increased number of interaction types. The use of ANDSystem, in combination with Pathway Studio and STRING, can improve the quality of the automated reconstruction of molecular and genetic networks. ANDSystem should provide a useful tool for researchers working in a number of different fields, including biology, biotechnology, pharmacology and medicine.

Consideration of tissue-specific gene expression in reconstruction and analysis of molecular genetic networks is necessary for a proper description of the processes occurring in a specified tissue. Currently, there are a number of computer systems that allow the user to reconstruct molecular-genetic networks using the data automatically extracted from the texts of scientific publications. Examples of such systems are STRING, Pathway Commons, MetaCore and Ingenuity. The MetaCore and Ingenuity systems permit taking into account tissue-specific gene expression during the reconstruction of gene networks. Previously, we developed the ANDSystem tool, which also provides an automated extraction of knowledge from scientific texts and allows the reconstruction of gene networks. The main difference between our system and other tools is in the different types of interactions between objects, which makes the ANDSystem complementary to existing well-known systems. However, previous versions of the ANDSystem did not contain any information on tissue-specific expression. A new version of the ANDSystem has been developed. It offers the reconstruction of associative gene networks while taking into account the tissue-specific gene expression. The ANDSystem knowledge base features information on tissue-specific expression for 272 tissues. The system allows the reconstruction of combined gene networks, as well as performing the filtering of genes from such networks using the information on their tissue-specific expression. As an example of the application of such filtering, the gene network of the extrinsic apoptotic signaling pathway was analyzed. It was shown that considering different tissues can lead to changes in gene network structure, including changes in such indicators as betweenness centrality of vertices, clustering coefficient, network centralization, network density, etc. The consideration of tissue specificity can play an important role in the analysis of gene networks, in particular solving the problem of finding the most significant central genes. Thus, the new version of ANDSystem can be employed for a wide range of tasks related to biomedical studies of individual tissues. It is available at http://www-bionet.sscc.ru/and/cell /.

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. 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. 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.

Glucose variability (GV) has been recognized recently as a promoter of complications and therapeutic targets in diabetes. The aim of this study was to reconstruct and analyze gene networks related to GV in diabetes and its complications. For network analysis, we used the ANDSystem that provides automatic network reconstruction and analysis based on text mining. The network of GV consisted of 37 genes/proteins associated with both hyperglycemia and hypoglycemia. Cardiovascular system, pancreas, adipose and muscle tissues, gastrointestinal tract, and kidney were recognized as the loci with the highest expression of GV-related genes. According to Gene Ontology enrichment analysis, these genes are associated with insulin secretion, glucose metabolism, glycogen biosynthesis, gluconeogenesis, MAPK and JAK-STAT cascades, protein kinase B signaling, cell proliferation, nitric oxide biosynthesis, etc. GV-related genes were found to occupy central positions in the networks of diabetes complications (cardiovascular disease, diabetic nephropathy, retinopathy, and neuropathy) and were associated with response to hypoxia. Gene prioritization analysis identified new gene candidates (THBS1, FN1, HSP90AA1, EGFR, MAPK1, STAT3, TP53, EGF, GSK3B, and PTEN) potentially involved in GV. The results expand the understanding of the molecular mechanisms of the GV phenomenon in diabetes and provide molecular markers and therapeutic targets for future research.

Pre-eclampsia is the most common complication occurring during pregnancy. In the majority of cases, it is concurrent with other pathologies in a comorbid manner (frequent co-occurrences in patients), such as diabetes mellitus, gestational diabetes and obesity. Providing bronchial asthma, pulmonary tuberculosis, certain neurodegenerative diseases and cancers as examples, we have shown previously that pairs of inversely comorbid pathologies (rare co-occurrences in patients) are more closely related to each other at the molecular genetic level compared with randomly generated pairs of diseases. Data in the literature concerning the causes of pre-eclampsia are abundant. However, the key mechanisms triggering this disease that are initiated by other pathological processes are thus far unknown. The aim of this work was to analyse the characteristic features of genetic networks that describe interactions between comorbid diseases, using pre-eclampsia as a case in point.