MicroRNAs as Potential Biomarkers of Post-Traumatic Epileptogenesis: A Systematic Review.

Structural or post-traumatic epilepsy often develops after brain tissue damage caused by traumatic brain injury, stroke, infectious diseases of the brain, etc. Most often, between the initiating event and epilepsy, there is a period without seizures-a latent period. At this time, the process of restructuring of neural networks begins, leading to the formation of epileptiform activity, called epileptogenesis. The prediction of the development of the epileptogenic process is currently an urgent and difficult task. MicroRNAs are inexpensive and minimally invasive biomarkers of biological and pathological processes. The aim of this study is to evaluate the predictive ability of microRNAs to detect the risk of epileptogenesis. In this study, we conducted a systematic search on the MDPI, PubMed, ScienceDirect, and Web of Science platforms. We analyzed publications that studied the aberrant expression of circulating microRNAs in epilepsy, traumatic brain injury, and ischemic stroke in order to search for microRNAs-potential biomarkers for predicting epileptogenesis. Thus, 31 manuscripts examining biomarkers of epilepsy, 19 manuscripts examining biomarkers of traumatic brain injury, and 48 manuscripts examining biomarkers of ischemic stroke based on circulating miRNAs were analyzed. Three miRNAs were studied: miR-21, miR-181a, and miR-155. The findings showed that miR-21 and miR-155 are associated with cell proliferation and apoptosis, and miR-181a is associated with protein modifications. These miRNAs are not strictly specific, but they are involved in processes that may be indirectly associated with epileptogenesis. Also, these microRNAs may be of interest when they are studied in a cohort with each other and with other microRNAs. To further study the microRNA-based biomarkers of epileptogenesis, many factors must be taken into account: the time of sampling, the type of biological fluid, and other nuances. Currently, there is a need for more in-depth and prolonged studies of epileptogenesis.

Mass Spectrometry as a Quantitative Proteomic Analysis Tool for the Search for Temporal Lobe Epilepsy Biomarkers: A Systematic Review.

Temporal lobe epilepsy (TLE) is the most common form of epilepsy in adults. Tissue reorganization at the site of the epileptogenic focus is accompanied by changes in the expression patterns of protein molecules. The study of mRNA and its corresponding proteins is crucial for understanding the pathogenesis of the disease. Protein expression profiles do not always directly correlate with the levels of their transcripts; therefore, it is protein profiling that is no less important for understanding the molecular mechanisms and biological processes of TLE. The study and annotation of proteins that are statistically significantly different in patients with TLE is an approach to search for biomarkers of this disease, various stages of its development, as well as a method for searching for specific targets for the development of a further therapeutic strategy. When writing a systematic review, the following aggregators of scientific journals were used: MDPI, PubMed, ScienceDirect, Springer, and Web of Science. Scientific articles were searched using the following keywords: "proteomic", "mass-spectrometry", "protein expression", "temporal lobe epilepsy", and "biomarkers". Publications from 2003 to the present have been analyzed. Studies of brain tissues, experimental models of epilepsy, as well as biological fluids, were analyzed. For each of the groups, aberrantly expressed proteins found in various studies were isolated. Most of the studies omitted important characteristics of the studied patients, such as: duration of illness, type and response to therapy, gender, etc. Proteins that overlap across different tissue types and different studies have been highlighted: DPYSL, SYT1, STMN1, APOE, NME1, and others. The most common biological processes for them were the positive regulation of neurofibrillary tangle assembly, the regulation of amyloid fibril formation, lipoprotein catabolic process, the positive regulation of vesicle fusion, the positive regulation of oxidative stress-induced intrinsic apoptotic signaling pathway, removal of superoxide radicals, axon extension, and the regulation of actin filament depolymerization. MS-based proteomic profiling for a relevant study must accept a number of limitations, the most important of which is the need to compare different types of neurological and, in particular, epileptic disorders. Such a criterion could increase the specificity of the search work and, in the future, lead to the discovery of biomarkers for a particular disease.

MicroRNAs as Biomarkers of Surgical Outcome in Mesial Temporal Lobe Epilepsy: A Systematic Review.

Mesial temporal lobe epilepsy is the most common type of epilepsy. For most patients suffering from TLE, the only treatment option is surgery. However, there is a high possibility of relapse. Invasive EEG as a method for predicting the outcome of surgical treatment is a very complex and invasive manipulation, so the search for outcome biomarkers is an urgent task. MicroRNAs as potential biomarkers of surgical outcome are the subject of this study. For this study, a systematic search for publications in databases such as PubMed, Springer, Web of Science, Scopus, ScienceDirect, and MDPI was carried out. The following keywords were used: temporal lobe epilepsy, microRNA, biomarkers, surgery, and outcome. Three microRNAs were studied as prognostic biomarkers of surgical outcome: miR-27a-3p, miR-328-3p, and miR-654-3p. According to the results of the study, only miR-654-3p showed a good ability to discriminate between patients with poor and good surgical outcomes. MiR-654-3p is involved in the following biological pathways: ATP-binding cassette drug transporters, glutamate transporter SLC7A11, and TP53. A specific target for miR-654-3p is GLRA2, the glycine receptor subunit. MicroRNAs, which are diagnostic biomarkers of TLE, and epileptogenesis, miR-134-5p, MiR-30a, miRs-143, etc., can be considered as potential biomarkers of surgical outcome, as they can be indicators of early and late relapses. These microRNAs are involved in the processes characteristic of epilepsy: oxidative stress and apoptosis. The study of miRNAs as potential predictive biomarkers of surgical outcome is an urgent task and should be continued. However, when studying miRNA expression profiles, it is important to take into account and note a number of factors, such as the type of sample under study, the time of sampling for the study, the type and duration of the disease, and the type of antiepileptic treatment. Without taking into account all these factors, it is impossible to assess the influence and involvement of miRNAs in epileptic processes.

Association of Single-Nucleotide Polymorphisms Rs2779249 (chr17:26128581 C>A) and Rs rs2297518 (chr17: chr17:27769571 G>A) of the NOS2 Gene with Tension-Type Headache and Arterial Hypertension Overlap Syndrome in Eastern Siberia.

Inducible nitric oxide (NO) synthase (iNOS), encoded by the NOS2 gene, promotes the generation of high levels of NO to combat harmful environmental influences in a wide range of cells. iNOS can cause adverse effects, such as falling blood pressure, if overexpressed. Thus, according to some data, this enzyme is an important precursor of arterial hypertension (AH) and tension-type headache (TTH), which are the most common multifactorial diseases in adults. The purpose of this study was to investigate the association of rs2779249 (chr17:26128581 C>A) and rs2297518 (chr17: chr17:27769571 G>A) of the NOS2 gene with TTH and AH overlap syndrome (OS) in Caucasians in Eastern Siberia. The sample size was 91 participants: the first group-30 patients with OS; the second group-30 patients AH; and the third group-31 healthy volunteers. RT-PCR was used for the determination of alleles and genotypes of the SNPs rs2779249 and rs2297518 of the NOS2 gene in all groups of participants. We showed that the frequency of allele A was significantly higher among patients with AH compared with healthy volunteers (p-value < 0.05). The frequency of the heterozygous genotype CA of rs2779249 was higher in the first group vs. the control (p-value = 0.03), and in the second group vs. the control (p-value = 0.045). The frequency of the heterozygous genotype GA of rs2297518 was higher in the first group vs. the control (p-value = 0.035), and in the second group vs. the control (p-value = 0.001). The allele A of rs2779249 was associated with OS (OR = 3.17 [95% CI: 1.31-7.67], p-value = 0.009) and AH (OR = 2.94 [95% CI: 1.21-7.15], p-value = 0.015) risks compared with the control. The minor allele A of rs2297518 was associated with OS (OR = 4.0 [95% CI: 0.96-16.61], p-value = 0.035) and AH (OR = 8.17 [95% CI: 2.03-32.79], p-value = 0.001) risks compared with the control. Therefore, our pilot study demonstrated that the SNPs rs2779249 and rs229718 of the NOS2 gene could be promising genetic biomarkers for this OS risk in Caucasians from Eastern Siberia.

Biomarkers of Drug Resistance in Temporal Lobe Epilepsy in Adults.

Temporal lobe epilepsy (TLE) is the most common type of focal epilepsy in adults. Experimental and clinical data indicate that neuroinflammation and neurodegeneration accompanying epileptogenesis make a significant contribution to the chronicity of epilepsy and the development of drug resistance in TLE cases. Changes in plasma and serum concentrations of proteins associated with neuroinflammation and neurodegeneration can be predictive biomarkers of the course of the disease. This study used an enzyme-linked immunosorbent assay of the following plasma proteins: brain-derived neurotrophic factor (BDNF), tumor necrosis factor alpha (TNFa), and high-mobility group protein B1 (HMGB1) in patients with mesial TLE to search for biomarkers of the disease. The objective of the study was to examine biomarkers of the neuroinflammation and neurodegeneration of plasma: BDNF, TNFa, and HMGB1. The aim of the study was to identify changes in the concentration of circulating pro-inflammatory and neurotrophic factors that are prognostically significant for the development of drug resistance and the course of TLE. A decrease in the concentration of BDNF, TNFa, and HMGB1 was registered in the group of patients with TLE compared with the control group. A significant decrease in the concentration of HMGB1 in patients with drug-resistant TLE was observed. Aberrations in plasma concentrations of BDNF, TNFa, and HMGB1 in patients with TLE compared with the controls have been confirmed by earlier studies. A decrease in the expression of the three biomarkers may be the result of neurodegenerative processes caused by the long course of the disease. The results of the study may indicate the acceptability of using HMGB1 and TNFa as prognostic biological markers to indicate the severity of the disease course and the risk of developing drug resistance.

Salivary oxytocin in autistic patients and in patients with intellectual disability.

Background: Assessing the role of oxytocin (OT) in the regulation of social interaction is a promising area that opens up new opportunities for studying the mechanisms of developing autism spectrum disorders (ASD). Aim: To assess the correlation between the salivary OT level and age-related and psychopathological symptoms of children with intellectual disability (ID) and ASD. Methods: We used the clinical and psychopathological method to assess the signs of ASD based on International Classification of Diseases (ICD-10), the severity of ASD was specified by the selected Russian type version "Childhood Autism Rating Scale" (CARS). Patients of both groups had an IQ score below 70 points. Results: The median and interquartile range of salivary OT levels in patients with ID and ASD were 23.897 [14.260-59.643] pg/mL, and in the group ID without ASD - Me = 50.896 [33.502-83.774] pg/mL (p = 0.001). The severity of ASD on the CARS scale Me = 51.5 [40.75-56.0] score in the group ID with ASD, and in the group ID without ASD-at the level of Me = 32 [27.0-38.0] points (p < 0.001). According to the results of correlation-regression analysis in the main group, a direct correlation was established between salivary OT level and a high degree of severity of ASD Rho = 0.435 (p = 0.005). There was no correlation between the salivary OT level and intellectual development in the group ID with ASD, Rho = 0.013 (p = 0.941) and we have found a relationship between oxytocin and intellectual development in the group ID without ASD, Rho = 0.297 (p = 0.005). There was no correlation between salivary OT and age, ASD and age. Conclusion: The results of this study indicate that patients in the group ID with ASD demonstrated a lower level of salivary OT concentration and a direct relationship between the maximum values of this indicator and the severity of autistic disorders, in contrast to patients in the group ID without ASD.

Genetic Predisposition to Schizophrenia and Depressive Disorder Comorbidity.

Background: Patients with schizophrenia have an increased risk of depressive disorders compared to the general population. The comorbidity between schizophrenia and depression suggests a potential coincidence of the pathophysiology and/or genetic predictors of these mental disorders. The aim of this study was to review the potential genetic predictors of schizophrenia and depression comorbidity. Materials and Methods: We carried out research and analysis of publications in the databases PubMed, Springer, Wiley Online Library, Taylor & Francis Online, Science Direct, and eLIBRARY.RU using keywords and their combinations. The search depth was the last 10 years (2010-2020). Full-text original articles, reviews, meta-analyses, and clinical observations were analyzed. A total of 459 articles were found, of which 45 articles corresponding to the purpose of this study were analyzed in this topic review. Results: Overlap in the symptoms and genetic predictors between these disorders suggests that a common etiological mechanism may underlie the presentation of comorbid depression in schizophrenia. The molecular mechanisms linking schizophrenia and depression are polygenic. The most studied candidate genes are GRIN1, GPM6A, SEPTIN4, TPH1, TPH2, CACNA1C, CACNB2, and BCL9.Conclusion: Planning and conducting genome-wide and associative genetic studies of the comorbid conditions under consideration in psychiatry is important for the development of biological and clinical predictors and a personalized therapy strategy for schizophrenia. However, it should be recognized that the problems of predictive and personalized psychiatry in the diagnosis and treatment of schizophrenia and comorbid disorders are far from being resolved.

Expression Profile of miRs in Mesial Temporal Lobe Epilepsy: Systematic Review.

Temporal lobe epilepsy (TLE) is one of the most common forms of focal epilepsy in children and adults. TLE is characterized by variable onset and seizures. Moreover, this form of epilepsy is often resistant to pharmacotherapy. The search for new mechanisms for the development of TLE may provide us with a key to the development of new diagnostic methods and a personalized approach to the treatment. In recent years, the role of non-coding ribonucleic acids (RNA) has been actively studied, among which microRNA (miR) is of the greatest interest. (1) Background: The purpose of the systematic review is to analyze the studies carried out on the role of miRs in the development of mesial TLE (mTLE) and update the existing knowledge about the biomarkers of this disease. (2) Methods: The search for publications was carried out in the databases PubMed, Springer, Web of Science, Clinicalkeys, Scopus, OxfordPress, Cochrane. The search was carried out using keywords and combinations. We analyzed publications for 2016-2021, including original studies in an animal model of TLE and with the participation of patients with TLE, thematic and systemic reviews, and Cochrane reviews. (3) Results: this thematic review showed that miR‒155, miR‒153, miR‒361‒5p, miR‒4668‒5p, miR‒8071, miR‒197‒5p, miR‒145, miR‒181, miR‒199a, miR‒1183, miR‒129‒2‒3p, miR‒143‒3p (upregulation), miR-134, miR‒0067835, and miR‒153 (downregulation) can be considered as biomarkers of mTLE. However, the roles of miR‒146a, miR‒142, miR‒106b, and miR‒223 are questionable and need further study. (4) Conclusion: In the future, it will be possible to consider previously studied miRs, which have high specificity and sensitivity in mTLE, as prognostic biomarkers (predictors) of the risk of developing this disease in patients with potentially epileptogenic structural damage to the mesial regions of the temporal lobe of the brain (congenital disorders of the neuronal migration and neurogenesis, brain injury, neuro-inflammation, tumor, impaired blood supply, neurodegeneration, etc.).

The Role of Extracellular Matrix in Skin Wound Healing.

Impaired wound healing is one of the unsolved problems of modern medicine, affecting patients' quality of life and causing serious economic losses. Impaired wound healing can manifest itself in the form of chronic skin wounds or hypertrophic scars. Research on the biology and physiology of skin wound healing disorders is actively continuing, but, unfortunately, a single understanding has not been developed. The attention of clinicians to the biological and physiological aspects of wound healing in the skin is necessary for the search for new and effective methods of prevention and treatment of its consequences. In addition, it is important to update knowledge about genetic and non-genetic factors predisposing to impaired wound healing in order to identify risk levels and develop personalized strategies for managing such patients. Wound healing is a very complex process involving several overlapping stages and involving many factors. This thematic review focuses on the extracellular matrix of the skin, in particular its role in wound healing. The authors analyzed the results of fundamental research in recent years, finding promising potential for their transition into real clinical practice.

Nucleic Acid Aptamers for Molecular Therapy of Epilepsy and Blood-Brain Barrier Damages.

Epilepsy is the fourth most prevalent brain disorder affecting millions of people of all ages. Epilepsy is divided into six categories different in etiology and molecular mechanisms; however, their common denominator is the inability to maintain ionic homeostasis. Antiepileptic drugs have a broad spectrum of action and high toxicity to the whole organism. In many cases, they could not penetrate the blood-brain barrier (BBB) and reach corresponding targets. Nucleic acid aptamers are a new and promising class of antiepileptic drugs as they are non-toxic, specific, and able to regulate the permeability of ion channels or inhibit inflammatory proteins. In this review, we summarize the mechanisms of epileptogenesis and its interconnection with the BBB and show the potential of aptamers for antiepileptic treatment.