Elmira A. Anderzhanova

Трансгенез по гену ACE2 усиливает память о психофизиологической травме в модели посттравматического стрессового расстройства у мышей

The neurobiological systems of maintenance and control of behavioral responses result from natural selection. We have analyzed the selection signatures for single nucleotide variants (SNV) of the genes of oxytocin (OXT, OXTR) and vasopressin (AVP, AVPR1A, AVPR1B) systems, which are associated with the regulation of social and emotional behavior in distinct populations. The analysis was performed using original WGS (whole genome sequencing) data on Eastern Slavs (SlEast), as well as publicly available data from the 1000 Genomes Project on GBR, FIN, IBR, PUR, BEB, CHB, and ACB populations (the latter were taken as reference). To identify selection signatures, we rated the integrated haplotype scores (iHS), the numbers of segregating sites by length (nSl), and the integrated haplotype homozygosity pooled (iHH12) measures; the fixation index Fst was implemented to assess genetic differentiation between populations. We revealed that the strongest genetic differentiation of populations was found with respect to the AVPR1B gene, with the greatest differentiation observed in GRB (Fst = 0.316) and CHB (Fst = 0.325) in comparison to ACB. Also, high Fst values were found for SNVs of the AVPR1B gene rs28499431, rs33940624, rs28477649, rs3883899, and rs28452187 in most of the populations. Selection signatures have also been identified in the AVP, AVPR1A, OXT, and OXTR genes. Our analysis shows that the OXT, OXTR, AVP, AVPR1A, and AVPR1B genes were subject to positive selection in a population-specific process, which was likely contributing to the diversity of adaptive emotional response types and social function realizations.

The polygenic nature of neurological and psychiatric syndromes and the significant impact of environmental factors on the underlying developmental, homeostatic, and neuroplastic mechanisms suggest that an efficient therapy for these disorders should be a complex one. Pharmacological interventions with drugs selectively influencing the epigenetic landscape (epidrugs) allow one to hit multiple targets, therefore, assumably addressing a wide spectrum of genetic and environmental mechanisms of central nervous system (CNS) disorders. The aim of this review is to understand what fundamental pathological mechanisms would be optimal to target with epidrugs in the treatment of neurological or psychiatric complications. To date, the use of histone deacetylases and DNA methyltransferase inhibitors (HDACis and DNMTis) in the clinic is focused on the treatment of neoplasms (mainly of a glial origin) and is based on the cytostatic and cytotoxic actions of these compounds. Preclinical data show that besides this activity, inhibitors of histone deacetylases, DNA methyltransferases, bromodomains, and ten-eleven translocation (TET) proteins impact the expression of neuroimmune inflammation mediators (cytokines and pro-apoptotic factors), neurotrophins (brain-derived neurotropic factor (BDNF) and nerve growth factor (NGF)), ion channels, ionotropic receptors, as well as pathoproteins (β-amyloid, tau protein, and α-synuclein). Based on this profile of activities, epidrugs may be favorable as a treatment for neurodegenerative diseases. For the treatment of neurodevelopmental disorders, drug addiction, as well as anxiety disorders, depression, schizophrenia, and epilepsy, contemporary epidrugs still require further development concerning a tuning of pharmacological effects, reduction in toxicity, and development of efficient treatment protocols. A promising strategy to further clarify the potential targets of epidrugs as therapeutic means to cure neurological and psychiatric syndromes is the profiling of the epigenetic mechanisms, which have evolved upon actions of complex physiological lifestyle factors, such as diet and physical exercise, and which are effective in the management of neurodegenerative diseases and dementia.

Polyamines (PAs), endogenous metabolites with a wide range of biological activities, are synthesized at a high rate in liver supporting hepatocyte proliferation and survival. The liver appears as an important regulator of plasma PAs; however, the perspective to exploit plasma PA measurements as indicators for liver function was not explored. This study aimed to evaluate the value of the plasma levels of PAs as a biomarker of pathological changes in the liver in patients with obstructive cholecystitis. The levels of polyamines and their acetylated forms were measured using HPLC/UV in the plasma of patients with obstructive cholecystitis and in healthy subjects. PA turnover was assessed by the ratio between an acetylated form of PA and PA. An effect of diet preference of cheese or meat, the major exogenous sources of PAs, smoking, and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in anamnesis was also evaluated in healthy subjects. We found that the plasma levels of spermine and acetylated spermidine decreased in patients with obstructive cholecystitis without a concurring increase in the total plasma bilirubin and amylase levels. The turnover of spermine and spermidine was also changed, suggesting a decrease in the rate of PA degradation in the liver. In healthy subjects, the PA levels tended to mirror chronic smoking and recent SARS-CoV-2 infection but were not relevant to diet factors. A number of observations indicated the role of physical exercise in the regulation of the plasma pool of PA. The decrease in plasma PA levels and index of PA turnover in the cholestasis syndrome indicate the liver’s metabolic function reduction. A conceivable effect of lung-related conditions on plasma PA, while indicating low specificity, nonetheless, speaks favorably about the high sensitivity of plasma PA measurement as an early diagnostic test in the clinic.