Conjugates of 3,5-Bis(arylidene)-4-piperidone and Sesquiterpene Lactones Have an Antitumor Effect via Resetting the Metabolic Phenotype of Cancer Cells.

In recent years, researchers have often encountered the significance of the aberrant metabolism of tumor cells in the pathogenesis of malignant neoplasms. This phenomenon, known as the Warburg effect, provides a number of advantages in the survival of neoplastic cells, and its application is considered a potential strategy in the search for antitumor agents. With the aim of developing a promising platform for designing antitumor therapeutics, we synthesized a library of conjugates of 3,5-bis(arylidene)-4-piperidone and sesquiterpene lactones. To gain insight into the determinants of the biological activity of the prepared compounds, we showed that the conjugates of 3,5-bis(arylidene)-4-piperidone and sesquiterpene lactones, which are cytotoxic agents, demonstrate selective activity toward a number of tumor cell lines with glycolysis-inhibiting ability. Moreover, the results of molecular and in silico screening allowed us to identify these compounds as potential inhibitors of the pyruvate kinase M2 oncoprotein, which is the rate-determining enzyme of glycolysis. Thus, the results of our work indicate that the synthesized conjugates of 3,5-bis(arylidene)-4-piperidone and sesquiterpene lactones can be considered a promising platform for designing selective cytotoxic agents against the glycolysis process, which opens new possibilities for researchers involved in the search for antitumor therapeutics among compounds containing piperidone platforms.

The EXCEL Study: Long-term Observation of the Effectiveness of Drug and Non-drug Rehabilitation in Patients with Ischemic Heart Failure.

AIM: To study the long-term effect of enhanced external counterpulsation (EECP) therapy on exercise tolerance, quality of life (QoL), and indicators of the structural and functional state of the cardiovascular system in patients with stable ischemic heart disease (IHD) complicated by chronic heart failure (CHF). MATERIAL AND METHODS: This open randomized EXCEL study included 120 patients with verified IHD complicated by NYHA II-III functional class CHF with reduced or mid-range left ventricular (LV) ejection fraction. Patients were randomized into group 1 (n=40), optimal drug therapy (ODT) and EECP (35 hours, 2 courses per year); group 2 (n=40), ODT and EECP (35 hours, 1 course per year); and group 3 (control; n=40), ODT and placebo counterpulsation (35 h, 1 course per year). All patients underwent a 6-minute walk test (6MWT), evaluation of clinical status, QoL with the MLHFQ and SF-36 questionnaires, structural and functional state of large blood vessels and microvasculature, measurement of brain natriuretic peptide precursor (NT-proBNP), and echocardiography at baseline and after 12 months. RESULTS: In groups 1 and 2 after 12 months, the 6MWT distance increased statistically significantly (44.5 and 24.9%, respectively) and the following indexes improved: QoL (SF-36, MLHFQ), the condition of large blood vessels (phase shift, radial augmentation index, central aortic systolic pressure (CASP)) and microvasculature (occlusion index, percentage of perfused capillaries, percentage of capillary recovery), and the LV systolic function (from 40.6±7.5 to 47.5±10.2% and from 41.3± 6.8 to 43.9±10.3%, respectively). The proportion of patients with a >20% increase in the 6MWT at 12 months was 97.5, 72.5, and 7.7%, respectively. A statistically significant decrease in NT-proBNP was observed in all groups. In group 3, the incidence of hospitalizations for CHF and the risk of the composite endpoint were significantly higher. CONCLUSION: For the 12-month study period, the effects of EECP in patients with IHD complicated by CHF included improvements in exercise tolerance, QoL, vascular and cardiac functional parameters, and a decrease in the incidence of adverse outcomes.

[Etymology of the meninges names in the work «Onomatologia anatomica¼ by Josef Hyrtl]. / Etimologiya naimenovanii obolochek golovnogo mozga v trude Iozefa Girtlya «Onomatologia anatomica¼.

The article represents the translation of chapters of the scientific work «Onomatologia anatomica¼ (1880) by the Austrian anatomist Josef Hyrtl devoted to terminology in the anatomy of the meninges, namely arachnoidea, pia mater, dura mater, meninx.

On the method and results of calculation of vibrational tetrahedral sub-level energies and resonance interactions in vibrational spectra of high symmetry molecules: CH4 and GeH4 as an application of the XY4 (Td) molecule.

We report here the analytical description of one of the important problems in the study of XY4 (Td) molecules, namely, description of vibrational tetrahedral sub-level structures and resonance interactions caused by the high symmetry of a molecule. The results obtained are applied to description of the vibrational energy spectrum of the CH4 and GeH4 molecules.

[Correction of gut dysbiosis as a promising direction in the prevention of neuroinflammation and cognitive impairment].

In recent years new data have been obtained on the role of intestinal dysbiosis in the pathogenesis mechanisms of neuroinflammation and neurodegeneration in Alzheimer's disease (AD), as well as on the influence of dietary patterns (Mediterranean diet, MIND diet) and probiotics on the correction of dysbiosis and slowing down the development of cognitive disorders. It seems reasonable to draw the attention of practicing physicians to the need to prevent cognitive dysfunction through dietary correction, probiotics and prebiotics intake. The purpose of the research was to study the possibility of using certain dietary patterns, as well as intake of probiotics and prebiotics for the correction of dysbiosis and early prevention of cognitive dysfunction, basing on the analysis of published data on the bidirectional communication between the colon microbiota and the brain and microbiota changes in patients with cognitive dysfunction and AD. Material and methods. We searched domestic and foreign literature devoted to gut microbiota, the "gut-brain" axis, microbiota disorders in AD patients; mechanisms of neuroinflammation and neurodegeneration; the role of dietary patterns, in particular MIND diet, pre- and probiotics in the prevention of cognitive dysfunction - via PubMed search engine, SemanticScholar Google Internet search platform and domestic scientific electronic library Cyberleninka. 72 literature sources were analyzed. Results. Intestinal dysbiosis and disruption of intestinal barrier integrity play an important role in the pathogenesis of neuroinflammation and neurodegeneration. Changes in the microbiota in patients with cognitive impairment and AD are associated with disease severity and are generally characterized by increased numbers of Gram-negative microorganisms in Bacteroidetes and Proteobacteria phyla and decreased numbers of Gram-positive microorganisms in Firmicutes and Actinobacteria phyla. An increase in gram-negative microorganisms abundance leads to elevated release of lipopolysaccharides (LPS) that disrupt the integrity of the intestinal mucous barrier and, through a series of steps, initiate neuroinflammation. Course application of probiotics containing representatives of Bifidobacterium and Lactobacillus genera, in particular, Bifidobacterium breve A1 и Lactobacillus plantarum С29 strains, leads to improved cognitive function, which can be explained by anti-inflammatory and antioxidant effects. Long-term prospective studies of the effects of dietary patterns such as the Mediterranean diet and the MIND diet clearly show delayed regression of cognitive function in older adults without initial dementia as well as in patients with AD. For example, according to various studies, individuals who have strictly adhered to the Mediterranean diet for 6-9 years have a 23-39% lower risk of developing cognitive impairment. Adherence to the MIND diet for 6 years has a statistically significant association with higher verbal memory scores. Correction of gut dysbiosis, including through the administration of probiotics, prebiotics and bringing the diet to the MIND diet pattern, is the most affordable and rational method for early prevention of cognitive dysfunction. Conclusion. A promising strategy in the early prevention of neuroinflammation, cognitive impairment and dementia is to maintain the balance of the gut microbiota. The solution to this problem is achieved by adjusting the dietary pattern, increasing the use of dietary fiber and prebiotics and reasonable use of probiotics.

The Role of a Pathological Interaction between ß-amyloid and Mitochondria in the Occurrence and Development of Alzheimer's Disease.

Alzheimer's disease (AD) is one of the most common neurodegenerative diseases in existence. It is characterized by an impaired cognitive function that is due to a progressive loss of neurons in the brain. Extracellular ß-amyloid (Aß) plaques are the main pathological features of the disease. In addition to abnormal protein aggregation, increased mitochondrial fragmentation, altered expression of the genes involved in mitochondrial biogenesis, disruptions in the ER-mitochondria interaction, and mitophagy are observed. Reactive oxygen species are known to affect Aß expression and aggregation. In turn, oligomeric and aggregated Aß cause mitochondrial disorders. In this review, we summarize available knowledge about the pathological effects of Aß on mitochondria and the potential molecular targets associated with proteinopathy and mitochondrial dysfunction for the pharmacological treatment of Alzheimer's disease.

High resolution FTIR spectroscopy of germane: First study of 76GeH4 in the region of Tetrad of the strongly interacting ν1+ν2,ν1+ν4,ν2+ν3 and ν3+ν4 ro-vibrational bands.

The infrared spectra of germane, purified and enriched up to 88.1% of 76GeH4, was measured at the temperature of (22.6±0.1) °C and different pressures with a Bruker Fourier transform infrared spectrometer IFS125HR and analyzed for the first time in the region of 2700-3200 cm-1 where the stretching-bending Tetrad (ν1+ν2,ν1+ν4, ν2+ν3 and ν3+ν4 bands) of the ro-vibrational Octad of germane is located. The 3595 transitions belonging to the eight sub-bands of the Tetrad were assigned and theoretically analysed in the frame of the effective Hamiltonian model. The obtained set of 106 fitted parameters reproduces the initial 3595 experimental line positions with the drms=6.81×10-4 cm-1. The presence of numerous resonance interactions in the Tetrad is discussed.

[Etymology of terms in anatomy of central nervous system]. / Etimologiya terminov v anatomii tsentral'noi nervnoi sistemy.

We consider the origin of neuroanatomical terms and their formation as such in the history of medicine. Along with the terms originating from common Indo-European roots and reflecting the typical process of metaphorization of trivial objects and phenomena, in this sphere we find semantic calques (one of the types of borrowing) and formations originating from late Latin. The prevailing simple metaphor testifies to the early origin of most terminological units.

[Congenital adrenal hyperplasia due to 11ß-hydroxylase deficiency: late diagnosis and gender reassignment in a two-year-old child].

11ß-hydroxylase deficiency is a rare autosomal recessive disorder due to impaired steroidogenesis in the adrenal cortex caused by pathogenic mutations in the CYP11B1 gene. The main clinical manifestations are determined by a deficiency of cortisol, ACTH hyperproduction, excessive androgens secretion and the accumulation of 11-deoxycorticosterone, which leads to the development of arterial hypertension. In the diagnostic search, it is important to take into account the ethnicity of the patient, since the frequency of the disease and the prevalence of mutations differ between ethnic groups. The article presents a clinical case of 11ß-hydroxylase deficiency as the result of compound heterozygous mutations in the CYP11B1 gene in a patient of Turkic origin. This case shows the clinical manifestations and the development of complications of 11ß-hydroxylase deficiency, the stages of differential diagnosis of patients with 21-hydroxylase deficiency.

[Etiology of purulent-inflammatory processes in the genital tract: suspicions of clinicians and problems of laboratory confirmation.]

Despite the long history of the study, laboratory diagnosis of gonococcal infection remains a complex task that does not have a clearly regulated effective solution. Aim of investigation was to assess the species diversity of the microbiota of the genital tract of men and women with suspected acute genital gonococcal infection (AGGI) using test systems of Russian manufacturers. A study of samples of the contents of the urethra of 69 men and posterior vaginal fornix fluids of 33 women of reproductive age with characteristic clinical manifestations and a presumptive diagnosis of AGGI was made. Cultivation was carried out using elective culture media with subsequent identification of strains by biochemical properties. Detection of DNA of Neisseria gonorrhoeae, Staphylococcus spp., Streptococcus spp., Enterobacteriaceae, Gardnerella vaginalis, Atopobium vaginae, Lactobacillus spp. performed by PCR using Vektor-Best and InterLab Service kits (Russia). All patients were divided into groups according to the results of the bacteriological method and PCR. A metagenomic study of 16S ribosomal RNA samples was performed on the Illumina MiSeq platform using the MiSeq Reagent Kits v3 kit (600-Cycle Kit). Statistical analysis of the data was performed using criterion x2. As a result of a laboratory study, the presumptive clinical diagnosis of «AGGI¼ found its bacteriological confirmation in 35.3% of cases only, among which fragments of the N. gonorrhoeae genome were detected in 63.9% of the samples only. Moreover, a wide variety of microorganisms in the genital tract of both men and women was found in metagenomic analysis. However, this technique does not allow us to assess the viability of the detected bacteria, and the microflora spectrum is excessively wide. In addition, the high level of genetic polymorphism of different strains of N. gonorrhoeae complicates the interpretation of the results. Deciphering the composition of microbiota allows the use of InterLab Service kits. The decoding of the etiology of purulent-inflammatory processes in the genital tract, which presents serious difficulties, is greatly facilitated by the use of Russian kits for molecular genetic analysis, which, in our opinion, provide the necessary and sufficient information for practice.

[Epigenetic regulation of clinical manifestations of Friedreich's disease]. / Épigeneticheskaia reguliatsiia klinicheskikh proiavlenii bolezni Fridreikha.

AIM: To study a methylation profile of FXN gene and its influence on the clinical phenotype of Friedreich's desease (FD). MATERIAL AND METHODS: The methylation pattern was analyzed in 17 patients with FD. Forty-five CpG-sites in the promoter region and the region of intron 1 of FXN: before the GAA-expansion (UP-GAA) and after the GAA-expansion (DOWN-GAA), were studied. RESULTS: Correlations between the methylation level of CpG-sites in UP-GAA and DOWN-GAA and the number of GAA repeats in both expanded FXN alleles in patients with FD were found. An analysis revealed an earlier onset and a more severe course of FD in cases with hypermethylation of several CpG-sites in the UP-GAA region. The correlation between the methylation pattern and the presence of extraneural manifestations of FD was also revealed. In FD patients with cardiomyopathy, a hypomethylated CpG-site in the promoter region was found. In FD patients with carbohydrate metabolism disorders, two hypomethylated CpG-sites in the DOWN-GAA region were observed. CONCLUSION: The results indicate a significant contribution of epigenetic modifications of FXN to the clinical presentation of FA.

[The history of the discovery of Gasserian ganglion]. / K voprosu ob istorii otkrytiia gasserova uzla.

The article presents in detail the history of the discovery of the trigeminal ganglion in the context to name it Gasserian ganglion. The historical, formal and logical methods of research, along with system analysis were used in the work. An in-depth research of little-known literature sources, which included scientific, publicistic and fiction components, was conducted. The authors for the first time translated into Russian the IV Chapter of Antonius Hirsch's dissertation 'Paris quinti nervorum encephali disquisition anatomica'. This researcher presented the anatomical views of the leading scientists of the time, and their own data on the mechanical properties, features of the topography and preparation of the trigeminal ganglion. The analysis of the literature allowed clearly following the chronology of the discovery of Gasserian ganglion, highlighting the most significant facts of the biography of scientists and recreating the history of anatomy in this area.

Wave-Like Dose-Dependence of the Stimulating Effects of Dimebon on Cognition in a Wide Dose Range.

Comparison of the cognition-stimulating effects of Dimebon in a wide dose range revealed a non-monotonic and nontrivial wave-like dose-dependence of its activity. Positive results were obtained at low (0.02-0.05 mg/kg) or high (5-10 mg/kg) doses of Dimebon, while intermediate doses were ineffective. This type of the dose dependence of the pharmacological effect can indicate that the substance has several targets. This fact should be taken into consideration when selecting the doses and concentrations of the substance and its analogues for further studies, and for planning treatment schemes and administration doses in clinical studies.

[Discoveries of Giulio Cesare Aranzi]. / Otkrytiia Dzhulio Chezare Arantsi.

The article provides a Russian translation of the 19th chapter of the work of Italian anatomist and surgeon Giulio Cesare Aranzi (Julius Caesar Arantius, 1530-1589) 'Observationes anatomicae', which describes his discoveries in the anatomy of the organ of vision: detection of m. levator palpebrae superioris and disproving of the then prevailing statement concerning the origin of external muscles of the eye from the dura mater. The article also gives a brief biography.

[Cognitive disorders in the middle-aged population and cerebrovascular risk factors]. / Kognitivnye narusheniia u lits srednego vozrasta i faktory riska tserebrovaskuliarnykh zabolevanii.

AIM: To study the frequency of subjective and objective cognitive disorders in the middle-aged population and their associations with main and additional cerebrovascular risk factors. MATERIAL AND METHODS: The authors examined 169 men and 239 women aged 40-59 years. Medical history study, blood tests, electrocardiography, brachiocephalic and common femoral arteries scan, echocardiography, magnetic resonance imaging of the brain (MRI) were performed. Luria and Munsterberg tests were done to assess cognitive dysfunction. Affective disorders were assessed by the Hospital scale of anxiety and depression. RESULTS AND CONCLUSION: Absence of subjective (SCI) and/or objective (OCI) cognitive impairments was found in 26,5%; 10% had purely SCI, more than 35,7% of complaints were accompanied by deviations in neuropsychological test results (OCI+), over 25% had only OCI-. The average age of patients with OCI+ was higher than in the control group. In women, the frequency of SCI was twice as high and OCI less frequent as in men. Absence of cognitive impairment and SCI were observed more frequently in individuals with higher education. The prevalence of multiple white matter lesions (WML) in MRI was 36%. Multiple WML and atherosclerosis of major arteries were more common in OCI+ group (47%). Mild affective disorders were more frequent in the studied groups. Anxiety disorders were more common than depressive ones. The amount of patients with affective disorders was highest in OCI+. Therefore, SCI is a common phenomenon among people aged 40-60 years. The use of simple neuropsychological tests in screening examination allows to identify individuals who are most appropriate for active search for vascular risk factors. Anxiety and depressive disorders cause a significant proportion of SCI among middle-aged people and are an important additional target for therapeutic measures.

[Biomarkers and mechanisms of early vascular damage]. / Biomarkery i mekhanizmy rannego povrezhdeniia sosudistoi stenki.

AIM: To assess the association of classic vascular risk factors, indicators of cerebral arteries wall damage and stress induction, and their role in early vascular and brain damage in middle age subjects without vascular events. MATERIAL AND METHODS: 87 patients were evaluated (49 women, 38 men, mean age 51.2±6.5). The following vascular risk factors were assessed: hypertension, diabetes, total cholesterol and low density lipoproteins levels, obesity and smoking. Patients underwent ultrasound of neck arteries, brain MRI and laboratory testing of blood parameters, probably associated with vascular wall damage: CRP, TNF-α, sICAM-1, sVCAM, HIF1-α, NO, VAP-1, VEGF-A, VEGF-C, sVEGF-R1, sVEGF-R2, TGF-ß1, general antioxidant status. RESULTS AND CONCLUSION: Mediating role of stress parameters in risk factors formation, initiation and maintenance of mechanisms of vascular damage was demonstrated. Hypercortisolemia suggested the association with age, atheromatosis, local inflammatory reactions via the TGF-ß1-HIF-1-VEGF family, systemic inflammation response via CRP, and elevated epinephrine levels were associated with TNF-α-mediated systemic inflammation. The association of TNF-α and MRI signs of cerebral small vessel disease (SVD) in non-hypertensive patients may indicate that TNF-α-mediated inflammation and increased permeability of vessel wall is an independent cause and potential biomarker of early small vessel damage. Influence of hypertension on age-dependent SVD is probably maintained by local vascular wall damage mechanisms via the TGF-ß1-HIF-1-VEGF family. However, hypertension heterogeneity and association of early cerebral vessels damage with various protective reactions require further clarification of the conditions for using these parameters as possible biomarkers of early SVD.

Psychotropic Activity of New Fluorinated Derivatives of Tetrahydrocarbasoles.

Psychotropic properties of CA-7043× and CA-7050×, new fluorinated derivatives of tetrahydrocarbasoles, were examined on outbred CD1 mice and transgenic 5×FAD mice with Alzheimer disease. Both agents exerted cognitive-stimulating and anxiolytic effects in a dose of 5 mg/kg. In the new cage test, they retarded extinction of orientation and exploratory behavior. CA-7043× produced an anxiolytic effect on CD1 mice assessed in the open-field test and exerted cognitive-stimulating action in the new location test. In the same tests, CA-7050× demonstrated the cognitive-stimulating and anxiolytic effects on transgenic 5×FAD mice.

[The history of discovery of bulbourethral glands].

The article outlines the chronology of the discovery of the bulbourethral glands. Their first image appeared in 1600 in a collection of anatomical tables by Italian anatomist Hieronymus Fabricius of Acquapendente. In the scientific literature, they were first mentioned in one of the editions of "Journal des scavans" in 1684 as discovered by the French surgeon Jean Mry. The first detailed description of the structure, topography and function of these glands was presented in the work of English physician and anatomist William Cowper in 1699.

[Analysis of results of drug therapy for symptomatic multiple myeloma].

Drug therapy for symptomatic multiple myeloma is comparable for both sexes in its effectiveness and safety. A 3-year event-free survival is comparable in men and women; overall survival in men is lower than in women.

[Tolerance in the substantiation of the maximum allowable content of antibiotics in food products].

Provides the ability to use the principle of tolerance in substantiation of the maximum permissible levels (MDU) residual amounts of antibiotics of tetracycline group (ATG) in meat and dairy products. Using the data of monitoring research of food products, carried out in 2005-2011, in the system of Rospotrebnadzor was conducted analysis of the levels of tolerance of residual quantities of ATG in the meat, meat by-products, chicken eggs, milk, dairy and other products. The conclusion weas made that the Russian Federation hygienic norm MDU of ATG of meat and dairy products - 0.,01 mg/kg (SanPiN2.3.2.2804-10) - justified, consistent with the principle of tolerance and reduces the risk of negative consequences for the population.