Vladimir A. Kulchitsky

National Academy of Sciences of Belarus | NAS B · Institute of Physiology

One of the unresolved issues in the problem of artificial intelligence is the question of the desirability of introducing elements of motivation and emotions into artificial neural networks. The attitude to this issue is still controversial. The coding system in the interfaces is based on the binary system of the "on-off" type. In the case that an emotional component is included into the artificial intelligence system, it is advisable to introduce, along with binary coding system, a positive or negative attitude to the decision which is being made by implementing a feedback system. Thus, the “on” or “off” due to the feedback can, at a certain level of “noise” or emotional disturbances, decline or turn into appropriate opposite. This article presents an attempt to critically understand the existing problem of an effective result of artificial intelligence in the presence of positive or negative emotional component of varying intensity and duration. It is important that all events associated with artificial intelligence functioning should be considered not as static ones, but as events developing simultaneously in time and space.

The article briefly describes advantages of autologous mesenchymal stem cells (MSCs) use in clinical conditions to correct structure and function of damaged areas in organs and tissues of humans and animals. The effectiveness of MSCs migration via per-ineural nerve spaces to inner organs was confirmed. Such method of cell therapy allows avoiding major surgeries and achieving more effective result in combination of classic treatment techniques with MSCs perineural delivery to damaged organs and tissues.

The problem of the functional reparation of injured internal organs, especially vital ones (heart, lungs) is socially significant, since it has not been solved until now. What body reserves and practical skills of clinicians are the bases for new ideas aimed at preventing and/or restoring impaired functions of internal organs? For the authors of the study, the postulate was the well-known idea that stem cells (SCs) are the foundation for the development of cells during ontogenesis and the implementation of reparative processes in organs and tissues of living organisms. Unfortunately, the endogenous potential of SCs in reality turns out to be insufficient with the development of pathological processes in a living organism. The existing methods of classical therapy, as well as the systemic administration of SCs for the purpose of additional activation of regenerative processes in the body, often turn out to be palliative and insufficient for restoring the working capacity of patients. It is advisable to find new technologies for the activation of reparative processes in the body during the development of pathological processes. The authors propose to supplement the existing technologies for the reparation of the functions of internal organs after their damage with the help of a fundamentally new method of introducing autologous SCs. The technique is based on the natural perineural migration of autologous SCs along the cranial, somatic or autonomic nerves to the site of destruction in the internal organs. As a result, an intensive reparative process is initiated in the damaged tissues. In order to initiate a regenerative process in tissues, a miniature surgery is required under local anesthesia, which is necessary for the perineural administration of autologous SCs. After perineural implantation of SCs, targeted and natural migration of SCs develops to the area of internal organ damage (heart, lungs, liver, pancreas, stomach, spleen, kidneys).

Perineural migration of stem cells (SCs) is the basis for the development of new ap-proaches for internal organ diseases treatment. The authors have previously proved in ex-perimental and clinical conditions the effectiveness of perineural migration of SCs through the cranial nerves in strokes and brain injury conditions. In recent studies, the feasibility of SCs delivery through the vagus nerve to heart, liver, pancreas has been confirmed. Thus, the use of nerve trunks as a migration pathway network for the delivery of SCs to the in-ternal organs is promising in the treatment of socially significant diseases (stroke, heart attack, diabetes, gastric ulcer) since they avoid complex surgical interventions. Keywords: Stem Cells; Perineural Transport; Cell migration; Nervous System; Diseases; Treatment

Kulchitsky Vladimir, Zamaro Alexandra, Koulchitsky Stanislav. Perineural Migration of Stem Cells in the Model of Damaged Heart Nodes. Biomed J Sci & Tech Res 14(4)-2019. BJSTR. MS.ID.002578. Unilateral vagotomy (n=15) with simultaneous injection of 10 thousand stem cells in 10µl of culture medium to intact vagus nerve (n=9) was performed on Wistar rats an-esthetized with ketamine-xylazine-acepromazine. Migration of stem cells to atriums and ventricles was tracked by fluorescent markers. Also protective role of perineural injection of stem cells was established in relation to development of destructive processes in heart ganglions. Unilateral vagotomy and injection of stem cells to intact vagus nerve resulted in preservation of cell structure in sinoatrial ganglion and recovery of cardiac rhythm. It was assumed that technique of perineural migration of stem cells along vagus nerve fibers to heart is promising for prevention of arrhythmias and heart failure development in pa-tients with impaired heart function.

ARTICLE INFO Hypothesis on reality of perineural migration of stem cells (SCs) along vagus nerve fibers to injured heart and brain stem regions was experimentally verified on ten Wistar rats. Heart injuries were simulated using unilateral vagotomy. Vagotomy led to degeneration of vagus nerve fibers in heart and brain stem. These destructive processes in tissues were the basis for SCs migration. FITC-labeled SCs were revealed in cardiac ganglions and nucleus tractus solitarii of brain stem. Experimental results should be used to test the technique in clinical conditions in patients with impaired cardiac function, namely with acute heart failure after myocardial infarction.

Abstract Zamaro A, Krivenchuk D, Denisov A, Koulchitsky S, Kulchitsky V. Topical Issues of Bioprinting Technology. Biomed J Sci & Tech Res. 2018; 12(1) 1-3. BJSTR. MS.ID.002195. DOI: 10.26717/ BJSTR.2018.12.002195. Brief analysis of positive and negative aspects of bioprinting was performed. Bioprinting has technical deficiencies and a range of unresolved issues, including the absence of bioprinting protocol strategy. It is necessary to develop bioprinting protocols as well as technologies of 4D production of biological tissues and techniques of formed organs and tissues combination with tissues of living organism to successfully resolve biocompatibility issues. Keywords: brain structure, brain functions, brain plasticity, brain reparation, bioprinting prospects.

Kletskov AV, Potkin VI, Kolesnik IA, Petkevich SA, Kvachonak AV, Dosina M.O., Loiko DO, Larchenko MV, Pashkevich SG, Kulchitsky VA (2018) Synthesis and Biological Activity of Novel Comenic Acid Derivatives Containing Isoxazole and Isothiazole Moieties. Natur. Product Communication (NPC) 13(11):1507-1510. Abstract: Methyl 5-hydroxy-4-oxo-4H-pyran-2-carboxylate was synthesized by esterification of methanol with comenic acid under acidic catalysis. The obtained ester was alkylated with 3-(chloromethyl)-5-phenylisoxazole and 4,5-dichloro-3-(chloromethyl)isothiazole to afford corresponding conjugates containing isoxazole and isothiazole moieties which then were transformed into water-soluble Li-salts. During the bioassays of synthesized isoxazole and isothiazole derivatives of comenic acid in mixtures with first-line antitumor drug Temobel (Temozolomid) used in brain tumors chemotherapy, a synergetic effect was observed. Keywords: Comenic acid, Isoxazole, Isothiazole, Esterification, Alkylation, Biological activity.

Kulchitsky V., Zamaro A., Zaykina N., Yaromenka Y., Hudny G., Krivenchuk D., Semenik-Philipovich T., Koulchitsky S., Andrianova T., Dosina M., Kaliadzich Z. (2018) The Role of Feedback in Breathing Self-Regulation in Health and Obstructive Sleep Apnea Syndrome Development. Biomed J Sci & Tech Res 11(3): 1-3. BJSTR. MS.ID.002103. DOI: 10.26717/ BJSTR.2018.11.002103. Abstract Hypothesis on efficiency of feedback from medullary chemoreceptors (MCh) which react to carbon dioxide excess in the organism was tested in patients with obstructive sleep apnea syndrome (OSAS). Attenuation of feedback from MCh to respiratory center was established in 62.5% of patients with OSAS and 43.8% of healthy volunteers after “rebreathing” test. Obtained data correspond to significant variability of MCh sensitivity to CO2 content in brain stem in health and disease which is accompanied with increase of CO2 content in the organism. It was concluded that revealed decreased sensitivity of MCh to hypercapnic stimulus in patients with OSAS is one of diagnostic criteria which will allow substantiating reasonability of CPAP (Continuous Positive Airway Pressure) and BiPAP (Biphasic Positive Airway Pressure)-therapy use in patients with OSAS to prevent fatal breathing stop during sleep. Keywords: Medullary Chemoreceptors; Breathing Regulation; Obstructive Sleep Apnea; “Rebreathing” Test; Patients. Abbreviations: BiPAP: Biphasic Positive Airway Pressure; СО2: Carbon dioxide; CPAP: Continuous Positive Airway Pressure; MCh: Medullary chemoreceptors; OSAS: Obstructive Sleep Apnea Syndrome; Qco2: Parameter Reflecting Degree of Central Chemoreceptors Functioning.

Abstract Zamaro A. Zhukava T., Kulchitsky V. Antitumor effects of allogenic mesenchymal stem cells. Arch Cancer Res. 2018. Vol. 6. DOI: 10.21767/2254-6081-C5-018 In conditions of ketamine-xylazine-acepromazine anaesthesia (55.6, 5.5, and 1.1 mg/kg respectively), Wistar rats (n=25) after scull trepanation of sensorimotor zone were implanted with 100 mcl of glioma C6 cell culture (500 cells/mcl). After trepanation rats were divided in 3 groups: 1st group (n=9), subjected to 3 intranasal mesenchymal stem cells injections (500 cell/mcl, with FITC labeled CD105) at one-week interval. 2nd group (n=6) animals were intranasally injected with saline 3 times with one-week interval. 3rd group (n=10) rats were studied without any subsequent interventions. Rat’s lifespan resulted in 22.7 days for 1st group, 16.8 days for 2nd, 18.1 days for 3rd. Only 1st group included top 4 animals, by lifespan, with mean of 36 days. Conclusion. So, the interaction of mesenchymal stem cells with glioma cells is accompanied by the occurrence of conditions in the body, which are manifested in the lifespan increase of laboratory animals.

Kulchitsky V, Zamaro A, Navitskaya V, Koulchitsky S, Shanko Y. Regulatory Effects of Mesenchymal Stem Cells in Brain. Biomed J Sci&Tech Res. 2018. 11(1): 1-3. BJSTR. MS.ID.002039. DOI: 10.26717/ BJSTR.2018.11.002039. Abstract The question on various functional effects of mesenchymal stem cells (MSCs) during different pathological processes development in brain was considered. Attention was paid to ability of MSCs to be involved in control of reparative processes in nerve tissue due to expression of many neurotrophic factors. Such feature of MSCs enhances their positive effects by realization of another potential – ability to progress in neuron-like direction. They also have an impressive ability to interact with immune competent cells in brain tissue to increase antitumor effect. It was shown that MSCs are able to synthesize and express lots of regulatory factors which inhibit growth of glioma cells. Therefore, vision of MSCs functional heterogeneity was expanded and their various regulatory effects were combined in realization of protective function both in health and disease. Keywords: Antitumor Effects; Brain Plasticity; Defensive Reactions; Neurotrophic Factors; Reparative Processes; Stem Cells; Transcription Factors Abbreviations: Ad-hMSCs: Adipose Human Mesenchymal Stem Cells; BDNF: Brain Derived Neurotrophic Factor; GDNF: Glial Cell Derived Neurotrophic Factor; NGF: Nerve Growth factor; NGFR: Nerve Growth Factor Receptor; MSCs: Mesenchymal Stem Cells; SCs: Stem Cells; Sox: (Sry-related HMG box) genes encode transcription factors.

Kulchitsky V, Zamaro A, Shanko Y, Koulchitsky S. Prospects of Perineural Implantation of Stem Cells in Recovery of Neural Networks’ Functions in Brain Diseases. Biomed J Sci&Tech Res. 2018. 10(3):1-4. BJSTR. MS.ID.001959. DOI:10.26717/ BJSTR.2018.10.001959 Abstract Background: The question on prospects of additional use of cellular therapy in standard protocols of brain neural networks recovery after neurodestructive processes of various etiology was analyzed. Data on low efficiency of existing methods of neurodestructive processes treatment gave a boost to authors to conduct series of studies related to brain diseases and cellular technologies. Existing treatment principles now should be updated with new methods – in particular, cellular technologies. This statement was based on stem cells (SC) presence in human brain. Nature has formed basis for neural network formation in the process of training and for recovery therapy in case of pathology. Unfortunately, recovery potential of brain SC appeared to be ineffective in neurodestructive processes. Therefore, SC should be additionally injected into brain. It is advisable to use autologous SC in order to avoid possible side effects, such as malignization of allogeneic and other SC. But in certain cases use of allogeneic SC can be approved. Methods: Autologous mesenchymal SC (MSC) are usually administered to patients in experimental and clinical conditions. Two ways of MSC delivery to brain are preferred: with cerebral blood flow after MSC injection into bloodstream and MSC implantation close to damaged area after additional skull trepanation. Authors experimentally developed and clinically evaluated new technique of perineural implantation of MSC. This method is based on natural ability of SC to migrate. MSC are implanted into the area of cranial nerve endings (mainly olfactory and trigeminal) and then they migrate along cranial nerves to cranial cavity. Results: The area of vomeronasal complex (VC) is preferred for MSC implantation because its mucosa has nerve endings of both olfactory and trigeminal nerves. Such technique of MSC implantation was substantiated by authors and was named perineural implantation of MSC when used in neurodestructive processes. Discussion and Conclusion: The article contains critical analysis and prospects of cellular technologies development for therapy of brain diseases. Special attention is paid in discussion to technology of perineural implantation of MSC in experimental and clinical conditions. Key words: neurodestructive processes, stem cells, mesenchymal stem cells, reparation of neural network functions, recovery of brain functions control, vomeronasal complex Abbreviations: SC, Stem Cells; MSC, Mesenchymal Stem Cells; VC, Vomeronasal Complex

Shanko Y, Navitskaya V, Zamaro A, Krivenko S, Zafranskaya M, Pashkevich S, Koulchitsky S, Takalchik Stukach Y, Denisov A, Kulchitsky V. Prospects of Perineural Administration of Autologous Mesenchymal Stem Cells of Adipose Tissue in Patients with Cerebral Infarction. Biomed J Sci&Tech Res 10(1)-2018. BJSTR. MS.ID.001884. DOI: 10.26717/ BJSTR.2018.10.001884.

Abstract Background: Neurodestructive processes of any etiology are related to problematic and socially important diseases due to ineffective therapeutic strategy and need to search for new successful ways of treatment and rehabilitation of patient with cerebral infarctions and brain attacks. Aims: Authors plan to verify hypothesis on viability of additional use of perineural implantation of autologous mesenchymal stem cells (MSC) in order to optimize standard therapy of patients with brain attacks. Such combined technology is aimed at extra activation of brain plasticity mechanisms during development of neurodestructive processes. Methods: The technique of MSC perineural migration to injured brain regions was experimentally verified on rats (n=40) paying attention to somatotopic organization of cranial nerves. This technique was clinically tested in pilot project. Phenotyping of autologous MSC from adipose tissue (AT) was performed in 23 patients with brain attacks. These 23 patients received standard treatment as per international guidelines together with three perineural implantations of autologous MSC from AT with 5-9 days intervals. The other group of patients (n=7) received only standard therapy as per international guidelines. Results: Additional use of cell therapy resulted in more rapid and effective recovery of disordered neurological functions in all cases compared to those who received standard therapy. The phenomenon of abrupt recovery of neurological functions was established during first 24 hours after each injection of autologous MSC. Cumulative recovery of functions progressed after each implantation. Discussion and Conclusion: Experimentally developed technique of perineural implantation of autologous MSC was successfully verified in clinical conditions in accordance with certified cell therapy guideline (The Ministry of Health of the Republic of Belarus) in combination with standard treatment of patients with cerebral infarctions. Cell therapy with autologous MSC from AT by means of perineural delivery to injured brain regions is the basis for activation of reparative potential of nerve tissue and progressive recovery of neurological functions in patients with cerebral infarctions. Citation: Shanko Y, Navitskaya V, Zamaro A, et al. Somatotopic principle of perineural implantation of stem cells in patients with brain injuries. J Neurol Stroke. 2018;8(5):259‒261. DOI: 10.15406/jnsk.2018.08.00321

Abstract The authors analyze the methods of chemotherapy, which will allow to preserve antitumor effects when the dose of the cytostatic is reduced. A combined use of a chemotherapeutic with heterocyclic compounds is necessary to achieve this effect. New possibilities are opened for different chemotherapeutic drugs that are used below those dosages recommended by international protocols when combined with nanoparticles and heterocyclic compounds. Such tactics is cost-effective. But for patients it is most important that this approach accompanies reduction of side effects. Kulchitsky V, Zamaro A, Potkin V, Gurinovich T., Koulchitsky S. Prospects of chemotherapy side effects minimization. Canc. Oncol. Open Access J. (2018);1(1):15-16.

Kulchitsky V, Zamaro A, Koulchitsky S. Hypoxia and Hypercapnia: Sensory and Effector Mechanisms. BJSTR MS. 2018 Vol.8 (4): 1-3 DOI: 10.2671/BJSTR.2018.08.001692 Key mechanisms of respiratory homeostasis control have been reviewed from the modern positions. These mechanisms are based on the principles of evolutionary enhancement of feedback of responses from vascular (peripheral) chemoreceptors which react mainly on shifts of oxygen content in blood and medullary (central) ones which keep track on levels of carbon dioxide and hydrogen ions in brain tissue. Concerted activity respiratory center neural network in the process of signal processing from central and peripheral chemoreceptors is the basis for effective control of respiratory homeostasis at slightest shifts of O2 content in blood and CO2 and H+ ions concentration in brain tissue.

ABSTRACT. In fact, it is proposed to bring in key element in the vision of pathological mechanisms of somatic diseases development – functional state of intestinal microbiota. The grade of intestinal dysbiosis affects formation of conditions for endotoxemia initiation and manifestation of pathological processes accompanied with development of systemic and local sites of inflammation in blood vessel walls and various organs. Confirmation of this hypothesis will allow creating reasonable methods of pathological processes correction at the stage of human intestine. Positive effects of different diets, e.g. Mediterranean one, significance of Chinese traditions of tea-drinking, relevance of products’ quality in food retail chains, parenting of nutrition ritual from an early age, etc. should be reviewed once again. Kulchitsky V., Zamaro A., Huo Po, Li Junbo, Chen X, Koulchitsky S. (2018) Association of Intestinal Dysbiosis Problem with Initiation and Development of Somatic Diseases. Biomed Sci&Tech Res 8(2): 1-3. BJSTR MS.ID.001630. DOI: 10.26717/ BJSTR.2018.08.001630

Data on the ability of perineurally implanted mesenchymal stem cells to form cell clusters around damaged brain region were obtained in in vivo experiments. High efficiency of neural network formation by dissociated cells of rat’s brain was established in in vitro experiments. Neural network processes are accompanied with increased effectiveness of central control recovery of somatic and visceral functions of the organism by means of activation of neuroplastic processes. Shanko Y, Zamaro A, Takalchik S Y, Koulchitsky S, Pashkevich S, Panahova E, Navitskaya V, Dosina M, Denisov A, Bushuk S, Kulchitsky V. Mechanisms of Neural Network Structures Recovery in Brain Trauma. Biomed J Sci&Tech Res 2018.7(5): 1-2. BJSTR MS.ID.001567.

Rubakhova V., Zamaro A., Grinchik N., Larchenko M., Koulchitsky S. et al. Biomed J Sci&Tech Res 7(3)- 2018, BJSTR. MS.ID.001503. DOI: 10.26717/ BJSTR.2018.07.001503 Extrusion technology is considered one of the most perspective and highly effective, which involves thermal, hydro- and mechanical processing and allows obtaining next-gen products with predefined properties. However, compared to traditional technologies of food preparing, which have been tested for ages, it is useful to conduct insightful fundamental and applied studies which will allow defining and improving conditions of extrusion products preparing. It is also quite important to determine conditions when side effects of these products may manifest. Biomed J Sci&Tech Res 7(3)- 2018 BJSTR. MS.ID.001503. DOI: 10.26717/ BJSTR.2018.07.001503