Estimation of the Ischemic Lesion in the Experimental Stroke Studies Using Magnetic Resonance Imaging (Review).

In translational animal study aimed at evaluation of the effectiveness of innovative methods for treating cerebral stroke, including regenerative cell technologies, of particular importance is evaluation of the dynamics of changes in the volume of the cerebral infarction in response to therapy. Among the methods for assessing the focus of infarction, MRI is the most effective and convenient tool for use in preclinical studies. This review provides a description of MR pulse sequences used to visualize cerebral ischemia at various stages of its development, and a detailed description of the MR semiotics of cerebral infarction. A comparison of various methods for morphometric analysis of the focus of a cerebral infarction, including systems based on artificial intelligence for a more objective measurement of the volume of the lesion, is also presented.

Therapeutic Efficacy and Migration of Mesenchymal Stem Cells after Intracerebral Transplantation in Rats with Experimental Ischemic Stroke.

We studied therapeutic efficacy and migration characteristics of mesenchymal stem cells isolated from the human placenta after their intracerebral (stereotactic) administration to rats with the experimental ischemic stroke. It was shown that cell therapy significantly improved animal survival rate and reduced the severity of neurological deficit. New data on the migration pathways of transplanted cells in the brain were obtained.

Dose-Dependent Effects of Intravenous Mesenchymal Stem Cell Transplantation in Rats with Acute Focal Cerebral Ischemia.

Intravenous transplantation of mesenchymal stem (stromal) cells (MSC) is a promising approach to the treatment of ischemic stroke. In the published reports of the already completed preclinical and clinical studies the dosages of transplanted MSC greatly vary. However, the optimal dosage has not been determined. The dose-dependent effect of intravenous MSC transplantation was studied, in rats with experimental cerebral infarction. To this end, 5×105 and 2×106 MSC were intravenously administered 24 h after modeling of acute focal ischemia followed by complex assessment of the therapeutic efficacy over 60 days. The rate and degree of the recovery of neurological functions in rats increased with increasing the dose of injected cells, which confirms the dose-dependent effect of intravenous MSC transplantation.

Methods of Generation of Induced Pluripotent Stem Cells and Their Application for the Therapy of Central Nervous System Diseases.

The use of induced pluripotent stem cells (IPSC) is a promising approach to the therapy of CNS diseases. The undeniable advantage of IPSC technology is the possibility of obtaining practically all types of somatic cells for autologous transplantation bypassing bioethical problems. The review presents integrative and non-integrative methods for obtaining IPSC and the ways of their in vitro and in vivo application for the study and treatment of neurological diseases.

Comparative Analysis of the Effects of Intravenous Administration of Placental Mesenchymal Stromal Cells and Neural Progenitor Cells Derived from Induced Pluripotent Cells on the Course of Acute Ischemic Stroke in Rats.

We compared the effects of placental mesenchymal stromal cells and neural progenitor cells derived from induced human pluripotent cells after their intravenous administration to rats in 24 h after transitory occlusion of the middle cerebral artery. The therapeutic effects were evaluated by the dynamics of animal survival, body weight, neurological deficit, and the volume of infarction focus in 7, 14, 30, and 60 days after surgery. Intravenous injection of neural progenitor cells produced a therapeutic effect on the course of experimental ischemic stroke by increasing animal survival in the most acute period and accelerating compensation of neurological deficit and body weight recovery. Neural progenitor cells were more effective than mesenchymal stromal cells from human placenta. The effectiveness of intravenous transplantation of neural progenitor cells in the model of occlusion of the middle cerebral artery is shown by us for the first time, although the therapeutic effect of their direct transplantation into the brain has already been described.

[Gastroenterological aspects of atherosclerosis].

The pathogenesis of atherosclerosis has been studied for over a hundred years, but so far no consensus on this issue doesn't exist. During this time, experts have gone from ideas of atherogenesis as a consequence of excess cholesterol in the diet to complex theories of the pathogenesis of atherosclerosis. Today generally accepted that one of the major risk factor for cardiovascular disease and atherosclerosis is dyslipidemia. When atherogenic dyslipidemia occur expressed disbiotic changes intestine and lead to endotoxemia, bacterial translocation and impaired liver function. The undoubted fact is that the liver plays an important role in the development of atherogenic dyslipidemia, and also is the target organ, which leads to the development of nonalcoholic fatty liver disease (NAFLD). Currently, NAFLD is a major risk factor for cardiovascular disease, it limits the possibility of adequate lipid-lowering therapy, increasing cardiovascular risk. Therefore, in the treatment of atherogenic dyslipidemia with statins and fibrates useful purpose hepatoprotectors. Choosing hepatoprotectors depends on the stage NAFLD.

[Advisability of using probiotics in the treatment of atherogenic dyslipidemia].

One of the main components of the metabolic syndrome is a non-alcoholic fatty liver disease (NAFLD). Currently, NAFLD is recognized as one of the main factors for cardiovascular disease because cholesterol synthesis is carried out mainly in the liver. In connection with this selection of lipid-lowering therapy, which has a known hepatotoxic effect, is a challenge. In the pathogenesis of NAFLD important role played by the violation of the colon microflora and, consequently, elevated levels of metabolic products of microorganisms (short chain fatty acids, endotoxin, nitric oxide), which must also be considered in the treatment of atherogenic dyslipidemia. In patients with NAFLD and atherogenic dyslipidemia appointment of combination therapy of statins and probiotics are more effective in lowering cholesterol and products of metabolism of intestinal microflora compared with monotherapy.

[Diagnostic value of nitric oxide and endotoxins at non-alcoholic fatty liver disease].

The aim of this examination was investigation of the nitrogen oxide (NO) role for the inflammation forming in the patients with nonalcoholic fat disease of the liver. 90 patients (male--25, women--65) were examined: steatohepatitis (SH)--60 patients, liver steatosis--30 patients). Index of body mass was increased on 40-45%. NO metabolites blood level was examined by Metelskaya V.A. (2005) method. The trustworthy increase of NO production in the SH patients in comparison in patients with steatosis liver and was increasing together with aminotransferases and GGTP. NO as inflammation marker may be real criterion of the liver inflammation in the patients with the early stage transformation of liver steatosis to SH.

[Intestinal dysbiosis and atherogenic dyslipidemia].

Numerous studies in recent years had proved pathogenetic correlation of the intestinal ecological community, not only with diseases of the gastrointestinal tract but also with diseases such as atherosclerosis and hypertension, urolithiasis and pyelonephritis, gallstones and hepatitis. In its role in maintaining homeostasis an intestinal microflora isn't inferior to any other vital organs. All this allowed to distinguish it as an independent body. Recently, as one of the most important factors for the development of dyslipidemia scientists consider breaking the functional state of the liver, as well as changes in blood lipid spectrum and disturbance of cholesterol metabolism begins at the level of the hepatocyte. However, in 2001, Carneiro de Moura proposed a theory of violation of the microbial community in the colon as one of the ways to lipid metabolism. By reducing the detoxification function of intestinal microflora associated with Microecological disorders of various origins, the first "hit" is to the host liver--is on one side. On the other--the vast majority of microorganisms are characterized by a pronounced ability of bile acids deconjugation, and therefore the increased reproduction in the ileum of bacteria (especially anaerobic, with enhanced activity against deconjugation activity to related bile acids) and the formation of toxic endogenous bile salts, acids are important prerequisites for the occurrence of violations of all functions of the liver, including the activities of Kupffer cells and the whole system of mononuclear macrophages. In this regard, the formation and progression of dyslipidemia, regardless of the target organ must be closely linked with the digestive tract by micro. Schematically it can be represented as follows: violation of microecology intestine --> accumulation of endotoxin in the gut --> entry of endotoxins in portal vein to the liver --> RES of liver cell damage --> strengthening the pathological effects of toxicants other (non-microbial) origin --> dysfunction of hepatocytes --> dislipoproteidemiya.

[Hypolipidemic therapy in patients with non-alcoholic fatty liver disease].

To date generally accepted that one of the major risk factors for cardiovascular disease (CVD) and atherosclerosis is dyslipidemia. The undoubted fact is that the liver plays an important role in the development of atherogenic dyslipidemia, and simultaneously being the target organs, which leads to the development of nonalcoholic fatty liver disease (NAFLD). NAFLD is a major risk factor for CVD, it limits the possibilities for adequate lipid-lowering therapy, increasing cardiovascular risk. In this regard, the treatment of atherogenic dyslipidemia with statins and fibrates appropriate to hepatoprotectors disposal. Hepatoprotectors choice depends on the stage of NAFLD. At the steatosis stage of the NAFLD expedient method of statins in combination with essential phospholipids. At the nonalcoholic steatohepatitis (NASH) stage of NAFLD patient should receive statin therapy combined with ursodeoxycholic acid (UDCA). Patients with high levels of hypercholesterolemia in achieving target levels of cholesterol--low lipoprotein density (LDL-cholesterol) and decrease the side effects is the best combination of statins with the cholesterol absorption inhibitor. The complex lipid-lowering therapy in patients with NAFLD should include drugs that normalize the intestinal microflora (intestinal antiseptic, pre- and probiotics).

[Drug (statine)-induced hepatitis].

In the article is presented the case of development of medicinal hepatitis as result of irrational use of statin treatment at patient with Ischemic heart disease and nonalcoholic Fatty Liver Disease against morbid obesity. The clinical observation reflects the necessity of usage of liver protectors in prevention of possible side effects of hypolipidemic statin treatment and emphasizes the advantage of double cholesterol inhibition.

[Cell therapy for ischemic stroke. Stem cell types and results of pre-clinical trials]. / Kletochnaia terapiia ishemicheskogo insul'ta. Tipy stvolovykh kletok i rezul'taty doklinicheskikh issledovanii.

The literature review addresses the use of stem cells (SC) in ischemic stroke (IS). Part 1 of the paper overviews the results of experimental animal studies. Characteristics of different SC types and results of their studies in experimental models of IS are presented in the first section, the second section considers pros and cons of the methods of SC injection.

[Cell therapy for ischemic stroke. Results of clinical trials and perspectives of clinical application in the Russian Federation]. / Kletochnaia terapiia ishemicheskogo insul'ta. Rezul'taty klinicheskikh issledovanii i perspektivy primeneniia v Rossiiskoi Federatsii.

The first part of the review summarized the results of preclinical animal studies using stroke models that demonstrated the efficacy of cell therapy. The second part presents the proposed mechanisms of action of stem cells, optimal therapeutic window for cell transplantation, the results of completed clinical trials on humans in the period from 2010 to 2017, as well as the legal aspects of the use of cell technologies in the Russian Federation.