Mitochondrial diseases (MD) are a heterogeneous group of multisystem disorders involving metabolic errors. MD are characterized by extremely heterogeneous symptoms, ranging from organ-specific to multisystem dysfunction with different clinical courses. Most primary MD are autosomal recessive but maternal inheritance (from mtDNA), autosomal dominant, and X-linked inheritance is also known. Mitochondria are unique energy-generating cellular organelles designed to survive and contain their own unique genetic coding material, a circular mtDNA fragment of approximately 16,000 base pairs. The mitochondrial genetic system incorporates closely interacting bi-genomic factors encoded by the nuclear and mitochondrial genomes. Understanding the dynamics of mitochondrial genetics supporting mitochondrial biogenesis is especially important for the development of strategies for the treatment of rare and difficult-to-diagnose diseases. Gene therapy is one of the methods for correcting mitochondrial disorders.Graphical Abstract

This paper is about a way of correction of endothelial dysfunction with the inhibitor of arginase: L-norvaline. There is an imbalance between vasoconstriction and vasodilatation factors of endothelium on the basis of endothelial dysfunction. Among vasodilatation agents, nitrogen oxide plays the basic role. Amino acid L-arginine serves as a source of molecules of nitrogen oxide in an organism. Because of the high activity of arginase enzyme which catalyzes the hydrolysis of L-arginine into ornithine and urea, the bioavailability of nitrogen oxide decreases. The inhibitors of arginase suppress the activity of the given enzyme, raising and production of nitrogen oxide, preventing the development of endothelial dysfunction.

The therapeutic effect of multipotent mesenchymal stem cells has been proven on various disease models. One of the mechanisms is the paracrine effect of the cells on the surrounding tissues.The aim. To investigate the secretome effectiveness of the multipotent mesenchymal stem cells in the treatment of adjuvant arthritis and contact-allergic dermatitis in Wistar rats.Materials and methods.Adjuvant arthritis was simulated in 26 female rats by the administration of Freund's complete adjuvant and then treated with the administration of 100 µl of multipotent mesenchymal stem cell secretome or saline. Contact-allergic dermatitis was modeled on 30 female rats by applying 200 μl of an oil solution of dinitrofluorobenzene to the skin on days 1, 5 and 6. Then the rats were treated with fluocinolone ointment (a positive control), baby cream (a negative control), baby cream with a secretome of native multipotent mesenchymal stem cells or from the cells processed with dexamethasone.Results.Judging by the indicators of the longitudinal and transverse dimensions of the paws in rats and a histological examination, the secretome did not have any anti-inflammatory effect on adjuvant arthritis. A cream with a secret from multipotent mesenchymal stem cells processed with dexamethasone, was the most effective on the model of contact-allergic dermatitis: the clinical improvement occurred on the 2^ndday. The secretome from native multipotent mesenchymal stem cells and fluocinolone had a therapeutic effect on the 3^rdday of application, the negative control - on the 4^thday. The lymphocytic infiltration coefficient was significantly lower (p <0.05) in all the cases compared to the negative control (2.8 ± 0.1). However, the lowest infiltration was observed when the cream with secretome from native (1.75 ± 0,1) and dexamethasone-stimulated (1.76 ± 0.1) multipotent mesenchymal stem cells was being used.Conclusion.The cream with the secretome of multipotent mesenchymal stem cells suppresses lymphocytic infiltration more strongly than the highly active topical glucocorticosteroid - fluocinolone - on the model of contact-allergic dermatitis, which is a classic local delayed-type hypersensitivity reaction. However, a further study of the therapeutic effect of the secretome on models of systemic inflammatory diseases is required after its preliminary purification from large-molecular proteins.

The aim of the study was to test whether P-αB can be positioned as a preventing and treating agent for cardiovascular diseases.Materials and methods. The study was performed on sexually mature male Wistar rats. Endothelial dysfunction was modulated by a 7-days intraperitoneal administration of L-NAME at the dose of 2.5 mg/100 g. P-αB, or erythropoietin (EPO), was used for therapy at the dose of 2.5 µg/100 g × 3 times for 7 days, the total dose was 7.5 µg/100 g. The function of endothelium was estimated by an endothelium-dependent and endothelium-independent vasodilation. In addition, a histological assessment of the abdominal aortic wall state and the analysis of eNos, Tnf and Il-1β genes expression were performed. To estimate prothrombotic properties, P-αB and EPO were administered, at the doses of 2.5 and 5 µg/100 g (3 times a day for 7 days, the total doses were 7.5 µg/100 g and 15 µg/100 g, respectively) and on the 8th day, the time of ferric (III) chloride-induced carotid artery thrombosis was estimated.Results. Theresults of the functional tests for endothelium-dependent and endothelium-independent vasodilatation, as well as the histological picture of the aorta have evidenced that P-αB and EPO do not affect L-NAME-induced hypertension but improve the endothelium function. At the same time, P-αB shows a significantly higher endothelial-protective activity, reducing the coefficient of endothelial dysfunction from 5.1±0.15 to 2.72±0.12. In addition, P-αB has significantly increased the expression of eNos and reduced the expression level of Tnf and Il-1β mRNA genes. Carrying out Ferric (III) chloride-induced carotid artery thrombosis has revealed that P-αB (5 µg/100 g × 3 times a day for 7 days, total dose was 15 µg/100 g) has a lower but statistically significant prothrombotic activity than EPO.Conclusion. P-αB can be positioned as an atheroprotector because of its ability to prevent the death of endothelial cells, as well as to reduce remodeling and proinflammatory activation of the vascular wall. However, the prothrombotic properties of P-αB limit its use as a preventing and treating agent for atherosclerosis-associated diseases.

Currently, there is no doubt surrounding a theory that the cardiotropic effects of sex hormones can be due to their direct effect on the cardiovascular system. In recent years, interest in the study of steroid glycosides has increased. We studied the effects of furostanol glycosides (protodioscin and deltozid) from the cell culture of the Dioscorea deltoidea (laboratory code DM-05) on the physiological and biochemical parameters of vascular endothelial function in hypoestrogen-induced endothelial dysfunction after bilateral ovariectomy. It was shown that the use of DM-05 at a dose of 1 mg/kg makes it possible to prevent the development of arterial hypertension (the level of systolic blood pressure (SBP) decreases by 9.7% (p < 0.05) and diastolic blood pressure (DBP) by 8.2%), to achieve a decrease in the coefficient of endothelial dysfunction by 1.75 times against the background of a hypoestrogenic state. With DM-05, an increase in the concentration of stable nitric oxide metabolites (NO_x) by 45.6% (p < 0.05) and an increase in mRNA endothelial nitric oxide synthase (eNOS) expression by 34.8% (p < 0.05) was established, which indicates a positive effect of furostanol glycosides on the metabolism of nitric oxide after ovariectomy. Positive dynamics in the histological structure of the heart and the abdominal aorta indicate the pronounced endothelio- and atheroprotective effects of DM-05.

An important task of pharmacology and ophtalmology is to find specific and highly effective agents for correcting retinal ischemia. The objective of this study is to increase the effectiveness of pharmacological correction of retinal ischemia by using new 3-hydroxypyridine derivative–l-isomer of ethylmethylhydroxypyridine malate. A modification to the retinal ischemia-reperfusion model was used, in which an increase in intraocular pressure is carried out by mechanical pressure (110 mmHg) to the front chamber of the eye for 30 min. The protective effects of l-isomer of ethylmethylhydroxypyridine malate in comparison with Emoxipine as pretreatment, with parabulbar injection, based on the model of retinal ischemia-reperfusion, were estimated by the changes in the ratio of the amplitudes of the a- and b-waves of electroretinography (the b/a coefficient) and ophthalmoscopy. The use of l-isomer of ethylmethylhydroxypyridine malate improves the retinal electrophysiological state after 72 h of reperfusion; in the group of rats treated with l-isomer of ethylmethylhydroxypyridine malate, the coefficient b/a was reliably increased by 9.5%, p < 0.05, in comparison with animals treated with Emoxipine, and by 91.7%, p < 0.05, in comparison with the group with no treatment. Furthermore, it prevents the development of ischemic changes in the retina observed in ophthalmoscopy to a greater extent than Emoxipine.