Injectable Hydrogels for Nervous Tissue Repair-A Brief Review.

The repair of nervous tissue is a critical research field in tissue engineering because of the degenerative process in the injured nervous system. In this review, we summarize the progress of injectable hydrogels using in vitro and in vivo studies for the regeneration and repair of nervous tissue. Traditional treatments have not been favorable for patients, as they are invasive and inefficient; therefore, injectable hydrogels are promising for the treatment of damaged tissue. This review will contribute to a better understanding of injectable hydrogels as potential scaffolds and drug delivery system for neural tissue engineering applications.

Evolution of staining methods in neuroanatomy: Impetus for emanation of neuron doctrine during the turn of 20th century.

The nervous system is distinctive as compared to other tissue systems in human body owing to intricate structural organization. Histological studies played a key role in unveiling complex details of nervous tissue. However, the process of developing suitable staining method for nerve cells was arduous and spanned across almost half a century. The present study explored details of the journey involving quest for propitious staining method in neuroanatomy culminating in promulgation of neuron doctrine at the onset of 20th century. Initial efforts involving hematoxylin (including its diverse modifications) and subsequent adoption of analogous dye-based stains (like Nissl's method) had limited success in visualization of different parts of a nerve cell and structural details of nervous tissue. This was due to inability of dye-based stains to penetrate the connective tissue sheath of nervous tissue. Eventually, advent of metallic stains in form of silver impregnation method (Golgi stain), reduced silver impregnation method with gold stain (Cajal's stain) and silver carbonate staining method of Río-Hortega unraveled the structure of nervous tissue. The evolution of staining methods catalyzed the refinement of theories pertinent to constitution of nervous tissue. Golgi's staining led to emergence of reticular theory (neurons exist as a network) and Nissl's staining was the basis of the concept of Nervösen Grau (nerve cells and glial cells are embedded in mass of gray matter). Finally, Cajal's staining method successfully elucidated the complex anatomy of nerve terminals and resulted in emanation of neuron doctrine (neurons exists as individual units with adjacent connections).

The Protective Impact of Aronia melanocarpa L. Berries Extract against Prooxidative Cadmium Action in the Brain-A Study in an In Vivo Model of Current Environmental Human Exposure to This Harmful Element.

Cadmium (Cd) is a prooxidant that adversely affects human health, including the nervous system. As exposure of the general population to this heavy metal is inevitable, it is crucial to look for agents that can prevent the effects of its toxic action. An experimental model on female rats of current lifetime human exposure to cadmium (3-24-months' treatment with 1 or 5 mg Cd/kg diet) was used to test whether low-level and moderate intoxication can exert a prooxidative impact in the brain and whether supplementation with a 0.1% extract from the berries of Aronia melanocarpa L. (Michx.) Elliott (AE; chokeberry extract) can protect against this action. Numerous parameters of the non-enzymatic and enzymatic antioxidative barrier, as well as total antioxidative and oxidative status (TAS and TOS, respectively), were determined and the index of oxidative stress (OSI) was calculated. Moreover, chosen prooxidants (myeloperoxidase, xanthine oxidase, and hydrogen peroxide) and biomarkers of oxidative modifications of lipids, proteins, and deoxyribonucleic acid were assayed. Cadmium dysregulated the balance between oxidants and antioxidants in the brain and led to oxidative stress and oxidative injury of the cellular macromolecules, whereas the co-administration of AE alleviated these effects. To summarize, long-term, even low-level, cadmium exposure can pose a risk of failure of the nervous system by the induction of oxidative stress in the brain, whereas supplementation with products based on aronia berries seems to be an effective protective strategy.

Production of a Bioink Containing Decellularized Spinal Cord Tissue for 3D Bioprinting.

For the past few years, three-dimensional (3D) bioprinting has emerged as a promising approach in the field of regenerative medicine. This technique allows for the production of 3D scaffolds to support cell transplantation due to its ability to mimic the extracellular environment. One alternative to enhancing cell adhesion, survival, and proliferation is the use of decellularized extracellular matrix as a bioink component. The aim of this study was to produce a bioink using lyophilized rat decellularized spinal cord tissue (DSCT) for 3D bioprinting of nervous tissue. DNA quantification, hematoxylin and eosin and DAPI staining indicated that 1% sodium dodecyl sulfate and 9 h processing were effective in removing the cells from the spinal cord samples. The cell viability assay showed that the decellularized matrix is not cytotoxic for PC12 cells. The hydrogel containing DSCT, alginate, and gelatine used as the base for the bioink has a shear thinning behavior and low G″/G' ratio, allowing for good printability without compromising cell viability after 3D bioprinting. The bioink supported long-term PC12 cell survival, with 93% of live cells 4 weeks after printing, and stimulated the production of laminin-1 and neurofilament-M. This bioink, therefore, represents an easily available biomaterial for central nervous system tissue engineering.

Effect of Coturnix japonica (quail) egg yolk in ethanol damage-induced mice

Introduction: The high prevalence of neurodegenerativediseases in the older adult population requires research fo-cused on functional foods with regulatory properties on redoxstate and with antioxidant potential. Quail egg yolk is a foodwith a great diversity of antioxidant compounds with neuro-protective activity. Objective: To evaluate the effect of Coturnix japonica eggyolk administration on the nervous tissue of mice againstethanol damage induction. Methodology: 35 mice received the following treatmentvia orogastric for five days: groups I and II water (10 mL/kg),group III egg yolk (5 mL/kg), group IV egg yolk (10 mL/kg)and group V egg yolk (15 mL/kg). On the fifth day, 99%ethanol was administered subcutaneously (5 g/kg) to groupsII-V. After four hours, the mice were decapitated to obtain thebrain and cerebellum and subsequently perform biochemicaltests and histopathological analysis. Results: Group IV presented neuronal proliferation phe-nomenon and Purkinje cells pluristratification in the brain andcerebellum respectively and additionally presented a betterGSH/GSSG ratio (p<0.05) in comparison to group II. Therewas no statistically significant difference between proteinlevels or protein sulfhydryl groups in any of the groups. Conclusions:Coturnix japonica egg yolk administrationresulted in better preservation of the brain and cerebellum’scytoarchitecture and increased GSH profile (AU)

Adverse neurological effects after exposure to copper, manganese, and mercury mixtures in a Spraque-Dawley rat model: an ultrastructural investigation.

Exposure to environmental metal pollutants is linked to oxidative stress and the subsequent development of neurological disease. In this study, the effects of copper, manganese, and mercury, were evaluated at X100 the World Health Organization safety limits for drinking water. Using a Sprague-Dawley rat model, following exposure for 28 days, the effects of these metals on biochemical blood parameters and tissue and cellular structure of the brain were determined. Biochemical analysis revealed no hepatocellular injury with minor changes associated with the hepatobiliary system. Minimal changes were found for renal function and the Na+/K+ ratio was reduced in the copper and manganese (Cu + Mn) and copper, manganese, and mercury (Cu, Mn + Hg) groups that could affect neurological function. Light microscopy of the brain revealed abnormal histopathology of Purkinje cells in the cerebellum and pyramidal cells in the cerebrum as well as tissue damage and fibrosis of the surface blood vessels. Transmission electron microscopy of the cerebral neurons showed microscopic signs of axonal damage, chromatin condensation, the presence of indistinct nucleoli and mitochondrial damage. Together these cellular features suggest the presence and influence of oxidative stress. Exposure to these metals at X100 the safety limits, as part of mixtures, induces changes to neurological tissue that could adversely influence neurological functioning in the central nervous system.

Histological Study on the Thickness of Gray Matter at the Summit and Bottom of Folium in Different Age Groups of Bangladeshi People.

Context The cerebellum is a part of the hindbrain and consists of cortical gray matter (GM) at the surface and a medullary core of white matter (WM). The GM contains a cell body of neurons that helps process and transmit any command type through nerve fibers found in the WM. The main functions of GM in the central nervous system empower persons to control motor activity, recollection, and passion. So, this research aims to assess the thickness of GM at the summit and bottom of folia by histologically studying the cerebellum cortex. Methods The collection of data was a descriptive type of cross-sectional study. The method was the purposive type. This study was conducted from August 2016 to March 2017, and the research was carried out at Mymensingh Medical College's Department of Anatomy, Bangladesh. Specimens containing cerebellum were preserved from Bangladeshi cadavers according to sexes and ages ranging in years. We chose fresh specimens from people who died within the last 12 hours and preserved them in 10% formol saline. The size of the tissue that was collected for the histological study was not more than 2 cm2 and not more than 4-5 mm thick. Then the tissue was placed in 10% formol saline. This fluid was used for quick fixation and partial dehydration of the tissue. After dehydration, each tissue segment is processed for infiltration and embedding separately. Every section was stained with hematoxylin and eosin stain (H&E) before being coated with dibutyl phthalate polystyrene xylene (DPX) coverslips on slides. Result The mean (±SD) thickness of GM at the summit of folium was 886.2±29.7µm in Group A, 925.2±25.9µm in Group B, 912.7±22.3µm in Group C, and 839.9±40.7µm in Group D. Mean (±SD) GM thickness at the bottom of the fissure was 395.6±12.2 µm, 403.9±26.0µm, 380.4±23.4 µm, and 375.8±28.8 µm in Groups A, B, C, and D respectively. Conclusion The thickness of the cortex is an essential factor in the normal development process, and it was similar in the current study. Normal aging, Alzheimer's disease, and other dementias cause reduced GM which makes the cortical sheet thin. Huntington's disease, corticobasal degeneration, amyotrophic lateral sclerosis, and schizophrenia are all examples of neurological disorders. Cortical thinning is typically locally localized, and the progression of atrophy can thus disclose much about a disease's history and causal variables. The present study correspondingly found that GM was reduced after the age of 50 years onward. Furthermore, longitudinal investigations of cortical atrophy have the potential to be extremely useful in measuring the efficacy of a wide range of treatments.

More than skin deep: cyclic peptides as wound healing and cytoprotective compounds.

The prevalence and cost of wounds pose a challenge to patients as well as the healthcare system. Wounds can involve multiple tissue types and, in some cases, become chronic and difficult to treat. Comorbidities may also decrease the rate of tissue regeneration and complicate healing. Currently, treatment relies on optimizing healing factors rather than administering effective targeted therapies. Owing to their enormous diversity in structure and function, peptides are among the most prevalent and biologically important class of compounds and have been investigated for their wound healing bioactivities. A class of these peptides, called cyclic peptides, confer stability and improved pharmacokinetics, and are an ideal source of wound healing therapeutics. This review provides an overview of cyclic peptides that have been shown to promote wound healing in various tissues and in model organisms. In addition, we describe cytoprotective cyclic peptides that mitigate ischemic reperfusion injuries. Advantages and challenges in harnessing the healing potential for cyclic peptides from a clinical perspective are also discussed. Cyclic peptides are a potentially attractive category of wound healing compounds and more research in this field could not only rely on design as mimetics but also encompass de novo approaches as well.

Zebrafish dnm1a gene plays a role in the formation of axons and synapses in the nervous tissue.

Classical dynamins (DNMs) are GTPase proteins engaged in endocytosis, a fundamental process for cargo internalization from the plasma membrane. In mammals, three DNM genes are present with different expression patterns. DNM1 is expressed at high levels in neurons, where it takes place in the recycling of synaptic vesicles; DNM2 is ubiquitously expressed, while DNM3 is found in the brain and in the testis. Due to the conservation of genes in comparison to mammals, we took advantage of a zebrafish model for functional characterization of dnm1a, ortholog of mammalian DNM1. Our data strongly demonstrated that dnm1a has a nervous tissue-specific expression pattern and plays a role in the formation of both axon and synapse. This is the first in vivo study that collects evidence about the effects of dnm1a loss of function in zebrafish, thus providing a new excellent model to be used in different scientific fields.

Identification of Ultrastructural Details of the Astrocyte Process System in Nervous Tissue of the Brain Using Correlative Scanning Probe and Transmission Electron Microscopy.

Nanoscale morphological features of branched processes of glial cells may be of decisive importance for neuron-astrocyte interactions in health and disease. The paper presents the results of a correlation analysis of images of thin processes of astrocytes in nervous tissue of the mouse brain, which were obtained by scanning probe microscopy (SPM) and transmission electron microscopy (TEM) with high spatial resolution. Samples were prepared and imaged using a unique hardware combination of ultramicrotomy and SPM. Astrocyte details with a thickness of several tens of nanometers were identifiable in the images, making it possible to reconstruct the three-dimensional structure of astrocytic processes by integrating a series of sequential images of ultrathin sections of nervous tissue in the future.

Is domestic polyester suitable for plastination of thin brain slices?

Plastination is a technique used to preserve biological tissues while retaining most of their original appearance. In the technique, developed by Dr. Gunther von Hagens in 1977, specimens were impregnated with a polymer, such as silicone, epoxy, or polyester. Considered the most suitable material for brain plastination, polyester has a wide application in teaching and research compared with imaging techniques. The materials for plastination are usually imported from Germany and more expensive than domestic products. If domestic polymers were to enter the market it would favor the expansion of plastination in Brazil. Hence, this study evaluated the feasibility of using domestic polyesters to replace the usual Biodur® (P40) in plastination of brain slices. For this evaluation, 2-mm-thick sections of bovine brains were prepared and plastinated with domestic polyester. Slices were compared before impregnation and after curing using standardized photographs taken after dehydration and after curing. Plastination followed the standard protocol: fixation, dehydration, forced impregnation, and curing. Fifteen brain slices were plastinated with each polyester (P40, P18, and C1-3). There was no significant difference in the percent shrinkage between groups after plastination of P18 and P40, but the curing time of Cristalan© polymer was too short for impregnation. Therefore, no initiator was used for C polymers impregnation. Thus, domestic polyester P18 was a viable option for the process.

[Isolation, culture and inflammatory characteristics of astrocytes in aged rats nervous tissue].

Objective: To establish an optimized method for the isolation and purification of astrocytes from the neural tissues of young and aged rats. Then, the morphological and functional differences of astrocytes between young and aged rats were compared to explore the functional changes of astrocytes after aging and its possible mechanism in the aging process. Methods: Young (2 months old) and aged (20 months old) SD rats were used. Astrocytes in brain and spinal cord tissue were purified by 50% - 35% percoll density gradient centrifugation. Each group of cells was set up with three duplicate wells. After 72 h of culture, Glial fibrillary acidic protein (GFAP) which was astrocyte specific marker were detected by immunofluorescence to evaluate the morphological characteristics. Cell senescence markers (p16 and p21) and ß- Galactosidase were detected by qPCR and staining respectively. The expressions of pro-inflammatory cytokines (IL-1ß, TNF-α) and anti-inflammatory cytokines were detected by qPCR. Results: Using 50%-35% percoll gradient separation, astrocytes were obtained with large number, good activity and purity of more than 95%, which could be used in subsequent experiments. Compared with the astrocytes in the nerve tissue of young rats, the astrocytes in the nervous tissue of the aged rats had fewer protrusions and tended to be activated in cell morphology; the positive rate of ß -galactosidase staining was increased significantly and the expressions of p16 and p21 were increased (P<0.01). The expressions of pro-inflammatory cytokines (IL-1ß, TNF-α) were increased (P<0.05), and the expression of anti-inflammatory cytokine (IL-10) was decreased (P<0.05) in astrocytes of the aged rats nervous tissue. Conclusion: The percoll gradient of 50% - 35% could be used as a method for separation, purification and primary culture of astrocytes. With the increase of age, astrocytes undergo cellular senescence, showing a pro-inflammatory phenotype, promoting inflammaging of the nervous system, which may be one of the mechanisms of nervous system aging and neurodegenerative diseases.

Spermidine Crosslinked Gellan Gum-Based "Hydrogel Nanofibers" as Potential Tool for the Treatment of Nervous Tissue Injuries: A Formulation Study.

Purpose: Aim of the work was to develop a potential neural scaffold, endowed with neuroprotective and neuroregenerative potential, to be applied at the site of nervous tissue injuries: nanofibers, consisting of gellan gum (GG), spermidine (SP) and gelatin (GL), were prepared via electrospinning. SP was selected for its neuroprotective activity and cationic nature that makes it an ideal GG cross-linking agent. GL was added to improve the scaffold bioactivity. Methods: Mixtures, containing 1.5% w/w GG and increasing SP concentrations (0-0.125% w/w), were prepared to investigate GG/SP interaction and, thus, to find the best mixture to be electrospun. Mixture rheological and mechanical properties were assessed. The addition of 0.1% w/w GL was also investigated. The most promising GG/SP/GL mixtures were added with poly(ethylene oxide) (PEO) and poloxamer (P407) and, then, electrospun. The resulting fibers were characterized in terms of size and mechanical properties and fiber morphology was observed after soaking in water for 24 hours. Nanofiber biocompatibility was assessed on Schwann cells. Results: More and more structured GG/SP mixtures were obtained by increasing SP concentration, proving its cross-linking potential. After blending with PEO and P407, the mixture consisting of 1.5% w/w GG, 0.05% w/w SP and 0.1% w/w GL was electrospun. The resulting nanofibers appeared homogenous and characterized by a plastic behavior, suggesting a good mechanical resistance when applied at the injury site. Nanofibers were insoluble in aqueous media and able to form a thin gel layer after hydration. GG/SP/GL nanofibers showed a higher compatibility with Schwann cells than GG/SP ones. Conclusion: SP and GL allowed the production of homogenous GG-based nanofibers, which preserved their structure after contact with aqueous media and showed a good compatibility with a neural cell line. After local application at the injury site, nanofibers should support and guide axonal outgrowth, releasing SP in a controlled manner.

Effects of neural mobilization in the treatment of chronic low back pain: a systematic review / Efectos de la movilización neural en el tratamiento del dolor lumbar crónico: una revisión sistemática

Introduction: Low back pain appears in approximately two thirds of the population at some point in life and when it exceeds more than 12 weeks, it evolves to chronic low back pain. Chronic low back pain is considered one of the most common causes of disability and absence from work. A therapeutic technique that can be used as a treatment for chronic low back pain is neural mobilization, capable of restoring compromised neurological structures, restoring movement by improving the elasticity of neural tissue and adjacent tissues. Objective: To verify the effects of neural mobilization in patients with chronic low back pain. Material and methods: All articles were carefully evaluated in order to obtain concrete and reliable information. The databases used were Google Scholar, Scielo, Medline and PubMed due to the methodological quality and articles in the area of interest. The keywords “low back pain”, “chronic low back pain”, “neural mobilization” and “physiotherapeutic intervention” were combined in the most diverse possibilities, in English and Spanish translations. Results: 86 articles were found, nine of which were included in this review. They had a score ≥ 5 on the PEDro Scale, which methodologically qualifies the articles. After analyzing the results obtained through the selected articles, all the data collected, as well as their respective results, were described in a table that contains data from the articles. Conclusions: Neural mobilization reduces pain and improves the extensibility of tissues, causing a reduction in painful sensation and increased flexibility. Therefore, it is necessary to continue research in order to verify new results obtained through this type of intervention (AU)

Introducción: La lumbalgia aparece en aproximadamente dos tercios de la población en algún momento de la vida y cuando supera las 12 semanas evoluciona a lumbalgia crónica. El dolor lumbar crónico se considera una de las causas más comunes de incapacidad y ausencia laboral. Una técnica terapéutica que se puede utilizar como tratamiento para el dolor lumbar crónico es la movilización neural, capaz de restaurar las estructuras neurológicas comprometidas, restaurando el movimiento al mejorar la elasticidad del tejido neural y los tejidos adyacentes. Objetivo: Verificar los efectos de la movilización neural en pacientes con dolor lumbar crónico. Material y métodos: Todos los artículos fueron cuidadosamente evaluados para obtener información concreta y confiable. Las bases de datos utilizadas fueron Google Scholar, Scielo, Medline y PubMed debido a la calidad metodológica y artículos del área de interés. Las palabras clave “lumbalgia”, “lumbalgia crónica”, “movilización neural” e “intervención fisioterapéutica” se combinaron en las más diversas posibilidades, en las traducciones al inglés y al español. Resultados: Se encontraron 86 artículos, nueve de los cuales fueron incluidos en esta revisión. Tuvieron puntaje ≥ 5 en la Escala PEDro, que califica metodológicamente los artículos. Luego de analizar los resultados obtenidos a través de los artículos seleccionados, todos los datos recolectados, así como sus respectivos resultados, fueron descritos en una tabla que contiene los datos de los artículos. Conclusiones: La movilización neural reduce el dolor y mejora la extensibilidad de los tejidos, provocando una reducción de la sensación dolorosa y un aumento de la flexibilidad. Por lo tanto, es necesario continuar con la investigación para verificar nuevos resultados obtenidos a través de este tipo de intervención (AU)

MicroRNA roles in regeneration: Multiple lessons from zebrafish.

MicroRNAs (miRNAs) are small noncoding RNAs with pivotal roles in the control of gene expression. By comparing the miRNA profiles of uninjured vs. regenerating tissues and structures, several studies have found that miRNAs are potentially involved in the regenerative process. By inducing miRNA overexpression or inhibition, elegant experiments have directed regenerative responses validating relevant miRNA-to-target interactions. The zebrafish (Danio rerio) has been the epicenter of regenerative research because of its exceptional capability to self-repair damaged tissues and body structures. In this review, we discuss recent discoveries that have improved our understanding of the impact of gene regulation mediated by miRNAs in the context of the regeneration of fins, heart, retina, and nervous tissue in zebrafish. We compiled what is known about the miRNA control of regeneration in these tissues and investigated the links among up-regulated and down-regulated miRNAs, their putative or validated targets, and the regenerative process. Finally, we briefly discuss the forthcoming prospects, highlighting directions and the potential for further development of this field.

Endoscopic confocal laser-microscopy for the intraoperative nerve recognition: is it feasible?

Surgeons lose most of their tactile tissue information during minimal invasive surgery and need an additional tool of intraoperative tissue recognition. Confocal laser microscopy (CLM) is a well-established method of tissue investigation. The objective of this study was to analyze the feasibility and diagnostic accuracy of CLM nervous tissue recognition. Images taken with an endoscopic CLM system of sympathetic ganglions, nerve fibers and pleural tissue were characterized in terms of specific signal-patterns ex-vivo. No fluorescent dye was used. Diagnostic accuracy of tissue classification was evaluated by newly trained observers (sensitivity, specificity, PPV, NPV and interobserver variability). Although CLM images showed low CLM image contrast, assessment of nerve tissue was feasible without any fluorescent dye. Sensitivity and specificity ranged between 0.73 and 0.9 and 0.55-1.0, respectively. PPVs were 0.71-1.0 and the NPV range was between 0.58 and 0.86. The overall interobserver variability was 0.36. The eCLM enables to evaluate nervous tissue and to distinguish between nerve fibers, ganglions and pleural tissue based on backscattered light. However, the low image contrast and the heterogeneity in correct tissue diagnosis and a fair interobserver variability indicate the limit of CLM imaging without any fluorescent dye.

Overview of sialylation status in human nervous and skeletal muscle tissues during aging.

Sialic acids (Sias) are a large and heterogeneous family of electronegatively charged nine-carbon monosaccharides containing a carboxylic acid and are mostly found as terminal residues in glycans of glycoproteins and glycolipids such as gangliosides. They are linked to galactose or N-acetylgalactosamine via α2,3 or α2,6 linkage, or to other Sias via α2,8 or more rarely α2,9 linkage, resulting in mono, oligo and polymeric forms. Given their characteristics, Sias play a crucial role in a multitude of human tissue biological processes in physiological and pathological conditions, ranging from development and growth to adult life until aging. Here, we review the sialylation status in human adult life focusing on the nervous and skeletal muscle tissues, which both display significant structural and functional changes during aging, strongly impacting on the whole human body and, therefore, on the quality of life. In particular, this review highlights the fundamental roles played by different types of glycoconjugates Sias in several cellular biological processes in the nervous and skeletal muscle tissues during adult life, also discussing how changes in Sia content during aging may contribute to the physiological decline of physical and nervous functions and to the development of age-related degenerative pathologies. Based on our current knowledge, further in-depth investigations could help to develop novel prophylactic strategies and therapeutic approaches that, by maintaining and/or restoring the correct sialylation status in the nervous and skeletal muscle tissues, could contribute to aging slowing and the prevention of age-related pathologies.

Tackling Dysfunction of Mitochondrial Bioenergetics in the Brain.

Oxidative phosphorylation (OxPhos) is the basic function of mitochondria, although the landscape of mitochondrial functions is continuously growing to include more aspects of cellular homeostasis. Thanks to the application of -omics technologies to the study of the OxPhos system, novel features emerge from the cataloging of novel proteins as mitochondrial thus adding details to the mitochondrial proteome and defining novel metabolic cellular interrelations, especially in the human brain. We focussed on the diversity of bioenergetics demand and different aspects of mitochondrial structure, functions, and dysfunction in the brain. Definition such as 'mitoexome', 'mitoproteome' and 'mitointeractome' have entered the field of 'mitochondrial medicine'. In this context, we reviewed several genetic defects that hamper the last step of aerobic metabolism, mostly involving the nervous tissue as one of the most prominent energy-dependent tissues and, as consequence, as a primary target of mitochondrial dysfunction. The dual genetic origin of the OxPhos complexes is one of the reasons for the complexity of the genotype-phenotype correlation when facing human diseases associated with mitochondrial defects. Such complexity clinically manifests with extremely heterogeneous symptoms, ranging from organ-specific to multisystemic dysfunction with different clinical courses. Finally, we briefly discuss the future directions of the multi-omics study of human brain disorders.

The "Angiogenic Switch" and Functional Resources in Cyclic Sports Athletes.

Regular physical activity in cyclic sports can influence the so-called "angiogenic switch", which is considered as an imbalance between proangiogenic and anti-angiogenic molecules. Disruption of the synthesis of angiogenic molecules can be caused by local changes in tissues under the influence of excessive physical exertion and its consequences, such as chronic oxidative stress and associated hypoxia, metabolic acidosis, sports injuries, etc. A review of publications on signaling pathways that activate and inhibit angiogenesis in skeletal muscles, myocardium, lung, and nervous tissue under the influence of intense physical activity in cyclic sports. Materials: We searched PubMed, SCOPUS, Web of Science, Google Scholar, Clinical keys, and e-LIBRARY databases for full-text articles published from 2000 to 2020, using keywords and their combinations. Results: An important aspect of adaptation to training loads in cyclic sports is an increase in the number of capillaries in muscle fibers, which improves the metabolism of skeletal muscles and myocardium, as well as nervous and lung tissue. Recent studies have shown that myocardial endothelial cells not only respond to hemodynamic forces and paracrine signals from neighboring cells, but also take an active part in heart remodeling processes, stimulating the growth and contractility of cardiomyocytes or the production of extracellular matrix proteins in myofibroblasts. As myocardial vascularization plays a central role in the transition from adaptive heart hypertrophy to heart failure, further study of the signaling mechanisms involved in the regulation of angiogenesis in the myocardium is important in sports practice. The study of the "angiogenic switch" problem in the cerebrovascular and cardiovascular systems allows us to claim that the formation of new vessels is mediated by a complex interaction of all growth factors. Although the lungs are one of the limiting systems of the body in cyclic sports, their response to high-intensity loads and other environmental stresses is often overlooked. Airway epithelial cells are the predominant source of several growth factors throughout lung organogenesis and appear to be critical for normal alveolarization, rapid alveolar proliferation, and normal vascular development. There are many controversial questions about the role of growth factors in the physiology and pathology of the lungs. The presented review has demonstrated that when doing sports, it is necessary to give a careful consideration to the possible positive and negative effects of growth factors on muscles, myocardium, lung tissue, and brain. Primarily, the "angiogenic switch" is important in aerobic sports (long distance running). Conclusions: Angiogenesis is a physiological process of the formation of new blood capillaries, which play an important role in the functioning of skeletal muscles, myocardium, lung, and nervous tissue in athletes. Violation of the "angiogenic switch" as a balance between proangiogenic and anti-angiogenic molecules can lead to a decrease in the functional resources of the nervous, musculoskeletal, cardiovascular, and respiratory systems in athletes and, as a consequence, to a decrease in sports performance.