How does training of the working memory effect the memory performance in young people?

One of the quality indicators of the medical education is a good study performance, which is very much influenced by the capacity of the working memory. Recent studies have reported that working memory can be improved by training. In this study, we were looking for association between the training of the working memory and its performance in healthy students at Kazakh National Medical University. A total of 676 students participated: 346 in study group and 346 – in control. Reading span test (RST) was used for working memory training and Dual N-back test was used for measurement of results. According to the results obtained, one-and-a-half-month RST training of the memory (RAM) statistically significantly increases the amount of the working memory on average by 12.3 %: min on 9.9 %; max on 15.5 % (р<0.001). Тhe present study examined the relationship of the working memory training and increase in its level in healthy young adults. Our findings indirectly confirm that training not only increases the level of the working memory, but also stimulates other cognitive functions: improving auditory and spatial memory in parallel to the visual one

Impacto de la cronodisrupción sobre la salud humana en el mundo de la luz

El descubrimiento del funcionamiento del sistema circadiano y de sus relojes (central y periférico) es uno de los más destacados en la última década. Prácticamente todas las funciones biológicas del organismo vivo cambian rítmicamente a lo largo del período de 24 horas, adaptándose a los cambios ambientales. El sistema circadiano del organismo está compuesto por el reloj circadiano central y los relojes periféricos. El reloj biológico central o el marcapasos en los mamíferos se localiza en el núcleo supraquiasmático, un grupo de neuronas del hipotálamo, que en respuesta al estímulo de luz-oscuridad libera la hormona melatonina. El reloj central expresa genes rítmicamente a través de un mecanismo de retroalimentación negativo, siendo los más importantes “genes reloj” Clock, Bmail1, Per y Cry [1]. Estos genes codifican una serie de proteínas que son responsables de la regulación rítmica de sueño, comportamiento alimentario, presión arterial y frecuencia cardíaca, entre otros. Actualmente se sabe que prácticamente todas las células del organismo tienen sus propios relojes periféricos. En muchos organismos, incluidos los humanos, la señal externa de luz-oscuridad es el controlador primario o zeitgeber utilizado para sincronizar el sistema circadiano a través de la liberación de la melatonina circulante

Role of c-miR-21, c-miR-126, Redox Status, and Inflammatory Conditions as Potential Predictors of Vascular Damage in T2DM Patients

The development of type 2 diabetes mellitus (T2DM) vascular complications (VCs) is associated with oxidative stress and chronic inflammation and can result in endothelial dysfunctions. Circulating microRNAs play an important role in epigenetic regulation of the etiology of T2DM. We studied 30 healthy volunteers, 26 T2DM patients with no complications, and 26 T2DM patients with VCs, to look for new biomarkers indicating a risk of developing VCs in T2DM patients. Peripheral blood samples were used to determine redox state, by measuring the endogenous antioxidant defense system (superoxide dismutase, SOD; catalase, CAT; glutathione reductase, GRd; glutathione peroxidase, GPx; and glucose-6-phosphate dehydrogenase, G6DP) and markers of oxidative damage (advanced oxidation protein products, AOPP; lipid peroxidation, LPO). Additionally, inflammatory marker levels (IL-1, IL-6, IL-18, and TNF- ), c-miR-21, and c-miR-126 expression were analyzed. T2DM patients showed the highest oxidative damage with increased GSSG/GSH ratios, LPO, and AOPP levels. In both diabetic groups, we found that diminished SOD activity was accompanied by increased CAT and decreased GRd and G6PD activities. Diabetic patients presented with increased relative expression of c-miR-21 and decreased relative expression of c-miR-126. Overall, c-miR-21, SOD, CAT, and IL-6 had high predictive values for diabetes diagnoses. Finally, our data demonstrated that IL-6 exhibited predictive value for VC development in the studied population. Moreover, c-miR- 21 and c-miR-126, along with GPx and AOPP levels, should be considered possible markers for VC development in future studies.University of GranadaEugenio Rodriguez Pascual Foundation ERP-2021CIBERfes (ISCIII, Spain) CB16-10-0023

Review Insights into the Role of Plasmatic and Exosomal microRNAs in Oxidative Stress-Related Metabolic Diseases

A common denominator of metabolic diseases, including type 2 diabetes Mellitus, dyslipidemia, and atherosclerosis, are elevated oxidative stress and chronic inflammation. These complex, multi-factorial diseases are caused by the detrimental interaction between the individual genetic background and multiple environmental stimuli. The cells, including the endothelial ones, acquire a preactivated phenotype and metabolic memory, exhibiting increased oxidative stress, inflammatory gene expression, endothelial vascular activation, and prothrombotic events, leading to vascular complications. There are different pathways involved in the pathogenesis of metabolic diseases, and increased knowledge suggests a role of the activation of the NF-kB pathway and NLRP3 inflammasome as key mediators of metabolic inflammation. Epigenetic-wide associated studies provide new insight into the role of microRNAs in the phenomenon of metabolic memory and the development consequences of vessel damage. In this review, we will focus on the microRNAs related to the control of anti-oxidative enzymes, as well as microRNAs related to the control of mitochondrial functions and inflammation. The objective is the search for new therapeutic targets to improve the functioning of mitochondria and reduce oxidative stress and inflammation, despite the acquired metabolic memoryCIBER-Consorcio Centro de Investigación Biomédica en Red-(CB16/10/00238Instituto de Salud Carlos III, Ministerio de Ciencia e InnovaciónGrant of the FUNDACIÓN EUGENIO RODRIGUEZ PASCUAL (ERP-2021),Call 2021, Spai

Understanding the Mechanism of Action of Melatonin, Which Induces ROS Production in Cancer Cells

Reactive oxygen species (ROS) constitute a group of highly reactive molecules that have evolved as regulators of important signaling pathways. In this context, tumor cells have an altered redox balance compared to normal cells, which can be targeted as an antitumoral therapy by ROS levels and by decreasing the capacity of the antioxidant system, leading to programmed cell death. Melatonin is of particular importance in the development of innovative cancer treatments due to its oncostatic impact and lack of adverse effects. Despite being widely recognized as a pro-oxidant molecule in tumor cells, the mechanism of action of melatonin remains unclear, which has hindered its use in clinical treatments. The current review aims to describe and clarify the proposed mechanism of action of melatonin inducing ROS production in cancer cells in order to propose future anti-neoplastic clinical applications.MCIN/AEI, SpainEuropean Commission SAF2017-85903-P ID2020-115112RB-I00Consejeria de Innovacion, Ciencia y Empresa Junta de Andalucia P07-CTS-03135 P10-CTS-5784 CTS-101University of Granada, Spain UCE-PP2017-05Spanish Governmen

Intratumoral injection of melatonin enhances tumor regression in cell line-derived and patient-derived xenografts of head and neck cancer by increasing mitochondrial oxidative stress

Head and neck squamous cell carcinoma present a high mortality rate. Melatonin has been shown to have oncostatic effects in different types of cancers. However, inconsistent results have been reported for in vivo applications. Consequently, an alternative administration route is needed to improve bioavailability and establish the optimal dosage of melatonin for cancer treatment. On the other hand, the use of patient-derived tumor models has transformed the field of drug research because they reflect the heterogeneity of patient tumor tissues. In the present study, we explore mechanisms for increasing melatonin bioavailability in tumors and investigate its potential as an adjuvant to improve the therapeutic efficacy of cisplatin in the setting of both xenotransplanted cell lines and primary human HNSCC. We analyzed the effect of two different formulations of melatonin administered subcutaneously or intratumorally in Cal-27 and SCC-9 xenografts and in patient-derived xenografts. Melatonin effects on tumor mitochondrial metabolism was also evaluated as well as melatonin actions on tumor cell migration. In contrast to the results obtained with the subcutaneous melatonin, intratumoral injection of melatonin drastically inhibited tumor progression in HNSCC-derived xenografts, as well as in patientderived xenografts. Interestingly, intratumoral injection of melatonin potentiated CDDP effects, decreasing Cal- 27 tumor growth. We demonstrated that melatonin increases ROS production and apoptosis in tumors, targeting mitochondria. Melatonin also reduces migration capacities and metastasis markers. These results illustrate the great clinical potential of intratumoral melatonin treatment and encourage a future clinical trial in cancer patients to establish a proper clinical melatonin treatment.European Regional Development Fund (B‐CTS‐071-UGR18)Consejería de Economía, Innovación, Ciencia y Empleo, Junta de Andalucía (P18-RT‐32222)Ministerio de Ciencia e Innovación/AEI: Agencia Estatal de Investigación/10.13039/501100011033Unión Europea “NextGenerationEU”/ PRTR (SAF2017-85903‐P; PID2020-115112RB‐I00)University of Granada (Grant “UNETE,” UCE‐PP2017-05)Ministerio de Educación Cultura y Deporte, Spai

Protective Effects of Melatonin on the Skin: Future Perspectives

When exposed to hostile environments such as radiation, physical injuries, chemicals, pollution, and microorganisms, the skin requires protective chemical molecules and pathways. Melatonin, a highly conserved ancient molecule, plays a crucial role in the maintenance of skin. As human skin has functional melatonin receptors and also acts as a complete system that is capable of producing and regulating melatonin synthesis, melatonin is a promising candidate for its maintenance and protection. Below, we review the studies of new metabolic pathways involved in the protective functions of melatonin in dermal cells. We also discuss the advantages of the topical use of melatonin for therapeutic purposes and skin protection. In our view, endogenous intracutaneous melatonin production, together with topically-applied exogenous melatonin and its metabolites, represent two of the most potent defense systems against external damage to the skin.Part of this review was co-funded by the Spanish Ministry of the Economy and Competitiveness, the FEDER Regional Development Fund (nos. SAF2013-49019 and SAF2017-85903), the Charles III Institute (no. CB/10/00238), and the Economy, Innovation, Science and Employment Council of the Junta de Andalucía (CTS-101). JF and LM are FPU (Professional University formation) Fellows of the Spanish Ministry of Education, Culture and Sport

Analysis of Plasma MicroRNAs as Predictors and Biomarkers of Aging and Frailty in Humans

Although circulating microRNAs (miRNAs) can modulate gene expression and affect immune system response, little is known about their participation in age-associated frailty syndrome and sarcopenia. The aim of this study was to determine miRNAs as possible biomarkers of age and frailty and their correlation with oxidative and inflammatory state in human blood. Three inflammation-related miRNAs (miR-21, miR-146a, and miR-223) and one miRNA related with the control of melatonin synthesis (miR-483) were analyzed. Twenty-two healthy adults, 34 aged robust, and 40 aged fragile patients were selected for this study. The expression of plasma miRNAs was assessed by RT-qPCR; plasma cytokines (IL-6, IL-8, IL-10, and TNFα) were analyzed by commercial kits, and plasma advanced oxidation protein products (AOPP) and lipid oxidation (LPO) were spectrophotometrically measured. Fragile subjects had higher miR-21 levels than control subjects, whereas miR-223 and miR- 483 levels increased at a similar extend in both aged groups. All cytokines measured increased in aged groups compared with controls, without differences between robust and fragile subjects. The fragile group had a TNFα/IL-10 ratio significantly higher than robust and control groups. Aged groups also had higher AOPP and LPO levels than controls. Women presented higher AOPP and LPO levels and increased expression of miR-483 compared with men. Positive correlations between miR-21 and AOPP and between miR-483 and IL-8 were detected. The expression of miR-21 and the TNFα/IL-10 ratio were correlated positively with the presence of frailty, which suggests that these markers can be considered as possible biomarkers for age-related frailty.This work was partially supported by grants from the Ministerio de Economía, Industria y Competitividad y por el Fondo de Desarrollo Regional Feder, Spain nos. RD12/ 0043/0005, PI13-00981, and CB16-10-00238 and from the Universidad de Granada, Spain no. CEI2014-MPBS3

The Impact of Melatonin Supplementation and NLRP3 Inflammasome Deletion on Age-Accompanied Cardiac Damage

This study was partially supported by grants from the Instituto de Salud Carlos III through the projects PI13-981, PI16-00519, PI19-01372, and CB/10/00238 (Co-funded by European Regional Development Fund/European Social Fund "Investing in your future"); the Conserjeria de Economia, Innovacion, Ciencia y Empleo, Junta de Andalucia (CTS-101), Spain, and also by Sohag University, Egypt. M.F.-O and J.F.-M are supported by a FPU fellowship from the Ministerio de Educacion, Spain.To investigate the role of NLRP3 inflammasome in cardiac aging, we evaluate here morphological and ultrastructural age-related changes of cardiac muscles fibers in wild-type and NLRP3-knockout mice, as well as studying the beneficial effect of melatonin therapy. The results clarified the beginning of the cardiac sarcopenia at the age of 12 months, with hypertrophy of cardiac myocytes, increased expression of beta-MHC, appearance of small necrotic fibers, decline of cadiomyocyte number, destruction of mitochondrial cristae, appearance of small-sized residual bodies, and increased apoptotic nuclei ratio. These changes were progressed in the cardiac myocytes of 24 old mice, accompanied by excessive collagen deposition, higher expressions of IL-1 alpha, IL-6, and TNF alpha, complete mitochondrial vacuolation and damage, myofibrils disorganization, multivesicular bodies formation, and nuclear fragmentation. Interestingly, cardiac myocytes of NLRP3(-/-) mice showed less detectable age-related changes compared with WT mice. Oral melatonin therapy preserved the normal cardiomyocytes structure, restored cardiomyocytes number, and reduced beta-MHC expression of cardiac hypertrophy. In addition, melatonin recovered mitochondrial architecture, reduced apoptosis and multivesicular bodies' formation, and decreased expressions of beta-MHC, IL-1 alpha, and IL-6. Fewer cardiac sarcopenic changes and highly remarkable protective effects of melatonin treatment detected in aged cardiomyocytes of NLRP3(-/-) mice compared with aged WT animals, confirming implication of the NLRP3 inflammasome in cardiac aging. Thus, NLRP3 suppression and melatonin therapy may be therapeutic approaches for age-related cardiac sarcopenia.Instituto de Salud Carlos III (European Regional Development Fund/European Social Fund "Investing in your future") PI13-981 PI16-00519 PI19-01372 CB/10/00238Junta de Andalucia CTS-101Sohag UniversityGerman Research Foundation (DFG

Age and Chronodisruption in Mouse Heart: Effect of the NLRP3 Inflammasome and Melatonin Therapy

Age and age-dependent inflammation are two main risk factors for cardiovascular diseases. Aging can also affect clock gene-related impairments such as chronodisruption and has been linked to a decline in melatonin synthesis and aggravation of the NF- B/NLRP3 innate immune response known as inflammaging. The molecular drivers of these mechanisms remain unknown. This study investigated the impact of aging and NLRP3 expression on the cardiac circadian system, and the actions of melatonin as a potential therapy to restore daily rhythms by mitigating inflammaging. We analyzed the circadian expression and rhythmicity of clock genes in heart tissue of wild-type and NLRP3-knockout mice at 3, 12, and 24 months of age, with and without melatonin treatment. Our results support that aging, NLRP3 inflammasome, and melatonin affected the cardiac clock genes expression, except for Rev-erba, which was not influenced by genotype. Aging caused small phase changes in Clock, loss of rhythmicity in Per2 and Rora, and mesor dampening of Clock, Bmal1, and Per2. NLRP3 inflammasome influenced the acrophase of Clock, Per2, and Rora. Melatonin restored the acrophase and the rhythm of clock genes affected by age or NLRP3 activation. The administration of melatonin re-established murine cardiac homeostasis by reversing age-associated chronodisruption. Altogether, these results highlight new findings about the effects aging and NLRP3 inflammasome have on clock genes in cardiac tissue, pointing to continuous melatonin as a promising therapy to placate inflammaging and restore circadian rhythm in heart muscle. Additionally, light microscopy analysis showed age-related morphological impairments in cardiomyocytes, which were less severe in mice lacking NLRP3. Melatonin supplementation preserved the structure of cardiac muscle fibers in all experimental groups.Instituto de Salud Carlos III (Ministerio de Economia y Competitividad, Spain) (European Regional Development Fund/European Social Fund "Investing in your future") PI13-981 PI16-00519 PI19-01372 CB16-10-00238 CB16/10/00239Junta de Andalucia CTS-101Spanish Governmen