Neddylation tunes peripheral blood mononuclear cells immune response in COVID-19 patients.

The COVID-19 pandemic caused by SARS-CoV-2 has reached 5.5 million deaths worldwide, generating a huge impact globally. This highly contagious viral infection produces a severe acute respiratory syndrome that includes cough, mucus, fever and pneumonia. Likewise, many hospitalized patients develop severe pneumonia associated with acute respiratory distress syndrome (ARDS), along an exacerbated and uncontrolled systemic inflammation that in some cases induces a fatal cytokine storm. Although vaccines clearly have had a beneficial effect, there is still a high percentage of unprotected patients that develop the pathology, due to an ineffective immune response. Therefore, a thorough understanding of the modulatory mechanisms that regulate the response to SARS-CoV-2 is crucial to find effective therapeutic alternatives. Previous studies describe the relevance of Neddylation in the activation of the immune system and its implications in viral infection. In this context, the present study postulates Neddylation, a reversible ubiquitin-like post-translational modification of proteins that control their stability, localization and activity, as a key regulator in the immune response against SARS-CoV-2. For the first time, we describe an increase in global neddylation levels in COVID-19 in the serum of patients, which is particularly associated with the early response to infection. In addition, the results showed that overactivation of neddylation controls activation, proliferation, and response of peripheral blood mononuclear cells (PBMCs) isolated from COVID-19 patients. Inhibition of neddylation, and the subsequent avoidance of activated PBMCs, reduces cytokine production, mainly IL-6 and MCP-1 and induce proteome modulation, being a critical mechanism and a potential approach to immunomodulate COVID-19 patients.

Déficit de vitamina D en una población pediátrica sana. La importancia de una adecuada profilaxis / Vitamin D insufficiency in a healthy pediatric population. The importance of early prophylaxis

Introducción: la vitamina D mantiene la concentración de calcio y fósforo dentro del rango fisiológico, permitiendo un metabolismo normal y la correcta mineralización de los huesos. Recientemente, la deficiencia de vitamina D se ha relacionado no solo con el raquitismo sino también con el aumento del riesgo de otras patologías. El objetivo de este estudio descriptivo, observacional y transversal fue conocer los niveles de concentración de vitamina D en una población pediátrica sana y la situación actual en cuanto a la profilaxis. La determinación de la vitamina D se midió mediante la concentración sérica de 25-hidroxivitamina D (25(OH)D). Material y métodos: se inscribieron 258 pacientes sanos de entre 3 meses y 15 años (6,77 ± 3,95 años; 73,6 % de hombres). Resultados: el valor medio de 25(OH)D fue de 26,60 ng/ml ± 8,02 ng/ml; el 20,9 % de la población mostró un nivel insuficiente. Se observaron diferencias estadísticamente significativas entre los niveles de vitamina D de las distintas edades (p = 0,002), grupos étnicos (p = 0,038) y fototipos (p = 0,000). Además, se observó una mayor prevalencia de la insuficiencia de vitamina D en los niños que nunca antes habían recibido suplementos de vitamina D (41,6 %) en comparación con los que habían tomado suplementos en el primer año de vida (16,7 %). Conclusiones: el presente estudio muestra una alta prevalencia del déficit de vitamina D en los niños sanos y el beneficio de una correcta profilaxis en edades tempranas con suplementos de vitamina D. (AU)

Introduction: vitamin D maintains the concentration of calcium and phosphorus within the physiological range, allowing normal metabolism and bone mineralization. Recently, vitamin D deficiency has been related not only with rickets but also with an increased risk of other pathologies. The aim of this descriptive, observational, cross-sectional study was to assess vitamin D concentration levels in a healthy pediatric population, as well as the current situation of prophylaxis. Vitamin D determination was measured by serum 25-hydroxyvitamin D (25(OH)D) concentration. Material and methods: a total of 258 healthy patients between 3 months and 15 years of age were enrolled (6.77 ± 3.95 years; 73.6 % were male). Results: the mean value of 25-hydroxyvitamin D was 26.60 ng/mL ± 8.02 ng/mL, and up to 20.9 % of the population showed insufficient levels. Statistically significant differences in vitamin D levels were observed between ages (p = 0.002), ethnicity groups (p = 0.038), and skin types (p = 0.000). In addition, a higher prevalence of vitamin D insufficiency in children who had never previously received vitamin D supplementation (41.6 %) was observed compared to those that had taken supplementation in the first year of life (16.7 %). Conclusion: our study shows a high prevalence of vitamin D deficiency among healthy children, and the benefit of prophylaxis with vitamin D supplementation. (AU)

[Vitamin D insufficiency in a healthy pediatric population. The importance of early prophylaxis]. / Déficit de vitamina D en una población pediátrica sana. La importancia de una adecuada profilaxis.

INTRODUCTION: Introduction: vitamin D maintains the concentration of calcium and phosphorus within the physiological range, allowing normal metabolism and bone mineralization. Recently, vitamin D deficiency has been related not only with rickets but also with an increased risk of other pathologies. The aim of this descriptive, observational, cross-sectional study was to assess vitamin D concentration levels in a healthy pediatric population, as well as the current situation of prophylaxis. Vitamin D determination was measured by serum 25-hydroxyvitamin D (25(OH)D) concentration. Methods: a total of 258 healthy patients between 3 months and 15 years of age were enrolled (6.77 ± 3.95 years; 73.6 % were male). Results: the mean value of 25-hydroxyvitamin D was 26.60 ng/mL ± 8.02 ng/mL, and up to 20.9 % of the population showed insufficient levels. Statistically significant differences in vitamin D levels were observed between ages (p = 0.002), ethnicity groups (p = 0.038), and skin types (p = 0.000). In addition, a higher prevalence of vitamin D insufficiency in children who had never previously received vitamin D supplementation (41.6 %) was observed compared to those that had taken supplementation in the first year of life (16.7 %). Conclusion: our study shows a high prevalence of vitamin D deficiency among healthy children, and the benefit of prophylaxis with vitamin D supplementation.

INTRODUCCIÓN: Introducción: la vitamina D mantiene la concentración de calcio y fósforo dentro del rango fisiológico, permitiendo un metabolismo normal y la correcta mineralización de los huesos. Recientemente, la deficiencia de vitamina D se ha relacionado no solo con el raquitismo sino también con el aumento del riesgo de otras patologías. El objetivo de este estudio descriptivo, observacional y transversal fue conocer los niveles de concentración de vitamina D en una población pediátrica sana y la situación actual en cuanto a la profilaxis. La determinación de la vitamina D se midió mediante la concentración sérica de 25-hidroxivitamina D (25(OH)D). Material y métodos: se inscribieron 258 pacientes sanos de entre 3 meses y 15 años (6,77 ± 3,95 años; 73,6 % de hombres). Resultados: el valor medio de 25(OH)D fue de 26,60 ng/ml ± 8,02 ng/ml; el 20,9 % de la población mostró un nivel insuficiente. Se observaron diferencias estadísticamente significativas entre los niveles de vitamina D de las distintas edades (p = 0,002), grupos étnicos (p = 0,038) y fototipos (p = 0,000). Además, se observó una mayor prevalencia de la insuficiencia de vitamina D en los niños que nunca antes habían recibido suplementos de vitamina D (41,6 %) en comparación con los que habían tomado suplementos en el primer año de vida (16,7 %). Conclusiones: el presente estudio muestra una alta prevalencia del déficit de vitamina D en los niños sanos y el beneficio de una correcta profilaxis en edades tempranas con suplementos de vitamina D.

Cryopreserved H2 O2 -preconditioned human adipose-derived stem cells exhibit fast post-thaw recovery and enhanced bioactivity against oxidative stress.

Human adipose-derived stem cells (ASCs), despite being one of the most attractive cell populations for tissue engineering and regenerative medicine, currently have certain limitations that reduce their therapeutic efficacy. One of the most serious problems is the poor engraftment of cryopreserved ASCs at injured tissue, attributed to the diminished biological activity of ASCs immediately post-thaw and their poor survival under harsh conditions of oxidative stress. Seeking to address these issues, we have developed a hormetic strategy to preadapt human ASCs to oxidative stress based on a new hydrogen peroxide preconditioning procedure, resulting in cells we call HC016. These cells rapidly recover their biological activity and functionality after cryopreservation while maintaining their mesenchymal stem cell status. Compared with non-preconditioned ASCs, HC016 cells showed (a) faster in vitro adhesion capacity and cell cycle progression immediately post-thaw, (b) enhanced cell survival under oxidative stress in a serum-free environment, and (c) heightened chemotaxis towards damage signals of oxidized glial cells. In addition, compared with ASC-conditioned medium, HC016-conditioned medium showed a greater cytoprotective and pro-recovery effect on oxidized fibroblasts under serum-free conditions. Consistent with these results, in HC016 cells exposed to oxidative stress, we observed markedly higher expression of insulin-like growth factor-1 (a key factor in cell survival and migration) and of 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 4 and pyruvate dehydrogenase kinase isozyme 1 (essential enzymes to upregulate glycolysis and downregulate oxidative phosphorylation) along with lower basal mitochondrial activity. Taking into account all the aforementioned advantages, HC016 cells might be considered an important breakthrough in ASC-based cell therapies.

Influences of physical fitness on bone mass in women with fibromyalgia.

The aim of this study was to provide information about the relationship of bone mineral content (BMC) and density (BMD) with some physical-fitness-related variables in a sample of women with fibromyalgia (FM) and age-matched women without FM. Twenty-eight women clinically diagnosed with FM (age 51.1 ± 8.4 yr, M ± SD) and 22 age-matched controls participated in the study. Whole-body BMC and BMD, lean mass, handgrip strength, quadriceps strength, and cardiovascular fitness were measured in all participants. The association between physical-fitness variables and bone-related variables was tested by linear regression controlling for body weight as a possible confounder. There were no differences in BMC or BMD between groups. Women with FM had lower values of handgrip strength, quadriceps strength, and VO2peak than the control group. Handgrip strength and aerobic capacity were associated with BMC and BMD and quadriceps strength was associated with BMD in women with FM; however, only VO2peak was associated with BMC in the group of women without FM. Bone mass of women with FM may be more susceptible to changes in physical fitness than that of the women without fibromyalgia.

Effect of endurance and resistance training on regional fat mass and lipid profile.

The purpose of this study was to investigate the effect of 10-week of endurance training or resistance training on regional and abdominal fat, and in the lipid profile, examining the associations among the changes in body composition, weight, waist circumference and lipid profile. Body composition, waist circumference and lipid profile were analyzed in 26 volunteers healthy young men (age 22.5 ± 1.9 yr), randomly assigned to: endurance group (EG), resistance group (RG) or control group (CG). The EG significantly decreased after training the body weight, body mass index, total body fat and percentage of fat, fat and percentage of fat at the trunk and at the abdominal region and High-Density Lipoprotein. The RG significantly increased total lean mass and decreased total cholesterol, High-Density and Low- Density Lipoprotein. Close relationship were found among changes in weight, total lean mass, regional fat mass, waist circumference and changes in lipid profile (all p < 0.05). We concluded that 10-week of endurance training decreased abdominal and body fat in young men, while 10-week of resistance training increased total lean mass. These types of training had also effects on lipid profile that seem to be to some extent associated to changes in body composition; however it requires additional investigation.

El objetivo de este estudio fue investigar el efecto de 10 semanas de entrenamiento de resistencia ó fuerza sobre la cantidad de grasa en la región abdominal y sobre el perfil lipídico, analizando las asociaciones entre los cambios en composición corporal, peso, circunferencia de la cintura y perfil lipídico. La composición corporal, la circunferencia de la cintura y el perfil lipídico fueron analizados en 26 jóvenes (edad 22.5 ± 1,9 AÑOs), que se asignaron aleatoriamente a un grupo de resistencia (EG), un grupo de fuerza (RG) o al grupo control (CG). El EG disminuye significativamente, después del entrenamiento, el peso corporal, el índice de masa corporal, la cantidad total de grasa y el porcentaje de grasa, la grasa y porcentaje de grasa en el tronco y en la región abdominal y la lipoproteina de alta densidad. El RG mejoró significativamente la masa muscular total y disminuyeron el colesterol total, HDL y LDL. Se observó una relación estrecha entre los cambios en el peso, la masa magra total, la masa grasa regional, la cintura de la cadera y los cambio lipídicos (p < 0,05). Concluimos que 10 semanas de entrenamiento de resistencia disminuyen la grasa abdominal y corporal en sujetos jóvenes, mientras que 10 semanas de entrenamiento de fuerza aumentan la masa muscular total. Estos entrenamientos tienen un efecto sobre el perfil lipídico que parecen estar asociado a cambios en la composición corporal, no obstante, son necesarios más estudios.

Effect of endurance and resistance training on regional fat mass and lipid profile / Efecto del entrenamiento de resistencia y fuerza sobre la masa grasa regional y el perfil lípido

The purpose of this study was to investigate the effect of 10-week of endurance training or resistance training on regional and abdominal fat, and in the lipid profile, examining the associations among the changes in body composition, weight, waist circumference and lipid profile. Body composition, waist circumference and lipid profile were analyzed in 26 volunteers healthy young men (age 22.5 ± 1.9 yr), randomly assigned to: endurance group (EG), resistance group (RG) or control group (CG). The EG significantly decreased after training the body weight, body mass index, total body fat and percentage of fat, fat and percentage of fat at the trunk and at the abdominal region and High-Density Lipoprotein. The RG significantly increased total lean mass and decreased total cholesterol, High-Density and Low-Density Lipoprotein. Close relationship were found among changes in weight, total lean mass, regional fat mass, waist circumference and changes in lipid profile (all p < 0.05). We concluded that 10-week of endurance training decreased abdominal and body fat in young men, while 10-week of resistance training increased total lean mass. These types of training had also effects on lipid profile that seem to be to some extent associated to changes in body composition; however it requires additional investigation (AU)

El objetivo de este estudio fue investigar el efecto de 10 semanas de entrenamiento de resistencia ó fuerza sobre la cantidad de grasa en la región abdominal y sobre el perfil lipídico, analizando las asociaciones entre los cambios en composición corporal, peso, circunferencia de la cintura y perfil lipídico. La composición corporal, la circunferencia de la cintura y el perfil lipídico fueron analizados en 26 jóvenes (edad 22.5 ± 1,9 años), que se asignaron aleatoriamente a un grupo de resistencia (EG), un grupo de fuerza (RG) o al grupo control (CG). El EG disminuye significativamente, después del entrenamiento, el peso corporal, el índice de masa corporal, la cantidad total de grasa y el porcentaje de grasa, la grasa y porcentaje de grasa en el tronco y en la región abdominal y la lipoproteina de alta densidad. El RG mejoró significativamente la masa muscular total y disminuyeron el colesterol total, HDL y LDL. Se observó una relación estrecha entre los cambios en el peso, la masa magra total, la masa grasa regional, la cintura de la cadera y los cambio lipídicos (p < 0,05). Concluimos que 10 semanas de entrenamiento de resistencia disminuyen la grasa abdominal y corporal en sujetos jóvenes, mientras que 10 semanas de entrenamiento de fuerza aumentan la masa muscular total. Estos entrenamientos tienen un efecto sobre el perfil lipídico que parecen estar asociado a cambios en la composición corporal, no obstante, son necesarios más estudios (AU)

Human mitochondrial haplogroup H: the highest VO2max consumer--is it a paradox?

Mitochondrial background has been demonstrated to influence maximal oxygen uptake (VO(2max), in mLkg(-1)min(-1)), but this genetic influence can be compensated for by regular exercise. A positive correlation among electron transport chain (ETC) coupling, ATP and reactive oxygen species (ROS) production has been established, and mitochondrial variants have been reported to show differences in their ETC performance. In this study, we examined in detail the VO(2max) differences found among mitochondrial haplogroups. We recruited 81 healthy male Spanish Caucasian individuals and determined their mitochondrial haplogroup. Their VO(2max) was determined using incremental cycling exercise (ICE). VO(2max) was lower in J than in non-J haplogroup individuals (P=0.04). The H haplogroup was responsible for this difference (VO(2max); J vs. H; P=0.008) and this group also had significantly higher mitochondrial oxidative damage (mtOD) than the J haplogroup (P=0.04). In agreement with these results, VO(2max) and mtOD were positively correlated (P=0.01). Given that ROS production is the major contributor to mtOD and consumes four times more oxygen per electron than the ETC, our results strongly suggest that ROS production is responsible for the higher VO(2max) found in the H variant. These findings not only contribute to a better understanding of the mechanisms underneath VO(2max), but also help to explain some reported associations between mitochondrial haplogroups and mtOD with longevity, sperm motility, premature aging and susceptibility to different pathologies.

Moroccan mitochondrial genetic background suggests prehistoric human migrations across the Gibraltar Strait.

Migrations into Africa from the Levant have greatly determined the mitochondrial genetic landscape of North Africa. After analyzing samples from North Morocco to Spain, we show that three fourths of the Moroccan individuals belong to Western Eurasian haplogroups and the frequencies of these are much more similar to those of the Iberian Peninsula than to those of the Middle East. This is particularly true for the mitochondrial haplogroups H1, H3 and V, which experienced a late-glacial expansion from this region, that repopulated much of Central and Northern Europe. Iberian Peninsula was also a source for prehistoric migrations to North Africa.

Steady exercise removes VO(2max) difference between mitochondrial genomic variants.

It has been clearly established that mitochondrial variants, among other potential factors, influence on VO(2max). With this study we sought to determine whether this genetic predisposition could be modified by steady exercise. Mitochondrial genetic variants were determined in 70 healthy controls (CON) and in 77 athletes who trained regularly (50 cyclists, aerobic training (AER), and 27 runners of 400m, anaerobic training (NoAER)). All of them were male Spanish Caucasian individuals. A maximum graded exercise test (GXT) in cycle-ergometer was performed to determine VO(2max) (mL kg(-1)min(-1)). Our results confirmed that, in CON, VO(2max) (P=0.007) was higher in Non-J than J individuals. Furthermore, we found that AER and NoAER showed, as it could be expected, higher VO(2max) than CON, but not differences between mitochondrial variants have been found. According with these findings, the influence of mitochondrial DNA (mtDNA) variants on VO(2max) has been confirmed, and a new conclusion has arisen: the steady exercise is able to remove this influence. The interest of these promising findings in muscular performance should be further explored, in particular, the understanding of potential applications in sport training and in muscle pathological syndromes.

Human mitochondrial variants influence on oxygen consumption.

This work investigates if human mitochondrial variants influence on maximal oxygen consumption (VO(2max)). With this purpose we recruited, as a uniform population in term of nutritional habits and life style, 114 healthy male Spanish subjects that practiced fitness exercises 3-4 times a week. Once mtDNA haplogroups were determined, we found that J presents with lower VO(2max) (P=0.02) than nonJ variants. J has been related with a lower efficiency of electron transport chain (ETC), diminished ATP and ROS production. Thus, the difficult to compensate the mitochondrial energetic deficiency could explain the accumulation of J haplogroup in LHON and multiple sclerosis. Furthermore, the lower ROS production associated to J could also account for the accrual of this variant in elderly people consequent to a decreased oxidative damage.

Association of mitochondrial haplogroup J and mtDNA oxidative damage in two different North Spain elderly populations.

This work investigates the association between longevity, mitochondrial DNA (mtDNA) variants and oxidative DNA damage in an older than 85 years population. The participants, similar in genetic and cultural background as well as gender distribution, come from villages near to the Pyrenees Mountains (900-1,400 m altitude) (n = 69) and the Ebro's Valley (200-300 m altitude) (n = 69) in Spain. Our results show an accumulation of the haplogroup J in elderly individuals with an over-representation of J2 in Pyrenees group but not in the Ebro's Valley, the former associating with a diminished DNA damage. In conclusion, our results suggest that J mitochondrial variant, that induce lower mtDNA damage, could present a phenotypic survival advantage to environmental conditions and, thus, accumulate in elderly population.