Synthesis, antioxidant and neuroprotective analysis of diversely functionalized α-aryl-N-alkyl nitrones as potential agents for ischemic stroke therapy.

Herein, we report the synthesis, antioxidant and biological evaluation of 32 monosubstituted α-arylnitrones derived from α-phenyl-tert-butyl nitrone (PBN) in the search for neuroprotective compounds for ischemic stroke therapy, trying to elucidate the structural patterns responsible for their neuroprotective activity. Not surprisingly, the N-tert-butyl moiety plays beneficious role in comparison to other differently N-substituted nitrone groups. It seems that electron donor substituents at the ortho position and electron withdrawing substituents at the meta position of the aryl ring induce good neuroprotective activity. As a result, (Z)-N-tert-butyl-1-(2-hydroxyphenyl)methanimine oxide (21a) and (Z)-N-tert-butyl-1-(2-(prop-2-yn-1-yloxy)phenyl)methanimine oxide (24a) showed a significant increase in neuronal viability in an experimental ischemia model in primary neuronal cultures, and induced neuroprotection and improved neurodeficit score in an in vivo model of transient cerebral ischemia. These results showed that nitrones 21a and 24a are new effective small and readily available antioxidants, and suitable candidates for further structure optimization in the search for new phenyl-derived nitrones for the treatment of ischemic stroke and related diseases.

The Golgi complex of dopaminergic enteric neurons is fragmented in a hemiparkinsonian rat model.

Since gastrointestinal disorders are early consequences of Parkinson's disease (PD), this disease is clearly not restricted to the central nervous system (CNS), but also significantly affects the enteric nervous system (ENS). Large aggregates of the protein α-synuclein forming Lewy bodies, the prototypical cytopathological marker of this disease, have been observed in enteric nervous plexuses. However, their value in early prognosis is controversial. The Golgi complex (GC) of nigral neurons appears fragmented in Parkinson's disease, a characteristic common in most neurodegenerative diseases. In addition, the distribution and levels of regulatory proteins such as Rabs and SNAREs are altered, suggesting that PD is a membrane traffic-related pathology. Whether the GC of enteric dopaminergic neurons is affected by the disease has not yet been analyzed. In the present study, dopaminergic neurons in colon nervous plexuses behave as nigral neurons in a hemiparkinsonian rat model based on the injection of the toxin 6-OHDA. Their GCs are fragmented, and some regulatory proteins' distribution and expression levels are altered. The putative mechanisms of the transmission of the neurotoxin to the ENS are discussed. Our results support the possibility that GC structure and the level of some proteins, especially syntaxin 5, could be helpful as early indicators of the disease. RESEARCH HIGHLIGHTS: The Golgi complexes of enteric dopaminergic neurons appear fragmented in a Parkinson's disease rat model. Our results support the hypothesis that the Golgi complex structure and levels of Rab1 and syntaxin 5 could be helpful as early indicators of the disease.

Development of Pharmacological Strategies with Therapeutic Potential in Ischemic Stroke.

Acute ischemic stroke constitutes a health challenge with great social impact due to its high incidence, with the social dependency that it generates being an important source of inequality. The lack of treatments serving as effective neuroprotective therapies beyond thrombolysis and thrombectomy is presented as a need. With this goal in mind, our research group's collaborative studies into cerebral ischemia and subsequent reperfusion concluded that there is a need to develop compounds with antioxidant and radical scavenger features. In this review, we summarize the path taken toward the identification of lead compounds as potential candidates for the treatment of acute ischemic stroke. Evaluations of the antioxidant capacity, neuroprotection of primary neuronal cultures and in vivo experimental models of cerebral ischemia, including neurological deficit score assessments, are conducted to characterize the biological efficacy of the various neuroprotective compounds developed. Moreover, the initial results in preclinical development, including dose-response studies, the therapeutic window, the long-term neuroprotective effect and in vivo antioxidant evaluation, are reported. The results prompt these compounds for clinical trials and are encouraging regarding new drug developments aimed at a successful therapy for ischemic stroke.

Cardiovascular risk in Cuban adolescents and young adults with congenital adrenal hyperplasia.

BACKGROUND: Hyperandrogenism and supraphysiologic glucocorticoid replacement may lead to subclinical atherosclerosis in people with congenital adrenal hyperplasia (CAH) and predispose the development of cardiovascular diseases from an early age. OBJECTIVES: To determine if cardiometabolic risk factors and subclinical atherosclerosis are more frequent in patients with CAH due to 21-hydroxylase deficiency (21OHD) and if there is an association with clinical, hormonal and treatment of 21OHD. MATERIAL AND METHODS: A descriptive prospective cross-sectional study exploring clinical variables, biochemical, hormonal variables, endothelial dysfunction (flow-mediated dilation < 5%) and carotid intima media thickness (≥ 95 percentile in adolescents and ≥ 75 percentile in adults) and epicardial fat. Adolescents and young patients with 21OHD were compared with controls matched by age, sex, body mass index and Tanner stage. RESULTS: Forty four subjects (22 with CAH), 36 (82%) females, with a mean age of 17.1 ± 5.5 years (range 10-30 years) were included. Family history revealed diabetes, hypertension, and hypercholesterolemia with high frequencies in both groups. The blood pressure was similar in both groups. Blood glucose levels were lower and triglycerides higher in patient (both p < 0.01). Epicardial fat was similar between groups and in patients with CAH it was related to cholesterol levels ​​(r = 0.679, p < 0.01), time since CAH diagnosis (r = 0.462, p = 0.03) and glucocorticoid dose (r = 0.499, p = 0.04). Carotid intima media thickness (CIMT) had a tendency to be increased in patients (p = 0.07) and was directly related to 17-hydroxyprogesterone (r = 0.510, p = 0.018), diastolic blood pressure (r = 0.444, p = 0.04) and the homeostatic model assessment (HOMA) index (r = 0.507, p = 0.01). Endothelial dysfunction was not different between groups. CONCLUSIONS: Some cardiometabolic risk factors were increased in patients with CAH and were associated with clinical, hormonal and treatment parameters of CAH. Cardiometabolic risk should be evaluated regularly in patients with CAH.

Bacterial molecular machinery in the Martian cryosphere conditions.

The exploration of Mars is one of the main objectives of space missions since the red planet is considered to be, or was in the past, potentially habitable. Although the surface of Mars is now dry and arid, abundant research suggests that water covered Mars billions of years ago. Recently, the existence of liquid water in subglacial lakes has been postulated below the South pole of Mars. Until now, experiments have been carried out on the survival of microorganisms in Martian surface conditions, but it remains unknown how their adaptation mechanisms would be in the Martian cryosphere. In this work, two bacterial species (Bacillus subtilis and Curtobacterium flacumfaciens) were subjected to a simulated Martian environment during 24 h using a planetary chamber. Afterward, the molecular machinery of both species was studied to investigate how they had been modified. Proteomes, the entire set of proteins expressed by each bacterium under Earth (named standard) conditions and Martian conditions, were compared using proteomic techniques. To establish this evaluation, both the expression levels of each protein, and the variation in their distribution within the different functional categories were considered. The results showed that these bacterial species followed a different strategy. The Bacillus subtilis resistance approach consisted of improving its stress response, membrane bioenergetics, degradation of biomolecules; and to a lesser extent, increasing its mobility and the formation of biofilms or resistance endospores. On the contrary, enduring strategy of Curtobacterium flacumfaciens comprised of strengthening the cell envelope, trying to protect cells from the extracellular environment. These results are especially important due to their implications for planetary protection, missions to Mars and sample return since contamination by microorganisms would invalidate the results of these investigations.

Masa ósea en mujeres de edad mediana del Policlínico 19 de abril / Bone Mass in Middle-Aged Women from Policlínico 19 de Abril of Havana

Introducción: La osteoporosis es una enfermedad esquelética difusa caracterizada por una disminución generalizada de la resistencia ósea, que predispone a un mayor riesgo de fracturas por fragilidad y está reconocida como un grave problema de salud. Objetivo: Determinar la masa ósea en mujeres de edad mediana y algunos factores relacionados con ella. Métodos: Se realizó un estudio descriptivo transversal en mujeres de edad mediana del Policlínico 19 de abril. De la planilla de recolección de datos se extrajeron: edad, color de la piel, etapa climatérica, número de partos, meses de lactancia, resultados hormonales. Se realizó densitometría para determinar mujeres con hueso normal, baja masa ósea u osteopenia y osteoporosis, y se asociaron con algunos factores de riesgo. Resultados: Se estudiaron 82 mujeres. El 67,07 por ciento tuvo masa ósea normal en la columna lumbar, un 19,51 por ciento baja masa ósea u osteopenia y un 13,42 por ciento osteoporosis. En la cadera izquierda la mayoría (91,46 por ciento) presentó masa ósea normal. De las perimenopáusicas, una entre 50 y 54 años presentó baja masa ósea; en posmenopáusicas predominó la osteoporosis en el grupo de 50-54 (50 por ciento), en las de 55-59, las que tenían hueso normal y osteopenia (41,2 por ciento cada una). En las posmenopáusicas, las que tenían la piel blanca fueron las que presentaron mayor afectación de la masa ósea. A mayor tiempo de posmenopausia menor masa ósea (p= 0,031*), a niveles más elevados de hormona luteinizante (p= 0,000) y foliculoestimulante (p= 0,000), menor densidad mineral ósea en la columna lumbar y cadera izquierda; a niveles más elevados de estradiol (p= 0,000), mayor densidad mineral ósea en ambas localizaciones. Conclusiones: Se concluye que la mayoría de las mujeres de edad mediana del policlínico 19 de abril tenían hueso normal; la osteoporosis predominó en los grupos de mayor edad y el color de la piel blanca. Mayor tiempo de posmenopausia y niveles elevados de hormona luteinizante y foliculoestimulante se asociaron con mala masa ósea; niveles elevados de estradiol con mejor masa ósea(AU)

Introduction: Osteoporosis is a diffuse skeletal disease characterized by a generalized decrease in bone resistance, which predisposes patients to an increased risk of fragility fractures and is recognized as a serious health problem. Objective: To determine bone mass in middle-aged women and some factors related to it. Methods: A descriptive and cross-sectional study was carried out in middle-aged women from the Policlínico 19 de Abril. The following data were extracted from the data collection form: age, skin color, climacteric stage, number of deliveries, breastfeeding months, hormonal results. Densitometry was performed to determine women with normal bone, low bone mass or osteopenia and osteoporosis, and these were associated with some risk factors. Results: A group of 82 women were studied. Of them, 67.07percent had normal bone mass in the lumbar spine, 19.51percent had low bone mass or osteopenia, and 13.42percent ad osteoporosis. On the left hip, the majority (91.46percent) had normal bone mass. Of the perimenopausal women, one aged 50-54 years had low bone mass; among postmenopausal women, osteoporosis predominated in the 50-54 age group (50percent), as well as in those aged 55-59, those with normal bone mass and osteopenia (41.2percent for each condition). In the postmenopausal women, those with white skin were the most affected in bone mass. The longer the postmenopausal period, the lower the bone mass (p = 0.031*); the higher the levels of luteinizing hormone (p = 0.000) and the follicle stimulating hormone (p = 0.000), the lower bone mineral density on the lumbar spine and left hip; the higher the levels of estradiol (p = 0.000), the higher bone mineral density on both locations. Conclusions: Most middle-aged women from the Policlínico April 19 were concluded to have normal bone; osteoporosis predominated in older age groups and white skin color. Longer postmenopausal time and higher levels of luteinizing hormone and the follicle stimulating hormone were associated with poor bone mass; high levels of estradiol were associated with better bone mass(AU)

Dihydropyrimidinase-Related Protein 2 Is a New Partner in the Binding between 4E-BP2 and eIF4E Related to Neuronal Death after Cerebral Ischemia.

Transient cerebral ischemia induces neuronal degeneration, followed in time by secondary delayed neuronal death that is strongly correlated with a permanent inhibition of protein synthesis in vulnerable brain regions, while protein translational rates are recovered in resistant areas. In the translation-regulation initiation step, the eukaryotic initiation factor (eIF) 4E is a key player regulated by its association with eIF4E-binding proteins (4E-BPs), mostly 4E-BP2 in brain tissue. In a previous work, we identified dihydropyrimidinase-related protein 2 (DRP2) as a 4E-BP2-interacting protein. Here, using a proteomic approach in a model of transient cerebral ischemia, a detailed study of DRP2 was performed in order to address the challenge of translation restoration in vulnerable regions. In this report, several DRP2 isoforms that have a specific interaction with both 4E-BP2 and eIF4E were identified, showing significant and opposite differences in this association, and being differentially detected in resistant and vulnerable regions in response to ischemia reperfusion. Our results provide the first evidence of DRP2 isoforms as potential regulators of the 4E-BP2-eIF4E association that would have consequences in the delayed neuronal death under ischemic-reperfusion stress. The new knowledge reported here identifies DRP2 as a new target to promote neuronal survival after cerebral ischemia.

The hidden microbial ecosystem in the perennial ice from a Pyrenean ice cave.

Over the last years, perennial ice deposits located within caves have awakened interest as places to study microbial communities since they represent unique cryospheric archives of climate change. Since the beginning of the twentieth century, the temperature has gradually increased, and it is estimated that by the end of this century the increase in average temperature could be around 4.0°C. In this context of global warming the ice deposits of the Pyrenean caves are undergoing a significant regression. Among this type of caves, that on the Cotiella Massif in the Southern Pyrenees is one of the southernmost studied in Europe. These types of caves house microbial communities which have so far been barely explored, and therefore their study is necessary. In this work, the microbial communities of the Pyrenean ice cave A294 were identified using metabarcoding techniques. In addition, research work was carried out to analyze how the age and composition of the ice affect the composition of the bacterial and microeukaryotic populations. Finally, the in vivo effect of climate change on the cellular machinery that allow microorganisms to live with increasing temperatures has been studied using proteomic techniques.

Valores de referencia para la tirotropina y hormonas tiroideas en embarazadas cubanas / Reference values for thyrotropin and thyroid hormones in pregnant women in Cuba

Introducción: Los parámetros de función tiroidea en las embarazadas se modifican durante el embarazo y son específicos para cada población. Objetivo: Establecer los valores de referencia para la tirotropina y las hormonas tiroideas en una población de embarazadas cubanas. Métodos: Estudio transversal, en el municipio Plaza de la Revolución de La Habana, Cuba, a 362 gestantes sin antecedentes personales o familiares de enfermedad tiroidea, con anticuerpos anti-tiroideos negativos y ausencia de lesiones en el ultrasonido tiroideo. Se analizaron edad materna, edad gestacional, raza, hábito de fumar, paridad, uso de suplementos yodados, índice de masa corporal, tirotropina, tiroxina total y libre, triyodotironina total y libre. Se establecieron los intervalos de referencia para cada parámetro mediante los percentiles 2,5 y 97,5 como límites inferior y superior, respectivamente. Resultados: Los valores de referencia en el primer, segundo y tercer trimestres fueron para la tirotropina 0,1-3,3 mUI/L, 0,6-3,4 mUI/L y 0,3-3,9 mUI/L; para la TT4 90,1-204,1 nmol/L, 92,2-189,2 nmol/L y 79,8-170,4 nmol/L; para la FT4 7,3-16,7 pmol/L, 6,3-17,3 pmol y 5,6-12,7 pmol/L; para la TT3 1,8-3,9 nmol/L, 1,8-3,9 nmol/L y 1,7-4,0 nmol/L y para la FT3 1,0-7,4 pmol/L, 0,7-6,3 pmol/L y 0,7-5,4 pmol/L, respectivamente. Conclusiones: Se determinaron por primera vez los valores de referencia para la tirotropina y las hormonas tiroideas en una población de embarazadas cubanas; estos difieren de los establecidos por los kits diagnósticos y de los recomendados por las guías internacionales previas (AU)

Introduction: Thyroid function parameters in pregnant women are modified during pregnancy and are specific for each population. Objective: To establish reference values for thyrotropin and thyroid hormones in a population of Cuban pregnant women. Methods: Cross-sectional study, in the Plaza de la Revolución municipality, of 362 pregnant women without personal or family history of thyroid disease, with negative anti-thyroid antibodies and absence of lesions in the thyroid ultrasound. Maternal age, gestational age, race, smoking, number of pregnancies, use of iodine supplements, body mass index, thyrotropin, total (TT4) and free (FT4) thyroxine, total (TT3) and free (FT3) triiodothyronine were analyzed. Reference intervals were established for each parameter using the 2.5 and 97.5 percentiles as lower and upper limits, respectively. Results: The reference values in the first, second and third trimesters were for thyrotropin 0.1-3.3 mIUI/L, 0.6-3.4 mIU/L and 0.3-3.9 mIU/L; for TT4 90.1-204.1 nmol/L, 92.2-189.2 nmol/L and 79.8-170.4 nmol/L; for FT4 7.3-16.7 pmol/L, 6.3-17.3 pmol and 5.6-12.7 pmol/L; for TT3 1.8-3.9 nmol/L, 1.8-3.9 nmol/L and 1.7-4.0 nmol/L and for FT3 1.0-7.4 pmol/L, 0.7-6.3 pmol/L and 0.7-5.4 pmol/L, respectively. Conclusions: Reference values for thyrotropin and thyroid hormones were determined for the first time in a population of Cuban pregnant women. These values differ from those established by the manufacturer of the diagnostic kits and from those recommended by previous international guidelines (AU)

Años de vida saludable perdidos por diabetes mellitus en Cuba / Years of Healthy Life Lost Due to Diabetes Mellitus in Cuba

Introducción: El reciente incremento de la prevalencia de la diabetes mellitus en Cuba sucedió con mayor celeridad, y las políticas encaminadas a su control requieren de su cuantificación sistemática. Objetivo: Identificar las diferencias en Cuba, según provincia y sexo, de los años de vida saludable perdidos por la diabetes mellitus en el 2015. Métodos: En el estudio de extensión nacional se obtuvieron los años de vida saludable perdidos como resultado de la suma de los años perdidos de vida potencial por mortalidad prematura y los años de vida perdidos por morbilidad y otros indicadores para identificar la mortalidad temprana en el año 2015. Resultados: En todas las provincias los índices de años de vida saludable perdidos por morbilidad superaron los de mortalidad prematura con predominio del sexo femenino, mientras en la mayoría de las provincias, las edades de las defunciones fueron más tempranas en el masculino. Las diferencias halladas permitieron agrupar a Artemisa, La Habana, Mayabeque, Matanzas, Villa Clara, Cienfuegos, Santi Spíritus y Camagüey, con los mayores promedios de años perdidos por morbilidad y fallecimientos más tardíos, y al resto de las provincias cubanas, con los menores años perdidos por morbilidad, pero con defunciones en edades más tempranas. Conclusiones: Las pérdidas de años de vida saludable difieren según el sexo y la provincia. Este conocimiento permite la identificación de diferentes patrones de morbimortalidad útiles para orientar las acciones de prevención y control de la enfermedad para cada territorio(AU)

Introduction: The recent increase in the prevalence of diabetes mellitus in Cuba occurred more rapidly, and policies aimed at its control require systematic quantification. Objective: To identify the differences in Cuba, according to province and sex, of the years of healthy life lost due to diabetes mellitus in 2015. Methods: The national extension study collected data on the healthy years of life lost as a result of the sum of years lost from potential life due to premature mortality and years of life lost due to morbidity and other indicators to identify early mortality in 2015. Results: In all provinces, the rates of years of healthy life lost due to morbidity exceeded those of premature mortality with a predominance of women, while in most provinces, the ages of death were earlier in the male sex. The differences found allowed to group Artemisa, Havana, Mayabeque, Matanzas, Villa Clara, Cienfuegos, Santi Spíritus and Camagüey provincesn with the highest averages of years lost due to morbidity and later deaths, and the rest of the Cuban provinces, with the lowest years lost due to morbidity, but with deaths at younger ages. Conclusions: Losses of years of healthy life differ by sex and province. This knowledge allows the identification of different patterns of morbidity and mortality useful to guide the prevention and control actions of the disease for each territory(AU)

Postischemic Neuroprotection of Aminoethoxydiphenyl Borate Associates Shortening of Peri-Infarct Depolarizations.

Brain stroke is a highly prevalent pathology and a main cause of disability among older adults. If not promptly treated with recanalization therapies, primary and secondary mechanisms of injury contribute to an increase in the lesion, enhancing neurological deficits. Targeting excitotoxicity and oxidative stress are very promising approaches, but only a few compounds have reached the clinic with relatively good positive outcomes. The exploration of novel targets might overcome the lack of clinical translation of previous efficient preclinical neuroprotective treatments. In this study, we examined the neuroprotective properties of 2-aminoethoxydiphenyl borate (2-APB), a molecule that interferes with intracellular calcium dynamics by the antagonization of several channels and receptors. In a permanent model of cerebral ischemia, we showed that 2-APB reduces the extent of the damage and preserves the functionality of the cortical territory, as evaluated by somatosensory evoked potentials (SSEPs). While in this permanent ischemia model, the neuroprotective effect exerted by the antioxidant scavenger cholesteronitrone F2 was associated with a reduction in reactive oxygen species (ROS) and better neuronal survival in the penumbra, 2-APB did not modify the inflammatory response or decrease the content of ROS and was mostly associated with a shortening of peri-infarct depolarizations, which translated into better cerebral blood perfusion in the penumbra. Our study highlights the potential of 2-APB to target spreading depolarization events and their associated inverse hemodynamic changes, which mainly contribute to extension of the area of lesion in cerebrovascular pathologies.

Preclinical Characterization of Antioxidant Quinolyl Nitrone QN23 as a New Candidate for the Treatment of Ischemic Stroke.

Nitrones are encouraging drug candidates for the treatment of oxidative stress-driven diseases such as acute ischemic stroke (AIS). In a previous study, we found a promising quinolylnitrone, QN23, which exerted a neuroprotective effect in neuronal cell cultures subjected to oxygen-glucose deprivation and in experimental models of cerebral ischemia. In this paper, we update the biological and pharmacological characterization of QN23. We describe the suitability of intravenous administration of QN23 to induce neuroprotection in transitory four-vessel occlusion (4VO) and middle cerebral artery occlusion (tMCAO) experimental models of brain ischemia by assessing neuronal death, apoptosis induction, and infarct area, as well as neurofunctional outcomes. QN23 significantly decreased the neuronal death and apoptosis induced by the ischemic episode in a dose-dependent manner and showed a therapeutic effect when administered up to 3 h after post-ischemic reperfusion onset, effects that remained 11 weeks after the ischemic episode. In addition, QN23 significantly reduced infarct volume, thus recovering the motor function in a tMCAO model. Remarkably, we assessed the antioxidant activity of QN23 in vivo using dihydroethidium as a molecular probe for radical species. Finally, we describe QN23 pharmacokinetic parameters. All these results pointing to QN23 as an interesting and promising preclinical candidate for the treatment of AIS.

An Exploratory Study of Itolizumab on the Preservation of Beta Cell Function in Adults with Recent-Onset Type 1 Diabetes.

We conducted a phase I-IIa, randomized, monocentric, double-blind, placebo-controlled clinical trial to evaluate the safety and impact of the combination treatment of Itolizumab and insulin on preserving beta cell function in adults with recent-onset type 1 diabetes. Twelve patients were randomly assigned to three treatment groups, each receiving a different Itolizumab dose (0.4/0.8/1.6 mg/kg body weight, respectively) and a placebo group. All patients received concomitant intensive multiple-dose insulin therapy. Endogenous insulin secretion was assessed by the measurement of C-peptide during the mixed-meal tolerance test. No serious adverse events were reported. No changes in the total daily insulin doses, glycated hemoglobin levels, and stimulated C-peptide were observed between the Itolizumab and placebo groups at 52 weeks. A significant decrease in stimulated C-peptide was observed during the follow-up period (p = 0.012). One subject treated with 1.6 mg of Itolizumab showed a marked increase in the levels of stimulated C-peptide three years after completion of the trial. Taken together, this is the first study to demonstrate that combination treatment with Itolizumab and insulin is safe in humans and does not affect the residual function of beta cells up to 52 weeks. The findings from our study show preliminary evidence that high doses of Itolizumab could potentially arrest the loss of beta cell function in the long term. Further studies with a longer follow-up and larger numbers of patients are envisaged to assess the effect with high dose Itolizumab.

Phosphorylation of Eukaryotic Initiation Factor 4G1 (eIF4G1) at Ser1147 Is Specific for eIF4G1 Bound to eIF4E in Delayed Neuronal Death after Ischemia.

Ischemic strokes are caused by a reduction in cerebral blood flow and both the ischemic period and subsequent reperfusion induce brain injury, with different tissue damage depending on the severity of the ischemic insult, its duration, and the particular areas of the brain affected. In those areas vulnerable to cerebral ischemia, the inhibition of protein translation is an essential process of the cellular response leading to delayed neuronal death. In particular, translation initiation is rate-limiting for protein synthesis and the eukaryotic initiation factor (eIF) 4F complex is indispensable for cap-dependent protein translation. In the eIF4F complex, eIF4G is a scaffolding protein that provides docking sites for the assembly of eIF4A and eIF4E, binding to the cap structure of the mRNA and stabilizing all proteins of the complex. The eIF4F complex constituents, eIF4A, eIF4E, and eIF4G, participate in translation regulation by their phosphorylation at specific sites under cellular stress conditions, modulating the activity of the cap-binding complex and protein translation. This work investigates the phosphorylation of eIF4G1 involved in the eIF4E/eIF4G1 association complex, and their regulation in ischemia-reperfusion (IR) as a stress-inducing condition. IR was induced in an animal model of transient cerebral ischemia and the results were studied in the resistant cortical region and in the vulnerable hippocampal CA1 region. The presented data demonstrate the phosphorylation of eIF4G1 at Ser1147, Ser1185, and Ser1231 in both brain regions and in control and ischemic conditions, being the phosphorylation of eIF4G1 at Ser1147 the only one found in the eIF4E/eIF4G association complex from the cap-containing matrix (m7GTP-Sepharose). In addition, our work reveals the specific modulation of the phosphorylation of eIF4G1 at Ser1147 in the vulnerable region, with increased levels and colocalization with eIF4E in response to IR. These findings contribute to elucidate the molecular mechanism of protein translation regulation that underlies in the balance of cell survival/death during pathophysiological stress, such as cerebral ischemia.

Focus on the Small GTPase Rab1: A Key Player in the Pathogenesis of Parkinson's Disease.

Parkinson's disease (PD) is the second most frequent neurodegenerative disease. It is characterized by the loss of dopaminergic neurons in the substantia nigra and the formation of large aggregates in the survival neurons called Lewy bodies, which mainly contain α-synuclein (α-syn). The cause of cell death is not known but could be due to mitochondrial dysfunction, protein homeostasis failure, and alterations in the secretory/endolysosomal/autophagic pathways. Survival nigral neurons overexpress the small GTPase Rab1. This protein is considered a housekeeping Rab that is necessary to support the secretory pathway, the maintenance of the Golgi complex structure, and the regulation of macroautophagy from yeast to humans. It is also involved in signaling, carcinogenesis, and infection for some pathogens. It has been shown that it is directly linked to the pathogenesis of PD and other neurodegenerative diseases. It has a protective effect against α-σψν toxicity and has recently been shown to be a substrate of LRRK2, which is the most common cause of familial PD and the risk of sporadic disease. In this review, we analyze the key aspects of Rab1 function in dopamine neurons and its implications in PD neurodegeneration/restauration. The results of the current and former research support the notion that this GTPase is a good candidate for therapeutic strategies.

Antiseizure medication for brain metastasis-related epilepsy: Findings of optimal choice from a retrospective cohort.

OBJECTIVE: To analyze the prevalence of antiseizure medication (ASM) in patients with brain metastasis-related epilepsy (BMRE) treated with radiosurgery and the relationship between ASM and psychiatric comorbidity. MATERIAL AND METHODS: This is a cross-sectional observational design study with retrospective review of medical records of all patients with brain metastases treated with volumetric modulated arc therapy radiosurgery (VMAT-RS) between 2012 and 2018 in a tertiary oncology center. We included those patients with BMRE, analyzing the clinical and demographic data, with special attention to psychiatric comorbidities and the use of ASM. RESULTS: Of the 121 patients with brain metastases included for treatment with VMAT-RS, a total of 38 presented BMRE. The most widely used ASM as first-line treatment was levetiracetam (89%). Only 8% of the patients received sodium channel blockers. The most common psychiatric comorbidity was depression (42.1%). CONCLUSIONS: Levetiracetam is the most widely used ASM in patients with BMRE treated with VMAT-RS. Nevertheless, common psychiatric comorbidities in this population might change the decision-making of ASM choice.

Differential Association of 4E-BP2-Interacting Proteins Is Related to Selective Delayed Neuronal Death after Ischemia.

Cerebral ischemia induces an inhibition of protein synthesis and causes cell death and neuronal deficits. These deleterious effects do not occur in resilient areas of the brain, where protein synthesis is restored. In cellular stress conditions, as brain ischemia, translational repressors named eukaryotic initiation factor (eIF) 4E-binding proteins (4E-BPs) specifically bind to eIF4E and are critical in the translational control. We previously described that 4E-BP2 protein, highly expressed in brain, can be a molecular target for the control of cell death or survival in the reperfusion after ischemia in an animal model of transient cerebral ischemia. Since these previous studies showed that phosphorylation would not be the regulation that controls the binding of 4E-BP2 to eIF4E under ischemic stress, we decided to investigate the differential detection of 4E-BP2-interacting proteins in two brain regions with different vulnerability to ischemia-reperfusion (IR) in this animal model, to discover new potential 4E-BP2 modulators and biomarkers of cerebral ischemia. For this purpose, 4E-BP2 immunoprecipitates from the resistant cortical region and the vulnerable hippocampal cornu ammonis 1 (CA1) region were analyzed by two-dimensional (2-D) fluorescence difference in gel electrophoresis (DIGE), and after a biological variation analysis, 4E-BP2-interacting proteins were identified by matrix-assisted laser desorption/ionization-time of flight (MALDI-TOF) mass spectrometry. Interestingly, among the 4E-BP2-interacting proteins identified, heat shock 70 kDa protein-8 (HSC70), dihydropyrimidinase-related protein-2 (DRP2), enolase-1, ubiquitin carboxyl-terminal hydrolase isozyme-L1 (UCHL1), adenylate kinase isoenzyme-1 (ADK1), nucleoside diphosphate kinase-A (NDKA), and Rho GDP-dissociation inhibitor-1 (Rho-GDI), were of notable interest, showing significant differences in their association with 4E-BP2 between resistant and vulnerable regions to ischemic stress. Our data contributes to the first characterization of the 4E-BP2 interactome, increasing the knowledge in the molecular basis of the protection and vulnerability of the ischemic regions and opens the way to detect new biomarkers and therapeutic targets for diagnosis and treatment of cerebral ischemia.

Privileged Quinolylnitrones for the Combined Therapy of Ischemic Stroke and Alzheimer's Disease.

Cerebrovascular diseases such as ischemic stroke are known to exacerbate dementia caused by neurodegenerative pathologies such as Alzheimer's disease (AD). Besides, the increasing number of patients surviving stroke makes it necessary to treat the co-occurrence of these two diseases with a single and combined therapy. For the development of new dual therapeutic agents, eight hybrid quinolylnitrones have been designed and synthesized by the juxtaposition of selected pharmacophores from our most advanced lead-compounds for ischemic stroke and AD treatment. Biological analyses looking for efficient neuroprotective effects in suitable phenotypic assays led us to identify MC903 as a new small quinolylnitrone for the potential dual therapy of stroke and AD, showing strong neuroprotection on (i) primary cortical neurons under oxygen-glucose deprivation/normoglycemic reoxygenation as an experimental ischemia model; (ii), neuronal line cells treated with rotenone/oligomycin A, okadaic acid or ß-amyloid peptide Aß25-35, modeling toxic insults found among the effects of AD.

Volumetric modulated arc radiosurgery for brain metastases from breast cancer: A single-center study / Radiocirugía con arcoterapia volumétrica modulada para el tratamiento de metástasis cerebrales de cáncer de mama: Un estudio monocéntrico

Abstract Background: Whole-brain radiation therapy (WBRT) and stereotactic radiosurgery (SRS) are two treatment modalities commonly utilized to treat brain metastases (BMs). Aim: The purpose of this study is to analyse retrospectively the local control and survival of patients with BMs of breast cancer (BC) treated via radiosurgery using Volumetric Modulated Arc Therapy (VMAT-RS). Methods: 18 patients with 41 BMs of BC and treated by VMAT-RS were studied. They were classified according to the molecular subtype of BC and the modified breast graded prognostic assessment -GPA- index. Patients presented 1-4 BMs, which were treated with 5 non-coplanar VMAT arcs. The spatial distribution of BMs, the influence of receptor status on the location of the lesions and survival assessed via the Kaplan-Meier model were analyzed. Results: The median survival time (MST) was 19.7 months. Statistically significant differences were determined in the MST according to the Karnofsky performance status (p= 0.02) and the HER2 status (p= 0.004), being more prolonged in the HER2+ patients. Finally, our results showed that the cerebellum is the predominant site of breast cancer BMs, and also suggested that HER2+BMs had a predilection for some structures of the posterior circulation, such as the cerebellum, brainstem and occipital lobes (p= 0.048). Conclusions: The VMAT-RS is a technique with an overall survival comparable to other radiosurgery techniques. The baseline situation at the time of treatment, the modified breast-GPA and the molecular subtypes, are factors that significantly influence patient survival.

Resumen Antecedentes: La radioterapia holocraneal (WBRT) y la radiocirugía estereotáctica (SRS) son dos modalidades de tratamiento comúnmente empleados para el tratamiento de las metástasis cerebrales (BMs). Objetivo: El propósito de este estudio es analizar de forma retrospectiva el control local y la supervivencia de los pacientes con BMs de cáncer de mama (BC) tratados mediante radiocirugía empleando arcoterapia volumétrica modulada (VMAT-RS). Métodos: Se analizaron 18 pacientes con 41 BMs de BC tratados mediante VMAT-RS. Se clasificaron según el subtipo molecular de BC y el GPA (Graded Prognostic Assessment) modificado de cáncer de mama. Los pacientes presentaron de 1-4 BMs, las cuales fueron tratadas con 5 arcos VMAT no coplanares. Se analizó la distribución espacial de las BMs, la influencia del status del receptor en la localización de las lesiones y la supervivencia evaluada mediante el modelo de Kaplan-Meier. Resultados: La mediana del tiempo de supervivencia (MST) fue de 19.7 meses. Se hallaron diferencias estadísticamente significativas en el MST según el índice de Karnofsky (p= 0.02) y el status de HER2 (p= 0.004), siendo más prolongado en las pacientes HER2+. Por último, nuestros resultados mostraron que el cerebelo es el lugar predominante de las BMs de cáncer de mama, y también sugirieron que las BMs HER2+ presentaban una predilección por algunas estructuras de la circulación posterior, como el cerebelo, el tronco cerebral y los lóbulos occipitales (p= 0.048). Conclusiones: VMAT-RS es una técnica con una supervivencia global comparable a otras técnicas de radiocirugía. La situación basal en el momento del tratamiento, el GPA modificado de cáncer de mama así como los subtipos moleculares de cáncer de mama, son factores que influyen de forma significativa en la supervivencia de los pacientes.

Enfermedad nodular tiroidea en personas con diagnóstico de acromegalia / Nodular thyroid disease in people diagnosed with acromegaly

La aparición de nódulos tiroideos en las personas con acromegalia es una consecuencia de la elevación crónica de la hormona de crecimiento y el factor de crecimiento similar a la insulina tipo 1. Su naturaleza varía según la zona geográfica, suficiencia de yodo y antecedentes patológicos familiares, entre otros factores. No se han publicado estudios cubanos sobre la enfermedad nodular tiroidea en estas personas. Objetivos: Describir las características clínicas, bioquímicas y ultrasonográficas de la glándula tiroidea, según la presencia o no de la enfermedad nodular tiroidea. Métodos: Estudio observacional descriptivo, transversal, que incluyó 73 pacientes con acromegalia entre enero de 2003 y diciembre de 2017. Se estudiaron las variables: edad, sexo, color de la piel, antecedentes familiares de la enfermedad nodular tiroidea, niveles de la hormona de crecimiento, hormona estimulante del tiroides, T4 libre, anticuerpos contra la peroxidasa tiroidea y contra la tiroglobulina, volumen tiroideo, patrón ecográfico nodular y estudio citológico. Resultados: La enfermedad nodular tiroidea se presentó en el 75,3 por ciento de los casos, con predominio del bocio multinodular. La edad al diagnóstico fue menor en los pacientes con la enfermedad (43,53 ± 9,67), que en los que no la tenían (49,33 ± 6,96 años) (p = 0,02). La hormona de crecimiento al diagnóstico de acromegalia, resultó menor en los pacientes con este padecimiento (18,73 ± 11,33 µg/L vs. 35,91 ± 21,68 µg/L; (p = 0,00). El volumen tiroideo mostró diferencias significativas entre ambos grupos (14,2 ± 4,5 mL en los casos positivos de la enfermedad nodular tiroidea y 10,5 ± 2,8 mL en los casos negativos; p = 0,002), siendo el nódulo de baja sospecha de malignidad el más frecuente. El resto de las variables resultaron similares entre los pacientes con y sin la enfermedad. La citología se informó como benigna en el 75 por ciento en los nódulos únicos, el 80 por ciento de los bocios nodulares y el 90 por ciento de los bocios multinodulares (p = 0,51). Conclusiones: La enfermedad nodular tiroidea fue frecuente en los casos de acromegalia, y se asoció a la menor edad y los niveles inferiores de la hormona de crecimiento al diagnóstico. El bocio multinodular constituyó la forma clínica más frecuente y los parámetros hormonales y de autoinmunidad no se asociaron al tipo de la enfermedad nodular tiroidea(AU)

The appearance of thyroid nodules in people with acromegaly is a consequence of chronic elevation of growth hormone (GH) and insulin-like growth factor type 1 (IGF-1). Its nature varies according to the geographical area, the iodine sufficiency and family pathological history, among other factors. No Cuban studies on thyroid nodular disease (TND) in these people have been published. Objectives: Describe some clinical characteristics, as well as biochemical and ultrasonographic ones related to the thyroid gland, according to the presence or not of TND, and to identify the possible association of clinical, biochemical, ultrasonographic and cytological factors with the different types of TND in patients with acromegaly. Methods: A descriptive, cross-sectional observational study that included 73 patients with acromegaly between January 2003 and December 2017. The following variables were studied: age, sex, skin color, family history of TND, GH levels, thyroid stimulating hormone, free T4, antibodies against thyroid peroxidase and thyroglobulin, thyroid volume, nodular ultrasound pattern and cytological study. Results: TND occurred in 75.3 percent of cases, with a predominance of multinodular goiter. The age at diagnosis time was lower in patients with TND (43.53 ± 9.67) than in those who did not have it (49.33 ± 6.96 years) (p=0.02). GH at diagnosis time of acromegaly was lower in patients with TND (18.73±11.33µg/L vs 35.91±21.68µg/L; (p=0.00). The thyroid volume showed significant differences between both groups (14.2±4.5mL in positive cases of TND and 10.5±2.8mL in negative cases; p=0.002), being the most frequent the nodule with low suspicion of malignancy. The rest of the variables were similar between patients with and without TNDs. Cytology was reported as benign in 75 percent in single nodules, 80 percent of nodular goiters and 90 percent of multinodular goiters (p=0.51). Conclusions: TND was frequent in cases of acromegaly, and was associated with lower age and lower GH levels at diagnosis time. Multinodular goiter was the most frequent clinical form and hormonal and autoimmunity parameters were not associated with the type of TND(AU)