Brain Perihematoma Genomic Profile Following Spontaneous Human Intracerebral Hemorrhage

BACKGROUND: Spontaneous intracerebral hemorrhage (ICH) represents about 15% of all strokes and is associated with high mortality rates. Our aim was to identify the gene expression changes and biological pathways altered in the brain following ICH. METHODOLOGY/PRINCIPAL FINDINGS: Twelve brain samples were obtained from four deceased patients who suffered an ICH including perihematomal tissue (PH) and the corresponding contralateral white (CW) and grey (CG) matter. Affymetrix GeneChip platform for analysis of over 47,000 transcripts was conducted. Microarray Analysis Suite 5.0 was used to process array images and the Ingenuity Pathway Analysis System was used to analyze biological mechanisms and functions of the genes. We identified 468 genes in the PH areas displaying a different expression pattern with a fold change between -3.74 and +5.16 when compared to the contralateral areas (291 overexpressed and 177 underexpressed). The top genes which appeared most significantly overexpressed in the PH areas codify for cytokines, chemokines, coagulation factors, cell growth and proliferation factors while the underexpressed codify for proteins involved in cell cycle or neurotrophins. Validation and replication studies at gene and protein level in brain samples confirmed microarray results. CONCLUSIONS: The genomic responses identified in this study provide valuable information about potential biomarkers and target molecules altered in the perihematomal regions

Proinsulin protects against age-related cognitive loss through anti-inflammatory convergent pathways

Brain inflammaging is increasingly considered as contributing to age-related cognitive loss and neurodegeneration. Despite intensive research in multiple models, no clinically effective pharmacological treatment has been found yet. Here, in the mouse model of brain senescence SAMP8, we tested the effects of proinsulin, a promising neuroprotective agent that was previously proven to be effective in mouse models of retinal neurodegeneration. Proinsulin is the precursor of the hormone insulin but also upholds developmental physiological effects, particularly as a survival factor for neural cells. Adeno-associated viral vectors of serotype 1 bearing the human proinsulin gene were administered intramuscularly to obtain a sustained release of proinsulin into the blood stream, which was able to reach the target area of the hippocampus. SAMP8 mice and the control strain SAMR1 were treated at 1 month of age. At 6 months, behavioral testing exhibited cognitive loss in SAMP8 mice treated with the null vector. Remarkably, the cognitive performance achieved in spatial and recognition tasks by SAMP8 mice treated with proinsulin was similar to that of SAMR1 mice. In the hippocampus, proinsulin induced the activation of neuroprotective pathways and the downstream signaling cascade, leading to the decrease of neuroinflammatory markers. Furthermore, the decrease of astrocyte reactivity was a central effect, as demonstrated in the connectome network of changes induced by proinsulin. Therefore, the neuroprotective effects of human proinsulin unveil a new pharmacological potential therapy in the fight against cognitive loss in the elderly.Postprint (published version

peIF4E as an independent prognostic factor and a potential therapeutic target in diffuse infiltrating astrocytomas

Malignant transformation in tumors is a complex process requiring accumulation of numerous oncogenic abnormalities. Brain tumors show considerable phenotypic and genetic heterogeneity. In a series comprising diffuse infiltrating astrocytomas () and reactive gliosis, we investigated the main factors associated with signaling pathways. We assessed expression levels and their association with tumor progression and survival. We studied 19 grade astrocytomas, 25 anaplastic astrocytomas (grade ), 60 glioblastomas (grade ), and 15 cases of reactive gliosis. Epidermal growth factor receptor (), , 4E-1, p4E-1, 6, 4E, and pe4E expression levels were evaluated using immunohistochemistry. Expression levels were semiquantitatively evaluated using a histoscore. Immunohistochemistry and were used for 1 mutations. Statistical analysis was based on the following tests: chi-square, Student's t, Pearson correlation, Spearman's rho, and Mann-Whitney; and Kaplan-Meier curves were constructed. A significant increase was observed between grades for expression of total and phosphorylated 4E-1 and for 4E, Ki67, , and cyclin D1. Although expression of ,4E, and Ki67 correlated with survival, only pe4E was an independent predictor of survival in the multivariate analysis. Combining the evaluation of different proteins enables us to generate helpful diagnostic nomograms. In conclusion, cell signaling pathways are activated in s; pe4E is an independent prognostic factor and a promising therapeutic target. Joint analysis of the expression of 4E-1 and pe4E could be helpful in the diagnosis of glioblastoma multiforme in small biopsy samples

Valor predictivo de la clasificación de Knosp en el grado de resección quirúrgica de los macroadenomas invasivos: esstudio prospectivo de una serie de 23 casos

Objetivos. Analizar y valorar el grado de resección y las complicaciones de la cirugía transesfenoidal en una serie de 23 casos de macroadenomas con invasión del seno cavernoso evaluados mediante la clasificación de Knosp. Material, métodos y resultados. Estudio prospectivo de 22 pacientes (23 operaciones) intervenidos en nuestro centro entre Mayo del 2002 y Diciembre del 2004 de macroadenomas hipofisarios con diferentes grados de invasión del seno cavernoso según la clasificación de Knosp15. Entre las variables del estudio se incluyeron los grados de invasión y de resección postoperatoria con un seguimiento radiológico medio a largo plazo de 15 meses. Nuestra serie consta de 15 varones y 7 mujeres, con una edad media de 48 años (27 - 75 años). Todos ellos presentaban macroadenomas con afectación de uno o ambos senos cavernosos. De acuerdo con la clasifi- cación de Knosp 4 pacientes fueron grado 1, 2 grado 2, 1 grado 3 y 16 grado 4. En 20 casos se utilizó una vía transesfenoidal clásica y en tres casos se hizo un abordaje transesfenoidal endoscópico. Según la RMN postoperatoria los grados de resección fueron: completo o total en todos los pacientes con grados 1 y 2 y en sólo 2 pacientes con grado 4; subtotal (>80%) en 1 paciente con grado 3 y en 6 pacientes con grado 4 y parcial (<80%) en 7 pacientes con grado 4 de Knosp. Se compararon los grados de resección versus los grados de invasión mediante el Test exacto de Fisher y las diferencias no fueron estadísticamente significativas (p=0.12). Discusión y conclusiones. Si bien únicamente la clasificación radiológica de Knosp por si sola no puede predecir el comportamiento biológico del tumor o si la pared medial del seno cavernoso está infiltrada o desplazada, en nuestra serie los tumores de grado 4 han sido los que han presentado un peor resultado de acuerdo al grado de resección. En los tumores que invaden el seno cavernoso, incluso en los casos en que la carótida está englobada es posible realizar resecciones completas con una morbimortalidad aceptable

Expression of Bone Morphogenetic Proteins in Multiple Sclerosis Lesions

Bone morphogenetic proteins (BMPs) are secreted proteins that belong to the transforming growth factor-β superfamily. In the adult brain, they modulate neurogenesis, favor astrogliogenesis, and inhibit oligodendrogenesis. Because BMPs may be involved in the failure of remyelination in multiple sclerosis (MS), we characterized the expression of BMP-2, BMP-4, BMP-5, and BMP-7; BMP type II receptor (BMPRII); and phosphorylated SMAD (pSMAD) 1/5/8 in lesions of MS and other demyelinating diseases. A total of 42 MS lesions, 12 acute ischemic lesions, 8 progressive multifocal leukoencephalopathy lesions, and 10 central nervous system areas from four nonneuropathological patients were included. Lesions were histologically classified according to the inflammatory activity. The expression of BMP-2, BMP-4, BMP-5, BMP-7, BMPRII, and pSMAD1/5/8 was quantified by immunostaining, and colocalization studies were performed. In MS lesions, astrocytes, microglia/macrophages, and neurons expressed BMP-2, BMP-4, BMP-5, and BMP-7; BMPRII; and pSMAD1/5/8. Oligodendrocytes expressed BMP-2 and BMP-7 and pSMAD1/5/8. The percentage of cells that expressed BMPs, BMPRII, and pSMAD1/5/8 correlated with the inflammatory activity of MS lesions, and changes in the percentage of positive cells were more relevant in MS than in other white matter-damaging diseases. These data indicate that BMPs are increased in active MS lesions, suggesting a possible role in MS pathogenesis

Proinsulin therapy protects against neuroinflammaging and cognitive loss in senescence-accelerated mice

Trabajo presentado en el IUBMB Focused Meeting on «Molecular aspects of aging and longevity», celebrado en Atenas, del 16 al 19 de octubre de 2017Chronic low-grade neuroinflammation is tightly associated with brain age-related changes and it is considered a crucial derangement that paves the way to neurodegeneration and dementia. Among other ailments, inflammation may lead to insulin resistance that is a risk factor for Alzheimer’s disease. In this scenario, the hormone precursor proinsulin may have a potential pharmacological use in preventing neuronal death. Proinsulin is a bioactive molecule regulating neural cell death in embryonic processes and it was proven neuroprotective in mouse models of retinal neurodegeneration. We aimed to prove the geroprotective effect of a chronic proinsulin treatment against neuroinflammaging and memory loss in the senescence-accelerated mouse SAMP8. We used a gene therapy procedure through peripheral muscle transduction with an adeno-associated viral vector bearing the human proinsulin gene (AAV-hPi) that yielded sustained release of proinsulin into the bloodstream. One-month old male mice of the SAMP8 strain and the control strain SAMR1 were injected with AAV-hPi or AAV-null vectors. At 6 months of age, proinsulin-treated SAMP8 mice showed totally preserved cognitive capacities both in spatial and recognition paradigms of learning and memory, in contrast to those SAMP8 mice injected with the null vector. Hippocampus analysis showed that proinsulin activated Akt and ATF1/CREB signaling pathways in both SAMR1 and SAMP8 mice. Furthermore, we identified a significant decrease of neuroinflammatory markers in the hippocampus of SAMP8 mice to levels of SAMR1 mice. Strikingly, the marker of astrocyte reactivity GFAP was decreased in both SAMR1 and SAMP8. Furthermore, the connectome network build with all changes induced by proinsulin showed that the decrease of astrocyte reactivity was a central effect in proinsulin neuroprotection. Therefore, the preventive and protective effects of human proinsulin against neuroinflammaging and senescence-related cognitive loss unveil a potential geroprotective therapy to increase healthy brain aging.This study was supported by CSD2010-00045, SAF2016-77703-C2-2-R, MTM2014-60127-P, MINECO and ERDF; PET08-0282, TRACE.Peer reviewe

Brain Perihematoma Genomic Profile Following Spontaneous Human Intracerebral Hemorrhage

Spontaneous intracerebral hemorrhage (ICH) represents about 15% of all strokes and is associated with high mortality rates. Our aim was to identify the gene expression changes and biological pathways altered in the brain following ICH. Twelve brain samples were obtained from four deceased patients who suffered an ICH including perihematomal tissue (PH) and the corresponding contralateral white (CW) and grey (CG) matter. Affymetrix GeneChip platform for analysis of over 47,000 transcripts was conducted. Microarray Analysis Suite 5.0 was used to process array images and the Ingenuity Pathway Analysis System was used to analyze biological mechanisms and functions of the genes. We identified 468 genes in the PH areas displaying a different expression pattern with a fold change between −3.74 and +5.16 when compared to the contralateral areas (291 overexpressed and 177 underexpressed). The top genes which appeared most significantly overexpressed in the PH areas codify for cytokines, chemokines, coagulation factors, cell growth and proliferation factors while the underexpressed codify for proteins involved in cell cycle or neurotrophins. Validation and replication studies at gene and protein level in brain samples confirmed microarray results. The genomic responses identified in this study provide valuable information about potential biomarkers and target molecules altered in the perihematomal regions