ABSTRACT
Autism and Alzheimer's disease (AD) are, respectively, neurodevelopmental and degenerative diseases with an increasing epidemiological burden. The AD-associated amyloid-ß precursor protein-α has been shown to be elevated in severe autism, leading to the 'anabolic hypothesis' of its etiology. Here we performed a focused microarray analysis of genes belonging to NOTCH and WNT signaling cascades, as well as genes related to AD and apoptosis pathways in cerebellar samples from autistic individuals, to provide further evidence for pathological relevance of these cascades for autism. By using the limma package from R and false discovery rate, we demonstrated that 31% (116 out of 374) of the genes belonging to these pathways displayed significant changes in expression (corrected P-values <0.05), with mitochondria-related genes being the most downregulated. We also found upregulation of GRIN1, the channel-forming subunit of NMDA glutamate receptors, and MAP3K1, known activator of the JNK and ERK pathways with anti-apoptotic effect. Expression of PSEN2 (presinilin 2) and APBB1 (or F65) were significantly lower when compared with control samples. Based on these results, we propose a model of NMDA glutamate receptor-mediated ERK activation of α-secretase activity and mitochondrial adaptation to apoptosis that may explain the early brain overgrowth and disruption of synaptic plasticity and connectome in autism. Finally, systems pharmacology analyses of the model that integrates all these genes together (NOWADA) highlighted magnesium (Mg(2+)) and rapamycin as most efficient drugs to target this network model in silico. Their potential therapeutic application, in the context of autism, is therefore discussed.
Subject(s)
Alzheimer Disease/genetics , Autistic Disorder/genetics , Cerebellum/metabolism , Connectome , Alzheimer Disease/drug therapy , Alzheimer Disease/pathology , Alzheimer Disease/physiopathology , Apoptosis/genetics , Autistic Disorder/drug therapy , Autistic Disorder/pathology , Autistic Disorder/physiopathology , Cerebellum/drug effects , Cerebellum/pathology , Cerebellum/physiopathology , Computer Simulation , Databases, Genetic , Drug Design , Gene Expression Profiling/methods , Gene Expression Regulation , Gene Regulatory Networks , Genetic Predisposition to Disease , Humans , Molecular Targeted Therapy , Oligonucleotide Array Sequence Analysis , Phenotype , Prognosis , Signal Transduction/genetics , Systems Biology , Transcription, GeneticABSTRACT
Se estudia una paciente de 27 años del sexo femenino que en 1995 inicia un cuadro de cefalea, vértigo, visión borrosa y diplopía en ojoizquierdo; sensación de parestesias en las cuatro extremidades y disminución de la fuerza en miembro superior (MS) izquierdo; Romberg positivo; temblor fino en MS izquierdo de intención,con descomposición final del movimiento; nistagmo horizontal con fase rápida a la izquierda; reflejos cutaneoabdominales asimétricos,izquierdo menor que derecho; hipopalestesia maleolar en miembro inferior (MI) derecho, e hiperreflexia osteotendinosa en MI....
Subject(s)
Humans , Female , Adult , Multiple Sclerosis/diagnosis , Multiple Sclerosis/drug therapy , Magnetic Resonance Spectroscopy , Immunologic Factors/therapeutic use , Steroids/therapeutic useABSTRACT
The RECK gene was initially isolated as a transformation suppressor gene encoding a novel membrane-anchored glycoprotein and later found to suppress tumor invasion and metastasis by regulating matrix metalloproteinase-9. Its expression is ubiquitous in normal tissues, but undetectable in many tumor cell lines and in fibroblastic lines transformed by various oncogenes. The RECK gene promoter has been cloned and characterized. One of the elements responsible for the oncogene-mediated downregulation of mouse RECK gene is the Sp1 site, where the Sp1 and Sp3 factors bind. Sp1 transcription factor family is involved in the basal level of promoter activity of many genes, as well as in dynamic regulation of gene expression; in a majority of cases as a positive regulator, or, as exemplified by the oncogene-mediated suppression of RECK gene expression, as a negative transcription regulator. The molecular mechanisms of the down-regulation of mouse RECK gene and other tumor suppressor genes are just beginning to be uncovered. Understanding the regulation of these genes may help to develop strategies to restore their expression in tumor cells and, hence, suppress the cells' malignant behavior.
Subject(s)
Genes, Tumor Suppressor/genetics , Membrane Glycoproteins/genetics , Neoplasm Metastasis/genetics , Sp1 Transcription Factor , Transcription, Genetic , Animals , Down-Regulation , GPI-Linked Proteins , MiceABSTRACT
The RECK gene was initially isolated as a transformation suppressor gene encoding a novel membrane-anchored glycoprotein and later found to suppress tumor invasion and metastasis by regulating matrix metalloproteinase-9. Its expression is ubiquitous in normal tissues, but undetectable in many tumor cell lines and in fibroblastic lines transformed by various oncogenes. The RECK gene promoter has been cloned and characterized. One of the elements responsible for the oncogene-mediated downregulation of mouse RECK gene is the Sp1 site, where the Sp1 and Sp3 factors bind. Sp1 transcription factor family is involved in the basal level of promoter activity of many genes, as well as in dynamic regulation of gene expression; in a majority of cases as a positive regulator, or, as exemplified by the oncogene-mediated suppression of RECK gene expression, as a negative transcription regulator. The molecular mechanisms of the downregulation of mouse RECK gene and other tumor suppressor genes are just beginning to be uncovered. Understanding the regulation of these genes may help to develop strategies to restore their expression in tumor cells and, hence, suppress the cells' malignant behavior
Subject(s)
Humans , Genes, Tumor Suppressor , Neoplasm Metastasis/genetics , Sp1 Transcription Factor , Transcription, Genetic , Genes, rasABSTRACT
Systematic physical training influences upon a series of changes which occurs in the body, not only improves the cardiovascular functioning, but every organ and system, it increases the functional capacity of the individual, reduces tension due to stress and controls arterial tension figures. Regarding the aforementioned aspects, a study in 50 patients representing 100% of hypertensive subjects involved in a physical exercise program without any other associated disease is made with the aim of determining the influence of systematic physical activity upon the treatment of arterial hypertension. Results show that in most of the patients who previously had high tension values, hypertension was controlled or improved by systematic physical training and the use of drugs was also reduced or eliminated.
Subject(s)
Ambulatory Care Facilities , Exercise , Hypertension/rehabilitation , Adult , Aged , Cuba , Female , Humans , Male , Middle Aged , Physical Education and Training , Remission InductionABSTRACT
TGF beta modulates the growth and differentiation of various cell types, in part by regulating the production of extracellular matrix proteins. In rat osteoblast-like cells TGF beta stimulates the production of collagen, osteopontin and osteonectin. On the other hand, TGF beta inhibits the production of osteocalcin, one of the most abundant non-collagenous bone matrix proteins, which is only expressed in osteoblasts. Inhibition of osteocalcin expression by TGF beta in the rat osteoblastic osteosarcoma, ROS 17/2.8 cells, occurs at least in part through transcriptional control.