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The development of new biomarkers for prediction and early detection of human diseases, as well as for monitoring the response to therapy is one of the most relevant areas of modern human genetics and genomics. Until recently, it was believed that the function of human Y chromosome genes was limited to determining sex and controlling spermatogenesis. Thanks to occurance of large databases of the genome-wide association study (GWAS), there has been a transition to the use of large samples for analyzing genetic changes in both normal and pathological conditions. This has made it possible to assess the association of mosaic aneuploidy of the Y chromosome in somatic cells with a shorter lifespan in men compared to women. Based on data from the UK Biobank, an association was found between mosaic loss of the Y chromosome (mLOY) in peripheral blood leukocytes and the age of men over 70, as well as a number of oncological, cardiac, metabolic, neurodegenerative, and psychiatric diseases. As a result, mLOY in peripheral blood cells has been considered a potential marker of biological age in men and as a marker of certain age-related diseases. Currently, numerous associations have been identified between mLOY and genes based on GWAS and transcriptomes in affected tissues. However, the exact cause of mLOY and the impact and consequences of this phenomenon at the whole organism level have not been established. In particular, it is unclear whether aneuploidy of the Y chromosome in blood cells may affect the development of pathologies that manifest in other organs, such as the brain in Alzheimer's disease, or whether it is a neutral biomarker of general genomic instability. This review examines the main pathologies and genetic factors associated with mLOY, as well as the hypotheses regarding their interplay. Special attention is given to recent studies on mLOY in brain cells in Alzheimer's disease.
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Aging is a natural process of extinction of the body and the main aspect that determines the life expectancy for individuals who have survived to the post-reproductive period. The process of aging is accompanied by certain physiological, immune, and metabolic changes in the body, as well as the development of age-related diseases. The contribution of genetic factors to human life expectancy is estimated at about 25-30%. Despite the success in identifying genes and metabolic pathways that may be involved in the life extension process in model organisms, the key question remains to what extent these data can be extrapolated to humans, for example, because of the complexity of its biological and sociocultural systems, as well as possible species differences in life expectancy and causes of mortality. New molecular genetic methods have significantly expanded the possibilities for searching for genetic factors of human life expectancy and identifying metabolic pathways of aging, the interaction of genes and transcription factors, the regulation of gene expression at the level of transcription, and epigenetic modifications. The review presents the latest research and current strategies for studying the genetic basis of human aging and longevity: the study of individual candidate genes in genetic population studies, variations identified by the GWAS method, immunogenetic differences in aging, and genomic studies to identify factors of "healthy aging." Understanding the mechanisms of the interaction between factors affecting the life expectancy and the possibility of their regulation can become the basis for developing comprehensive measures to achieve healthy longevity. Supplementary Information: The online version contains supplementary material available at 10.1134/S1022795422120067.
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The problem of memory enhancement is extremely important in intellectual activity areas and therapy of different types of dementia, including Alzheimer's disease (AD). The attempts to solve this problem have come from different research fields. In the first part of our review, we describe the results of targeting certain genes involved in memory-associated molecular pathways. The second part of the review is focused on the deep stimulation of brain structures that can slow down memory loss in AD. The third part describes the results of the use of non-invasive brain stimulation techniques for memory modulation, consolidation, and retrieval in healthy people and animal models. Integration of data from different research fields is essential for the development of efficient strategies for memory enhancement.
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Enfermedad de Alzheimer/patología , Encéfalo/metabolismo , Memoria , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/terapia , Animales , Proteína de Unión a CREB/genética , Proteína de Unión a CREB/metabolismo , Estimulación Encefálica Profunda , Regulación de la Expresión Génica , Humanos , Factor II del Crecimiento Similar a la Insulina/genética , Factor II del Crecimiento Similar a la Insulina/metabolismoRESUMEN
LINE1 retrotransposons are members of a class of mobile genetic elements capable of retrotransposition in the genome via a process of reverse transcription. LINE1 repeats, integrating into different chromosomal loci, affect the activity of genes and cause different genomic mutations. Somatic variability of the human genome is linked to the activity of some subfamilies of LINE1, in particular, a high level of LINE1 retrotranspositions has been observed in brain tissues. However, the contribution of LINE1 to genomic variability during normal aging and in age-related neurodegenerative diseases is poorly understood. We conducted quantitative real-time PCR analysis of active subfamilies of LINE1 repeats (aL1) using genomic DNA extracted from brain specimens of Alzheimer's disease (AD) patients and individuals without neuropsychiatric pathologies, as well as DNA extracted from blood specimens of individuals of different ages (healthy and AD subjects). Inter-individual quantitative variations of active families of aL1 repeats in the genome were observed. No significant age-dependent differences were identified. Likewise, no difference of aL1 copy number in brain and blood were indicated between AD patients and the aged-matched control group without dementia. These data imply that aging and the AD-associated neurodegenerative process are not the major factors contributing to the retrotransposition processes of active LINE1 repeats.
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Envejecimiento , Enfermedad de Alzheimer/patología , Elementos de Nucleótido Esparcido Largo/genética , Regiones no Traducidas 5' , Anciano , Enfermedad de Alzheimer/metabolismo , Estudios de Casos y Controles , Femenino , Lóbulo Frontal/metabolismo , Genoma Humano , Humanos , Masculino , Persona de Mediana Edad , ARN Ribosómico 5S/genética , ARN Ribosómico 5S/metabolismo , Reacción en Cadena en Tiempo Real de la PolimerasaRESUMEN
Three genes mutations in which cause familial forms of Alzheimer's disease are known to date:PSEN1, PSEN2 and APP; and APOE gene polymorphism is a strong risk factor for Alzheimer's disease. We have evaluated allele and genotype frequency distribution of rs11136000 polymorphism in clusterin (CLU) gene (or apolipoprotein J, APOJ) in populations of three Russian regions and i nAlzheimhner's diseasepatients. Genome-wideassociation studies in samples from several European populations have recently revealed highly significant association o fCLU gene with AD (p = 8.5 x 10(-10)). We found no differences in allele and genotype frequencies of rs11136000 between populations from Moscow, Ural and Siberia regions. The allele frequencies are close to those in European populations. The genetic association analysis in cohort of Alzheimer's disease patients and normal individuals (>500 individuals ineach group) revealed no significant association of the rs11136000 polymorphism in CLU with Alzheimer's disease in Russian populations. Although our resultsdo not confirm the role of CLU gene as a majorgenetic factor forcommon form of Alzheimer's disease, the data do not rule out the possibility of modest effect of CLU and interaction between CLU and APOE genotypes in etiology of Alzheimer's disease.
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Alelos , Enfermedad de Alzheimer/genética , Clusterina/genética , Frecuencia de los Genes/genética , Polimorfismo Genético/genética , Adulto , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/epidemiología , Estudios de Cohortes , Femenino , Estudio de Asociación del Genoma Completo , Humanos , Masculino , Persona de Mediana Edad , Federación de Rusia/epidemiologíaRESUMEN
The ability of artificial ribonucleases to cause in the concentration-dependent manner death of cancer cells has been studied. The cytotoxic activity of artificial ribonucleases is observed at rather low concentration of these compounds (10(-5) M). Analysis of the mechanism of artificial ribonucleases cytotoxicity revealed that compounds under the study exhibit membranotropic activity in addition to ribonucleases activity found earlier. This activity is responsible for effective penetration of these compounds inside cells. The results obtained show that artificial ribonucleases induce cell death via damage of cells membrane, detachment of plasmalemma and derangement its macromolecular organization. In the case of short-term exposure of cells to the compounds, cells, even with damaged membrane, survive.
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Antineoplásicos/farmacología , Imidazoles/farmacología , Piperazinas/farmacología , Ribonucleasas/farmacología , Animales , Muerte Celular/efectos de los fármacos , Línea Celular , Línea Celular Tumoral , Membrana Celular/efectos de los fármacos , Membrana Celular/ultraestructura , Perros , Humanos , Imidazoles/química , Piperazinas/químicaRESUMEN
A number of tetracationic compounds capable of phosphodiester bond cleavage within a 21 -membered ribooligonucleotide were designed and synthesized. The artificial ribonucleases represent two residues of quaternized 1,4-diazabicyclo[2.2.2]octane bearing alkyl substituents of various lengths and connected with a rigid linker. The efficiency of cleavage of phosphodiester bonds in an RNA target depends on the linker structure and the length of alkyl substituent.
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Piperazinas/química , Poliaminas/química , ARN/química , Ribonucleasas/química , Secuencia de Bases , Catálisis , Hidrólisis , Espectroscopía de Resonancia Magnética , Estructura Molecular , Oligorribonucleótidos/química , Poliaminas/síntesis química , Polielectrolitos , Ribonucleasas/síntesis químicaRESUMEN
A series of RNA-hydrolyzing constructions was synthesized on the basis of peptide-like molecules containing residues of L-lysine, histamine and histidine methyl ester. These were shown to hydrolyze RNA effectively at neutral pH values. The in vitro transcript of tRNA(Lys) from human mitochondria and a tRNA-like fragment of RNA of Turnip Yellow Mosaic Virus were used in the experiments. Our chemical RNases quantitatively depolymerize some definite sequences (CA > or = UA > CG >> UC, CC, or CU) in both RNA molecules under optimum conditions. Moreover, no other sites were affected and no statistical hydrolysis was observed even after prolonged RNA incubation with the compounds of this series. The depolymerization rate of the RNA substrates exhibits a complex dependence on the concentration of ions of monovalent metals and on the concentration of the artificial ribonucleases.
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Imidazoles/metabolismo , Lisina/metabolismo , ARN de Transferencia de Lisina/metabolismo , ARN Viral/metabolismo , Proteínas de Unión al ARN/metabolismo , Ribonucleasas/síntesis química , Humanos , Hidrólisis , Virus del Mosaico/genética , Ribonucleasas/química , Ribonucleasas/metabolismo , Especificidad por SustratoRESUMEN
The paper reports a rare case of intranasal meningoencephalocele in a 64-year-old female, simulating clinically a nasal polyp. A histological investigation of the removed polyp showed that it was composed mainly of malformed brain tissue with meninx vasculosa. The authors suggest a congenital nature of this formation.