Las células senescentes como factores patogénicos y posibles dianas terapéuticas en osteoporosis / Cellular senescence as a pathogenic factor and potential therapeutic target in osteoporosis

La senescencia celular es un proceso inducido por varios tipos de estrés que causan una detención irreversible del ciclo celular y un cambio en las características y la funcionalidad de las células, además de la adquisición de un fenotipo secretor que genera un ambiente proinflamatorio. Si bien en determinados contextos es beneficiosa para los tejidos y promueve el desarrollo del organismo, la senescencia es un destino celular implicado en el proceso de envejecimiento y en las patologías degenerativas relacionadas con la edad. Los senolíticos son fármacos que eliminan específicamente a las células senescentes y los senomórficos son fármacos que suprimen su fenotipo secretor asociado a senescencia (SASP) sin inducir la muerte celular. Así, las estrategias terapéuticas enfocadas en las células senescentes (senolíticos y senomórficos) como mecanismo subyacente al envejecimiento, se erigen en una alternativa con gran potencial para luchar contra las enfermedades relacionadas con la edad en su conjunto, y no de forma individual. Una de estas patologías es la osteoporosis, donde además se han descrito, a nivel experimental, que fármacos como el ácido zoledrónico tiene efecto sobre los preosteoblastos y actúa sobre las células senescentes, prolongando la supervivencia y abriendo la puerta a la posibilidad de tratar las enfermedades relacionadas con la edad con fármacos que ya se empleen en la práctica, y que puedan tener un efecto más allá del propio hueso y aumentar la supervivencia. En este trabajo se va a realizar una revisión en este campo de vertiginoso crecimiento en los últimos años y con indudable interés traslacional.(AU)

Cellular senescence is a process induced by various types of stress that irreversibly cause cell cycle arrest and changes tothe characteristics and functionality of cells, as well as the acquisition of a secretory phenotype that generates a pro-in-flammatory environment. While, in certain contexts, it is beneficial for tissues and promotes organism development, senes-cence is a cellular fate implicated in the process of aging and age-related degenerative conditions. Senolytics are drugs thatspecifically eliminate senescent cells, and senomorphics are drugs that suppress their senescence-associated secretoryphenotype (SASP) without inducing cell death. Therefore, therapeutic strategies targeting senescent cells (senolytics andsenomorphics) as an underlying mechanism of aging emerge as an alternative with great potential to fight age-relateddiseases as a whole rather than individually. One of these conditions is osteoporosis where it has been experimentallydescribed that drugs such as zoledronic acid have effects on preosteoblasts and act on senescent cells extending survivaland opening up the possibility of treating age-related diseases with drugs already used in practice, which may have effectsbeyond the bone itself and increase overall survival. In this study, a review will be conducted in this rapidly growing fieldin recent years of undeniable translational interest.(AU)

Telómeros, telomerasa y envejecimiento. Una visita al Premio Nobel de Fisiología y Medicina de 2009 / Telomeres, telomerase and aging. A visit to the 2009 Nobel Prize in Physiology and Medicine

Introducción: En octubre de 2009, Elizabeth H. Blackburn, Carol W. Greider y Jack W. Szostak fueron galardonados por sus descubrimientos sobre los telómeros y la enzima telomerasa con el Premio Nobel de Fisiología y Medicina. Posteriormente muchas investigaciones, entre las que destacan la de científicos españoles han demostrado el papel de los telómeros en el envejecimiento y en algunas patologías relacionadas.Métodos: Para la realización de este trabajo se ha revisado tres aspectos: a) la información dada por el Comité del Nobel sobre las investigaciones de los tres galardonados; b) los mecanismos moleculares implicados en el proceso de protección de los telómeros por la acción de la telomerasa y c) la relación entre envejecimiento y sistema telómeros/telomerasa.Resultados: En las células eucariotas los telómeros constituyen el extremo terminal de los cromosomas, los cuales se acortan en cada división celular. Cuando el acortamiento es crítico, se induce daño persistente al ADN en estos extremos, senescencia, apoptosis y pérdidas de la capacidad regenerativa de los tejidos. Dada la imposibilidad de replicación completa de los telómeros por la ADN polimerasa después de cada división celular, la telomerasa, una ribonucloproteína retrotranscriptasa, actúa alargando los extremos de los cromosomas, utilizando como molde una porción de su propio ARN. Muchos factores determinan la longitud de los telómeros, sobresaliendo el acortamiento de los telómeros y la pérdida de actividad telomerásica. Además, existen multitud de factores que condicionan las diferencias entre edad fisiológica y edad cronológica.Conclusión: Entre las muchas teorías sobre el envejecimiento sobresale la que relaciona el acortamiento de los telómeros con la senescencia. No obstante se requieren más estudios en los que se determine qué mecanismos epigenéticos y de otra índole condicionan la pérdida de actividad telomerásica y la longitud de los telómeros.(AU)

Introduction: In October 2009, Elizabeth H. Blackburn, Carol W. Greider, and Jack W. Szostak were awarded the Nobel Prize in Physiology and Medicine for their discoveries about telomeres and the enzyme telomerase. Subsequently, many investigations, including that of Spanish scientists, have demonstrated the role of telomeres in aging and in some very prevalent pathologies.Methods: Three topics were reviewed to perform this article: a) the information given by the Nobel Committee on the research of the three winners of 2009 award; b) the molecular mechanisms involved in the protection process of telomeres by the telomerase enzyme; and c) the relationship between aging and the telomere/telomerase system.Results: In eukaryotic cells, telomeres constitute the terminal end of chromosomes, which are shortened within each cell division. When the shortening becomes critical, persistent DNA damage at these ends, senescence, apoptosis and loss of the tissues regenerative capacity are induced. Given the unfeasibility of telomeres complete replication by the DNA polymerase after each cell division, the telomerase, a reverse transcriptase ribonucloprotein, works by lengthening the ends of chromosomes, using as a template a portion of its own RNA. Several factors determine the length of telomeres and/or the loss of telomerase activity, with aging standing out. In addition, there are many factors that determine the differences between physiological and chronological age.Conclusion: Among aging theories, the one relating the shortening of telomeres with senescence stands out. However, more studies are required to determine which epigenetic and other mechanisms determine the loss of telomerase activity and the length of telomeres.(AU)

LINC01255 combined with BMI1 to regulate human mesenchymal stromal senescence and acute myeloid leukemia cell proliferation through repressing transcription of MCP-1

Background Long non-coding RNAs (lncRNAs) govern fundamental biochemical and cellular biology processes, for example, participate in chromatin remodeling, imprinting, splicing, transcriptional regulation and translation. Dysregulation of lncRNA expression is act as a feature of various diseases and cancers, including hematopoietic malignancies. However, the clinical relevance of myelodysplastic syndrome (MDS) and acute myeloid leukemia preceded by MDS (MDS-AML) requires further research. Recently, lncRNAs have been demonstrated, which play an important role in hematopoiesis, thus, to further finding more functional lncRNA seemed particularly important. Methods Western blotting, real-time PCR, RNA-pulldown, RIP (RNA immunoprecipitation), Chromatin immunoprecipitation (ChIP), cellular compartments extraction assays, SA-β-gal staining, lentivirus transfection, cell viability assay and cell proliferation assays were used to examine the relationship between lncRNA LINC01255 and its regulation of p53–p21 pathway in human mesenchymal stromal and acute myeloid leukemia cells. Results LncRNA LINC01255 is highly expressed in bone marrow cells of AML patients, CD34+ cells of MDS-AML patients and AML cell lines and the higher expression of LINC01255 is associated with poor survival rate of AML patients. LINC01255 can interact with BMI1 and repress the transcription of MCP-1 to active p53–p21 pathway, thus inhibiting the senescence of human mesenchymal stromal and proliferation of acute myeloid leukemia cell. Conclusions We discovered a novel functional lncRNA LINC01255, which can regulate the senescence of human mesenchymal stromal and the proliferation of acute myeloid leukemia cell through inhibiting the transcription of MCP-1 (AU)

Senescent thyroid tumor cells promote their migration by inducing the polarization of M2-like macrophages

Purpose An in-depth understanding of the mechanism of thyroid cancer progression will help identify patients with thyroid cancer with a high risk of recurrence and metastasis. Although studies have pointed out that the senescence of thyroid tumor cells may stimulate TAMs and cause a series of changes. However, the role of TAMs in aging thyroid cancer cells is still unknown. The aim of this study was to investigate the function of TAMs in aging thyroid cancer cells. Methods We conducted in vitro model studies based on the K1 cell line to induce tumor cell senescence and study its effect on the differentiation of macrophages, flow cytometry was used to confirm polarization of macrophages, transwell assay was used to confirm changes of invasion and migration of tumor cells. Result Our data indicate that aging thyroid tumor cell lines trigger the polarization of M2-like macrophages, accompanied by increased expression of CCL17, CCL18, IL-18, and TGFβ1. This event is caused by the activation of the NFκB pathway upregulation of CXCL2 and CXCL3 is related. Further studies have shown that differentiated M2-like macrophages promote tumor cell migration (but have no effect on cell proliferation). Conclusion Our study indicating that the interaction between tumor and TAMs also occurs in the advanced stages of thyroid tumors and will lead to faster tumors progress (AU)

Regulación de la plasticidad celular y senescencia encondrocitos articulares: conexina 43 como diana terapéutica para el tratamiento de la artrosis / A novel therapeutic target for osteoarthritis: control of cellular plasticity and senescence using connexin43

Introducción: La artrosis (OA) es una enfermedad musculo esquelética degenerativa que afecta aproximadamente al13% de la población occidental. A día de hoy no existe un tratamiento eficaz que evite el progreso de la misma o facilite la regeneración del cartílago articular. La conexina43 (Cx43) es una proteína transmembrana que se encuentra en niveles elevados en el cartílago y en la membrana sinovial de pacientes con OA. Esta proteína forma canales que permiten el intercambio de moléculas e iones entre dos células en contacto o entre la célula y su entorno, denominados uniones co‐municantes (UCs) y hemicanales, respectivamente. En este estudio se investigó la función de la Cx43 y de las UCs en la degradación del cartílago articular de pacientes con OA. Material y métodos: Se han aislado condrocitos primarios del cartílago de donantes OA y sanos. Se evaluaron los niveles proteicos mediante Western blot, inmunofluorescencia y citometría de flujo. La expresión génica se ha evaluado mediante RT‐qPCR, mientras que la comunicación celular se estudió mediante el ensayo scrape loading/dye transfer. La senescencia celular se evaluó midiendo la actividad de la β‐galactosidasa mediante citometría celular o microscopía. Resultados: Los resultados obtenidos indican que la sobre actividad de la Cx43 y de la comunicación intercelular a través de UCs detectadas en OA están implicadas con el progreso de la enfermedad al activar procesos de desdiferenciación celular hacia un estado inmaduro y senescencia celular. Utilizando condrocitos en cultivo aislados del cartílago de donantes con OA hemos demostrado que el incremento de la Cx43 activa factores implicados en la transición epitelio‐me sénquima (TEM), como el factor de transcripción Twist‐1. El incremento en el número de células desdiferenciadas y con altos índices de proliferación celular desencadena en senescencia celular vía p53/p16INK4a, activando el fenotipo secretor asociado a senescencia (SASP, del inglés Senescence-Associated Secretory Phenotype) que incluye la síntesis y liberación de factores inflamatorios como la interleuquina 6 (IL‐6). La disminución de los niveles de la Cx43 utilizando pequeñas moléculas como la oleuropeína o técnicas de edición genética como CRISPR/Cas9 revirtió el proceso dando lugar a re‐diferenciación celular, mejorando el fenotipo celular con incremento en proteínas implicadas en formación del tejido y diminuyendo la síntesis de MMPs y del componente inflamatorio y senescencia. Conclusiones: La disminución de la Cx43 en condrocitos artrósicos restaura regeneración tisular, por activación de re‐diferenciación celular y disminución de senescencia. Estos resultados corroboran el uso de la Cx43 como una diana terapéutica eficaz para restaurar regeneración del cartílago en pacientes con OA y evitar la progresión de la enfermedad

Introduction: Osteoarthritis (OA) is a degenerative musculoskeletal disease, which affects approximately the 13% of western population. Nowadays, there is no effective treatment for OA to avoid disease progression or to promote cartilage regeneration. Connexin43 (Cx43) is a transmembrane protein increased in cartilage and synovium from OA patients.Cx43 forms membrane channels that allow the exchange of molecules and ions between two adjacent cells through gapjunctions (GJs), or between a cell and its environment through hemichannels. In this study we investigated the involvement of Cx43 and GJ intercellular communication in the degradation of articular cartilage in chondrocytes from patientswith OA. Material and methods:Primary chondrocytes were obtained from cartilage from OA and healthy donors. Protein levelswere evaluated by western‐blot, immunofluorescence and flow cytometry. RNA expression was evaluated by RT‐qPCR.A scrape loading/dye transfer assay was used to evaluate cell communication. Cell senescence was analysed by flowcytometry or by light microscopy using β‐galactosidase assay.Results:Cx43 and GJs overactivities were correlated with the progression of OA, by promoting chronic cell dedifferen‐tiation and senescence in vitroassays. We found that Cx43 over expression activates factors involved in epithelial‐to‐me‐senchymal transition, such as Twist‐1. Increased levels of dedifferentiated cells, with high rates of cell proliferation, led to cell senescence via p53/p16INK4a, activating the senescence‐associated secretory phenotype (SASP) and promoting the synthesis and liberation of inflammatory factors, including the interleukin‐6 (IL‐6). Cx43 down regulation by using small molecules, such as oleuropein, or by genetic edition with CRISPR technology, led to the chondrocyte redifferentiation and an improved phenotype, with increased synthesis of extracellular matrix proteins such as Col2A1 and down‐regulating the synthesis of MMPs, inflammation and senescence. Conclusions: Down regulation of Cx43 in OA chondrocytes restores regeneration by activating chondrocyte re‐differentiation and decreasing cellular senescence. These results corroborate the use of Cx43 as an effective therapeutic target in order to restore cartilage regeneration and avoid OA progression

PTRF acts as an adipokine contributing to adipocyte dysfunctionality and ectopic lipid deposition

Adipose tissue (AT) expands under obesogenic conditions. Yet, when the growth exceeds a certain limit, AT becomes dysfunctional and surplus lipids start depositing ectopically. Polymerase I and transcription release factor (PTRF) has been proposed as a mechanism leading to a dysfunctional AT by decreasing the adipogenic potential of human adipocyte precursors. However, whether or not PTRF can be secreted by the adipocytes into the bloodstream is not yet known. For this work, PTRF presence was investigated in plasma. We also produced a recombinant PTRF (rPTRF) and examined its impact on the functional interactions between the adipocyte and the hepatocyte in vitro. We demonstrated that PTRF can be found in human plasma, and is at least in part, carried by exosomes. In vitro treatment with rPTRF increased the hypertrophy and senescence of 3T3-L1 adipocytes. In turn, those rPTRF-treated adipocytes increased lipid accumulation in hepatocytes. Lastly, we found a positive correlation between circulating PTRF and the concentration of PTRF in the visceral fat depot. All these findings point toward the presence of an enlarged and dysfunctional visceral adipose tissue which secretes PTRF. This circulating PTRF behaves as an adipokine and may partially contribute to the well-known detrimental effects of visceral fat accumulation

The protective effects of metformin in an in vitro model of aging 3T3 fibroblast under the high glucose conditions

Metformin is the most widely used anti-diabetic drug in the world. It reduces advanced glycation end product (AGEs)-induced ROS generation in high glucose condition. Protein glycation contributes to skin aging as it deteriorates the existing collagen by crosslinking. The progressive increase of AGE during aging not only causes oxidative damage to cellular macromolecules but also modulates the activation of transcription factors nuclear factor kappa-B(NF-kB). However, it is still unclear whether metformin can change collagen production and NF-kB activity induced by high glucose conditions in 3T3 fibroblast. The effects of metformin on proliferation, apoptosis, and collagen levels and NF-kB activity of in vitro cell aging model of 3T3 fibroblast cells in high glucose conditions. At first, we investigated the effects of 50 mM high glucose concentration, with or without metformin, on 3T3 fibroblast proliferation, by BrdU immunostaining for cell proliferation. Apoptotic levels were analyzed by flow cytometric assay. NF-kB(p65) activity was measured by transcription factor assay kit and collagen I and III levels by Collagen Estimation Assay through ELISA. We observed that metformin exposure leads to decreased apoptosis levels and increased proliferation of 3T3 fibroblast in high glucose media. We also determined that metformin exposure leads to increased production of collagen I-III and decreased activation of NF-kB(p65) activity. The data are consistent with the observation that metformin has a protective effect in this in vitro model of aging 3T3 fibroblasts under high glucose conditions inducing cell proliferation, collagen I and III production, protection from apoptosis, and reducing NF-kB(p65) activity

Mitochondrial ROS and mtDNA fragments inside nuclear DNA as a main effector of ageing: the «cell aging regulation system» / Fragmentos de mitocondria ROS y mtDNA dentro del ADN nuclear como principal efector del envejecimiento: el sistema de regulación celular de envejecimiento

The updated mitochondrial free radical theory of aging (MFRTA) is reviewed as part of the cell aging regulatory system (CARS). Any valid theory of aging should explain why different animal species age at so different rates. Only two known parameters correlate with species longevity in the right sense: the mitochondrial rate of reactive oxygen species production (mitROSp) and the degree of fatty acid unsaturation of tissue membranes calculated as the double bond index (DBI). Both are low in long-lived animals. Dietary restriction (DR), which increases longevity, also decreases mitROSp and % free radical leak (FRL) at complex I and oxidative damage to mtDNA. This can increase longevity by decreasing mtDNA fragments accumulation inside nuclear DNA which revitalizes MFRTA. Lowered mitROSp and FRL at complex I also occurs during protein or methionine restriction, and rapamycin treatment (which also increases longevity). The decrease in mitROSp during DR (dietary restriction) is due to restriction of a single substance, methionine, and occurs at the matrix domain of complex I. This updated MFRTA focuses on low mitROSp and low sensitivity of membranes to oxidation in long-lived animals. The three best known aging effectors of the genetic Aging Program of aerobic tissues are mitROSp, membrane fatty acid unsaturation, and autophagy. This program reacts to cytoplasmic signaling proteins, influenced by nutrients, drugs and hormones, varying the activity of the mitROSp and macroautophagy aging effectors. An analogous program, although with additional gene clusters of aging involved, and different output activity, can determine longevity in different animal species (AU)

Se revisa la teoría del envejecimiento por radicales libres de origen mitocondrial (MFRTA) como parte del Sistema de Regulación Celular del Envejecimiento (CARS). Cualquier teoría del envejecimiento debe explicar porqué las especies animales envejecen a velocidades tan diferentes. Solo dos parámetros conocidos correlacionan con la longevidad de las especies en el sentido correcto: la producción mitocondrial de radicales de oxígeno (mitROSp) y el grado de insaturación de los ácidos grasos de las membranas celulares. Ambos están disminuidos en las especies longevas. La restricción calórica, de proteínas, o de metionina, y la rapamicina, que aumentan la longevidad, también disminuyen la mitROSp y la fuga % de radicales libres en el complejo I y el daño oxidativo al ADNmt. Esto puede aumentar la longevidad disminuyendo la acumulación de fragmentos del ADNmt dentro del ADN nuclear con la edad, lo cual revitaliza la MFRTA. El descenso en mitROSp durante la restricción calórica se debe sólo a la restricción de metionina, y ocurre en el dominio de membrana del complejo I. La mitROSp, el grado de insaturación de los ácidos grasos, y la autofagocitosis son los tres efectores de envejecimiento conocidos dependientes del programa genético pro-envejecimiento (PAP, que es parte del CARS). El PAP responde a proteínas de señalización celular en función de la disponibilidad de nutrientes y hormonas en los medios ambiente e interno. Este programa, aunque con más clusters génicos del envejecimiento implicados, y con diferente intensidad efectora, podría ser responsable de la regulación de la longevidad de las distintas especies animales (AU)

Envejecimiento y reprogramación epigenética / No disponible

La epigenética del envejecimiento es un campo emergente extraordinariamente prometedor. Las vías epigenéticas, la metilación del DNA y la modificación de las histonas, determinan el desarrollo normal y cambian con la edad. Alguna de las alteraciones epigenéticas descritas en el envejecimiento, como la hipermetilación en promotores específicos y la disminución de la metilación global del DNA están también asociadas al desarrollo tumoral. Los cambios epigenéticos que ocurren durante el desarrollo y la vejez pueden ser estocásticos o depender del ambiente. El desafío futuro es estudiar los mecanismos moleculares que originan las variaciones epigenéticas dependientes de la edad y cómo esos cambios afectan al fenotipo en la edad avanzada (AU)

Epigenetics of aging is an emerging field that promises exciting revelations in the near future. Epigenetic pathways, including DNA methylation and histone modification, are determinants of normal development and can change during aging. Some of the epigenetic alterations described during aging, as hypermethylation at specific promoters and decrease of global DNA methylation, are also associated with tumor development. The epigenetic changes occurring during development and aging can be stochastic or depend on environmental factors. Future challenges in the field involve the determination of the precise molecular mechanisms that create age-dependent epigenetic variation and how these epigenetic changes affect the aging phenotype (AU)

El sistema de regulación celular de envejecimiento / No disponible

Los animales longevos tienen niveles bajos de producción mitocondrial de ROS y de insaturación de los ácidos grasos de las membranas celulares. La restricción de calorías, de proteínas, o de metionina, y la rapamicina, que son las cuatro manipulaciones experimentales conocidas que aumentan la longevidad de los mamíferos, también disminuyen la producción mitocondrial de ROS en el complejo I y el daño oxidativo al ADNmt. Esto parece contribuir a aumentar la longevidad porque disminuye la acumulación de fragmentos del ADNmt insertados dentro del ADN nuclear. La señalización pre-nuclear de la longevidad, el programa nuclear del envejecimiento, y los efectores de envejecimiento, son los tres constituyentes principales del sistema de regulación del envejecimiento celular (CARS). Los tres efectores del envejecimiento mejor conocidos de los tejidos aerobios son la producción mitocondrial de ROS, la insaturación de los ácidos grasos de las membranas, y la autofagia. El programa de envejecimiento nuclear reacciona a las proteínas citoplásmicas de señalización influenciadas a su vez por nutrientes, fármacos y hormonas, variando al menos dos efectores, la producción mitocondrial de ROS y la autofagia. Un programa análogo, aunque con clusters génicos adicionales implicados, y con mayor nivel de expresión génica, puede determinar la longevidad de las distintas especies animales (AU)

The mitochondrial rate of reactive oxygen species (ROS) production and the degree of fatty acid unsaturation of cellular membranes are low in longlived animals. Dietary restriction, protein and methionine restriction, and rapamycin, the four known experimental manipulations which increase mammalian longevity, also decrease mitROSp at complex I and oxidative damage to mtDNA. This could increase longevity by decreasing mtDNA fragments accumulation inside nuclear DNA. Pre-nuclear signaling of longevity, the nuclear aging program, and the aging effectors are the three main constituents of the cellular aging regulation system (CARS). The three best known aging effectors of the genetic aging program of aerobic tissues are mitochondrial ROS production, membrane fatty acid unsaturation, and autophagy. This program reacts to cytoplasmic signaling proteins, influenced by nutrients, drugs and hormones, varying the activity of the mitROSp and autophagy aging effectors. An analogous program, although with additional gene clusters of aging involved and wider output activity, can determine longevity in different animal species (AU)

Gamma-Tocotrienol prevents cell cycle arrest in aged human fibroblast cells through p16INK4a pathway

Human diploid fibroblasts (HDFs) proliferation in culture has been used as a model of aging at the cellular level. Growth arrest is one of the most important mechanisms responsible for replicative senescence. Recent researches have been focusing on the function of vitamin E in modulating cellular signaling and gene expression. Therefore, the aim of this study was to elucidate the effect of palm γ-tocotrienol (vitamin E) in modulating cellular aging through p16INK4a pathway in HDF cells. Primary culture of senescent HDFs was incubated with 70 μM of palm γ-tocotrienol for 24 hours. Silencing of p16INK4a was carried out by siRNA transfection. RNA was extracted from the different treatment groups and gene expression analysis was carried out by real-time reverse transcription polymerase chain reaction. Proteins that were regulated by p16INK4a were determined by western blot technique. The finding of this study showed that p16INK4a mRNA was overexpressed in senescent HDFs, and hypophosphorylated-pRb and cyclin D1 protein expressions were increased (p < 0.05). However, downregulation of p16INK4a and hypophosphorylated-pRb and cyclin D1 protein expressions (p < 0.05) by γ-tocotrienol led to modulation of the cell cycle regulation during cellular aging. In conclusion, senescent HDFs showed change in biological process specifically in cell cycle regulation with elevated expression of genes and proteins which may contribute to cell cycle arrest. Palm γ-tocotrienol may delay cellular senescence of HDFs by regulating cell cycle through downregulation of p16INK4a and hypophosphorylated-pRb and cyclin D1 protein expressions (AU)

No disponible

Los cuerpos de Marinesco. Estudio de 8 casos y revisión de la literatura / Marinesco bodies. Report of 8 cases and review of the literature

Introducción: Los cuerpos de Marinesco (CM) son inclusiones intranucleares de patogenia desconocida que aparecen en las neuronas pigmentadas de la sustancia negra. Clásicamente, se han asociado al envejecimiento celular y al estrés metabólico. Las últimas investigaciones refieren su mayor frecuencia de aparición en algunas enfermedades neurodegenerativas y plantean la hipótesis de un papel patológico aún no aclarado. Material y métodos: Seleccionamos 8 casos de autopsia del periodo 2002 a 2004 para un estudio semicuantitativo y morfológico de los CM con hematoxilina-eosina y ubicuitina. Ningún caso tenía enfermedad neurodegenerativa de base. Las variables en estudio son: el número, tamaño, relación con el nucléolo y patrón de inmunotinción. Resultados: Los CM son inclusiones esféricas, eosinófilas, homogéneas y bien delimitadas. Los encontramos en el 9% de las neuronas pigmentadas (5,2-14,9%). Con mayor frecuencia aparecen 1 o 2 CM, menores que el nucléolo y localizados en su vecindad, pero no adosados al mismo. Identificamos 4 patrones de inmunotinción con ubicuitina: homogéneo, concéntrico, en anillo y formas intermedias. Conclusiones: Los CM se han relacionado con el envejecimiento aunque nuestra pequeña serie no revela diferencias morfológicas ni cuantitativas significativas con la edad. Por otro lado, identificamos hasta 4 patrones de inmunotinción con ubicuitina no descritos previamente. Este estudio ofrece una descripción detallada y sistemática de las características morfológicas de los CM y aporta novedades sobre su expresión inmunohistoquímica (AU)

Introduction: Marinesco bodies (MBs) are intranuclear inclusions of unknown origin found in substantianigra pigmented neurons. Classically, they have been associated with ageing and metabolic stress. The most recent research has shown an increased frequency of the appearance of MBs in some neurodegenerative diseases, although their role remains as yet undefined Material and methods: A semi-quantitative and morphological study of MBs on H&E and ubiquitin-stained sections was carried out on 8 cases from autopsies performed between 2002 and 2004. None had neurodegenerative disease. Variables were: number, size, relation to nucleoli and ubiquitin immunohistochemical pattern. Results: MBs generally are spherical, eosinophilic, homogeneous and well-defined inclusions occurring in 9% of the pigmented neurons (5.2-14.9%). More frequently, we found 1 or 2 MBs that were smaller than the nucleoli and located in close vicinity, but not back to back. We identified 4 patterns of ubiquitin-immunostaining: homogeneous, concentrical, ring-like and intermediate. Conclusions: MBs appear to be related to ageing, although our small series did not find significant morphological or quantitative differences with age. Conversely, we identified up to four ubiquitin-immunostaining patterns not previously reported in the literature. This study gives a detailed and systematic description of MBs together with new findings about their immunohistochemical expression (AU)

Telómeros, envejecimiento y síndrome de Cushing: ¿están relacionados? / Telomeres, aging and Cushing's syndrome: Are they related?

El síndrome de Cushing se debe a una hipersecreción de cortisol, asociado a una mayor mortalidad y una elevada morbilidad, que no es totalmente reversible a pesar del control bioquímico, presentando un conjunto de manifestaciones sistémicas similares a las que aparecen en el envejecimiento. El estrés crónico, que también conlleva una hiperestimulación del eje adrenal, se ha relacionado con el acortamiento telomérico acelerado, el daño oxidativo y el envejecimiento celular. A pesar de que el envejecimiento prematuro de los pacientes con síndrome de Cushing podría relacionarse con factores ambientales, no puede descartarse que la exposición crónica al hipercortisolismo determine un acortamiento telomérico y, por lo tanto, envejecimiento. En esta revisión se repasan las evidencias existentes que podrían relacionar el síndrome de Cushing y el envejecimiento celular prematuro (AU)

Cushing's syndrome is due to excess cortisol secretion and is associated to increased mortality and severe morbidity that are not fully reversible despite biochemical control. The syndrome consists of a set of systemic manifestations similar to those found in aging. Chronic stress, which also causes hyperstimulation of the hypothalamic-pituitary-adrenal axis, has been related to accelerated telomere shortening, oxidative damage, and cell aging. Although premature aging in patients with Cushing's syndrome could be related to environmental factors, the possibility that chronic exposure to hypercortisolism causes telomere shortening, and thus premature aging, cannot be ruled out. This review discusses the available evidence supporting a link between Cushing's syndrome and cell aging (AU)

Forkhead-box-O1 locus y marcadores metabólicos en los ancianos: estudio de asociación / Forkhead-box-O1 locus and metabolic markers in the elderly: An association study

Introducción. Las mutaciones del gen forkhead-box-O1 (FoxO1) en el locus 13q14.1 provocan alteraciones en los parámetros bioquímicos conduciendo al envejecimiento prematuro. La proteína FoxO1 participa en la regulación de procesos bioquímicos, que influyen en la regulación del perfil lipídico y glucémico. Estos parámetros son un factor de riesgo de mortalidad en la población anciana. El objeto del estudio fue investigar la relación entre el locus FoxO1 y los marcadores metabólico-nutricionales. Material y métodos. Se investigaron los polimorfismos de nucleótido único (SNP, del inglés single-nucleotide polymorphisms) rs2721069, rs4943794 y rs7981045 en 594 ancianos hospitalizados (65-99 años) en una sección geriátrica, probando la asociación con los marcadores biológicos mediante el análisis de covarianza (ANCOVA) y del modelo estadístico Genotype Score. Resultados. El análisis de ANCOVA bajo distintos modelos genéticos reveló una asociación significativa. Asumiendo un modelo genético dominante se observó una asociación significativa con los niveles de la glucosa para rs2721069 (p=0,034) y rs4943794 (p=0,012). Para rs4943794 se observó también una asociación significativa si considerado libre de modelos genéticos (p=0,039) confirmada en el modelo aditivo (p=0,012). El modelo estadístico Genotype Score confirmó una asociación significativa entre FoxO1 SNP y la glucosa, teniendo en cuenta los SNP rs2721069 y rs4943794 en conjunto (p=0,048; Beta=3,198). Conclusiones. El envejecimiento es un proceso complejo, resultante de la interacción entre varios factores, como los ambientales y los genéticos. Nuestros hallazgos sugieren que el locus FoxO1 puede influir en los niveles séricos de glucemia en pacientes hospitalizados mayores, siendo entonces uno de los factores genéticos que contribuyen a un envejecimiento saludable(AU)

Introduction. Mutations of forkhead-box-O1 (FOXO1) gene at locus 13q14.1 cause changes in biochemical parameters leading to premature aging. Protein FoxO1 participates in the regulation of biochemical pathways, including those influencing the regulation of lipid profile and glucose metabolism. These parameters are a risk factor for all-cause mortality in the elderly population. The aim of this study was to investigate the relationship between FOXO1 locus and metabolic-nutritional markers. Material and methods. Single-nucleotide polymorphisms (SNP) rs2721069, rs4943794 and rs7981045 were determined in 594 hospitalized elderly (65-99 years), patients consecutively admitted to a geriatric ward, and tested the association of FOXO1 variants with biological markers by the analyses of co-variance (ANCOVA) and by Genotype Score Model statistic. Results. The ANCOVA analysis, under different genetic models, revealed significant associations. In particular, assuming a dominant genetic model, a significant association with serum levels of fasting glucose was observed for rs2721069 (P=.034) and rs4943794 (P=.012). For rs4943794 a significant association assuming a free genetic model (P=.039) and an additive one (P=.012) was also observed. No significant relationship was observed between rs7981045 and the analyzed markers. The Genotype Score Model analysis confirmed a significant association between FOXO1 SNP and fasting glucose, taking the SNP rs2721069 and rs4943794 together (P=.048; Beta=3.198). Conclusions. Aging is a complex process, resulting from the interaction between several factors, including environmental and genetic ones. Our findings suggest that FOXO1 locus may influence blood glucose levels in hospitalized older patients, thus being one of the genetic factors contributing to healthy aging(AU)

Bypassing cellular senescence by genetic screening tools

Bypassing cellular senescence is a prerequisite step in the tumorigenic transformation. It has long been known that loss of a key tumour suppressor gene, such as p53 or pRB, is necessary but not sufficient for spontaneous cellular immortalisation. Therefore, there must be additional mutations and/or epigenetic alterations required for immortalisation to occur. Early work on these processes included somatic-cell genetic studies to estimate the number of senescence genes and nowadays are completed by in vivo models and with the requirements to bypass senescence induced by oncogenic transformation in stem cells. These principal studies laid the foundation for the field of senescence/immortalisation but were labour intensive and the results were somewhat limited. Using retroviral-based functional genetic screening, we and others identified universal genes regulating senescence/immortalisation (either by gain or loss of function) and found that some of these genes are widely altered in human tumours. We also explored the molecular mechanisms throughout these genes that regulate senescence and established the causality of the genetic alteration in tumorigenesis. The identification of genes and pathways regulating senescence/immortalisation could provide novel molecular targets for the treatment and/or prevention of cancer (AU)

Reduced Electroencephalographic Coherence Asymmetry in the Chernobyl Accident Survivors

An electroencephalograph (EEG) study was carried out from 1990 to 2006, using power spectra, averaged coherence, and integral EEG coherence asymmetry coefficients to compare 189 clean-up workers of the Chernobyl accident with 63 age-matched healthy controls. Most of the Chernobyl workers showed three abnormal EEG patterns, as indicated by EEG power mapping. The higher power, most prominent in slow alpha and theta bands, or in fast alpha frequencies, were observed in persons 3-5 years after the clean-up works (the early stage). The lower EEG power in alpha band was found in Chernobyl workers 10 or more years after the accident (the late stage). EEG coherence analysis revealed the existence of two stages in EEG alterations following the Chernobyl clean-up. In the early stage, an increase of EEG coherence in the central brain areas was observed, whereas at the later stage, a decrease of EEG coherence, most prominent in the frontal brain areas, and reduced brain asymmetry prevailed. These results allow us to propose that the described EEG signs may be a reflection of radiation-induced brain dysfunction at the late period after the Chernobyl clean-up and were similar to the EEG markers of brain ageing. The results, in comparison to data of the literature, provide additional support to the premature brain ageing hypothesis in Chernobyl survivors as a result of the radiation brain damage after-effect (AU)

Se llevó a cabo un estudio electroencefalográfico (EEG) desde 1990 a 2006, empleando los espectros de energía, la coherencia promediada y los coeficientes integrales de asimetría de coherencia de EEG para comparar 189trabajadores que participaron en la limpieza después del accidente de Chernobyl con un grupo control de 63individuos sanos de la misma edad. La mayoría de los trabajadores de Chernobyl mostraron tres patrones anormales de EEG, como indica el mapeo de energía del EEG. La energía más alta, más prominente en las bandas lentas alfa y theta (1) o en frecuencias rápidas alfa (2), se observó en personas estudiadas 3 a 5 años después de los trabajos de limpieza (la fase temprana). La energía en el EEG más baja, en la banda alfa (3),se encontró en los trabajadores de Chernobyl 10 años o más después del accidente (la fase tardía). El análisis de coherencia del EEG reveló la existencia de dos fases en las alteraciones del EEG después de la limpieza de Chernobyl. En la fase temprana, se observó un incremento de la coherencia del EEG en las áreas centrales del cerebro, mientras que en la fase tardía, se observó una reducción de la coherencia del EEG, más prominente en las áreas frontales del cerebro, y prevaleció la reducción de la asimetría del cerebro. Estos resultados nos permiten proponer que los signos EEG descritos pueden ser un reflejo de disfunción cerebral inducida por radiación en la fase tardía después de la limpieza de Chernobyl y que son similares a los marcadores EEG del envejecimiento del cerebro. Los resultados, en comparación con los datos de la literatura, proporcionan apoyo adicional a la hipótesis del envejecimiento cerebral prematuro del cerebro en los supervivientes de Chernobyl como resultado del efecto secundario de lesiones cerebrales por radiación (AU)

Marcadores de senescencia celular en cáncer y precáncer oral / Cellular senescence markers in oral cancer and precancer

Estudios recientes han demostrado la capacidad del organismo humano para detener el crecimiento de potenciales células cancerígenas y paralizarlas. Este mecanismo antitumoral, que actúa como freno del proceso maligno, se conocía ya en estudios de laboratorio “in vitro”, pero se ha comprobado también su presencia en modelos “in vivo”, tanto en ratones como en muestras de tejido de pacientes con cáncer. A este mecanismo se le denomina senescencia celular y se define como un sistema de defensa de emergencia de las células que están en camino de convertirse en cancerosas, una respuesta ante el estímulo de un oncogén. Se trataría pues de un freno a la progresión de las lesiones cancerizables, condenando a esas células a una “cadena perpetua celular”. Este artículo de revisión se propone describir este mecanismo y poner al día la evidencia al respecto de este proceso, así como los marcadores de senescencia existentes en relación con el cáncer y precáncer oral This article reviews the paper of oral biopsy on the precancerous lesions diagnosis and on the oral cancer early diagnosis. Different techniques, procedures, materials, indications and other surgical aspects are debated. It proposes to do incisional biopsies on malignant lesions and on malignant suspicious lesions, while doing excisional biopsies on precancerous lesions when the size allows it ( AU)

Recent studies have demonstrated the capacity of the human organism to prevent the growth of potentially carcinogenic cells, paralyzing them. This antitumor mechanism, which acts as a brake on the malignant process, was already known in lab studies “in vitro” but has now also been verified “in vivo” in mice and in tissue samples from cancer patients. This mechanism is known as cellular senescence and is defined as an emergency defense system for cells on the way to becoming cancerous, i.e., a response to the stimulation of an oncogene. These cells are sentenced to “life imprisonment”, impeding the progression of premalignant lesions. This review aims to describe this mechanism and present an update of the evidence on this phenomenon in the setting of oral cancer and precance This article reviews the paper of oral biopsy on the precancerous lesions diagnosis and on the oral cancer early diagnosis. Different techniques, procedures, materials, indications and other surgical aspects are debated. It proposes to do incisional biopsies on malignant lesions and on malignant suspicious lesions, while doing excisional biopsies on precancerous lesions when the size allows it (AU)

Trans-platinum(II) complexes with cyclohexylamine as expectator ligand induce necrosis in tumour cells by inhibiting DNA synthesis and RNA transcription

BACKGROUND: Enhanced removal of cisplatin-DNA adducts has been reported as one of main causes of cell resistance to cisplatin. This particular resistance mechanism may be circumvented by platinum complexes that bind differently to DNA. One line of work is focussed on trans platinum complexes, some of which exhibit antitumour activity similar to or even higher than that of their cis counterparts. METHODS: We synthesised new trans platinum complexes, trans-[PtCl2(cyclohexylamine)(dimethylamine)] and trans-[PtCl2(OH)2(cyclohexylamine)(dimethylamine)], previously evaluated as cytotoxic agents towards different cancer and normal cell lines. These trans platinum compounds were highly effective against a panel of tumoral cell lines either sensitive to or with acquired resistance to cisplatin. RESULTS: In the present work we examined the mechanisms induced by these compounds to cause tumour cells toxicity. We have found that these compounds induced a complete blockade at the S phase of the cell cycle inhibiting total mRNA transcription and precluding p53 activation. CONCLUSION: In contrast to other DNA-damaging agents, these compounds do not induce senescence-associated permanent arrest. Furthermore, only a small percentage of these cells enter into apoptosis, with most of the population dying by a necrosis-like mechanism (AU)

Genomic instability: on the birth and death of cancer

The presence of an abnormal chromosomal content is probably the most universally conserved hallmark of cancer cells. Predicted at the beginning of the 20th century as the origin of tumours, and extensively documented thereafter, genomic instability lies at the core of neoplastic development. Regardless of this classic model, the actual impact that deficient control of genomic integrity has on human health and particularly on cancer development only started to gain attention from the scientific community two decades ago. From a bird's eye view and with a cancer-oriented perspective, in this work we will try to cover some of the concepts obtained from recent research in genomic instability. The review will end up presenting suggestive evidence which proposes that genomic instability might turn out to be not just the driving force but also the Achilles' heel of cancer (AU)