RESUMEN
Regular exercise promotes whole-body health and prevents disease, but the underlying molecular mechanisms are incompletely understood1-3. Here, the Molecular Transducers of Physical Activity Consortium4 profiled the temporal transcriptome, proteome, metabolome, lipidome, phosphoproteome, acetylproteome, ubiquitylproteome, epigenome and immunome in whole blood, plasma and 18 solid tissues in male and female Rattus norvegicus over eight weeks of endurance exercise training. The resulting data compendium encompasses 9,466 assays across 19 tissues, 25 molecular platforms and 4 training time points. Thousands of shared and tissue-specific molecular alterations were identified, with sex differences found in multiple tissues. Temporal multi-omic and multi-tissue analyses revealed expansive biological insights into the adaptive responses to endurance training, including widespread regulation of immune, metabolic, stress response and mitochondrial pathways. Many changes were relevant to human health, including non-alcoholic fatty liver disease, inflammatory bowel disease, cardiovascular health and tissue injury and recovery. The data and analyses presented in this study will serve as valuable resources for understanding and exploring the multi-tissue molecular effects of endurance training and are provided in a public repository ( https://motrpac-data.org/ ).
Asunto(s)
Entrenamiento Aeróbico , Multiómica , Condicionamiento Físico Animal , Resistencia Física , Animales , Femenino , Humanos , Masculino , Ratas , Acetilación , Sangre/inmunología , Sangre/metabolismo , Enfermedades Cardiovasculares/genética , Enfermedades Cardiovasculares/inmunología , Enfermedades Cardiovasculares/metabolismo , Bases de Datos Factuales , Epigenoma , Enfermedades Inflamatorias del Intestino/genética , Enfermedades Inflamatorias del Intestino/inmunología , Enfermedades Inflamatorias del Intestino/metabolismo , Internet , Lipidómica , Metaboloma , Mitocondrias/metabolismo , Enfermedad del Hígado Graso no Alcohólico/genética , Enfermedad del Hígado Graso no Alcohólico/inmunología , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Especificidad de Órganos/genética , Especificidad de Órganos/inmunología , Especificidad de Órganos/fisiología , Fosforilación , Condicionamiento Físico Animal/fisiología , Resistencia Física/genética , Resistencia Física/fisiología , Proteoma/metabolismo , Proteómica , Factores de Tiempo , Transcriptoma/genética , Ubiquitinación , Heridas y Lesiones/genética , Heridas y Lesiones/inmunología , Heridas y Lesiones/metabolismoRESUMEN
Visualizing precise spatial patterns of an organ-wide gene and protein expression among diverse cell types can provide critical insights into the fundamental processes underlying normal tissue homeostasis and disease development. Here, we describe an optimized protocol for single-molecule RNA in situ hybridization (smRNA-ISH), immunohistochemistry, and cell lineage analysis of the female reproductive tract organs using commercially available smRNA-ISH probes, antibodies, and inducible Cre-mice. The high-resolution multispectral fluorescence imaging is performed using wide-field epifluorescence or confocal microscopy combined with a slide scanner. For complete details on the use and execution of this protocol, please refer to Chumduri et al. (2021).
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Genitales Femeninos , Histocitoquímica/métodos , Proteoma/análisis , ARN , Animales , Femenino , Genitales Femeninos/química , Genitales Femeninos/citología , Genitales Femeninos/metabolismo , Procesamiento de Imagen Asistido por Computador , Ratones , Microscopía Fluorescente , Especificidad de Órganos/genética , Especificidad de Órganos/fisiología , ARN/análisis , ARN/genética , Transcriptoma/genéticaRESUMEN
Tissue-resident macrophages (TRMΦ) are important immune sentinels responsible for maintaining tissue and immune homeostasis within their specific niche. Recently, the origins of TRMΦ have undergone intense scrutiny, in which now most TRMΦ are thought to originate early during embryonic development independent of hematopoietic stem cells (HSCs). We previously characterized two distinct subsets of mouse peritoneal cavity macrophages (MΦ) (large and small peritoneal MΦ) whose origins and relationship to both fetal and adult long-term (LT) HSCs have not been fully investigated. In this study, we employ highly purified LT-HSC transplantation and in vivo lineage tracing to show a dual ontogeny for large and small peritoneal MΦ, in which the initial wave of peritoneal MΦ is seeded from yolk sac-derived precursors, which later require LT-HSCs for regeneration. In contrast, transplanted fetal and adult LT-HSCs are not able to regenerate brain-resident microglia. Thus, we demonstrate that LT-HSCs retain the potential to develop into TRMΦ, but their requirement is tissue specific in the peritoneum and brain.
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Encéfalo/citología , Células Madre Hematopoyéticas/fisiología , Macrófagos/fisiología , Peritoneo/citología , Animales , Linaje de la Célula , Desarrollo Embrionario , Femenino , Ratones , Especificidad de Órganos/fisiología , Embarazo , RegeneraciónRESUMEN
Cells cooperate as groups to achieve structure and function at the tissue level, during which specific material characteristics emerge. Analogous to phase transitions in classical physics, transformations in the material characteristics of multicellular assemblies are essential for a variety of vital processes including morphogenesis, wound healing, and cancer. In this work, we develop configurational fingerprints of particulate and multicellular assemblies and extract volumetric and shear order parameters based on this fingerprint to quantify the system disorder. Theoretically, these two parameters form a complete and unique pair of signatures for the structural disorder of a multicellular system. The evolution of these two order parameters offers a robust and experimentally accessible way to map the phase transitions in expanding cell monolayers and during embryogenesis and invasion of epithelial spheroids.
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Fenómenos Biofísicos/fisiología , Procesamiento de Imagen Asistido por Computador/métodos , Especificidad de Órganos/fisiología , Transición de Fase , Animales , Ciclo Celular , Movimiento Celular , Proliferación Celular , Células Epiteliales/citología , Humanos , Morfogénesis , Neoplasias , Esferoides Celulares/citología , Cicatrización de HeridasRESUMEN
In recent years, attention has turned to examining the biodistribution of EVs in recipient animals to bridge between knowledge of EV function in vitro and in vivo. We undertook a systematic review of the literature to summarize the biodistribution of EVs following administration into animals. There were time-dependent changes in the biodistribution of small-EVs which were most abundant in the liver. Detection peaked in the liver and kidney in the first hour after administration, while distribution to the lungs and spleen peaked between 2-12 h. Large-EVs were most abundant in the lungs with localization peaking in the first hour following administration and decreased between 2-12 h. In contrast, large-EV localization to the liver increased as the levels in the lungs decreased. There was moderate to low localization of large-EVs to the kidneys while localization to the spleen was typically low. Regardless of the origin or size of the EVs or the recipient species into which the EVs were administered, the biodistribution of the EVs was largely to the liver, lungs, kidneys, and spleen. There was extreme variability in the methodology between studies and we recommend that guidelines should be developed to promote standardization where possible of future EV biodistribution studies.
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Vesículas Extracelulares/metabolismo , Vesículas Extracelulares/trasplante , Distribución Tisular/fisiología , Animales , Disponibilidad Biológica , Sistemas de Liberación de Medicamentos/métodos , Humanos , Especificidad de Órganos/efectos de los fármacos , Especificidad de Órganos/fisiologíaRESUMEN
Metabolic diseases are associated with an increased risk of severe COVID-19 and conversely, new-onset hyperglycemia and complications of preexisting diabetes have been observed in COVID-19 patients. Here, we performed a comprehensive analysis of pancreatic autopsy tissue from COVID-19 patients using immunofluorescence, immunohistochemistry, RNA scope and electron microscopy and detected SARS-CoV-2 viral infiltration of beta-cells in all patients. Using SARS-CoV-2 pseudoviruses, we confirmed that isolated human islet cells are permissive to infection. In eleven COVID-19 patients, we examined the expression of ACE2, TMPRSS and other receptors and factors, such as DPP4, HMBG1 and NRP1, that might facilitate virus entry. Whereas 70% of the COVID-19 patients expressed ACE2 in the vasculature, only 30% displayed ACE2-expression in beta-cells. Even in the absence of manifest new-onset diabetes, necroptotic cell death, immune cell infiltration and SARS-CoV-2 viral infection of pancreatic beta-cells may contribute to varying degrees of metabolic dysregulation in patients with COVID-19.
Asunto(s)
Enzima Convertidora de Angiotensina 2/metabolismo , COVID-19/patología , Células Secretoras de Insulina/virología , Receptores de Coronavirus/metabolismo , SARS-CoV-2/aislamiento & purificación , Serina Endopeptidasas/metabolismo , Adulto , Anciano , Autopsia , Complicaciones de la Diabetes/patología , Complicaciones de la Diabetes/virología , Diabetes Mellitus/patología , Dipeptidil Peptidasa 4/metabolismo , Femenino , Proteínas HMGN/metabolismo , Humanos , Células Secretoras de Insulina/metabolismo , Masculino , Persona de Mediana Edad , Neuropilina-1/metabolismo , Especificidad de Órganos/fisiologíaRESUMEN
Ageing of the immune system, or immunosenescence, contributes to the morbidity and mortality of the elderly1,2. To define the contribution of immune system ageing to organism ageing, here we selectively deleted Ercc1, which encodes a crucial DNA repair protein3,4, in mouse haematopoietic cells to increase the burden of endogenous DNA damage and thereby senescence5-7 in the immune system only. We show that Vav-iCre+/-;Ercc1-/fl mice were healthy into adulthood, then displayed premature onset of immunosenescence characterized by attrition and senescence of specific immune cell populations and impaired immune function, similar to changes that occur during ageing in wild-type mice8-10. Notably, non-lymphoid organs also showed increased senescence and damage, which suggests that senescent, aged immune cells can promote systemic ageing. The transplantation of splenocytes from Vav-iCre+/-;Ercc1-/fl or aged wild-type mice into young mice induced senescence in trans, whereas the transplantation of young immune cells attenuated senescence. The treatment of Vav-iCre+/-;Ercc1-/fl mice with rapamycin reduced markers of senescence in immune cells and improved immune function11,12. These data demonstrate that an aged, senescent immune system has a causal role in driving systemic ageing and therefore represents a key therapeutic target to extend healthy ageing.
Asunto(s)
Envejecimiento/inmunología , Envejecimiento/fisiología , Sistema Inmunológico/inmunología , Sistema Inmunológico/fisiología , Inmunosenescencia/inmunología , Inmunosenescencia/fisiología , Especificidad de Órganos/inmunología , Especificidad de Órganos/fisiología , Envejecimiento/efectos de los fármacos , Envejecimiento/patología , Animales , Daño del ADN/inmunología , Daño del ADN/fisiología , Reparación del ADN/inmunología , Reparación del ADN/fisiología , Proteínas de Unión al ADN/genética , Endonucleasas/genética , Femenino , Envejecimiento Saludable/inmunología , Envejecimiento Saludable/fisiología , Homeostasis/inmunología , Homeostasis/fisiología , Sistema Inmunológico/efectos de los fármacos , Inmunosenescencia/efectos de los fármacos , Masculino , Ratones , Especificidad de Órganos/efectos de los fármacos , Rejuvenecimiento , Sirolimus/farmacología , Bazo/citología , Bazo/trasplanteRESUMEN
The cerebral cortex is an intricate structure that controls human features such as language and cognition. Cortical functions rely on specialized neurons that emerge during development from complex molecular and cellular interactions. Neurodevelopmental disorders occur when one or several of these steps is incorrectly executed. Although a number of causal genes and disease phenotypes have been identified, the sequence of events linking molecular disruption to clinical expression mostly remains obscure. Here, focusing on human malformations of cortical development, we illustrate how complex interactions at the genetic, cellular, and circuit levels together contribute to diversity and variability in disease phenotypes. Using specific examples and an online resource, we propose that a multilevel assessment of disease processes is key to identifying points of vulnerability and developing new therapeutic strategies.
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Corteza Cerebral/anomalías , Trastornos Mentales/metabolismo , Enfermedades del Sistema Nervioso/metabolismo , Neurogénesis/fisiología , Neuronas/fisiología , Animales , Conducta , Movimiento Celular/genética , Movimiento Celular/fisiología , Corteza Cerebral/metabolismo , Corteza Cerebral/ultraestructura , Regulación del Desarrollo de la Expresión Génica , Humanos , Trastornos Mentales/genética , Ratones , Enfermedades del Sistema Nervioso/genética , Vías Nerviosas/anomalías , Vías Nerviosas/metabolismo , Vías Nerviosas/ultraestructura , Neurogénesis/genética , Neuronas/citología , Especificidad de Órganos/genética , Especificidad de Órganos/fisiologíaRESUMEN
Metabolic modeling enables the study of human metabolism in healthy and in diseased conditions, e.g., the prediction of new drug targets and biomarkers for metabolic diseases. To accurately describe blood and urine metabolite dynamics, the integration of multiple metabolically active tissues is necessary. We developed a dynamic multi-tissue model, which recapitulates key properties of human metabolism at the molecular and physiological level based on the integration of transcriptomics data. It enables the simulation of the dynamics of intra-cellular and extra-cellular metabolites at the genome scale. The predictive capacity of the model is shown through the accurate simulation of different healthy conditions (i.e., during fasting, while consuming meals or during exercise), and the prediction of biomarkers for a set of Inborn Errors of Metabolism with a precision of 83%. This novel approach is useful to prioritize new biomarkers for many metabolic diseases, as well as for the integration of various types of personal omics data, towards the personalized analysis of blood and urine metabolites.
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Biología Computacional/métodos , Metabolómica/métodos , Biología de Sistemas/métodos , Biomarcadores/sangre , Biomarcadores/orina , Simulación por Computador , Humanos , Modelos Biológicos , Especificidad de Órganos/genética , Especificidad de Órganos/fisiologíaRESUMEN
Obesity and type 2 diabetes (T2D) have become a global health concern. The prevalence of obesity and T2D is significantly higher in shift workers compared to people working regular hours. An accepted hypothesis is that the increased risk for metabolic health problems arises from aberrantly timed eating behavior, that is, eating out of synchrony with the biological clock. The biological clock is part of the internal circadian timing system, which controls not only the sleep/wake and feeding/fasting cycle, but also many metabolic processes in the body, including the timing of our eating behavior, and processes involved in glucose homeostasis. Rodent studies have shown that eating out of phase with the endogenous clock results in desynchronization between rhythms of the central and peripheral clock systems and between rhythms of different tissue clocks (eg, liver and muscle clock). Glucose homeostasis is a complex process that involves multiple organs. In the healthiest situation, functional rhythms of these organs are synchronized. We hypothesize that desynchronization between different metabolically active organs contributes to alterations in glucose homeostasis. Here we summarize the most recent information on desynchronization between organs due to shift work and shifted food intake patterns and introduce the concept of phenotypic flexibility, a validated test to assess the contribution of each organ to insulin resistance (IR) in humans. We propose this test as a way to provide further insight into the possible desynchronization between tissue clocks. Because different types of IR benefit from different therapeutic approaches, we also describe different chronotherapeutic strategies to promote synchrony within and between metabolically active organs.
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Relojes Circadianos/fisiología , Ritmo Circadiano/fisiología , Resistencia a la Insulina/fisiología , Diabetes Mellitus Tipo 2/fisiopatología , Humanos , Obesidad/fisiopatología , Especificidad de Órganos/fisiología , Horario de Trabajo por TurnosRESUMEN
Chromatin immunoprecipitation with sequencing (ChIP-seq) has been instrumental in understanding transcription factor (TF) binding during gene regulation. ChIP-seq requires specific antibodies against desired TFs, which are not available for numerous species. Here, we describe a tissue-specific biotin ChIP-seq protocol for zebrafish and chicken embryos which utilizes AVI tagging of TFs, permitting their biotinylation by a co-expressed nuclear biotin ligase. Subsequently, biotinylated factors can be precipitated with streptavidin beads, enabling the user to construct TF genome-wide binding landscapes like conventional ChIP-seq methods. For complete details on the use and execution of this protocol, please see Lukoseviciute et al. (2018) and Ling and Sauka-Spengler (2019).
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Biotina/química , Inmunoprecipitación de Cromatina/métodos , Análisis de Secuencia de ADN/métodos , Animales , Biotina/metabolismo , Células Cultivadas , Pollos/genética , Especificidad de Órganos/fisiología , Estreptavidina/química , Estreptavidina/metabolismo , Factores de Transcripción/química , Factores de Transcripción/metabolismo , Pez Cebra/genéticaRESUMEN
The organisms have the capacity to sense and adapt to their surroundings for their life in a dynamic environment. In response to amino acid starvation, cells activate a rectifying physiological program, termed the integrated stress response (ISR), to restore cellular homeostasis. General controlled non-repressed (GCN2) kinase is a master regulator of the ISR and modulates protein synthesis in response to amino acid starvation. We previously established the GCN2/ATF4/4E-BP pathway in development and aging. Here, we investigated the tissue-specific roles of GCN2 upon dietary restriction of amino acid in a Drosophila model. The knockdown of GCN2 in the gut and fat body, an energy sensing organ in Drosophila, abolished the beneficial effect of GCN2 in lifespan extension upon dietary restriction of amino acids. Proteome analysis in an autosomal dominant retinitis pigmentosa (ADRP) model showed that dietary restriction of amino acids regulates the synthesis of proteins in several pathways, including mitochondrial translation, mitochondrial gene expression, and regulation of biological quality, and that gcn2-mutant flies have reduced levels of these mitochondria-associated proteins, which may contribute to retinal degeneration in ADRP. These results indicate that the tissue-specific regulation of GCN2 contributes to normal physiology and ADRP progression.
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Envejecimiento/metabolismo , Proteínas de Drosophila/metabolismo , Drosophila/metabolismo , Longevidad/genética , Mitocondrias/metabolismo , Proteínas Quinasas/metabolismo , Proteoma/metabolismo , Retinitis Pigmentosa/metabolismo , Envejecimiento/genética , Aminoácidos/metabolismo , Animales , Dietoterapia , Modelos Animales de Enfermedad , Proteínas de Drosophila/genética , Cuerpo Adiposo/metabolismo , Técnicas de Silenciamiento del Gen , Genes Dominantes , Intestinos/fisiología , Mitocondrias/genética , Especificidad de Órganos/genética , Especificidad de Órganos/fisiología , Análisis de Componente Principal , Biosíntesis de Proteínas/genética , Proteínas Quinasas/genética , Retinitis Pigmentosa/genética , Transducción de Señal/genéticaRESUMEN
Metabolism is a highly compartmentalized process that provides building blocks for biomass generation during development, homeostasis, and wound healing, and energy to support cellular and organismal processes. In metazoans, different cells and tissues specialize in different aspects of metabolism. However, studying the compartmentalization of metabolism in different cell types in a whole animal and for a particular stage of life is difficult. Here, we present MEtabolic models Reconciled with Gene Expression (MERGE), a computational pipeline that we used to predict tissue-relevant metabolic function at the network, pathway, reaction, and metabolite levels based on single-cell RNA-sequencing (scRNA-seq) data from the nematode Caenorhabditis elegans. Our analysis recapitulated known tissue functions in C. elegans, captured metabolic properties that are shared with similar tissues in human, and provided predictions for novel metabolic functions. MERGE is versatile and applicable to other systems. We envision this work as a starting point for the development of metabolic network models for individual cells as scRNA-seq continues to provide higher-resolution gene expression data.
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Proteínas de Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/metabolismo , Regulación de la Expresión Génica/genética , Transcriptoma/genética , Algoritmos , Animales , Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/genética , Biología Computacional , Simulación por Computador , Redes Reguladoras de Genes , Gónadas/metabolismo , Mucosa Intestinal/metabolismo , Redes y Vías Metabólicas , Neuroglía/metabolismo , Especificidad de Órganos/genética , Especificidad de Órganos/fisiología , RNA-Seq , Análisis de la Célula Individual , Tejido Subcutáneo/metabolismoRESUMEN
Metamorphosis is a postembryonic developmental process that involves morphophysiological and behavioral changes, allowing organisms to adapt into a novel environment. In some amphibians, aquatic organisms undergo metamorphosis to adapt in a terrestrial environment. In this process, these organisms experience major changes in their circulatory, respiratory, digestive, excretory and reproductive systems. We performed a transcriptional global analysis of heart, lung and gills during diverse stages of Ambystoma velasci to investigate its metamorphosis. In our analyses, we identified eight gene clusters for each organ, according to the expression patterns of differentially expressed genes. We found 4064 differentially expressed genes in the heart, 4107 in the lung and 8265 in the gills. Among the differentially expressed genes in the heart, we observed genes involved in the differentiation of cardiomyocytes in the interatrial zone, vasculogenesis and in the maturation of coronary vessels. In the lung, we found genes differentially expressed related to angiogenesis, alveolarization and synthesis of the surfactant protein. In the case of the gills, the most prominent biological processes identified are degradation of extracellular matrix, apoptosis and keratin production. Our study sheds light on the transcriptional responses and the pathways modulation involved in the transformation of the facultative metamorphic salamander A. velasci in an organ-specific manner.
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Proteínas Anfibias/biosíntesis , Embrión no Mamífero/embriología , Regulación del Desarrollo de la Expresión Génica/fisiología , Metamorfosis Biológica/fisiología , Transcriptoma/fisiología , Ambystoma , Animales , Especificidad de Órganos/fisiologíaRESUMEN
SUMMARY: Chronic pain impacts on many aspects of patient life affecting autonomy, sleep, social activities and also employment. Adequate pain control is often challenging in patients with chronic pain, despite the availability of many medications and interventional techniques. Limitations to successful pain treatment are the poor understanding of contributing mechanisms and the lack of a mechanism based approach in clinical practice. The purpose of this article is to identify the factors contributing to pain generation in order to guide a personalized treatment. We analyze tissue specificity for chemical and physical stresses potentially causing pain, the changes that occur in the peripheral and central pain pathways during disease, the stimuli that, acting on a pathological pain pathway, can trigger pain. The pain generating factors should be recognized in each patient and addressed with pharmacological, rehabilitation and invasive interventions.
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Dolor Crónico/etiología , Dolor Crónico/terapia , Percepción del Dolor/fisiología , Humanos , Nociceptores/fisiología , Especificidad de Órganos/fisiología , Dolor/fisiopatología , Manejo del Dolor/métodos , Medicina de PrecisiónRESUMEN
Cancer metastasis poses a challenging problem both clinically and scientifically, as the stochastic nature of metastatic lesion formation introduces complexity for both early detection and the study of metastasis in preclinical models. Engineered metastatic niches represent an emerging approach to address this stochasticity by creating bioengineered sites where cancer can preferentially metastasize. As the engineered niche captures the earliest metastatic cells at a nonvital location, both noninvasive and biopsy-based monitoring of these sites can be performed routinely to detect metastasis early and monitor alterations in the forming metastatic niche. The engineered metastatic niche also provides a new platform technology that serves as a tunable site to molecularly dissect metastatic disease mechanisms. Ultimately, linking the engineered niches with advances in sensor development and synthetic biology can provide enabling tools for preclinical cancer models and fosters the potential to impact the future of clinical cancer care.
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Bioingeniería/métodos , Metástasis de la Neoplasia/patología , Metástasis de la Neoplasia/terapia , Medicina de Precisión , Microambiente Tumoral , Animales , Bioingeniería/tendencias , Biopsia , Técnicas Biosensibles/métodos , Movimiento Celular/fisiología , Humanos , Neoplasias/diagnóstico , Especificidad de Órganos/fisiología , Biología Sintética , Hipoxia Tumoral/fisiologíaRESUMEN
Loss of KBTBD2 in all tissues causes the teeny phenotype, characterized by insulin resistance with late failure of insulin production, severe hyperglycemia/diabetes, lipodystrophy, hepatosteatosis, and growth retardation. KBTBD2 maintains insulin sensitivity in adipocytes by restricting the abundance of p85α. However, the possible physiological contribution or contributions of KBTBD2 have not yet been examined in other tissues. Here we show that mice with an adipocyte-specific knockout of Kbtbd2 accumulate p85α in white and brown adipose tissues, causing insulin resistance, moderate rather than severe hyperglycemia, sustained hyperinsulinemia without late failure of insulin production, and lipodystrophy leading to ectopic lipid accumulation in the liver. Adipocyte-extrinsic insulin resistance was observed in liver and muscle. None of these abnormalities were observed in liver- or muscle-specific Kbtbd2 knockout mice. Mice with Kbtbd2 knockout in adipocytes, liver, and muscle all showed normal growth, suggesting that KBTBD2 may be necessary to ensure IGF1 signaling in other tissues, notably bone. While much of the teeny phenotype results from loss of KBTBD2 in adipocytes, some features are adipocyte-extrinsic.
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Adipocitos/metabolismo , Resistencia a la Insulina/fisiología , Lipodistrofia/metabolismo , Complejos de Ubiquitina-Proteína Ligasa/metabolismo , Animales , Fosfatidilinositol 3-Quinasa Clase Ia/metabolismo , Diabetes Mellitus/metabolismo , Masculino , Ratones , Ratones Noqueados , Especificidad de Órganos/fisiología , FenotipoRESUMEN
Over the past decades, substantial advances have been made in both the early diagnosis and accurate prognosis of numerous cancers because of the impressive development of novel proteomic strategies. Selenium (Se) is an essential trace element in humans and animals. Se deficiency could lead to Keshan disease in humans, mulberry heart disease in pigs and damage of tissues including cardiac injury, apoptosis in the liver, reduction in the immune responses in spleen and cerebral lesions in chickens. However, it is well know that plasma biomarkers are not specific and also show alterations in various diseases including those caused by Se deficiency. Therefore, new definition biomarkers are needed to improve disease surveillance and reduce unnecessary chicken losses due to Se deficiency. To identify new biomarkers for Se deficiency, we performed exploratory heart, liver, spleen, muscle, vein, and artery proteomic screens to further validate the biomarkers using Venn analysis, GO enrichment, heatmap analysis, and IPA analysis. Based on the bioinformatics methods mentioned above, we found that differentially expressed genes and proteins are enriched to the PI3K/AKT/mTOR signal pathway and insulin pathway. We further used western blot to detect the expression of proteins related to the two pathways. Results showed that the components of the PI3K/AKT/mTOR signal pathway were definitely decreased in heart, liver, spleen, muscle, vein and artery tissues in the Se deficient group. Expression IGF and IGFBP2 of the insulin pathway were differentially increased in the heart, liver, and spleen in Se deficient group samples and decreased in muscle and artery. In conclusion, 5 proteins, namely PI3K, AKT, mTOR, IGF, and IGFBP2, were differentially expressed, which could be potentially useful Se deficient biomarkers. In the present study, proteomic profiling was used to elucidate protein biomarkers that distinguished Se deficient samples from the controls, which might provide a new direction for the diagnosis and targeted treatment induced by Se deficiency in chickens.
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Especificidad de Órganos/fisiología , Proteoma , Selenio , Transducción de Señal/fisiología , Animales , Apoptosis/fisiología , Biomarcadores , Pollos , Proteoma/análisis , Proteoma/química , Proteoma/metabolismo , Proteómica , Selenio/deficiencia , Selenio/metabolismoRESUMEN
Senescent cells in tissues and organs are considered to be pivotal to not only the aging process but also the onset of chronic disease. Accumulating evidence from animal experiments indicates that the magnitude of senescence can vary within and between aged tissue samples from the same animal. However, whether this variation in senescence translates across to human tissue samples is unknown. To address this fundamental question, we have conducted a systematic review and meta-analysis of all available literature investigating the magnitude of senescence and its association with chronological age in human tissue samples. While senescence is higher in aged tissue samples, the magnitude of senescence varies considerably depending upon tissue type, tissue section, and marker used to detect senescence. These findings echo animal experiments demonstrating that senescence levels may vary between organs within the same animal.