Nicotinamide N-methyltransferase (NNMT) regulates the glucocorticoid signaling pathway during the early phase of adipogenesis.

Obesity is associated with adipose tissue dysfunction through the differentiation and expansion of pre-adipocytes to adipocytes (hyperplasia) and/or increases in size of pre-existing adipocytes (hypertrophy). A cascade of transcriptional events coordinates the differentiation of pre-adipocytes into fully differentiated adipocytes; the process of adipogenesis. Although nicotinamide N-methyltransferase (NNMT) has been associated with obesity, how NNMT is regulated during adipogenesis, and the underlying regulatory mechanisms, remain undefined. In present study we used genetic and pharmacological approaches to elucidate the molecular signals driving NNMT activation and its role during adipogenesis. Firstly, we demonstrated that during the early phase of adipocyte differentiation NNMT is transactivated by CCAAT/Enhancer Binding Protein beta (CEBPB) in response to glucocorticoid (GC) induction. We found that Nnmt knockout, using CRISPR/Cas9 approach, impaired terminal adipogenesis by influencing the timing of cellular commitment and cell cycle exit during mitotic clonal expansion, as demonstrated by cell cycle analysis and RNA sequencing experiments. Biochemical and computational methods showed that a novel small molecule, called CC-410, stably binds to and highly specifically inhibits NNMT. CC-410 was, therefore, used to modulate protein activity during pre-adipocyte differentiation stages, demonstrating that, in line with the genetic approach, chemical inhibition of NNMT at the early stages of adipogenesis impairs terminal differentiation by deregulating the GC network. These congruent results conclusively demonstrate that NNMT is a key component of the GC-CEBP axis during the early stages of adipogenesis and could be a potential therapeutic target for both early-onset obesity and glucocorticoid-induced obesity.

DNA Methylomes and Epigenetic Age Acceleration Associations with Poor Metabolic Control in T1D.

Type 1 diabetes (T1D) is an autoimmune disease that leads to insulin deficiency and hyperglycemia. Little is known about how this metabolic dysfunction, which substantially alters the internal environment, forces cells to adapt through epigenetic mechanisms. Consequently, the purpose of this work was to study what changes occur in the epigenome of T1D patients after the onset of disease and in the context of poor metabolic control. We performed a genome-wide analysis of DNA methylation patterns in blood samples from 18 T1D patients with varying levels of metabolic control. We identified T1D-associated DNA methylation differences on more than 100 genes when compared with healthy controls. Interestingly, only T1D patients displaying poor glycemic control showed epigenetic age acceleration compared to healthy controls. The epigenetic alterations identified in this work make a valuable contribution to improving our understanding of T1D and to ensuring the appropriate management of the disease in relation to maintaining healthy aging.

Chromatin regulation by Histone H4 acetylation at Lysine 16 during cell death and differentiation in the myeloid compartment.

Histone H4 acetylation at Lysine 16 (H4K16ac) is a key epigenetic mark involved in gene regulation, DNA repair and chromatin remodeling, and though it is known to be essential for embryonic development, its role during adult life is still poorly understood. Here we show that this lysine is massively hyperacetylated in peripheral neutrophils. Genome-wide mapping of H4K16ac in terminally differentiated blood cells, along with functional experiments, supported a role for this histone post-translational modification in the regulation of cell differentiation and apoptosis in the hematopoietic system. Furthermore, in neutrophils, H4K16ac was enriched at specific DNA repeats. These DNA regions presented an accessible chromatin conformation and were associated with the cleavage sites that generate the 50 kb DNA fragments during the first stages of programmed cell death. Our results thus suggest that H4K16ac plays a dual role in myeloid cells as it not only regulates differentiation and apoptosis, but it also exhibits a non-canonical structural role in poising chromatin for cleavage at an early stage of neutrophil cell death.

Diseño y desarrollo de una bomba manual para la nutrición enteral en bolos / Design and development of a manual pump for bolus enteral nutrition

Introducción: La nutrición enteral (NE) se basa en la administración de soluciones líquidas en el aparato digestivo mediante el uso de una sonda. Tras identificar dificultades prácticas no resueltas en la administración de NE por bolos mediante jeringa de volumen, se planteó un nuevo dispositivo que superara estas dificultades técnicas. Material y métodos: Para su diseño se utilizaron tecnologías específicas (CAD, impresión 3D) en colaboración con la Fundación PRODINTEC (Gijón, Asturias). Mediante el asesoramiento legal de Clarke Modet, especialistas en derecho intelectual, se buscaron fórmulas para la protección de la invención. Resultados y discusión: El dispositivo obtenido se corresponde a una bomba manual para la infusión de NE a los pacientes. Solventa problemas previamente identificados, siendo altamente funcional y compacto. Permitiría una administración, de forma cómoda y segura, de soluciones líquidas. La integración de una botella en el propio dispositivo y su dimensionamiento facilitan su transporte y favorecen la movilidad del paciente. De acuerdo con la configuración descrita, la presente invención presenta múltiples ventajas respecto a las técnicas previamente conocidas, como simplificar las técnicas de administración dentro del campo de la NE intermitente, mejorando la técnica de aporte nutricional de referencia, que en este caso es el uso de jeringas de volumen, facilitando la labor de los cuidadores y al mismo tiempo promoviendo los autocuidados y la autonomía de los pacientes. Fue acreditada novedad de diseño, actividad inventiva y capacidad de explotación industrial, pendiente de concesión de una patente mundial por la Oficina Europea de Patentes (AU)

Introduction: Enteral nutrition (EN) is based on administration of liquid solutions into the gastrointestinal tract using a tube. After identifying unsolved practical difficulties in administration of EN using volume syringes, a new device to overcome such technical difficulties was proposed. Material and methods: Specific technologies (CAD, 3D printing) were used in collaboration with the PRODINTEC Foundation (Gijón, Asturias). Clarke Modet, a law firm specialized in intellectual property, provided legal advice on formulas for legal protection of the invention. Results and discussion: The resulting device is a manual pump for infusion of EN to patients that solves previously identified problems and is highly functional and compact. It would allow for comfortable and safe administration of solutions. Integration of a bottle into the device itself and pump dimensions facilitate transport and patient mobility. According to the described configuration, this invention has many advantages over the previously known procedures, such as a simpler administration within the field of intermittent EN, improving the standard nutritional support technique, which in this case is use of volume syringes. This would facilitate the work of caregivers while promoting patient self-care and autonomy. The pump was accredited novelty of design, inventive activity and industrial exploitation potential by the European Patent Office (EPO), to which a patent has been requested (AU)

Design and development of a manual pump for bolus enteral nutrition. / Diseño y desarrollo de una bomba manual para la nutrición enteral en bolos.

INTRODUCTION: Enteral nutrition (EN) is based on administration of liquid solutions into the gastrointestinal tract using a tube. After identifying unsolved practical difficulties in administration of EN using volume syringes, a new device to overcome such technical difficulties was proposed. MATERIAL AND METHODS: Specific technologies (CAD, 3D printing) were used in collaboration with the PRODINTEC Foundation (Gijón, Asturias). Clarke Modet, a law firm specialized in intellectual property, provided legal advice on formulas for legal protection of the invention. RESULTS AND DISCUSSION: The resulting device is a manual pump for infusion of EN to patients that solves previously identified problems and is highly functional and compact. It would allow for comfortable and safe administration of solutions. Integration of a bottle into the device itself and pump dimensions facilitate transport and patient mobility. According to the described configuration, this invention has many advantages over the previously known procedures, such as a simpler administration within the field of intermittent EN, improving the standard nutritional support technique, which in this case is use of volume syringes. This would facilitate the work of caregivers while promoting patient self-care and autonomy. The pump was accredited novelty of design, inventive activity and industrial exploitation potential by the European Patent Office (EPO), to which a patent has been requested.

The Impact of External Factors on the Epigenome: In Utero and over Lifetime.

Epigenetic marks change during fetal development, adult life, and aging. Some changes play an important role in the establishment and regulation of gene programs, but others seem to occur without any apparent physiological role. An important future challenge in the field of epigenetics will be to describe how the environment affects both of these types of epigenetic change and to learn if interaction between them can determine healthy and disease phenotypes during lifetime. Here we discuss how chemical and physical environmental stressors, diet, life habits, and pharmacological treatments can affect the epigenome during lifetime and the possible impact of these epigenetic changes on pathophysiological processes.

DNA methylation signatures identify biologically distinct thyroid cancer subtypes.

OBJECTIVE: The purpose of this study was to determine the global patterns of aberrant DNA methylation in thyroid cancer. RESEARCH DESIGN AND METHODS: We have used DNA methylation arrays to determine, for the first time, the genome-wide promoter methylation status of papillary, follicular, medullary, and anaplastic thyroid tumors. RESULTS: We identified 262 and 352 hypermethylated and 13 and 21 hypomethylated genes in differentiated papillary and follicular tumors, respectively. Interestingly, the other tumor types analyzed displayed more hypomethylated genes (280 in anaplastic and 393 in medullary tumors) than aberrantly hypermethylated genes (86 in anaplastic and 131 in medullary tumors). Among the genes indentified, we show that 4 potential tumor suppressor genes (ADAMTS8, HOXB4, ZIC1, and KISS1R) and 4 potential oncogenes (INSL4, DPPA2, TCL1B, and NOTCH4) are frequently regulated by aberrant methylation in primary thyroid tumors. In addition, we show that aberrant promoter hypomethylation-associated overexpression of MAP17 might promote tumor growth in thyroid cancer. CONCLUSIONS: Thyroid cancer subtypes present differential promoter methylation signatures, and nondifferentiated subtypes are characterized by aberrant promoter hypomethylation rather than hypermethylation. Additional studies are needed to determine the potential clinical interest of the tumor subtype-specific DNA methylation signatures described herein and the role of aberrant promoter hypomethylation in nondifferentiated thyroid tumors.

Aging genetics and aging.

The process of aging refers to the decay of an organism's structure and function, in which molecular and cellular modifications can have various effects at the individual level over the course of a lifetime. The accumulation of molecular errors that compromise adult stem cell functions occurs because of genetic and epigenetic interactions and depends on hereditary, environmental, and stochastic factors. Here we review the known genetic factors involved in aging.

Epigenetic regulation of aging.

Aging is one of the most challenging and unresolved problems in biology owing to its highly complex nature. Public interest in aging has increased not only because all of us can expect to live to a ripe old age but also because we wish to avoid those age-related changes that lead to physical invalidity or other diseases (cancer, depression) and may ultimately cause social isolation. Aging is a process of genetic and epigenetic interactions at all biological levels, where epigenetics has an important function in determining the phenotypic differences that arise. Epigenetics also plays a key role in the development of diseases associated with aging and explains the relationship between an individual's genetic background, the environment, aging, and disease. DNA plasticity is mediated in part by the epigenetic changes that lead the role of a cell, and can be passed on to future generations. Epigenetics establishes the idea that our health can be affected not only by the interplay of our genes and environment but also by the inherited effects of our ancestors' genes and environment.

Soluble MHC class I chain-related protein B serum levels correlate with disease activity in relapsing-remitting multiple sclerosis.

Recent studies demonstrated that dysregulation of NKG2D and its ligands, leading to activation of autoreactive effector cells, can trigger autoimmune diseases, but soluble forms of these ligands can downmodulate NKG2D expression in T effector cells. We investigated the presence of soluble major histocompatibility complex class I chain-related A or B (MICA or MICB) molecules in sera of multiple sclerosis (MS) patients and whether they play a role in the progression of the disease. Although soluble MICA serum levels did not differ, soluble MICB serum levels were higher in MS patients compared with controls. Moreover, the highest MICB levels were in MS patients during relapses. Using immunohistochemistry techniques, it was possible to locate MIC expression in neurons of MS demyelinating plaques that were intracellularly accumulated. Elevated soluble MICB levels exist in serum of multiple sclerosis patients related with disease activity. This may contribute to the modulation of immune response activity during relapses.

The allele MICB 0050204, over-represented in the Caucasian population, has an additional exon resulting from a new splice junction sequence.

We report that the allele MICB 0050204(1) allele, present in the majority of the Spanish population (70% of healthy controls) is characterized by the presence of an extra exon found between the sequence corresponding to exon 1 and 2. This is generated by a dinucleotide polymorphism in the first MICB intron that introduces a new splice junction, which can generate, by alternative splicing, transcripts with an additional exon. This new exon contains a premature stop codon and therefore the transcript does not produce a functional protein.