Nicotinamide N-methyltransferase catalyses the N-methylation of the endogenous ß-carboline norharman: evidence for a novel detoxification pathway

Nicotinamide N-methyltransferase (NNMT) is responsible for the N-methylation of nicotinamide to 1-methylnicotinamide. Our recent studies have demonstrated that NNMT regulates cellular processes fundamental to the correct functioning and survival of the cell. It has been proposed that NNMT may possess β-carboline (BC) N-methyltransferase activity, endogenously and exogenously produced pyridine-containing compounds which, when N-methylated, are potent inhibitors of Complex I and have been proposed to have a role in the pathogenesis of Parkinson's disease. We have investigated the ability of recombinant NNMT to N-methylate norharman (NH) to 2-N-methylnorharman (MeNH). In addition, we have investigated the toxicity of the BC NH, its precursor 1,2,3,4-tetrahydronorharman (THNH) and its N-methylated metabolite MeNH, using our in vitro SH-SY5Y NNMT expression model. Recombinant NNMT demonstrated NH 2N-methyltransferase activity, with a Km of 90 ± 20 µM, a kcat of 3 × 10(-4) ± 2 × 10(-5) s(-1) and a specificity constant (kcat/Km) of 3 ± 1 s(-1) M(-1) THNH was the least toxic of all three compounds investigated, whereas NH demonstrated the greatest, with no difference observed in terms of cell viability and cell death between NNMT-expressing and non-expressing cells. In NNMT-expressing cells, MeNH increased cell viability and cellular ATP concentration in a dose-dependent manner after 72 and 120 h incubation, an effect that was not observed after 24 h incubation or in non-NNNT-expressing cells at any time point. Taken together, these results suggest that NNMT may be a detoxification pathway for BCs such as NH

Development of low blood glucose readings in nine non-diabetic patients treated with tumor necrosis factor-alpha inhibitors: a case series

<p>Abstract</p> <p>Introduction</p> <p>Treatment with various biological agents in disease states such as rheumatoid arthritis has been associated with multiple side effects. Whereas many of these are frequently reported in the literature, hypoglycemia, a possible side effect of tumor necrosis factor-alpha inhibitors, may be underpublicized.</p> <p>Case presentation</p> <p>We report nine cases of non-diabetic Caucasian women who were between 29 and 68 years of age and who developed low glucose readings after treatment with tumor necrosis factor-alpha inhibitors. We provide a more detailed discussion of existing evidence of the role of tumor necrosis factor-alpha in the pathogenesis of inflammation and its impact on glycemic equilibrium.</p> <p>Conclusions</p> <p>Physicians using tumor necrosis factor-alpha inhibitors in the treatment of various rheumatic and other autoimmune diseases should be aware of the potential for the development of glycemic disturbance in these patients. A further role of tumor necrosis factor-alpha inhibitors in the glycemic equilibrium warrants larger controlled trials in patients with and those without a history of diabetes.</p

Higher expression levels of SOCS 1,3,4,7 are associated with earlier tumour stage and better clinical outcome in human breast cancer

Background Suppressors of cytokine signaling (SOCS) are important negative feedback regulators of the JAK/STAT signaling pathway, and have been recently investigated for their role in the development of different cancers. In this study, we examined the expression of SOCS1-7 genes in normal and breast cancer tissue and correlated this with several clinico-pathological and prognostic factors. Methods SOCS1-7 mRNA extraction and reverse transcription were performed on fresh frozen breast cancer tissue samples (n = 127) and normal background breast tissue (n = 31). Transcript levels of expression were determined using real-time PCR and analyzed against TNM stage, tumour grade and clinical outcome over a 10 year follow-up period. Results SOCS1,4,5,6 and 7 expression decreased with increased TNM stage (TNM1 vs. TNM3 p = 0.039, TNM1 vs. TNM4 p = 0.016, TNM2 vs. TNM4 p = 0.025, TNM1 vs. TNM3 p = 0.012, and TNM1 vs. TNM3 p = 0.044 respectively). SOCS2 and 3 expression decreased with increased Nottingham Prognostic Index (NPI) (NPI1 vs. NPI3 p = 0.033, and NPI2 vs. NPI3 p = 0.041 respectively). SOCS7 expression decreased with higher tumour grade (Grade 3 vs. Grade 2 p = 0.037). After a median follow up period of 10 years, we found higher levels of SOCS1,2 and 7 expression among those patients who remained disease-free compared to those who developed local recurrence (p = 0.0073, p = 0.021, and p = 0.039 respectively). Similarly, we found higher levels of SOCS 2,4, and 7 expression in those who remained disease-free compared to those who developed distant recurrence (p = 0.022, p = 0.024, and p = 0.033 respectively). Patients who remained disease-free had higher levels of SOCS1 and 2 expression compared to those who died from breast cancer (p = 0.02 and p = 0.033 respectively). The disease free survival (DFS) and overall survival (OS) curves showed that higher levels of SOCS1, 3 and 7 were significant predictors of higher DFS (p = 0.015, p = 0.024 and 0.03 respectively) and OS (p = 0.005, p = 0.013 and p = 0.035 respectively). Higher levels of SOCS 4 were significant in predicting better OS (p = 0.007) but not DFS. Immunohistochemical staining of representative samples showed a correlation between SOCS1, 3, 7 protein staining and the SOCS1, 3, 7 mRNA expression. Conclusion Higher mRNA expression levels of SOCS1, 3, 4 and 7 are significantly associated with earlier tumour stage and better clinical outcome in human breast cancer

Inhibitors of nicotinamide:N -methyltransferase designed to mimic the methylation reaction transition state

Nicotinamide N-methyltransferase (NNMT) is an enzyme that catalyses the methylation of nicotinamide to form N'-methylnicotinamide. Both NNMT and its methylated product have recently been linked to a variety of diseases, suggesting a role for the enzyme as a therapeutic target beyond its previously ascribed metabolic function in detoxification. We here describe the systematic development of NNMT inhibitors derived from the structures of the substrates involved in the methylation reaction. By covalently linking fragments of the NNMT substrates a diverse library of bisubstrate-like compounds was prepared. The ability of these compounds to inhibit NNMT was evaluated providing valuable insights into the structural tolerances of the enzyme active site. These studies led to the identification of new NNMT inhibitors that mimic the transition state of the methylation reaction and inhibit the enzyme with activity on par with established methyltransferase inhibitors

Identification of a Novel, Small Molecule Partial Agonist for the Cyclic AMP Sensor, EPAC1

Screening of a carefully selected library of 5,195 small molecules identified 34 hit compounds that interact with the regulatory cyclic nucleotide-binding domain (CNB) of the cAMP sensor, EPAC1. Two of these hits (I942 and I178) were selected for their robust and reproducible inhibitory effects within the primary screening assay. Follow-up characterisation by ligand observed nuclear magnetic resonance (NMR) revealed direct interaction of I942 and I178 with EPAC1 and EPAC2-CNBs in vitro. Moreover, in vitro guanine nucleotide exchange factor (GEF) assays revealed that I942 and, to a lesser extent, I178 had partial agonist properties towards EPAC1, leading to activation of EPAC1, in the absence of cAMP, and inhibition of GEF activity in the presence of cAMP. In contrast, there was very little agonist action of I942 towards EPAC2 or protein kinase A (PKA). To our knowledge, this is the first observation of non-cyclic-nucleotide small molecules with agonist properties towards EPAC1. Furthermore, the isoform selective agonist nature of these compounds highlights the potential for the development of small molecule tools that selectively up-regulate EPAC1 activity

Endogenous Nmnat2 Is an Essential Survival Factor for Maintenance of Healthy Axons

We conclude that endogenous Nmnat2 prevents spontaneous degeneration of healthy axons and propose that, when present, the more long-lived, functionally related WldS protein substitutes for Nmnat2 loss after axon injury. Endogenous Nmnat2 represents an exciting new therapeutic target for axonal disorders

Lipolysis drives expression of the constitutively active receptor GPR3 to induce adipose thermogenesis

Thermogenic adipocytes possess a therapeutically appealing, energy-expending capacity, which is canonically cold-induced by ligand-dependent activation of β-adrenergic G protein-coupled receptors (GPCRs). Here, we uncover an alternate paradigm of GPCR-mediated adipose thermogenesis through the constitutively active receptor, GPR3. We show that the N terminus of GPR3 confers intrinsic signaling activity, resulting in continuous Gs-coupling and cAMP production without an exogenous ligand. Thus, transcriptional induction of Gpr3 represents the regulatory parallel to ligand-binding of conventional GPCRs. Consequently, increasing Gpr3 expression in thermogenic adipocytes is alone sufficient to drive energy expenditure and counteract metabolic disease in mice. Gpr3 transcription is cold-stimulated by a lipolytic signal, and dietary fat potentiates GPR3-dependent thermogenesis to amplify the response to caloric excess. Moreover, we find GPR3 to be an essential, adrenergic-independent regulator of human brown adipocytes. Taken together, our findings reveal a noncanonical mechanism of GPCR control and thermogenic activation through the lipolysis-induced expression of constitutively active GPR3

Effects of body weight and alcohol consumption on insulin sensitivity

<p>Abstract</p> <p>Background</p> <p>Obesity is a risk factor for the development of insulin resistance, which can eventually lead to type-2 diabetes. Alcohol consumption is a protective factor against insulin resistance, and thus protects against the development of type-2 diabetes. The mechanism by which alcohol protects against the development of type-2 diabetes is not well known. To determine the mechanism by which alcohol improves insulin sensitivity, we fed water or alcohol to lean, control, and obese mice. The aim of this study was to determine whether alcohol consumption and body weights affect overlapping metabolic pathways and to identify specific target genes that are regulated in these pathways.</p> <p>Method</p> <p>Adipose tissue dysfunction has been associated with the development of type-2 diabetes. We assessed possible gene expression alterations in epididymal white adipose tissue (WAT). We obtained WAT from mice fed a calorie restricted (CR), low fat (LF Control) or high fat (HF) diets and either water or 20% ethanol in the drinking water. We screened the expression of genes related to the regulation of energy homeostasis and insulin regulation using a gene array composed of 384 genes.</p> <p>Results</p> <p>Obesity induced insulin resistance and calorie restriction and alcohol improved insulin sensitivity. The insulin resistance in obese mice was associated with the increased expression of inflammatory markers Cd68, Il-6 and Il-1α; in contrast, most of these genes were down-regulated in CR mice. Anti-inflammatory factors such as Il-10 and adrenergic beta receptor kinase 1 (Adrbk1) were decreased in obese mice and increased by CR and alcohol. Also, we report a direct correlation between body weight and the expression of the following genes: Kcnj11 (potassium inwardly-rectifying channel, subfamily J, member 11), Lpin2 (lipin2), and Dusp9 (dual-specificity MAP kinase phosphatase 9).</p> <p>Conclusion</p> <p>We show that alcohol consumption increased insulin sensitivity. Additionally, alterations in insulin sensitivity related with obesity were coupled with alterations in inflammatory genes. We provide evidence that alcohol may improve insulin sensitivity by up-regulating anti-inflammatory genes. Moreover, we have indentified potential gene targets in energy metabolic pathways and signal transducers that may contribute to obesity-related insulin resistance as well as calorie restriction and alcohol-induced insulin sensitivity.</p

Nuevas socialidades, y configuraciones de mundo entorno a las redes sociales digitales. Un estudio situado con jóvenes estudiantes

Ulla, Cecilia. (2013). Universidad Nacional de Córdoba. Escuela de Ciencias de la Información. Argentina.Emanuelli, Paulina B. (2013). Universidad Nacional de Córdoba. Escuela de Ciencias de la Información. Argentina.Ardini, Claudia. (2013). Universidad Nacional de Córdoba. Escuela de Ciencias de la Información. Argentina.Vargas, Laura. (2013). Universidad Nacional de Córdoba. Escuela de Ciencias de la Información. Argentina.Ortúzar, Isabel. (2013). Universidad Nacional de Córdoba. Escuela de Ciencias de la Información. Argentina.Redolfi, Cecilia. (2013). Universidad Nacional de Córdoba. Escuela de Ciencias de la Información. Argentina.Masera, Marta. (2013). Universidad Nacional de Córdoba. Escuela de Ciencias de la Información. Argentina.Trimano, Luciana. (2013). Universidad Nacional de Córdoba. Escuela de Ciencias de la Información. Argentina.Zárate, Zulma. (2013). Universidad Nacional de Córdoba. Escuela de Ciencias de la Información. Argentina.Calderón, Angelina. (2013). Universidad Nacional de Córdoba. Escuela de Ciencias de la Información. Argentina.Rey, Mariana. (2013). Universidad Nacional de Córdoba. Escuela de Ciencias de la Información. Argentina.Ferrari, Mariana. (2013). Universidad Nacional de Córdoba. Escuela de Ciencias de la Información. Argentina.Massetti, Carolina. (2013). Universidad Nacional de Córdoba. Escuela de Ciencias de la Información. Argentina.Manzanares, Belén. (2013). Universidad Nacional de Córdoba. Escuela de Ciencias de la Información. Argentina.Altieri, Ana Clara. (2013). Universidad Nacional de Córdoba. Escuela de Ciencias de la Información. Argentina.Moroni, Luciano. (2013). Universidad Nacional de Córdoba. Escuela de Ciencias de la Información. Argentina.Valdez, Lucas. (2013). Universidad Nacional de Córdoba. Escuela de Ciencias de la Información. Argentina.Moreno, Soledad. (2013). Universidad Nacional de Córdoba. Escuela de Ciencias de la Información. Argentina.Ulla, Cecilia. Universidad Nacional de Córdoba. Escuela de Ciencias de la Información. Argentina.Vivimos en la denominada revolución virtual donde los procesos comunicativos son mediados por tecnologías digitales. En una nueva forma de intercambio simbólico y construcción de relaciones interpersonales dentro de un grupo específico, la juventud, que va a constituir un nuevo mundo compartido y construido por sus miembros en base a las representaciones sociales e imaginarios colectivos, con fuerte implicaciones intersubjetivas. Así las Tribus Urbanas a modo de expresión y alejamiento de la monotonía de lo institucionalizado, van a ser representantes de un nuevo espíritu del tiempo que se puede llamar con el nombre de socialidad. En éste marco nos interrogamos: ¿Qué cosmovisión tienen los jóvenes de ingresantes a primer año de la Escuela de Ciencias de la Información, del espacio, tiempo, territorio, relaciones, emociones, del trabajo y los Valores hegemónicos?Ulla, Cecilia. (2013). Universidad Nacional de Córdoba. Escuela de Ciencias de la Información. Argentina.Emanuelli, Paulina B. (2013). Universidad Nacional de Córdoba. Escuela de Ciencias de la Información. Argentina.Ardini, Claudia. (2013). Universidad Nacional de Córdoba. Escuela de Ciencias de la Información. Argentina.Vargas, Laura. (2013). Universidad Nacional de Córdoba. Escuela de Ciencias de la Información. Argentina.Ortúzar, Isabel. (2013). Universidad Nacional de Córdoba. Escuela de Ciencias de la Información. Argentina.Redolfi, Cecilia. (2013). Universidad Nacional de Córdoba. Escuela de Ciencias de la Información. Argentina.Masera, Marta. (2013). Universidad Nacional de Córdoba. Escuela de Ciencias de la Información. Argentina.Trimano, Luciana. (2013). Universidad Nacional de Córdoba. Escuela de Ciencias de la Información. Argentina.Zárate, Zulma. (2013). Universidad Nacional de Córdoba. Escuela de Ciencias de la Información. Argentina.Calderón, Angelina. (2013). Universidad Nacional de Córdoba. Escuela de Ciencias de la Información. Argentina.Rey, Mariana. (2013). Universidad Nacional de Córdoba. Escuela de Ciencias de la Información. Argentina.Ferrari, Mariana. (2013). Universidad Nacional de Córdoba. Escuela de Ciencias de la Información. Argentina.Massetti, Carolina. (2013). Universidad Nacional de Córdoba. Escuela de Ciencias de la Información. Argentina.Manzanares, Belén. (2013). Universidad Nacional de Córdoba. Escuela de Ciencias de la Información. Argentina.Altieri, Ana Clara. (2013). Universidad Nacional de Córdoba. Escuela de Ciencias de la Información. Argentina.Moroni, Luciano. (2013). Universidad Nacional de Córdoba. Escuela de Ciencias de la Información. Argentina.Valdez, Lucas. (2013). Universidad Nacional de Córdoba. Escuela de Ciencias de la Información. Argentina.Moreno, Soledad. (2013). Universidad Nacional de Córdoba. Escuela de Ciencias de la Información. Argentina.Ulla, Cecilia. Universidad Nacional de Córdoba. Escuela de Ciencias de la Información. Argentina.Otras Comunicación y Medio